The Severity of Menstrual Dysfunction as a Predictor of Insulin Resistance in PCOS

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1 JCEM ONLINE Brief Report Endocrine Research The Severity of Menstrual Dysfunction as a Predictor of Insulin Resistance in PCOS Meredith Brower, Kathleen Brennan, Marita Pall, and Ricardo Azziz Department of Obstetrics and Gynecology (M.B., K.B., R.A.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095; Department of Obstetrics and Gynecology and Center for Androgen-Related Disorders (M.P., R.A.), Cedars-Sinai Medical Center, Los Angeles, California 90048; and Departments of Obstetrics and Gynecology, and Medicine (R.A.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia Objective: The objective of the study was to evaluate the relationship between the severity of menstrual disturbances and the degree of insulin resistance in women with polycystic ovary syndrome (PCOS). Design: This was a cross-sectional study. Setting: The study was conducted at a tertiary care academic medical center. Patients: Four hundred ninety-four women diagnosed with PCOS by the Rotterdam criteria and 138 eumenorrheic, nonhirsute, control women participated in the study. Interventions: Interventions in the study included history and physical examination and blood sampling. Main Outcome Measure(s): Physical assessment and total and free T, dehydroepiandrosterone sulfate, fasting glucose, and insulin levels and calculated homeostatic model assessment values for insulin resistance (HOMA-IR) were measured. Results: Overall, 80% of PCOS subjects included had clinically evident oligomenorrhea. The remainder demonstrated vaginal bleeding intervals of fewer than 35 days (ie, with either polymenorrhea or clinically apparent eumenorrhea). Only 10% of PCOS subjects studied were ovulatory. After adjusting for body mass index, age, and race, all PCOS subjects with menstrual cycles longer than 35 days had significantly higher mean HOMA-IR levels than controls, and those with cycles longer than 3 months had the highest HOMA-IR levels. There was no difference in mean HOMA-IR levels between PCOS with regular vaginal bleeding (apparent eumenorrhea), regardless of whether they were anovulatory or not, or those with cycles fewer than 26 days, when compared with controls. Conclusions: Women with PCOS and overt oligomenorrhea comprise the vast majority of PCOS subjects seen clinically and have significantly more insulin resistance than controls. About 20% of PCOS women seen reported vaginal bleeding intervals of fewer than 35 days in length and did not generally have overt insulin resistance, regardless of whether they were ovulatory or not. Overall, the presence of clinically evident menstrual dysfunction can be used to predict the presence and possibly the degree of insulin resistance in women with PCOS. (J Clin Endocrinol Metab 98: E1967 E1971, 2013) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2013 by The Endocrine Society Received July 10, Accepted September 26, First Published Online October 3, 2013 Abbreviations: BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FT, free T; HOMA-IR, homeostatic model assessment values for insulin resistance; mfg, modified Ferriman-Gallwey; PCOS, polycystic ovary syndrome; TT, total T. doi: /jc J Clin Endocrinol Metab, December 2013, 98(12):E1967 E1971 jcem.endojournals.org E1967

2 E1968 Brower et al Menstrual Dysfunction and Insulin Resistance J Clin Endocrinol Metab, December 2013, 98(12):E1967 E1971 Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with multiple phenotypes that affects approximately 5% 8% of all reproductive-age women (1), making it the most common endocrine disorder in that age group. Women with PCOS are known to be at significantly increased risk for insulin resistance, dyslipidemia, impaired glucose tolerance, type 2 diabetes mellitus, and possibly cardiovascular disease (2, 3). These relationships persist after correcting for obesity and other risk factors for impaired glucose tolerance, including age, ethnicity, and family history. Population-based studies have suggested that women with irregular cycles are more likely to have unfavorable metabolic profiles (4, 5). The vast majority of women with PCOS, regardless of how defined, demonstrate anovulation and frequently overt menstrual dysfunction (1). However, not all anovulatory women with PCOS have clinically evident menstrual dysfunction. In fact, approximately 40% of women with hirsutism and apparent