Polycystic ovary syndrome. Phenotypic comparison of Caucasian and Asian women with polycystic ovary syndrome: a cross-sectional study

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1 henotypic comparison of and women with polycystic ovary syndrome: a cross-sectional study Erica T. Wang, M.D., M.A.S., a Chia-Ning Kao, M.S., b Kanade Shinkai, M.D., h.d., c Lauri asch, h.d., d Marcelle I. Cedars, M.D., b and Heather G. Huddleston, M.D. b a Department of Obstetrics & Gynecology, Cedars Sinai Medical Center, Los Angeles, California; b Department of Obstetrics, Gynecology, and Reproductive Sciences, c Department of Dermatology, and d Department of sychiatry, University of California San Francisco, San Francisco, California Objective: To determine whether manifestations of polycystic ovary syndrome (COS), particularly androgen excess, differ between and women in the San Francisco Bay Area. Design: Cross-sectional study. Setting: Multidisciplinary COS clinic at a tertiary academic center. atient(s): 121 and 28 women, aged 18 44, examined between 2006 and 2011 with COS verified by a reproductive endocrinologist and dermatologist according to the Rotterdam criteria. Intervention(s): Transvaginal ultrasounds, comprehensive dermatologic exams, and serum testing. Main Outcome Measure(s): Hirsutism defined as a modified Ferriman-Gallwey (mfg) score R8, acne, androgenic alopecia, and biochemical hyperandrogenism. Result(s): and women had a similar prevalence of all measures of androgen excess. Both groups had similar total mfg scores and site-specific mfg scores, except women had a lower site-specific mfg score for the chest. Although women were more likely to use laser hair removal, the results were unchanged when the women with a history of laser hair removal were excluded. Conclusion(s): and women with COS living in the same geographic region had a similar prevalence of hirsutism as well as other markers for androgen excess. Further studies are necessary to evaluate the need for ethnic-specific mfg scores in women with COS. (Fertil Steril Ò 2013;100: Ó2013 by American Society for Reproductive Medicine.) Key Words: Ethnicity, hirsutism, polycystic ovary syndrome Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/wanget-polycystic-ovary-syndrome-hirsutism/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. olycystic ovary syndrome (COS) is a heterogeneous endocrine disorder marked by anovulation, androgen excess, and polycystic ovaries (1 3). henotypic differences for COS have been reported in women of diverse ethnic groups (4 8); however, ethnicity and its impact on the phenotypic presentation of COS is not accounted for in the diagnostic criteria for COS. Hirsutism is defined by the presence of excessive terminal hair in androgen-sensitive areas of the female body. The modified Ferriman- Gallwey (mfg) scores 9 of the 11 body areas (upper lip, chin, chest, upper and lower back, upper and lower abdomen, arm, forearm, thigh, and lower leg) originally proposed by Ferriman and Gallwey, excluding the lower legs and forearms (9). Traditionally a mfg score R8 has been used to define hirsutism based on a population (9). Whether this criterion is Received October 30, 2012; revised February 15, 2013; accepted March 4, 2013; published online April 1, E.T.W. has nothing to disclose. C.-N.K. has nothing to disclose. K.S. is supported by a Dermatology Foundation Career Development Award. L.. has nothing to disclose. M.I.C. has nothing to disclose. H.G.H. has nothing to disclose. Reprint requests: Erica T. Wang, M.D., M.A.S., Cedars Sinai Medical Center, 8635 W 3rd Street, Suite 160 W, Los Angeles, California ( erica.wang@cshs.org). Fertility and Sterility Vol. 100, No. 1, July /$36.00 Copyright 2013 American Society for Reproductive Medicine, ublished by Elsevier Inc. appropriate for all ethnicities is a question that has yet to be resolved. Studies in the literature suggest that the appropriate mfg score to define hirsutism in women, excluding those from the Indian subcontinent, is less than 8. In a large population-based study in China of 3,000 women, mfg R5 was found to be associated with COS symptomatology (10). In Thailand, among women seeking preventative gynecologic care, the 97.5th percentile for mfg score was R3 (11). However, among women in the United States a cross-sectional study of 170 and 20 women with COS in Boston showed a similar prevalence of hirsutism defined by mfg score R9 and mean mfg score (6). The aim of 214 VOL. 100 NO. 1 / JULY 2013

