X/98/$03.00/0 Vol. 83, No. 9 Journal of Clinical Endocrinology and Metabolism Copyright 1998 by The Endocrine Society

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1 X/98/$03.00/0 Vol. 83, No. 9 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright 1998 by The Endocrine Society Prevalence of the Polycystic Ovary Syndrome in Unselected Black and White Women of the Southeastern United States: A Prospective Study* E. S. KNOCHENHAUER, T. J. KEY, M. KAHSAR-MILLER, W. WAGGONER, L. R. BOOTS, AND R. AZZIZ Departments of Obstetrics and Gynecology (E.S.K., W.W., L.R.B., R.A.), Occupational Health (T.J.K.), Genetics (M.M.-K.), and Medicine (R.A.), University of Alabama, Birmingham, Alabama ABSTRACT Estimates of the prevalence of the polycystic ovary syndrome (PCOS) in the general population have ranged from 2 20%. The vast majority of these reports have studied White populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the United States and address these limitations, we prospectively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women (174 White and 195 Black; aged yr), examined at the time of their preemployment physical. Body measures were obtained, and body hair was quantified by a modified Ferriman-Gallwey (F-G) method. All exams were initially performed by 2 trained nurses, and any subject with an F-G score above 3 was reexamined by a physician, the same for all patients. Of the 369 women, 277 (75.1%) also agreed to complete a questionnaire and have additional blood drawn. Subjects were studied regardless of current estrogen/progestin hormonal use (28.5%). PCOS was defined as 1) oligoovulation, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) exclusion of other related disorders, such as hyperprolactinemia, thyroid abnormalities, and nonclassic adrenal hyperplasia. Hirsutism was defined by a F-G score of 6 or more, and hyperandrogenemia was defined as a total or free THE POLYCYSTIC ovary syndrome (PCOS) was first reported in 1935 (1) and has been considered to be the most common cause of oligoovulatory infertility (2). These patients are at higher risk for developing infertility, dysfunctional uterine bleeding and endometrial carcinoma, and a number of metabolic disorders, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease (3 9). Notwithstanding the significant reproductive, endocrine, and metabolic morbidity of PCOS, little is known of its prevalence in the general population, particularly in the United States. The prevalence of PCOS, like that of any other complex multifactorial disorder, greatly depends on which criteria are used to define it. Most past studies have defined PCOS using a limited number of features, particularly morphological evidence of polycystic ovaries. When the presence of PCOS is Received February 17, Revision received May 19, Accepted May 29, Address requests for reprints to: Ricardo Azziz, M.D. M.P.H., University of Alabama, 618 South 20th Street, OHB 549, Birmingham, Alabama * This was supported in part by Grant RO1-HD-29364, an administrative supplement to Grant RO1-HD-29364, from the NIH (to R.A.). testosterone, androstenedione, and/or dehydroepiandrosterone sulfate level above the 95th percentile of control values [i.e. all eumenorrheic women in the study, who had no hirsutism (F-G 5) or acne and were receiving no hormonal therapy; n 98]. Considering all 369 women studied, White and Black women had similar mean ages ( and yr, respectively), although White women had a lesser body mass than Black women ( vs kg/m 2, respectively; P 0.001). Of these 7.6%, 4.6%, and 1.9% demonstrated a F-G score of 6 or more, 8 or 10, respectively, and there was no significant racial difference, with hirsutism prevalences of 8.0%, 2.8%, and 1.6% in Whites, and 7.1%, 6.1%, and 2.1% in Blacks, respectively. Of the 277 women consenting to a history and hormonal evaluation, 4.0% had PCOS as defined, 4.7% (6 of 129) of Whites and 3.4% (5 of 148) of Blacks. In conclusion, in our consecutive population of unselected women the prevalence of hirsutism varied from 2 8% depending on the chosen cut-off F-G score, with no significant difference between White and Black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of Blacks and 4.7% of Whites had PCOS as defined. These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women. (J Clin Endocrinol Metab 83: , 1998) defined solely by the finding of polycystic ovaries at either surgery or sonography, between 1 20% of unselected women have been reported to be affected (10 13). However, this marker is relatively nonspecific, because up to 25% of patients with this ovarian morphology on sonography are asymptomatic (14). In addition, not all patients with hyperandrogenic oligoovulation demonstrate polycysticappearing ovaries (13 16). A more comprehensive definition of PCOS arose from a conference on the disorder in April 1990, sponsored by the NIH/NICHHD. Although a clear-cut consensus was never reached, the majority of participants believed that PCOS should be defined by 1) ovulatory dysfunction, 2) clinical evidence of hyperandrogenism (hirsutism, acne, androgenic alopecia) and/or hyperandrogenemia, and 3) exclusion of related disorders, such as hyperprolactinemia, thyroid disorders, and nonclassic adrenal hyperplasia (NCAH) (17). No indication of how to define ovulatory dysfunction, hirsutism, or hyperandrogenemia was given. It is this definition of PCOS that is used in this report. In addition to limiting the criteria for the disorder, most reports examining the prevalence of PCOS have also used populations of women seeking medical care (10 13), albeit 3078

2 PREVALENCE OF PCOS IN THE U.S for reasons unrelated to hyperandrogenic complaints, a potential bias. Furthermore, no study has been made of non- White populations, particularly Black women. Because of the potentially significant public health impact of PCOS, we undertook the following prospective study of 369 consecutive women (195 Black and 174 White), evaluated during the time of a mandated preemployment physical, to assess the prevalence of the disorder and the extent of hirsutism. Subjects and Methods Subjects and protocol All prospective employees to the University of Alabama at Birmingham (UAB) from resident staff to environmental workers undergo an entrance physical that includes a brief history and physical and blood sampling by the Division of Occupational Health and Safety of the Department of Family Medicine. It should be noted that UAB is the single largest employer in the city of Birmingham and the third largest employer in the state of Alabama. Consecutive females aged yr who were being evaluated for employment to UAB were asked to participate. The study was approved by the institutional review board of UAB. Two occupational health nurses were trained to score the degree of hirsutism using a previously described modified Ferriman-Gallwey (F-G) method, quantitating the presence of terminal hairs over nine body areas (i.e. upper lip, chin, chest, upper and lower abdomen, thighs, upper and lower back, and upper arms) (18). All women seen by these nurses for their employment physical had the extent of hirsutism scored. They also recorded the presence of acne, although no specific scoring system was applied. Informed consent was provided, and if the subject agreed, an additional standardized history form was completed, with emphasis on menstrual dating and regularity, hirsutism and acne, gynecological history, medications, and family history. In those women who consented, a 30-cc sample of blood was obtained in plain-top tubes for subsequent hormonal analysis. Serum was stored at 70 C until assayed. To maximize uniformity all subjects with an F-G score above 3 according to the occupational health nurses were recalled, and hirsutism was rescored by one of the investigators (E.S.K.). To minimize treatment bias we included all women regardless of hormonal therapy or prior hysterectomy or oophorectomy. This was particularly important, as PCOS may predispose to the use of hormonal therapy and/or to surgical hysterectomy or castration. In these women, we determined menstrual history before their hormonal/surgical therapy and the reason for treatment. Circulating androgen levels were not obtained in either oophorectomized women or those receiving hormonal treatment. Defining the presence of PCOS As noted above, the presence of PCOS in these unselected women was defined by the presence of 1) ovulatory dysfunction, 2) clinical hyperandrogenism (i.e. hirsutism) and/or hyperandrogenemia, and 3) the exclusion of other known disorders, as previously reported (17). Specifically, these individual criterion were defined as follows. 1) Clinical hyperandrogenism was diagnosed by the presence of hirsutism (i.e. F-G score 6; see above). 2) Hyperandrogenemia was defined as a total and/or free testosterone (T), androstenedione (A4), and/or dehydroepiandrosterone sulfate (DHEAS) level above the upper 95th percentile of those race-matched women from the study population who were normal, i.e. those with regular menstrual cycles (26 34 days in length), who were nonhirsute (i.e. F-G score of 0 5), had no evidence of acne, and were taking no hormonal therapy. 