eumenorrhea demonstrate oligoovulation (ie, PCOS) when examined more closely (6, 7). There is a paucity of data exploring the relationships between the degree of clinically evident menstrual irregularity and metabolic dysfunction in anovulatory women with PCOS. If a relationship does exist between the degree of cycle irregularity and metabolic parameters in patients with PCOS, then menstrual dysfunction could be used as a simple clinical marker to identify patients at the greatest risk for metabolic abnormalities. The aim of the present study was to evaluate the relationship between the severity of menstrual disturbances and the degree of insulin resistance in women with PCOS. Materials and Methods Subjects Four hundred ninety-four women with PCOS and 138 controls recruited between 2003 and 2009 were included. The study was approved and conducted according to the guidelines of the Institutional Review Board of the Cedars-Sinai Medical Center. PCOS subjects were recruited from patients presenting to the Center for Androgen Related Disorders at Cedars-Sinai Medical Center for the evaluation of symptoms potentially related to androgen excess. PCOS was diagnosed by the Rotterdam 2003 criteria and was defined by the presence of two of the following three features: 1) oligo- or anovulation, 2) clinical and/or biochemical signs of hyperandrogenism, and 3) the presence of polycystic ovarian morphology on ultrasound (8). PCOS was diagnosed only after other related disorders had been excluded. One hundred thirty-eight non-pcos controls were recruited by local advertising. Control subjects had a long-term history of regular vaginal bleeding (26 34 d) consistent with ovulatory cycles, were nonhirsute [modified Ferriman-Gallwey (mfg) score 3], and did not have polycystic ovarian morphology on ultrasonography. Subjects were excluded if no cycle length information was available or if they had been on hormonal medication within 3 months of evaluation. The majority of, but not all, subjects had data available for the main outcome measures. Irrespective of missing data, subjects were eligible for inclusion if they could be categorized as PCOS or controls. Protocol All subjects completed a uniform questionnaire providing information regarding age, race, and menstrual history. Subjects with PCOS were grouped according to the interval between episodes of vaginal bleeding and classified as less than 26 days, days, days, 6 weeks to 3 months, and longer than 3 months, consistent with the data of Treloar et al and others (9, 10). Women with 26- to 34-day bleeding intervals were considered eumenorrheic and their ovulatory function assessed by measuring a menstrual cycle day progesterone level. Those women with a progesterone level less than 4 ng/ml were considered anovulatory (ie, classified as d 26 34, anovulatory), whereas the remainder were considered to be ovulatory (ie, classified as d 26 34, ovulatory) (11). Fasting baseline blood samples were obtained in all subjects in the follicular or preovulatory phase of the cycle, unless amenorrheic when the sample was obtained at random. All patients underwent a thorough physical examination, including assessment of body and facial masculine-type terminal hair growth by the mfg scoring method (12), and hirsutism was defined by an mfg score of 6 or greater (13). All patients were examined and assigned an mfg score by only one examiner (R.A.). Polycystic ovarian morphology was determined by transvaginal ultrasonography (Philips EnVisor C HD Ultrasound) and defined as at least one ovary containing 12 or more cystic structures measuring 2 9 mm and/or an ovarian volume of more than 10 cc (8). Related disorders were excluded by assessing the levels of TSH to exclude thyroid dysfunction, prolactin to exclude hyperprolactinemia, and 17-hydroxyprogesterone to exclude 21- hydroxylase-deficient nonclassic adrenal hyperplasia. Screening for Cushing s syndrome and androgen-secreting neoplasms was performed if clinically indicated. Laboratory analysis Blood was drawn after an overnight fast. Fasting blood samples were analyzed for insulin and glucose. Plasma glucose was measured in-house by quantitative enzymatic assay. Plasma insulin was measured using a chemiluminescent immunoassay (ARUP Laboratories). Total T (TT) was measured using high-turbulence liquid chromatography tandem mass spectrometry, and free T (FT) was determined by equilibrium dialysis. Serum levels of dehydroepiandrosterone sulfate (DHEAS) were measured by a competitive immunoassay (Quest Laboratories). Statistical analysis For analysis, subjects with PCOS were grouped according to the interval between menstrual cycles and classified as less than 26 days (polymenorrheic), days-ovulatory, days-anovulatory, days, 6 weeks to 3 months,

