POLYCYSTIC ovary syndrome (PCOS) appears to be a

Transcription

1 X/99/$03.00/0 Vol. 84, No. 11 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 1999 by The Endocrine Society A Survey of the Polycystic Ovary Syndrome in the Greek Island of Lesbos: Hormonal and Metabolic Profile EVANTHIA DIAMANTI-KANDARAKIS, CHRYSSA R. KOULI, ANGELIKI T. BERGIELE, FANNY A. FILANDRA, THOMAIS C. TSIANATELI, GIOVANNA G. SPINA, EVANGELIA D. ZAPANTI, AND MICHAEL I. BARTZIS Endocrine Section, First Department of Medicine, University of Athens Medical School, Laiko General Hospital, Goudi Athens, Greece ABSTRACT Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, and oligomenorrhea (O/M). PCOS has variable clinical phenotypes, biochemical features, and metabolic abnormalities. To determine the prevalence of PCOS in the Greek population as well as the metabolic parameters, we performed a cross-sectional study of 192 women of reproductive age (17 45 yr), living on the Greek island of Lesbos. They were divided into 4 groups according to the presence of hirsutism (defined as a Ferriman-Gallwey score 6) and O/M: group N (n 108), regular menses and absence of hirsutism; group 1 (n 56), regular menses and hirsutism; group 2 (n 10), O/M and absence of hirsutism; and group 3 (n 18), O/M and hirsutism. Body mass index, waist to hip ratio, and mean blood pressure did not differ among the studied groups. Hormonal profile was assessed by measuring free testosterone (FT). The prevalence of PCOS, defined by the presence of O/M and biochemical hyperandrogenism (FT 95th percentile of the normal women), was estimated to be 6.77% (13 women of 192). Higher FT levels were observed in group 3 (O/M and hirsutism) compared with groups N (P ) and 1 (P ) and in groups 1 (hirsutism) and 2 (O/M) compared with group N (P and P 0.005, respectively). Sex POLYCYSTIC ovary syndrome (PCOS) appears to be a common endocrine disorder of women of reproductive age. It is characterized by chronic anovulation and hyperandrogenism and can be clinically expressed with hirsutism, acne, or androgen-dependent alopecia (1, 2). It is clinically heterogeneous regarding the presence and severity of the clinical manifestations of hyperandrogenism, menstrual irregularities, and infertility. Additionally, PCOS seems to be associated with obesity and metabolic abnormalities, such as insulin resistance and dyslipidemia, factors that exaggerate the clinical presentation, increase the morbidity, and, lastly, may play a central role in the pathogenesis of the syndrome (2 4). PCOS is not distinguished by other forms of hyperandrogenism by a unique phenotype or a distinct biochemical abnormality; this may explain the difficulty in introducing generally accepted diagnostic criteria. The most widely accepted criteria, from the 1990 NIH-NICHHD conference on PCOS, are 1) ovulatory dysfunction, 2) clinical evidence of hyperandrogenism and/or hyperandrogenemia, and 3) exclusion of other known disorders, such as congenital adrenal Received December 30, Revision received May 19, Rerevision received July 28, Accepted June 18, Address all correspondence and requests for reprints to: E. Diamanti- Kandarakis, M.D., First Department of Medicine, Laiko General Hospital, 17 Agiou Thoma Street, Athens, Greece. hormone-binding globulin levels were lower in women with PCOS and in groups 1 and 3 than those in group N (P 0.002, P 0.02, and P 0.002, respectively) independently of the body mass index. The metabolic profile was investigated by measurements of fasting glucose (FG), fasting insulin (FI), and estimation of the fasting glucose to insulin ratio (FG:I ratio). After covariance adjusted for the BMI, FI levels were higher in group 3 and in women with PCOS than in the normal (P and P 0.002, respectively) and the hirsute (P 0.05 and P 0.02, respectively) women, whereas FG levels did not differ among the studied groups. The FG:I ratio was lower in group 3, group 1, and in women with PCOS than in normal women (P 0.05). Finally, a high incidence of family history of diabetes mellitus (P 0.001) and menstrual disorders (P 0.01) was observed in women with PCOS, in contrast to the normal and hirsute women. In conclusion, PCOS appears to be a particularly common endocrine disorder in the Greek population under study (prevalence, 6.77%); furthermore, it is associated with certain metabolic abnormalities. These data also suggest that the severity of the fasting hyperinsulinemia is associated with the severity of the clinical