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

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

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Semin Reprod Med 2014;32:222–229

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Table 1 PCOS phenotype in the perimenopause Diagnostic criteria

Changes in the perimenopause


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


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



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


May be more strongly correlated with obesity rather than PCOS


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


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


Increased risk; likely further elevated in obese women


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


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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Menopausal Implications of Polycystic Ovarian Syndrome

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.


12 13


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.







References 1 Carmina E. Diagnosis of polycystic ovary syndrome: from NIH





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8 9

criteria to ESHRE-ASRM guidelines. Minerva Ginecol 2004;56(1): 1–6 Franks S. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab 2006;91(3):786–789 Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome; towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1992:377–384 Azziz R. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 2006;91(3):781–785 Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev 2012;33(6):981–1030 Taffe JR, Dennerstein L. Menstrual patterns leading to the final menstrual period. Menopause 2002;9(1):32–40 Van Voorhis BJ, Santoro N, Harlow S, Crawford SL, Randolph J. The relationship of bleeding patterns to daily reproductive hormones in women approaching menopause. Obstet Gynecol 2008;112(1): 101–108 Vollman RF. The menstrual cycle. Major Probl Obstet Gynecol 1977;7:1–193 Dahlgren E, Johansson S, Lindstedt G, et al. Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones. Fertil Steril 1992;57(3):505–513









Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles. Fertil Steril 2003;79(5): 1154–1160 Harlow SD, Gass M, Hall JE, et al; STRAW þ 10 Collaborative Group. Executive summary of the Stages of Reproductive Aging Workshop þ 10: addressing the unfinished agenda of staging reproductive aging. J Clin Endocrinol Metab 2012;97(4):1159–1168 Shah D, Bansal S. Polycystic ovaries - beyond menopause. Climacteric. Epub, October 28, 2013 Schmidt J, Brännström M, Landin-Wilhelmsen K, Dahlgren E. Reproductive hormone levels and anthropometry in postmenopausal women with polycystic ovary syndrome (PCOS): a 21-year follow-up study of women diagnosed with PCOS around 50 years ago and their age-matched controls. J Clin Endocrinol Metab 2011; 96(7):2178–2185 Hudecova M, Holte J, Moby L, et al. Androgen levels, insulin sensitivity, and early insulin response in women with polycystic ovary syndrome: a long-term follow-up study. Fertil Steril 2011; 95(3):1146–1148 Davison SL, Bell R, Donath S, Montalto JG, Davis SR. Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 2005;90(7):3847–3853 McConnell DS, Stanczyk FZ, Sowers MR, Randolph JF Jr, Lasley BL. Menopausal transition stage-specific changes in circulating adrenal androgens. Menopause 2012;19(6):658–663 Stanczyk FZ, Lee JS, Santen RJ. Standardization of steroid hormone assays: why, how, and when? Cancer Epidemiol Biomarkers Prev 2007;16(9):1713–1719 Alsamarai S, Adams JM, Murphy MK, et al. Criteria for polycystic ovarian morphology in polycystic ovary syndrome as a function of age. J Clin Endocrinol Metab 2009;94(12):4961–4970 Hudecova M, Holte J, Olovsson M, Sundström Poromaa I. Longterm follow-up of patients with polycystic ovary syndrome: reproductive outcome and ovarian reserve. Hum Reprod 2009; 24(5):1176–1183 Webber LJ, Stubbs S, Stark J, et al. Formation and early development of follicles in the polycystic ovary. Lancet 2003;362(9389): 1017–1021 van Disseldorp J, Faddy MJ, Themmen AP, et al. Relationship of serum antimüllerian hormone concentration to age at menopause. J Clin Endocrinol Metab 2008;93(6):2129–2134 Dólleman M, Faddy MJ, van Disseldorp J, et al. The relationship between anti-Müllerian hormone in women receiving fertility assessments and age at menopause in subfertile women: evidence from large population studies. J Clin Endocrinol Metab 2013;98(5): 1946–1953 Mulders AG, Laven JS, Eijkemans MJ, de Jong FH, Themmen AP, Fauser BC. Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility. Hum Reprod 2004;19(9): 2036–2042 Tehrani FR, Solaymani-Dodaran M, Hedayati M, Azizi F. Is polycystic ovary syndrome an exception for reproductive aging? Hum Reprod 2010;25(7):1775–1781 Holte J, Bergh T, Gennarelli G, Wide L. The independent effects of polycystic ovary syndrome and obesity on serum concentrations of gonadotrophins and sex steroids in premenopausal women. Clin Endocrinol (Oxf) 1994;41(4):473–481 Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab 2011;96(12):3794–3803 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997; 18(6):774–800

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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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28 Solomon CG, Hu FB, Dunaif A, et al. Long or highly irregular