3) Ovulatory dysfunction was surmised by a history of eight or fewer menstrual cycles in a year. 4) All subjects who after initial examination (and reexamination) and hormonal analysis potentially had PCOS (i.e. oligomenorrhea with hirsutism or acne, and/or hyperandrogenemia) had their serum samples further assayed for circulating PRL, TSH, and 17-hydroxyprogesterone (17-HP) levels to exclude hyperprolactinemia, thyroid dysfunction, and 21-hydroxylase-deficient NCAH, respectively. All women who had an elevated screening 17-HP level (i.e nmol/l) underwent an acute ACTH stimulation test to exclude 21- hydroxylase-deficient NCAH, as previously described (19). As the level of 17-HP, which is used to screen for NCAH (19), is increased in the luteal phase of the menstrual cycle, a serum progesterone (P4) level was also measured in all serum samples. If the P4 level was nmol/l or less, the subject was considered to be in the follicular phase. If the P4 level was above nmol/l, the subject was considered to have been in the luteal phase of the menstrual cycle, and any values of 17-HP above 6.36 nmol/l were disregarded. In this event, the patient was recalled, and the test was repeated in the follicular phase of a subsequent cycle. The diagnosis of PCOS was also excluded in women with persistent elevations of PRL (i.e. 29 g/l) or abnormal TSH values ( 5 miu/l or 1 miu/l). Finally, Cushing s syndrome and androgenic tumors were excluded by appropriate testing if suspected clinically, as previously described (20). All study subjects with abnormal findings were notified of the results of their evaluations, and those individuals with abnormal physical, historical, or biochemical findings were encouraged to undergo further investigation and/or therapy. Hormonal analysis Excluding those samples from women who either did not consent, were oophorectomized, or were receiving hormonal treatment, serum samples were analyzed for total and free T, sex hormone-binding globulin (SHBG), DHEAS, A4, and P4. Selected individuals (see above) also underwent measurements of PRL, TSH, and 17-HP. Samples were batched at regular intervals for analysis to minimize the impact of interassay variability while providing study subjects with timely information. Total T was measured by an in-house RIA method after serum extraction, as previously described (21, 22). SHBG activity was measured by diffusion equilibrium dialysis, using Sephadex G-25 and [ 3 H]T as the ligand, and free T was calculated, as previously described (23). DHEAS, P4, A4, PRL, TSH, and 17-HP were measured by direct RIA, using commercially available kits (DHEAS and P4 from Diagnostic Products Corp., Los Angeles, CA; A4 from Diagnostics Systems Laboratories, Webster, TX; and TSH and PRL from Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay variances for 17-HP and A4 (19) and for total T (21, 22) have been previously reported. The intraand interassay coefficients of variances for the DHEAS assay were 3.2% and 1.6%, and 2.6% and 6.0% for low and high levels, respectively; for SHBG, they were 7.8% and 4.1%, and 5.1% and 6.8%, respectively; for TSH, they were 12.0% and 1.9%, and 13.0% and 5.7%, respectively; and for PRL, they were 6.4% and 6.45, and 13.4% and 5.0%, respectively. Sample size, power calculations, and statistical analysis The primary objective of this investigation was to generate an estimate of the prevalence of PCOS separately for White and Black women in the Birmingham area. Published reports indicated that the prevalence in the general population ranged from 1 20%, with an average of 5 10% (10 13). We further assumed that the overall prevalence of PCOS was similar in White and Black women. Consequently, we selected a sample size sufficient to generate a relatively narrow confidence interval around the point estimate. With a sample size of 150 in each racial group, the size of a two-sided 95% confidence interval ranged from %, assuming a prevalence of 5%, and from % for a prevalence of 10%. P 0.05 was considered significant. A statistical software package was used to perform Student s t test on the continuous data, a Mann- Whitney test (nonparametric comparison) was used for discrete data, and a 2 test was used for the discontinuous variables (Kiwkstat-Winks 4.21 Basic, TexasSoft, Cedar Hill, TX). Power analysis was performed using PASS software (Jerry Hintze, Kayville, UT). Results A total of 369 women (174 White and 195 Black) were initially screened. Mean age was similar between Black and White women ( vs yr), although Black women had a higher mean body mass index (BMI) than Whites ( vs kg/m 2, respectively; P 0.001). Of the total 369 subjects, 7.6%, 4.6%, and 1.9% demonstrated an F-G score of 6 or more, 8, or 10, respectively.