phenotype of hyperandrogenism independently of obesity. (J Clin Endocrinol Metab 84: , 1999) hyperplasia, hyperprolactinemia, or Cushing s syndrome (1). Additionally the finding of polycystic ovaries on ultrasonography, which was originally the hallmark for the diagnosis of the syndrome, perhaps represents a sign of a wide variety of disorders and appears to be a nonspecific finding in approximately 20% of asymptomatic women (5, 6). The prevalence of PCOS in premenopausal women is estimated to be about 5 10% (1). In the past, most prospective studies attempting to define the prevalence of PCOS used the ultrasonographic appearance of polycystic ovaries as a prerequisite for the diagnosis of PCOS; however, this is not included in the current diagnostic criteria. These studies demonstrated that 21 23% of unselected women appear to be affected (6 8). In a recent study, using the current criteria for the diagnosis of PCOS, the prevalence of PCOS in a population of unselected U.S. Black and White women was reported to be 4% (9). However, as there are significant ethnic and racial variations in the clinical presentation of PCOS, the frequency of obesity, insulin resistance, and the incidence of diabetes mellitus, it seems reasonable that the prevalence of PCOS could differ among different populations (10, 11). The current study was undertaken 1) to determine the prevalence of the PCOS in a sample of the population of a Greek island, 2) to identify hormonal and metabolic parameters of women with PCOS and, in particular, among women 4006

2 SURVEY OF PCOS: METABOLIC PROFILE 4007 with clinical signs of hyperandrogenemia, and 3) to investigate associations of the above-mentioned clinical manifestations with family history of diabetes mellitus, menstrual disorders, cardiovascular disease, hirsutism, and premature baldness in male relatives. Subjects and Methods Subjects and protocol We studied 192 women of reproductive age who lived on the Greek island of Lesbos and accepted our invitation of free medical examination. A large scale informational campaign took place before the study from the local authorities (local TV channel, newspaper, and radio station). All women were offered a free medical examination by an endocrinologist, and no reference was made to the specific disorders being studied. The protocol was approved by the institutional review committee of Bostanion General Hospital in Lesbos. The age of the women finally enrolled in this protocol ranged between yr. None of them received oral contraceptives or other drugs that could interfere with the hormonal and metabolic studies. All of them were clinically healthy, none of them suffered from chronic or acute disease, and all were euthyroid according to the clinical evaluation. Postmenopausal women were excluded from the study. Personal medical history was obtained from every woman according to a customized preprepared questionnaire. Menstrual cycle history was carefully detected and included a general review since menarche and a detailed recall of the last 2- to 3-yr interval. Ovulatory dysfunction was defined as less than eight cycles per yr, and regular menstrual cycle as days in length. Emphasis was placed upon family history regarding diabetes mellitus in the first and second degree relatives, menstrual disorders, hirsutism, and early baldness in male relatives (father and/or brothers). A family history of menstrual disorders and hirsutism was positive when oligomenorrhea and/or hirsutism existed during the youth of the mother according to the report of the studied women. Physical examination was performed in each person by two doctors. Obesity was assessed by estimating body mass index (BMI; weight/ height 2, kilograms per m 2 ), with normal ranging between , overweight between 26 30, and obese over Body fat distribution was assessed by measurements of the waist to hip girth ratio (WHR) (12). A Ferriman and Gallwey score of 6 or greater (F-G, 6) was considered hirsutism (13). Additionally, blood pressure was measured in with subjects in the sitting position, and the mean blood pressure (MBP) was estimated [MBP diastolic (systolic/3)]. According to the history and the physical examination, the subjects under study were divided into four groups. Group N consisted of women with normal menstrual cycles ( 35 days) and absence of hirsutism (F-G, 6), group 1 included women with hirsutism and/or acne and regular menstrual cycles, group 2 included women with oligomenorrhea and absence