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Menopausal Implications of Polycystic Ovarian Syndrome Rashmi Kudesia, MD1

Genevieve S. Neal-Perry, MD, PhD1,2

1 Division of Reproductive Endocrinology and Infertility, Department

of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine 2 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York

Address for correspondence Genevieve S. Neal-Perry, MD, PhD, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Mazer 426, Bronx, NY 10461 (e-mail: [email protected]).

Abstract Keywords

► menopause ► PCOS ► hormone therapy

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting up to 8 to 10% of reproductive-aged women. Although the medical and metabolic consequences of PCOS are well-described in young reproductive-aged women, its impact on female reproductive senescence and the menopausal transition is poorly understood. This review summarizes current knowledge regarding the effect of PCOS is menopausal and perimenopausal women. We also highlight areas that are ripe for clinical research.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that is clinically characterized by ovulatory dysfunction with amenorrhea or oligomenorrhea, hyperandrogenism, as well as polycystic ovaries. PCOS affects up to 8 to 10% of reproductive-aged women and is associated with reproductive and metabolic dysfunction. Although there are clear pathophysiological consequences related to the diagnosis of PCOS, the progress of PCOS-related research has been hampered by the diversity in criteria used to define PCOS. In an attempt to standardize the definition of PCOS in 2003, the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine sponsored a conference in Rotterdam that resulted in a wide acceptance of diagnostic criteria that combined the 1990 National Institutes of Health (NIH) criteria of hyperandrogenism and chronic anovulation with sonographic finding of polycystic ovaries, thus allowing for a more inclusive approach to diagnosis.1–3 Despite this heroic collaborative effort to uniformly define PCOS, considerable controversy still exists regarding the broad grouping of PCOS phenotypes, especially because different PCOS phenotypes may translate into different health risks. For example, the risk for metabolic syndrome in lean women with PCOS and hyperandrogenic ovulatory dysfunction is less than that of obese hyperandrogenic and obese women with PCOS.4,5

Issue Theme Developmental Origins and Future Fate in PCOS: Providence or Peril?; Guest Editor, Kathleen M. Hoeger, MD, MPH

Although the medical consequences of PCOS on fertility are well described in medical as well as lay literature, the role of PCOS in female reproductive senescence and the menopausal transition is under studied and less appreciated. The goal of this review is to outline the current understanding about the impact of PCOS on the menopausal transition and menopause and to highlight areas that are ripe for additional study.

Menopausal Phenotype Defining the manifestations of PCOS in older women is complicated by the fact that the clinical observations that typify the menopausal transition overlap with clinical findings that define women with PCOS; the most notable finding being oligomenorrhea and oligo-ovulation (►Table 1). We will consider the three diagnostic criteria of PCOS in turn.

Amenorrhea or Oligomenorrhea As women approach perimenopause, women with a history of regular menses typically experience oligomenorrhea, menometrorrhagia, as well as metrorrhagia.6,7 Indeed, between 65 and 77% of perimenopausal women report cycles that are 25 or 36 days.6,8 Conversely, menstrual cycles in women with a history of PCOS tend to become more regular as they approach menopause.9,10 In light of this observation, the Stages of Reproductive Aging Workshop (STRAW) þ 10 workshop concluded that given the limited understanding of how menstrual cycles

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1371094. ISSN 1526-8004.

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Table 1 PCOS phenotype in the perimenopause Diagnostic criteria

Changes in the perimenopause

Amenorrhea/oligomenorrhea

Cycles tend to become more regular (opposite of what occurs in non-PCOS women)

Hyperandrogenism

Hirsutism persists Androgen levels fall (possibly an effect of chronologic age rather than menopausal status) Menopausal levels of steroid hormones often fall below sensitivity thresholds of direct radioimmunoassays

Polycystic ovaries

The ovaries of reproductively senescing women may no longer meet diagnostic criteria

change in perimenopausal women with PCOS, STRAW menstrual cycle criteria should not be used to predict the menopausal transition in these women.11 Further research is needed to characterize menstrual cycle patterns in women with PCOS making the transition into menopause.