45 Elting MW, Korsen TJ, Schoemaker J. Obesity, rather than men-

menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 2001;286(19):2421–2426 Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2010;16(4):347–363 Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Poromaa IS. Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome—a long term follow-up. Hum Reprod 2011; 26(6):1462–1468 Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril 2012;97(1):28–38.e25 Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 2003;163(4):427–436 Glueck CJ, Dharashivkar S, Wang P, et al. Obesity and extreme obesity, manifest by ages 20-24 years, continuing through 32-41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy. Eur J Obstet Gynecol Reprod Biol 2005;122(2): 206–212 Dunaif A, Graf M, Mandeli J, Laumas V, Dobrjansky A. Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 1987;65(3):499–507 Panidis D, Tziomalos K, Chatzis P, et al. Association between menstrual cycle irregularities and endocrine and metabolic characteristics of the polycystic ovary syndrome. Eur J Endocrinol 2013;168(2):145–152 Panidis D, Tziomalos K, Macut D, et al. Age- and body mass indexrelated differences in the prevalence of metabolic syndrome in women with polycystic ovary syndrome. Gynecol Endocrinol 2013;29(10):926–930 ESHRE Capri Workshop Group. Hormones and cardiovascular health in women. Hum Reprod Update 2006;12(5):483–497 Grundy SM, Cleeman JI, Daniels SR, et al; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112(17):2735–2752 Bajuk Studen K, Jensterle Sever M, Pfeifer M. Cardiovascular risk and subclinical cardiovascular disease in polycystic ovary syndrome. Front Horm Res 2013;40:64–82 Spanos N, Tziomalos K, Macut D, et al. Adipokines, insulin resistance and hyperandrogenemia in obese patients with polycystic ovary syndrome: cross-sectional correlations and the effects of weight loss. Obes Facts 2012;5(4):495–504 Murri M, Luque-Ramírez M, Insenser M, Ojeda-Ojeda M, EscobarMorreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): a systematic review and meta-analysis. Hum Reprod Update 2013;19(3):268–288 Toulis KA, Goulis DG, Mintziori G, et al. Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod Update 2011;17(6):741–760 Beydoun HA, Beydoun MA, Wiggins N, Stadtmauer L. Relationship of obesity-related disturbances with LH/FSH ratio among postmenopausal women in the United States. Maturitas 2012;71(1): 55–61 Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, SundstromPoromaa I. Prevalence of the metabolic syndrome in women with a previous diagnosis of polycystic ovary syndrome: long-term follow-up. Fertil Steril 2011;96(5):1271–1274

strual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2001; 55(6):767–776 Carmina E. PCOS: metabolic impact and long-term management. Minerva Ginecol 2012;64(6):501–505 Carmina E. Obesity, adipokines and metabolic syndrome in polycystic ovary syndrome. Front Horm Res 2013;40:40–50 Welt CK, Carmina E. Lifecycle of polycystic ovary syndrome (PCOS): from in utero to menopause. J Clin Endocrinol Metab 2013;98(12):4629–4638 Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health—National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008;93(4): 1276–1284 Krentz AJ, von Mühlen D, Barrett-Connor E. Searching for polycystic ovary syndrome in postmenopausal women: evidence of a dose-effect association with prevalent cardiovascular disease. Menopause 2007;14(2):284–292 Cibula D, Cífková R, Fanta M, Poledne R, Zivny J, Skibová J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum Reprod 2000;15(4):785–789 Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS. Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 1998;51(7):581–586 Wild S, Pierpoint T, Jacobs H, McKeigue P. Long-term consequences of polycystic ovary syndrome: results of a 31. year follow-up study. Hum Fertil (Camb) 2000;3(2):101–105 ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Hum Reprod Update 2012;18(5):586–599 Hosseinpanah F, Barzin M, Tehrani FR, Azizi F. The lack of association between polycystic ovary syndrome and metabolic syndrome: Iranian PCOS prevalence study. Clin Endocrinol (Oxf) 2011;75(5):692–697 Da Fonseca AM, Bagnoli VR, Souza MA, et al. Impact of age and body mass on the intensity of menopausal symptoms in 5968 Brazilian women. Gynecol Endocrinol 2013;29(2):116–118 Gambacciani M, Ciaponi M, Cappagli B, et al. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab 1997;82(2): 414–417 Espeland MA, Stefanick ML, Kritz-Silverstein D, et al; Postmenopausal Estrogen-Progestin Interventions Study Investigators. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. J Clin Endocrinol Metab 1997;82(5): 1549–1556 Rachoń D, Teede H. Ovarian function and obesity—interrelationship, impact on women’s reproductive lifespan and treatment options. Mol Cell Endocrinol 2010;316(2):172–179 Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online 2009;19(3):398–405 Haoula Z, Salman M, Atiomo W. Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod 2012;27(5):1327–1331 Schildkraut JM, Schwingl PJ, Bastos E, Evanoff A, Hughes C. Epithelial ovarian cancer risk among women with polycystic ovary syndrome. Obstet Gynecol 1996;88(4 Pt 1):554–559 Dumesic DA, Lobo RA. Cancer risk and PCOS. Steroids 2013;78(8): 782–785









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Kudesia et al.

