Maturitas 78 (2014) 40–44

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Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

A review of vitamin D and Parkinson’s disease Amie L. Peterson a,b,∗ a b

Oregon Health Sciences University, Mail Code: OP32, 3181, SW Sam Jackson Park Road, Portland, OR 97239, USA Portland VA, 3710 SW US Veterans Hospital Road, Mail Code: P3PADRECC, Portland, OR 97239, USA

a r t i c l e

i n f o

Article history: Received 21 February 2014 Accepted 24 February 2014 Keywords: Vitamin D Parkinson’s disease Vitamin D receptor

a b s t r a c t The role of vitamin D in bone health has been known for over a century. More recent research has suggested that vitamin D may play a role in the muscular, immune, endocrine, and central nervous systems. Animal research suggests that vitamin D may have some protective effects against toxic insults that are known to damage dopamine cells, the primary cells to degenerate in PD. Persons with PD tend to have lower vitamin D levels than persons of similar ages without PD. Vitamin D levels are generally associated with bone mineral density (BMD) in persons with PD, but simply giving vitamin D does not appear to improve BMD. Results of genetic studies examining polymorphism of the vitamin D receptor and PD risk, severity, or age at onset have shown variable results, with FokI CC seeming to possibly carry some increased risk of PD. Amount of sun exposure and vitamin D levels in earlier life may influence the risk of developing PD. Cross-sectional research suggests a relationship between vitamin D levels and severity of PD symptoms. A single intervention study did show some improvement in PD with vitamin D supplementation. Vitamin D may have effects on PD symptoms and perhaps even on the risk of disease development or disease progression. More well designed intervention studies are needed to confirm the effect of vitamin D on PD symptoms. Human neuroprotection studies are needed, but probably not feasible until better biomarkers are established. Published by Elsevier Ireland Ltd.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results/discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Vitamin D appears neuroprotective in animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vitamin D is often low in persons with PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Vitamin D is related to bone health in PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. The relationship between the vitmain D receptor and PD risk is unclear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Vitmain D exposure may predict the risk of developing PD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Vitamin D appears to be related to the severity of PD symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Correspondence to: Oregon Health Sciences University, Mail Code: OP32, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. Tel.: +1 503 494 7231; fax: +1 503 494 9059. E-mail address: [email protected] http://dx.doi.org/10.1016/j.maturitas.2014.02.012 0378-5122/Published by Elsevier Ireland Ltd.

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1. Introduction The importance of vitamin D in bone health was realized in the early 1900s [1]. More recent research suggests that vitamin D may have effects on the muscular, immune, endocrine, and central nervous systems [2]. The final enzyme to convert vitamin D to the active form and the vitamin D receptor are known to be present throughout the human brain [3]. Vitamin D comes from two main sources – diet and skin [4]. Human skin makes D3 from 7-dehydrocolesterol when exposed to UV-B rays from the sun [4]. For most persons this is the primary source of vitamin D. Vitamin D can also come in the form of D2 and D3 from food sources and supplements [4]. Thirty minutes of full body sun exposure equates to about 10,000 international units (IU’s) of vitamin D [5]. The darkness of a person’s skin effect how efficiently they make vitamin D with darker skinned persons making less vitamin D with equivalent sun exposure [5]. Common food sources of vitamin D include wild salmon, tuna, and milk with approximately 600–100 IU, 230 IU, and 100 IU respectively per serving [5]. There is some disagreement, but currently defined optimal levels of vitamin D are generally based on bone health, specifically parathyroid hormone levels (PTH). Vitamin D levels lower than 30–40 ng/ml are inversely associated with PTH levels. Vitamin D deficiency is commonly defined as <20 ng/ml, insufficiency as 20–30 ng/ml and, sufficiency as >30 ng/ml [5]. PD is a neurodegenerative disease with four cardinal features: resting tremor, rigidity (stiffness), bradykinesias (slowness), and postural instability. The motor symptoms are thought to largely be due to a loss of dopamine cells in the basal ganglia. A diagnosis of PD is made clinically and disease severity is judged by clinical ratings. There are two major clinical scales used: the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn & Yahr Scale (H&Y) [6,7]. The motor section of the UPDRS is the most often used section with a maximum of 108 points; with a higher score indicating more severe disease. Each individual piece is scored on a four-point scale with points for the following: speech, facial expression, tremor at rest (face, limbs), action or postural tremor (arms), rigidity (neck, limbs), three types of rapid alternating movements (arms), leg agility, arising from a chair, posture, gait, postural stability, and overall slowness. The H&Y is a scale of 1–5. It is rated on if symptoms are unilateral – 1, bilateral – 2, or how balance/gait is affected. If postural reflexes are affected – 3, severe disability but able to walk or stand unassisted – 4, or confined to bed or wheelchair unless aided – 5. 2. Methods A Medline search was done using the terms “Parkinson’s disease” and “vitamin D.” Abstracts for all articles in English were reviewed for relevance with appropriate articles included. All of these articles were read, including reviews. Any primary research from the review references were also included if relevant. Finally a Pubmed search was completed using the search terms “vitamin D” and “Parkinson’s or parkinson” and any unique publications in English were included. Not all review articles are presented, but all primary data related to PD and vitamin D is included. 3. Results/discussion 3.1. Vitamin D appears neuroprotective in animal studies There are a number of in vitro and in vivo animals studies in PD examing potential neuroprotective effects of vitamin D. Nissou found that the mRNA of 27 genes was increased by at least 1.9-fold when neuron-glial cell cultures were exposed to

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1,25-dihydroxyvitamin D3 [8]. Seventeen of these genes were known to be related to neurodegeneration, psychiatric disease, or brain morphogenesis with three having specific relationships with PD: CBS – involved in hydrogen sulfide production, SLC1A1 – involved in glutatione synthesis, ITGA8 – required for hippocampal long term potentiation. An in vitro study using rat mesencephalic neurons and lbuthionine sulfoximine (BCO) and 1-methyl-4-phenylpyridium ion (MPP+), which are known to cause particular damage to dopamine neurons, showed that pretreatment for 24 h with vitamin D was protective till it reached a toxic threshold at high concentrations [9]. There was also a dose response when looking at glutathione production and vitamin D exposure. A reduction in glutathione is seen in early PD and may be a primary event in the development of PD [10]. Both experiments showed benefit and harm at similar concentrations of vitamin D. In vivo animal studies include one in rats where vitamin D was given intraventricularly seven days before then one day or up to four weeks after intraventricular injection of 6-hydroxydopamine (6-OHDA), a compound that induces symptoms similar to PD [11]. Benefits were only seen in the group of rats that received vitamin D before and for the longer duration (3.5–4 weeks) after the 6-OHDA. Specifically an increase in strial dopamine, potassium and amphetamine evoked over flow of dopamine, and dopamine metabolites. They also looked at levels of glial derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) in animals who received 8 days of vitmain D or saline, but did not undergo lesioning with 6-OHDA. There was an increase in GDNF in the substantia nigra, but not the striatum, in the rats receiving vitamin D. There were no significant difference in levels of BDNF. Another study in rats gave vitamin D for eight days prior to 6OHDA and found an increase in tyrosine hydroxylase (TH) labelled cells (presumably dopamine cells) in the rats that received vitamin D [12]. Two other studies, one in rats using 6-OHDA and one in mice using (1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP – another means of inducing a PD model), gave vitamin D for seven days prior to the insult [13]. They looked at inflammation via microglial activation and found in both models vitamin D increased TH positive cells and reduced activated microglial cells. A study using a genetic PD mouse model did find conflicting results. Specifically showing more TH positive cells in the substantia nigra pars compacta and ventral tegmental area, when the mice were vitamin D restricted [14]. Neuroprotection or disease modification is a somewhat controversial topic in PD, but is certainly the hope of any therapy. Animals studies often suggest therapies that offer protection, but when human studies are performed the results are often disappointing. 3.2. Vitamin D is often low in persons with PD The prevalence of vitamin D deficiency appears to be higher in persons with PD than other populations. Evatt showed in a 2008 paper that 55% of persons with PD were insufficient compared to 41% of person with another neurodegenerative disorder, Alzheimer’s disease, and compared to 36% in a control population that was age matched [15]. Numerous studies by Sato have shown insufficient and deficient vitamin D levels are common in PD [16–18]. In a population in the Pacific Northwest United States, we found 40% of persons with PD had insufficient vitamin D levels [19]. The one study that appears in disagreement with these data was done in an Iranian population and did not show significantly lower vitamin D in the PD population compared to controls, however there may have be some confounding issues related to gender [20].

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3.3. Vitamin D is related to bone health in PD There are a large number of studies related to PD and bone health and details on all studies will not be presented. The overarching theme is that vitamin D levels tend to be lower in persons with PD and that vitamin D and bone mineral density (BMD) generally correlate [16–18,21–29]. Sato’s group in Kurume, Japan carried out the majority of these studies. There are numerous reasons why persons with PD would be at risk for low BMD. Levodopa may itself or through homocysteine result in reduced BMD [30]. PD for a variety of reasons may lead to poor nutrition, lower body weight, and decreased muscle strength. Decreased mobility from PD may lead to lower vitamin D and exacerbated related bone loss [30]. Highlighting some of the interesting findings, a paper by AbouRaya found that at baseline persons with PD had less sun exposure, with 74% having less than 15 min a day compare to 19% in a control group [21]. The PD group took in less calcium and vitamin D with 59% taking in less than 200 IU a day, compared to 4% in the control group [21]. A study by Lorefalt found that lower BMD’s were seen in persons with PD who were less active, had lower body weights, and surprisingly those with less rigidity [31]. Sato’s group has done two intervention studies with bisphosphonates [16,26]. In these two studies the control groups received 1000 IU of vitamin D along with the placebo. In both studies the vitamin D levels rose considerably in the course of the 2 years, from 11.3 ng/ml to 35.1 ng/ml and from 12.5 ng/ml to 37.5 ng/ml. Somewhat surprisingly however, the BMD’s decreased in both control (vitamin D) groups by about 3% over the two year period in spite of the elevation in vitamin D levels. Sato in a 1999 paper looking at an active vitamin D3 analogue, suggesting that there may be a defect in renal synthesis of the active form of vitamin D [32]. With supplementation with the active vitamin D, there was only a 1.2% decrease in BMD over 18 months. Another means of increasing vitamin D is sunlight. In a 2011 study, again by Sato’s group, they tested the effect of increased sun exposure [28]. Participants were followed for two years. Those in the intervention group were asked to spend 15 min outside on clear days. In the sunlight group vitamin D levels increased to 10.8–20.8 ng/ml and BMD increased by over 3%. The other studies with oral vitamin D had larger increases in vitamin D levels but, still had reduction in BMD. This suggests that there is something beyond vitamin D at play, perhaps increased physical activity. The sunlight group also had improved strength and lower risk of hip fracture (OR3.9 in no intervention vs. sunlight). The study design also did not have an active control arm so placebo effect cannot be ruled out. Yet another study by Sato’s group looked at stooped posture and vertebral fractures [25]. Over 120 women over age 50 with PD and without stooped posture at enrollment were followed yearly for five years to evaluate compression fractures. At the end of the study 34 had developed stooped posture. This group had lower vitamin D intake, lower BMD, and higher rates of vertebral fractures at the time of study enrollment. The BMD also decreased more quickly in the stooped posture group. 3.4. The relationship between the vitmain D receptor and PD risk is unclear The VDR receptor is an intranuclear receptor. It is encoded by a large gene, over 100 kb, on chromosome 12q12-14 [33]. It is made up of two promoter regions, eight protein-coding exons, and six untranslated exons [33]. An animal study knocking out the VDR resulted in rats with muscular and motor impairments, alopecia, short stature, lower body weight, shorter gait, and impairments on rotarod testing (measures gait and balance) [34]. The mice did not appear to have cognitive impairments.

There are over 60 identified polymorphisms for VDR. Polymorphisms are mutations with an allele frequency of at least 1% in a given population. These subtle DNA sequence variation, which occur often in the population, can have a modest but real biological effect. Polymorphisms can effect enhanced/reduced transcription, altered posttranscriptional or posttranslational activity, or the tertiary structure of the gene product [33]. A number of studies have tried to examine if VDR phenotypes relate to PD, primarily looking at either risk of development or age of onset. A fairly large US study was done using two populations, first doing a discovery phase (770 Caucasian families with a history of PD) then a validation phase (267 cases, 267 controls) [35]. In the discovery phase one single nucleotide polymorphism (SNP) met threshold for overall risk, rs4334089. There were five other SNPs that met threshold for early onset risk. In the validation phase however there were no associations with any of these SNPs. There were three other SNPs that met threshold in the validation phase for early age on onset of PD, but none met threshold for PD risk. The rs4334089 has also been studied in other populations. Lv examined this SNP along with rs731236 in a Chinese Han population (483 persons with PD, 498 controls) [36]. The Han population makes up 92% of the Chinese population and is considered the largest ethnic group in the world. Lv’s study found no associations to PD risk or age of onset with either rs4334089 or rs721236 [36]. In a Taiwanese population no association was seen with rs 4334089 or five other SNPs examined [37]. Another study in a Han population examined FokI(rs10735810) and BsmI(rs1544410), polymorphisms that may be associated with risk of MS [38]. FokI involves the presence of a cytosine (C) or thymine (T) allele. Han found increased frequency of C allele in PD group and late-onset PD group when compared to controls. There were no relationships seen with the BsmI polymorphism. A Hungarian study also found an association between PD and the FokI C allele [39]. No associations were seen with BsmI, ApaI, or TaqI in the Hungarian population. Kim examined polymorphisms in a Korean population (85 cases and 231 controls) [40]. Looking at BsmI, specifically the absense (B) or the presense (b) of a restriction site, there was an increased frequency of bb genotype in the PD group (84.7% vs. 72.7%; p = 0.043) and increased frequency of b allele (91.2% vs. 85.7%, p = 0.069). Also the bb genotype and b allele were more common in persons with postrual instability, gait deficits predominant PD (PIDG) vs. the tremor predominant form of PD. In a Japanese population, Suzuki examined PD severity, vitamin D levels, five VDR polymorphisms, and two vitamin D binding protein (VDBP) polymorphism in 137 persons with PD [41]. There was an association between polymorphisms and vitamin D levels. Specifically the vitamin D bindging protein polymorphisms, TT genotype of GC1 and AA genotype of GC2, were associated with lower 25OHD levels. In regard to the polymorphisms and disease severity, the FokI CC genotype for VDR polymorphism was associated with a milder form of PD. In a Faroe Island populations no associtaions were seen with the polymorphisms assessed, ApaI, BsmI, and TaqI, but there was an association between vitamin D levels and Apal/AC genotype [42]. In regard to polymorphisms, the FokI CC genotype is associated with PD risk in multiple studies. VDR and VDBP themselves are potential biomarkers for PD. VDR expression in the blood may be increased in persons with PD [43]. VDBP protein in the CSF may help to predcit PD when used as part of a multianalyte profile [44,45]. 3.5. Vitmain D exposure may predict the risk of developing PD There have been a few studies looking at diet and PD risk with varying results. Some have shown an increase risk of PD in men who consumed more dairy [46–48]. One of these studies however, did not show any increase risk in PD when looking at overall vitamin D

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intake [47]. A study by Anderson did find a relationship with vitamin D rich foods, but this relationship disappeared when correcting for animal fat intake [49]. A final study found no relationship of PD risk with diary, calcium, or vitamin D consumption [50]. Considering the variable results and the amount of vitamin D that is often obtained from non-food sources it is unclear how to interpret this data. In regard to sun exposure and risk of PD, two using the same 1960s US data set, demonstrated a north-south gradient for PD mortality similar to those seen in multiple sclerosis [51,52]. A study using US data from 1981 found a west-east gradient [53]. A final study, using US data from 1988, showed a north-south gradient, but only in a white population [54]. A large Danish study (3819 men with PD and 19,282 controls) found decreased risk of PD in persons who had occupations associated with outdoor work [55]. The OR was 0.72 (95% CI 0.63–0.82) when comparing persons with maximal outdoor work to persons with exclusive indoor work. A US study with a much smaller sample (447 persons with PD and 578 controls) showed a trend towards decreased risk in persons who did only outdoor work compared to only indoor work with an OR of 0.74 (95% CI 0.44–1.25) [56]. A 2010 looked at vitamin D in 3173 people 29 years prior and compared the 50 people who developed PD. Those with PD had a borderline significance lower mean vitamin D level of 11.5(5.8) ng/mL vs. 13.1(6.1) ng/mL (p = 0.05) [57]. When breaking the PD group into quartiles there was a significant trend (p = 0.006) for higher relative risk of PD as vitamin D levels decreased.

3.6. Vitamin D appears to be related to the severity of PD symptoms A number of studies have looked at the relationship between PD symptoms and vitamin D levels. In Sato’s 2005 paper he showed a correlation between the mUPDRS score and 1,25-dihydroxy vitamin D levels [17]. In his 2007 paper which included a lot of advanced stage persons with PD, he found that the mean level of person with H&Y’s 3–4 was 8.9 (3.2) compared to 21.7(8.5) in H&Y 1–2 and 21.6 (3.1) in person without PD [16]. Suzuki in another Japanese populations found significant relationships between 25-hydroxyvitamin D (No Reference Selected) and H&Y scores (p = .002) and 25-hydroxyvitamin D and UPDRS scores using linear regression (p = 0.004) [41]. We also found a relationship between UPDRSm and vitamin D in two of our studies, r = −0.33, p = 0.04 and r = −0.242, p = 0.0025 [19,58]. A 2011 paper, used data from DATATOP, examined vitamin D levels and disease progression [59]. No relationship was found between vitamin D concentrations and disease progression but the follow up time averaged only 18 months and patients had generally mild disease (mean H&Y 1.7 at start 2.1 at completions) [59]. A study with slightly more advanced patients did show a relationship between vitamin D level and UPDRS motor at baseline and with progression of symptoms in follow-up [60]. A case report in 1997, describes a person with PD for 10 years who developed hypophosphoremia, hypocalcium, and low vitamin D and with 4000 IU of D3 and 1000 mg of calcium had some improvement in his PD symptoms and was able to lower his levodopa dose to about half of his previous dose [61]. We have also looked at vitamin D concentrations and balance, cognition, and mood. One of our pilot studies showed a relationship with some measures of balance and vitamin D levels [19]. This was an exploratory study and data was not corrected for multiple comparisons. An Iranian study did not find a relationship between overall disease severity and vitamin D levels, but did find an association between lower vitamin D and more severe postural instability, freezing of gait, and abnormal postures [62]. In looking at neuropsychological function in a different PD population we found

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an association between vitamin D levels and verbal fluency, verbal memory, and depression in persons without dementia [58]. There is one published vitamin D intervention study. It was conducted in Tokyo and enrolled 114 persons aged 45–85 with a diagnosis of PD [63]. It was a double-blinded, randomized, placebo controlled study compairing 1200 IU vitamin D3 daily for three months. Measures included disease severity, quality or life, cognition (MMSE), laboratory testing (calcium, parahyroid hormone, BUN, creatinine, and 25-OHD), and genotyping (VDR and vitamin D binding protein). H&Y stage increased significantly in the control vs. vitamin D group – 0.33 vs. 0.02 (p = 0.005) and the number needed to treat was calculated as six. They also examined vitamin D polymorphisms and found that Fokl TT geneotype were the most improved by vitamin D, CT intermediately so, and CC not at all. 4. Conclusion The data that seems most consistent is the relationship between vitamin D levels and symptom severity. Most of this research however is cross-sectional and causation cannot be infered. The one intervention study looking at PD symptoms did show improvement in PD symptoms. These data are certainly hopeful that vitamin D therapy may be benefiial. More well randomized, placebocontrolled intervention studies are needed to confirm an effect of vitamin D on PD symptoms. The area with the most publications, bone health, suggests that vitamin D alone is not enough to prevent bone loss in persons with PD. Interestingly however, recommendation to spend as little as 15 min outside on sunny days did result in increases in bone mineral density, possibly related to increased physical activity. The possibility of neuroprotection is the most exciting aspect of vitamin D therapy, but it is also the most complicated area of research. Animal studies show some promising data, but translation to humans is always difficult. Without better biomarkers in the field of PD examining vitamin D’s effect on disease progression or its potential neuroprotective effects seems unlikely. Contributors Dr. Amie Peterson was the sole contributor to this article. Competing interest Dr. Peterson is currently conducting a vitamin D intervention study in Parkinson’s disease funding by Veterans Affairs. She has no other conflict of interest. Funding There was no funding received for this article. Provenance and peer review Commissioned and externally peer reviewed. References [1] Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective. Pediatrics 2003;112(August (2)):e132–5. [2] Kulie T, Groff A, Redmer J, Hounshell J, Schrager S. Vitamin D: an evidence-based review. J Am Board Family Med 2009;22(November–December (6)):698–706. [3] Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005;29(January (1)):21–30. [4] Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 2007;7(9):684–700. [5] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(July (3)):266–81.

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[32] Sato Y, Manabe S, Kuno H, Oizumi K. Amelioration of osteopenia and hypovitaminosis D by 1 alpha-hydroxyvitamin D3 in elderly patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;66(January (1)):64–8. [33] Kostner K, Denzer N, Muller CS, Klein R, Tilgen W, Reichrath J. The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature. Anticancer Res 2009;29(September (9)):3511–36.

[34] Burne TH, McGrath JJ, Eyles DW, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. Behav Brain Res 2005;157(February (2)):299–308. [35] Butler MW, Burt A, Edwards TL, et al. Vitamin D receptor gene as a candidate gene for Parkinson disease. Ann Hum Genet 2011;75(March (2)):201–10. [36] Lv Z, Tang B, Sun Q, Yan X, Guo J. Association study between vitamin D receptor gene polymorphisms and patients with Parkinson disease in Chinese Han population. Int J Neurosci 2013;123(January (1)):60–4. [37] Lin CH, Chen KH, Chen ML, Lin HI, Wu RM. Vitamin D receptor genetic variants and Parkinson’s disease in a Taiwanese population. Neurobiol Aging 2014;35(May (5)):1212.e11–3. [38] Han X, Xue L, Li Y, Chen B, Xie A, Vitamin. D receptor gene polymorphism and its association with Parkinson’s disease in Chinese Han population. Neurosci Lett 2012;525(September (1)):29–33. [39] Torok R, Torok N, Szalardy L, et al. Association of vitamin D receptor gene polymorphisms and Parkinson’s disease in Hungarians. Neurosci Lett 2013;551(September (13)):70–4. [40] Kim JS, Kim YI, Song C, et al. Association of vitamin D receptor gene polymorphism and Parkinson’s disease in Koreans. J Korean Med Sci 2005;20(June (3)):495–8. [41] Suzuki M, Yoshioka M, Hashimoto M, et al. 25-hydroxyvitamin D, vitamin D receptor gene polymorphisms, and severity of Parkinson’s disease. Mov Disord 2012;27(February (2)):264–71. [42] Petersen MS, Bech S, Christiansen DH, Schmedes AV, Halling J. The role of vitamin D levels and vitamin D receptor polymorphism on Parkinson’s disease in the Faroe Islands. Neurosci Lett 2014;561(February (21)):74–9. [43] Scherzer CR, Eklund AC, Morse LJ, et al. Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc Natl Acad Sci U S A 2007;104(January (3)):955–60. [44] Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol 2008;129(April (4)):526–9. [45] Abdi F, Quinn JF, Jankovic J, et al. Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J Alzheimer’s Dis 2006;9(August (3)):293–348. [46] Chen H, O’Reilly E, McCullough ML, et al. Consumption of dairy products and risk of Parkinson’s disease. Am J Epidemiol 2007;165(May (9)):998–1006. [47] Chen H, Zhang SM, Hernan MA, Willett WC, Ascherio A. Diet and Parkinson’s disease: a potential role of dairy products in men. Ann Neurol 2002;52(December (6)):793–801. [48] Park M, Ross GW, Petrovitch H, et al. Consumption of milk and calcium in midlife and the future risk of Parkinson disease. Neurology 2005;64(March (6)):1047–51. [49] Anderson C, Checkoway H, Franklin GM, Beresford S, Smith-Weller T, Swanson PD. Dietary factors in Parkinson’s disease: the role of food groups and specific foods. Mov Disord 1999;14(January (1)):21–7. [50] Miyake Y, Tanaka K, Fukushima W, et al. Lack of association of dairy food, calcium, and vitamin D intake with the risk of Parkinson’s disease: a case–control study in Japan. Parkinsonism Relat Disord 2011;17(February (2)):112–6. [51] Kurtzke JF, Goldberg ID. Parkinsonism death rates by race, sex, and geography. Neurology 1988;38(October (10)):1558–61. [52] Lux WE, Kurtzke JF. Is Parkinson’s disease acquired? Evidence from a geographic comparison with multiple sclerosis. Neurology 1987;37(March (3)):467–71. [53] Betemps EJ, Buncher CR. Birthplace as a risk factor in motor neurone disease and Parkinson’s disease. Int J Epidemiol 1993;22(October (5)):898–904. [54] Lanska DJ. The geographic distribution of Parkinson’s disease mortality in the United States. J Neurol Sci 1997;150(September (1)):63–70. [55] Kenborg L, Lassen CF, Ritz B, et al. 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Reversible parkinsonism, hypophosphoremia, and hypocalcemia under vitamin D therapy. Mov Disord 1997;12(4):612–3. [62] Moghaddasi M, Mamarabadi M, Aghaii M. Serum 25-hydroxyvitamin D3 concentration in Iranian patients with Parkinson’s disease. Iran J Neurol 2013;12(2):56–9. [63] Suzuki M, Yoshioka M, Hashimoto M, et al. Randomized, double-blind, placebocontrolled trial of vitamin D supplementation in Parkinson disease. Am J Clin Nutr 2013;97:1004–13.

Maturitas 78 (2014) 3–7

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Chiropractic intervention in the treatment of postmenopausal climacteric symptoms and insomnia: A review Viviane Goto a,b , Cristina Frange b , Monica L. Andersen b , José M.S. Júnior a , Sergio Tufik b , Helena Hachul a,b,∗ a b

Department of Gynecology, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil Department of Psychobiology, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil

a r t i c l e

i n f o

Article history: Received 5 February 2014 Accepted 10 February 2014 Keywords: Insomnia Sleep disturbance Menopause Postmenopause Chiropractic

a b s t r a c t Introduction: Insomnia is a frequent postmenopausal symptom and may be due to hormonal changes, depressive states related to this period of life, hot flashes or nocturia. Chiropractic care has been demonstrated to be effective in the treatment of these symptoms. Objectives: The aim of this study was to review chiropractic interventions in postmenopausal women as a possible management approach to menopausal symptoms and insomnia. Methods: A PubMed search was conducted by cross-referencing the key words insomnia, sleep, and menopause with chiropractic. The search used an end date of January 2014 and retrieved 17 articles. Results: Three articles were eligible for the study. All epidemiological data from large surveys demonstrated a lack of evidence for chiropractic intervention as a complementary and alternative therapeutic method in the management of menopausal symptoms and insomnia. Conclusions: There is no evidence for the effectiveness of chiropractic intervention as a complementary and alternative therapy for menopausal symptoms and insomnia. Further studies with proper methodological designs are warranted. © 2014 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Universidade Federal de São Paulo, Rua Napoleao de Barros 925, Vila Clamentino, Sao Paulo, SP, Brazil. Tel.: +55 11 2149 0155/+55 11 991556539; fax: +55 11 5572 5092. E-mail addresses: [email protected], [email protected] (H. Hachul). http://dx.doi.org/10.1016/j.maturitas.2014.02.004 0378-5122/© 2014 Published by Elsevier Ireland Ltd.

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V. Goto et al. / Maturitas 78 (2014) 3–7

1. Introduction Menopause is a stage of life that affects every woman around the world. However, the physical and mental impact of this physiological state inevitability varies both within and across cultures [1]. Although it is a normal biological process that begins at the last menstrual period and occurs at an average age of 51 years, women experience life change, as menopause marks the end of fertility [2]. These associated changes are both physical, with reduced functioning of the ovaries due to aging that results in lower levels of estrogen and other hormones with consequent effects on the body, and physiological, as menopausal symptoms are frequently reported by women to their doctors [1]. Sleep disorders are a common complaint among women experiencing menopause. These disorders include insomnia [3,5], poor sleep efficiency [4], sleep breathing irregularities [5,6], and hot flashes [5]. Some studies suggest that women in the transition to menopause (i.e., perimenopausal) or those who are postmenopausal have a higher frequency of sleep problems compared to premenopausal women [7,8]. The possible causes of insomnia or sleep disorders associated with menopause include symptoms of vasomotor disturbances (e.g., hot flashes or night sweats), mood disorders (anxiety and depressive states), sleep-disordered breathing [9,10] (e.g., sleep apnea), or chronic pain [11]. Stress and other factors (e.g., restless leg and periodic limb movement syndromes) may also contribute to sleep disturbances [12]. Changes in sleep architecture, particularly changes that result in the reduction of slow-wave sleep, are often accompanied by the loss of diurnal and alert functions of memory, a decrease in work performance, worsening of chronic pain, and a series of neuroendocrine changes including increased glucose intolerance and changes in the production and secretion of prolactin, of growth hormone and of cortisol [13–15]. The presence of insomnia during the menopausal transition and postmenopause may have negative social effects and may impact women’s quality of life. The traditional treatment for many postmenopausal complaints including insomnia is hormone therapy (HT) [16,17], as estrogen regulates the synthesis and release of neurotransmitters and neuromodulators that affect many functions of the brain, including mood, behavior, cognition and sleep [18,19]. Studies on the effects of HT by the World Health Initiative (WHI) were suspended in 2002 after 5.2 years of follow-up when investigators observed a significant increase in coronary heart disease, breast cancer, stroke and pulmonary embolism among women who were using HT. Thus, following the publication of the main results of the WHI, patients and doctors have become more reluctant to use long-term estrogen therapy, particularly in women at high risk for cardiovascular disease or breast cancer. Subsequently, the demand for non-hormonal therapies such as non-controlled drugs, antidepressants or behavioral therapies to manage these symptoms has increased [11,20]. For postmenopausal women, the use of HT should be carefully considered with regard to other risks because the vascular side effects of hormone replacement may exceed its beneficial effects on sleep [21]. Therefore, the use of complementary and alternative (CAM) therapies is becoming more frequent with demonstrated effectiveness [22]. Massage therapy was rated by an Australian study as the most effective therapy, followed by chiropractic therapy [23]. Chiropractic care emphasizes manual therapy and includes spinal manipulation, mobilization, device-assisted spinal manipulation, heat/ice, massage, soft tissue therapies, strengthening and stretching exercises and education about modifiable lifestyle factors [24]. The most common therapeutic procedure performed by chiropractic practitioners is known as “spinal manipulation”, also called “chiropractic adjustment”. The purpose of manipulation is to restore joint mobility by manually applying a controlled

force to joints that have become hypomobile (i.e., restricted in their movement) as a result of a tissue injury. Manipulation or adjustment of the affected joint and tissues restores mobility, thereby alleviating pain and muscle tightness and allowing tissues to heal [25]. Chiropractic care is used most often to treat neuromusculoskeletal complaints but is not limited to joint pain and headaches [25]. In this regard, chiropractic has been shown to be effective for relieving pain [26] and stress-related conditions [27]. Massage has been recognized to decrease cortisol levels, increase serotonin and dopamine levels [28] and to reduce blood pressure [29] and heart rate [30]. Our previous studies revealed that mind-body therapies could improve sleep [31], while massage was able to decrease insomnia in a randomized controlled trial of postmenopausal women [32]. Although relaxation techniques have been found to be beneficial in reducing menopausal symptoms [33,34], no research has been conducted on the direct effect of chiropractic intervention on postmenopausal symptoms. Thus, the aim of this study was to review chiropractic interventions in post-menopausal women as a possible management approach for menopausal symptoms and insomnia. 2. Methods A search for original and review articles focusing on chiropractic care, sleep and postmenopause was performed in PubMed. The search terms were “chiropractic” (MeSH), “sleep” and “menopause”. The general search strategy (“chiropractic” intersected with “sleep” keywords and “menopause”) retrieved 1 article. No filters were used. Next, “chiropractic” intersected with “insomnia” and “menopause” keywords did not retrieve any articles. A search using “chiropractic” intersected with “insomnia” and “climacteric symptoms” also retrieved no articles. We next searched for “chiropractic” intersected with “insomnia” and retrieved 7 articles and subsequently for “chiropractic” intersected with “menopause” and retrieved 9 articles. Two authors (VG and CF) reviewed the titles and abstracts of the retrieved studies independently against the inclusion and exclusion criteria. The inclusion criteria were as follows: women at menopause or postmenopause and having or attended a chiropractic intervention for relief of menopausal symptoms. The full-text article was read when the abstracts were unclear. All articles were restricted to abstracts in English. We also searched the reference lists of identified articles for additional papers. Secondary insomnia was not considered in this review. The cut-off date for this search was January 2014. A total of 17 original articles were identified, and 3 were eligible for inclusion in this review. 3. Results There were no studies of chiropractic intervention to treat climacteric symptoms and insomnia in postmenopausal women. Table 1 depicts the evidence for chiropractic in menopausal symptoms. In summary, the three studies reported epidemiological data [22,23,35] and evaluated patients through questionnaires and the perceived effects of chiropractic care. Newton and colleagues [22] reported the prevalence of the use of alternative therapies for menopause symptoms and the characteristics associated with their use in a self-reported survey. Among women who used CAM, 22.1% used it to treat symptoms of menopause. Chiropractic as an alternative therapy was used by 31.6% of this sample and 0.9% of the chiropractic-using subset used chiropractic for menopausal symptoms. Women who used CAM therapies for menopause symptoms were predominantly positive in their assessment of their effectiveness and nearly two-thirds favored natural approaches to managing menopause [22].

V. Goto et al. / Maturitas 78 (2014) 3–7

5

Table 1 Published studies showing evidence of chiropractic effects on menopausal symptoms. Authors

Study design

N (years)

Measures

Main outcomes

Newton et al. [22]

Longitudinal (6 months)

886 (45–65)

Telephone survey (questionnaires)

Brett and Keenan [35]

Cross sectional

3621 (45–57)

Telephone survey (questionnaires)

Van der Sluijs et al. [23]

Cross sectional

1296 (45–65)

Self-administered written survey (questionnaires)

31.6% Of the women used chiropractic as a CAM therapy 0.9% Used it to manage menopausal symptoms 9.4% Of the women used chiropractic as a CAM therapy 3% of the women used it to manage menopausal symptoms Chiropractic intervention was considered the second most effective of the CAM therapies Chiropractic were used for tenseness, sleeping difficulties and pain Sleep difficulties were rated as the most troublesome complaint

CAM: complementary and alternative medicine.