of hirsutism, and, lastly, group 3 included women presenting with oligomenorrhea and hirsutism. Blood samples were collected between h and plasma free testosterone (FT; picograms per ml), sex hormone-binding globulin (SHBG; nanomoles per L), LH (units per L), FSH (units per L), fasting insulin (microunits per ml), and glucose (milligrams per dl) were measured. The fasting glucose (FG) to insulin (FI) ratio was estimated (FG:I ratio; milligrams per 10 4 U) and was used as an indicator of insulin sensitivity (14). In the cases of impaired fasting glucose (FG, mg/dl), a 75-g oral glucose tolerance test was performed; subjects with overt diabetes mellitus and impaired glucose tolerance were excluded from the above metabolic study. Additionally, serum PRL (nanograms per ml), TSH (microunits per ml), and 17-hydroxyprogesterone (17-OHProg; nanograms per ml) levels were detected in blood samples of women with oligomenorrhea (groups 2 and 3) to exclude other causes of menstrual disorders (15, 16). Diagnosis of PCOS PCOS was diagnosed in women presenting with oligomenorrhea (as defined above) and hyperandrogenism; related disorders with similar clinical presentation were excluded (1990 NIH Consensus Conference on the PCOS). Hyperandrogenism was defined as FT levels above the 95th percentile of the levels detected in the group of normal cycling nonhirsute women (group N). The polycystic ovarian morphology detected by ultrasound was not considered an essential criterion for the diagnosis of the syndrome, as it is reported that approximately 20% of normal women could present the above ultrasonographic appearance (6). Assays Plasma glucose was determined by the glucose oxidase method (glucose analyzer, Beckman Coulter, Inc., Palo Alto, CA). Blood samples were centrifuged immediately, and serum was stored at 20 C until assayed. Serum insulin levels were measured using the RIA INSU- LIN-CT kit from CIS-Bio International (Gif-sur-Yvette, France). Duplicate plasma samples were analyzed for FT using the commercially available Coat-A-Count Free Testosterone kit from Diagnostic Products (Los Angeles, CA). The absolute range for FT in ovulating females was nondetectable to 3.9 pg/ml. SHBG serum levels were measured by immunoradiometric assay (IRMA) using the SHBG IRMA 125 I (RADIM S.A., Liège, Belgium). PRL was measured using the PRL IRMA kit from MEDGENIX DIAGNOSTICS. 17OHProg levels were measured using a RIA kit from Diagnostics Systems Laboratories, Inc. (Wesbster, TX). LH and FSH were measured using the LHsp and FSH IRMA kits from Biosource Technologies, Inc., Europe S.A. TSH was measured using the human TSH IRMA kit from INCSTAR Corp. (Stillwater, MN). The intraand interassay coefficients of variation for FT were 4.3% and 5.5%, and 3.2% and 3.4% for low and high levels respectively; for SHBG, they were 5.1% and 5.1%, and 5.6% and 4.6%, respectively; for insulin, they were 8.2% and 8.8%, and 5.4% and 6.4%, respectively; for PRL, they were 4.0% and 7.1%, and 6.4% and 6.8%, respectively; for 17OHProg, they were 9.3% and 9.7%, and 9.5% and 10.8, respectively; for LH, they were 6.5% and 8.8%, and 3.5% and 4.5%, respectively; for FSH, they were 2.7% and 5.3%, and 1.6% and 3.6%, respectively; and for TSH, they were 3.2% and 5.7%, and 3.3% and 4.9%, respectively. Statistical analysis Results are reported as the mean se. Multivariate analysis of covariance, using BMI as a covariant, was performed. For individual comparisons, Tukey s test for unequal sample sizes was used. Regarding family history cross-tabulation of the four studied groups, residual analysis was performed using 2 as the statistical indicator. The partitioning of the table referring to family history in women with PCOS, the normal and the hirsute groups, was performed as described by Siegel and Castellan (17). Analysis was performed using the STATISTICA/w software package (version ). Results Clinical characteristics In the studied population, 108 of 192 women had regular menstrual cycles as defined above and no signs of hyperandrogenism (H/A), hirsutism, and/or acne (group N). Fiftysix of 192 women (29%) demonstrated hirsutism with a F-G score ranging from 6 12 and regular menstrual cycles (group 1). Moreover, 18 of 192 women (9.4%) presented moderate to severe hirsutism, with a F-G score ranging from 13 20, and oligomenorrhea (O/M; group 3); 10 of these 18 women presented with acne. In all cases, hirsutism had an onset in adolescence and did not progressively worsen. Additionally, 10 of 192 examined women (5.2%) had menstrual disorders without hirsutism and/or acne (F-G, 6; group 2). The characteristics (age, BMI, and WHR) of the four groups of the studied population are shown in Table 1. No statistically significant differences existed in age (group N, ; group 1, ; group 2, ; group 3, , yr), BMI (group N, ; group 1, ; group 2, ; group 3, kg/m 2 ), or WHR (group N, ; group 1, ; group 2, 0.73