3 doi: /jc jcem.endojournals.org E1969 Table 1. Characteristics of PCOS Subjects Based on Menstrual Cycle Length Compared With Controls Controls (Reference) All PCOS Subjects <26 Days Days, Ovulatory Days, Anovulatory Days 6 Weeks to 3 Months >3 Months n, % of total in PCOS (3.2%) 51 (10.3%) 29 (5.9%) 50 (10.1%) 133 (26.9%) 215 (43.5%) Age, y Mean a a a a a a a BMI, kg/m Mean a a a a Waist to hip ratio Mean a a a a mfg score Mean a a a a a a a TT, ng/dl b Mean a a a a a a a FT, ng/dl b Mean a a a a a a a DHEAS, g/dl Mean a a a a a a a Fasting insulin, U/mL b Mean a a Fasting glucose, mg/dl b n Mean a a a a HOMA-IR (unadjusted) b n Mean a a This was an unadjusted, bivariate analysis. Values are presented as means SD, unless indicated otherwise. a P.05 compared with control. b Values presented as geometric means. and longer than 3 months. The homeostasis model assessment for insulin resistance (HOMA-IR) calculation was used as a proxy for the degree of insulin resistance. The HOMA-IR value was calculated, as follows (14): fasting serum glucose (millimoles per liter) fasting serum insulin (microinternational units per milliliter) /22.5. HOMA-IR is presented as geometric means unless otherwise noted. We should note that two models exist for determining HOMA-IR. HOMA1 is a simple calculation that has been shown to closely mirror the insulin sensitivity derived from the glucose clamp technique (15). HOMA2 is a more complex computer calculation that attempts to account for variations in hepatic and peripheral glucose resistance and the decreased specificity of older insulin assays. Because there is greater experience with the use of the HOMA1 calculation and documented correlation to more accurate measures of insulin sensitivity, this formula for HOMA-IR was used in the present study. Mean age, body mass index (BMI), waist to hip ratio, mfg, TT, FT, fasting insulin, fasting glucose, and HOMA-IR were compared between controls and all subjects with PCOS using one-way ANOVA. Pairwise post hoc mean comparisons under this ANOVA model were judged significant using the Fisher least significant difference criterion. A similar analysis was performed to compare the means between controls and each of the PCOS cycle length subgroups. A stepwise multiple regression analysis was used to compare the mean HOMA-IR of controls with each cycle length group while controlling for BMI, race, and age. A P.05 was considered significant. Results As a whole, subjects with PCOS had significantly higher TT, FT, DHEAS, and fasting glucose levels than controls. PCOS women had significantly higher BMIs, waist to hip ratios, and mfg scores and were slightly, although statistically significantly younger, than controls (Table 1). Subjects with PCOS were grouped according to the interval between episodes of vaginal bleeding (Table 1). Overall, 70% of PCOS subjects included in this referral population had significant oligomenorrhea, with vaginal bleeding intervals of at least 6 weeks. PCOS subjects with vaginal bleeding intervals of days comprised 10% of the total, and 19.4% had bleeding intervals of less than 35 days (ie, with either polymenorrhea or clinically apparent eumenorrhea). Only 10% of the PCOS subjects in this study were ovulatory (and were eumenorrheic). The clinical and biochemical characteristics of each cycle length group compared with controls are summarized in Table 1. Only PCOS subject with menstrual cycles 6 weeks to 3 month and longer than 3 months had HOMA-IR levels that were significantly higher than controls. Those women with PCOS and vaginal bleeding episodes of 35- to 45-day intervals tended to have higher HOMA-IR levels than controls, a difference that did not reach significance (P.06). After adjusting for BMI, age, and race, all PCOS subjects with cycles longer than 35-day intervals had significantly higher mean HOMA-IR levels than controls (Figure 1). Those with cycle lengths longer than 3 months had the highest HOMA-IR levels, followed by those with 35- to 45-day bleeding intervals. There was no difference in mean HOMA-IR levels in PCOS subjects with apparent eumenorrhea (whether ovulatory or not) or those with cycles less than 26 days when compared with controls.