Brett and Keenan [35] conducted a survey to obtain national estimates of CAM use in the United States. The data were collected from the National Health Interview Survey, which included a CAM supplementary questionnaire in 2002 and a specific question about menopausal symptoms status. They found that among women who had used CAM in the previous 12 months, 45% considered the use of CAM to have been very important to their health. Of these modalities, 15% were massage and chiropractic interventions used to alleviate menopausal symptoms, among others. The treatment of pain was the most cited reason for using CAM, with only 3% mentioning menopause. However, the likelihood for the use of CAM was almost twice as high for women with menopausal symptoms compared to women with no symptoms (odds ratio: 1.9–95% CI: 1.6–2.2) [35]. Van der Sluijs and coworkers [23] investigated CAM use among women for the alleviation of menopausal symptoms and was the only study among these three that assessed sleep complaints. They demonstrated that 53.8% of women used at least one type of CAM intervention during the past year to alleviate menopausal symptoms. Chiropractic care was one of the most effective therapies and was considered to be the next most effective (90%) after massage (94%). They reported that the most common symptoms of menopause that troubled respondents using massage and chiropractic were tenseness, pain and sleeping difficulties (p = 0.001). Of the total sample of 1296 women, 39.4% reported having moderate sleeping difficulties, 34.5% had no sleep difficulties and 26.1% had severe sleeping difficulties [23]. 4. Discussion We aimed to review chiropractic interventions in postmenopausal women as a possible approach in the management of menopausal symptoms and specifically for insomnia. In this context, there is a lack of evidence in the literature. No previous study has assessed the effect of chiropractic intervention in postmenopausal women with climacteric symptoms and insomnia. One exploratory study conducted by Jamison [36] investigated the relationship between chiropractic care and insomnia through patients’ and chiropractors’ expectations and the perceptions of their care on self-perceived sleep parameters. Patients were from both sexes and ranged from 18 to 65 years in age [36]. This study surveyed chiropractors and patients about sleeping difficulties and the chiropractic intervention, and it also evaluated patients with insomnia after 3 months of chiropractic treatment. In this study, no objective parameters were measured. Of the 20 subjects who reported sleep disturbances, 46% reported night arousals, 43% had problems falling asleep and 17% reported early awakenings. After the chiropractic care of a total of 154 patients, 66% reported no change in their sleeping behaviors. Of the patients who did note a change, 24% reported sleeping more soundly, 6% felt they slept

longer and 4% reported that they fell to sleep more quickly. Finally, this study did not show any evidence of the effectiveness of chiropractic care for insomnia symptoms’, with no clear patterns emerging between chiropractic care and sleep. Quantifying sleep parameters in a chiropractic study sample is warranted to evaluate its effectiveness as a CAM modality because chiropractic intervention has been found to be effective for relieving pain [26] and stress-related conditions [27]. After alleviating pain, restful sleep could possibly ensue. Chiropractic treatment has been shown to be effective in the treatment of chronic pain and chronic pain syndromes [37,38]. Furthermore, as pain is likely to have a substantial impact on sleep, any relationship between insomnia and chiropractic care is likely to be confounded by pain. Newton and coworkers [22] showed that alternative therapies for menopausal symptoms encompass a wide variety of methods, including chiropractic. They described sleep disturbances as associated with a four-fold increase in the use of massage and chiropractic therapy to manage menopausal symptoms; however, they did not describe the types of sleep disturbances and did not explore the patient’s augmented risk or even their potential associations with augmented risk. Thus, the question remains: How can such therapies contribute to the alleviation of poor and non-restorative sleep as well as be potential therapeutic alternatives for menopausal symptoms given that sleep disturbances might be one of these symptoms? Chiropractic treatment can offer relief to people suffering from sleep disorders through mechanical manipulation. Of great value in this regard would be the investigation of the mechanism by which chiropractic impacts insomnia and menopausal symptoms. An understanding of the basic neurophysiologic mechanisms of manipulation-induced analgesia is needed to establish its evidence. Chiropractic spinal manipulative therapy may affect types 1 and 2 mechanoreceptors by exciting a ␥-aminobutyric acid-ergic (GABAergic) inhibitory neuron. This neuron interrupts the transmission of nociceptive impulses from the thalamus to the limbic system [39]. Both galanin and GABA, released from the ventrolateral preoptic nucleus, are known to inhibit the locus coeruleus, a major site of norepinephrine synthesis, thereby allowing relaxation of the mind, thus promoting non-rapid eye movement (NREM) sleep [40]. Pathways have been postulated, but no conclusive evidence exists [39]. Mechanisms to elucidate the analgesic effects of chiropractic have been postulated [41]. Kingston and colleagues [42] reviewed the chiropractic literature in 2010 for evidence of chiropractic therapy to treat primary insomnia, although not in menopausal women, and they found an improvement in insomnia after manual therapy but with minimal evidence to support the use of chiropractic for insomnia [42]. Chiropractors evaluate sleep complaints by taking a meticulous sleep history and performing a thorough physical examination, paying particular attention to neurologic, cardiopulmonary, and

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V. Goto et al. / Maturitas 78 (2014) 3–7

psychological functions. Chiropractors are often the clinician of choice for patients with pain [43]. Although anecdotal evidence suggests that chiropractic may modulate dysfunctional sleep patterns, supportive objective evidence is lacking. Nonetheless, the research has yet to incontrovertibly support the efficacy of spinal manipulation for the relief of musculoskeletal pain [44,45]. 5. Conclusions According to the literature, chiropractic interventions might reduce climacteric symptoms, particularly insomnia, and consequently improve the quality of life for menopausal women. However, thus far there is no evidence to support such claims in the literature. Menopausal symptoms as well as insomnia are complex and varied entities. The lack of evidence of chiropractic research in these areas strongly argues in favor of future research. Large randomized controlled trials are required to assess the validity of chiropractic therapy as an evidence-based treatment for menopausal symptoms and insomnia. Contributors Goto V wrote the review, directly and actively supervised all phases of the research and completed the manuscript together with Frange C. Andersen ML assisted with all phases of the research, helped with the data analyses and read and corrected the manuscript. Jose MS Junior significantly contributed to the drafting and correcting of the manuscript. Tufik S directly contributed to the interpretation of the results and elaboration of the discussion. Hachul H corrected the manuscript and updated the discussion. Competing interest The authors declare no competing interest. Funding information Our study received the support of the Associac¸ão Fundo de Incentivo a Pesquisa (AFIP). Provenance and peer review Not commissioned, externally peer reviewed. Acknowledgment Our study received the support of the Associac¸ão Fundo de Incentivo a Pesquisa (AFIP). References [1] Melby MK, Lock M, Kaufert P. Culture and symptom reporting at menopause. Hum Reprod Update 2005;11(5):495–512. [2] Philp HA. Hot flashes—a review of the literature on alternative and complementary treatment approaches. Altern Med Rev 2003;8(3):284–302. [3] Shaver JL, Zenk SN. Sleep disturbance in menopause. J Womens Health Gend Based Med 2000;9(2):109–18. [4] Baker A, Simpson S, Dawson D. Sleep disruption and mood changes associated with menopause. J Psychosom Res 1997;43(4):359–69. [5] Woodward S, Freedman RR. The thermoregulatory effects of menopausal hot flashes on sleep. Sleep 1994;17(6):497–504. [6] Saaresranta T, Polo-Kantola P, Rauhala E, Polo O. Medroxyprogesterone in postmenopausal females with partial upper airway obstruction during sleep. Eur Respir J 2001;18(6):989–95. [7] Dennerstein LE, Dudley EC, et al. A prospective population based study of menopausal symptoms. Obstet Gynecol 2000;96(3):315–8.

[8] Shin C, Lee S, Lee T, et al. Prevalence of insomnia and its relationship to menopausal status in middle-aged Korean women. Psychiatry Clin Neurosci 2005;59(4):395–402. [9] Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96(3):351–8. [10] Krystal AD, Edinger J, Wohlgemuth W, Marsh GR. Sleep in perimenopausal and post-menopausal women. Sleep Med Rev 1998;2(4):243–53. [11] Soares CN. Insomnia during menopause and perimenopause—clinical characteristics and therapeutic options. Rev Psiq Clín 2006;33(2):103–9. [12] Polo Kantola P, Erkkola R. Sleep and the menopause. J Br Menopause Soc 2004;10(4):145–50. [13] Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA. Quality of life in people with insomnia. Sleep 1999;22(2):S379–85. [14] Backhaus J, Junghanns K, Hohagen F. Sleep disturbances are correlated with decreased morning awakening salivary cortisol. Psychoneuroendocrinology 2004;29(9):1184–91. TM, Schatzberg AF. On the interactions of the [15] Buckley hypothalamic–pituitary–adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 2005;90(5):3106–14. [16] Elliott TE, Renier CM, Palcher JA. Chronic pain, depression, and quality of life: correlations and predictive value of the SF-36. Pain Med 2003;4:331–9. [17] Polo Kantola P, Erkkola R, Irjala K, et al. Effect of short-term transdermal estrogen replacement therapy on sleep: a randomized, double-blind crossover trial in postmenopausal women. Fertil Steril 1999;71(5):873–80. [18] Polo Kantola P, Erkkola R, Helenius H, Irjala K, Polo O. When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;178(5):1002–9. [19] McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev 1999;20(3):279–87. [20] Bardel A, Wallander MA, Svärdsudd K. Hormone replacement therapy and symptom reporting in menopausal women. Maturitas 2002;41(1):7–15. [21] Tranah GJ, Parimi N, Blackwell T, et al. Postmennopausal hormones and sleep quality in the elderly: a population based study. BMC Women’s Health 2010;4:10–5. [22] Newton KM, Buist DSM, Keenan NL, Anderson LA, LaCroix AZ. Use of alternative therapies for menopause symptoms: results of a population-based survey. Obstet Gynecol 2002;100(1):18–25. [23] Van der Sluijs CP, Bensoussan A, Liyanage L, Shah S. Women’s health during mid-life survey: the use of complementary and alternative medicine by symptomatic women transitioning through menopause in Sydney. Menopause 2007;14(3):397–403. [24] Bryans R, Descarreaux M, Duranleau M, et al. Evidence-based guidelines for the chiropractic treatment of adults with headache. J Manipulative Physiol Ther 2011;34(5):274–89. [25] Chapman-Smith David. The chiropractic profession. West Des Moines, IA: NCMIC Group Inc, 11a; 2000. p. 70–1. [26] Polkinghorn BS, Colloca CJ. Chiropractic management of chronic chest pain using mechanical force, manually assisted short-lever adjusting procedures. J Manipulative Physiol Ther 2003;26(2):108–15. [27] Tuchin PJ, Pollard H, Bonello DC. A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. J Manipulative Physiol Ther 2000;23(2):91–5. [28] Field T, Hernandez-Reif M, Diego M, Schanberg S, Kuhn C. Cortisol decreases and serotonin and dopamine increase following massage therapy. Int J Neurosci 2005;115(10):1397–413. [29] Aourell M, Skoog M, Carleson J. Effects of Swedish massage on blood pressure. Complement Ther Clin Pract 2005;11(4):242–6. [30] Chenoy R, Hussain S, Tayob Y, O’Brien PMS, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ 1994;308(6927):501–3. [31] Kozasa EH, Hachul H, Monson C, et al. Mind-body interventions for the treatment of insomnia: a review. Rev Bras Psiquiatr 2010;32(4):437–43. [32] Hachul H, Oliveira D, Tufik S, Bittencourt L. Effect of massage in postmenopausal women with insomnia: a pilot study. Clinics 2011;66(2):343–6. [33] Wijma K, Melin A, Nedstrand E, Hammar M. Treatment of menopausal symptoms with applied relaxation: a pilot study. J Behav Ther Exp Psychiatry 1997;28(4):251–61. [34] Freedman RR, Woodward S. Behavioral treatment of menopausal hot flashes: evaluation by ambulatory monitoring. Am J Obstet Gynecol 1992;167(2):436–9. [35] Brett KM, Keenan NL. Complementary and alternative medicine use among midlife women for reasons including menopause in the United States: 2002. Menopause 2007;14(2):300–7. [36] Jamison JR. Insomnia does chiropractic help? J Manipulative Physiol Ther 2005;28(3):179–86. [37] Muller R, Giles L. Long term follow up of a randomized clinical trial assessing the efficacy of medication, acupuncture, and spinal manipulation for chronic mechanical spinal pain syndromes. J Manipulative Physiol Ther 2003;28(1):3–11. [38] Hains G, Hains F. Combined ischemic compression and spinal manipulation in the treatment of fibromyalgia: a preliminary estimate of dose and efficacy. J Manipulative Physiol Ther 2000;23(4):225–30. [39] Seaman DR. Chiropractic and pain control. third ed. Baltimore, MD: Williams & Wilkins: DRS systems Inc; 1995. p. 46–50.

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[43] Carrick FR. What’s new about sleep? J Am Chiropr Assoc 2001:64. [44] Abenhaim L, Bergeron AM. Twenty years of randomized clinical trials of manipulative therapy for back pain: a review. Clin Invest Med 1992;15(6): 527–35. [45] Ernst E. Manual therapies for pain control: chiropractic and massage. Clin J Pain 2004;20(1):8–12.

Maturitas 78 (2014) 45–50

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Classical and newly recognised non-contraceptive benefits of combined hormonal contraceptive use in women over 40 Nicolas Mendoza ∗ , Rafael Sanchez-Borrego University of Granada, Obstetric and Gynecologic, Maestro Montero, 21, Granada, Spain

a r t i c l e

i n f o

Article history: Received 18 February 2014 Received in revised form 24 February 2014 Accepted 28 February 2014 Keywords: Menopause transition Hormonal contraception Combined hormonal contraception Non-contraceptive benefits Natural estrogens

a b s t r a c t Although age is the most crucial predictor of a woman’s reproductive capacity, it is assumed that there is still a risk of pregnancy in menopause transition, as occasional spontaneous ovulation is possible. Moreover, age alone is not sufficient to contraindicate the use of any contraceptive method, whether hormonal or not. The use of new CHC in women over 40 has not only been associated with an improved safety profile but has also been associated with other non-contraceptive benefits or the consolidation of already-known benefits. The studies with new CHC have demonstrated that efficacy and safety do not differ from the corresponding parameters observed in younger women. Additionally, the new CHC offers specific and especially useful benefits for women over 40 in the treatment of menstrual disorders. Finally, interest is currently focused on the potential of early diagnosis and the prevention of cardiovascular disease and depression, both of which may be alleviated by the CHC. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Health problems in women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Combined hormonal contraception over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Use of CHC in women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. On efficacy and the missed pill in women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. It is necessary to monitor the use of CHC in women over 40? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Risks of CHC in women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Classical non-contraceptive benefits of CHC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Is there a CHC or a regimen that is best for the woman over 40? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.1. Shorten or eliminate the hormone-free period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. CHC with natural estrogens for women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The menopausal transition is an indefinite period in a woman’s life between the time that the first changes in the menstrual cycle occur and the year following the definitive cessation of

∗ Corresponding author. Tel.: +34 653673769. E-mail address: [email protected] (N. Mendoza). http://dx.doi.org/10.1016/j.maturitas.2014.02.017 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

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menstruation [1]. Although age is the most crucial predictor of a woman’s reproductive capacity, it is assumed that there is still a risk of pregnancy in perimenopause, as occasional spontaneous ovulation is possible. Moreover, age alone is not sufficient to contraindicate the use of any contraceptive method, whether hormonal or not [2]. Most reviews dedicated to combined hormonal contraception (CHC) during menopausal transition describe the indications for CHC use, the potential risks, and when/how to discontinue CHC

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[3]. However, these reviews lack a discussion of the potential noncontraceptive benefits of CHC use among women over 40. While there is strong evidence demonstrating that CHC use is associated with reductions in menstrual bleeding, menstrual cramping, and gynaecological cancers in young women, data regarding CHC use among women over 40 are lacking. The objective of this review is to determine whether the noncontraceptive benefits of CHC observed in other age groups can be extrapolated to women over 40, if there are other specific benefits for them who do not have the youngest and if new CHC methods are best suited to the needs and characteristics of women over 40. 1.1. Health problems in women over 40 The menopausal transition is accompanied by complex processes that result from the cessation of ovarian activity. Although various neuroendocrine changes in the menopausal transition have been described, the central biological event of this period is the phasing out of ovarian activity, both in the number of follicles and in the quality of oocytes. Consequently, menopausal transition is a period of low fertility that is characterised by anovulation and poor oocyte quality. The serum levels of follicle stimulating hormone (FSH), oestrogen and progesterone fluctuate around menopause, while the LH levels are maintained within the normal range. An increase in FSH not only stimulates ovarian folliculogenesis at an accelerated rate until the onset of menopause but also increases the risk of multiple pregnancies. The increased folliculogenesis causes a greater production of oestrogens, which may contribute to irregular bleeding and symptoms such as bloating and breast tenderness [4]. Furthermore, some gestational complications increase with maternal age (i.e., gestational diabetes, hypertension, growth restriction, placental pathology and prematurity). As a result, both the number of operative or instrumental deliveries and the perinatal and maternal mortality and morbidity are increased in women over 40. Consequently, reproductive counselling is necessary to inform women about the risks regarding conception that age confers [1,5]. In addition to irregular bleeding and the deterioration of ovarian function, many women also complain of hot flashes and other symptoms that have been described in post menopause (sleep disturbances, irritability, premenstrual syndrome, mood changes, skin changes, musculoskeletal disorders, balance disorders and vaginal dryness). Although menopause transition affects most women, it is estimated that quality of life is affected in a meaningful way in 20% of women [6]. Recently, the importance of ovarian function cessation in depression and cardiovascular disease (CVD) risk was assessed, and a bi-directional relationship between these two conditions seems to exist, with both of these conditions also associated with the possibility of menstrual cycle alteration. Various neuroendocrine mechanisms are involved in this process, although the link that unites these conditions is the ovarian dysfunction. From this perspective, women in the menopausal transition period experience greater mood changes, even more than during the subsequent period, which is when the CD risk increases [7]. 2. Combined hormonal contraception over 40 2.1. Use of CHC in women over 40 In Spain, the use of CHC in women over the age of 40 is low (13.9% of women 40–44 years, and 5.6% of women over 45), well below the average of the population (21.6%) and lower than CHC use in the past [8], while the abortion rate has increased in these women in the last decade [9]. These reports indicated that the main

reasons for non-compliance with CHC in women over 40 were a fear of cancer and possible CHC-related side effects. 2.2. On efficacy and the missed pill in women over 40 In terms of contraceptive efficacy, data extracted from articles involving women over 40 demonstrate more favourable efficacy given that fertility decreases significantly with age. Additionally, compliance is also improved because the majority of women over 40 have already used some contraceptive method or are familiar with the administration of CHC [2]. The decrease in fertility may present an advantage for the older woman over the younger woman in the case of missed or delayed CHC pill taking. However, two recent systematic reviews about missed and delayed CHC pills do not address the question of age [10,11]. When the particular endocrinology of the ovarian cycle in women over 40 is considered, with its higher basal levels of FSH and greater recruitment of follicles, we found no cause to modify the usual recommendations regardless of the woman’s age [12]. 2.3. It is necessary to monitor the use of CHC in women over 40? In general, prior to the initiation of CHC, the performance of a medical history that aims to identify the facts that may contraindicate or do not favour CHC use is recommended, especially with regard to a personal and family history of thrombosis. When monitoring CHC, the consensus recommendation is for patient contact, if any, at three or six months from the start of the treatment to improve adherence, without a recommendation for specific periodic check-ups due to the use of contraceptives. For women over 40, the decision to discontinue CHC should be based on individualised contraceptive counselling, as there is no current evidence that confirms the time at which ovarian function ceases; moreover, fertility in women over 50 years of age is extremely low [13]. 2.4. Risks of CHC in women over 40 Most of the evidence regarding the risks and benefits of CHC is derived from studies of oral CHC use in women younger than 35 years of age, results from which have been extended to older women and to other routes of administration (patch or vaginal ring). However, a Cochrane Database Systematic Review show that patch users had more side effects and ring users generally had fewer adverse events than oral CHC users [14]; and a recent cohort study show that vaginal ring use and oral CHC use were associated with a similar arterial or venous thrombotic (VT) risk during routine clinical use [15]. In the same way, the risks and benefits of CHC have been observed mostly in women younger than 35 years, but there appears to be consensus that age alone does not imply any limitation in the use of CHC [16]. Age is associated with an increased risk of venous thrombosis, which increases after age 39 among women using CHC pills. Epidemiological studies have reported an increase in myocardial infarctions, which are believed to be associated with a thrombotic mechanism rather than with the development of atherosclerotic plaques and an increase in cardiovascular mortality in users of the CHC pill who smoke and are over 35. A consensus panel suggested that CHCs should not be given to women over 35 who smoke more than 15 cigarettes per day, but they can be considered in women who smoke fewer than 15 cigarettes per day, even for those >35 years old who have an occasional cigarette, since the risks of pregnancy in this age group are greater than the risks associated with OC use [17]. However, we agree with those who consider that smoking above the age of 35 is a contraindication to the use of CHC [18]. The relationship between smoking, the use of oral CHC and CVD may be associated with high concentrations of intravascular plasma

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fibrinogen and fibrin deposition and with the enhanced expression of tissue factor from monocytes. Also, CHC should be avoided in women over 40 with obesity, hypertension or migraine headaches, in which case could bee candidates for progestin-only contraception [19,20]. Anyway, for healthy non-smoking women, age is not an obstacle to the use of hormonal methods. Although age by itself increases the risk of breast cancer, it is unclear whether this risk is increased with the use of CHC. However, the risk of suffering from breast cancer is greater in premenopausal women than in postmenopausal women of the same age, but again, there is no evidence that CHC increases this risk more at this age than at any other, so age is not considered enough to modify the patterns of the prescription of CHC [21]. Moreover, the latest report of the Oxford-Family Planning Association contraceptive study (Oxford-FPA) reveals that CHC use had no effect on non-reproductive cancers or on breast cancer [22]. In a recent review of the timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers, the effect of timing was limited to breast cancers diagnosed before age 40 (OR 1.40; 95% CI 1.14–1.70; P = 0.001). The risk of early-onset breast cancer increased by 11% with each additional year of pill use when such use was initiated prior to age 20 (OR 1.11; 95% CI 1.03–1.20; P = 0.008). No associated increase was observed for women diagnosed at or after the age of 40 (OR 0.97; 95% CI 0.79–1.20; P = 0.81) [23]. In relation to the thrombotic risk, the latest revision of the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) did not issue a cause for concern or new reasons that alter the balance between the risks and benefits of CHC. This report established different risks depending on the progestagen and mentioned age as an isolated factor of thrombotic risk [24]. Regarding the type of progestin, the PRAC confirming the data observed in large series [25,26] and indicates that the VT risk is lowest with the CHCs containing levonorgestrel, norgestimate and Norethisterone (5 and 7 cases yearly per 10,000 women), and higher with etonogestrel and norelgestromin (6 and 12 cases) or gestodene, desogestrel, drospirenona (9 and 12 cases). For CHCs containing chlormadinone, dienogest and nomegestrol, the available data are insufficient to know how the risk compares with the other CHCs, but further studies are ongoing or planned. The risk of arterial thromboembolism is very low and there is no evidence for a difference in the level of risk between products depending on the type of progestogen. On the other hand, most progestagenonly contraceptive methods do not increase VT risk significantly, and a considerable literature demonstrate the non-contraceptive health benefits of the levonorgestrel-releasing intrauterine system in women over 40 relate to disturbances of menstruation and related symptom (heavy menstrual bleeding, iron deficiency, pelvic pain and endometrial hyperplasia) [27]. However, these risks are independent of age, and at no point in the document did it state that the use of CHC must be restricted in women over 40 [24]. 2.5. Classical non-contraceptive benefits of CHC The articles that review CHC use during perimenopause frequently do not cite the potential non-contraceptive benefits [3]. While there is strong evidence showing that CHC use is associated with reductions in menstrual bleeding, menstrual cramping, and gynaecological cancers in young women, the data among women in menopausal transition are lacking. Indeed, the great majority of studies evaluating these benefits have been conducted in women younger than 40, commonly in women less than 35 years of age [28]. Altogether, CHC has been used successfully to treat menstrual disorders in women over 40. Some guidelines have even suggested that the use in healthy women without menstrual disorders may

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reduce gynaecological cancers, bone mass loss, and premenstrual syndrome [29], although there is insufficient evidence to recommend the use of CHC solely for the primary prevention of any of these conditions at any age [24]. Additionally, there is little controversy regarding the use of CHC among women over 40 due to the above-mentioned benefits; however, it is known that some gynaecological cancers increase with age, as does menstrual irregularity, and that both are reduced with CHC use [30]. Consequently, there is no apparent reason to not extend the benefits demonstrated in younger women to women over 40. With regard to the prevention of bone resorption, the maintenance of bone mineral density (BMD) will occur with CHC use, primarily in hypo-oestrogenic women over 40. Any type of CHC has been proven to be effective for osteoporosis prevention, although this effectiveness does not exceed the benefits obtained with certain sports [31]. A systematic review of 6 randomised prospective studies performed in women over 40 demonstrated that the use of CHC reduces bone resorption and might significantly increase BMD, even at a low dose. In contrast with these data, cross-sectional studies evaluating BMD in perimenopausal women have failed to detect any significant difference between COC users (even current users) and nonusers [32]. Moreover, there is no evidence that COC use reduces the risk of fracture prior to menopause [33]. CHC has been shown to reduce dysphoric disorder and premenstrual syndrome, including in women over 40 [34,35], although these benefits are more evident with the use of extended and continuous regimens (see next section). In addition, CHC can also provide symptomatic relief for women over 40 complaining of hot flushes, vaginal dryness or insomnia associated with fluctuating oestrogen levels [36]. Classically, other non-contraceptive benefits in other conditions have been considered; however, some of these (acne, dysmenorrhoea, hyperandrogenism and endometriosis) are not very common at age 40 and beyond, and many of these conditions may arise at any age (myoma, pelvic inflammatory disease, rheumatoid arthritis, multiple sclerosis, asthma, etc.). But above all, the main non-contraceptive benefit of the CHC in women over 40 is the reduction of maternal deaths, just by reducing the number of unintended pregnancies, the improve of perinatal outcomes and child survival, essentially by increase interpregnancy intervals [37]. 2.6. Is there a CHC or a regimen that is best for the woman over 40? 2.6.1. Shorten or eliminate the hormone-free period In women over 40, continuous or extended hormonal contraception regimens (CR/ER) have shown similar rates of efficacy, safety, and compliance compared to the standard 28-day regimen and may also improve the specific symptoms associated with the hormonefree period [38]. Women with premenstrual syndrome or menstrual symptoms during the hormone-free interval who used conventional regimens were shown to benefit from the use of CR/ER, according to the 7 RCTs that assessed these regimens in women over 40 [39–45]. In a retrospective study, contraceptive vaginal ring users also showed lower frequencies of migraine with aura related to menstruation [46]. It should be noted that studies that have assessed the degree of satisfaction of users of CR/ER were aimed primarily at the improvement or elimination of regular bleeding, and these results showed that female satisfaction was higher when the number of bleeding periods of any type decreased. Additionally, reducing menstruation is a strategy used to treat women with heavy menstrual bleeding (HMB), anaemia, and endometriosis. In the case of HMB, most studies have noted that the bleeding rate and the intensity of

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bleeding were lower and that the amenorrhoea rate was higher in CR/ER users [38,39,43,44]. In fact, a guideline on continuous and extended use of CHC has recommended these regimens in women with HMB or blood dyscrasias [47]. The risk of endometrial cancer is reduced in CHC users, and there appears to be a residual protective effect after CHC discontinuation. It appears unlikely that CR/ER would alter this benefit, considering the results of endometrial biopsies [48,49]. 2.6.2. CHC with natural estrogens for women over 40 More recently, newer CHC that incorporates natural estrogens (NE) instead of ethinyl-estradiol (EE) has been demonstrated to be highly effective, well tolerated, and associated with a high level of user satisfaction. These formulations also appear to improve certain parameters (haemostasis and metabolism), which makes them especially attractive to women over 40. NE has a lower impact on oestrogen-hepatic proteins, and is more readily metabolised by the liver than EE (the ethinyl group on which slows down that process). The structure increases the bioavailability of EE compared with NE, but may also contribute to an increased likelihood of oestrogenrelated adverse events [50,51]. One of the new oral CHC combines estradiol valerate and dienogest (E2V/DNG) in a 26/2 regimen and has an indication in the treatment of HMB. Apart from those matters that have improved their safety, an interesting observation is that most of the volunteers in trials that have permitted the use of E2V/DNG for the treatment of HMB have been older than 40. For the first time, this will allow details of contraceptive efficacy, safety and effects on other symptoms to emerge from this group of women, data that have been unavailable with other CHC [52,53]. In this regard, the data that enabled the adoption of E2V/DNG as CHC and for HMB treatment were derived from studies performed in Europe, the USA and Canada, all of which followed the 26/2 regimen. Only two of these studies included women over 40, which can be examined together as a measurement of high contraceptive efficacy, especially in older women. The total number of reported pregnancies was 13 in 2175 volunteers who were exposed for more than 23,000 cycles, with only one pregnancy in a woman over 35 [54,55]. Additionally, most of the women presented with normal or low menses, with 4 days of bleeding on average, which tended to decrease with successive cycles, and with a drop-out rate of only 2.5% due to menstrual irregularity. As a result, these benefits apply not only to women with HMB but also to women who value a reduction in normal menstrual bleeding. Despite the absence of prospective studies that compare the new CHC with the LNG-IUD, the latest revision of the Guide to the National Institute for Health and Clinical Excellence of the United Kingdom (NICE) establishes that the LNG-IUD is the first treatment of choice for women with HMB who do not wish to become pregnant [54]. In these studies, headaches and pelvic pain associated with the hormone-free period were also less frequent with E2V/DNG. Additionally, a diary-based pilot study has indicated that the use of a pill containing E2V/DNG for six cycles has a positive effect in women with menstrually related migraine and suggests an association between dysmenorrhoea and COC use as a potential feature of refractory head pain [55]. Additionally, although considered a rare side effect, some women experience a decrease in sexual desire and sexual response associated with the use of CHC, which may also be considered a cause of abandonment. However, improvement as measured by the Female Sexual Function Index has been observed with E2V/DNG with regard to other CHC with EE/LNG in women up to 50 years of age [56]. In another study of women up to 48 years of age, E2V/DNG also improved the quality of their sex lives as measured by specific scales [57].

The metabolic and haemostatic profiles of the new CHC are more favourable than those observed with old CHC [58,59]. Currently, particular importance has been assigned to the relationship between SHBG and the risk of VT, not because this protein is directly related to coagulation or fibrinolysis, but rather because EE will stimulate SHBG synthesis, which suggests that this action is also accompanied by an increased production of proteins involved in haemostasis and blood pressure. In this regard, some authors consider the SHBG increase as an indirect marker of the thrombotic risk, a hypothesis that presents an advantage to CHC with NE [60], although a recent comparative study did not demonstrate differences in SHBG levels or resistance to activated protein C between CHC with or without NE [61]. With regard to the cardiovascular safety profile of E2V/DNG, one reported case of leg DVT subsequent to a sprained ankle occurred in a 40-year-old woman 9 days after completing treatment with E2V/DNG. Notably, this woman had initiated contraception with depot medroxyprogesterone acetate in the interim. In addition, there was a single case of myocardial infarction in this study, which occurred in a 47-year-old woman who was in violation of the exclusion criteria (smoker aged >30 years at study entry) [49]. Additionally, the superiority of E2V/DNG for the treatment of hormone withdrawal-associated symptoms (HWAS), including headache, pelvic pain and bloating, has been demonstrated in women up to 50 years in HARMONY I and II trials [62,63]. In conclusion, E2V/DNG appears to represent a new NEcontaining CHC with advantages with respect to those containing EE, not only in the treatment of HMB but also for women who wish to experience lighter bleeding and for women who are comfortable with the idea of using an NE as well as women seeking to allay their concerns associated with the general use of hormones. E2V/DNG may also improve sexual dysfunction or migraine associated with menstruation or with the use of other ACH. Although the metabolic and haemostatic data appear favourable, confirmatory studies are needed. Other CHC with NE has been formulated with 2.5 mg of nomegestrol acetate (NOMAC) and 1.5 mg of 17␤-estradiol (E2) in a monophasic oral 24/4 regimen [64]. Two large, international, randomised controlled trials have been conducted in women aged 36–50 years without changes in contraceptive efficacy or side effect with age [65,66].

3. Future perspectives CHC has been successfully used to treat menstrual disorders in women over 40. Some guidelines have also suggested that the use of CHC in healthy women over 40 without menstrual disorders may reduce gynaecological cancers, bone mass loss, and menstrual symptoms. Recently, the importance of ovarian function cessation in depression and cardiovascular risk was assessed, and a bi-directional relationship between these two conditions appears to exist, with both of these conditions also associated with the possibility of menstrual cycle alteration. Various neuroendocrine mechanisms are involved in this process, although the link that unites these conditions is the ovarian dysfunction. In this sense, CHC may reduce levels of depressive symptoms among young women [67]. Therefore, women in the menopausal transition period experience greater mood changes, even more than during the subsequent postmenopausal period, which is when the cardiovascular risk increases [7]. Similar to what was proposed for menopause hormone treatment (HT), where a “window of opportunity” exists during which the cardiovascular effects of HT outweigh the risks [68], a “window of vulnerability” for cardiovascular disease and depression during perimenopause might also exist [69]. Could the new CHC mitigate

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these risks and be considered as protective during this window of vulnerability? The new CHC has been associated with superior haemostatic and metabolic profiles. Indeed, current studies have recently begun to demonstrate positive results in postmenopausal women (ELITE, KEEPS, etc.). However, the effects of any CHC on cardiovascular parameters require further study, as strategies once believed to reduce disease risk have been shown to increase this risk if the hormone type, dose, or timing was not appropriate, as in the lessons learned from HT. As a result, further studies are required to investigate these and other possible beneficial effects of CHC in women over 40. In addition to therapeutic value, a recent review suggests that CHC are cost-effective medications for many medical disorders in women (premenstrual tension, dysmenorrhoea, and menstrual bleeding) [70]. However, at present, we have insufficient data to determine whether any specific CHC or regimen is more efficient than any other at preventing such costs.

4. Conclusions The main conclusion of this review is the reinforcement of the prevailing concept in nearly all guidelines regarding contraception: age is not a factor that contraindicates the use of any contraceptive method. Therefore, the choice of a contraceptive method for a woman over 40 should only be informed by her state of health, her life habits and her previous experience with other methods. Regarding CHC, certain potential risks also increase with age, predominantly VT; however, according to published data, the incidence of VT in CHC users over 40 does not differ from that observed in younger women. Nevertheless, this claim must be interpreted with caution because most of the RCTs that have analysed the efficacy and safety of CHC included predominantly women younger than 35 years of age, and only rarely have they included volunteers older than 40. The use of new CHC has not only been associated with an improved safety profile but has also been associated with other non-contraceptive benefits or the consolidation of already-known benefits. Interestingly, some RCTs with the new CHC have been conducted primarily in women over 40. These studies have demonstrated that efficacy and safety do not differ from the corresponding parameters observed in younger women. Additionally, the new CHC offers specific and especially useful benefits for women over 40 in the treatment of menstrual disorders. Finally, interest is currently focused on the potential of early diagnosis and the prevention of CVD and depression, both of which may be alleviated by the new CHC.

Contributors Nicolas Mendoza and Rafael Sanchez-Borrego: conception and design of the idea, data interpretation and preparation of manuscript.

Competing interest None.

Funding No one is on speaker’s bureaus, received research funding or consulting. There was no funding source and no editorial assistance for this position statement.

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Provenance and peer review Commissioned and externally peer reviewed.

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Maturitas 78 (2014) 56–61

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Cognitive behaviour therapy for menopausal symptoms following breast cancer treatment: Who benefits and how does it work? Joseph Chilcot, Sam Norton, Myra S. Hunter ∗ Institute of Psychiatry, King’s College London, UK

a r t i c l e

i n f o

Article history: Received 18 December 2013 Received in revised form 19 January 2014 Accepted 20 January 2014 Keywords: Menopause Hot flushes Cognitive behaviour therapy CBT Mediator Moderator

a b s t r a c t Objectives: Cognitive behaviour therapy (CBT) has been found to reduce the impact of menopausal symptoms, hot flushes and night sweats. This study investigates the moderators and mediators of CBT for women who had problematic menopausal symptoms following breast cancer treatment. Study design: Analysis of 96 patients with breast cancer induced menopausal symptoms recruited to the MENOS1 trial; 47 were randomly assigned to Group CBT and 49 to usual care. Questionnaires were completed at baseline, 9 and 26 weeks post randomisation. Potential moderators and mediators, including sociodemographic, clinical and psychological factors, of the treatment effect on the primary outcome were examined. Main outcome measure: Hot Flush Problem Rating. Results: CBT was effective at reducing problem rating at 9 weeks regardless of age, BMI, time since breast cancer diagnosis, menopausal status at time of diagnosis, or type of cancer treatment (radiotherapy or chemotherapy or endocrine treatment). The treatment effect was significantly greater in women not receiving chemotherapy, those with higher levels of psychological distress at baseline and for non-white women. Beliefs about control/coping with hot flushes were the main mediators of improvement in problem rating following CBT. Beliefs about hot flushes in a social context, depressed mood and sleep problems were also identified as mediators. Conclusions: These findings suggest that CBT is widely applicable for breast cancer patients who are experiencing treatment related menopausal symptoms, and that CBT works mainly by changing beliefs and improving mood and sleep. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Hot flushes and night sweats (HFNS) are commonly reported by women who have had breast cancer but are challenging to treat [1]. Between 65% and 85% of women treated for breast cancer report having HFNS, 60% rate them as severe, and these symptoms impact on quality of life, sleep, and mood [2,3]. Chemotherapy or adjuvant endocrine treatments can result in rapid reduction of oestrogen concentrations, which in turn induce or exacerbate HFNS. Hormone replacement therapy is generally contraindicated because it can increase the likelihood of recurrence, and, if left untreated, HFNS can reduce adherence to endocrine therapy [4,5]. A Cochrane review of non-hormonal medical treatments concluded that selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine

∗ Corresponding author at: Health Psychology Section, 5th Floor Bermondsey Wing, Guy’s Campus, King’s College London, London SE1 9RT, UK. Tel.: +44 02071880189/0. E-mail address: [email protected] (M.S. Hunter). 0378-5122/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.maturitas.2014.01.007

and gabapentin are mild to moderately effective in reducing the frequency of HFNS in women with a history of breast cancer [6] but side-effects were often reported [8]. Non-medical treatments tend to be preferred by breast cancer survivors [4] but non-pharmacological therapies, such as vitamins, herbal remedies, in general, do not have a strong evidence base [7]. There is increasing awareness that multidisciplinary approaches are needed [8], and growing evidence from three recent randomised controlled trials that cognitive behaviour therapy (CBT) can effectively reduce the impact of HFNS for women who have had breast cancer [9,10] and for well women during the menopause transition [11]. The three trials used group CBT (four to six weekly sessions of CBT; 8 h in total) developed by Hunter and colleagues. The MENOS1 trial [9,12] is an RCT of CBT (n = 47) versus treatment as usual (TAU) (n = 49) targeted at improving HFNS in breast cancer survivors. At 9 weeks after randomisation HFNS problem rating scores were significantly lower in the CBT group compared to usual care (adjusted mean difference [AMD] = −1.67, 95% CI −2.43 to −0.91, p < .001), an effect that was maintained at 26 weeks (AMD = −1.76, 95% CI −2.54 to −0.99); relating to standardised mean differences of d = 1.19 and d = 1.07, respectively [9].