3 4008 DIAMANTI-KANDARAKIS ET AL. JCE&M 1999 Vol 84 No 11 TABLE 1. Clinical characteristics, mean blood pressure (MBP), fasting glucose (FG) and LH to FSH ratio of the studied population (total n 192) N (n 108) HIRS(1) (n 56) O/M (2) (n 10) HIRS O/M(3) (n 18) Age (yr) BMI (kg/m 2 ) WHR MBP (mm Hg) FG (mg/dl) LH/FSH Values are the mean SE. No significant differences were observed by analysis of covariance. Groups according to clinical presentation: group N, normal; group 1, HIRS (hirsutism); group 2, O/M (oligomenorrhea); and group 3, HIRS O/M. FIG. 1. Mean FT levels in the four studied groups and the PCOS women (group N, normal women; group HIRS, hirsutism; group O/M, oligomenorrhea; group HIRS O/M, oligomenorrhea and hirsutism). *, P vs. N; **, P vs. N; ***, P vs. N and HIRS. 0.01; group 3, ). MBP (group N, ; group 1, ; group 2, ; group 3, mm Hg) did not differ even after BMI and age were used as covariates. Hormonal profile The data are summarized in Table 1. Although the unadjusted mean values se are displayed in Table 1 and Fig. 1, the P values are taken from the data after covariance adjusting for changes in the BMI. Women with hirsutism only (group 1) compared to normal women (group N) showed higher levels of FT ( vs pg/ml; P ). Additionally, women with oligomenorrhea (group 2) showed higher FT levels compared to group N (FT; vs pg/ml; P 0.005). Women with hirsutism and oligomenorrhea (group 3) had higher FT levels than those in group 1 ( vs pg/ml; P ) or group N ( vs pg/ml; P ); no statistically significant difference was found in FT levels between women of group 3 and women of group 2 (Fig. 1). Metabolic profile One woman of group N had diabetes mellitus and was not included in the metabolic studies as well as two obese women, one from group 1 (hirsutism) and the other from group 3 (hirsutism and O/M), who showed impaired glucose tolerance. The data are summarized in Table 1. Although the unadjusted mean se are displayed in Table 1 and Figs. 2 4, the P values are taken from the data after covariance adjusting for changes in the BMI. FG did not differ among the four groups, whereas FI in group 3 (hirsutism and O/M) was higher than that in group N ( vs U/mL; P 0.005) or group 1 (hirsutism; vs U/mL; P 0.05; Fig. 2). The FG:I ratio was lower in group 3 compared to group N ( vs mg/10 4 U; P 0.05). Additionally, women with simple hirsutism (group 1) had a lower FG:I ratio compared to the normal women ( vs mg/ 10 4 U; P 0.05; Fig. 3). SHBG levels in women with simple hirsutism (group 1) were lower than those in group N ( vs nmol/l; P 0.02). Additionally, SHBG levels in women with hirsutism and oligomenorrhea (group 3) were lower than those in group N ( vs nmol/l; P 0.002; Fig. 4). There was a noticeable trend for an increase in fasting insulin levels and a decrease in the FG:I ratio and SHBG levels from group N to group 3 (Figs. 2 4). Prevalence of PCOS Women with hirsutism and/or oligomenorrhea (groups 2 and 3) who presented with hyperandrogenemia were diagnosed as having PCOS. As defined, none of the subjects suspected of PCOS had evidence of thyroid disease, hyper-

4 SURVEY OF PCOS: METABOLIC PROFILE 4009 FIG. 2. Mean FI levels in the four studied groups and the PCOS women (group N, normal women; group HIRS, hirsutism; group O/M, oligomenorrhea; group HIRS O/M, oligomenorrhea and hirsutism). *, P 0.05 vs. N and HIRS; **, P 0.02 vs. N and HIRS. FIG. 3. Mean FG:I ratio in the four studied groups and the PCOS women (group N, normal women; group HIRS, hirsutism; group O/M, oligomenorrhea; group HIRS O/M, oligomenorrhea and hirsutism). *, P 0.05 vs. N; **, P 0.05 vs. N. prolactinemia, Cushing s syndrome, or androgenic tumor. 