3 3080 KNOCHENHAUER ET AL. JCE&M 1998 Vol 83 No 9 None of the subjects with an F-G score below 6 had a history of more than 10 sessions of electrology on the neck, chin, upper lip, chest, or abdomen (excluding thighs, eyebrows, and pubic area), which could have suggested occult hirsutism. Overall, 4.6% of all women studied had acne. There was no significant racial difference in the prevalence of excess hair growth, with 8.0%, 2.8%, and 1.7% of White women and 7.1%, 6.1%, and 2.1% of Black women affected, respectively. Overall, the distribution of F-G scores did not demonstrate a significant difference between Black and White patients. There was also no difference in the incidence acne between White and Black women (5.2% vs. 4.1%, respectively). Of the remaining 45 women with an F-G score above 3, 33 were able to be reexamined (73%). Reasons why subjects were not reexamined included refusal to participate in the study (n 2), refusal to return for exam (n 5), moving out of the area (n 1), and inability to contact (n 4), as not all subjects undergoing the preemployment physical were actually hired or remained at the university. Of the 33 women reexamined, only 1 had a change in her original F-G score by more than 5 points, from a score of 20 down to 8. In the vast majority of women reexamined by the investigator (28 of 33, or 85%) the F-G scores did not change by more than 2 points compared to the research nurse s assessment. None of those changes affected the subsequent diagnosis of PCOS in these patients. Of the total of 369 women screened, 24.9% (45 White and 47 Black) refused to participate beyond the initial exam. Most of the women refusing to participate did not want to complete the questionnaire. The 92 women who refused to participate did not differ in racial composition (24.1% Black vs. 25.8% White) or mean BMI ( vs kg/m 2, respectively) from those agreeing to enter the study, although they did differ in mean age ( vs yr, respectively; P 0.001) and mean initial F-G score ( vs , respectively; P 0.001), from those 277 women consenting to the full study. It should be noted that of the 45 women with F-G scores above 3, only 2 (4.4%) refused to participate in the full study. The 2 women who did not agree to participate had F-G scores of 4 each, as initially screened by the research nurse. The racial composition of the 277 subjects agreeing to participate further in the study was divided almost equally between Black (n 148) and White (n 129) women (P 0.05). Of these, 198 (118 Black and 80 White) were taking no hormonal therapy, and their sera were assayed as noted above. Seventy-nine women (28.5%; 30 Black and 49 White) were receiving estrogen/progestin therapy, of whom 56 (24 Black and 32 White) were taking an oral contraceptive pill solely for the purpose of birth control. Ninety-eight women (45 White and 53 Black) were nonhirsute (i.e. F-G score 5), nonacneic, eumenorrheic (regular cycles at 35-day intervals), and taking no hormonal therapy. These women then composed the normal population from which the upper control limits of the androgen values were drawn. As there was no statistical (or clinically apparent) difference in mean androgen values between Black and White women, their hormonal data were pooled to establish the upper control 95th percentile values of androgens, as follows: total T, 2.94 nmol/l; free T, nmol/l; DHEAS, 6.64 mol/l; and A4, 8.73 nmol/l. Of the 277 (75.1%) women who consented to further evaluation, 35 (11.9%) had a history consistent with oligoovulation, with no significant difference between Black and White women (12.2% vs. 13.2%, respectively). Overall, of the 277 women studied by history and exam, 11 (4.0%) had PCOS as previously defined, with no significant difference between the races (6 of 129 or 4.7% of Whites, and 5 of 148 or 3.4% of Blacks). In total, 8 of the 11 subjects with PCOS had hyperandrogenemia (subjects 1 8 in Table 1); 3 of the women were diagnosed with PCOS solely based on their F-G score and history of oligomenorrhea (subjects 9 11 in Table 1), as the androgen levels in subject 9 were normal, and serum androgen levels were not determined in subjects 10 and 11, as they were concurrently receiving oral contraceptive pills. As defined, none of the women diagnosed with PCOS had evidence of thyroid disease, hyperprolactinemia, Cushing