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A recently conducted gap analysis of UK breast cancer research highlighted the need for the development of effective theorybased interventions for treatment-related symptoms experienced by breast cancer survivors, with analysis of moderators and mediators and identified components [13]. This paper reports on planned analyses of the MENOS1 study to consider moderators and mediators of the treatment effect – that is, to identify for whom CBT works and how. The MENOS1 study included a relatively heterogeneous sample, involving women of different menopausal stages at diagnosis and on different treatments. While there is evidence that CBT is effective for women with HFNS, who were premenopausal when diagnosed with breast cancer [10], we do not know whether CBT can be confidently offered to different subgroups of women, for example those who had had chemotherapy or were having endocrine treatments. Similarly, does educational level, age or ethnicity influence CBT outcomes? In addition, while the main reports determined efficacy of CBT for breast cancer patients, neither considered the mechanisms by which CBT works [14]. Based on a cognitive model of HFNS [15] we hypothesised that CBT works by changing overly negative beliefs concerning HFNS and by helping women to use more adaptive behavioural strategies, which reduce the perceived impact of HFNS rather than their frequency. 2. Materials and methods 2.1. Study design The design of the MENOS1 RCT, and intervention procedure, is described in detail in the trial protocol [12] and main outcome paper [9]. Recruitment took place between March 2009 and August 2010 from breast cancer clinics in London, UK. Patients having at least ten problematic HFNS per week, who had completed medical treatment for breast cancer (surgery, radiotherapy, or chemotherapy), with no evidence of other cancers or metastases were included. Those taking adjuvant endocrine treatment were eligible. Sample characteristics are shown in Table 1. Following baseline assessment they were randomised to Group CBT or TAU and reassessed after 9 and 26 weeks; Group CBT involved 6 weeks of 1.5 h of CBT in groups of 6–8 women. All participants gave written, informed consent before taking part. Ethical approval was obtained from the UK NHS Research Ethics Committee. 2.2. Measures 2.2.1. HFNS measures The primary outcome was the HFNS problem rating (Hot Flush Rating Scale) [16] at 9 weeks after randomisation, which is the mean of three 10 point scales assessing the extent to which symptoms are problematic and interfere with daily life; 10 indicates most problematic HFNS. A difference of two points or more is regarded as clinically relevant. The scale had good reliability in the MENOS1 sample (Cronbach ˛ = 0.89). HFNS frequency subscale measures the total number of HFNS reported in the past week [16]. Sternal skin conductance (SSC) was included to measure physiological HFNS frequency using the Bahr SSC monitor [Simplex Scientific; MiddleYs ton, WI, USA]. A 6-cm by 6-cm monitor measured SSC every 10´ by passing an electric current across two electrodes attached to the sternal region of the chest. 2.2.2. HFNS beliefs and behaviours Hot Flush Beliefs Scale [17] is a 27-item scale comprising three subscales: (i) beliefs about HF in social context (e.g. everyone is looking at me), (ii) beliefs about coping/control of hot flushes (e.g. when I have a HF I think they will never end), and (iii) beliefs about night sweats and sleep (e.g. if I have NS I’ll never get back to

57

sleep). The HFNS Behaviour Scale [18] was developed using factor analysis and includes three subscales measuring, (i) positive coping behaviour, e.g. accepting HFNS, using breathing and calming responses; (ii) avoidance behaviour, and (iii) cooling behaviours, such as fanning oneself. 2.2.3. Stress and mood measures The Perceived Stress Scale [19] includes 14 items, on a scale from 0 never to 4 very often; items are summed to form a 0–56 scale with a high score representing high stress. Subscales of the Women’s Health Questionnaire (WHQ) [20] were used to measure depressed mood, anxiety and sleep problems. The WHQ was standardised on women aged 45–65 years and has been widely used to evaluate interventions for menopausal symptoms. 2.2.4. Personality measures The Somatosensory Amplification Scale (SSAS) [21] has 10 items rated on 5 point scales measuring respondent’s tendency to experience somatic sensation as intense, noxious and disturbing. Dispositional optimism. The Revised Life Orientation Test (LOT-R) [22] measures dispositional optimism on a 6-item scale rated on a 5 point scale. High scores indicate greater dispositional optimism. 2.2.5. Demographic and health behaviour variables Demographic and health behaviour factors were recorded at baseline including: age, height, weight, ethnicity, education, employment status, smoking, and exercise frequency. Breast cancer treatments, use of concomitant medications and therapies were also recorded. 2.3. Statistical analysis The moderator analysis extended the model used in the main study to test changes in HFNS problem rating over the study. This involved the estimation of linear mixed effects model with random intercepts for participant and cohort group. Time, treatment group, baseline HFNS problem rating score and age at randomisation were included in the model as covariates. A time by treatment group interaction term was also included to allow the calculation of adjusted means at individual time points. This model was extended to allow for the testing of potential moderators of the effect of CBT on HFNS problem rating at 9 weeks by including the main effect of the moderator variable, and two and three-way interactions of the moderator variable with time and treatment group. Inclusion of moderator by time by treatment group interaction terms allowed for the assessment of effect modification at 9 weeks. To aid interpretation effect sizes were calculated for the moderator effects. Effect sizes were standardised mean differences (Cohen’s d) for the categorical variables and standardised regression coefficients for continuous variables (beta’s). Although the study was not specifically powered to detect moderator variables, power was adequate: assuming 80% power, a medium sized moderator effect was detectable (R2 = 7.7). The original trial identified that patients receiving CBT reported significantly less depression symptoms, anxiety, stress and sleep problems at 9 weeks compared to those receiving TAU. In the present analysis, we evaluated whether HFNS beliefs and behaviours also altered over the intervention using ANCOVA to estimate the effect of treatment on the variable at 9 weeks, adjusted for the baseline level of the variable [23]. Using the variables identified as changing significantly from the original trial and analysis conducted here (HFNS beliefs and behaviours), mediation was evaluated using path models that estimated the indirect effect of treatment group on HFNS problem rating at 26-weeks through the residualised change in the potential mediator at the 9-week followup. Both the potential mediator at 9 weeks and HFNS problem

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Table 1 Demographic and baseline clinical characteristics, with test for CBT effect moderation and adjusted mean difference in HFNS problem rating at 9 weeks or simple slope. TAU n Ethnicity 40 White Non−white 9 Education beyond 16 years Yes 33 No 16 Employed 32 Yes 15 No Menopausal status at diagnosis Pre 24 Peri/post 24 Chemotherapy Yes 37 12 No Radiotherapy 41 Yes 8 No Endocrine treatment 36 Yes 13 No Smoking status 23 Never 47 Current/ex Exercise frequency (times/week) 18 <2 2–3 19 12 >3

Age (years) Body mass index Time since diagnosis (months) Depression Anxiety

CBT

Adjusted mean difference

Effect size

Moderator

(d)

p-value

(−2.14, −0.78) (−5.95, −2.21)

−0.72 −2.02

0.01

−2.17 −1.07

(−2.95, −1.38) (−2.24, 0.10)

−1.07 −0.53

0.127

64 36

−2.06 −1.44

(−2.92, −1.21) (−2.46, −0.41)

−1.02 −0.71

0.356

24 21

51 44

−2.31 −1.37

(−3.25, −1.36) (−2.32, −0.43)

−0.67 −1.14

0.162

76 24

26 21

55 45

−1.3 −2.86

(−2.11, −0.49) (−4.01, −1.71)

−0.64 −1.42

0.029

84 16

36 11

77 23

−1.79 −1.79

(−2.53, −1.06) (−3.21, −0.37)

−0.89 −0.89

0.996

73 27

34 13

72 28

−1.53 −3.47

(−2.21, −0.84) (−5.35, −1.58)

−0.76 −1.72

0.058

47 53

17 36

30 64

−2.26 −1.41

(−3.26, −1.26) (−2.27, −0.55)

−1.12 −0.7

0.212

23 40 36

11 19 17

37 39 24

−3.39 −1.81 −0.17

(−4.61, −2.17) (−2.80, −0.82) (−1.36, 1.02)

−1.68 −0.9 −0.08

0.001

%

n

%

82 18

42 5

89 11

−1.46 −4.08

67 33

30 17

64 36

35 35

30 17

49 49

95% CI

Mean

SD

Mean

SD

Simple slope

95% CI

Effect size (beta)

Moderator p-value

54.05 27.51 31.08 0.31 0.45

7.76 6.9 30.63 0.27 0.3

53.16 27.13 47.75 0.23 0.34

8.1 5.3 53.38 0.26 0.25

−0.01 0.03 −0.01 −3.36 −2.09

(0.09, 0.08) (−0.08, 0.14) (−0.02, 0.01) (−5.28, −1.44) (−5.34, −0.45)

−0.08 0.18 −0.43 −1.01 −0.87

0.908 0.598 0.56 0.001 0.02

rating at 26-weeks were adjusted for their baseline level, treatment cohort, and age at randomisation. 3. Results 3.1. Moderators of CBT: who benefits? Demographic and clinical characteristics at baseline are shown in Table 1. At baseline HFNS were frequent and problematic with a mean of 69 per woman (SD = 39) per week for an average of 2 years, with a mean problem rating of 6.3 out of 10. Moderators of the effect of CBT on HFNS problem rating score at 9 weeks were considered (Table 1) with interaction plots shown for those observed to be significant (Fig. 1). The graphs show the adjusted problem rating scores for each group (CBT and TAU) at 9 weeks divided into categories depending on the baseline moderators described, e.g. chemotherapy versus no chemotherapy. The only demographic variable observed to be a significant moderator of treatment effect was ethnicity. HFNS problem rating score at 9 weeks was lower in the CBT group compared to usual care for both white and non-white ethnic groupings, but the difference was greater for non-white women (−4.08, 95% CI −5.95 to −2.21, p < 0.001) compared to white women (−1.46, 95% CI −2.14 to −0.78, p < 0.001). The only baseline clinical characteristic observed to moderate the CBT effect was chemotherapy, with a larger difference in HFNS problem rating score at 9 weeks for those not receiving chemotherapy (−2.86, 95% CI −4.01 to −1.71, p < 0.001) compared to those who did (−1.30, 95% CI −2.11 to −0.49, p = 0.002). These findings, for both ethnicity and chemotherapy, remained significant even after controlling for baseline levels of depression.

Concerning health behaviours, exercise frequency, but not smoking status, was observed to significantly moderate the effect of CBT. Further analysis revealed that the significant moderating effect was due to no significant difference in adjusted HFNS problem rating at 9 weeks between the CBT and usual care groups (−0.17, 95% CI −1.36 to 1.02, p = 0.779) for patients who exercised four or more times per week. However, after controlling for baseline depression the moderating effect of exercise became non-significant, suggesting that the finding is likely to be due to lower levels of distress in those who exercise more frequently. Depressed mood (−3.36, 95% CI −5.28 to −1.44, p = 0.001) and anxiety (−2.90, 95% CI −5.34 to −0.45, p = 0.020) were significant moderators of treatment effect at 9 weeks. The simple slopes relate to a difference in the adjusted mean difference between CBT and TAU of −0.83, −1.15 and −0.82 in HFNS problem rating at 9 weeks, respectively, for a one standard deviation higher score on the moderator variable. Together these observations indicate that CBT is most effective for individuals reporting high levels of psychological distress at baseline (Fig. 1). Non-significant treatment effects were indicated for individuals scoring zero on the WHQ depression and anxiety subscales. 3.2. Mediators of CBT: how does it work? There were no significant changes in sternal skin conductance – the physiological measure of HFNS frequency, between the groups over the intervention period. With regards to HFNS beliefs and behaviours those receiving CBT reported more positive social HFNS beliefs (adjusted mean difference = −0.77, 95% CI −1.12 to −0.38, p < 0.01), HF coping/control beliefs (adjusted mean difference =

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Fig. 1. HFNS problem rating at 9 weeks post-randomisation stratified by significant moderator variables, adjusted for age and baseline HFNS problem rating.

−0.97, 95% CI −1.33 to −0.60, p < 0.01) and beliefs about NS and sleep (adjusted mean difference = −0.99, 95% CI −1.40 to −0.60, p < 0.01), and reported more positive coping behaviours (adjusted mean difference = 0.88, 95% CI 0.60 to 1.17, p < 0.01) at 9 weeks compared to those receiving TAU. Accordingly these potential process variables were selected for the mediation analysis. Table 2 summarises the mediation analysis showing the estimate of the indirect treatment effect via each potential mediator on HFNS problem rating at 26 weeks and the proportion of the total treatment effect that is mediated by the variable. Changes in depressed mood, sleep problems and social beliefs all significantly mediated the treatment effect, although, the mediation was partial since in each path model the direct effect of treatment on HFNS problem rating at 26 weeks was significant. This suggests that CBT successfully reduced depression and sleeping problems and altered social beliefs regarding the impact of hot flushes, which in turn accounted for some of the improvements in HFNS problem rating. However, the largest mediation effect was HF coping/control beliefs (standardised beta = 0.50, p < 0.01), which accounted for 60.3% of the total effect of treatment on HFNS problem rating. 4. Discussion The results of this study suggest that CBT is effective in reducing the impact of HFNS for women following breast cancer treatment regardless of age, BMI, time since breast cancer diagnosis, menopausal status at time of diagnosis, or type of cancer treatment (radiotherapy or chemotherapy or endocrine treatment). However, while CBT worked well for women who had received chemotherapy, it worked rather better for those who did not. This could not be explained by initial level of mood or hot flushes, as we adjusted for baseline scores; it is possible that there are physiological explanations given that chemotherapy can induce HFNS. Interestingly, the physiological measure of HFNS frequency (sternal skin conductance) did not significantly change in this trial, whereas in a parallel study of well women going through the menopause

transition or postmenopause (MENOS2) there were small but significant reductions following CBT [24]. Women of non-white ethnicity improved more following CBT than those of white ethnicity. This was the case after we controlled for baseline mood and HFNS, and also for the moderating effect of mood. Ethnic differences in HFNS reporting have been previously documented [25], and other factors might explain this result. The finding requires replication, as there were only 14 women in this category (nine black British and five of Asian or mixed ethnicity), but overall these findings suggest that CBT is beneficial regardless of ethnicity. Interestingly, we found that those who were more distressed at baseline, in terms of depressed mood and anxiety scores, reported greater improvement. The only sub-group of women who showed no benefit were those who on entry to the trial participated in high levels of exercise (four times a week or more), but this finding became non-significant when the moderating effect of depression was controlled. Exercise has been associated with lower prevalence rates of HFNS and with lower levels of depressed mood and was found to impact on HFNS frequency in a recent trial [26]. Therefore, in women who frequently undertake exercise and report low levels of psychological distress CBT may either be unnecessary or ineffective at reducing HFNS. When we examined how the CBT works, we found that the main mediator was beliefs about coping and control over hot flushes, and additional mediation was provided by depressed mood, sleep and changes in beliefs about hot flushes in social situations. Thus learning to control and cope with the HFNS was an important factor in reducing problem rating of HFNS. These results generally support the cognitive model of HFNS [15,27] and suggest that CBT works mainly by changing cognitions, i.e. the cognitive appraisal of HFNS, but also mood and sleep problems. The CBT targeted cognitions, behavioural reactions, stress/wellbeing and the impact of night sweats upon sleep, so these results are heartening as they show that improvement in these areas was clearly associated with clinical outcomes. It is generally not easy to find satisfactory control conditions for complex psychological interventions, in the same

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Table 2 Summary of the indirect effects between treatment group and Hot Flush Problem Rating. Mediator

Indirect effect (95% CI) Group → mediator → HF Problem rating

% of total effect explained by the mediator

Depression Anxiety Stress Sleep problems Social beliefs Control beliefs Sleep beliefs Positive coping behaviours

0.18* (0.00 to 0.36) 0.23 (−0.04 to 0.51) 0.09 (−0.03 to 0.20) 0.24* (0.04 to 0.43) 0.24* (0.03 to 0.46) 0.50** (0.15 to 0.90) 0.32 (−0.05 to 0.70) 0.28 (−0.04 to 0.61)

24.3 31.1 11.5 30.6 29.1 60.3 41.2 33.5

Indirect estimates are the standardised change in Hot Flush Problem rating. * p < 0.05. ** p < 0.01.

way that placebos are used for medical trials [26] so mediation analysis is important to show that the treatment, such as CBT, is actually changing what it is intending to change and that the effects cannot be entirely explained by attention or ‘non-specific factors’. These results are supported by those of a qualitative study based on interviews with women who had CBT in the MENOS1 trial [28]. The women reported that CBT improved their ability to cope with their HFNS and that they ‘regained a sense of control’, which is consistent with our findings that changes in beliefs about HFNS mediate improvements in symptom experience. A sense of control over HFNS has been associated with subjective HFNS distress and overall wellbeing [17], and it has been argued that interventions to counter lack of control could be particularly beneficial for cancer patients experiencing treatment related symptoms [29]. Study limitations include the sample size; some non-significant potential moderators and mediators might not have been detected due to power considerations. While we did not correct for multiple testing because the analysis was exploratory [30], it is useful to note that even using a conservative Bonferroni correction the effects of exercise and depression would have remained significant. Further confirmatory research could include larger samples in multicentre trials in which the impact of variables such as ethnicity could be clarified. In conclusion, this study shows that CBT is beneficial to breast cancer survivors with troublesome treatment related symptoms and significantly reduces the impact of HFNS. Those who were most distressed benefited more but there were no contraindications to CBT. CBT appeared to work by changing HFNS beliefs, i.e. cognitive appraisal, and by improving mood and sleep, suggesting that the treatment might be tailored to individuals depending on their scores on these active components. Contributors J.C. wrote the first draft; J.C. and S.N. conducted the statistical analysis; M.S.H. designed the study; all authors contributed to writing, interpretation and the final manuscript. Competing interest The authors have no competing interests to declare. Funding This study (C8303/A6130).

was

supported

by

Cancer

Research

UK

Ethics Ethical approval was obtained from the UK NHS Research Ethics Committee (South East London 2 REC, ref: 08/H0802/106).

Patient consent We confirm that consent was obtained from participants in the study.

References [1] Kaplan M, Mahon S, Cope D, Keating E, Hill S, Jacobson M. Putting evidence into practice: evidence-based interventions for hot flashes resulting from cancer therapies. Clinical Journal of Oncology Nursing 2011;15(2):149–57. [2] Gupta P, Sturdee DW, Palin SL, et al. Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life. Climacteric: The Journal of the International Menopause Society 2006;9(1):49–58. [3] Hunter MS, Grunfeld EA, Mittal S, et al. Menopausal symptoms in women with breast cancer: prevalence and treatment preferences. Psycho-oncology 2004;13(11):769–78. [4] Biglia N, Cozzarella M, Cacciari F, et al. Menopause after breast cancer: a survey on breast cancer survivors. Maturitas 2003;45(1):29–38. [5] Cella D, Fallowfield LJ. Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. Breast Cancer Research and Treatment 2008;107(2):167–80. [6] Rada G, Capurro D, Pantoja T, et al. Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database of Systematic Reviews 2010, http://dx.doi.org/10.1002/14651858.CD004923.pub2. [7] Boekhout AH, Vincent AD, Dalesio OB, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Oncology 2011;29(29):3862–8. [8] Hickey M, Emery LI, Gregson J, Doherty DA, Saunders CM. The multidisciplinary management of menopausal symptoms after breast cancer: a unique model of care. Menopause 2010;17(4):727–33. [9] Mann E, Smith MJ, Hellier J, et al. Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncology 2012;13(3):309–18. [10] Duijts SF, van Beurden M, Oldenburg HS, et al. Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2012;30(33):4124–33. [11] Ayers B, Smith M, Hellier J, Mann E, Hunter MS. Effectiveness of group and self-help cognitive behavior therapy in reducing problematic menopausal hot flushes and night sweats (MENOS 2): a randomized controlled trial. Menopause 2012;19(7):749–59. [12] Mann E, Smith M, Hellier J, Hunter MS. A randomised controlled trial of a cognitive behavioural intervention for women who have menopausal symptoms following breast cancer treatment (MENOS 1): trial protocol. BMC Cancer 2011;11:44, http://dx.doi.org/10.1186/1471-2407-11-44. [13] Eccles S, Aboagye E, Ali S, et al. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Research 2013;15:R92. [14] Prigerson HG. Mind over menopausal symptoms in women breast cancer. Lancet Oncology 2012;13(3):227–9, with http://dx.doi.org/10.1016/S1470-2045(11)70381-3. [15] Hunter MS, Mann E. A cognitive model of menopausal hot flushes and night sweats. Journal of Psychosomatic Research 2010;69(5):491–501. [16] Hunter MS, Liao KL. A psychological analysis of menopausal hot flushes. British Journal of Clinical Psychology 1995;34(Pt 4):589–99. [17] Rendall MJ, Simonds LM, Hunter MS. The Hot Flush Beliefs Scale: a tool for assessing thoughts and beliefs associated with the experience of menopausal hot flushes and night sweats. Maturitas 2008;60(2):158–69. [18] Hunter MS, Ayers B, Smith M. The Hot Flush Behavior Scale: a measure of behavioral reactions to menopausal hot flushes and night sweats. Menopause 2011;18(11):1178–83.

J. Chilcot et al. / Maturitas 78 (2014) 56–61 [19] Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. Journal of Health and Social Behavior 1983;24(4):385–96. [20] Hunter M. The women’s health questionnaire: a measure of mid-aged women’s perceptions of their emotional and physical health. Psychology & Health 1992;7(1):45–54. [21] Barsky AJ, Wyshak G, Klerman GL. The somatosensory amplification scale and its relationship to hypochondriasis. Journal of Psychiatric Research 1990;24(4):323–34. [22] Scheier MF, Carver CS, Bridges MW. Distinguishing optimism from neuroticism (and trait anxiety, self-mastery, and self-esteem): a reevaluation of the Life Orientation Test. Journal of Personality and Social Psychology 1994;67(6):1063–78. [23] Van Breukelen GJ. ANCOVA versus change from baseline: more power in randomized studies, more bias in nonrandomized studies [corrected]. Journal of Clinical Epidemiology 2006;59(9):920–5. [24] Stefanopoulou E, Hunter MS. Does pattern recognition software using the Bahr monitor improve sensitivity, specificity and concordance of

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ambulatory skin conductance monitoring of hot flushes. Maturitas 2013, http://dx.doi.org/10.1016/j.maturitas.2013.09.013 (in press). Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40–55 years of age. American Journal of Epidemiology 2000;152(5):463–73. Avis NE. Breast cancer survivors and hot flashes: the search for nonhormonal treatments. Journal of Clinical Oncology 2008;26(31):5008–10. Hunter MS, Chilcot J. Testing a cognitive model of menopausal hot flushes and night sweats. Journal of Psychosomatic Research 2013;74(4):307–12. Fenlon DR, Rogers AE. The experience of hot flushes after breast cancer. Cancer Nursing 2007;30:E19–26. Balabanovic J, Ayers B, Hunter MS. Women’s experiences of Group Cognitive Behaviour Therapy for hot flushes and night sweats following breast cancer treatment: an interpretative phenomenological analysis. Maturitas 2012;72(3):236–42. Bender R, Lange S. Adjusting for multiple testing – when and how? Journal of Clinical Epidemiology 2001;54(4):343–9.

Maturitas 78 (2014) 74

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Corrigendum

Corrigendum to “Muscle strength and quality are associated with severity of menopausal symptoms in peri- and post-menopausal women” [Maturitas 76 (2013) 88–94] Jee-Yon Lee, Duk-Chul Lee ∗ Department of Family Medicine, Severance Hospital, Yonsei University, College of Medicine, 250 Seongsanno, Seodaemun-gu 120-752, Republic of Korea

The authors regret that the grant number in this paper was incorrect. The correct grant number is 6-2011-0202. The authors would like to apologise for any inconvenience caused.

DOI of original article: http://dx.doi.org/10.1016/j.maturitas.2013.06.007. ∗ Corresponding author. Tel.: +82 2 2228 2330; fax: +82 2 362 2473. E-mail address: [email protected] (D.-C. Lee). http://dx.doi.org/10.1016/j.maturitas.2014.03.001 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

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Maturitas 78 (2014) 62–66

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Effects of mild and global cognitive impairment on the prevalence of fear of falling in community-dwelling older adults Kazuki Uemura a,d,∗ , Hiroyuki Shimada a , Hyuma Makizako a,d , Takehiko Doi a , Kota Tsutsumimoto a , Daisuke Yoshida a , Yuya Anan a , Tadashi Ito a , Sangyoon Lee b , Hyuntae Park b , Takao Suzuki c a

Section for Health Promotion, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Obu, Japan Section for Physical Functioning Activation, Department of Functioning Activation, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Obu, Japan c Research Institute, National Center for Geriatrics and Gerontology, Obu, Japan d Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan b

a r t i c l e

i n f o

Article history: Received 20 November 2013 Received in revised form 11 February 2014 Accepted 25 February 2014 Keywords: Falls Cognitive decline Mini-Mental State Examination Mild cognitive impairment Anosognosia

a b s t r a c t Objectives: Few studies have reported the relationship between fear of falling (FoF) and mild and global cognitive impairment in community-dwelling older adults. We aimed to determine whether the status of cognitive impairment affects the prevalence of FoF in community-dwelling older adults. Study design: Cross-sectional study among 4474 community-dwelling older adults who participated in the Obu Study of Health Promotion for the Elderly. Main outcome measures: Participants underwent cognitive tests and were divided into three groups: cognitive healthy, mild cognitive impairment (MCI), and global cognitive impairment (GCI). FoF and related variables, such as fall history, physical function, and depression, were also investigated. Results: The prevalence of FoF was significantly different by group (p < 0.001; healthy: 43.6%, MCI: 50.6%, GCI: 40.6%). Logistic regression analysis showed that GCI (odds ratio = 0.63; 95% confidence interval = 0.526–0.76) was independently associated with FoF, after controlling for confounding factors. Older adults with GCI showed the lowest prevalence of FoF, although they had the lowest physical function comparing with the other groups (p < 0.001). Conclusion: MCI and GCI in community-dwelling older adults affect the prevalence of FoF in a completely different manner. Further study is required to determine whether insensitivity to FoF with GCI increases the risk of falling in older adults. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Fear of falling (FoF) is defined as “a lasting concern about falling that leads to an individual avoiding activities that he/she remains capable of performing” [1]. The main consequences of FoF are an increased risk for falling, restriction and avoidance of activities, and ultimately, deteriorated physical and mental performance, as well as decreased quality of life [2]. The prevalence of FoF ranges from

∗ Corresponding author at: Section for Health Promotion, Department for Research and Development to Support Independent Life of Elderly Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, 35 Gengo Morioka, Obu, Aichi 474-8511, Japan. Tel.: +81 562 44 5651; fax: +81 562 46 8294. E-mail addresses: [email protected], [email protected] (K. Uemura). http://dx.doi.org/10.1016/j.maturitas.2014.02.018 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

33% to 85%, being higher in women than in men, and increases with age [3,4]. FoF is associated with a history of falls, gait speed, use of walking aids, polypharmacy, and depression [5,6]. In spite of a number of reports regarding various factors associated with FoF, few studies have examined the relationship between FoF and cognitive decline, although it is almost universal in the general elderly population and increases with age [7]. Cognitive impairment, such as impairment of global cognition and executive function, contributes to the deterioration in the ability to carry out tasks in activities of daily living (ADL) [8,9]. Additionally, these cognitive impairments have been identified as a fall risk factor in clinical practice guidelines [10]. FoF also has been recognized as an important psychological factor associated with accidental falls and restricting everyday functioning [11]. However, whether the prevalence of FoF is affected according to the severity

K. Uemura et al. / Maturitas 78 (2014) 62–66

of cognitive impairment is still unclear. In addition to studying the risk of falling, investigation of FoF may be important in medical management of older adults with cognitive impairment. Although many studies have reported that global cognitive impairment (GCI) confers a moderate to high risk of serious fall-related injury [10], recent evidence indicates that even mild cognitive impairment (MCI) is a risk factor for falls [12]. MCI is conceptualized to be the earliest feature of cognitive disorders and a prodromal condition between normal and dementia [13]. We have previously reported that memory decline is associated with a lower prevalence of FoF among older adults [14]. However, the sample size of our previous study was relatively small (n = 101) and the variety of cognitive impairments (i.e. MCI and GCI) was not considered in that study. Therefore, the purpose of this study was to examine the effects of severity of cognitive impairment on the prevalence of FoF in a larger cohort of community-dwelling older adults. We hypothesized that mild and global cognitive impairment influence the prevalence of FoF in a different manner because of a difference in the nature of cognitive deficits.

2. Methods 2.1. Participants We performed a cohort study “Obu Study of Health Promotion for the Elderly” (OSHPE) from August in 2011 to February in 2012. Enrollment in the OSHPE was available to 15,974 older people living in Obu, Japan. Inclusion criteria required that participants lived in Obu and were aged 65 years or older at examination in 2011 or 2012. Before recruitment, 1661 people were excluded because they had participated in another study, required hospitalization or residential care, or were certified as requiring more than level 3 care, requiring support or care by the Japanese public long-term care insurance (LTCI) system. Recruitment was conducted by mail sent to 14,313 people and 5104 people underwent a health check. A total of 4474 subjects satisfied the inclusion criteria and conducted all assessments. The inclusion criterion in this study was persons not certified as any grade requiring support or care by the Japanese public LTCI system. The participants were classified into three groups: cognitive healthy (n = 2735; mean age ± standard deviation [SD], 71.3 ± 5.1 years), MCI (n = 938; age ± SD = 71.9 ± 5.5 years) and GCI (n = 801; age, M = 74.4 ± 6.2 years). GCI was defined as a deficit in general cognitive function; the Mini-Mental State Examination (MMSE) score was 23 or lower [15]. The criteria of MCI were those described by Petersen [13]. These criteria involved the following: (1) having subjective memory complaint, (2) having objective cognitive decline, (3) intact general cognitive function; MMSE score >23 [15], (4) absent from of clinical criteria for dementia, and (5) independent in ADL. Objective cognitive decline was defined as a lower cognitive function in multiple domains more than 1.5 SD from the healthy database. Cognitive functions in multiple domains were assessed using the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT). NCGG-FAT contains cognitive battery tests and the contents of measurement were described in detail in a previous study [16]. The battery consists of eight tasks to assess memory, attention and execution, processing speed, and visuospatial skill. The term “cognitive healthy” in this study was defined as having intact cognitive ability, and not having objective cognitive impairment. Informed consent was obtained from all participants prior to their inclusion in the study, and the Ethics Committee of the National Center for Gerontology and Geriatrics approved the study protocol.

63

2.2. FoF/fall history FoF and fall history was assessed by face-to-face interview with participants. FoF was assessed by a fourth-ordered choice, closedended question about participants’ general FoF. The question was phrased as follows: “Are you afraid of falling?” Participants who responded “very much” or “somewhat” were assigned to the fear group. Participants who responded “a little” or “not at all” were assigned to the no-fear group [14,17], which has a high test–retest reliability [18]. The question “Do you have any history of a fall within the past year?” was used for detecting fall. A fall was defined as “an unexpected event in which the person comes to rest on the ground, floor, or lower level” [19]. Falls resulting from extraordinary environmental factors (e.g. traffic accidents or falls while riding a bicycle) were excluded. On the basis of their fall history, participants were classified as fallers if they fell twice or more times within the past year [20]. 2.3. Potential correlates with FoF Demographic data were recorded, including age, gender, and educational history. Participants completed a questionnaire on medical condition, including current medications and lifestyle. The medical questionnaire found a variety of diseases (hypertension, heart disease, stroke, and diabetes mellitus) and total medication used administered by a nurse. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS) [21]. The timed up & go test (TUG) was used to assess physical performance [22]. The TUG involves rising from a chair, walking 3 meters, turning around, walking back to the chair, and sitting down. Participants were instructed to complete the task at their usual walking pace. The score for this test represents the time (in seconds) that the participant needed to complete the assessment. Lower times indicate better physical performance. Participants were also asked about their use of walking aids in daily life. 2.4. Statistical analysis One-way analysis of variance (ANOVA) was used to test differences between groups. When a significant main effect was found from these analyses, the Bonferroni post hoc test was employed was performed to determine differences between pairs of means. The Chi-square test was used to test differences in proportions between groups. When there is a large number of cell sizes for some of the crosstabulations, it can be difficult to determine which groups have significant differences within the analyses. Therefore, standardized adjusted residuals were calculated for each of the cells to determine which cell differences contributed to the Chi-square test results. Cells with significant standardized adjusted residuals (>±1.96) are indicated by underlining their percentages in the tables [23,24]. Logistic regression analysis, performed as a stepwise analysis, was carried out to examine whether the classification schema based on cognitive function was independently associated with FoF. In this analysis, the presence or absence of FoF was used as the dependent variable (no-fear = 0, fear = 1). Individual group classification was entered as dichotomous categorical variables (fitting into that group = 1; others = 0). Other independent variables also included possible confounders were age, gender, educational history, TUG, use of walking aids, GDS, and medications. Gender, fall history, and use of walking aids were created as categorical variables (male = 0, female = 1; non-faller = 0, faller = 1; non-user = 0, user = 1). All analyses were performed using commercially available software, IBM SPSS statistics software (Version 20; IBM Corp., Chicago). Statistical significance was set at p < 0.05 a priori.

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K. Uemura et al. / Maturitas 78 (2014) 62–66

Table 1 Demographic characteristics, and health outcomes of the groups.

Age (years) Gender (males) Educational history (years) MMSE (points) Fear of falling Fall history (fallers) Medical illness (%) Hypertension Heart disease Stroke Diabetes mellitus TUG (s) Walking aids use GDS (points) Total number of medication doses

Cognitive healthy (n = 2735)

MCI (n = 938)

GCI (n = 801)

p-Value

71.3 ± 5.1 1298 (47.5) 11.9 ± 2.5 27.4 ± 1.8 1193 (43.6) 110 (4.0)

71.9 ± 5.5†† 451 (48.1) 10.9 ± 2.4†† 26.6 ± 1.8†† 475 (50.6) 67 (7.1)

74.4 ± 6.2$$ , ** 325 (60.3) 10.3 ± 2.5 21.6 ± 1.8$$ , ** 325 (40.6) 48 (6.0)

<0.001 <0.001a <0.001 <0.001 <0.001a <0.001a

1237 (45.2) 443 (16.2) 98 (3.6) 362 (13.2) 8.1 ± 1.5 60 (2.2) 2.6 ± 2.5 1.9 ± 2.1

464 (49.5) 193 (20.6) 61 (6.5) 138 (14.7) 8.6 ± 2.3†† 37 (4.0) 3.4 ± 2.7†† 2.3 ± 2.2††

395 (49.3) 128 (15.9) 64 (7.9) 102 (12.7) 9.2 ± 3.2$$ , ** 67 (8.4) 3.4 ± 2.8$$ , ** 2.2 ± 2.2**

<0.001a 0.006a <0.001a 0.41a <0.001 <0.001a <0.001 <0.001

Underlined % = cells with significant adjusted standardized residuals; MMSE: Mini-Mental State Examination; TUG: timed up & go test; GDS: Geriatric Depression Scale. a Values are means ± SD or n (%). All p-values were generated from one-way ANOVA or Chi-square. †† Significant difference between cognitive healthy and MCI (Bonferroni test, p < 0.01). ** Significant difference between cognitive healthy and GCI (Bonferroni test, p < 0.01). $$ Significant difference between MCI and GCI (Bonferroni test, p < 0.01).

3. Results The characteristics in participants and comparison between groups are summarized in Table 1. Cognitive healthy participants were significantly younger, had a higher educational history, higher MMSE, faster TUG, lower rate of walking aids use, GDS, and number of medications than those with MCI and GCI (p < 0.001). Participants with GCI were significantly older, had a lower educational history, lower MMSE, slower TUG, and a higher rate of walking aid use than the other groups (p < 0.001). The rate of males was significantly different by group (p < 0.001; healthy: 47.5%, MCI: 48.1%, GCI: 60.3%). The prevalence of FoF was significantly different by group (p < 0.001; healthy: 43.6%, MCI: 50.6%, GCI: 40.6%). Participants with MCI showed the highest prevalence of FoF (standardized adjusted residuals = 4.2), while those with GCI showed the lowest prevalence of FoF (standardized adjusted residuals = −2.5). The prevalence of fallers was significantly different by group (p < 0.001; healthy: 4.0%, MCI: 7.1%, GCI: 6.0%). Participants with MCI showed the highest prevalence of fallers (standardized adjusted residuals = 3.3), while cognitive healthy participants showed the lowest prevalence of fallers (standardized adjusted residuals = −3.9). Logistic regression analysis showed that classification to GCI (odds ratio [OR] = 0.63; 95% confidence interval [CI] = 0.53–0.76; p < 0.001) was independently associated with FoF accounting for the following confounding factors: age (OR = 1.03; 95% CI = 1.02–1.05; p < 0.001), gender (OR = 0.28; 95% CI = 0.25–0.32; p < 0.001), educational history (OR = 0.96; 95% CI = 0.93–0.99; p = 0.003), TUG (OR = 1.1; 95% CI = 1.06–1.16; p < 0.001), use of walking aids (OR = 2.07; 95% CI = 1.33–3.23; p < 0.001), GDS (OR = 1.16; 95% CI = 1.13–1.19; p < 0.001), and number of medications (OR = 1.08; 95% CI = 1.04–1.12; p < 0.001). Fall history, and classification to cognitive healthy and MCI did not show a significant relationship. The model was well calibrated between declines of observed and expected risk (Hosmer–Lemeshow 2 = 8.0, p = 0.44) (Table 2).

4. Discussion This is the first study to clarify the effect of cognitive impairment, by dividing participants into several groups based on cognitive performance, on the prevalence of FoF in communitydwelling older adults. The present study found that MCI and GCI in community-dwelling older adults affect the prevalence of FoF in

a completely different manner; the prevalence of FoF was highest with MCI and lowest with GCI. Furthermore, GCI was independently associated with a lower prevalence of FoF, even after accounting for confounding factors, such as demographic, physical, and mental factors. Subjects with GCI might have underestimated their functional deficits and disregarded their risk of falling because they had the lowest prevalence of FoF, despite having the lowest physical function (i.e. slowest TUG and highest rate of users with walking aids). Older adults with dementia are often unable to appreciate or recognize their own deficiencies in motor, behavioral or cognitive functioning, which are evident to clinicians and caregivers [25]. This condition is regarded as “anosognosia” and is described as lack of awareness of impairments in ADL or of neuropsychological deficits [26], particularly in patients with Alzheimer’s disease [27]. This impaired awareness is significantly correlated with the severity of global cognitive impairment, as assessed by the MMSE [28]. Therefore, GCI may contribute to insensitivity to FoF and be more likely to lead to adopting dangerous behaviors, and is likely to be observed in Alzheimer’s disease [27]. Subjects with MCI had a higher prevalence of FoF and fallers than the cognitive healthy subjects and lower physical function than them. This is in line with a previous study, which found that MCI increases the risk of falling in older adults [12]. Anosognosia (i.e. lack of awareness) is frequent in patients with Alzheimer’s

Table 2 Factors associated with FoF in stepwise logistic regression. Factor

OR

95% CI

p-Value

Age Gender Educational history TUG Walking aids usage GDS No. of medication GCI Cognitive healthy MCI MMSE Fall history

1.03 0.28 0.96 1.1 2.07 1.16 1.08 0.63 – – – –

1.02–1.05 0.25–0.32 0.93–0.99 1.06–1.16 1.33–3.23 1.13–1.19 1.04–1.12 0.53–0.76 – – – –

<0.001 <0.001 0.003 <0.001 0.001 <0.001 <0.001 <0.001 0.26 0.26 0.99 0.06

FoF, fear of falling; TUG, timed up & go test; GDS, Geriatric Depression Scale; GCI, global cognitive impairment; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination.