Hyperandrogenism Hirsutism, a clinical sign of hyperandrogenism, persists, and has even been reported to be more prevalent among menopausal women with PCOS compared with controls.12 A recent 21-year longitudinal study of PCOS women that was designed to determine if postmenopausal women with PCOS differ from controls regarding cardiovascular risk factors, myocardial infarction (MI), stroke, and mortality found reproductive aged (44%) and menopausal (64%) women with PCOS reported higher rates of hirsutism than young (6%) and menopausal (9%) age-matched controls.13 Sex hormone concentrations change in women making the transition into menopause. Free androgens generally decrease over time.14 Multiple studies of women with PCOS demonstrate reductions in testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEAS) to levels comparable to non-PCOS women.14,15 It is proposed that androgen decline may reflect chronologic age rather than menopausal status.15 However, it has also been reported that the free androgen index remains elevated in some menopausal PCOS women.13 Thus, gaps in knowledge about the effect of age compared with menopausal status on androgen production in control and PCOS women making the transition into menopause exist, and research is needed in this area. Estradiol levels fall and estrone levels, which are generally higher in women with PCOS, also fall to levels comparable to control menopausal women.13 It is important to appreciate that changes in estrogen levels reflect ovarian aging as well as age-related changes in adrenal synthesis of DHEAS and other steroid hormones. Indeed, it has been suggested that changes in adrenal hormone production may contribute more than declining ovarian function to the menopausal shift in the estrogen–androgen balance.16 A major challenge for studies designed to delineate the effect of PCOS and the menopausal transition on the steroid hormone environment is the sensitivity of previously and currently available hormone assays. Many laboratory-based steroid hormone assays are constrained by the lower limits of detection. For example, though direct radioimmunoassays are commonly used to quantify estradiol in premenopausal

women, these assays have insufficient sensitivity, specificity, precision, as well as accuracy to quantify estradiol levels in postmenopausal women. Problems with reduced sensitivity, specificity, and precision also plague many of the assays used to quantify other estrogens and testosterone.17 This technical limitation has prohibited the study of gonadal steroids in menopausal women and makes it difficult to translate and compare assays across studies. The development of inexpensive, sensitive, and specific assays that can be readily used to determine hormone levels in perimenopausal as well as menopausal women will add value to research efforts and will significantly advance our knowledge about the steroid hormone milieu of aging women.

Polycystic Ovaries Ovarian morphology changes over time in women with PCOS. A recent longitudinal cross-sectional study for 7 to 15 years duration that was designed to assess ovarian volume in women with and without PCOS found ovarian volume decreased in all women with aging.18 The reduction in log ovarian volume was significantly less in PCOS than control women. However, when compared with aged-matched controls, the ovaries of reproductively senescing women with PCOS no longer meet morphologic criteria for PCOS. Although women with a history of PCOS fail to exhibit typical ovarian phenotype, the authors suggest using a logistic regression model that includes age, log ovarian volume, follicle number, and testosterone to reliably distinguish older PCOS women from controls. The novelty of this model is that it does not require information regarding menstrual cycle length or evidence of hirsutism.

Reproductive Physiology Common measurements of ovarian reserve, including antral follicle count and anti-Müllerian hormone (AMH), are typically elevated in women with PCOS.19 Women with PCOS are hypothesized to have a larger follicular pool at birth.20 In addition, AMH can be used to predict the age at menopause21,22 in eugonadotropic regularly cycling women. Women with eugonadotropic anovulation have higher AMH levels than ovulatory controls. Of note, in PCOS women, the age-related reduction in AMH is less pronounced.23 Given this information, one might surmise that if the rate of follicular pool depletion in PCOS women was similar to the rate of reproductively senescing control women, then women with Seminars in Reproductive Medicine

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Abbreviation: PCOS, polycystic ovary syndrome.