s syndrome, androgenic tumor, or 21-hydroxylase deficient NCAH. In screening for NCAH, none of the subjects suspected of PCOS had an initial 17-HP level above 2 ng/ml, effectively ruling out the disorder, as previously described (19). None of the PCOS subjects detected had a previous diagnosis of hypertension (all had normal blood pressure measurements) or diabetes, although no specific effort to diagnosis the latter was made at this time. In addition to TABLE 1. Characteristics of women diagnosed with PCOS Subject no. Age (yr) BMI (kg/m 2 ) Race Oligomenorrhea F-G score Acne Total T (nmol/l) Free T (nmol/l) DHEAS ( mol/l) A4 (nmol/l) Black Yes 5 No a Black Yes 0 No a Black Yes 0 No a Black Yes 4 No a a Black Yes 0 No a White Yes 4 No a White Yes 3 Yes a White Yes 0 No a White Yes 6 Yes White Yes 7 No ND b ND b ND b ND b White Yes 6 Yes ND b ND b ND b ND b Oligomenorrhea was defined as having menstrual cycles at more than 35-day intervals. Subjects 12 and 13 were receiving oral contraceptive medications, and circulating androgen levels were not determined. a Greater than the 95th percentile of normal. b ND is not determined secondary to receiving oral contraceptive pills.

4 PREVALENCE OF PCOS IN THE U.S those patients diagnosed with PCOS, 26 women (13 Black and 13 White) solely had hyperandrogenemia, whereas 12 women (8 Black and 4 White) had both hyperandrogenemia and hirsutism, but regular menstrual cycles. Discussion If PCOS is defined histopathologically (i.e. by the presence of polycystic ovaries upon oophorectomy or wedge resection) between % of unselected women and % of infertile women demonstrate evidence of the disorder (12). Alternatively, if PCOS is defined by the ultrasonographic appearance of polycystic ovaries, 21 23% of unselected women appear to be affected (10, 11, 13). However, this is probably an overestimation, because this marker of PCOS is relatively nonspecific. Up to 25% of patients with this sonographic picture may be entirely asymptomatic (14), and not all patients with hyperandrogenemia demonstrate polycystic ovaries (13 16) even when using the more sophisticated computerized measurements of ovarian stroma (24). However, the prevalence of PCOS defined endocrinologically has never been previously determined. We now have used a more widely accepted endocrine definition of PCOS (17), arising from an NIH/NICHHD-sponsored conference in 1990, and have estimated that 6.2% of 129 White and 3.4% of 145 Black women have the disorder. It should be noted that defining obesity as a BMI above 30 kg/m 2 (25), 36% (4 of 11) or our PCOS women were overweight, consistent with the findings of others (26). We have tried to minimize selection bias in the inclusion of subjects in this study. All subjects were undergoing a mandated preemployment physical exam, which includes all medical, nursing, clerical, and support staff seeking employment to UAB. Furthermore, racial and socio-economic bias is minimized, as UAB is the single largest employer in the city of Birmingham. However, our study was biased toward underestimating the prevalence of PCOS, as clinical hyperandrogenism was defined only by the presence of hirsutism, circulating androgen levels could not be determined in women already receiving hormonal therapy, and ovulatory function was estimated from menstrual history. For example, acne and androgenetic alopecia may also be peripheral signs of hyperandrogenism. As the optimum system for acne scoring remains highly disputed (27), we elected to simply record its presence, without a grade, in our subjects. In our population, three women (two Black and one White) had evidence of acne, and their consideration would have increased the overall incidence of PCOS to 5.1%. In our population, 25% of subjects were receiving either oral contraceptive pills or a progestin only contraceptive; two thirds of these were taking these for contraceptive purposes. Of the 79 women receiving hormonal therapy, 2 were categorized as having PCOS according to F-G score and menstrual history alone. Of the remaining 77 subjects receiving hormonal therapy, 10 had a history of irregular menses but no hirsutism. If we assume that 50% of these treated patients with menstrual irregularity (i.e. 5) actually had PCOS without hirsutism (i.e. hyperandrogenemia and oligoovulation), then the overall prevalence