K. Uemura et al. / Maturitas 78 (2014) 62–66

disease but not in those with MCI [25,29]. However, having anxiety is the most frequent behavioral symptom in MCI subjects [30]. Fall experience, decreased physical function, and feeling anxiety may contribute to the increased prevalence of FoF in MCI subjects. Therefore, the feeling of FoF may depend on the severity of cognitive impairment, and there may have been prevalent differences between the MCI and GCI groups in the present study. GCI has been reported as a major risk factor of fall and serious fall-related injury [10]. GCI subjects might be unable to recognize their risks of falling and select a safety strategy during ambulation and transfer, despite having decreased physical function. This insensitivity to FoF may be one of the characteristics of psychological changes in older adults with GCI and account for an increased risk of falling derived from GCI. However, the design of the current study, as with other cross sectional studies, limits the interpretation of the results with regard to causality between FoF and associated factors. A longitudinal study is necessary to examine whether the insensitivity to FoF in GCI subjects who have decreased physical function leads to an increased incidence of accidental falls. If this hypothesis is verified, education and an exercise program specifically designed to address the cognitive needs and insensitivity to FoF among participants with GCI may be beneficial for preventing falls. Another limitation of this study is the sub-optimal use of the single-item FoF measure. Further study is needed to examine the relationship between cognitive impairment and fear of falling during various activities of daily living using measures of falls efficacy which has been validated in older people with cognitive impairment [31,32]. However, as it is reported that single item FoF measurement shows good correlation with the Fall Efficacy ScaleInternational [33], a single question regarding FoF has been found to have high validity with continuous measures of FoF [34]. Thus, we consider that the relevance of our research is not lost by the way of FoF measurement. Finally, the incidence of falling in our subjects was relatively low compared with that in other studies [35], while a recent systematic review estimated that the incidence of falls among older people ranged from 14.7% to 34% [36]. Additionally, Milat and colleague [37] reported that older adults who fell more than twice were only 9.9% of all participants. These differences may be due to differences between races and/or physical function status of the participants. The findings of the present study differ from available comparable studies in which fall history was associated with FoF [5,6]. However, Austin and colleague [3] also reported that fall history was not found to predict FoF. Like this previous study, low rate of fall incidence might have weakened any relationship between falls and FoF. The strengths of the present study include its much larger sample size and that it is the first study to clarify the significant difference in prevalence of FoF between cognitive statuses which were classified strictly based on objective assessment measures.

5. Conclusion Older adults with GCI have lower prevalence of FoF despite having lower physical function. GCI is independently associated with a lower prevalence of FoF while accounting for confounding factors, such as demographic, physical, and mental factors. However, MCI subjects have a higher prevalence of FoF and fallers than those with GCI and cognitive healthy subjects. GCI may induce disparity between awareness and function, which leads to insensitivity to FoF. Further study is required to determine whether insensitivity to FoF with GCI induces the risk of falling in older adults.

65

Contributors Kazuki Uemura, Hiroyuki Shimada, Hyuma Makizako and Takehiko Doi were responsible for study concept and design; Takao Suzuki and Hyuntae Park contributed to study supervision and funding; Kota Tsutsumimoto, Daisuke Yoshida, Yuya Anan, Tadashi Ito and Sangyoon Lee contributed to data analysis, interpretation and draft of the manuscript; all the authors did critical revisions of the manuscript and approved the final manuscript. Competing interest The authors declare no conflict of interest. Funding This work received financial support from a grant from the Health Labour Sciences Research Grant (23-001) from the Japanese Ministry of Health, Labour and Welfare and the Research Funding for Longevity Sciences (22-16) from National Center for Geriatrics and Gerontology (NCGG), Japan. Ethical approval Informed consent was obtained from all participants prior to their inclusion in the study, and the Ethics Committee of the National Center for Gerontology and Geriatrics approved the study protocol. Acknowledgment We thank the Obu city office for assistance with participant recruitment. References [1] Tinetti ME, Powell L. Fear of falling and low self-efficacy: a case of dependence in elderly persons. J Gerontol 1993;48. Spec No: 35-8. [2] Scheffer AC, Schuurmans MJ, van Dijk N, van der Hooft T, de Rooij SE. Fear of falling: measurement strategy, prevalence, risk factors and consequences among older persons. Age Ageing 2008;37:19–24. [3] Austin N, Devine A, Dick I, Prince R, Bruce D. Fear of falling in older women: a longitudinal study of incidence, persistence, and predictors. J Am Geriatr Soc 2007;55:1598–603. [4] Zijlstra GA, van Haastregt JC, van Eijk JT, van Rossum E, Stalenhoef PA, Kempen GI. Prevalence and correlates of fear of falling, and associated avoidance of activity in the general population of community-living older people. Age Ageing 2007;36:304–9. [5] Friedman SM, Munoz B, West SK, Rubin GS, Fried LP. Falls and fear of falling: which comes first? A longitudinal prediction model suggests strategies for primary and secondary prevention. J Am Geriatr Soc 2002;50:1329–35. [6] Perez-Jara J, Olmos P, Abad MA, Heslop P, Walker D, Reyes-Ortiz CA. Differences in fear of falling in the elderly with or without dizziness. Maturitas 2012;73:261–4. [7] Park HL, O’Connell JE, Thomson RG. A systematic review of cognitive decline in the general elderly population. Int J Geriatr Psychiatry 2003;18:1121–34. [8] Ishizaki T, Yoshida H, Suzuki T, Watanabe S, Niino N, Ihara K, et al. Effects of cognitive function on functional decline among community-dwelling nondisabled older Japanese. Arch Gerontol Geriatr 2006;42:47–58. [9] Johnson JK, Lui LY, Yaffe K. Executive function, more than global cognition, predicts functional decline and mortality in elderly women. J Gerontol A Biol Sci Med Sci 2007;62:1134–41. [10] Muir SW, Gopaul K, Montero Odasso MM. The role of cognitive impairment in fall risk among older adults: a systematic review and meta-analysis. Age Ageing 2012;41:299–308. [11] Deshpande N, Metter EJ, Bandinelli S, Lauretani F, Windham BG, Ferrucci L. Psychological, physical, and sensory correlates of fear of falling and consequent activity restriction in the elderly: the Inchianti study. Am J Phys Med Rehabil 2008;87:354–62. [12] Delbaere K, Kochan NA, Close JC, Menant JC, Sturnieks DL, Brodaty H, et al. Mild cognitive impairment as a predictor of falls in community-dwelling older people. Am J Geriatr Psychiatry 2012;20:845–53. [13] Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004;256:183–94.

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[14] Uemura K, Shimada H, Makizako H, Yoshida D, Doi T, Tsutsumimoto K, et al. A lower prevalence of self-reported fear of falling is associated with memory decline among older adults. Gerontology 2012;58:413–8. [15] Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [16] Makizako H, Shimada H, Park H, Doi T, Yoshida D, Uemura K, et al. Evaluation of multidimensional neurocognitive function using a tablet personal computer: test–retest reliability and validity in community-dwelling older adults. Geriatr Gerontol Int 2012;13:860–6. [17] Maki BE, Holliday PJ, Topper AK. Fear of falling and postural performance in the elderly. J Gerontol 1991;46:M123–31. [18] Yamada M, Tanaka B, Nagai K, Aoyama T, Ichihashi N. Rhythmic stepping exercise under cognitive conditions improves fall risk factors in communitydwelling older adults: preliminary results of a cluster-randomized controlled trial. Aging Ment Health 2011;15:647–53. [19] Lamb SE, Jorstad-Stein EC, Hauer K, Becker C. Development of a common outcome data set for fall injury prevention trials: the prevention of falls network Europe consensus. J Am Geriatr Soc 2005;53:1618–22. [20] Melzer I, Kurz I, Shahar D, Levi M, Oddsson L. Application of the voluntary step execution test to identify elderly fallers. Age Ageing 2007;36: 532–7. [21] Yesavage JA. Geriatric depression scale. Psychopharmacol Bull 1988;24: 709–11. [22] Podsiadlo D, Richardson S. The timed up & go: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991;39:142–8. [23] Saewyc EM, Brown D, Plane M, Mundt MP, Zakletskaia L, Wiegel J, et al. Gender differences in violence exposure among university students attending campus health clinics in the United States and Canada. J Adolesc Health 2009;45:587–94. [24] Agresti A. Categorical data analysis. 2nd ed. New York: Wiley; 2002. [25] Orfei MD, Varsi AE, Blundo C, Celia E, Casini AR, Caltagirone C, et al. Anosognosia in mild cognitive impairment and mild Alzheimer’s disease: frequency and neuropsychological correlates. Am J Geriatr Psychiatry 2010;18: 1133–40. [26] Lin F, Wharton W, Dowling NM, Ries ML, Johnson SC, Carlsson CM, et al. Awareness of memory abilities in community-dwelling older adults with

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EMAS position statement: Menopause for medical students Janet Brockie a,∗ , Irene Lambrinoudaki b , Iuliana Ceausu c,d , Herman Depypere e , C. Tamer Erel f , Faustino R. Pérez-López g , Karin Schenck-Gustafsson h , Yvonne T. van der Schouw i , Tommaso Simoncini j , Florence Tremollieres k , Margaret Rees a a

Women’s Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK Second Department of Obstetrics and Gynecology, National and Capodestrian University of Athens, Greece c Department of Obstetrics and Gynecology, ‘Carol Davila’ University of Medicine and Pharmacy, Romania d Department of Obstetrics and Gynecology, ‘Dr. I. Cantacuzino’ Hospital, Bucharest, Romania e Breast Clinic and Menopause Clinic, University Hospital, De Pintelaan 185, 9000 Gent, Belgium f Department of Obstetrics and Gynecology, Istanbul University, Cerrahpasa School of Medicine, Valikonagi Cad. No. 93/4, Nisantasi, 34365 Istanbul, Turkey g Department of Obstetrics and Gynecology, Zaragoza University Facultad de Medicina, Hospital Clínico, Zaragoza 50009, Spain h Department of Medicine, Cardiology Unit and Head Centre for Gender Medicine, Karolinska Institutet and Karolinska University Hospital, Thorax N3:06, SE 17176 Stockholm, Sweden i Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands j Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy k Menopause and Metabolic Bone Disease Unit, Hôpital Paule de Viguier, F-31059 Toulouse cedex 09, France b

Discussions with patients about the menopause are becoming more complex because of women’s increasing longevity, the wide range of therapeutic options, the controversies regarding menopausal hormone therapy (MHT) and the increasing use of alternative and complementary therapies. The aim of this document is to provide guidance in bullet-point style on the essential issues that medical students need to know about the stages of reproductive aging, menopause terminology, menopause and postmenopausal health [1]. • The menopause, or the cessation of the menstrual cycle, is the result of ovarian aging and is a natural event experienced by most women in their late 40s or early 50s. With increasing longevity the menopause can now be considered to be a midlife event. Thus managing postmenopausal health is a key issue for all health professionals, not just gynecologists. • While for most women the menopause is a natural process, it can be induced by medical intervention such as bilateral oophorectomy or iatrogenic ablation of ovarian function by chemotherapy, radiotherapy or treatment with gonadotrophin-releasing hormone analogs and occur earlier (see premature/early menopause). In the absence of surgery, induced menopause may be permanent or temporary. • Ovarian insufficiency leads to estrogen deficiency and potentially debilitating menopausal symptoms such as hot flushes, night sweats and vaginal dryness (urogenital atrophy). Although hot flushes and night sweats usually are present for less than five

∗ Corresponding author. Tel.: +44 1865 221546; fax: +44 1865 221890. E-mail address: [email protected] (J. Brockie). http://dx.doi.org/10.1016/j.maturitas.2014.02.007 0378-5122/© 2014 Published by Elsevier Ireland Ltd.

years, some women will continue to flush beyond the age of 60 years. Self reported menopausal symptoms vary considerably between races and ethnic groups. The chronic conditions affecting postmenopausal health are osteoporosis, cardiovascular disease, dementia and cognitive decline. Again risk of chronic disease depends on ethnic group, medical history, diet and lifestyle. • Measurement of follicle-stimulating hormone (FSH) is helpful only if the diagnosis is in doubt, such as in women with suspected premature ovarian failure and the levels are reported in the menopausal range (>25 IU/l). In menstruating women, measurement of FSH should be performed at the beginning of the follicular phase (days 2–5 of the cycle) to avoid ovulation-induced elevations of FSH. Measurement of thyroid stimulating hormone (TSH) and prolactin are also helpful in investigating menstrual irregularity [2]. Levels of FSH do not predict when the last menstrual period will occur and are not a guide to fertility status, as increased levels can occur in the presence of ovulatory cycles. Estimates of the levels of luteinizing hormone, estradiol, progesterone and testosterone are of no value in the diagnosis of ovarian failure, but may provide information about other menstrual cycle disorders. • Assessment should include detailing symptoms and their impact on quality of life, menstrual history including the type of menopause (natural or iatrogenic) and contraception. Family or personal history should include that of breast, ovarian, endometrial and colon cancer; venous thromboembolism, migraine, and risk factors for osteoporosis, heart disease and stroke. The women’s preference about treatment must be recorded. Physical examination should include recording of weight, height, waist-hip ratio and blood pressure. Whether breast or pelvic examination, mammography or transvaginal ultrasound should

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J. Brockie et al. / Maturitas 78 (2014) 67–69

be undertaken initially and then at regular intervals is a controversial area with practice varying worldwide [3]. Women should be encouraged to participate in national screening programs for cervical and breast cancer. Patients at risk of osteoporosis are identified opportunistically using a case finding strategy. FRAX can be used for people aged between 40 and 90 years, either with or without measuring bone mineral density [4]. There is increasing evidence that life-style factors, such as nutrition, physical activity, smoking and alcohol consumption have a profound effect on health and menopause symptoms. Women gain on average 10 kilos from 40 to 60 years independently of menopause. Thus women should be encouraged to stop smoking, to have a balanced healthy diet rich in fiber, fruit and vegetables and to exercise regularly, aiming to prevent the midlife increase in body weight and to preserve their muscle mass [5–7]. Menopausal hormone therapy (MHT) can either be systemic or topical. Systemic MHT consists of estrogen-only preparations for hysterectomized women. Women with an intact uterus should receive in addition a progestogen for at least 10 days per month to prevent endometrial hyperplasia [8]. The estrogen dose is inversely related to the age of the woman: younger women need higher doses, while older women need lower doses. Both estrogens and progestogens can be given orally or transdermally; in addition the progestogen levonorgestrel can be delivered directly into the uterus. Estrogen is administered continuously. The progestogen can be administered either continuously or intermittently, usually, every 10–14 days per month. Continuous administration results in amenorrhea, while intermittent administration leads to withdrawal bleeding. Tibolone is a synthetic steroid with estrogenic progestogenic and weak androgenic activity indicated for the management of menopausal symptoms and urogenital atrophy in postmenopausal women. It does not require the addition of a progestogen in women with an intact uterus. Topical low dose vaginal estrogens are given for symptoms associated with urogenital atrophy and do not require the addition of a progestogen, as systemic absorption is low [9]. MHT is the most effective treatment for menopausal symptoms and reduces the risk of osteoporotic fracture. Benefits of MHT are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause. Transdermal estrogen delivery is associated with a lower risk of venous thromboembolism than oral therapy. The risk of breast cancer in women over 50 years associated with MHT is primarily associated with the addition of a progestogen to estrogen therapy and related to the duration of use. The risk of breast cancer attributable to MHT is small and decreases after treatment is stopped. Safety data do not support the use of MHT in women with a history of breast or other estrogen-sensitive cancer. Non estrogen based treatments can be used for vasomotor symptoms and those associated with urogenital atrophy [10]. They are used in women who do not wish to take estrogens either through choice or because of concerns about comorbidities such as personal or family history of breast cancer or venous thromboembolism. They tend to be less effective than systemic or topical estrogens. A variety of agents can be used for hot flushes which include clonidine, paroxetine, fluoxetine, citalopram, venlafaxine, desvenlafaxine, gabapentin and pregabalin. Many lubricants and vaginal moisturizers are available. Lubricants are usually used to relieve vaginal dryness during intercourse and moisturizers provide symptom relief from vaginal dryness. Non estrogen based treatments for osteoporosis include bisphosphonates (alendronate, risedronate, ibandronic acid, zoledronic acid), denosumab, Selective Estrogen Receptor Modulators (SERMS: raloxifene and bazedoxifene) and parathormone analogs

(teriparatide and intact recombinant PTH) [11]. Women at risk for an osteoporotic fracture who receive MHT for the management of menopausal symptoms do not require additional treatment for osteoporosis. Asymptomatic women at high risk for fracture, however, should receive non-estrogen based treatment for osteoporosis. The choice of the drug depends on the medical history of the patient and the efficacy and safety profile of the particular treatment [12]. • New preparations for menopause management will become available such as ospemifene for urogenital atrophy and bazedoxifene combined with estrogen for menopausal symptoms and osteoporosis [13]. • Alternative and complementary therapies are popular in that they are perceived as ‘natural’ and safe. However evidence from randomized trials that they improve menopausal symptoms or reduce the risk of osteoporotic fracture is poor. There are concerns about herb–drug interactions and adverse effects. The use of bioidentical hormone therapy is unregulated, under-researched and therefore not recommended [8]. • Premature ovarian insufficiency (POI) is the exhaustion of ovarian follicles resulting in amenorrhea before the age of 40. Early menopause refers to menopause before the age of 45 [14]. Ovulation may occur intermittently after diagnosis of POI, possibly resulting in menstrual bleeding and pregnancy and thus fertility and contraception need to be discussed. Untreated it increases the risk of osteoporosis, cardiovascular disease, dementia, cognitive decline and Parkinsonism. The treatment of choice is MHT until the average age of the natural menopause (i.e. late 40s early 50s). In women under age 50 MHT use is not associated with an increased risk of breast cancer compared to that found in normally menstruating women. Few data are available on the efficacy of alternatives such as bisphosphonates in women with POI or early menopause and the long-term effects on the skeleton of any offspring are unknown. Contributors JB, IL and MR prepared the initial draft, which was circulated to EMAS board members for comment and approval; production was coordinated by MR and IL. Competing interests The authors have no conflicting interests to declare. Funding None was sought or secured for writing this statement. Provenance and peer review EMAS position statement. References [1] Harlow SD, Gass M, Hall JE, et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Fertil Steril 2012;97:843–51. [2] Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician 2013;87:781–8. [3] Dreisler E, Ulrich LG. Routine pelvic ultrasound before starting menopausal hormone therapy: should we do it? Maturitas 2013, December, http://dx.doi.org/10.1016/j.maturitas.2013.12.002. pii:S0378-5122(13)003745 [Epub ahead of print]. [4] Compston J, Bowring C, Cooper A, et al. Diagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013. Maturitas 2013;75:392–6 http://www.maturitas.org/article/S0378-5122(13)00176-X/abstract

J. Brockie et al. / Maturitas 78 (2014) 67–69 [5] Lambrinoudaki I, Ceasu I, Depypere H, et al. EMAS position statement: diet and health in midlife and beyond. Maturitas 2013;74:99–104. [6] Li Z, Heber D. Sarcopenic obesity in the elderly and strategies for weight management. Nutr Rev 2012;70:57–64. [7] Davis SR, Castelo-Branco C, Chedraui P, et al. Understanding weight gain at menopause. Climacteric 2012;15:419–29. [8] de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Maturitas 2013;74:391–2. [9] Rees M, Pérez-López FR, Ceausu I, et al. EMAS clinical guide: low-dose vaginal estrogens for postmenopausal vaginal atrophy. Maturitas 2012;73:171–4. [10] Guttuso Jr T. Effective and clinically meaningful non-hormonal hot flash therapies. Maturitas 2012;72:6–12.

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[11] Pinkerton JV, Thomas S, Dalkin AC. Osteoporosis treatment and prevention for postmenopausal women: current and future therapeutic options. Clin Obstet Gynecol 2013;56:711–21. [12] Kanis JA, McCloskey EV, Johansson H, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2013;24:23–57. [13] Pinkerton JV, Thomas S. Use of SERMs for treatment in postmenopausal women. J Steroid Biochem Mol Biol 2013, December, http://dx.doi.org/10.1016/j.jsbmb.2013.12.011. pii:S0960-0760(13)00284-7 [Epub ahead of print]. [14] Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010;65:161–6.

Maturitas 78 (2014) 11–16

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Frozen shoulder – A stiff problem that requires a flexible approach P.M. Guyver a,∗ , D.J. Bruce a , J.L. Rees b a

Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX37HE, United Kingdom Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, The Botnar Research Institute, University of Oxford, Old Road, Headington, Oxford OX37LD, United Kingdom b

a r t i c l e

i n f o

Article history: Received 11 February 2014 Accepted 14 February 2014 Keywords: Frozen shoulder Adhesive capsulitis Manipulation Arthroscopic release Hydrodilatation

a b s t r a c t Frozen shoulder is a specific, painful and debilitating condition effecting patients mainly in middle age. While it has been recognised for over 100 years, it is still mis-diagnosed, with a natural history that is poorly understood and with limited evidence for the efficacy for various treatments. This review considers what is known about this common painful condition and the treatments available. © 2014 Elsevier Ireland Ltd. All rights reserved.

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4.

5.

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Pathoanatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conservative treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Physical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Intra-articular steroid injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Intra-articular sodium hyaluronate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Oral steroid therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interventional treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Distension arthrography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Surgery – manipulation under anaesthetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Surgery – arthroscopic capsular release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Clinical Fellow in Shoulder and Elbow Surgery, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX37HE, United Kingdom. Tel.: +44 1865 741155; fax: +44 1865 738056. E-mail addresses: [email protected] (P.M. Guyver), [email protected] (D.J. Bruce), [email protected] (J.L. Rees). http://dx.doi.org/10.1016/j.maturitas.2014.02.009 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

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Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Box 1: British Elbow and Shoulder Society (BESS) survey-definition of frozen shoulder [8] Definition of Frozen Shoulder Symptoms

True (deltoid insertion) shoulder pain Night pain of incedious onset

Signs

Painful restriction of active and passive motion Passive elevation less than 100◦ Passive external rotation less than 30◦ Passive internal rotation less than L5 All other shoulder conditions excluded

Investigations

Plain radiographs normal Arthroscopy shows vascualr granulation tissue in the rotator interval

1. Background Frozen shoulder is an extremely painful and debilitating condition leading to stiffness and disability. The prevalence of shoulder complaints in the UK is estimated to be 14%, with 1–2% of adults consulting their general practitioner annually regarding new-onset shoulder pain [1]. Many of these patients may have apparent or true ‘stiffness’. Apparent stiffness can occur either through muscle weakness (such as a rotator cuff tear) or through pain inhibition, whereas ‘true’ stiffness from frozen shoulder has characteristic features of pain and physical restriction of movements of the glenohumeral joint (ball and socket), in the presence of normal X-rays. This important difference is often not appreciated and frequently leads to an over and misdiagnosis of frozen shoulder [2,3]. Reasons for this range from education; variations in definition and clearly defined diagnostic criteria; common inaccurate terms used alongside frozen shoulder. Frozen shoulder has also been referred to as periarthritis, retractile capsulitis, adhesive capsulitis, and steroidsensitive arthritis. These terms indicate a false pathology of the condition and are misleading. The pathology of this condition is a soft tissue fibrosing and inflammatory one. There are no ‘adhesions’ within the joint. More recently, there has been an acknowledgement of the absence of a specific definition [5,6] and of diagnostic criteria for this condition [6] which both the British Elbow and Shoulder Society (BESS) and American Shoulder and Elbow Surgeons (ASES) have endeavoured to rectify. These societies tried to improve on the long established definition of Codman [7] who described the common features of a slow onset of pain felt near the insertion of the deltoid muscle, inability to sleep on the affected side with restriction in both active and passive elevation and external rotation, yet with normal radiographic appearance. A survey of the members of BESS overwhelmingly agreed with the definition of frozen shoulder as seen in Box 1 [8]. Frozen shoulder can be either primary (idiopathic – as in there are no detectable underlying cause) or secondary. Secondary frozen shoulder is defined as that associated with trauma, cardiovascular disease, hemiparesis or diabetes. The ASES and Robinson et al. [2,6] collectively agreed that frozen shoulder should be classified into primary and secondary types with secondary diabetic frozen shoulder being considered as a separate type since their disease course is usually more severe and protracted.

15 15 15 15

Clinical presentation is classically in three overlapping phases [9]: • Phase 1: Lasting 2–9 months; Painful phase or pain predominant phase, with progressive stiffening and increasing pain on movement. • Phase 2: Lasting 4–12 months; Stiffening, freezing or stiffness predominant phase, where there is gradual reduction of pain but stiffness persists with considerable restriction in range of motion. • Phase 3: Lasting 12–42 months; Resolution or thawing phase, where there is improvement in range of motion with resolution of stiffness. While frozen shoulder has been recognised for over 100 years, there still remains a lack of reliable evidence on the natural and variable history of this condition. In addition there is a lack of up to date high quality studies dealing with the variety of treatment options available. As such, it is sensible to involve patients in shared decision making about their treatment. We recommend a ‘flexible’ approach to frozen shoulder management, tailoring treatment choices to the needs of each individual patients dependent on factors such as symptom severity, age, occupation, patient requirements and longevity of symptoms. 1.1. Epidemiology Frozen shoulder is estimated to affect 2–2.4% of the general population [10,11], with a cumulative incidence of 11.2 per 1000 person-years [12]. It typically occurs in the 5th and 6th decades of life, thus affecting individuals of working age. It is rare before the age of 40 years and is unusual in patients over 70 years. Women are marginally more affected than men [13–15]. 20% of contralateral shoulders can develop similar problems but bilateral simultaneous frozen shoulder is rare. Recurrence in the same shoulder is also very rare [14–16]. There is no current evidence to suggest a racial predisposition but there is some evidence of a genetic link with twins having up to a threefold increased risk [17]. The incidence of frozen shoulder in people with diabetes is higher and reported to be 10–36% with a combined prevalence of a diabetic predisposition and frozen shoulder estimated to be as high as 71.5%. Diabetics have a 2–4 times greater risk and a 10–20% lifetime risk of developing frozen shoulder compared to the general population and more importantly their disease course is usually more severe and protracted [9,11,18–20]. 1.2. Natural history The natural and apparent variable history of this condition is poorly understood. Many studies suggest that frozen shoulder is a self-limiting condition, with most cases recovering within 2–3 years [7,21], while others indicate a proportion of patients that do not regain full shoulder motion [9]. It has been suggested that up to 40% of patients may experience persistent symptoms with 7–15% having some degree of permanent loss of movement [22,23]. However the majority of these symptoms are usually mild and cause limited functional loss [22,24]. The two most comprehensive natural history studies are by Hand et al. [22] and Shaffer et al. [25]. Hand et al. [22] published the largest series of 223 patients with a mean follow up of 4.4 years showing that 59% made a full recovery

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whilst 35% had mild to moderate symptoms with pain being the most common complaint and 6% had severe symptoms at follow up. 20% reported bilateral symptoms, but there were no recurrent cases. Shaffer et al. [25] evaluated 62 patients with a mean follow up of 7 years demonstrating 50% of patients were reported to still have some mild pain and 60% had some ongoing stiffness mostly in external rotation although again this caused limited functional impairment. 1.3. Pathoanatomy Frozen shoulder can be described pathologically as a fibrotic inflammatory contracture of the rotator interval, capsule and ligaments. It is therefore a soft tissue problem and not a boney one. It limits gleno-humeral joint movement by the thickening and shortening of these tissues. Macroscopically at arthroscopy (keyhole surgery), the capsule is thickened and inflamed with vasculitic ‘frond’ like projections (villonodular synovitis) in the rotator interval (front and upper part of the shoulder). This progresses to a more glass like fibrotic appearance over time. Historically, Neviaser [4], DePalma [26] and Neer [27] all described the same arthroscopic findings of frozen shoulder with thickening and shortening of the soft tissues in and around the rotator interval. Cadaveric studies confirmed these findings and concluded that the rotator interval played an important role in gleno-humeral motion and stability. In particular plication of the anterosuperior capsular caused selective restriction of external rotation with an adducted arm, characteristic of frozen shoulder [28,29]. Other studies have further supported these results demonstrating that the structures primarily involved are the coracohumeral ligament, the rotator interval (comprising of the superior gleno-humeral ligament and the rotator interval capsule), the anterior capsule and the inferior gleno-humeral ligament [30–32]. While histological studies of the capsule have confirmed significant increases in fibroblasts myofibroblasts and inflammatory cells including mast cells, T cells, B cells and macrophages [15], there remains disagreement about the underlying pathological process. Opinions vary from an inflammatory cause, to fibrosis or even an algo-neurodystrophic process. 2. Clinical assessment 2.1. History Frozen shoulder is a clinical diagnosis with characteristic signs and symptoms. Therefore a thorough history and physical examination are required to establish an accurate diagnosis. It is a rare diagnosis before the age of 35 years and is unusual in patients over 70 years, with women marginally more affected than men [13–15]. Frozen shoulder needs to be considered in diabetics with shoulder pain and restricted movement due to their high reported incidence of this condition being 10–36%. The pain is characteristically felt around the deltoid insertion but also diffusely around the shoulder. A patient usually describes the pain as severe, wakes them at night and interferes with their normal daily activities [33,34]. The pain can radiate down the arm and it seems to pass through three distinct phases as described above [35]. 2.2. Examination You will usually find global loss of all gleno-humeral movements. In particular, loss of passive external rotation, both with the arm in neutral and in abduction is usually a pathognomonic sign of frozen shoulder. Most clinicians would agree that external rotation should be reduced by more than 50% compared to the unaffected side to consider a diagnosis of frozen shoulder. There

13

are other causes of loss of external rotation, but these bony causes can be ruled out with plain radiographs of the shoulder (arthritis, locked posterior dislocation, malignancy). 2.3. Investigation As early as 1934 [7] Codman indicated the importance of a normal radiograph in confirming a diagnosis of frozen shoulder and this still stands true today. To diagnose this soft tissue problem, a normal X-ray of the gleno-humeral joint is needed to exclude the bony causes of pain and restricted movement. There is no current evidence to support USS and MRI studies in reliably diagnosing frozen shoulder. 2.4. Treatment Recently a full evidence synthesis and systematic review assessing treatments for frozen shoulder was conducted. It concluded that there was limited clinical evidence and economic evidence on the effectiveness of treatments for primary frozen shoulder [36]. In addition the authors concluded that there is currently no formal consensus on the optimal management of frozen shoulder with different groups of healthcare professionals favouring different treatment pathways and thus further high-quality primary research is required [37]. The following section highlights the current best evidence or consensus for both conservative and interventional treatments of frozen shoulder. It must be remembered that most patients can be managed with non-operative treatment, often in the primary care setting, utilising a multidisciplinary approach. Secondary frozen shoulder tends to be more refractory to conservative management and interventional approaches can be used earlier [2]. 3. Conservative treatment Conservative options such as education and analgesia, physical therapy or in combination with an intra-articular steroid injection were found to be the most common non-surgical treatment options for idiopathic frozen shoulder offered by UK healthcare professionals [37]. While there is a lack of evidence in the form of high quality randomised controlled trials (RCTs) to support these common treatment options [36], they are non-interventional, cheap and come with minimal risk. However, what is important to focus on in the early stages of this condition is how to relieve pain. The combination use of appropriate analgesia, patient education and some active exercises seems to help relieve pain, reduce frustration and improves patient compliance towards treatment [38]. A single quasi-experimental study favoured ‘supervised neglect’ as a treatment modality verses intensive physiotherapy. However, the lack of randomisation, small sample size and short follow-up precluded any firm conclusions [39]. 3.1. Physical therapy Physical therapy encompasses various techniques, such as physiotherapy and osteopathy, and various modalities, including ultrasound and laser therapy. The recent NIHR commissioned systematic review identified ten RCTs that assessed physical mobilisation therapies either against a control group or alternative physical therapies. However, the overall quality of data available was poor with only one of these studies being of satisfactory rigour [36]. A six- to twelve-week course of physiotherapy is commonly prescribed for many patients suffering with shoulder pain with the aim of improving limitations in range of movement. This may involve passive mobilisation and capsular stretching. However this may be

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inappropriate for a patient during the acute inflammatory painful phase of frozen shoulder with many patients finding this painful [2]. The evidence for any particular physical treatment modality is lacking [36]. An RCT of 100 patients compared physiotherapy using high-grade mobilisation techniques (where mobilisation is applied with greater intensity) to low grade mobilisation techniques (where the joint is mobilised only in a pain-free range). While it concluded that high-grade techniques more effectively improved mobility of the gleno-humeral joint and led to reduced disability, the differences between the groups was small with only a minority of outcome measures reaching clinical significance and there was no control group [40]. The use of physical therapies involving heating tissues as adjuncts to mobilisation has been reported in several studies. The rationale is that the viscoelastic properties of the connective tissues are changed. There are various techniques for achieving deep tissue heating, including ultrasound and shortwave diathermy. Ultrasound is also postulated to produce mechanical effects. Shortwave diathermy in combination with stretching compared to stretching alone found some improvements in pain relief and disability in a small RCT [38]. Overall, the evidence is limited with no particular physical therapy shown to be superior. 3.2. Intra-articular steroid injection Intra-articular corticosteroid injections are given to help reduce inflammation and provide analgesia. While their use has been evaluated in several RCTs, a criticism of most trials is that steroid injection was frequently administered in combination with other treatments and control groups were therefore not adequate [36]. An RCT of 93 patients, comparing a single injection of triamcinolone hexacetonide with or without physiotherapy against placebo, found that corticosteroid injection in combination with a home exercise programme improved shoulder pain and range of motion at three months. The addition of a supervised physiotherapy programme led to more rapid improvements in range of motion but supervised physiotherapy alone provided limited benefit. However, by 12 months, the outcomes were similar regardless of the treatment provided [41]. 3.3. Intra-articular sodium hyaluronate Sodium hyaluronate, a component of connective tissue, has been investigated as a treatment for osteoarthritis. It is thought to affect the metabolism of articular cartilage and synovial tissue. Some studies reported to show some benefit and have suggested its use as an alternative treatment [42]. However, the few RCTs of this treatment modality do not show consistent evidence of benefit compared to physical therapy or steroids and the treatment is not licensed for use in frozen shoulder. Consequently, it is not commonly used [36]. 3.4. Oral steroid therapy A systematic review in 2006 identified five RCTs, which indicated that oral steroids provide improvements in pain, range of movement and function but only for a period of less than six week [43]. This is not a recommended or commonly prescribed treatment in the UK [36]. 3.5. Acupuncture Acupuncture is said to act by stimulating endogenous opioid secretion and inhibiting the transmission of pain signals to the brain

[44]. A Cochrane review including nine studies suggested a possible short-term benefit for pain and function. However, there was evidence that other pain-control measures, such as supra-scapular nerve block, were more effective [44,45]. The data available is at high risk of bias and provides only short-term follow up. It is therefore not possible to make any firm conclusions about the efficacy of acupuncture for frozen shoulder [36]. 4. Interventional treatment The most frequent indications for invasive treatments are persistent and severe functional restrictions that are resistant to conservative measures. However, the data from high-quality RCTs of invasive interventions is even more limited than for conservative interventions. 4.1. Distension arthrography This procedure is performed under fluoroscopic guidance (or USS) by an interventional radiologist, and does not require general anaesthesia. A characteristic contracted arthrogram appearance is initially confirmed before local anaesthetic is injected into the joint. Sterile water is then injected under pressure with the aim of stretching the fibrotic joint capsule. Many radiologists feel that this technique can cause the required capsular rupture that surgery achieves. This technique is usually then always completed with an intra-articular injection of steroid. Physiotherapy is usually commenced immediately after the procedure in order to maintain any improved range of movement. In the extended literature there is limited evidence of clinical benefit from capsular distension with only mild or no improvements being reported with distension in the short and medium term when compared with steroid [46,47] or placebo [48] or physiotherapy [49]. Three RCT’s [46–48] were identified by a recent systematic review [35] with only one being judged of sufficient quality with the others having a high risk of bias. This study [48] stated that there was no significant difference in terms of pain, function and range of movement between arthrographic distension with steroid and placebo (arthrogram only) at 6 or 12 weeks. Due to the insufficient evidence available for distension all that can be concluded is that further trials need to be performed in this area. However this treatment is still considered an easier and useful alternative to more interventional procedures such as Manipulation or Capsular Release which are operations requiring general anaesthetic. Indeed patient preference to avoid surgical procedures tends to lead to the prescription of this treatment option. 4.2. Surgery – manipulation under anaesthetic Manipulation under anaesthesia (MUA) can be used alone or in combination with a steroid injection and/or with an arthroscopic capsular release. Manipulation is performed with a patient under a general anaesthetic. The capsule of the gleno-humeral joint is deliberately torn by controlled manipulation of the arm through a specific sequence of movements. It is avoided in the elderly or osteoporotic bone, due to the risk of humeral fracture. It is often supplemented with an intra-articular injection of steroid and physiotherapy is then prescribed to maintain the improved range of movement. Evidence to support MUA remains limited with very few high quality studies [48] but with underpowered Level 4 evidence suggesting good to excellent results in the long-term [50–53]. Of the three RCT’s described in the recent systematic review [36], only one [54] was deemed of sufficient quality with the other two having differing risks of bias [55,56]. The study of adequate quality demonstrated no statistically significant difference between MUA

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(and home exercise) compared to home exercise alone in terms of pain, function and range of motion at 6 weeks, 3, 6 and 12 months [54].

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version of the paper. Jonathan Rees: Review of research proposal, finalising research proposal, provision of expert opinion, final manuscript review and final editing. Approved the final version of the paper.