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Table 2 Reproductive consequences of PCOS

Obesity

Characteristic

Changes in the perimenopause

Ovarian reserve

PCOS women have lower FSH and higher AMH levels relative to non-PCOS women Unclear whether reproductive lifespan is lengthened

Abbreviations: AMH, anti-Müllerian hormone; FSH, follicle-stimulating hormone; PCOS, polycystic ovary syndrome.

PCOS would experience a delayed menopause (►Table 2). Consistent with this proposal, a recent model designed to predict ovarian aging in a population-based cohort with AMH predicted that the reproductive lifespan of PCOS women would be increased by 2 years, thereby delaying age at menopause.24 However, a diagnosis of PCOS does not confer a significantly delayed menopause. This finding has been observed in multiple studies.9,25,26 These data suggest that intraovarian factors other than follicular volume determine the age of menopause in women with PCOS. Animal models of PCOS may help explain the changes in ovarian physiology that result in this surprising outcome.

Metabolic Consequences Though the exact pathophysiology of PCOS is unknown, the disorder is often associated with multiple metabolic disruptions, such as impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2), and dyslipidemia.27–30 Findings of insulin resistance are more common in women meeting the classic NIH criteria of hyperandrogenism and chronic anovulation, as opposed to women who meet Rotterdam criteria but cycle regularly.31 As the risk for cardiovascular disease (CVD) increases after menopause in all women,12,32 there is concern that the lifelong metabolic profile associated with classic PCOS confers a greater cardiovascular risk profile for perimenopausal and menopausal PCOS women (►Table 3).31

Although obesity is not part of the definition of PCOS, obesity is often a comorbidity of PCOS. The United States has one of the highest rates of obesity among women with PCOS.33 Of note, when compared with weight-matched controls, women with PCOS tend to have upper body fat distribution, which is considered metabolically active and associated with insulin resistance.25 Although obesity frequently coexists in women with PCOS and metabolic derangements, obesity is not a prerequisite for metabolic morbidity in PCOS women. For example, while 20% of obese women meet criteria for IGT or frank diabetes, such metabolic derangements are still seen in PCOS women with a normal body mass index (BMI); however, women without PCOS and a normal BMI do not manifest such pathophysiology.27,34 Indeed, a large meta-analysis demonstrated an increased incidence of IGT, DM2, and metabolic syndrome in women with PCOS independent of BMI.29 However, other data have suggested that obesity, along with age, is better predictors of metabolic syndrome in PCOS adolescents and women up to 39 years of age than the PCOS diagnosis itself.35,36 Though the mechanism by which PCOS creates metabolic pathology is unclear, it should be viewed as a distinct risk for metabolic disease.37 It is well recognized that an increased waist-to-hip ratio as well as increased weight represent independent risk factors for CVD and metabolic syndrome.38 Compared with young control women, young PCOS women have increased rates of obesity and an increased waist-to-hip ratio. They also have higher rates of metabolic syndrome and more cardiovascular risk factors.39,40 However, by the time of the menopausal transition, the incidence of increased waist-to-hip ratio among women with PCOS approach levels observed in control women and by the time of the menopause, there is no significant difference between the women with a history of PCOS compared with control women.26

Markers of Cardiovascular Health As noted above, increased BMI is frequently found in women with PCOS when compared with non-PCOS women. In

Table 3 Metabolic consequences of PCOS Characteristic

Changes in the perimenopause

Waist-to-hip ratio

Elevated rates in premenopausal women normalize

Lipid profile

Deteriorations may be more strongly correlated to age rather than PCOS status

Insulin resistance

May be more strongly correlated with obesity rather than PCOS

Dyslipidemia

May be more strongly correlated with obesity rather than PCOS

Hypertension

May be more strongly correlated with obesity rather than PCOS

Metabolic syndrome

Elevated in premenopausal women; no clear increased risk in perimenopausal and menopausal women