4 E1970 Brower et al Menstrual Dysfunction and Insulin Resistance J Clin Endocrinol Metab, December 2013, 98(12):E1967 E1971 Mean adjusted HOMA-IR Of note, when the clinical and biochemical characteristics were compared between the six PCOS subgroups, based on cycle length, there were few differences noted, likely due to the small number of subjects in each subgroup (Supplemental Table 1, published on The Endocrine Society s Journals Online web site at jcem.endojournals.org). No statistically significant differences were found between any groups for BMI, DHEAS, fasting insulin, or HOMA-IR. Interestingly, the mean difference in the mfg score was significantly higher among women with PCOS and apparent eumenorrhea, compared with those who were ovulatory (4.33, P.01), despite having similar T levels. The higher mfg score likely reflects the greater (although not measurable) androgenicity of anovulatory subjects, although neither groups demonstrated a disturbance in insulin resistance when compared to controls. Discussion control < 26 days days ovulatory days anovulatory 2.17* 2.05* 2.31* days 6 wks-3 mos > 3 mos Figure 1. Insulin resistance as determined by HOMA-IR values, adjusted for age, BMI, and ethnicity, in PCOS according to cycle length. *, P.05 compared with controls. Analysis includes 56 controls, 13 PCOS subjects with cycles of less than 26 days, 29 PCOS subjects with ovulatory cycles of days, 19 PCOS subjects with anovulatory cycles of days, 45 PCOS subjects with 35- to 45-day cycles, 98 PCOS subjects with cycles of 6 weeks to 3 months, and 164 PCOS subjects with cycles of longer than 3 months. Overall, we observed in the PCOS population studied a significant relationship between the degree of overt menstrual (vaginal bleeding) dysfunction and the degree of insulin resistance present. After adjusting for BMI, age, and race, all PCOS subjects with menstrual cycles longer than 35 days had significantly higher mean HOMA-IR levels than controls, with those with cycle lengths longer than 3 months having the highest HOMA-IR levels. Alternatively, there was no difference in mean HOMA-IR levels between PCOS women with regular vaginal bleeding (ie, apparent eumenorrhea), regardless of whether they were anovulatory or not, or those with cycles less than 26 days, when compared with controls. In agreement, Strowitzki et al (16) recently reported that in patients with PCOS, insulin resistance was significantly worse in amenorrheic patients (cycle length 6 mo) when compared with those with normal cycles. In our study population, more than 40% of the women with PCOS referred to our clinic had cycle lengths longer than 3 months (ie, were amenorrheic), whereas 27% and 10% had cycle intervals that were between 6 weeks and 3 months or between 35 days and 6 weeks, respectively. Thus, more than 80% of PCOS women seen demonstrated overtly irregular vaginal bleeding (oligoamenorrhea). In contrast, approximately 20% of PCOS subjects seen had cycle intervals less than 35 days in length, and only 10% of the total were ovulatory (and eumenorrheic). These data suggest that the ovulatory PCOS phenotype (1) is relatively uncommon. However, these phenotypic frequencies were observed in a referral population. The prevalences of these cycle abnormalities may vary in unselected women with PCOS (17) because they reflect the subgroup of PCOS women who have sought medical attention and thus are more likely to demonstrate a more severe phenotype. We conclude that women with PCOS and overt oligomenorrhea (vaginal bleeding intervals of 35 d) comprise the vast majority of PCOS subjects seen clinically, and these patients have significantly more insulin resistance than controls. However, approximately 20% of the PCOS women seen reported regular vaginal bleeding intervals or, rarely, polymenorrhea. These latter women did not tend to demonstrate overt insulin resistance, regardless of whether they were ovulatory or not. Overall, these data suggest that the presence of clinically evident menstrual dysfunction can be used to predict the presence and possibly the degree of insulin resistance in women with PCOS, a feature that could be used to refine the current recommendations concerning the screening of PCOS subjects for metabolic dysfunction (2, 18, 19).