2 Fertility and Sterility TABLE 1 Baseline characteristics of polycystic ovary syndrome study participants. Characteristic Age, y Body mass index, kg/m Waist circumference, cm Oligomenorrhea, n (%) (87.0) 28 (100).04 Antral follicle count R12 a (85.1) 23 (82.1).69 Ovarian volume R10 ml b (44.6) 14 (50.0).61 Fasting glucose, mg/dl hour glucose, mg/dl Fasting insulin, miu/ml Total cholesterol, mg/dl HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglycerides, mg/dl Current medication use, n (%) c Oral contraceptive pills (22.3) 4 (14.8).45 Metformin 15 (12.4) 3 (11.1) 1.0 Spironolactone 8 (6.6) 0.35 rior laser hair removal, n (%) (13.9) 8 (32.0).03 a Dichotomous observation with at least one ovary with R12 antral follicles. b Dichotomous observation with at least one ovary with volume R10 ml. c Based on clinic instructions, patients discontinued oral contraceptive pills and spironolactone at least 1 month before the assessment. Wang. and women with COS. Fertil Steril this study was to determine whether clinical manifestations of androgen excess, in particular hirsutism, differ between and women presenting to a multidisciplinary COS clinic in San Francisco. MATERIALS AND METHODS This was a cross-sectional study in which participants were consecutively recruited from a monthly multidisciplinary COS clinic at the University of California at San Francisco (UCSF) over 5 years ( ). This clinic was targeted toward women who were not seeking fertility treatment. Approval was obtained from the UCSF Committee on Human Research. articipants were included if they self-identified as or and fulfilled the COS diagnosis by Rotterdam criteria, with two out of three of the following: oligo-ovulation, clinical and/or biochemical hyperandrogenism, and the presence of 12 or more antral follicles per ovary and/or ovarian volume >10 ml (1). articipants were excluded if they reported a mixed ethnic background (e.g., - or -African American). We also excluded women who specifically identified themselves as South (n ¼ 4). Studies have reported that South women may have a higher mean mfg score, with one study of 47 South women with COS reporting a mean mfg score as high as 18 (7). articipants presented for a one-time visit in which they completed a self-administered questionnaire and underwent anthropometric measurements and a transvaginal ultrasound to determine ovarian morphology. The patients were evaluated by a dermatologist at the same visit to determine their total mfg score and to assess for the presence of other cutaneous manifestations of hyperandrogenism, including acne and androgenic alopecia. Serum androgen results, but not menstrual history or ovarian morphology, were available to the dermatologist. Site-specific mfg scores were available for a subset of the study group. Serum total testosterone, free testosterone, dehydroepiandrosterone-sulfate (DHEA-S), and androstenedione were obtained at commercial laboratories based on individual insurance plans. In general, two commercial laboratories were used. Because of the difference in assays used, we chose not to report continuous measures of serum androgens, but rather to look at whether s were elevated based on the specific reference range of each laboratory. Congenital adrenal hyperplasia was ruled out with a normal 17-hydroxyprogesterone level. Metabolic testing included a 75 gram 2-hour oral glucose tolerance test and fasting lipids. articipants were asked to discontinue oral contraceptives pills or spironolactone at least 1 month before the clinic visit, and to refrain from waxing, shaving, or plucking for at least 1 week before the clinic visit. This time frame was determined based on realistic expectations of the patient population. We did not want to require a longer time frame off medications and treatments, which may have been prohibitive for patients wishing to be evaluated in the clinic. We examined four dichotomous markers of androgen excess: hirsutism defined as mfg score R8, acne, androgenic alopecia, and elevated serum androgens. articipants were defined as having elevated serum androgens if they had any for total testosterone, free testosterone, DHEA-S, or androstenedione greater than the reference range of the specific laboratory. Statistical analyses were performed using the t test, chisquare test, and Fisher's exact test as appropriate. The number of included for each variable of interest is shown in Tables 1 3. RESULTS Of the 336 women seen at the multidisciplinary COS clinic from 2006 to 2011, there were 237 women who fulfilled the VOL. 100 NO. 1 / JULY

3 ORIGINAL ARTICLE: RERODUCTIVE ENDOCRINOLOGY TABLE 2 Markers of androgen excess in polycystic ovary syndrome study participants. Marker Hirsutism, n (%) (48.8) 13 (46.4).82 Acne, n (%) (67.9) 17 (73.9).57 Androgenic (20.4) 4 (20.0).97 alopecia, n (%) Elevated serum androgens, n (%) (63.5) 12 (48.0).15 Wang. and women with COS. Fertil Steril Rotterdam criteria. Of the 237 women, 121 were women and 28 women (Table 1). Among the women with COS, 20 identified themselves as / American (71%), 7 as East (25%), and 1 as acific Islander (3.4%). The two groups of women were similar in terms of age and metabolic profile (Table 1). One hundred percent of women with COS had oligomenorrhea, whereas 87.0% of women reported oligomenorrhea (¼.04). Both groups had similar ovarian morphology, even in age-adjusted analyses. Eighty-five percent of women and 82.1% of women had antral follicle counts R12 in one ovary (¼.69), and 44.6% of women and 50.0% of women had at least one ovary