4.3. Surgery – arthroscopic capsular release Competing interests Arthroscopic capsular release [AR] is now becoming the more common surgical intervention performed for the treatment of frozen shoulder. The surgery begins with an arthroscopic inspection of the gleno-humeral joint to confirm the diagnosis and to identify any coincident pathology. The contracted structures of the rotator interval (coracohumeral ligament, anterior capsule, superior and middle gleno-humeral ligaments) are then released (divided) usually using radiofrequency ablation. The anterior capsule and anterior band of the inferior gleno-humeral ligament are also divided. At this point the release can normally be completed with a controlled MUA that requires much less force. Some clinicians advocate a further arthroscopic release of the posterior and inferior capsule or a ‘360-degree’ release [57]. However, great care has to be taken to avoid iatrogenic injury to the axillary nerve. Physiotherapy is again prescribed to maintain the improved range of movement. The evidence to support this intervention is still limited. There are no RCTs or comparative studies involving arthroscopic capsular release. There are three case series of over 50 patients supporting the use of AR that have been reported to date. The three reported case series of 66 [58], 136 [59] and 183 [60] patients found significant improvements in pre and post operative pain, function and range of movement measurements at mean follow up of 10, 12 and 29 months, respectively [58–60]. 5. Conclusion In summary the great frustration with frozen shoulder for both clinicians and patients, is that despite it being so painful and restrictive, we are no further on 100 years after its recognition in providing evidence based information and treatment. As such, correct diagnosis is important and most patients with primary frozen shoulder are best initially treated symptomatically with pain modification and supportive physiotherapy using adjunctive intra-articular steroid injection when required. However until more evidence from well constructed trials indicates otherwise, a pragmatic ‘flexible’ approach to the management of frozen shoulder, involving the patient and their needs is recommended. The degree of symptoms encountered does seem to vary greatly between patients and further highlights the importance of a shared decision making approach with the ability to step up treatment to more invasive options if deemed appropriate. Failures of initial treatment to control pain, or considerable functional compromise from stiffness, or doubt about diagnosis are good reasons for referral to specialist secondary care. It seems distension arthrography is being increasingly used as a first line of invasive treatment and is being considered more and more by patients and clinicians before surgical intervention. Future national multi-centre trials are essential to evaluate the efficacy of the various treatment options available for frozen shoulder but until such time a pragmatic, flexible and escalating model as alluded to in the text is advised. Contributors Paul Guyver: Compilation and revision of research proposal, literature review, manuscript preparation with revisions and submission. Approved the final version of the paper. David Bruce: Literature review and manuscript preparation. Approved the final

The authors declare no conflict of interest. Funding The authors have received no funding for this article. Provenance and peer review Commissioned and not externally peer reviewed. References [1] Urwin M, Symmons D, Allison T, et al. Estimating the burden of musculoskeletal disorders in the community: the comparative prevalence of symptoms at different anatomical sites, and the relation to social deprivation. Ann Rheum Dis 1998;557:649–55. [2] Robinson CM, Seah KTM, Chee YH, Hindle P, Murray IR. Frozen shoulder. J Bone Joint Surg Br 2012;94B(1):1–9. [3] Wiley AM. Arthroscopic appearance of frozen shoulder. Arthroscopy 1991;7(2):138–43. [4] Neviaser JS. Adhesive capsulitis of the shoulder. J Bone Joint Surg 1945;27:211–21. [5] Schellingerhout JM, Verhagen AP, Thomas S, Koes BW. Lack of uniformity in diagnostic labeling of shoulder pain: time for a different approach. Man Therap 2008;13:478–83. [6] Zuckerman J, Rokito A. Frozen shoulder: a consensus definition. J Shoulder Elbow Surg 2010;20:322–5. [7] Codman EA. Tendinitis of the short external rotators. In: Ruptures of the supraspinatus tendon and other lesions in or about the subacromial bursa. Boston: Thomas Todd and Co; 1934. [8] Bunker TD, Schranz PJ. Clinical challenges in orthopaedics: the shoulder. Oxford, UK: ISIS Medical Media; 1998. [9] Dias R, Cutts S, Massoud S. Frozen shoulder. BMJ 2005;331:1453–6. [10] Shah N, Lewis M. Shoulder adhesive capsulitis: systematic review of randomised trials using multiple corticosteroid injections. Br J Gen Pract 2007;57:662–7. [11] Bridgman JF. Periarthritis of the shoulder and diabetes mellitus. Ann Rheum Dis 1972;31:69. [12] Van Der Windt DA, Koes BW, De Jong BA, Bouter LM. Shoulder disorders in general practice: incidence, patient characteristics, and management. Ann Rheum Dis 1995;54:959–64. [13] Wright V, Haq AM. Periarthritis of the shoulder: aetiological considerations with particular reference to personality factors. Ann Rheum Dis 1976;35:213–9. [14] Rizk TE, Pinals RS. Frozen shoulder. Semin Arthritis Rheum 1982;11:440–52. [15] Hand GC, Athanasou NA, Matthews T, Carr AJ. The pathology of frozen shoulder. J Bone Joint Surg Br 2007;89B:928–32. [16] Zuckerman JD, Cuomo FC. Frozen shoulder. In: Matsen 3rd FA, Fu FH, Hawkins RJ, editors. The shoulder: a balance of mobility and stability. Rosemont: American Academy of Orthopaedic Surgery; 1993. p. 253–67. [17] Hakim AJ, Cherkas LF, Spector TD, MacGregor AJ. Genetic associations between frozen shoulder and tennis elbow: a female twin study. Rheumatology (Oxford) 2003;42:739–42. [18] Tighe CB, Oakley Jr WS. The prevalence of a diabetic condition and adhesive capsulitis of the shoulder. South Med J 2008;101:591–5. [19] Anton HA. Frozen shoulder. Can Fam Physician 1993;39:1773–8. [20] Lundberg BJ. The frozen shoulder: clinical and radiographical observations: the effect of manipulation under general anesthesia: structure and glycosaminoglycan content of the joint capsule: local bone metabolism. Acta Orthop Scand Suppl 1969;119:1–59. [21] Grey RG. The natural history of idiopathic frozen shoulder. J Bone Joint Surg Am 1978;60A:564. [22] Hand C, Clipsham K, Rees JL, Carr AJ. Long term outcome of frozen shoulder. J Shoulder Elbow Surg 2008;17:231–6. [23] Hazleman BL. The painful stiff shoulder. Rheumatol Phys Med 1972;11:413–21. [24] Binder AI, Bulgen DY, Hazleman BL, Roberts S. Frozen shoulder: a long-term prospective study. Ann Rheum Dis 1984;43:361–4. [25] Shaffer B, Tibone JE, Kerlan RK. Frozen shoulder: a long-term follow-up. J Bone Joint Surg Am 1992;74A:738–46. [26] DePalma AF. Loss of scapulohumeral motion (frozen shoulder). Ann Surg 1953;135(2):194–204. [27] Neer CS, Saterlee CC, Dalsey RM, Flatlow EL. The anatomy and potential effects of contracture of the coracohumeral ligament. Clin Orthop 1992;280:182–5.

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[28] Gerber C, Werner CM, Macy JC, Jacob HA, Nyffeler RW. Effect of selective capsulorrhaphy on the passive range of motion of the glenohumeral joint. J Bone Joint Surg Am 2003;85A:48–55. [29] Harryman DT, Sidles JA, Harris SL, Matsen FA. The role of the rotator interval capsule. J Bone Joint Surg 1992;74A:53–65. [30] Jost B, Koch PP, Gerber C. Anatomy and functional aspects of the rotator interval. J Shoulder Elbow Surg 2000;9:336–41. [31] Ozaki J, Nakagawa Y, Sakurai G, Tamai S. Recalcitrant chronic adhesive capsulitis of the shoulder: role of contracture of the coracohumeral ligament and rotator interval in pathogenesis and treatment. J Bone Joint Surg Am 1989;71A:1511–5. [32] Mengiardi B, Pfirrmann CW, Gerber C, Hodler J, Zanetti M. Frozen shoulder: MR arthrographic findings. Radiology 2004;233:486–92. [33] Neviaser RJ, Neviaser TJ. The frozen shoulder: diagnosis and management. Clin Orthop 1987;223:59–64. [34] Nicholson GP. Arthroscopic capsular release for stiff shoulders: effect of etiology on outcomes. Arthroscopy 2003;19:40–9. [35] Hannafin JA, Chiaia TA. Adhesive capsulitis: a treatment approach. Clin Orthop 2000;372:95–109. [36] Maund E, Craig D, Suekarran S, Neilson A, Wright K, Brealey S, et al. Management of frozen shoulder: a systematic review and cost-effectiveness analysis. Health Technol Assess 2012;16.(11). [37] Dennis L, Brealey S, Rangan A, Rookmoneea M, Watson J. Managing idiopathic frozen shoulder: a survey of health professionals’ current practice and research priorities. Shoulder Elbow 2010;2(4):294–300. [38] Leung MS, Cheing GL. Effects of deep and superficial heating in the management of frozen shoulder. J Rehabil Med 2008;40(2):145–50. [39] Diercks RL, Stevens M. Gentle thawing of the frozen shoulder: a prospective study of supervised neglect versus intensive physical therapy in seventy-seven patients with frozen shoulder syndrome followed up for two years. J Shoulder Elbow Surg 2004;13(5):499–502. [40] Vermeulen HM, Rozing PM, Obermann WR, Le Cessie S, Vlieland TPV. Comparison of high-grade and low-grade mobilization techniques in the management of adhesive capsulitis of the shoulder: randomized controlled trial. Phys Ther 2006;86(3):355–68. [41] Carette S, Moffet H, Tardif J, et al. Intraarticular corticosteroids, supervised physiotherapy, or a combination of the two in the treatment of adhesive capsulitis of the shoulder: a placebo-controlled trial. Arthritis Rheum 2003;48(3):829–38. [42] Calis M, Demir H, Ulker S, Kirnap M, Duygulu F, Calis HT. Is intraarticular sodium hyaluronate injection an alternative treatment in patients with adhesive capsulitis? Rheumatol Int 2006;26(6):536–40. [43] Buchbinder R, Green S, Youd J, Johnston R. Oral steroids for adhesive capsulitis. Cochrane Database Syst Rev 2006;4. [44] Favejee MM, Huisstede BMA, Koes BW. Frozen shoulder: the effectiveness of conservative and surgical interventions—systematic review. Br J Sports Med 2011;45(January (1)):49–56.

[45] Green S, Buchbinder R, Hetrick S. Acupuncture for shoulder pain. Cochrane Database Syst Rev 2005;2. [46] Tveita EK, Tariq R, Sesseng S, Juel NG, et al. Hydrodilatation, corticosteroids and adhesive capsulitis: a randomised controlled trial. BMC Musculoskelet Disord 2008;9:53. [47] Gam AN, Schydlowsky P, Rossel I, et al. Treatment of ‘frozen shoulder’ with distension and glucocorticoid compared with glucocorticoid alone: a randomised controlled trial. Scand J Rheumatol 1998;27:425–30. [48] Buchbinder R, Green S, Forbes A, Hall S, Lawler G. Arthrographic joint distension with saline and steroid improves function and reduces pain in patients with painful stiff shoulder: results of a randomised, double blind, placebo controlled trial. Ann Rheum Dis 2004;63:302–9. [49] Khan AA, Mowla A, Shakoor MA, Rahman MR. Arthrographic distension of the shoulder joint in the management of frozen shoulder. Mymensingh Med J 2005;14:67–70. [50] Hill Jr JJ, Bogumill H. Manipulation in the treatment of frozen shoulder. Orthopedics 1988;11:1255–60. [51] Thomas WJ, Jenkins EF, Owen JM, et al. Treatment of frozen shoulder by manipulation under anaesthetic and injection: does the timing of treatment affect the out-come? J Bone Joint Surg Br 2011;93B:1377–81. [52] Haggart GE, Dignam RJ, Sullivan TS. Management of the frozen shoulder. J Am Med Assoc 1956;161:1219–22. [53] Harmon PH. Methods and results in the treatment of 2,580 painful shoulders, with special reference to calcific tendinitis and the frozen shoulder. Am J Surg 1958;95:527–44. [54] Kivimaki J, Pohjolainen T, Malmivaara A, et al. Manipulation under anaesthesia with home exercises versus home exercises alone in the treatment of frozen shoulder: a randomised controlled trial. J Shoulder Elbow Surg 2007; 16:722–6. [55] Jacobs LG, Smith MG, Khan SA, Smith K, Joshi M. Manipulation or intraarticular steroids in the management of adhesive capsulitis of the shoulder. J Shoulder Elbow Surg 2009;18:348–53. [56] Quraishi NA, Johnston P, Bayer J, Crowe M, Chakrabarti AJ. Thawing the frozen shoulder, a randomised controlled trial comparing manipulation under anaesthesia with hydrodilatation. J Bone Joint Surg Br 2007;89:1197–200. [57] Jerosch J. 360 degrees arthroscopic capsular release in patients with adhesive capsulitis of the glenohumeral joint: indication, surgical technique, results. Knee Surg Sports Traumatol Arthrosc 2001;9:178–86. [58] Austgulen OK, Oyen J, Hegna J, Solheim E. Arthroscopic capsular release in treatment of primary frozen shoulder. Tidsskr Nor 2007;127:1356–8. [59] Smith CD, Hamer P, Bunker TD. Arthroscopic capsular release for idiopathic frozen shoulder with intraarticular injection and a controlled manipulation. Ann R Coll Surg Engl 2014;96:55–60. [60] Chen S-K, Chien S-H, Fu Y-C, Huang P-J, Chou P-H. Idiopathic frozen shoulder treated by arthroscopic debridement. Kaohsiung J Med Sci 2002;18: 289–94.

Maturitas 78 (2014) 8–10

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Health benefits of encore careers for baby boomers Anya Topiwala, Shivani Patel, Klaus P. Ebmeier ∗ Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK

a r t i c l e

i n f o

Article history: Received 6 February 2014 Accepted 10 February 2014 Keywords: Retirement Pension Dementia Depression

a b s t r a c t Baby boomers now represent an aging population group at risk of the diseases of older age. Their relatively high education, amongst other attributes, means that they can make a significant contribution to the work force beyond the statutory retirement age. On an individual level, potential health benefits may motivate them to pursue encore careers. We review some of the evidence supporting such a trend. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Health benefits of occupation on psychiatric morbidity and mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.1. Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.2. Cognitive impairment and dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3. Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1. Introduction The great population bulge of the 50–68 year olds (the “baby boomers”), has caused some anxiety to policy makers, as the pension-paying younger generations are getting smaller and smaller, and already need to be supplemented in many Western countries by younger overseas immigrants and their children. UK projections estimate that baby boomers will live on average another 15.8–20.9 years [1]. They will thus represent a substantial section of the population (26% in the US) [2]. Yet in the UK, median retirement age is 64.6 for men, and 62.3 years for women, respectively [3]. Public health focus has been on the risk of illnesses common after retirement, such as depression (point prevalence of

4.6–9.3% in >75 year olds) [4] and dementia (5.9–7.0% of >65 year olds) [5]. While pension ages are being increased to catch up gradually with the projected budget deficits, the question arises, if this may not confer benefits on this generation, rather than just representing an economic sacrifice to be made. Certainly, baby boomers are well placed to work on a paid or voluntary basis into older age. US statistics show that as a group they are better educated (28.8% have at least a bachelor’s degree), are more likely to be employed (74.1%) and wealthier (only 8.9% in poverty) than are any other age strata of the population [2]. 2. Health benefits of occupation on psychiatric morbidity and mortality 2.1. Depression

∗ Corresponding author. Tel.: +44 1865 226469; fax: +44 1865 793101. E-mail address: [email protected] (K.P. Ebmeier). http://dx.doi.org/10.1016/j.maturitas.2014.02.005 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

Prolonged unemployment accounts for a proportion of depression across adult age groups [6–8]. Unemployed, but also part-time

A. Topiwala et al. / Maturitas 78 (2014) 8–10

and retired workers are more likely to be depressed than those in full-time work [6]. In many cases it may be difficult to establish whether unemployment led to depression or vice versa, but some studies have claimed that unemployment is causally related to depression [9,10]. Loss of regular income has been identified as a critical factor contributing toward depressive symptoms. Men at retirement age, who were working for pay, were less likely to be depressed than men who were not being paid for their work [11]. Similarly, the low-income unemployed suffer most with depression, further supporting the idea that loss of financial security is a critical factor [12]. Regularity of work has also been identified as important in reducing reported depressive symptoms. Full-time workers, compared with ‘non-standard’ or temporary workers, reported fewer depressive symptoms, even after adjusting for education, occupational class and income [13]. This suggests that in addition to providing a livelihood, paid employment gives workers a sense of purpose and self-worth that is removed with retirement. Social isolation (particularly the size of the social network and subjective social support) has been identified as important in predicting depression in the elderly retired population [14]. Those who engage in fewer social activities have a significantly higher incidence of depression [15]. Social support appears relevant to chronicity of major depressive illness more than its severity [16]. As going to work is the main form of social interaction for many, retirement may thus predispose older individuals toward depression, which would be mitigated by an encore career. 2.2. Cognitive impairment and dementia A number of studies have demonstrated a link between high lifetime occupational attainment (i.e. non-manual/white collar) and a reduced incidence of all cause [17], vascular [18], and Parkinson’s disease dementia [19]. Duration of employment may determine the strength of such associations [18]. Additionally, one study has hinted at a negative impact of retirement upon cognitive function [20]. No study has to date examined the association between later life careers and dementia risk. However, it seems reasonable to extrapolate from studies of mental activity and social interaction, which would be components of the majority of encore careers. A meta-analysis in 2004 concluded that social and mental activities have a beneficial effect on cognition and a protective effect against dementia [21]. Longitudinal studies associate cognitively stimulating leisure activities (one can argue for a similarity with mental work) with a decreased risk of dementia [22], Alzheimer’s disease [23], vascular dementia [24], as well as with a later age of dementia onset [25]. Similarly, the majority of studies have shown reduced cognitive decline with increasing leisure activity [26]. Such activities are diverse and include computer use [22], odd jobs and knitting [27]. The majority (10/12) of longitudinal studies have shown that increased social interaction is associated with reduced dementia incidence [28] or later onset [25]. Similarly, 17 of 18 studies have demonstrated a significant correlation between increased social activity and reduced cognitive decline [29]. Of course, one must make causal interpretations in such studies with care. The vast majority of participants were >65 years at baseline, hence decreased mental or social activity may be the result of pre-existing subtle cognitive impairments. 3. Mortality There is a substantial evidence base suggesting that unemployment in middle age increases mortality. In one prospective study of 40–59 year olds, those unemployed in the five years after screening

9

had approximately double the risk of dying (from cardiovascular disease or cancer) compared with those continuously employed, even after adjustment for multiple confounders [30]. However, the relationship between employment and mortality is likely to be complicated, and one cannot necessarily extrapolate that encore careers would decrease mortality. Temporary (rather than permanent) employment may actually increase mortality [31] – the relationship between total working hours and mortality may actually be u-shaped [32]. Correspondingly, several studies have found mortality is higher amongst those retiring early (<65 years) [33], although this association may be confounded by those retiring early on grounds of ill health. Following adjustment for this, early retirees spent fewer days in hospital in the preceding two years and had no change in mortality [34]. One can make a compelling argument that encore careers may decrease suicides in baby boomers. Unemployment [35], retirement [36], and a restricted social network [37] are all risk factors for elderly suicide. A meta-analysis found that having a hobby or active participation in an organization decreased the risk of suicide in >65 year olds (although this was not significant following adjustment for life events, psychosocial variables and mental health) [38]. 4. Conclusions Baby boomers now represent an aging population and are at risk from debilitating diseases of older age. Their relatively high education, amongst other attributes, means that they could make a significant contribution to the work force beyond the statutory retirement age. On an individual level, potential health benefits may motivate them to pursue encore careers. Mental and social activities seem to decrease the risk of dementia; employment, income and social contact decrease the risk of depression; and mortality (particularly from suicide) is decreased by employment and social contact. Depression, dementia or lethal morbidity may of course result in early retirement rather than vice versa. However, physical and mental activity seems to improve mood and cognitive performance supporting the argument that employment confers a beneficial impact on health [39,40]. Contributors All authors were involved in the first draft (part) and full revision of the manuscript. Competing interest Anya Topiwala and Shivani Patel both declared no competing interest and Klaus P. Ebmeier reports consultation fees received from Lily in relation to Amyvid TM. Funding Anya Topiwala – UK Medical Research Council (G1001354) – Clinical Lecturer. Shivani Patel – North East Thames Foundation School. Klaus P. Ebmeier – UK Medical Research Council (G1001354), the Gordon Edward Small’s Charitable Trust (SC008962), and the HDH Wills 1965 Charitable Trust. Provenance and peer review Commissioned and externally peer reviewed.

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[19] Helmer C, Letenneur L, Rouch I, et al. Occupation during life and risk of dementia in French elderly community residents. J Neurol Neurosurg Psychiatry 2001;71(3):303–9. [20] Roberts BA, Fuhrer R, Marmot M, Richards M. Does retirement influence cognitive performance? The Whitehall II Study. J Epidemiol Community Health 2011;65(11):958–63. [21] Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol 2004;3(6):343–53. [22] Almeida OP, Yeap BB, Alfonso H, Hankey GJ, Flicker L, Norman PE. Older men who use computers have lower risk of dementia. PLoS ONE 2012;7(8):e44239. [23] Akbaraly TN, Portet F, Fustinoni S, et al. Leisure activities and the risk of dementia in the elderly: results from the Three-City Study. Neurology 2009;73(11):854–61. [24] Verghese J, Cuiling W, Katz MJ, Sanders A, Lipton RB. Leisure activities and risk of vascular cognitive impairment in older adults. J Geriatr Psychiatry Neurol 2009;22(2):110–8. [25] Paillard-Borg S, Fratiglioni L, Xu W, Winblad B, Wang HX. An active lifestyle postpones dementia onset by more than one year in very old adults. J Alzheimers Dis 2012;31(4):835–42. [26] Wang HX, Jin Y, Hendrie HC, et al. Late life leisure activities and risk of cognitive decline. J Gerontol A: Biol Sci Med Sci 2013;68(2):205–13. [27] Fabrigoule C, Letenneur L, Dartigues JF, Zarrouk M, Commenges D, BarbergerGateau P. Social and leisure activities and risk of dementia: a prospective longitudinal study. J Am Geriatr Soc 1995;43(5):485–90. [28] Crooks VC, Lubben J, Petitti DB, Little D, Chiu V. Social network, cognitive function, and dementia incidence among elderly women. Am J Public Health 2008;98(7):1221–7. [29] James BD, Wilson RS, Barnes LL, Bennett DA. Late-life social activity and cognitive decline in old age. J Int Neuropsychol Soc 2011;17(6):998–1005. [30] Morris JK, Cook DG, Shaper AG. Loss of employment and mortality. Br Med J 1994;308(6937):1135–9. [31] Kivimaki M, Vahtera J, Virtanen M, Elovainio M, Pentti J, Ferrie JE. Temporary employment and risk of overall and cause-specific mortality. Am J Epidemiol 2003;158(7):663–8. [32] Sokejima S, Kagamimori S. Working hours as a risk factor for acute myocardial infarction in Japan: case–control study. Br Med J 1998;317(7161):775–80. [33] Tsai SP, Wendt JK, Donnelly RP, de Jong G, Ahmed FS. Age at retirement and long term survival of an industrial population: prospective cohort study. Br Med J 2005;331(7523):995. [34] Brockmann H, Muller R, Helmert U. Time to retire–time to die? A prospective cohort study of the effects of early retirement on long-term survival. Soc Sci Med 2009;69(2):160–4. [35] Voss M, Nylen L, Floderus B, Diderichsen F, Terry PD. Unemployment and early cause-specific mortality: a study based on the Swedish twin registry. Am J Public Health 2004;94(12):2155–61. [36] Qin P, Agerbo E, Westergard-Nielsen N, Eriksson T, Mortensen PB. Gender differences in risk factors for suicide in Denmark. Br J Psychiatry 2000;177:546–50. [37] Beautrais AL. A case control study of suicide and attempted suicide in older adults. Suicide Life Threat Behav 2002;32(1):1–9. [38] Rubenowitz E, Waern M, Wilhelmson K, Allebeck P. Life events and psychosocial factors in elderly suicides—a case–control study. Psychol Med 2001;31(7):1193–202. [39] Valkanova V, Eguia Rodriguez R, Ebmeier KP. Mind over matter – what do we know about neuroplasticity in adults? Int Psychogeriatr 2014:1–19. [40] Behrman S, Ebmeier KP. Can exercise prevent cognitive decline? Practitioner 2014;258(1767):17–21.

Maturitas 78 (2014) 73

Contents lists available at ScienceDirect

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Letter to the Editor Health benefits of hormonal contraception夽 Keywords: Perimenopause Hormonal contraception Non-contraceptive benefits

Dear Editor, We are grateful to Dr. Nicolás Mendoza and Dr. Rafael SánchezBorrego for bringing attention to the subject of non-contraceptive benefits of hormonal contraceptives (HCs), which is not included in our recent review of contraceptive use during perimenopause [1]. Just as there is data lacking on contraceptive effectiveness of HCs for women over age 40, there is also a paucity of data for non-contraceptive benefits in this age group, such as decreased menstrual bleeding. We do present data particular to perimenopausal and postmenopausal women for the benefits of the levonorgestrel intrauterine system (LNG-IUS), which include reduction in total menstrual blood loss, endometrial protection, and avoidance of hysterectomy [2,3]. We agree that research focused on the benefits of combined HCs in this population would be helpful.

夽 Dr. Jensen has received payments for consulting from Bayer Healthcare, Merck, Agile Pharmaceuticals, HRA Pharma, and the Population Council, and for giving talks for Bayer and Merck. He has also received research funding from Abbott Pharmaceuticals, Bayer, the Population Council, the National Institute of Health, and the Bill & Melinda Gates Foundation. These companies and organizations may have a commercial or financial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by OHSU. http://dx.doi.org/10.1016/j.maturitas.2014.02.019 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

References [1] Baldwin MK, Jensen JT. Contraception during the perimenopause. Maturitas 2013;76(3):235–42. [2] Milsom I. The levonorgestrel-releasing intrauterine system as an alternative to hysterectomy in peri-menopausal women. Contraception 2007;75(6 Suppl.):S152–4. [3] Sitruk-Ware R. The levonorgestrel intrauterine system for use in peri- and postmenopausal women. Contraception 2007;75(6 Suppl.):S155–60.

Maureen K. Baldwin ∗ Jeffrey T. Jensen Oregon Health & Science University, Portland, OR, United States ∗ Corresponding

author at: 3181 SW Sam Jackson Park Road, Mailcode: UHN 50, Portland, OR 97239, United States. Tel.: +1 503 494 9762; fax: +1 503 494 3111. E-mail address: [email protected] (M.K. Baldwin) 27 February 2014

Maturitas 78 (2014) 22–29

Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

How to overcome male infertility after 40: Influence of paternal age on fertility Stephanie Belloc a,1 , Andre Hazout a,1 , Armand Zini b,2 , Philippe Merviel c,3 , Rosalie Cabry c,3 , Hikmat Chahine d,4 , Henri Copin c,3 , Moncef Benkhalifa c,∗ a

Eylau/Unilabs Laboratory, Reproductive Biology Unit, 55 Rue Saint Didier, 75016 Paris, France Department of Surgery, McGill University, St. Mary’s Hospital, Montreal, Quebec, H3T 1M5 Canada c Reproductive Medicine & Medical, Cytogenetics Department, Regional University Hospital & School of Medicine, Picardie University Jules Verne, CGO, 124 Rue Camille Desmoulins, 80054 Amiens, France d Andrology Unit, ForteBio Laboratory, 16 Rue Fusilllés, 40100 Dax, France b

a r t i c l e

i n f o

Article history: Received 9 December 2013 Received in revised form 19 February 2014 Accepted 21 February 2014 Keywords: Paternal age Fertility disorders Sperm parameters Diagnosis and treatment

a b s t r a c t The recent trend toward delayed parenthood raises major safety concerns because of the adverse effects of aging on couple fertility. Studies have demonstrated that aging clearly affects female fertility, but can also affect male fertility. Although several theories have been proposed, the exact mechanisms responsible for the observed age-related decline in male fertility remain to be elucidated. It has been shown that advanced paternal age (PA) is associated with reduced semen volume as well as, reduced sperm count, motility and morphology. Recent studies have also reported that paternal aging is associated with a significant increase in the prevalence of both genomic and epigenomic sperm defects. In the context of natural and intrauterine insemination (IUI) conception, advanced paternal age has been associated with lower pregnancy rates and increased rates of spontaneous abortion (independent of maternal age). In IVF and oocyte donation programs, a significant decrease in late blastocyst development has been seen in those cycles using spermatozoa of men older than 55. However, no significant relationship between paternal age and IVF or ICSI pregnancy rates has been observed. Although there are no treatments that can fully restore the age-related decline in male fertility, various measures have been shown to optimize male fertility potential. Specific therapies (e.g. varicocelectomy) and lifestyle changes (e.g. dietary antioxidant supplements) may help minimize some of the age-related deleterious effects on spermatogenesis, such as, oxidative stress and endocrine abnormalities. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Influence of paternal age on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Age-related changes in reproductive hormones and sexual function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Age-related changes in conventional sperm parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Chromatin dispersion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23 23 23 23 23

∗ Corresponding author. Tel.: +33 322533677; fax: +33 322533679. E-mail addresses: [email protected] (S. Belloc), [email protected] (A. Hazout), [email protected] (A. Zini), [email protected] (P. Merviel), [email protected] (R. Cabry), [email protected] (H. Chahine), [email protected] (H. Copin), [email protected] (M. Benkhalifa). 1 Tel.: +33 141439600; fax: +33 141439595. 2 Tel.: +1 514 345 3511x6372; fax: +1 514 734 2719. 3 Tel.: +33 322533677; fax: +33 322533679. 4 Tel.: +33 558909192; fax: +33 558909191. http://dx.doi.org/10.1016/j.maturitas.2014.02.011 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

S. Belloc et al. / Maturitas 78 (2014) 22–29

2.4. Age-related changes in sperm chromatin and DNA integrity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Paternal age and natural fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Paternal age and ART outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. Paternal age and offspring health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Strategies to optimize fertility potential in the aging male . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Varicocele Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Adopting a healthy lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Antioxidants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Overcoming paternal age effect with new advances in ARTs – IMSI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Cell free DNA and infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction As women age, their ovarian reserve and oocyte integrity (function and ploidy), gradually decrease. Taken together, these events explain the age-related decline in reproductive capacity (e.g. low rates of natural conception) and the poor results obtained with assisted reproduction technologies (ARTs) [1,2]. Women also experience an increased risk of pregnancy complications (perinatal morbidity and mortality) and of adverse perinatal and post-natal offspring outcomes as they age [3–5]. Finally, female fertility reaches a natural limit and altogether ceases with menopause. Unlike the abrupt decline in reproductive capacity seen in all women, men maintain a certain level of reproductive function lifelong but this function declines very gradually over time. Studies have shown that advanced paternal age (PA) is associated with changes in reproductive hormone production, sexual function, sperm production and fertility. Advanced PA has also been associated with adverse pregnancy outcomes, an increased risk of sperm de novo mutations, birth defects and offspring diseases. 2. Influence of paternal age on fertility 2.1. Age-related changes in reproductive hormones and sexual function It has been reported that advanced PA is associated with progressive changes in several reproductive hormones. The most clinically relevant hormone alterations associated with male aging are increasing follicle-stimulating hormone (FSH) serum levels and decreasing testosterone serum levels. The increasing concentration of serum FSH in aged men has been linked to reduced Sertoli cell function, germ cell degeneration during meiosis and reduced daily sperm production [6]. The decreasing concentrations of serum testosterone levels in aged men has been linked to andropausal symptoms, such as, poor libido, fatigue and loss of cognitive functions [7]. Male sexual function and sexual frequency both decrease with aging [8–10]. Although male sexual dysfunction does not directly impact on male fertility potential, the infertility experienced by older couples may, in part, be due to a decline in sexual activity. 2.2. Age-related changes in conventional sperm parameters Most studies have shown that paternal aging is associated with changes in semen parameters. Specifically, advancing PA is related to declining semen volume, sperm motility and morphology [11,12]. Although sperm concentration has not been consistently shown to decrease with aging, a decline in sperm count has been

23

23 24 24 24 25 25 25 25 26 26 26 26 26 26 26 27

reported [2,3,13]. The underlying cause of the age-related decline in semen parameters has not been clearly defined. However, possible etiologies include age-related vascular insufficiency, increasing prevalence of co-morbidities (e.g. diabetes, hypertension), chronic infections (e.g. prostatitis), obesity, hormonal insufficiency and accessory gland dysfunction [14–17]. The significance of the observed age-related changes in semen parameters remains a subject of ongoing controversy. This is in part due to the notable biologic variability of conventional semen parameters and the fact that these parameters are poor predictors of male fertility potential [18,19]. As such, additional markers of male fertility potential (e.g. sperm DNA damage) have been examined to ascertain the observed relationship between age and semen quality. 2.3. Chromatin dispersion A mature sperm has a chromatin tightly compacted, because more than 80% of the histones are replaced by protamines, during the spermatogenesis. Two types of protamines were investigated, Protamine 1 and Protamine 2, and a ratio close to 1 reflects the good quality of this compaction. Chromatin dispersion may potentially result in lack of fertilization and/or early embryonic development defects. These are relatively common situations IVF/ICSI programs which lead to very early embryonic development arrests or spontaneous abortions in the first quarter. The mechanisms of DNA dispersion are still poorly known. Moreover chromatin dispersion exposes the nucleus to a greater vulnerability to oxidative stress. Several studies demonstrated the impact of chromatin packaging in fertility and embryonic development [11–17]. There is really no consensus on the DNA dispersion level exposing to pathologic embryo development; some suggest a cut-off of 20% and others consider that more than 30% is potentially harmful. 2.4. Age-related changes in sperm chromatin and DNA integrity Sperm chromatin and DNA tests measure nuclear chromatin compaction and DNA damage, respectively. These sperm function markers were first designed to increase our understanding of spermatogenesis, sperm physiology and reproductive biology [20–29]. More recently, tests of sperm chromatin and DNA damage have been used in the clinic, in the hope that these tests may provide a more accurate diagnosis than is possible with conventional semen parameters. Conventional sperm parameters (sperm concentration, motility and morphology) exhibit a high degree of biological variability and are only fair measures of fertility potential [18,30]. Sperm chromatin and DNA tests have also been studied in the

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context of assisted reproductive technologies (ARTs) in order to evaluate the ability of these tests to predict reproductive outcomes after assisted reproduction because conventional sperm parameters are poor predictors of ART outcomes [31–33]. To date, prospective studies of couples with unknown fertility status have shown that sperm DNA damage is associated with a lower probability of conception (odds ratio = ∼7) and a prolonged time to pregnancy [34–37]. These studies have also shown that sperm DNA testing is a better predictor of pregnancy than conventional sperm parameters in this context [35]. A systematic review of ART studies has shown that sperm DNA damage is associated with lower intrauterine insemination (IUI) and conventional in vitro fertilization (IVF) pregnancy rates, but not with intracytoplasmic sperm injection (ICSI) pregnancy rates [32,38–40]. Moreover, several clinicians have observed a higher rate of spontaneous pregnancy loss in men with sperm DNA damage and two systematic reviews suggest that this damage is indeed associated with an increased risk of pregnancy loss (after an established natural and IVF or ICSI pregnancy) [32,41]. The impact of sperm DNA fragmentation is potentially underestimated because some of this damage can be repaired by the oocyte (of young, healthy women) [42–44]. However, the oocyte’s repair capacity will decrease as women age [45]. The intra-cytoplasmic injection of a single morphological normal spermatozoon (selected using standard magnification) does not preclude the possibility of injecting a DNA-damaged sperm. It has been shown that spermatozoa with DNA fragmentation may fertilize oocytes with the same efficiency as normal spermatozoa [46]; nonetheless, if critical genes are damaged at the time of genomic activation (on day 3 after fertilization), embryo development may be arrested [47]. Once incorporated into the embryonic genome, fragmented sperm DNA may lead to errors in replication, transcription and translation during embryogenesis. Although it is unknown whether sperm DNA damage (as measured by assays such as TUNEL – terminal deoxynucleotidyl transferase-mediated dUTP Nick End-Labeling or SCSA – sperm chromatin structure assay) will result in adverse health outcomes in offspring, in theory this damage may contribute to birth malformations, not only for the first generation, but also in subsequent generations [48]. Recent experimental (animal) studies have shown that sperm DNA damage is associated with adverse reproductive outcomes after ARTs (lower pregnancy rates, chromosomal abnormalities, pregnancy loss, reduced longevity and birth defects) [49–52]. A number of retrospective studies have shown that PA is associated with a higher percentage of sperm with DNA damage [53–61]. Although most of the studies have evaluated infertile men, a similar relationship has also been observed in a population of healthy men [62]. Moreover, the prevalence of an isolated sperm DNA defect is higher in older compared to younger men [61]. This suggests that a higher than expected proportion of older men with normal semen parameters will have sperm DNA damage. 2.5. Paternal age and natural fertility Advancing age of the mother is unequivocally associated with reduced fertility and a prolonged time to pregnancy (TTP) [2,63]. The reduced fertility in aging women is primarily due to declining ovarian reserve and to dysfunctional ovulation. Although most studies have observed that paternal aging is associated with adverse changes in semen parameters and sperm DNA integrity, the studies relating PA and fertility provide conflicting results. These contradictory results may be attributed to (1) the fact that maternal fertility is not perfectly related to maternal age (most studies control for maternal age) and (2) the decline in male sexual activity can impact on the PA effects on fertility, as the frequency of intercourse decreases with age. Nonetheless, a general

consensus is that PA is associated with reduced fertility, at least in couples where men are older than 40 years and women are at least 35 years (probably because after 35, maternal age is more closely linked to maternal fertility status) [63–68]. A number of very large studies have observed that paternal aging is associated with an increased risk of pregnancy loss after an established natural pregnancy [69–72]. These data provide some evidence that paternal age may affect the sperm genome or epigenome integrity such that it impacts negatively on late embryo development. 2.6. Paternal age and ART outcomes In keeping with the natural pregnancy findings, advancing PA has been associated with a lower probability of pregnancy following intrauterine insemination [73]. Although some studies have shown that advancing PA is associated with a lower probability of IVF/ICSI pregnancy [74], other studies have not observed a similar association [75–77]. A recent analysis of 10 IVF and/or ICSI studies suggests that there is no significant relationship between PA and ART pregnancy rates [78]. In a very recent study using ovum donation model, the authors demonstrated that advanced PA has an adverse impact on ART outcomes [46]. After adjusting for number and embryo grades transferred, a younger PA has a more favorable ART outcome. Two large studies have observed that paternal aging is associated with an increased risk of pregnancy loss after an established IUI pregnancy [76,79] again supporting the concept that PA may affect the sperm genomic integrity such that it impacts negatively on late embryo development. In contrast, a meta-analysis of 7 IVF and IVF/ICSI studies has shown that paternal aging is not associated with an increased risk of pregnancy loss after an established IVF or IVF/ICSI pregnancy [78]. Although the natural and IUI study findings appear to contradict the IVF/ICSI studies on the relationship between pregnancy loss and PA, it is important to note that the natural and IUI pregnancies are from men with relatively homogeneous (and “normal”) sperm parameters whereas with IVF/ICSI the population of men is so heterogeneous that an age effect may be diluted by more important variations in the severity of the infertility. 2.7. Paternal age and offspring health It is well established that the risk of chromosomal and genetic abnormalities in the offspring increases with advanced maternal age [80,81]. This risk has led to the establishment of specific prenatal guidelines for management of pregnancy in older women [82]. In contrast, a relationship between advanced PA and the risk of chromosomal and genetic abnormalities in the offspring has only been recently identified [83]. Moreover, there are no established prenatal guidelines for management of pregnancy in couples with advanced PA because the relationship between advanced PA and the risk of genetic abnormalities in the offspring remains poorly defined. In women, germ cell replication is completed at birth, oocytes remain meiotically arrested (meiosis I) for up to 50 years and meiosis resumes prior to ovulation. As women age, meiotic recombination errors occur more frequently because meiotic divisions are of lower fidelity and this leads to oocyte aneuploidy [84]. In contrast, spermatozoa are subject to acquire de novo single nucleotide variants (SNVs) or mutations because spermatogenesis is a continuous process involving numerous pre-meiotic spermatogonial divisions (asymmetric divisions) and, as men age, the testicular environment (increased oxidative stress) is more prone to DNA injury [84]. Moreover, errors in post-meiotic chromatin remodeling and DNA repair may also lead to de novo mutations [85].