Coronary artery disease

Higher prevalence in PCOS postmenopausal women

Cardiovascular events (MI, stroke)

Conflicting data suggesting same or elevated risk compared with non-PCOS women

Cardiovascular mortality

No apparent increase in risk

Risks of MHT

No studies available

Abbreviations: MI, myocardial infarction; MHT, menopausal hormone therapy; PCOS, polycystic ovary syndrome. Seminars in Reproductive Medicine

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addition, elevated levels of serum markers of CVD (C-reactive protein (CRP), homocysteine, tumor necrosis factor-α, plasminogen activator inhibitor-1, lipoprotein-a, advanced glycation end products, vascular endothelial growth factor, interleukin-6, asymmetric dimethylarginine, endothelin-1, and fibrinogen), as well as markers of oxidative stress (homocysteine, malondialdehyde, asymmetric dimethylarginine, and superoxide dismutase activity) are observed in PCOS women.41,42 An elevated luteinizing hormone to follicle stimulating hormone ratio, a pattern of gonadotropin release that can be observed in women with PCOS, is also linked to elevated CRP and dyslipidemia in menopausal women.43 Although PCOS in young women is clearly linked to metabolic syndrome, the impact of PCOS on the severity and number of metabolic risk factors that exist or emerge in women making the transition into the menopause is less clear. A recent study suggested that deteriorating lipid profiles in PCOS women making the menopausal transition may reflect somatic age rather than a pre-existing diagnosis of PCOS.44 Consistent with this hypothesis, after adjusting for PCOS, Elting et al, reported hyperinsulinemia, dyslipidemia, and hypertension in a population of aging women were related to obesity rather than PCOS.45 These data suggest that PCOS may not increase baseline CVD risks in reproductively senescing women over and beyond that which characterizes the menopausal transition and the menopause. Additional studies are needed to definitively confirm this suggestion.

Metabolic Syndrome Metabolic syndrome is a constellation of several clinical findings that increase the risk of CVD. Metabolic syndrome has been defined in various ways, but one of the most commonly used definitions, the National Cholesterol Education Program-Adult Treatment Panel III, requires three or more of the following five disorders: elevated waist circumference (88 cm in women), hypertriglyceridemia (1.7 mmol/L), low high-density lipoprotein cholesterol level (< 1.3 mmol/L in women), high blood pressure (systolic blood pressure 130 mm Hg and/or diastolic blood pressure 85 mm Hg and/or pharmacological treatment), and elevated fasting glucose (5.6 mmol/L and/or pharmacological treatment).38 Given the pathophysiological significance of metabolic syndrome and the commonality of clinical findings in women with PCOS, several investigators have attempted to specifically characterize its incidence in women with PCOS. A 2010 meta-analysis that reviewed 18 articles that assessed metabolic syndrome in PCOS women found statistically significant increased odds ratio (OR) (1.75–3.01) for metabolic syndrome.29 Available data suggest that this elevation in prevalence of metabolic syndrome does not change over time.46–48

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prevalence of noninsulin–dependent diabetes mellitus and coronary artery disease is also demonstrated in perimenopausal women with PCOS.51 However, higher rates of hypertension and hypertriglyceridemia in postmenopausal women with a history of PCOS have not been correlated with elevated rates of MI, stroke, or diabetes as compared with control menopausal women.26 These data suggest that a history of PCOS in the mid-reproductive years does not confer an increased risk for MI or stroke relative to the baseline risk associated with the postmenopausal state, alone. Consistent with this hypothesis, several retrospective cohort studies fail to demonstrate increased cardiovascular mortality rates in women with PCOS. One study of 786 women in the United Kingdom, followed for an average of 30 years, concluded that PCOS women did not have a significantly higher risk of mortality from circulatory disease compared with national rates.52 A subsequent study of 319 women from the original cohort also failed to show a difference in morbidity or mortality resulting from coronary heart disease.53 In summary, women with PCOS, particularly the classic NIH phenotype, have an increased risk for metabolic disease and should be appropriately screened and managed regardless of age.54 Additional prospective longitudinal studies should be designed to elucidate the association between different PCOS phenotypes, cardiovascular markers, and cardiovascular morbidity and mortality. Equally important, investigators should be aware of the effect of race and ethnicity on the existence of a priori risks for CVD in women with PCOS.31 For example, a population-based study in Iran found an increased risk of insulin resistance, but not metabolic syndrome, in Iranian women with PCOS.55