with volume R10 ml (¼.61) (Table 1). Although there was no statistically significant difference between and women in the use of oral agents including oral contraceptive pills, metformin, and spironolactone, a higher proportion of women reported prior use of laser hair removal (32.0% vs. 13.9%, ¼.03). There were no statistically significant differences in the prevalence of hirsutism, acne, androgenic alopecia, or elevated serum androgens between and women in this study (Table 2). Approximately 50% of both groups fulfilled the criteria for hirsutism. women were more likely to have elevated serum androgens, but this was not statistically significant. TABLE 3 Modified Ferriman Gallwey (mfg) score for polycystic ovary syndrome study participants. Area Total mfg a Lip b Chin Chest <.0001 Upper back Lower back Upper abdomen Lower abdomen Upper arm Thighs a Total mfg score ranges from 0 to 36. b Site-specific mfg score ranges from 0 to 4. Wang. and women with COS. Fertil Steril We subsequently focused on the mfg score, both total and site specific(table 3). Total mfg scores were comparable between and women ( vs , ¼.21). The only site in which the two groups of women differed in mfg score was the chest: and for women and women, respectively (<.0001). Although it was not statistically significant, we noticed a trend toward lower mfg scores in women for the upper trunk, which also included the upper back, shoulders, and upper abdomen. In a sensitivity analysis of the women who did not report prior use of laser hair removal, the mean mfg score of women was also not statistically different compared with women ( vs , ¼.89). It is interesting that, of the women who did report prior use of laser hair removal, the mean mfg score of women was statistically significantly higher than women ( vs , ¼.04). DISCUSSION In this exploratory analysis, we compared and women with COS in the San Francisco Bay Area, as defined by the Rotterdam criteria. The two groups of women had a similar prevalence of clinical measures of androgen excess, including hirsutism, acne, androgenic alopecia, and biochemical hyperandrogenism. Total and site-specific mfg scores were also comparable, with the exception of women with COS having a lower mfg score at the chest. and women in this study reported comparable use of oral agents for COS symptomatology; however, women were more likely to report prior use of laser hair removal. Of the women who reported prior use of laser hair removal, women had a statistically significant higher mfg score than women. This suggests that there may be a small subset of women with COS who have more severe and/or treatment resistant hirsutism compared with their counterparts. Recently, the Amsterdam ESHRE/ASRM-sponsored 3rd COS Consensus Workshop Group concluded that geographic location, ethnic origin, and cultural/social practices are likely contributors to the differing manifestations of COS and should be recognized in routine clinical practice and that hirsutism, considering ethnic differences, is a good marker for hyperandrogenism (12). However, the group did not specify whether ethnic-specific mfg scores are needed to define hirsutism in women with COS. Although the Androgen Excess and olycystic Ovary Syndrome Society have suggested ethnic-specific cutoffs for the use of mfg scores to define hirsutism, their recommendations are based on unselected populations of premenopausal women living in countries outside of the United States (13). opulation-based studies in East Asia suggest that hirsutism may be defined by mfg scores of <8. In Thailand, among premenopausal women seeking preventative gynecologic care, the 97.5th percentile for mfg score was R3 (11). In a large population-based study in China of 3,000 women, the investigators observed an mfg score R5 in 10% and a score of R2 in 25% of the participants (10). They also 216 VOL. 100 NO. 1 / JULY 2013

4 Fertility and Sterility determined that mfg R5 was associated with COS symptomatology, including acne, menstrual irregularities, and polycystic ovaries, leading to their conclusion that a mfg score of R5 should be used as a cutoff to define hirsutism in this population. Two additional studies reported similar results: [1] a study of 915 women living in southern China demonstrated a 2.2% prevalence of COS, and none of the women with COS were noted to have hirsutism (mfg scores 0 3) (4), and [2] another study evaluating 547 women with COS in China reported a mean mfg score 3.6 (5). The aforementioned studies focused on East women with COS living in their native countries. Several studies have evaluated the COS phenotype by ethnicity in the United States. The regnancy in olycystic Ovary Syndrome (COS) Study recruited 623 infertile women with COS classified by race into four groups:, African-American,, and American Indian or Alaska Native (14). Of these, 17 women were. Across all four groups, there was no statistically significant difference in the mean mfg score, with scores of and for women and women, respectively (14). Another