21-Hydroxylase deficiency was excluded by measuring 17OHProg; none of the suspected women had an initial level above 2 ng/ml, effectively ruling out the disorder (15). H/A was defined as a FT level above the 95th percentile of the mean value in the normal women (group N; i.e. 3.3 pg/ml). Thirteen women fulfilled the criteria, 2 from group 2 (O/M) and 11 from group 3 (O/M and hirsutism). Therefore, the prevalence of PCOS in the population under study was 6.77% (13 of 192). Moreover, 6 of 56 women from group 1 (10.7%) had H/A according to the above definition. However, as they reported regular menses, they were not included in the estimation of the prevalence of the syndrome. FIG. 4. Mean SHBG levels in the four studied groups and the PCOS women (group N, normal women; group HIRS, hirsutism; group O/M, oligomenorrhea; group HIRS O/M, oligomenorrhea and hirsutism). *, P 0.02 vs. N; **, P vs. N. Anthropometric, hormonal, and metabolic parameters of the PCOS group The 13 women diagnosed with PCOS were compared to the normal and hirsute groups (groups N and 1, respectively). Age ( , yr), BMI ( , kg/m 2 ), WHR ( ), and MBP ( mm Hg) of the PCOS women did not differ compared to those in groups N and 1. PCOS women had higher FI levels ( U/mL) compared with groups N and 1 (P and P 0.02, respectively), whereas FG levels ( mg/dl) did not differ (Fig. 2 and Table 1). The FG:I ratio ( , mg/10 4 U) and SHBG level ( nmol/l) were also lower in the PCOS group compared with the normal group (P 0.05 and P 0.002, respectively; Figs. 3 and 4); these findings were independent of the BMI. Finally, the LH to FSH ratio ( ) did not differ compared with those in the other groups. Family history The observed frequencies of positive family history regarding diabetes mellitus, menstrual disorders, hirsutism, and early baldness in male relatives are shown in Table 2.

5 4010 DIAMANTI-KANDARAKIS ET AL. JCE&M 1999 Vol 84 No 11 TABLE 2. The observed frequencies (percentages) of positive family history in the four studied groups according the clinical presentation and in the PCOS group compared with the normal (N) and hirsute (HIRS) groups N HIRS(1) O/M(2) O/M HIRS(3) PCOS Diabetes mellitus a 66.6 a 71 b Menstrual disorders c 33.3 c 46 d Hirsutism e 0 39 e 30 Early baldness f f 7.6 Probability level (P) was estimated using 2 analysis. a P vs. the other groups. b P vs. groups N and HIRS(1). c P 0.04 vs. the other groups. d P 0.01 vs. groups N and HIRS(1). e P vs. the other groups. f P 0.04 vs. the other groups. Women with hirsutism and/or oligomenorrhea (groups 2 and 3) showed a more frequently positive family history of diabetes mellitus (60% and 66.6%, respectively; P 0.006) and menstrual disorders (40% and 33.3%, respectively; P ) compared with the normal and hirsute women (groups N and 1). Women with hirsutism, regardless of the presence of menstrual irregularities (groups 1 and 3), more often had a positive family history of hirsutism (21.4% and 39%, respectively; P ) than nonhirsute women (groups N and 2). A family history of premature baldness in male relatives was less often observed in group N than in the rest of the groups (P 0.04). Women with PCOS showed a high incidence of a positive family history of diabetes mellitus, recorded in 71% (10 of 13; P 0.001), and of menstrual disorders, recorded in 46% (6 of 13; P 0.01), compared with the regular cycling women (groups N and 1). A family history of hirsutism, recorded in 30% (4 of 13), and premature male balding, recorded in 7.6% (1 of 13), did not prove to be more common in the PCOS group (Table 2). Discussion The prevalence of PCOS in the studied sample of the Greek population was 6.77% (13 of 192), in accord within the range of the estimated prevalence (5 10%) (1). This also appears to be close to the prevalence of PCOS in a sample of the U.S. population (Whites and Blacks) reported in a recent study by Knochenhauer et al. (9). In the present study the examined population was homogeneous regarding racial and ethnic variations. This is the first study undertaken in Europe attempting to determine the prevalence of PCOS using the current diagnostic criteria (NIH consensus 1990). The ultrasonographic appearance of polycystic ovaries as a diagnostic criterion is controversial and does not seem to be either a sensitive or a specific finding (6, 18, 19). Taking into account the bioavailability of the androgens, FT was chosen to be measured for hormonal analysis as the most representative ovarian androgen with minimal menstrual variation (20 22). The incidence of oligomenorrhea (14.6%; 28 of 192) in the studied population may be overestimated because of the definition we used, i.e. less than 8 cycle/yr; this definition was also used in the recent study by Knochenhauer et al. (9). H/A was confirmed in 6.77% of the examined women with oligomenorrhea or oligomenorrhea and hirsutism. The majority of the