Menopausal Hormone Therapy Given the uncertainty of cardiovascular health in women with PCOS entering the perimenopause, the risks of menopausal hormone therapy (MHT) are unknown. Prior research has indicated that obesity is associated with increased frequency and severity of hot flashes, a primary indication for MHT utilization.56 In our review of the literature, we did not identify studies that specifically address the relationship between PCOS status and MHT risks. Interestingly, studies focused on MHT use in obese women suggest MHT may prevent or delay insulin resistance and abdominal fat deposition, though these putative benefits are significantly offset by an increased risk of breast malignancy as well as venous thromboembolic events.57–59 The approach to the use of MHT for bothersome vasomotor symptoms in women with PCOS is the same as it is for other symptomatic women: the lowest effective dose for the shortest time.37 Nonetheless, it is the individual provider’s responsibility to balance a woman’s medical comorbidities, including PCOS as well as obesity, when deciding whether or not to prescribe MHT.

Cardiovascular Morbidity and Mortality The evidence linking PCOS to an increased risk for CVD morbidity and mortality is conflicting and inconclusive. Postmenopausal women with hyperandrogenism and a history of irregular menses are hypothesized to have more cardiovascular events49 and atherosclerotic CVD.50 A higher

PCOS, Reproductive Aging, and Oncologic Consequences Long periods of unopposed estradiol exposure in PCOS women with oligomenorrhea or amenorrhea are a risk factor for Seminars in Reproductive Medicine

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hormone-dependent malignancies, particularly of the endometrium and breast (►Table 4). Many of these cancers are more prevalent as women approach menopause; therefore, they represent another potential layer of complexity to gynecologic care that may uniquely affect women with PCOS making the transition into menopause.

and prolonged unopposed estrogen exposure, are hypothesized to increase the risk for the development of neoplasia in the breast. In the meta-analysis by Chittenden et al, as described above, 59 cases of breast cancer were reported in women with PCOS compared with 74 breast cancer cases in the controls. The source studies were case–control analyses of women aged 50 to 75, 20 to 54, and 23 to 74, that relied on patient recall of a physician diagnosis of PCOS.64–66 The pooled data suggested an OR of 0.88 (95% CI, 0.44–1.77), showing no significant association. However, a cross-sectional study that relied on familial associations rather than medical history recall reported a positive association between PCOS and breast cancer (20 vs. 5%, p < 0.05).67 More comprehensive studies are needed to definitively define the relationship between PCOS and breast cancer.

Endometrium The data are perhaps most compelling for a relationship between PCOS and endometrial pathology. Risk factors for endometrial carcinoma include obesity, hypertension, DM2, unopposed estrogen exposure, and nulliparity; conditions that are often seen in women with PCOS.60 A systematic review by Chittenden et al, explored the link between PCOS and endometrial cancer by including four studies that encompassed a total of 4,056 women. The aggregated data suggested an increased risk for endometrial cancer with an OR of 2.70 (95% confidence interval [CI], 1.00–7.29), translating into a rate of 46/100,000 for endometrial cancer among PCOS women compared with 17/100,000 for controls. Another cross-sectional analysis that was not included in the metaanalysis also reported that PCOS women have a sixfold increased odds of developing endometrial carcinoma as compared with non-PCOS women.53 The most recent systematic review on this topic concluded that the risk of endometrial cancer in PCOS women is increased threefold, from 3 to 9% in Caucasian women without and with PCOS, respectively.61