study compared 127 and 21 women with COS living in the same geographic region: Welt et al. (6) determined that the and women with COS living in Boston had similar mfg scores of 15.4 and 15.7, respectively. Both of these studies used the National Institutes of Health (NIH) criteria for COS. Our study is most like that of Welt et al. (6) as we were also comparing and women with COS living in the same geographical region of the United States. and women in our study had mean mfg scores of 8.6 and 7.4, which is significantly lower compared with both the aforementioned studies. This may be due to the fact that our participants were scored by a dermatologist instead of gynecologists or reproductive endocrinologists, which may have also contributed to a lower range of mfg scores. In addition, the COS cohort (14) and Welt et al. (6) used the NIH criteria whereas our study classified women based on the Rotterdam criteria. Thus, a proportion of our participants would be normoandrogenic with either oligomenorrhea or CO-appearing ovaries, which could explain the lower mfg scores. Our study further expands on the current literature with the assessment of site-specific mfg scores. We identified lower chest hair scores in women, as well as a trend in lower scores across the upper trunk (upper back, upper arms, upper abdomen), which may indicate subtle ethnic differences in site-specific hirsutism patterns that should be explored further in a larger population. This underscores the importance of a comprehensive full-body exam for hirsutism in COS patients. Although population-based studies in East Asia suggest lower mfg scores in women with COS, our study, together with Welt et al. (6), suggests that women with COS living in the United States are more similar to women with COS than their counterparts living in East Asia. This suggests a role for a geographic and environmental influences, potentially through diet, on the phenotype of hirsutism. Although studies on the role of migration and endogenous hormone levels suggest that androgen levels are lower in Western-born women than their counterparts born in Asia or akistan (15, 16), small trials of women with COS suggest that diet may influence sex hormonebinding globulin (SHBG) levels and androgen levels (17 20). One trial of 28 overweight women with COS demonstrated that with energy restriction the participants experienced weight loss and increased SHBG levels accompanied by decreased testosterone levels (17). Another trial of 24 overweight women with COS who underwent a lowcalorie diet (1,500 kcal) resulted in a decrease in body mass index (BMI), increase in SHBG, and decrease in free testosterone, with no additional benefit when metformin was added to the diet (19). Thus, if women with COS living in the United States are consuming a diet of higher caloric intake than their counterparts living in East Asia, their SHBG levels may be decreased, allowing for a higher concentration of free testosterone and subsequently hirsutism. The question remains as to whether prior treatment for unwanted hair growth may have confounded the results of this study. Although we asked participants to discontinue oral contraceptive pills and spironolactone at least 1 month before the clinic assessment, this may not have been an adequate amount of time to eliminate the treatments' effects on hirsutism; however, the clinic did not want to set up a longer duration of time off medications as a prerequisite because this may have decreased the number of patients willing to be evaluated. We did conduct a sensitivity analysis of women who did not report prior use of laser hair removal, in which the mean mfg scores remained comparable between and women, supporting our conclusions. Although we excluded the women who identified themselves as specifically South Indian, the women included may still be a heterogeneous group: 7 of the 28 women specified East backgrounds, but there were 20 women who identified as / American for whom we did not have additional details. We recognize that our patient population was a select group of women who sought a multidisciplinary approach for COS at a tertiary care center, which may not be applicable to the general population. However, strengths of our study include a systematic evaluation of and women with COS living in the same geographic region, and our participants were independently evaluated by a dermatologist for mfg score and additional skin findings. Our study highlights the similar phenotypic presentation of hyperandrogenism between women and women who fulfill the Rotterdam criteria for COS in a geographically restricted region. Both groups had similar total and site-specific mfg scores, with the exception of the women having a lower site-specific mfg score for the chest. Larger studies accounting for prior treatment may be necessary to evaluate the need for ethnic-specific mfg scores to define hirsutism in women with COS. REFERENCES 1. Rotterdam EA-SCWG. 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