64 Talamini R, Franceschi S, Favero A, Negri E, Parazzini F, La Vecchia C.

76 Nandalike K, Strauss T, Agarwal C, et al. Screening for sleep-

Selected medical conditions and risk of breast cancer. Br J Cancer 1997;75(11):1699–1703 Baron JA, Weiderpass E, Newcomb PA, et al. Metabolic disorders and breast cancer risk (United States). Cancer Causes Control 2001; 12(10):875–880 Gammon MD, Thompson WD. Polycystic ovaries and the risk of breast cancer. Am J Epidemiol 1991;134(8):818–824 Atiomo WU, El-Mahdi E, Hardiman P. Familial associations in women with polycystic ovary syndrome. Fertil Steril 2003;80(1):143–145 Adami S, Zamberlan N, Castello R, Tosi F, Gatti D, Moghetti P. Effect of hyperandrogenism and menstrual cycle abnormalities on bone mass and bone turnover in young women. Clin Endocrinol (Oxf) 1998;48(2):169–173 Carmina E, Guastella E, Longo RA, Rini GB, Lobo RA. Correlates of increased lean muscle mass in women with polycystic ovary syndrome. Eur J Endocrinol 2009;161(4):583–589 Good C, Tulchinsky M, Mauger D, Demers LM, Legro RS. Bone mineral density and body composition in lean women with polycystic ovary syndrome. Fertil Steril 1999;72(1):21–25 Kassanos D, Trakakis E, Baltas CS, et al. Augmentation of cortical bone mineral density in women with polycystic ovary syndrome: a peripheral quantitative computed tomography (pQCT) study. Hum Reprod 2010;25(8):2107–2114 To WW, Wong MW. A comparison of bone mineral density in normal weight and obese adolescents with polycystic ovary syndrome. J Pediatr Adolesc Gynecol 2012;25(4):248–253 Schmidt J, Dahlgren E, Brännström M, Landin-Wilhelmsen K. Body composition, bone mineral density and fractures in late postmenopausal women with polycystic ovary syndrome - a long-term follow-up study. Clin Endocrinol (Oxf) 2012;77(2):207–214 de Sousa G, Schlüter B, Buschatz D, et al. A comparison of polysomnographic variables between obese adolescents with polycystic ovarian syndrome and healthy, normal-weight and obese adolescents. Sleep Breath 2010;14(1):33–38 Gopal M, Duntley S, Uhles M, Attarian H. The role of obesity in the increased prevalence of obstructive sleep apnea syndrome in patients with polycystic ovarian syndrome. Sleep Med 2002;3(5):401–404

disordered breathing and excessive daytime sleepiness in adolescent girls with polycystic ovarian syndrome. J Pediatr 2011; 159(4):591–596 Shreeve N, Cagampang F, Sadek K, et al. Poor sleep in PCOS; is melatonin the culprit? Hum Reprod 2013;28(5):1348–1353 Vgontzas AN, Legro RS, Bixler EO, Grayev A, Kales A, Chrousos GP. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab 2001;86(2):517–520 Guidozzi F. Sleep and sleep disorders in menopausal women. Climacteric 2013;16(2):214–219 Veltman-Verhulst SM, Boivin J, Eijkemans MJ, Fauser BJ. Emotional distress is a common risk in women with polycystic ovary syndrome: a systematic review and meta-analysis of 28 studies. Hum Reprod Update 2012;18(6):638–651 Ching HL, Burke V, Stuckey BG. Quality of life and psychological morbidity in women with polycystic ovary syndrome: body mass index, age and the provision of patient information are significant modifiers. Clin Endocrinol (Oxf) 2007;66(3):373–379 Jedel E, Waern M, Gustafson D, et al. Anxiety and depression symptoms in women with polycystic ovary syndrome compared with controls matched for body mass index. Hum Reprod 2010; 25(2):450–456 Cronin L, Guyatt G, Griffith L, et al. Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 1998;83(6): 1976–1987 Ewens KG, Jones MR, Ankener W, et al. Type 2 diabetes susceptibility single-nucleotide polymorphisms are not associated with polycystic ovary syndrome. Fertil Steril 2011;95(8):2538–2541, e1–e6 Ewens KG, Jones MR, Ankener W, et al. FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome. PLoS ONE 2011;6(1):e16390 Goodarzi MO, Jones MR, Li X, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet 2012;49(2):90–95


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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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