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Nonetheless, spermatozoa of older fathers may also have an increased frequency of chromosomal aneuploidy [86]. Direct evidence for an increasing rate de novo sperm single nucleotide variants (SNVs) or mutations with aging was recently reported in studies involving genome wide sequencing of parentoffspring trios (mother, father and child) [87,88]. Using multiple regression analysis, Kong et al. [87] observed that the rate de novo mutation in the offspring was strongly correlated to PA but was not related to maternal age. The paternal contribution to offspring novo mutations was estimated to increase by 4% per year (of paternal age). Studies have shown that advanced paternal age is associated with an increased risk of birth defects and childhood disease in the offspring [89]. An underlying genetic and/or epigenetic factor is believed to be responsible for most of these offspring defects. For example, advanced PA is associated with a greater risk of fibroblast growth factor receptor 2 (FGFR2) and fibroblast growth factor receptor 3 (FGFR3) sperm mutations [90–92] (FGFR2 and FGFR3 mutations have been associated with an increased risk of achondroplasia and Apert syndrome, respectively). Clinical studies have shown that children of older fathers show an increased risk of birth defects [93–95], childhood cancers [96,97], schizophrenia [98–100] and autism [101,102]. However, the relative risk in most of these studies is generally low (in the range of 1.1–1.5) suggesting that some of these associations need to be viewed with caution. The relationship between advanced PA and the risk of disease and genetic abnormalities in the offspring is certainly a cause for concern. As we better define the risk to the offspring and the societal burden it will be important to educate the public and establish prenatal guidelines for the management and counseling of couples with advanced PA. 3. Strategies to optimize fertility potential in the aging male A number of therapies have been used to optimize fertility potential in men. Although few of these therapies have been extensively studied in the aging male, the rationale for treating older men is generally the same as that for treating younger men. Varicocele repair is one of the specific therapies (i.e. a therapy aimed at a specific pathology or specific factor) that have been studied in older men. Lifestyle modifications and antioxidant therapy are non-specific therapies that may improve fertility potential in the aging male, although there is limited data to demonstrate a benefit in the aging male population, specifically. 3.1. Varicocele Repair A recent meta-analysis of prospective varicocelectomy studies has shown varicocele repair can significantly improve conventional sperm parameters [103]. Moreover, several studies have reported that varicocele repair can also significantly improve sperm DNA integrity [104]. Although there are very few randomized trials on the effect varicocelectomy on pregnancy outcome, recent meta-analyses suggest that varicocelectomy is associated with an increased probability of pregnancy [103–105]. A number of studies have demonstrated that the benefit of varicocele repair is also evident in older men but the number of studies addressing this topic is few in number [105–107]. As such, varicocele repair should be performed in older men so as to optimize male fertility potential. 3.2. Adopting a healthy lifestyle Several studies have reported reduced sperm concentration and motility in cigarette smokers [108–111]. However, the impact of

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cigarette smoking on male fertility potential remains controversial because (1) it is difficult to exclude the effect of smoking on the female partner and (2) changes in semen parameters do not necessarily translate into reduced pregnancy outcomes [18,108,112,113]. Nonetheless, there is growing concern that smoking may lead to alterations in seminal antioxidant capacity, accumulation of sperm DNA adducts and defects in the genomic integrity of the sperm DNA and result in adverse post-natal outcomes [114–117]. As such, men should be counseled to stop smoking [118]. The impact of alcohol consumption on male fertility potential remains controversial. In men, chronic alcohol consumption has been associated with adverse effects such as testicular atrophy, decreased libido, and decreased semen volume [119–121]. However, there is no strong evidence to show that chronic alcohol consumption reduces male fertility potential [122]. As such, there is little supporting evidence to counsel men to stop drinking alcohol altogether. However, excessive alcohol intake should be avoided. It is well known that exposure to occupational and environmental toxins can reduce sperm quality [123,124]. Moreover, scrotal heat stress can adversely impact on spermatogenesis [125–127]. Specific lifestyle measures, such as, minimizing testicular hyperthermia can improve sperm quality [128]. 3.3. Antioxidants Oxidative stress leads to an increased oxidation of biomolecules (e.g. proteins, lipid membranes) and is one of the proposed mechanisms responsible for the functional deterioration of cells and tissues related to aging in mammals. Indeed, lipid peroxidation, protein oxidation and oxidation of nuclear DNA have been associated with aging [129]. In addition, factors that reduce oxidative stress and enhance antioxidant capacity were shown to be associated with longer lifespan in animals [130]. Antioxidants protect cells against free radical-induced damage. Antioxidants may be enzymatic (e.g. superoxide dismutase, catalase and glutathione peroxidase) and small, non-enzymatic molecules (e.g. vitamin E, vitamin C, carotenoids, and ubiquinone). In the elderly, the lack of natural antioxidant defense mechanisms (due to prevalent vitamin and mineral deficiency) can compound the oxidative stress associated with aging [131]. This is particularly true in frail and institutionalized individuals, and, is often accompanied by cognitive impairment, poor wound healing, anemia, and increased propensity for developing infections [132]. Oxidative stress (OS) represents one of the main factors in the pathogenesis of sperm dysfunction and sperm DNA damage [133–135]. Although low levels of semen oxidants or reactive oxygen species (ROS) are required for sperm physiology (sperm hyperactivation, capacitation) and sperm fertilizing capacity, the uncontrolled release of ROS (by immature germ cells and leukocytes) causes lipid peroxidation, loss of motility and sperm DNA damage [136–138]. Spermatozoa are particularly susceptible to oxidative injury due to the abundance of polyunsaturated fatty acids on the plasma membrane. Seminal plasma is a rich source of antioxidants and this is believed to protect spermatozoa from oxidative stress [135]. The rationale for antioxidant therapy for infertile men with sperm abnormalities (e.g. poor motility, DNA damage) comes from the observed inherent susceptibility of human spermatozoa to oxidative injury and the fact that over 25% of infertile men have high levels of semen ROS (fertile men do not have high levels of semen oxidants) [135]. Furthermore, some studies suggest that infertile men have a poor seminal oxidant scavenging capacity. In view of the expected increase in oxidative stress with aging, we suspect that older men are more likely to experience ROS-induced sperm dysfunction [139–141].

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Treatment of oxidative stress should first involve strategies to reduce or eliminate stress-provoking conditions including smoking, varicocele, genital infection, gonadotoxins and hyperthermia. The rationale for treating infertile men with oral antoxidants is based on the premise that seminal oxidative stress (common in infertile men) is due in part to a deficiency in seminal antioxidants. The practice of prescribing oral antioxidant is supported by the lack of serious side effects related to antioxidant therapy [142]. Ideally, an oral antioxidant should reach high concentrations in the reproductive tract and replete a deficiency of vital elements important for spermatogenesis. Additionally, the antioxidant supplement should augment the scavenging capacity of seminal plasma and reduce the levels of semen ROS [143]. However, the levels of semen ROS should not be entirely suppressed (by oral antioxidants) as this may impair normal sperm functions (e.g. sperm capacitation and hyperactivation) that normally require low levels of ROS [137,138,144]. Studies have shown that men will generally experience a significant improvement in semen parameters after oral intake of antioxidants and a recent paper suggests that vitamin supplements may be particularly beneficial in older men [145]. Although there are no randomized-controlled trials (RCTs) specifically aimed at the aging male population, a number of RCTs have demonstrated a beneficial effect of oral vitamins and antioxidants (used as single agents or in combination) in men with infertility. These studies have demonstrated a beneficial effect on sperm parameters and, in some cases, pregnancy outcomes following intake of vitamins C and E, selenium, zinc, folic acid, N-acetyl cysteine, l-carnitine and coenzymeQ10 [146–161]. However, it is hard to arrive at a clear consensus regarding the role of antioxidant supplements due to the heterogeneity of the study designs, the short duration of treatment (3 to 6 months only) and the variable treatment regimens (combination and dosage of antioxidants) [162]. 3.4. Overcoming paternal age effect with new advances in ARTs – IMSI We have known for some time that the sperm activates its genome at the time of embryo genomic activation and this crucial step determines the development of the embryo until the blastocyst stage and beyond [163]. More recently, we have learned that alterations in sperm DNA (fragmentation or dispersion) can impact on embryo development or lead to epigenetic abnormalities in the offspring [47,48]. However, in the early days of advanced ARTs (e.g. ICSI), biologists paid little attention to semen quality because the data suggested that ICSI outcomes were largely independent of semen parameters [164]. Indeed, the only requirement for a successful ICSI is the presence of a few motile and morphologically normal sperm [165]. These observations have led several clinicians to perform a better sperm selection prior to ICSI (e.g. using high power magnification) so as to improve outcomes. With conventional ICSI, a 400× magnification is used to choose the so-called “best” spermatozoon. Recently, a high magnification sperm selection method (Motile Sperm Organelle Morphology Examination or MSOME, using 1000–6000× magnification) has permitted embryologists to eliminate the poor morphology spermatozoa based on specific head and base criteria [166–168]. Several sperm anomalies have been identified and classified by MSOME (e.g. nuclear vacuoles, head and base shape) and these specific anomalies have been shown to impact on embryonic development [168]. Using the MSOME rating scale with scores ranging from 0 (deformations of the head and the head-base) to 6 (normal sperm) it has been shown that an oocyte microinjected with a “0” score spermatozoon does not reach the blastocyst stage [168]. Moreover, work done by the same group of investigators showed a relationship between low scores and decondensation of the sperm

nuclear chromatin. Recently, Cassuto et al., evaluated a cohort of 1070 children born after ICSI and IMSI (intracytoplasmic injection of morphologically selected spermatozoa), and observed that the risk of major malformations was lower after IMSI (where exclusion of spermatozoa with a poor MSOME score was performed) suggesting that high magnification morphological sperm selection may be beneficial [169]. However, the data on IMSI remains controversial largely because there are too few well-designed ICSI vs. IMSI studies to support the use of IMSI over ICSI [170,171]. 3.5. Cell free DNA and infertility Cell free DNA (cfDNA) is DNA fragments released from nucleus due to apoptosis or necrotic cells [39]. Circulating free DNA can be isolated from both plasma and serum, but serum contains an approximately 6-times higher DNA concentration. CfDNA has been studied in a wide range of physiological and pathological conditions, including inflammatory disorders, oxidative stress and malignancy. It is present in normal healthy individuals at low concentrations [40]. High concentrations were found in pregnant women plasma and particularly in cases of pre eclampsia and in infertile men [40]. The question was to know where cfDNA comes from, especially in infertile men. The cfDNA is not a specific tissue; however, the elevated levels of cf DNA seem to be the result of an increase of the apoptotic process [41]. 4. Conclusions Advanced paternal age (PA) is associated with alterations in reproductive hormone levels and declining sexual function, sperm production and fertility potential. Advanced PA has also been associated with an increased risk of sperm DNA damage, sperm de novo mutations, pregnancy loss, birth defects and offspring diseases. Although very few fertility treatments have been studied extensively in the management of older infertile men, a number of effective therapies used to optimize male fertility potential can be applied to older men. There is evidence to show that varicocele repair, lifestyle modifications and antioxidant supplements may improve fertility potential in the aging male. Recent studies suggest that advances in ARTs (e.g. IMSI) may also help overcome some of the sperm defects associated with paternal aging. Provenance and peer review Commissioned and externally peer reviewed. Contributors Authors contribute equally to the manuscript preparation. Funding This manuscript was funded by Jules Verne University and Unilabs France. Competing interests The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript. Dr Zini is shareholder in Yad Yeli a neutraceuticals company.

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Contents lists available at ScienceDirect

Maturitas journal homepage: www.elsevier.com/locate/maturitas

Review

Management of infertility in women over 40 Rosalie Cabry a,1 , Philippe Merviel a,1 , Andre Hazout b,2 , Stephanie Belloc b,2 , Alain Dalleac b,2 , Henri Copin a,1 , Moncef Benkhalifa a,∗ a Reproductive Medicine and Medical Cytogenetics Department, Regional University Hospital and School of Medicine, Picardie University Jules Verne, CGO, 124 rue Camille Desmoulins, 80054 Amiens, France b Eylau/Unilabs Laboratory, Reproductive Biology Unit, 55 Rue Saint Didier, 75016 Paris, France

a r t i c l e

i n f o

Article history: Received 2 December 2013 Received in revised form 19 February 2014 Accepted 21 February 2014 Keywords: Female over 40 Fertility potential Assisted reproductive technology

a b s t r a c t Women’s fertility potential is declining with age because of multiples intrinsic and extrinsic factors such as life style, oxidative stress and/or endocrine disruptors and is affecting the ability of these women to conceive naturally. This declining fertility potential and the late age of motherhood is increasing significantly the number of patients consulting infertility specialists. Different strategies of investigation and management are proposed to patients over 40 in order to overcome their infertility and improve the live birth rate in these patients. Intra Uterine Insemination (IUI) in women over 40 is associated with a low rate of ongoing pregnancy and IUI should not therefore be offered always as the first line of treatment. When the predictive factors are positive IVF/ICSI seem to be good alternatives until 43 years of age. Customized ovarian stimulation and flexible laboratory methods such as in vitro maturation (IVM), preimplantation genetic diagnosis (PGD), embryo vitrification and transfer after thawing in subsequent natural or artificial cycles can improve the success rate of ART in patients over 40. Meanwhile, oocyte and embryos donation remain good options for patient over 40 with a bad prognosis and can lead to successful ongoing pregnancies until 45 years of age. Ovarian tissue cryopreservation, oocyte vitrification at the germinal vesicle (GV) stage or metaphase II stage present a breakthrough for fertility preservation but the ideal age for starting fertility preservation is still debated as well as the minimum number of oocytes to be vitrified in order to optimize the chances of pregnancy when needed at an older age. This manuscript reports the results of our own experience from patients older than 40 in the light of the published data and discusses the different therapeutic alternatives which can be proposed to patients over 40 consulting ART centres. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ART for women over 40: facts and clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intra uterine insemination for women over 40 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oocytes and embryo donation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Self fertility preservation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18 18 19 19 20

∗ Corresponding author. Tel.: +33 322533677; fax: +33 322533679. E-mail addresses: [email protected] (R. Cabry), [email protected] (P. Merviel), [email protected] (A. Hazout), [email protected] (S. Belloc), [email protected] (A. Dalleac), [email protected] (H. Copin), [email protected] (M. Benkhalifa). 1 Tel.: +33 322533677; fax: +33 322533679. 2 Tel.: +33 143140879811; fax: +33 142277306. http://dx.doi.org/10.1016/j.maturitas.2014.02.014 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

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6.

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The number of women over 40 years of age seeking infertility treatment has been steadily increasing in the past decades due to postponing childbearing in career women as well as the desire of pregnancy in couples starting a second family [1]. In addition to various treatments to enhance ovulation in these women, the percentage of women over 40 requiring assisted reproductive technology (ART) has increased significantly from 10% to 15% in the 2000s [2] to 20% to 25% in 2009 [3]. This emphasizes the importance of optimizing the medical and clinical management strategies in these patients treated with various forms of ART. Studies have shown that the effectiveness of ART techniques decrease with female age and this is in accordance with the natural fertility performance after 40 years of age. Women over 40 must be informed about the low success rate as well as the high risks related to maternal age in pregnancy. These includes an increased risk of hypertension, preeclampsia, gestational diabetes, placenta praevia, placental abruption, caesarean section, genomic disorders, prematurity, low foetal birth weight and neonatal morbidity [4]. Consequently, various alternatives are being offered to young women in order to preserve their fertility potential, increase their take home baby rate while minimizing the risks and adverse effects of pregnancy when this is achieved after 40 years of age. These include different treatments to preserve fertility such as food supplements and hormonal therapy as well as assisted reproductive technologies combined or not to pre implantation genetic diagnosis where the repeated collection and vitrification of the oocytes earlier in life for use in later years is becoming a real option for those women before resorting to oocyte or embryo donation. The objective of this manuscript is to present our own experience in managing and preserving the fertility of women older than 40 in the light of the published literature and emphasize the different therapeutic alternatives that can be proposed to these women to improve their fertility potential. 2. ART for women over 40: facts and clinical data The negative impact of maternal age on IVF/ICSI success rate is mainly due to the diminished quantity and quality (maturation and competence) of collected oocytes regardless of the stimulation protocol [5]. Published studies report a clinical pregnancy rate of 10–15% in women over 40 undergoing IVF or ICSI [6]. In our centre, from January 2007 to December 2011, a total of 500 IVF/ICSI cycles in women over 40 were attempted leading to 425 oocytes retrievals, an ovarian stimulation failure of 15%. The average number of collected oocytes per retrieval attempt was 8.6 while no oocytes were collected in 1.5% of the cycles. The fertilization rate was 50.2% with an average of 3.4 embryos per cycle obtained on day 3. Of these embryos, 41.9% were of grade A according the classification of Terrioux et al. [6]. From our study, from 425 patients who had oocyte retrieval, 334 proceeded to embryo transfer (78%) with an average of 2.1 embryos per transfer. The biochemical pregnancy was 17.6%, the ongoing pregnancy was 8.9% while the live birth rate was 7.4% (see the detail of our study in Table 1). Our transfer cancellation rate was therefore 22% and the miscarriage rate was 49%.

20 20 20 20 20 21 21

These data from our centre are in line with other published studies. In the study of Tsafir et al., 381 patients older than 40, were started on ART therapy. Of these, 83.4% proceeded to ovum pick up and 62.6% had embryo transfers. The clinical pregnancy rate was 7.3%, the rate of spontaneous abortions was 33% and the live birth rate was 4.7% [7]. Similarly, Bongain et al. studied 194 IVF cycles in a group of patients with a mean age of 40.9 years. They reported a mean number of 4.6 oocytes per retrieval and a 3.6% live birth rate [8]. Several studies have also reported low birth rates from patients over 40. This observation is caused mainly by early miscarriages (33–42%) and embryo aneuploidies [4,5,9]. In a series of patients with a mean age of 45.4 years who underwent IVF/ICSI treatment, Spandorfer et al. [10] observed that 85.3% of patients miscarried after implantation. These data confirm that the fertility potential is declining with age and particularly after 43 years. From standard IVF cycles, Ron-El et al. [11] obtained a clinical pregnancy rate of 14%, 9%, 26% and 0% in women aged 41, 42, 43 and 44, respectively while the delivery rate was 7%, 2%, 13% and 0% in the same respective groups. In another study of 843 cycles in women aged 42 and over, Ciray et al. [12] obtained a clinical pregnancy rate of 7.7% in those aged 42, 5.4% in those aged 43, 1.9% at age 44, while no pregnancy occurred in 54 cycles in patients over 45. In an analysis of live births after 3 cumulative IVF/ICSI cycles with embryo transfers, Klipstein et al. [9] obtained a clinical pregnancy rate of 25, 3% in women aged 40 versus 18.8% at age 41–42, 9.6 at age 43 and 1.6 at age 44. All these studies show clearly that there is a cut-off for ART efficiency after 44. Since age is a major limiting factor for fertility potential, it is important to evaluate the predictive factors of pregnancy in women over 40. The ovarian reserve assessment tests using the antral follicles count, the plasma concentration of anti-Müllarian hormone (AMH), FSH and oestradiol have been proposed as methods to predict the risk of ovarian failure. However, most of the authors correlate ovarian failure to the number of retrieved oocytes, with patients providing more than 5 oocytes considered as having a good prognosis with preserved ovarian activity. On the other hand, patients producing less than 5 oocytes are labelled as poor responders with a diminished ovarian reserve [8]. From 1114 embryo transfers in patients over 40 with a mean age of 41.6 years, Ciray et al. [12] obtained 11% of ongoing pregnancies with 5.9% of live birth from patients who produced a minimum of 5 matures oocytes versus 24.3% of pregnancy and 15% of live birth from patients who produced a minimum of 6 mature oocytes. Our own series showed a significant difference in clinical and ongoing pregnancy rates per transfer between patients who provide more than 5 oocytes compared to those who produce 5 or less (P < 0.001) (Table 1). The age of the woman seems to be a better predictive factor than the level of plasma FSH. From a cohort of patient aged from 40 to 43 years, with an FSH lower than 15 IU and a minimum of 6 antral folicles, Van Disseldorp et al. [13] obtained a clinical pregnancy rate of 8% and a cumulative pregnancy rate of 17% after 3 cycles of treatment. When patients over 40 years of age with plasma FSH levels of > 15 IU were compared to patients older than 41 with FSH levels < 15 IU, Van Rooij et al. [14] reported better implantation and ongoing pregnancy rates in the younger group. This observation

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Table 1 Relation between the number of collected oocytes and clinical outcome from patients over 40’s after a minimum of 2-repeated IVF/ICI failure. Number of collected complex cumulus cells

≤5 Oocytes

6–14

≥15

Average maternal age (year) Average paternal age (year) Infertility duration (year) Day 3 FSH level (UI/l) Number of cycles Rank of attempt Total administrated FSH (UI) Oestradiol the day of hCG (pg/ml) Cancellation rate (%) Completed cycles via OPU Average collected cumulus Average métaphase II Fertilization rate (%) Cleavage rate (%) 50.1 Mean transferred embryos/transfer Clinical pregnancy/transfer (%) Implantation rate/embryo (%) Ongoing pregnancy/transfer (%) Live birth/transfer (%)

41.5 ± 1.1a 42.3 ± 5.7 3.4 ± 1.8d 8 ± 2.7 g 181 2.2 ± 1.3j 5055 ± 1545o 1446 ± 363r 23.2 139 3.4 ± 1.3u 2.5 ± 1.4u 46.4 50.1 1.7 ± 1a 7.9d 5 3.4f 2.2h

41 ± 1c 41.7 ± 5.6 4 ± 3.2f 6.8 ± 2.1i 260 2.5 ± 1.5k 3667 ± 1514q 2101 ± 960t 11.1 231 9.3 ± 2.5w 7 ± 2.9w 51.6 54.4 2.2 ± 1c 21.7e 10.4 11.1g 10.1i

40.7 ± 0.8b 41.2 ± 5.9 5.5 ± 4e 6.5 ± 1.6 h 59 2.6 ± 1.5 2953 ± 1142p 2685 ± 375s 6.7 55 18.8 ± 3.6v 13.7 ± 4.4v 48.9 50.5 2.5 ± 1b 18.7 7.4 10.4 6.2

a-c: < 0.0001; a-b: < 106 ; b-c: < 0.02; d-f: < 0.03; d-e: < 0.001; f-e: < 0.01; g-i: < 104 ; g-h: < 104 ; j-k: < 0.05; o-q: < 109 ; q-p: < 0.001; o-p: < 109 ; r-t: < 109 ; t-s: < 109 ; r-s: < 109 ; u-w et w-v et u-v: < 109 ;a -c : < 0.0001; a -b : < 104 ; d -e : < 0.01; f -g : < 0.05; h -i : < 0.05; j -k : < 109 .

demonstrates that the maternal age remain the main limiting factor regardless of the plasma levels of FSH. If the number of collected oocytes after pick up is a significant factor limiting the chance of success for patient older than 40, the remaining question is: “what would be the most suitable ovarian stimulation protocol to optimize the quantity and the quality of oocyte cumulus complexes retrieved?” The study of Van Rooij et al. [14] comparing the use of long and short GnRH agonist protocols reported that the long stimulation protocol produces more oocytes (5.3 versus 3.3) but there were no significant difference in the number of transferred embryos and in the delivery rate. On the contrary, in women older than 40, Sbracia et al. [15] obtained a higher number of oocytes and embryos with a better clinical pregnancy rate per transfer in 281 cycles treated with the short protocol compared to 283 cycles using the long protocol. GnRH antagonists protocols have also been tried in these patients. However, results show that patients older than 40 with a diminished ovarian reserve and submitted to GnRH antagonist or short GnRh agonist (± micro doses) protocols obtain the same results in term of ongoing pregnancy [16]. In our experience it seems that in patients with an adequate ovarian reserve, GnRH long agonist protocol leads to a better clinical pregnancy rate. There are no clear data showing the superiority of one gonadotropin or one protocol over another. However, a recent meta-analysis [17] showed that the supplementation of various ovarian stimulation protocols with recombinant LH seems to improve the implantation and clinical pregnancy rates in patients over 35 years of age. Mild stimulation associated to low dose of gonadotropins under antagonist is also an interesting alternative for patients with poor ovarian reserve [18]. Compared to classical protocols this alternative may produce more good quality embryos, better implantation and pregnancy rates when the same number of embryos is transferred [19]. Based on this observation, mild stimulation could be a beneficial option to patients over 40. The number of transferred embryos is also a predictor of pregnancy. Tsafir et al. [7] reported a significantly higher clinical pregnancy rate in patients who received 3 embryos per transfer and Klipstein [9] found a significantly higher birth rate when 2 embryos were transferred versus the transfer of a single embryo. The same conclusion was observed when 3 embryos were transferred versus only 2 and 4 versus 3, etc. It was suggested that 5 embryos is the best number of embryos to be transferred to reach an acceptable pregnancy and live birth rate in women over 40 [20]. Revisiting the

literature, only Ciray et al. [12] did not find a statistically difference after the transfer of 3 or more embryos. It also seems logical to observe the relation between the indication of ART and the success rate and whether this is performed for tubal, male or idiopathic indications. In our experience we did not find any significant difference in terms of pregnancy rates according to the indication. 3. Intra uterine insemination for women over 40 Infertile women over 40 years of age with bilateral tubal patency, acceptable ovarian reserve and without major sperm disorders can be offered intrauterine insemination. In a series of 82 IUI cycles in patients aged between 40 and 42 years old, Haebe et al. [21] reported a live birth rate of 9.8% but the analysis of 24 cycles from patients older than 43 years showed a delivery rate of only 4.2%. This study confirms the rational of offering IUI to patients over 40 but not to those over 43 years of age. However, offering IUI to patient over 40 in cases of idiopathic indication is still a debatable point and Frederick et al. [22] reported a low clinical pregnancy rate of 5% and a live birth rate of 1.4% in those patents. Conflicting studies were published by several authors. For example, Corsan et al. [23] studied 4 groups of patients and obtained an ongoing pregnancy rate of 9.6%, 5.2%, 2.4% and 0% in patients aged 40, 41, 42 and over 43 years, respectively. In this cohort Corsan et al. [23] reported a spontaneous miscarriage rate of 34.4%. From a homogeneous group of patients over 40 undergoing IUI, Andersen et al. [24] obtained an ongoing pregnancy rate of 9.7%, while Lamarche et al. [25] reported 10.5% and 5.8% of live births reported a 10.5% and 5.8% of live birth. In 2007, Custers et al. [26] proposed a statistical model to establish a score to assess the chances of pregnancy after IUI. In this model, the main limiting factor was the woman’s age, but other parameters used were the cause and the duration of infertility, the uterine characteristics and the couple’s history. 4. Oocytes and embryo donation In infertile women over 40 years of age and treated with IVF/ICSI, using donated oocytes from young patients can be offered as a good efficient alternative to improve their pregnancy and delivery rates [27]. The Spanish experience [28] shows a clinical pregnancy rate of reported 53.4% per cycle with a delivery rate of 42.6%. The cumulative pregnancy rate after 4 cycles of embryos transfer is

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nearly 94%, showing no effect of the recipient patient’s age on the efficiency of oocyte donation programme. These data should be analyzed carefully because there is always a risk of a negative effect of the endometrial receptivity and the immunological status of aged patients on the implantation rate and ongoing pregnancy loss. These high success rates can be explained by the efficiency of patient preparation protocols prior to embryo transfer, the experience of the specialist managing the donation and the borderline age of recipients. In fact, in a large meta-analysis, Vernaeve et al. [29] found lower chances of pregnancy in recipients over 45 years of age. The advantage of oocyte or embryo donation to patient over 40’s is the absence of the risks associated with ovarian stimulation. However, obstetrical complications such as gestational diabetes, pre-eclampsia and thrombosis should be considered in older patients even with oocyte or embryo donation [30]. Today the remaining question is: “What is the cut off age to minimize the risks of complications in those patients?” and this has not so far been answered with a clear consensus. From the follow up of 22 patients over 50 who became pregnant after oocyte donation, Sauer et al. [27] reported obstetrical complications in 47% of them. In another study, the follow up of 123 pregnancies achieved through oocyte donation in elderly women reported that 63% of patients over 45 needed hospitalization compared to 22% in those aged between 45 and 49 [31]. In practice embryo donation is more commonly used in cases of combined male and female infertility, especially if specific genomes and/or epigenome decays are diagnosed and not corrected after multiple treatments. Both oocyte and embryos donation possibilities are different from country to country and raise ethical and legal issues such as financial compensation of the donors, their anonymity and the waiting time of enrolled patients in the donation programme.

5. Self fertility preservation There is a growing shortage of oocytes and embryos available for donation because of the fertility declining trends in the general population. In addition, couples treated with IVF/ICSI are increasingly being reluctant to donate oocytes and embryos to other couples because of moral and/or ethical reasons. Consequently, self fertility preservation has been developed to preserve oocytes or ovarian tissue of women for use in later years of their lives. With the efficiency of cryobiology technology and mainly of vitrification, early self oocyte banking appears to be a solution for later motherhood and for the decline in fertility related to hormonal disorders or biological ageing. The ideal age of oocyte collection and cryopreservation is still debated as the predictors of ovarian failure are poorly understood. Oocyte collection can be proposed at a young age but no later than 30–35 years during which the ovarian reserve is still satisfactory and when the opportunity of natural pregnancy is still present. The debatable points are: (a) how should we manage patients to minimize the complication risks of ovarian stimulation, (b) how many stimulation cycles can be proposed to patients in relation to age and ovarian reserve, and (c) what is the minimum number of oocytes that can be vitrified and used in subsequent IVF/ICSI cycles to improve the success. According Stoop et al. [32] nearly 22 vitrified metaphase II oocytes are needed to achieve pregnancy in women aged between 23 and 37 years. Knowing that the average number of collected oocytes is 8 per stimulation cycle in this age group, this implies that 2–3 ovarian stimulation and oocyte pick up cycles are needed to achieve a live birth. For patients aged 38–43 years, a minimum of 55 vitrified metaphase II oocytes is needed to achieve a pregnancy [32]. For all ages Cobo et al. [33] recommend that at least 12 metaphase II vitrified oocytes are

needed to achieve clinical pregnancy in an oocyte cryopreservation programme. Ovarian tissue cryopreservation is another alternative. Today, it is mainly offered to cancer patients. Its application for social reasons, later motherhood or to rescue declining fertility is still rare but could be an alternative to classical ovarian stimulation by the cryo preservation of Germinal Vesicles oocytes followed by in vitro maturation and/or Metaphase II oocyte vitrification. The effects of long term vitrification and the maternal age limit for the use of vitrified material is still debated as well as the relation between ovarian ageing and the biological age of the patient. Meanwhile, precautions should be taken concerning endometrium receptivity and immuno-tolerance to achieve pregnancy with a lower risk of complications. 6. Conclusions Many women are currently postponing motherhood to an older age for various reasons. It is possible that some changes concerning the life style, food habits, special care to reduce the effect of oxidative stress and pollution as well as hormonal therapies may minimize the risk of physiological disorders and keep a better fertility potential over 40 years of age. Data from our own IVF/ICSI programme and from other groups are consistent with the metaanalysis of Amstrong et al. [34] showing that the success rate from IUI is below 5% while IVF and ICSI remain ideal options by giving a live birth rate of 10–15%. Patients should be clearly informed that IUI cannot be proposed as a first line option even with good sperm parameters and should also be informed about the risk of spontaneous miscarriage and complications. Ovarian tissue and oocyte preservation are becoming an option for patients with early risk of fertility decline. In case of ovarian reserve failure with good prognostic of implantation, oocyte and embryos donation offer rescue alternatives prior to adoption. Infertile women over 40 need help to achieve pregnancies and live births. This includes financial, legal and ethical support to minimize complication risks during the clinical management and to improve the clinical outcome. Finally, the community should have the wisdom not to abuse ART programmes after a number of IVF/ICSI failures and to orient patient to other options such as oocyte/embryo donation or adoption. Recent studies have also reported the negative effects of toxic agents and endocrine disruptors on follicular development and fertility potential leading to their decline with age between generations [35,36]. Oxydative stress and reactive oxygen species can also affect the oocyte environment and early embryo development potential [37]. Contributors Authors contribute equally to manuscript preparation Competing interests None of the authors have a conflict of interest or competing interests. Provenance and peer review Commissioned and externally peer reviewed. Funding This manuscript is funded by Jules Verne University and Unilabs France.

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Acknowledgements We would like to thank Professor Hassan Sallam. MD. Ph. D from Oby & Gyn Dept. Alexandria University. Egypt, for manuscript reading, comments and improvement. References [1] Craig BM, Donovan KA, Fraenkel L, Watson V, Hawley S5, Quinn GP. A generation of childless women: lessons from the United States. Womens Health Issues 2014;24(1):21–7. [2] Nyboe Andersen A, Gianaroli L, Nygren KG, European IVF-monitoring programme, European Society of Human Reproduction and Embryology. Assisted reproductive technology in Europe, 2000. Results generated from European registers by ESHRE. Hum Reprod 2004;19(March (3)):490–503. [3] Ferraretti AP, Goossens V, Kupka M, et al. Assisted reproductive technology in Europe, 2009: results generated from European registers by ESHRE. Hum Reprod 2013;28(September (9)):2318–31. [4] Suchartwatnachai C, Wongkularb A, Srisombut C, Choktanasiri W, Chinsomboon S, Rojanasakul A. Cost-effectiveness of IVF in women 38 years and older. Int J Gynecol Obstet 2000;69:143–8. [5] Toner J. Age = egg quality, FSH level = egg quantity. Fertil Steril 2003;79: 491. [6] Terriou P, Giorgetti C, Auquier P, et al. Value of an embryo score to predict implantation. Contracept Fertil Sex 1996;24:657–60. [7] Tsafir A, Simon A, Revel A, Reubinoff B, Lewin A, Laufer N. Retrospective analysis of 1217 IVF cycles in women aged 40 years old and older. RBM Online 2007;14:348–55. [8] Bongain A, Castillon JM, Isnard V, Benoit B, Donzeau M, Gillet JY. In vitro fertilization in women over 40 years of age. A study on retrospective data for eight years. Eur J Obstet Gynecol Reprod Biol 1998;76:225–31. [9] Klipstein S, Regan M, Ryley D, Goldman M, Alper M, Reindollar R. One last chance for pregnancy: a review of 2705 in vitro fertilization cycles initiated in women age 40 years and above. Fertil Steril 2005;84:435–45. [10] Spandorfer S, Bendikson K, Dragisic K, Schattman G, Davis O, Rosenwaks Z. Outcome of in vitro fertilization in women 45 years and older who use autologous oocytes. Fertil Steril 2007;87:74–6. [11] Ron-El R, Raziel A, Strassburger D, Schachter M, Kasterstein E, Friedler S. Outcome of assisted reproductive technologie in women over the age of 41. Fertil Steril 2000;74:471–5. [12] Ciray HN, Ulug U, Tosun S, Erden HF, Bahceci M. Outcome of 1114 ICSI and embryo transfer cycles of women 40 years of age and over. Reprod Biomed Online 2006;13:516–22. [13] Van Disseldorp J, Eijkermans MJC, Klinkert ER, Te Velde ER, Fauser BC, Broekmans FJM. Cumulative live birth rates following IVF in 41–43 year old women presenting with favourable ovarian reserve characteristics. RBM Online 2007;14:455–63. [14] Van Rooij I, Bancsi L, Broekmans F, Looman C, Habbema J, Te Velde E. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril 2003;79:482–8. [15] Sbracia M, Farina A, Poverini R, MorGia F, Schimberni M, Aragona C. Short versus long gonadotropin-releasing hormone analogue suppression protocols for superovulation in patients ≥40 years old undergoing intracytoplasmic sperm injection. Fertil Steril 2005;84:644–8.