5 doi: /jc jcem.endojournals.org E1971 Acknowledgments Address all correspondence and requests for reprints to: Ricardo Azziz, MD, Georgia Regents University, Department of Obstetrics and Gynecology, th Street, AA-311, Augusta, GA This work was supported by National Institutes of Health Grant R01-HD29364 and an endowment from the Helping Hand of Los Angeles, Inc (to R.A.). Disclosure Summary: The authors have nothing to disclose. References 1. Azziz R, Carmina E, Dewailly D, et al. The Androgen Excess and PCOS Society Criteria for the Polycystic Ovary Syndrome: the complete task force report. Fertil Steril. 2009;91: Salley KE, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. Glucose intolerance in polycystic ovary syndrome a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007;92: Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95: Roumain J, Charles MA, De Courten MP, et al. The relationship of menstrual irregularity to type 2 diabetes in Pima Indian women. Diabetes Care. 1998;21: Solomon CG, Hu FB, Dunaif A, et al. Long or highly irregular menstrual cycles as a marker for type 2 diabetes mellitus. JAMA. 2001; 286: Azziz R, Waggoner WT, Ochoa T, Knochenhauer ES, Boots LR. Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertil Steril. 1998;70: Carmina E. Prevalence of idiopathic hirsutism. Eur J Endocrinol. 1998;139: Rotterdam ESHRE/ASRM sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovarian syndrome. Fertil Steril. 2004;81: Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil. 1967; 12: Chiazze L Jr, Brayer FT, Macisco JJ Jr, Parker MP, Duffy BJ. The length and variability of the human menstrual cycle. JAMA. 1968; 203: Wathen NC, Perry L, Lilford RJ, Chard T. Interpretation of single progesterone measurements in diagnosis of anovulation and defective luteal phase: observations on analysis of the normal range. Br Med J. 1984;288: Yildiz BO, Bolour S, Woods K, Moore A, Azziz R. Visually scoring hirsutism. Hum Reprod Update. 2010;1: Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Bots LR, Azziz R. Prevalence of polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 1998;83: Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and -cell function from fasting plasma glucose and insulin concentration in man. Diabetologica. 2000;43: Bonora E, Targher G, Alberichie M, Bonadonna RC, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care. 2000;23: Strowitzki T, Capp E, von Eye Corleta H. The degree of cycle irregularity correlates with the grade of endocrine and metabolic disorders in PCOS patients. Eur J Obstet Gynecol Reprod Biol. 2010; 149: Ezeh U, Yildiz BO, Azziz R. Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98: Palmert MR, Gordon CM, Kartashov AI, Legro RS, Emans SJ, Dunaif A. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87: Vrbíková J, Fanta M, Pelikánová T, Skrha J, Marek J; Czech Endocrine and Czech Diabetological Societies, Androgen Excess Society. [A recommended approach to evaluate cardiovascular risk and to prevent cardiovascular diseases and type 2 diabetes mellitus in women with polycystic ovary syndrome]. Vnitr Lek. 2012;58:56 57.

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0021-972X/06/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 91(1):2 6 Printed in U.S.A. Copyright 2006 by The Endocrine Society doi: 10.1210/jc.2005-1457 EXTENSIVE CLINICAL EXPERIENCE Relative