Other Health Consequences Bone Health It has been theorized that the higher androgen levels associated with PCOS may confer a benefit with regard to muscle mass and bone mineral density (BMD); though some studies have shown higher BMD in young women with PCOS, others have found no difference, and one study showed lower BMD in nonobese adolescents with PCOS (►Table 5).68–72 A recent study that evaluated postmenopausal women showed no difference in muscle mass, BMD, or fracture incidence in those with and without a history of PCOS.73

Ovary

Sleep Dysfunction

Only one study allowed for assessment of ovarian carcinoma. Findings yielded an elevated OR of 2.52 (95% CI, 1.08–5.89); however, extrapolation is limited by the fact that there were only seven women with PCOS among the 476 cases.62 Additional studies are needed to address the gap in knowledge about the risk for ovarian cancer in women with a history of PCOS.

Adolescents and premenopausal women with PCOS have been repeatedly shown to have elevated rates of obstructive sleep apnea, sleep disturbances, and abnormal sleep architecture.74–78 The menopausal transition is associated with sleep dysfunction, especially insomnia, nocturnal breathing disturbances, and sleep disorders.79 Thus, one might hypothesize that the rate of sleep dysfunction is increased in women with a history of PCOS, and is increased over the baseline rates associated with the menopausal transition. However, in our search, we did not identify any studies that determined if a history of PCOS corresponded to increased rates of sleep dysfunction during the menopausal transition or the

Breast Breast malignancies are often estrogen sensitive.63 As such, conditions frequently associated with PCOS, including obesity

Table 4 Oncologic consequences of PCOS Type of malignancy

Risk modification due to PCOS

Endometrium

Increased risk; likely further elevated in obese women

Ovary

Minimal data suggest same or elevated risks OCP use is more common among PCOS women. OCP use is known to be protective against ovarian malignancy

Breast

Possibly elevated risk; further study needed

Abbreviation: PCOS, polycystic ovary syndrome; OCP, oral contraceptive pill. Seminars in Reproductive Medicine

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Table 5 Other health consequences of PCOS Characteristic

Changes in the perimenopause

Bone health

Conflicting evidence in bone mineral density in adolescents No evidence for difference in postmenopausal women

Sleep dysfunction

No direct studies

Psychological health

PCOS known to negatively impact quality of life No direct studies on impact of PCOS at menopause

Abbreviation: PCOS, polycystic ovary syndrome.

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Psychological Health Having PCOS is known to be specifically associated with emotional distress and diminished quality of life (QOL), related to the potentially synergistic impact of its components, including obesity, hirsutism, and infertility.80–82 The relationship between PCOS and altered QOL is such that a separate QOL instrument for PCOS patients has been created, validated, and widely used.83 However, it is not clear if the psychological impact of PCOS is a consequence of the disease process or the result of social complications of reproductive impact associated with the disorder.31

10 Elting MW, Kwee J, Korsen TJ, Rekers-Mombarg LT, Schoemaker J.

11

12 13

14

Conclusions In summary, PCOS is a challenging condition that affects women of all ages, body shapes, races, and ethnicities. Different subgroups within the PCOS diaspora, as well as different genetic predispositions related to ethnicity, suggest that existing research may understate the various risks and consequences of PCOS. Genomic research, now well underway, may provide a critical workaround to these confounders.6,84–86 Nonetheless, there are adverse health consequences of having PCOS. However, the impact of the menopausal transition and the menopause on the various consequences is minimally understood, and further research in this area will help optimize care for at-risk women.

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menopause. Thus, there are gaps in our knowledge about rates of sleep dysfunction and the menopausal transition in women with a history of PCOS.

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Menopausal Implications of Polycystic Ovarian Syndrome

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Menopausal implications of polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting up to 8 to 10% of reproductive-aged women. Although the medical and metabolic co...
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