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[16] Pu D, Wu J, Liu J. Comparisons of GnRH antagonist versus GnRH agonist protocol in poor ovarian responders undergoing IVF. Human Reprod 2011;26:2742–9. [17] Hill M, Levens E, Levy G, et al. The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and met-analysis. Fertil Steril 2012;97:1108–14. [18] Zarek S, Muasher S. Mild/minimal stimulation for in vitro fertilization: an old idea that needs to be revisited. Fertil Steril 2011;95:2449–55. [19] Ubaldi F, Rienzi L, Baroni E, et al. facts about mild ovarian stimulation. RBM Online 2007;14:675–81. [20] Combelles CMH, Orasanu B, Ginsburg ES, Racowsky C. Optimum number of embryos to transfer in women more than 40 years of age undergoing treatment with assisted reproductive technologies. Fertil Steril 2005;84:1637–42. [21] Haebe J, Martin J, Tekepety F, Tummon I, Shepherd K. Success of intrauterine insemination in women aged 40–42 years. Fertil Steril 2002;78:29–33. [22] Frederick JL, Denker MS, Rojas A, et al. Is there a role for ovarian stimulation and intra uterine insemination after age 40. Hum Reprod 1994;9:2284–6. [23] Corsan G, Trias A, Trout S, Kemmann E. Ovulation induction combined with intra uterine insemination in women 40 years of age and older: is it worthwhile. Hum Reprod 1996;11:1109–12. [24] Andersen AN, Gianorelli L, Felberbaum R, et al. Assisted reproductive technolohy in Europe, 2001.Results generated from european registersby ESHRE. Hum Reprod 2005;20:1158–76. [25] Lamarche C, Levy R, Felloni B, et al. Assisted reproductive techniques in women aged 38 years or more. Gynecol Obstet Fertil 2007;35:420–9. [26] Custers IM, Steures P, Van der Steeg JW, et al. External validation of a prediction model for an ongoing pregnancy after intrauterine insemination. Fertil steril 2007;88:425–31. [27] Sauer MV, Paulson RJ, Lobo RA. Pregnancy in women 50 or more years of age: outcomes of 22 consecutively established pregnancies from oocyte donation. Fertil Steril 1995;64:111–5. [28] Remohi J, Yalil S, Gartner B, Simon C, Gallardo E, Pellicer A. Pregnancy and birth rates after oocyte donation. Fertil Steril 1997;67:717–23. [29] Vernaeve V, Reis Soares S, Budak E, Bellver J, Remohi J, Pellicer A. Clinical factors associated with the outcome of oocyte donation. Gynecol Obstet Fertil 2007;35:1015–23. [30] Michalas S, Loutradis D, Drakakis P, et al. Oocyte donation to women over 40 years of age: pregnancy complications. Eur J Obstet Gynecol Reprod Biol 1996;64:175–8. [31] Simchen MJ, Yinon Y, Moran O, Schiff E, Sivan E. Pregnancy outcome after age 50. Obstet Gynecol 2006;108:1084–8. [32] Stoop D, De Munck N, Jansen E, et al. Clinical validation of a closed vitrification system in an oocyte donation program. RBM Online 2012;24:180–5. [33] Cobo A, Diaz C. Clinical application of oocyte vitrification: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2011;96:277–85. [34] Amstrong S, Akande V. What’s the best treatment option for infertile women aged 40 and over. J Assit Reprod Genet 2013;30(5):667–71. [35] Bhattacharya P, Keating A. Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity. Toxicol Appl Pharmacol 2012;261:227–35. [36] Uzumcu M, Zachow R. Developmental exposure to environmental endocrine disruptors: consequences within the ovary and female reproductive function. Reprod Toxicol 2007;23:337–52. [37] Babuˇska V, Cedíková M, Rajdl D, et al. Comparison of selective oxidative stress parameters in the follicular fluid of infertile women and healthy fertile oocyte donors. Ceska Gynekol 2012;77:543–848.

Maturitas 78 (2014) 72

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Letter to the Editor Non-contraceptive benefits of hormonal contraceptive use during perimenopause? Dear Editor, We enthusiastically read Baldwin and Jensen’s review of contraceptive use during perimenopause [1]. In the section dedicated to hormonal contraceptives (HCs), the authors meticulously describe the indications for HC use, the potential risks, and when/how to discontinue use. However, we feel that this review lacks a section dedicated to the potential non-contraceptive benefits of HC use among perimenopausal women. While there is strong evidence showing that HC use is associated with reductions in menstrual bleeding, menstrual cramping, and gynaecological cancers in young women, data among perimenopausal women are lacking. Indeed, the large majority of studies evaluating these benefits have been conducted on women younger than 40, commonly those less than 35. HCs have been successfully used to treat menstrual disorders in women of all ages. Some guidelines have even suggested that the use of HCs in healthy women over 40 without menstrual disorders may reduce gynaecological cancers, bone mass loss, and cardiovascular disease (CD). Although there is little controversy regarding the use of HCs among perimenopausal women due to the above-mentioned benefits, we also know that some gynaecological cancers increase with age and menstrual irregularity and that these conditions are reduced with HC use. Perimenopause is a period of increased bone remodelling, and we know that HCs can maintain bone mass density. However, the effect of HCs on CD requires further study, as strategies once thought to reduce disease risk were shown to increase this risk if the hormone type, dose, or timing were not appropriate; specifically, this was the lesson learned from hormone therapy (HT).[2] Recently, the importance of ovarian function cessation in depression and CD risk was assessed, and a bi-directional relationship between these two conditions seems to exist, with both of these conditions also associated with the possibility of menstrual cycle alteration. Various neuroendocrine mechanisms are involved in this process, although the link that unites these conditions is the ovarian dysfunction. From this perspective, women in the menopausal transition period experience greater mood changes,

http://dx.doi.org/10.1016/j.maturitas.2014.02.003 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

even more than during the subsequent period, which is when the CD risk increases [3]. Similar to what was proposed for hormone treatment, where a “window of opportunity” exists in which the benefits of HT (fundamentally cardiovascular) outweigh the risks, a “window of vulnerability” for CD and depression during perimenopause could exist [4]. Could HC mitigate these risks and be considered a protective factor during this window of vulnerability? Indeed, current studies have recently begun to publish positive results in postmenopausal women (ELITE, KEEPS, etc.). However, further studies are required to investigate these – and other possible beneficial effects – of HCs in perimenopausal women. References [1] Baldwin MK, Jensen JT. Contraception during the perimenopause. Maturitas 2013;76:235–42. [2] de Villiers TJ, Gass ML, Haines CJ, et al. Global consensus statement on menopausal hormone therapy. Maturitas 2013;74:391–2. [3] Bleil ME, Bromberger JT, Latham MD, et al. Disruptions in ovarian function are related to depression and cardiometabolic risk during premenopause. Menopause 2013;20:631–9. [4] Mendoza N, Sanchez-Borrego R, Cancelo MJ, et al. Position of the Spanish Menopause Society regarding the management of perimenopause. Maturitas 2013;74:283–90.

Nicolás Mendoza ∗ Department of Obstetrics and Gynecology, University of Granada, Granada, Spain Rafael Sánchez-Borrego Clínica Diatros, Barcelona, Spain ∗ Corresponding

author at: Maestro Montero, 21, 18004 Granada, Spain. Tel.: +34 958120206; fax: +34 958120206. E-mail addresses: [email protected] (N. Mendoza), [email protected] (R. Sánchez-Borrego) 7 February 2014

Maturitas 78 (2014) 70

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Letter to the Editor Pelvic floor dysfunction: does hormone deficiency matter? Dear Editors, We have read the paper of Trutnovsky et al. [1] with great interest. The issue of female pelvic floor muscle dysfunction (FPFMD) is a rather complex one, hence studies addressing distinct aspects of it are surely welcome by readers from healthcare profession, especially if they are large scale and so well documented as this one. It has been commonly assumed, that ovarian hormone deficiency – at least on a longer run – might be accountable as a contributing factor for development of this condition. In this respect we regret that FPFMD and female pelvic organ prolapse (FPOP) are often used interchangeably by many authors. On the contrary, we propose that wherever possible anatomical (e.g. trauma at delivery) and functional (e.g. hormonal) anomalies must be handled separately when factors leading to either FPFMD or FPOP are under scrutiny. Concerning pelvic floor muscle (PFM) contractility according to Frawley [2] “higher correlations for the Modified Oxford Scale (MOS) and manometry have been reported [3] than between ultrasound and the MOS [4], suggesting that no single measurement tool tests all aspects of PFM contractility”. Interestingly, Trutnovsky et al. report a convincingly good correlation of both, “menopausal” and “calendaric” ages with the Oxford grading in Table 3; r:−0.23, p: <0.0001 and r:−0.28, p: <0.0001, respectively. At first glance it seems to support the notion, that the length of time spent in a hormone deficient state might have an effect on PFM function. In Table 4, with standardized coefficients (ˇ), however, no correlation is presented with the very same variables. Whether this contradiction reflects the controversial statistical practice of variable standardization method as detailed in a report by Bring [5] or is it attributable to some other circumstances we cannot decide. Nevertheless, it sheds some doubt on one of the main conclusions of the paper, i.e. “Hormone deficiency does not seem to have a major independent effect on (. . .) pelvic floor muscle.” This doubt is further strengthened by the fact, that exact information on neither the type nor the duration of either present or previous HRT was available from those patients who reported HRT use in this paper. Saying so we have to admit, that in a smaller interventional study using combined oral plus local estrogen for 3 months prior

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to and following colporrhaphic surgery we were also unable to demonstrate positive effects on PFM contractile function as assessed by FemiScan surface EMG, but an improvement of the muscles’ ability to relax was detected. (Hock et al. unpublished) It remains to be seen whether larger scale studies with longer lasting hormonal interventions using more methods including MOS, EMG ultrasound and others addressing FPFMD could resolve the issue of benefits (if any) of HRT in the future. Conflict of interest The authors declare no conflict of interest. References [1] Trutnovsky G, Guzman-Rojas R, Martin A, Dietz HP. Pelvic floor dysfunction: does hormone deficiency matter? Maturitas 2014;78:70. [2] Frawley H. Pelvic floor muscle strength testing. (Clinimetrics). Australian Journal of Physiotherapy 2006;52:307. [3] Isherwood PJ, Rane A. Comparative assessment of pelvic floor strength using a perineometer and digital examination. British Journal of Obstetrics and Gynaecology 2000;107:1007–11. [4] Thompson JA, O’Sullivan PB, Briffa NK, Neumann P. Assessment of voluntary pelvic floor muscle contraction in continent and incontinent women using transperineal ultrasound, manual muscle testing and vaginal squeeze pressure measurements. International Urogynecology Journal and Pelvic Floor Dysfunction 2006;17:624–30. [5] Bring J. How to standardize regression coefficients. The American Statistician 1994;48:209–13.

Márta Hock ∗ József Bódis János Garai Institute of Physiotherapy and Human Nutritional Science, Faculty of Health Sciences, University of Pécs, H-7623 Pécs, Rét St. 4, Hungary ∗ Tel.:

+36 72 535 992; fax: +36 72 535 984. E-mail addresses: [email protected], [email protected] (M. Hock) 3 February 2014

Maturitas 78 (2014) 51–55

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Somatosensory amplification and menopausal symptoms in breast cancer survivors and midlife women Janet S. Carpenter a,∗ , Christele M. Igega a , Julie L. Otte a , Debra S. Burns b , Menggang Yu c , Jingwei Wu a a

School of Nursing, Indiana University, Indianapolis, IN 46202, United States School of Engineering and Technology, Indiana University-Purdue University, Indianapolis, IN 46202, United States c Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, United States b

a r t i c l e

i n f o

Article history: Received 18 December 2013 Received in revised form 6 February 2014 Accepted 11 February 2014 Keywords: Menopause Menopausal symptoms Somatosensory amplification Women’s health

a b s t r a c t Objectives: Somatosensory amplification is the experience of sensing everyday bodily sensations as intense, agitating, and unpleasant. Using data from menopausal breast cancer survivors and midlife women without cancer, the study purposes were to (1) explore the psychometric properties of the Somatosensory Amplification Scale and (2) to describe somatosensory amplification and its relationship to menopausal symptoms of hot flashes, mood and sleep disturbance. Study design: This was a cross-sectional, descriptive, correlational study using demographic, e-diary, and questionnaire data from 99 breast cancer survivors and 138 midlife women. Main outcome measures: Somatosensory amplification, hot flashes (frequency, severity, bother, interference, perceived control), mood, and sleep. Results: Cronbach’s alphas for the scale were low. When an 8-item version of the scale was evaluated, alphas improved and item-total correlations remained strong or improved. Midlife women and breast cancer survivors did not have significantly different somatosensory amplification total or item scores after adjusting for group differences in demographics. Somatosensory amplification was significantly correlated with hot flash interference, perceived control over hot flashes, and mood and sleep disturbance in both groups but the patterns of correlations differed slightly between groups and depending on whether the 10-item or 8-item scale was used. Conclusion: Somatosensory amplification may be a relevant concept to assess in relation to the menopausal symptom experience of midlife women with and without breast cancer as it may represent a potential intervention target to improve the menopausal symptom experience. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Somatosensory amplification refers to the ability to perceive every day or normal bodily sensations at a more intense, agitating, and unpleasant level [1]. Somatosensory amplification is sometimes referred to as “amplification”. Greater understanding of somatosensory amplification and menopausal symptoms could provide a better understanding of women’s symptom experiences. Other studies have linked somatosensory amplification to symptoms in individuals with upper respiratory infections and migraines [2], as well as overall health worries [3]. Because breast cancer survivors are known to be more symptomatic at menopause

∗ Corresponding author at: Indiana University, School of Nursing, 1111 Middle Drive NU E409, Indianapolis, IN 46202, United States. Tel.: +1 317 278 6093. E-mail addresses: [email protected], [email protected] (J.S. Carpenter). http://dx.doi.org/10.1016/j.maturitas.2014.02.006 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

than midlife menopausal women [4], understanding differences in somatosensory amplification between these two groups could lead to a new avenue for intervention research. To the best of our knowledge, there is no published research exploring somatosensory amplification in relation to menopausal symptoms. Using the PubMed search engine, a literature search was conducted to identify articles on somatosensory amplification and menopausal symptoms. The goal was to find English language, human subjects, original research studies. Search phrases were (1) (somatosensory amplification) and (menopause or hot flashes or sleep) and (2) (somatosensory amplification) and (menopause and mood). The first search phrase produced 2 results, neither of which was relevant. The second search phrase produced no articles. These search results indicated that somatosensory amplification had not been previously studied in menopausal women, suggesting the need to explore the psychometric properties of the Somatosensory Amplification Scale (SSAS) in this population

52

J.S. Carpenter et al. / Maturitas 78 (2014) 51–55

and explore relationships between this concept and menopausal symptoms. Therefore, using data from menopausal breast cancer survivors and midlife women without cancer, the study purposes were to (a) explore the psychometric properties of the Somatosensory Amplification Scale and (b) to describe somatosensory amplification and its relationship to menopausal symptoms of hot flashes, mood and sleep disturbance. We explored Cronbach’s alpha and itemtotal correlations as measures of internal consistency reliability, group differences in somatosensory amplification, and relationships between somatosensory amplification and menopausal symptoms.

2. Methods This was a cross-sectional, descriptive, correlational study. Data used was from information collected at baseline of a larger hot flash intervention study. All study procedures were approved by an Institutional Review Board and the Cancer Center’s Scientific Review Committee. The study population included 99 breast cancer survivors and 138 midlife women without cancer [5]. Participants were recruited from the breast cancer and high risk clinics at a Midwestern National Cancer Institute-designated cancer center and from the community using mass mailings of brochures and flyers, website and newsletter advertisements, and word of mouth. Eligible and interested women provided written informed consent, written approval to use health information, and completed a packet of questionnaires at baseline before being randomized in the intervention study. Data from all women who completed baseline questionnaires are used here for this analysis. Demographics were assessed using a questionnaire. Questions were both personal characteristics (e.g., age, race, marital status) and medical information (e.g., comorbidities, use of hot flash treatments). The 10-item Somatosensory Amplification Scale includes a 5-item Likert-type response scale for participants to indicate the degree they are bothered by different somatic and visceral sensations [6]. A higher total score suggests greater symptom amplification with the scores ranging between 10 and 50. An electronic hot flash diary was used to collect real-time, prospective ratings of hot flash frequency, severity and bother. Women carried a small monitor in a waist pack and pressed buttons on the monitor each time they had a hot flash. Severity and bother of each hot flash was rated by pressing the buttons and using a 0 (not at all) to 10 (extremely) scale. Women wore the monitor for a minimum of 24-h and a maximum of 7-days based on their personal preference. Twenty-four hour average hot flash frequency, severity, and bother were calculated. The 10-item hot flash related daily interference scale [7] was used to assess hot flash interference or disruption. Participants rated each of the items using a 0–10 numeric rating scale. Scores range from 0 to 100 with higher scores indicating greater interference. The Perceived Control over Hot Flashes Index (PCI) is a 15-item questionnaire (e.g., If I do all the right things, I can successfully manage hot flush symptoms) that uses a 4-point Likert scale (ranging from ‘strongly disagree’ to ‘strongly agree’) [8]. Higher total scores convey more perceived control over hot flashes. The 37-item Profile of Mood States (POMS) questionnaire is a psychological self-report assessment using a 5-point Likert scale that measures affective mood states [9]. It yields a total mood disturbance score as well as 6 sub-scores with higher scores signifying greater mood disturbance on all except vigor/activity. The subscales are tension/anxiety, anger/hostility, fatigue/inertia, depression/dejection, vigor/activity and confusion/bewilderment.

The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire that evaluates sleep quality and patterns over the past month [10]. Nineteen items generate seven subscale scores: sleep quality, sleep latency, sleep duration, sleep disturbance, sleep medication, daytime sleep and sleep efficiency. These seven scores are used to distinguish good sleep from poor sleep and the total of these subscales produces one global score. A global sum of 5 or greater signifies a poor sleeper. Descriptive statistics (means, standard deviations, frequencies, percentages) were used to describe demographic characteristics in each group. Cronbach’s alpha coefficients item-total Pearson correlations for the SSAS were calculated in each group. Cronbach’s alpha is a measure of internal consistency reliability, or a measure of how similar the scale items are to one another. Alpha ranges from 0 to 1.00 with >70 generally seen as an acceptable cutoff for a new scale and >80 acceptable for an existing scale. Between group comparisons on demographics and baseline measures were done using t-tests and chi-squared analyses. Pearson correlations were used to evaluate relationships between item and total scores in both groups. An analysis of covariance was done to compare somatosensory amplification between groups controlling for baseline demographic differences. Spearman correlations were used to evaluate relationships between total scores and menopausal symptom variables because of the skewed distribution of the latter. Because this was a correlative study from a larger clinical trial [5] and because no formal hypotheses were stipulated for this descriptive analysis, no corresponding sample size justification was made related to these outcomes in the original clinical trial protocol. Given the descriptive/exploratory nature of our analyses, our moderately large sample size seemed appropriate to address our purpose. 3. Results 3.1. Sample characteristics As shown in Table 1, there were no group differences in ethnicity, employment status, menopausal status, age, body mass index, or years of education. However, compared to midlife women, breast cancer survivors were more likely to be White, married, have less difficulty paying for basics, less likely to be smokers, more likely to be using a hot flash treatment, more likely to be taking Tamoxifen/aromatase inhibitor (both of which cause hot flashes) and using more medications in general. Breast cancer survivors were a mean of 7.57 years post diagnosis (SD = 7.61). There were no differences between groups in hot flash frequency, severity, bother, interference, perceived control over hot flashes or sleep (p > 0.05). Total mood disturbance was significantly higher in the midlife women than in the breast cancer survivors (p < 0.05). 3.2. SSAS psychometrics When using the full 10-item scale, Cronbach’s alpha coefficient was sub-optimal in both groups (0.66 breast cancer group, 0.68 midlife women group) and item-total correlations ranged from 0.270 to 0.610 in the breast cancer group and 0.365 to 0.615 in the midlife women (Table 2). Based on these results, we removed the items most poorly correlated with total scores in both groups: item #1 “I can’t stand smoke, smog, or pollutants in the air” and item #3 “When I bruise myself, it stays noticeable for a long time”. Removal of these two items resulted in slightly improved alphas (0.70 both groups). For the 8-item scale, most item-total correlations improved ranging from 0.441 to 0.660 in the breast cancer group and 0.447 to 0.644 in the menopausal women (Table 2). For

J.S. Carpenter et al. / Maturitas 78 (2014) 51–55 Table 1 Group differences in demographics and menopausal symptoms. BCS % (n)

MW % (n)

Ethnicity Latina Non-latina

1 (1) 99 (98)

2 (3) 98 (135)

Race White/Caucasian Other

86 (85) 14 (14)

57 (78) 43 (60)

Marital Married/living with partner Single, widowed Other

75 (74) 20 (20) 5 (5)

53 (73) 4 (5) 43 (60)

Employment Full time Part time Not employed

63 (62) 13 (13) 24 (24)

65 (90) 14 (19) 21 (29)

Difficulty paying for basics None Some A lot

82 (81) 15 (15) 3 (3)

66 (91) 27 (37) 7 (10)

Smoker Never Former or current

72 (71) 28 (28)

59 (81) 41 (57)

Menopausal status Early peri/late peri Early post Late post

1 (1) 9 (9) 90 (85)

5 (6) 16 (21) 79 (102)

Current use of hot flash treatments No Yes

p

SSAS item

<0.001

<0.001

0.841

0.024

0.393

0.088

0.031 55 (76) 45 (62)

Use of SERM No, not currently Yes, currently

64 (63) 36 (36)

99 (136) 1 (2)

Use of AI No, not currently Yes, currently

75 (74) 25 (25)

100 (138) 0 (0)

Age Body mass index Years of education Concurrent medications Comorbid conditions Years since last menses Electronic hot flash diary days 24-h hot flash frequency 24-h hot flash severity 24-h hot flash bother Total hot flash related daily interference Perceived control over hot flashes POMS total mood disturbance PSQI global sleep

Table 2 SSAS item-total correlations by group.

0.642

41 (40) 59 (58)

53

<0.001

1. I can’t stand smoke, smog, or pollutants in the air 2. I am often aware of various things happening within my body 3. When I bruise myself, it stays noticeable for a long time 4. I sometimes can feel the blood flowing in my body 5. Sudden loud noises really bother me 6. I can sometimes hear my pulse or my heartbeat throbbing in my ear 7. I hate to be too hot or too cold 8. I am quick to sense the hunger contractions in my stomach 9. Even something minor, like an insect bite or a splinter really bothers me 10. I can’t stand pain

10-item SSAS total

8-item SSAS total

BCS

MW

BCS

MW

0.452***

0.434***

NA

NA

0.565***

0.500***

0.520***

0.462***

0.270**

0.365***

NA

NA

0.596***

0.417***

0.591***

0.447***

0.425***

0.615***

0.441***

0.581***

0.598***

0.518***

0.660***

0.558***

0.610***

0.571***

0.601***

0.599***

0.494***

0.559***

0.563***

0.628***

0.519***

0.602***

0.593***

0.644***

0.514***

0.559***

0.601***

0.605***

Breast cancer survivors (BCS) n = 99; midlife women (MW) n = 138. ** p < 0.01. *** p < 0.001. NA – item not included in the 8-item total score.

<0.001

(M, SD) p (M, SD) 53.10 (8.10) 52.36 (5.17) 0.388 28.80 (6.02) 30.17 (8.01) 0.136 15.22 (2.48) 14.78 (2.13) 0.146 2.74 (2.00) 1.96 (1.93) 0.003 2.11 (1.05) 1.46 (1.35) <0.001 7.57 (7.61) 6.32 (7.00) 0.211 3.82 (3.30) 4.00 (2.65) 0.600 6.94 (4.30) 6.34 (4.39) 0.303 2.07 (1.59) 2.08 (1.65) 0.940 1.83 (1.49) 1.88 (1.63) 0.818 39.98 (24.61) 45.49 (24.08) 0.091 37.59 (5.05)

37.61 (4.72)

0.9741

39.04 (22.48) 7.84 (3.19)

45.62 (24.86) 8.07 (3.68)

0.0418 0.620

SERM, selective estrogen receptor modulator; AI, aromatase inhibitor.

consistency with other studies and accounting for the psychometric instability, we present findings for both the full 10-item original SSAS and the modified 8-item SSAS.

3.3. Group differences in somatosensory amplification Group differences in SSAS total scores and SSAS items are shown in Table 3. Although there was a tendency for total and items scores to be higher in midlife women, group differences were not statistically significant after adjusting for covariates. Findings held for

Table 3 Differences in SSAS total scores and SSAS items between groups. MW M (SD)

pa

26.55 (5.75) 20.20 (5.09)

28.41 (6.13) 22.01 (5.29)

0.3666 0.5056

3.72 (1.33)

6.62 (1.38)

0.5927

3.64 (1.05)

3.87 (0.97)

0.4005

2.63 (1.30)

2.78 (1.27)

0.0499

1.58 (0.96)

1.74 (1.12)

0.6795

2.24 (1.18)

2.49 (1.20)

0.0572

2.26 (1.28)

2.22 (1.35)

0.8373

3.84 (1.12) 2.86 (1.23)

4.06 (0.99) 3.15 (1.24)

0.8178 0.6037

1.69 (0.97)

1.95 (1.16)

0.8471

2.10 (1.11)

2.54 (1.28)

0.9044

BCS M (SD) 10-item total score 8-item total scoreb 1. I can’t stand smoke, smog, or pollutants in the air 2. I am often aware of various things happening within my body 3. When I bruise myself, it stays noticeable for a long time 4. I sometimes can feel the blood flowing in my body 5. Sudden loud noises really bother me 6. I can sometimes hear my pulse or my heartbeat throbbing in my ear 7. I hate to be too hot or too cold 8. I am quick to sense the hunger contractions in my stomach 9. Even something minor, like an insect bite or a splinter really bothers me 10. I can’t stand pain

Breast cancer survivors (BCS) n = 98; midlife women (MW) n = 138. a p value of differences controlling for demographic differences in race, marital status, ability to pay for basics, smoking, current use of hot flash treatment (yes, no), current use of SERM/AI (yes, no), and number of concurrent medications. b 8-item total omits items #1 and #3.

54 Table 4 Spearman correlations menopausal symptoms.

J.S. Carpenter et al. / Maturitas 78 (2014) 51–55

between

HF frequency HF severity HF bother HF interference HF perceived control Total mood disturbance Tension/anxiety Anger/hostility Fatigue/inertia Depression/dejection Vigor/activity Confusion/bewilderment Global sleep disturbance Sleep quality Sleep latency Sleep duration Sleep disturbance Sleep medication Daytime sleep Sleep efficiency

somatosensory

amplification

(SSAS)

and

10-item SSAS

8-item SSAS

BCS

MW

BCS

MW

0.03 0.07 0.09 0.39*** −0.24* 0.36*** 0.36*** 0.15 0.37*** 0.28** −0.19 0.33*** 0.26** 0.24* 0.03 0.21* 0.24* 0.02 0.40*** 0.01

−0.01 0.03 0.11 0.30*** −0.19* 0.25** 0.26** 0.24** 0.18* 0.21* −0.15 0.23** 0.14 0.17* 0.06 −0.04 0.20* 0.15 0.33*** 0.01

−0.05 0.08 0.10 0.34*** −0.19 0.38*** 0.37** 0.17 0.39*** 0.30** −0.23* 0.36*** 0.27** 0.26* 0.03 0.25* 0.23* 0.01 0.41*** 0.02

−0.02 0.03 0.10 0.30*** −0.17* 0.29*** 0.31*** 0.29*** 0.18* 0.24** −0.13 0.27** 0.14 0.14 0.09 −0.05 0.22** 0.16 0.34*** 0.01

Breast cancer survivors (BCS) n = 99; midlife women (MW) n = 138. * p < 0.05. ** p < 0.01. *** p < 0.001.

both the 10-item and 8-item versions of the scale. Thus, both groups appeared to have the same level of somatosensory amplification. 3.4. Correlations between somatosensory amplification and menopausal symptoms The 10-item SSAS total scores were significantly related to hot flash interference and perceived control (Table 4). In both groups, greater somatosensory amplification was associated with greater hot flash interference and less perceived control over hot flashes. Somatosensory amplification was also related to mood in both groups, though the pattern of correlations differed slightly (Table 4). In breast cancer survivors and midlife women, higher somatosensory amplification was related to increased tension/anxiety, fatigue/inertia/depression/dejection, and confusion/bewilderment. However, higher somatosensory amplification was related to greater anger/hostility only among the menopausal women. In addition, greater somatosensory amplification was related to poorer sleep (Table 4). In both breast cancer survivors and menopausal women, low sleep quality, higher sleep disturbances and increased daytime sleepiness were significantly related to a higher somatosensory awareness. In breast cancer survivors only, greater amplification was significantly related to longer sleep duration. Results for the 8-item SSAS total scores followed a similar pattern with only a few exceptions. In the breast cancer group, the 8-item SSAS showed no relationship to perceived hot flash control and a negative relationship with vigor/activity. 4. Conclusions The findings in this study offer a new understanding concerning the concept of somatosensory amplification and the role it plays in the hot flash, mood and sleep experience of healthy menopausal women and menopausal women with a history of breast cancer. No difference was found in the SSAS total and individual item total between the two groups. This indicates that somatosensory amplification affects menopausal women at a similarly steady level regardless of exposure to breast cancer diagnosis and treatment. The effect of somatosensory amplification on hot flash experience

appears to be one that can be generalized across women. Both groups reported comparable levels of hot flash severity, frequency, and bother as well as mood and sleep disturbance in contrast to prior studies showing a more severe symptom experience in cancer survivors. [4,11] This similarity may have (a) been due to the fact that all were seeking treatment in this intervention study and (b) contributed to the lack of group differences in somatosensory amplification. Somatosensory amplification was related to hot flash interference and perceived control but not with other hot flash variables. It is important to note that the hot flash variables that had no correlation with somatosensory amplification were variables that were measured in real-time using the electronic diary while the other variables were assessed over the past week or two weeks using standardized questionnaires. This may indicate the necessity to look further into women’s personal interpretation of their hot flash experience and to seek out methods may positively alter that interpretation. This finding also seems to point to the need for interventions that focus more on the perception of hot flashes instead of on trying to diminish the symptom itself. Higher sleep and mood disturbance scores were both found to be significantly related to a higher somatosensory amplification for breast cancer survivors and midlife women. These outcomes are consistent with the results found in the literature review that link poor sleep with mood disturbance in the overall menopausal experience [12]. An individual who has a heightened somatosensory awareness could possibly perceive poor sleep and mood disturbance as more distressing than the average individual, though this was not directly studied here. Limitations of this study included the following. The Cronbach’s alpha calculated for the SSAS was low (alpha = 0.66). Improved alphas were seen with a shorter version of the scale but they were still considered low for an established scale (alpha = 0.70). It is possible that the SSAS is not a reliable tool to use to measure the tendency to amplify somatic symptoms. Data used in this analysis were cross-sectional and therefore do not provide information about whether or how these relationships might change over time. The sample had a relatively high percentage of Caucasian women. There were more women without cancer available for the analysis than women with breast cancer. The results of this study suggest that future menopausal symptom management interventions for midlife women could focus on altering somatosensory amplification. Assisting women to change how they sense and interpret their menopausal symptoms may help women decrease hot flash interference and mood and sleep disruption and may also help increase a woman’s perceived control over hot flashes. Focusing interventions on decreasing somatosensory awareness may have a successful effect on increasing the perception of sleep quality.

Contributors Janet S. Carpenter contributed to the securing funding for the work, data collection, data management and analysis, paper conceptualization, writing and editing. Christele M. Igega contributed to the paper conceptualization, writing and editing. Julie L. Otte contributed to the paper conceptualization, writing and editing. Debra S. Burns contributed to the securing funding for the work, data collection, data management and analysis, paper conceptualization, writing and editing. Menggang Yu contributed to the securing funding for the work, data management and analysis, paper conceptualization, writing and editing. Jingwei Wu contributed to the securing funding for the work, data collection, data management and analysis, paper conceptualization, writing and editing.

J.S. Carpenter et al. / Maturitas 78 (2014) 51–55

Competing interest The authors declare no conflict of interest. Funding This project was funded by the Indiana University-Purdue University Indianapolis Diversity Scholars Research Program and award number R01CA132927 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Ethical approval and informed consent All study procedures were approved by an Institutional Review Board and the cancer center’s Scientific Review Committee and written informed consent was obtained from participants. References [1] Barsky AJ, Goodson JD, Lane RS, Cleary PD. The amplification of somatic symptoms. Psychosom Med 1988;50:510–9.

55

[2] Yavuz BG, Aydinlar EI, Dikmen PY, Incesu C. Association between somatic amplification, anxiety, depression, stress and migraine. J Headache Pain 2013;14:53. [3] Freyler A, Kohegyi Z, Köteles F, Kökönyei G, Bárdos G. Modern health worries, subjective somatic symptoms, somatosensory amplification, and health anxiety in adolescents. J Health Psychol 2013;18:773–81. [4] Carpenter JS, Johnson D, Wagner L, Andrykowski M. Hot flashes and related outcomes in breast cancer survivors and matched comparison women. Oncol Nurs Forum 2002;29:E16–25. [5] Carpenter JS, Burns DS, Wu J, Otte JL, Schneider B, Ryker K, et al. Paced respiration for vasomotor and other menopausal symptoms: a randomized, controlled trial. J Gen Intern Med 2013;28:193–200. [6] Barsky A, Wyshak G, Klerman G. The somatosensory amplification scale and its relationship to hypochondriasis. J Psychiatr Res 1990;24:323–34. [7] Carpenter J. The hot flash related daily interference scale: a tool for assessing the impact of hot flashes on quality of life following breast cancer. J Pain Symptom Manage 2001;22:979–89. [8] Reynolds FA. Perceived control over menopausal hot flushes: exploring the correlates of a standardised measure. Maturitas 1997;27: 215–21. [9] Regestein QR. Hot flashes, sleep, and mood. Menopause 2010;17:16–8. [10] Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index (PSQI): a new instrument for psychiatric research and practice. Psychiatry Res 1989;28:193–213. [11] Harris PF, Remington PL, Trentham-Dietz A, Allen CI, Newcomb PA. Prevalence and treatment of menopausal symptoms among breast cancer survivors. J Pain Symptom Manage 2002;23:501–9. [12] Nowakowski S, Meliska CJ, Fernando Martinez L, Parry BL. Sleep and menopause. Curr Neurol Neurosci Rep 2009;9:165–72.

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Response to Letter to the Editor The complexity of hormone therapy in urogynaecology Thank you for the possibility to respond to the letter by Hock et al., commenting on our article on pelvic floor dysfunction. In our urogynaecology center based study we explored the effect of menopause and hormone replacement therapy on symptoms and signs of female pelvic organ prolapse (FPOP) and pelvic floor muscle function (PFMF) [1]. We agree that FPOP needs to be regarded separately from female pelvic floor muscle dysfunction, since FPOP may not only be influenced by impaired muscle function, but also by weakening of other supportive genital tract tissue, e.g. sacrouterine ligaments and rectovaginal septum. However, the integrity of the pelvic floor muscle plays a major role in the support of pelvic organs. Therefore we do not agree that it is feasible or useful to differentiate between anatomical and functional abnormalities. A recent study demonstrated the association between vaginal delivery related muscular trauma and reduced contractile function of the pelvic floor. Both macrotrauma, i.e. levator defect (avulsion), and microtrauma, i.e. irreversible overdistension of the levator hiatus, were associated with a reduction of pelvic floor muscle contractility on sonographic parameters and Modified Oxford Scale (MOS) [2]. We agree that no single measurement tool tests all aspects of PFMF – hence we used clinical and sonographic measures to assess not only contractility, but also tissue distensibility and muscle bulk. Out of these parameters only MOS showed a significant correlation with menopausal age (number of menopausal years) on univariate analysis. After adjustment for potential confounders, such as calendaric age, body mass index, vaginal child birth and levator defect, there was no evidence for menopausal age as an independent predictor of MOS. Multiple logistic regression as used in our analysis is a standard statistical method for multivariate analysis and can hardly be classified as controversial. In our study current HRT use had no detectable effect on PFMF. Although we did not assess length of hormone replacement therapy in all patients, we did so in a subgroup of 80 women. The results of this subgroup analysis did not differ from the main analysis and we found no evidence for HRT use as an independent predictor of PFMF. However, we appreciate that this issue is not settled and are currently undertaking a much larger study to further investigate the effect of length of systemic HRT use.

http://dx.doi.org/10.1016/j.maturitas.2014.02.010 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

The role of estrogen in the treatment of pelvic floor dysfunctions is undergoing reassessment. Although hormone therapy has long been considered to be beneficial, there is accumulating evidence that systemic hormone therapy may have no effect or even worsen pelvic floor dysfunction, especially urinary incontinence [3–6]. On the other hand, local estrogen therapy is likely to improve vaginal atrophy and urge symptoms [5]. Further research will need to explore the complex role of hormone therapy in urogynaecology. Competing interests The authors declare no conflicts of interest. References [1] Trutnovsky G, Guzman-Rojas R, Martin A, Dietz HP. Pelvic floor dysfunction – does menopause duration matter? Maturitas 2013;76:134–8. [2] Guzman Rojas R, Wong V, Shek KL, Dietz HP. Impact of levator trauma on pelvic floor muscle function. Int Urogynecol J 2013 [Epub ahead of print], PMID: 24085143. [3] Lawrence JM, Lukacz ES, Nager CW, Hsu JW, Luber KM. Prevalence and cooccurrence of pelvic floor disorders in community-dwelling women. Obstet Gynecol 2008;111:678–85. [4] Trutnovsky G, Rojas RG, Mann KP, Dietz HP. Urinary incontinence: the role of menopause. Menopause 2013 [Epub ahead of print], PMID: 24061048. [5] Cody JD, Jacobs ML, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev 2012;10:CD001405. [6] Ismail SI, Bain C, Hagen S. Oestrogens for treatment or prevention of pelvic organ prolapse in postmenopausal women. Cochrane Database Syst Rev 2010:CD007063.