of PCOS would be increased to 5.4%. Finally, in an unrelated study we noted that up to 40% of hirsute women who claiming to have regular menses actually have oligoovulation when evaluated more closely (28). Applying this finding to our current study population, we note that 28 subjects had hirsutism (i.e. F-G score 6), and all participated in the study. Of these, 3 were categorized as PCOS based on menstrual history. Hence, if we assumed that 40% of the remaining subjects (i.e. 25) claiming to have regular menses actually had ovulatory dysfunction (and therefore PCOS), then the overall prevalence of PCOS would have increased to 7.6%. Based on these assumptions, our overall population of patients with PCOS could have been as high as 29 of the 277 subjects fully studied, i.e. including those women with oligomenorrhea and acne, and those fractions of subjects with either oligomenorrhea during hormonal therapy or hirsutism and regular menstrual cycles, assumed to have PCOS. This would yield an overall maximum prevalence for the disorder of 10.5%. Alternatively, we may have overestimated the prevalence of PCOS by not being able to consider those women who refused to participate further in the study, i.e. complete a thorough gynecological history form and provide serum samples. It is possible that these women may have been, as a population, less affected than those participating, resulting in their lesser interest in the study. If all the women who refused participation were assumed to not be affected, then the overall prevalence of PCOS could have been as low as 3.0% (11 of 369). It should be noted that it was not possible to adequately control for the time of the day of serum sampling because exams are performed between h, nor for the day of the menstrual cycle. Nonetheless, although total T and A4 measured by RIA increase slightly in the late follicular and luteal phase in normal premenopausal women, these values generally remain within normal limits (29 31). In addition, total T does not have significant diurnal variation, at least in postmenopausal women (32). Although some investigators have noted that A4 levels follow the adrenocortical circadian cycle (32), we were unable to demonstrate a significant difference in mean A4 levels obtained between h and h in five healthy control women sampled every 5 min (33). DHEAS does not vary with menstrual cycle (29) and, at least in men, varies little diurnally (34). Finally, SHBG, used to determine the concentration of free T, does not demonstrate a consistent alteration with the menstrual cycle (23, 35) or the circadian rhythm (36). Overall, neither the time of exam nor the day of the menstrual cycle appears to have a significant impact on the clinical value of circulating androgens. In addition to determining the prevalence of PCOS, this study also allowed us to crudely establish the overall incidence of hirsutism. Various investigators have noted that excess hairiness occurs in 5 15% of consecutive Caucasian women (29, 37 40). In the present study of 369 consecutive unselected women, the prevalence of hirsutism varied from 2 8%, depending on the chosen cut-off F-G score, with no significant difference between White and Black women. We chose an F-G score of 6 or more as indicating the presence of significant hirsutism. In the original study by Ferriman and Gallwey (41), a score of 6 or greater was observed in only 5% of the general population. Furthermore, Lorenzo (42) studied

5 3082 KNOCHENHAUER ET AL. JCE&M 1998 Vol 83 No unselected female medical patients, using a modification of the F-G score with lesser areas assessed, and did not observe a score over 5 among them. In conclusion, we have observed that in an unselected minimally biased population of consecutive women, the overall prevalence of PCOS appears to be approximately 4.6%, although it could be as low as 3.5% and as high as 11.2%, using the NIH/NICHHD 1990 criteria. There appeared to be no significant difference in prevalence between White and Black women. Our data support the concept that PCOS is one of most common reproductive endocrinological disorders of women. References 1. Stein IF, Leventhal ML Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 29: Hull MG Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. 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