Gerda Trutnovsky ∗ Medical University of Graz, Obstetrics and Gynecology, Auenbruggerplatz, 8036 Graz, Austria Hans P. Dietz Sydney Medical School Nepean, Obstetrics and Gynaecology, University of Sydney, NSW 2006, Australia ∗ Corresponding

author. Tel.: +43 316 385 81081; fax: +43 316 385 14197. E-mail address: [email protected] (G. Trutnovsky) 12 February 2014

Maturitas 78 (2014) 1–2

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Editorial

The SPIRIT 2013 Statement

Maturitas, alongside many other journals, aims to increase the transparency and trust in clinical research by promoting accurate and complete reporting of the results of clinical trials by recommending the use of reporting guidelines, in particular the CONSORT 2010 Statement for randomised clinical trials [1]. This enables the critical assessment of methodological quality, examination of possible biases and comparison of findings both beneficial and harmful across different studies. However these guidelines only address the transparency and clarity of reporting and not the actual conduct of the study and there is increasing evidence that clinical trials results are not being fully and accurately disclosed and that critical information regarding study methods and outcomes are frequently missing or incomplete [2,3]. One method for improving the transparency and accuracy of reporting is to ensure that the clinical trial protocol, the foundation stone for all clinical research, is complete, accurate and transparent. To this end an international group of stakeholders have developed the SPIRIT 2013 Statement (Standard Protocol Items for Interventional Trials). The SPIRIT Statement is an evidence-based guidance for protocol content that offers a checklist of 33 key items to be described in a clinical trial protocol [4]. It was rigorously developed by the group with the aid of two systematic reviews and a Delphi consensus process, which involved key interested groups who conduct, review, fund and publish clinical trials [5]. A companion SPIRIT Explanation and Elaboration paper presents the rationale for each checklist item, furnishes protocol examples, from actual protocols, and cites the supporting evidence [6]. The goal of the SPIRIT 2013 Statement is to enhance transparency and to foster full description of the planned trial rather than stipulating how the trial should be designed and conducted. The SPIRIT checklist can therefore be used to measure trial quality. Utilising the SPIRIT 2013 checklist when planning a clinical trial should enable trials to be better designed, conducted and reported by informing investigators about critical matters to consider during planning. The checklist contains the following items: Administrative information: title, registration, version number, funder, sponsor and roles and responsibilities of various contributors including relevant committees; Introduction: background, objectives and trial design; Methods – participants, interventions and outcomes: study setting, eligibility criteria, interventions, outcomes, participant timeline, sample size and http://dx.doi.org/10.1016/j.maturitas.2014.02.008 0378-5122/© 2014 Published by Elsevier Ireland Ltd.

recruitment strategies; Methods – assignment of interventions (for controlled trails): sequence generation, allocation concealment mechanism and implementation of the randomisation and blinding (masking), including who is blinded at which time-points; Methods – data collection, management and analysis: data collection methods, data management and statistical methods; Methods – monitoring: data monitoring, harms and auditing; Ethics and dissemination: research ethics approval, protocol amendments, consent or assent, confidentiality, declaration of interests, access to data, ancillary and post-trial care and dissemination policy; Appendices: informed consent material and biological specimens. SPIRIT promotes a higher level of consistency by defining the minimum protocol content and enabling the quality of the clinical research to be compared. Further information is available from www.spirit-statement.org. Maturitas believes that the publishing of study protocols, following the SPIRIT 2013 guidelines, will improve the transparency and accuracy of reporting and the standard of medical research and therefore welcomes submission of study protocols for proposed or ongoing trials that have not completed patient recruitment at the time of submission.

Contributor Susan J Dutton is the sole author.

Competing interest None.

Funding None was sought or received for writing this editorial.

References [1] Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 2010;340:c332. PMID: 20332509.

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Editorial / Maturitas 78 (2014) 1–2

[2] Chan A-W, Hrobjartssom A, Haahr MT, Gotzsche PC, Altman DG. Empirical evidence for selective reporting of outcomes in randomised trials: comparison of protocol to published articles. JAMA 2004;291:2457–65. [3] Mhasker R, Djulbegovich B, Magazin A, Soares HP, Kumar A. Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols. J Clin Epidemiol 2012;65:602–9. [4] Chan A-W, Tetzlaff JM, Altman DG, et al. SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Ann Intern Med 2013;158: 200–7. [5] Tetslaff JM, Moher D, Chan AW. Developing a guideline for clinical trial protocol content: Dlephi consensus survey. Trials 2012;13:176. [6] Chan A-W, Tetzlaff JM, Gøtzsche PC, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346: e7586.

Maturitas Statistical Editor Susan J Dutton ∗ Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, University of Oxford, Botnar Research Centre, Windmill Road, Oxford OX3 7LD, UK ∗ Tel.: +44 1865 223 451. E-mail address: [email protected]

Maturitas 78 (2014) 30–39

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Review

Vitamin D and brain volumetric changes: Systematic review and meta-analysis Cedric Annweiler a,b,∗ , Thierry Annweiler c , Manuel Montero-Odasso d , Robert Bartha b , Olivier Beauchet a,e a Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, UNAM, Angers, France b Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada c Department of Radiology, University Hospital of Saint-Etienne, France d Gait and Brain Lab, Lawson Health Research Institute, Parkwood Hospital, The University of Western Ontario, London, Ontario, Canada e Biomathics, France

a r t i c l e

i n f o

Article history: Received 21 February 2014 Accepted 24 February 2014 Keywords: Brain Neuroimaging Magnetic resonance imaging Meta-analysis Neuroendocrinology Vitamin D

a b s t r a c t Vitamin D has multiple functions in the nervous system. Our objective was to systematically review and quantitatively synthesize evidence on the location and nature of brain morphometric changes linked to vitamin D depletion or repletion. A Medline search was conducted in February 2014, without limit of date and language restriction, using the MeSH terms “Vitamin D” OR “Ergocalciferols” combined with “Brain Mapping” OR “Magnetic Resonance Imaging” OR “Tomography, X-ray Computed” OR “Tomography, Emission-Computed, Single-Photon” OR “Positron-Emission Tomography” OR “Nuclear Medicine” OR “Radionucleide Imaging”. Of the 376 selected studies, nine observational studies – two animal and seven human studies – met the selection criteria. The number of participants ranged from 20 to 333 (40–79% female). Three studies were eligible for fixed-effects meta-analysis of bias-corrected effect size of the difference in lateral ventricle volume between cases with vitamin D depletion and controls. Results showed that vitamin D depletion was associated with lower brain volume, specifically larger lateral ventricles. The pooled effect size was 1.01 [95% CI: 0.62; 1.41], a ‘large’ effect size indicating that the ventricle volume was 1.01 SD higher with vitamin D depletion. Results on brain subvolumes were mixed, and indicated that brain atrophy with vitamin D depletion could be explained not by temporal lobe atrophy but rather by loss of matter at the cranial vertex, possibly in the precuneus cortex. In conclusion, despite increasing evidence arguing for an action of vitamin D in the brain, data is sparse regarding brain morphological changes related to vitamin D depletion. The retrieved association between vitamin D depletion and brain atrophy provides a scientific base for vitamin D replacement trials. © 2014 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Study selection and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Definition of outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Meta-analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31 31 31 31 34 34

∗ Corresponding author at: Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, 49933 Angers Cedex 9, France. Tel.: +33 2 41 35 54 86; fax: +33 2 41 35 48 94. E-mail address: [email protected] (C. Annweiler). http://dx.doi.org/10.1016/j.maturitas.2014.02.013 0378-5122/© 2014 Elsevier Ireland Ltd. All rights reserved.

C. Annweiler et al. / Maturitas 78 (2014) 30–39

3.

4. 5.

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Vitamin D and whole-brain volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Vitamin D and brain subvolumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix 1. Publications meeting the initial inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Publications meeting the final inclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D not outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . No brain imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stroke or leukoaraiosis as outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metabolic changes as outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory injury as outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain calcifications as outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain tumors as outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tracer test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Besides its classical function of bone metabolism regulation, vitamin D has exhibited multiple biological targets mediated by its nuclear hormone receptor, the Vitamin D Receptor (VDR) [1–3]. VDRs are present in neurons and influence a number of physiological processes in the nervous system [2,3]. Consistently, low serum 25-hydroxyvitamin D (25OHD) concentrations have been associated with behavioral disorders in animals [4] and with multiple sclerosis [5], cognitive disorders [6] and degenerative dementia [7] in humans. Longitudinal prospective studies have further shown that hypovitaminosis D precedes the onset of degenerative dementia [8,9]. However, causality cannot be inferred from observational studies [10] since the design prevents determining whether neurodegeneration precipitates hypovitaminosis D or whether hypovitaminosis D has a role in precipitating neurodegenerative lesions. What is more, the results of the few intervention studies were controversial; some found a preventive effect of vitamin D supplementation on cognitive decline [11,12], although others reported inconclusive results [13,14]. Concrete evidence to infer causality would be to visualize an impact of vitamin D depletion or repletion on the size of the brain [15]. Although the links between vitamin D and risk of ischemic strokes [16], brain calcifications [17] and inflammatory brain injury [18] have already been studied extensively, the relationship between vitamin D and brain morphometric changes has not yet received a structured critical evaluation. The purpose of this systematic review and meta-analysis was to systematically review and quantitatively synthesize evidence on the location and nature of brain morphometric changes linked to vitamin D depletion or repletion.

2. Methods 2.1. Literature search A systematic Medline literature search was conducted in February 2014, without limit of date and language restriction, using the Medical Subject Heading (MeSH) terms “Vitamin D” OR “Ergocalciferols” combined with “Brain Mapping” OR “Magnetic Resonance Imaging” OR “Tomography, X-ray Computed” OR “Tomography, Emission-Computed, Single-Photon” OR

31

34 34 35 35 36 37 37 37 37 37 37 37 37 37 38 38 38 38 38 38 38 38

“Positron-Emission Tomography” OR “Nuclear Medicine” OR “Radionuclide Imaging”. An iterative process was used to ensure all relevant articles had been obtained. A further hand search of bibliographic references of extracted papers and existing reviews was also conducted to identify potential studies not captured in the electronic database searches.

2.2. Study selection and analysis One member of the team (CA) screened abstracts from the initial search and obtained articles deemed potentially relevant. Initial screening criteria for the abstracts were: (1) preclinical studies, (2) observation epidemiological studies (case report, case series, cross-sectional, case-control and cohort studies were included), (3) intervention studies, (4) data collection of brain mapping (whether morphological, metabolic or functional) and serum vitamin D concentration as outcomes, and (5) article written in Latin alphabet. If a study met the initial selection criteria or its eligibility could not be determined from the title and abstract, the full text was retrieved. Two reviewers (CA and OB) then independently assessed the full text for inclusion status. Disagreements were resolved by a third reviewer (TA). The full articles were screened using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist which describes items that should be included in reports of cohort studies [19], and the Consolidated Standards of Reporting Trials (CONSORT) statement for clinical trials [20]. Final selection criteria were applied when brain morphometry was examined among animals or humans in relation to serum 25OHD concentration, or alternatively following vitamin D supplementation. The study selection is shown on a flow diagram (Fig. 1). Of the 376 originally identified abstracts, 25 met the initial inclusion criteria (see Appendix 1). Following thorough examination, we excluded 16 of those 25 studies because no data were available for vitamin D (n = 1) or brain imaging (n = 1), or because the brain outcome was not morphological (stroke/leukoaraiosis, n = 3; inflammatory injury, n = 6; metabolic changes, n = 2; tumors, n = 1; calcifications, n = 1; tracer, n = 1). The remaining nine studies were included in this review [23–31]. Important details regarding the methods and results were extracted from selected articles and summarized (Table 1).

Table 1 Summary of included studies.

Preclinical studies Eyles et al. [23]

Animal study

Animal study

Settings/population

12 Sprague-Dawley rats born to vitamin D3-deficient mothers 12 controls

10 Sprague-Dawley rats born to vitamin D3-deficient mothers with depletion until birth 10 Sprague-Dawley rats born to vitamin D3-deficient mothers with depletion until weaning (3 weeks of age) 10 controls

Vitamin D

Brain

Association between vitamin D and brain morphometry?

Methods

Measure

Methods

Measure

Vitamin D depletion until birth

Cases of vitamin D depletion versus controls

Histology within 12 h of birth Measurements from digitized section images (×20) using NIH Image software

Brain weight (g)

Yes, depleted vs controls, P < 0.0001

Hemisphere length (mm) Hemisphere width (mm) Hemisphere length/width Cortical volume (mm3 ) Lateral ventricle volume (mm3 ) Lateral ventricle volume/hemisphere (vol) Third ventricle volume/brain area Hippocampal area/brain cross-sectional area Cortical mantle thickness/brain area Corpus callosum width (mm) Brain weight (g)

Yes, 6 depleted vs controls, P < 0.01 No, depleted vs controls, P ≥ 0.05 Yes, depleted vs controls, P < 0.05 Yes, depleted vs controls, P < 0.0001 Yes, depleted vs controls, P < 0.01

Vitamin D depletion until birth (n = 10) or until weaning (n = 10)

Cases of vitamin D depletion versus controls

Histology within 10 weeks of age Measurements from digitized section images (×20) using NIH Image software

Brain length (mm) Brain width (mm) Brain length/width Lateral ventricle volume (mm3 ) Lateral ventricle volume/hemisphere (vol) Third ventricle volume (mm3 ) Third ventricle volume/brain volume Hippocampal area/brain cross-sectional area Cortical mantle thickness at PFC level (mm) Cortical mantle thickness at AC level (mm) Anterior commissure width (mm) Corpus callosum width (mm)

Yes, depleted vs controls, P < 0.05 No, depleted vs controls, P ≥ 0.05 No, 2 depleted vs controls, P ≥ 0.05 Yes, depleted vs controls, P < 0.01 No depleted vs controls, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05

No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 Yes, weaning vs control, P < 0.05 Yes, weaning vs control, P < 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 No, birth vs control and weaning vs control, P ≥ 0.05 Yes, birth vs control, P < 0.05 No, birth vs control and weaning vs control, P ≥ 0.05

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Féron et al. [24]

Design

32

Reference

Table 1 (Continued) Reference

Design

Settings/population

Vitamin D

Methods Clinical studies Buell et al. [25]

Location: Boston, MA,USA (42.2◦ N) N = 318 Mean age 73.5 ± 8.1 y; 72.6% females Community-dwellers, age ≥ 60 y, receiving home-help services, free of major neurological illness

Weinstock-Guttman et al. [26]

Cross-sectional study

Location: Buffalo, NY, USA (42.5◦ N) N = 193 Mean age 46.1 ± 8.4 y; 79% females With multiple sclerosis, age ≥ 18 y

Annweiler et al. [27]

Cross-sectional study

Location: Angers, France (47.5◦ N) N = 92 Mean age 72.2 ± 6.2 y; 46.7% females Community-dwellers, age ≥ 60 y, without normal pressure hydrocephalus, with memory complaint

NAME study

GAIT study

Farid et al. [28]

Cross-sectional study

Bowman et al. [29]

Cross-sectional study

OBAS

Location: Paris, France (48◦ N) N = 20 Mean age 72.2 ± 6.2 y Community-dwellers, n = 12 with Alzheimer disease, n = 8 with Lewy body dementia Location: Portland, OR, USA (45.3◦ N) N = 104 Mean age 87 ± 10 y; 62% females Community-dwellers, age ≥ 65 y, without vascular disease, CDR ≤ 0.5

Measure

Radioimmunoassay Low serum (DiaSorin Inc., 25OHD Stillwater, MN, concentration USA) on fasting (thresholds: 10 blood sample and 20 ng/mL) Semiquantitative Low vitamin D dietary intake FFQ (thresholds: 400 and 600 IU/day) LC–MS/MS Deseasonalised values of log 25OHDtot, log 25OHD2 , log 25OHD3 , log 1,25OHD3 , log 24,25OHD3 , used as continuous variables Radioimmunoassay Low serum (Incstar Corp., 25OHD Stillwater, MN) concentration (threshold: 20 ng/mL)

INA

Serum 25OHD concentration, used as a continuous variable

Radioimmunoassay Nutrient (Immunodiagbiomarker nostics patterns high in serum Systems Inc., Scottsdale, AZ) vitamin D (among others)

Association between vitamin D and brain morphometry?

Methods

Measure

1.5-T MRI scanner (Siemens, Iselin, NJ) AnalyzeTM image analysis software (Biomedical Imaging Resource, 1986–2004)

Total brain volume/intracranial volume Sulcal grade Medial temporal lobe Bilateral amygdala Bilateral hippocampi

1.5-T MRI scanner (General Electric, Milwaukee, WI)

Brain parenchymal volume/total intracranial volume

1.5-T MRI scanner (Siemens Medical Solutions, Erlangen, Germany)

Lateral ventricle volume (mm3 )

Yes, vitamin D insufficient vs controls, P = 0.026

Main ventricles body volume (mm3 ) Temporal horns volume (mm3 ) Neurodegeneration estimated from regional cerebral blood flow

Yes, vitamin D insufficient vs controls, P = 0.025 No, vitamin D insufficient vs controls, P = 0.112 Yes, in the left precuneus cortex (Talairach coordinates: −14, −42, 63) among Alzheimer patients

Brain volume/intracranial volume

Yes, ˇ = 1.56 with P = 0.018 after adjustment for age, gender, education, APOE4, hypertension and depression

SPECT/CT (Siemens Molecular Imaging, Erlangen, Germany) using technetium-99m-ethyl cysteinate dimmer SPM version 5 Voxel-based multiple regression 1.5-T MRI scanner Semi-automated REGION image analysis software

No, <10 ng/mL vs 10–20 vs >20, P ≥ 0.05 <400 UI/d vs 400–600 vs >600, P ≥ 0.05 No, <10 ng/mL vs 10–20 vs >20, P ≥ 0.05 <400 UI/d vs 400–600 vs >600, P ≥ 0.05 No, <10 ng/mL vs 10–20 vs >20, P ≥ 0.05 <400 UI/d vs 400–600 vs >600, P ≥ 0.05 No, <10 ng/mL vs 10–20 vs >20, P ≥ 0.05 <400 UI/d vs 400–600 vs >600, P ≥ 0.05 No, <10 ng/mL vs 10–20 vs >20, P ≥ 0.05 <400 UI/d vs 400–600 vs >600, P ≥ 0.05 No with each metabolite separately (P ≥ 0.20) Yes with ratio 25OHD3 /24,25OHD3 (ˇ = −0.009 with P = 0.004)

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Cross-sectional study

Brain

33

No, r = 0.06 with P = 0.34

No, r = −0.003 with P = 0.97

Normalized gray matter volume

Normalized brain volume

3.0-T MRI scanner LC–MS/MS

Deseasonalised values of log 25OHD3 , used as a continuous variable

Optic chiasm volume, mm3

Yes, r = 0.57 with P = 0.008 Measure Methods

3.0-T MRI scanner (Siemens, Erlangen, Germany) FreeSurfer software

Measure Methods

Zivadinov et al. [31]

Gait & Brain study

Cross-sectional study

Location: London, ON, Canada (43.0◦ N) N = 20 Mean age 73.2 y; 40% females With mild cognitive impairment, age ≥ 65 y Location: Buffalo, NY, USA (42.5◦ N) N = 333 Mean age 46.9 ± 10 y; 76.5% females n = 264 with multiple sclerosis, age 18–65 y Cross-sectional study Annweiler et al. [30]

Radioimmunoassay Serum 25OHD concentration, (DiaSorin Inc., Stillwater, MN) used as a continuous variable

Brain Vitamin D Settings/population Design Reference

Table 1 (Continued)

25OHD, 25-hydroxyvitamin D; AC: anterior commissure; APOE4: Apolipoprotein E4; CDR, clinical dementia rating; INA, information not available; GAIT, gait and Alzheimer interactions tracking; FFQ, food frequency questionnaire; LC–MS/MS: liquid chromatography–tandem mass spectrometry; MMSE, mini-mental state examination; NAME, nutrition and memory in elders; OBAS, Oregon brain aging study; PFC: prefrontal cortex; SPECT/CT, radionuclide brain single-photon emission computed tomography/computed tomography; SPM, statistical parametric mapping.

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Association between vitamin D and brain morphometry?

34

2.3. Definition of outcomes We examined the serum concentration of 25OHD since this assay is generally accepted as a better indicator of vitamin D status than 1,25-dihydroxycholecalciferol (1,25OH2 D) [1]. Alternatively, we examined vitamin D dietary intake. Volumes of the whole brain or of various regions of interest were calculated from imaging of the brain, generally MRI. 2.4. Meta-analysis We meta-analyzed all the (sub)volumes of the brain that were measured among Cases with vitamin D depletion and among Controls without vitamin D depletion in at least three studies. Results were expressed in terms of corrected ‘effect size’ of the volume difference between cases and controls. An Effect Size Calculator worksheet was used to derive bias-corrected effect sizes from mean, standard deviation and size of each group (Coe’s Calculator retrieved 10.02.14 from: http://www.cemcentre.org/evidencebased-education/effect-size-calculator) (Table 2). Qualitative descriptors of the effect sizes obtained were less than 0.3, small; 0.4–0.8, moderate; and greater than 0.8, large [21]. A fixed-effects meta-analysis was performed on the estimates to generate summary values (Review Manager version 5.1, The Nordic Cochrane Centre, Copenhagen, Denmark). Results are presented as forest plots. Heterogeneity between studies was assessed using Cochran’s Chi-squared test for homogeneity (Chi2 ), and amount of variation due to heterogeneity was estimated by calculating the I2 [22]. 3. Results 3.1. Study characteristics Table 1 summarizes the nine studies included in this review [23–31]. Data collection was based on animal studies [23,24] or cross-sectional human studies [25–31]. No prospective longitudinal studies and no trials were identified. Furthermore, the research process identified no previous literature review on this issue specifically. The two preclinical studies were published before 2005 [23,24], and all clinical studies have been published since 2010 [25–31]. The number of participants was 24–30 in animals studies, and ranged from 20 [28,30] to 333 [31] in clinical studies, with 40% [30] to 79% women [26]. All adult ages were addressed in clinical studies: two studies focused on younger to middle-aged adults [26,31] and five studies focused on older adults [25,27–30]. Regarding the outcomes, all studies examined serum 25OHD concentration, and two also assessed 1,25OH2 D and 24,25OH2 D concentrations [26,31]. As reported in Table 1, different methods were used to determine 25OHD concentrations, the most frequent one being radioimmunoassay [25,27,29,30]. No study addressed the genetic polymorphism of the VDR. The assessment of brain morphometry was made from MRI in most clinical studies [25–27,29–31], except one study using radionuclide brain single-photon emission computed tomography/computed tomography (SPECT/CT) [28]. In preclinical studies, animals were sacrificed and digitized section images of the brain were acquired for measurements [24,25]. Various semi-automated and automated image analysis softwares were used across studies for the measurements of brain volume and subvolumes. In total, the whole-brain volume was measured either directly and normalized for intracranial volume [24–26,31] or estimated from the length and width of hemispheres [23] and brain [24], or from the measure of the lateral cerebral ventricle volume [24,25,27], which is an excellent aggregate measure of cerebral matter loss and brain atrophy since cerebrospinal fluid is under pressure and any adjacent parenchymal

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Records identified through database searching n=368

35

Additional records identified through other sources n=8

Records considered n=376 Records after duplicates removed n=296 Records screening Excluded, n=271 Position paper or literature review or editorial or protocol (16) Vitamin D not outcome (62) Brain imaging not outcome (193) Text in non-Latin alphabet (0) Full-text articles retrieved n=25 Full-text articles assessment for eligibility Excluded, n=16 Vitamin D not outcome (1) No brain imaging (1) No volumetric outcome (14) Stroke / leukoaraiosis (3) Inflammatory injury (6) Metabolic changes (2) Tumors (1) Calcifications (1) Tracer test (1)

Studies included in qualitative synthesis N=9

Studies included in quantitative synthesis (meta-analysis) N=3 Fig. 1. Flow diagram of selection of studies focusing on vitamin D and brain volumetric changes.

loss results in passive ventricle expansion [32]. In parallel, studies also evaluated the subvolumes of various regions of interest including the cortex [23,24,31], the hippocampus [23–25], the amygdala [25], the anterior commissure [24], the corpus callosum [23,24], and the optic chiasm [30]. One study also examined the regional cerebral blood flow as an illustration of local neurodegeneration [28]. Finally, three of nine studies could contribute to a meta-analysis comparing the volume of the cerebral lateral ventricles among cases with vitamin D depletion and controls [23,24,27]. 3.2. Vitamin D and whole-brain volume Three of five studies examining whole-brain morphometry found lower brain volume in participants with lower 25OHD concentration compared to the others [23–25,29,31]. One of the two inconclusive studies still found that increased ratio of 25OHD/24,25OH2 D, a marker of 25OHD catabolism [1], was associated with lower whole-brain volume [26]. In addition, the three studies that examined lateral ventricle volume found larger ventricles among cases with vitamin D depletion [23,24,27]. For ease of interpretation, results of studies were meta-analyzed to compute the differences in lateral ventricle volume between 55 cases with vitamin D depletion and 81 controls without vitamin D depletion (Fig. 2). All effect sizes were positive, ranging from 0.49 to 4.51 (Table 2), on a scale where 0 corresponds to no difference between cases and controls, and positive effect sizes indicate that cases have greater lateral ventricle volume than controls. The lower limits of the effect size’s confidence interval (CI) were greater than zero in all studies [23,24,27]. The summary effect size of 1.01 [95% CI: 0.62;

1.41] (Chi2 = 38.6, P < 0.001; I2 = 95.0%) indicated that the average member of cases group had a lateral ventricle volume that was 1.01 standard deviations (SD) above the average lateral ventricle volume of controls (Fig. 2). This represents a ‘large’ association of vitamin D depletion with expansion of lateral ventricles [21], which is ‘clinically significant’ according to Wolf et al. (e.g., something is really changed) [33]. Using the ‘Common Language Effect Size’ approach of McGraw and Wong, the probability is about 100% that an individual with vitamin D depletion would have greater lateral ventricle volume than an individual without vitamin D depletion if both individuals were chosen at random from a population [34].

3.3. Vitamin D and brain subvolumes Brain subvolumes were insufficiently explored to conduct metaanalyzes. Results were mixed and depended on the location considered. For instance, three of the four studies that examined cortical gray matter found no association with vitamin D [23–25,31]. Similarly, no study found an association of vitamin D with the size of the hippocampus [23–25] nor with measures of the temporal lobe volume [25,27]. In contrast, in one study, decreased serum 25OHD concentration was associated with a greater volume of the main bodies of the lateral ventricles [27], which reflects matter loss at the cranial vertex [32]. Animals studies found an association of vitamin D with the width of the anterior commissure [24], but not with that of the corpus callosum [23,24]. Finally, serum 25OHD concentration was positively associated with the regional cerebral blood flow in the left precuneus cortex among Alzheimer

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Fig. 2. Forest plot comparing the volume of cerebral lateral ventricles among cases with vitamin D depletion and controls. The black box area is proportional to the sample size of each study, and horizontal lines correspond to the 95% confidence interval. Black diamond represents the summary value. The vertical line corresponds to an effect size of 0.0, equivalent to no difference.

patients in one study [28], and with the volume of the optic chiasm among older adults in another study [30]. 4. Discussion This systematic review and meta-analysis provides evidence that vitamin D depletion is associated with lower brain volume, specifically larger lateral ventricles. Our results indicated a ‘large’ association between depletion in vitamin D and expansion of the cerebral lateral ventricles, with ventricle volume being 1.0 SD higher among participants with vitamin D depletion compared to the others (Fig. 2). Results for brain subvolumes were more mixed, and indicated that the brain atrophy observed in the case of vitamin D depletion could be explained not by temporal lobe atrophy but rather by a loss of matter at the cranial vertex, possibly in the precuneus cortex. Exactly how vitamin D concentration and whole-brain volume are associated and if this association is causal is not fully elucidated. First, it could be argued that brain atrophy and related loss of autonomy lead to insufficient dietary intakes of vitamin D and sunlight exposure, with subsequent depletion in vitamin D [1,10]. This hypothesis is yet not supported by the lack of difference in body mass index and autonomy between participants with and without hypovitaminosis D in clinical studies [27]. Furthermore, the depletion in vitamin D in preclinical studies was experimentally induced prior to brain changes [23,24]. Consequently, a scenario of reverse causation appears likely, with vitamin D depletion resulting in lower brain volume. Experimental evidence precisely supports a role for vitamin D in influencing brain volume. In particular, vitamin D seems to have a trophic function in the differentiation and maturation of neurons by controlling the rate of mitosis and the levels of neurotrophins [35–37]. For instance, vitamin D increases in vitro the synthesis of neurotrophic agents such as the Nerve Growth Factor (NGF), the Glial cell line-Derived Neurotrophic Factor (GDNF) or the neurotrophin 3 (NT-3), as well as the synthesis of low-affinity p75NTR receptors [35–37]. It also accelerates dendritic growth in a dose-dependent manner in rodent hippocampal cell cultures [36]. This result is consistent with the in vivo observation that rats born to vitamin D-deficient mothers had an enlargement of the lateral ventricles compared to controls [23,24], which was explained by parenchyma atrophy consistent with a decline in the

mitotic cell proliferation resulting from a decrease in NGF and GDNF in the brain of the depleted newborns [23]. Vitamin D also promotes neuronal calcium homeostasis by down-regulating the expression and density of calcium channels, and via the synthesis of calciumrelated cytoplasmic proteins such as parvalbumine or calbinding protein [38,39]. As an illustration, in one study, vitamin D treatment protected neurons against amyloid-␤ peptide toxicity by downregulating calcium channels and inducing NGF release [39]. Vitamin D also has antioxidant effects in cultures of rat mesencephalic cells [40]. Finally, vitamin D has exhibited anti-inflammatory effects in the brain [41], consistent with reduced inflammatory brain injury in the case of vitamin D repletion [18], and it may also reduce the severity of cerebrovascular damage [42], two mechanisms that originate loss of brain white matter [43]. The findings of this systematic review and meta-analysis are consistent with previous neuropsychological literature. Indeed, neurological signs are directly related to the strategic location of brain damage. We highlighted here an association of vitamin D depletion with brain atrophy, specifically at the cranial vertex, possibly in the precuneus cortex, rather than in the temporal lobe (Table 1). Since the precuneus cortex links with areas involved in executive functions, working memory and motor planning [44], and since the medial temporal lobe is involved in episodic memory [45], our systematic review is consistent with previous findings that hypovitaminosis D is not associated with episodic memory disorders, but with executive dysfunction, notably impaired working memory [46]. Similarly, the association we reported between lower serum 25OHD concentration and lower volume of optic chiasm, suggestive of optical neuropathy [30], was consistent with the finding that people with hypovitaminosis D exhibit worse visual acuity than the others [47]. The findings of our systematic review need to be tempered by a number of limitations. First, this is a relatively new and emerging area of research, and few studies have been conducted to date, which narrowed the amount of studies to be included in this systematic review and meta-analysis (only two animal and seven clinical studies). Therefore, our conclusions need to be confirmed in larger studies. The heterogeneity of included populations should also be considered. For instance, two studies recruited younger adults with multiple sclerosis [26,31], while older adults with memory complaint [27], mild cognitive impairment [30], or

Table 2 Volume of the cerebral lateral ventricles in studies comparing cases with vitamin D depletion and controls, with effect size estimates for the difference. Reference

Eyles et al. [23] Féron et al. [24] Annweiler et al. [27] CI: confidence interval. a Hedges’ correction.

Cases with vitamin D depletion

Controls without vitamin D depletion

Effect size

n

Mean

Standard deviation

n

Mean

Standard deviation

Uncorrected

Bias correcteda

Standard error

95% CI

12 10 33

2.41 6.62 46.9

0.56 0.66 26.8

12 10 59

0.84 3.98 36.6

0.17 0.44 16.4

3.79 4.71 0.50

3.66 4.51 0.49

0.67 0.84 0.22

2.35; 4.97 2.86; 6.16 0.06; 0.93

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Alzheimer disease and Lewy body dementia [28] were included in other studies. It is also possible that the small size of studied samples may have exposed the analysis to a lack of statistical power with the risk of missing significant differences of brain subvolumes according to vitamin D status. Moreover, the duration of vitamin D depletion was not reported in selected studies. The length of exposure appears yet to be an important factor to take into account when considering morphological changes. Someone with a short duration of vitamin D depletion would likely have less brain atrophy than someone with a long history of depletion. In addition, the nine studies selected in our literature review did not assess the same morphological measurements and did not use the same imaging techniques and image analysis software. Harmonization of outcome measures seems thus desirable. Finally, some potential limitations of the meta-analysis should be considered. In particular, while a meta-analysis of effect sizes is equivalent to a meta-analysis of odds ratios – albeit with loss of power – when there is an underlying normal distribution and common variance [48], this assumption may be not entirely correct in the populations selected in our review because of their relatively small sample sizes. What is more, the summary effect size we found should be interpreted with caution as the qualitative and quantitative analyses indicated substantial heterogeneity. This heterogeneity was likely related to the use of data from both preclinical and clinical studies, which complicated the comparability of studies. It is nonetheless to avoid this interspecies variability that we chose to compute effect sizes rather than summary mean differences. This approach allowed us to compare the sizes of intraspecies betweengroup differences rather than the interspecies volumes in absolute values, which would have been meaningless. 5. Conclusion In conclusion, this systematic review and meta-analysis provides evidence that participants with vitamin D depletion have smaller brain volume and enlarged lateral ventricles than participants without vitamin D depletion. Mechanisms implicated could be based on reduced bioavailability of neurotrophic agents and on the loss of the neuroprotective effects of vitamin D, making the central nervous system less resistant and/or more sensitive to any stress. These results reinforce the conceptualization of vitamin D as a ‘neurosteroid hormone’ [2]. Of note lower 25OHD concentrations and brain atrophy are two frequently reported findings in older adults [1,49]. We and others hypothesize that lower vitamin D concentrations may contribute to brain decline while aging; however further well-designed prospective observational and interventional studies are needed for a better understanding of the involvement of vitamin D depletion in brain morphometric changes. Future studies should include a clear description of the population stratified by health condition and length of vitamin D depletion, robust structural, functional and metabolic imaging techniques, and standardized protocols for image analysis. Understanding the neuroanatomical correlates of chronic vitamin D depletion may offer a powerful mechanism to act on brain changes in older adults and maintain function late in life. Contributors CA has full access to all of the data in the study, takes responsibility for the data, the analyses and interpretation, and the conduct of the research, and has the right to publish any and all data, separate and apart from the attitudes of the sponsor. CA: Study concept and design, data analysis, drafting of the manuscript, Administrative, technical, or material support, and study supervision. CA, OB, and TA: Acquisition of data and interpretation of data. TA, MMO, RB, and OB: Critical revision of the manuscript for important

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intellectual content. Obtained funding: not applicable. All of the authors reviewed the manuscript prior to submission. Competing interest The authors report no conflict of interest. Funding No sources of funding were used to assist in the preparation of this article. Provenance and peer review Commissioned and externally peer reviewed. Acknowledgments We are grateful to the authors of the selected articles for providing additional data required for meta-analysis. Appendix 1. Publications meeting the initial inclusion criteria Publications meeting the final inclusion criteria - Eyles D, Brown J, Mackay-Sim A, McGrath J, Feron F. Vitamin D3 and brain development. Neuroscience 2003;118:641–53. - Féron F, Burne TH, Brown J, Smith E, McGrath JJ, Mackay-Sim A, et al. Developmental Vitamin D3 deficiency alters the adult rat brain. Brain Res Bull 2005;65:141–8. - Buell JS, Dawson-Hughes B, Scott TM, Weiner DE, Dallal GE, Qui WQ, et al., 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010;74:18–26. - Weinstock-Guttman B, Zivadinov R, Qu J, Cookfair D, Duan X, Bang E, et al. Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2011;82:189–95. - Annweiler C, Montero-Odasso M, Hachinski V, Seshadri S, Bartha R, Beauchet O. Vitamin D concentration and lateral cerebral ventricle volume in older adults. Mol Nutr Food Res 2013;57:267–76. - Farid K, Volpe-Gillot L, Petras S, Plou C, Caillat-Vigneron N, Blacher J. Correlation between serum 25-hydroxyvitamin D concentrations and regional cerebral blood flow in degenerative dementia. Nucl Med Commun 2012;33:1048–52. - Bowman GL, Silbert LC, Howieson D, Dodge HH, Traber MG, Frei B, et al. Nutrient biomarker patterns, cognitive function, and MRI measures of brain aging. Neurology 2012;78:241–9. - Annweiler C, Beauchet O, Bartha R, Graffe A, Milea D, MonteroOdasso M. Association between serum 25-hydroxyvitamin D concentration and optic chiasm volume. J Am Geriatr Soc 2013;61:1026–8. - Zivadinov R, Treu CN, Weinstock-Guttman B, Turner C, Bergsland N, O’Connor K, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry 2013;84:1075–1081. Vitamin D not outcome - Lorentzon M, Mellström D, Haug E, Ohlsson C. Smoking is associated with lower bone mineral density and reduced cortical thickness in young men. J Clin Endocrinol Metab 2007;92:497–503.

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No brain imaging

Brain tumors as outcome

- Holmøy T, Moen SM, Gundersen TA, Holick MF, Fainardi E, Castellazzi M, et al., 25-Hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis. Mult Scler 2009;15:1280–5.

- Trouillas P, Honnorat J, Bret P, Jouvet A, Gerard JP. Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long term 1-alpha-hydroxycholecalciferol. J Neurooncol 2001;51:57–66.

Stroke or leukoaraiosis as outcome

Tracer test

- Brøndum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M. 25Hydroxyvitamin D and symptomatic ischemic stroke: an original study and meta-analysis. Ann Neurol 2013;73:38–47. - Wang Y, Chiang YH, Su TP, Hayashi T, Morales M, Hoffer BJ, et al. Vitamin D(3) attenuates cortical infarction induced by middle cerebral arterial ligation in rats. Neuropharmacology 2000;39:873–80. - Payne ME, Anderson JJ, Steffens DC. Calcium and vitamin D intakes may be positively associated with brain lesions in depressed and nondepressed elders. Nutr Res 2008;28:285–92.

- Bonasera TA, Grue-Sørensen G, Ortu G, Binderup E, Bergström M, Björkling F, et al. The synthesis of [26,27-11C]dihydroxyvitamin D(3), a tracer for positron emission tomography (PET). Bioorg Med Chem 2001;9:3123–8.

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