studied women fulfilling the criteria for PCOS (11 from the overall 13) belonged to the group characterized by the main clinical manifestations of the syndrome (group 3). In this group were included 18 women with oligomenorrhea and hirsutism/or acne. The remaining 7 women, with the clinical manifestations of the syndrome but without proven hyperandrogenemia (normal FT), cannot be entirely excluded from the diagnosis of PCOS, because another nonmeasured androgen could have been elevated. Therefore, the prevalence of PCOS in our sample could have been approximately 10.4% (20 of 192) if another elevated androgen was detected. PCOS women appeared to have fasting hyperinsulinemia, lower FG/I ratio, and decreased SHBG levels compared with the normal women, independently of the BMI. Insulin resistance in PCOS has been estimated in small groups of women by highly sophisticated methods (i.e. ivgtt, hyperinsulinemiceuglycemic clamps) (1, 3, 23). In this study, for the first time, we used fasting hyperinsulinemia and the FG/I ratio, which have been considered adequate and sensitive screening markers for insulin resistance, to determine in a large sample of premenopausal women the presence of insulin resistance in association with hyperandrogenic manifestations (14, 24). The gradual increase, a dose-dependent-like pattern, of fasting insulin levels from the group of normal women to the group with the clinical and biochemical abnormalities of the syndrome, indicates that the severity of fasting hyperinsulinemia is associated with the severity of the clinical phenotype, independently of the degree of obesity. It is noteworthy that statistical significance is achieved between the group of normal women and the group that presents the full-blown syndrome. The above finding suggests that fasting hyperinsulinemia is a characteristic accompanying feature of PCOS (3, 23). It should also be noted that obesity, defined as a BMI above 30 kg/m 2, was observed in 38% (5 of 13) of the women with PCOS, consistent with other reports (4, 9). Regarding the metabolic studies, in women with idiopathic hirsutism mean FI levels were in between the levels of normal and PCOS women without reaching statistical significance compared to the normal group. Nevertheless, the FG/I ratio was significantly lower in the studied hirsute women compared to normal women. This finding raises the question of whether women with so-called idiopathic hirsutism are a heterogeneous group exhibiting not only a cosmetic problem but subtle metabolic disturbances as well. The reported incidence of idiopathic hirsutism varies from 5 15% in Caucasian women (13, 25). However, in our study 29% (56 of 192) of the examined women presented with idiopathic hirsutism. This rather impressive percentage could be due to the ethnic variation of the Mediterranean people. The possible role of ethnicity in the prevalence and features of PCOS has been reported in other populations (i.e. Caribbean-Hispanic) (26, 27). Nevertheless, it should be borne in mind that the recruitment of women in the present study was not fully randomized, and that hairiness represents for many women a cosmetic problem that merits serious consideration. The studied women with idiopathic hirsutism demonstrated a statistically significant lower SHBG level and higher FT level compared to normal women, although the mean FT value was within the normal range. It should be noted that 10.7% of the studied hirsute women

6 SURVEY OF PCOS: METABOLIC PROFILE 4011 were hyperandrogenemic, with FT levels exceeding the 95th percentile of the normal women. Therefore, idiopathic hirsutism is not a homogeneous clinical and biochemical entity and, instead, may include a variety of disorders in androgen metabolism (28) as well as subclinical metabolic aberrations. Furthermore, nonhirsute women with oligomenorrhea presented higher FT levels than normal women, independently of BMI. Moreover, two of them had H/A, as defined, and were diagnosed with PCOS. As noted by other investigators, oligomenorrhea seems to be associated with subtle or overt elevations of androgens even in the absence of hirsutism or acne and may present a discrete form of PCOS (29, 30). It is controversial whether women with PCOS have elevated blood pressure. In the studied population, mean blood pressure, estimated by a random measurement, did not differ in women with PCOS and normal women. This observation is in accordance with other studies focussed on this matter (31). Regarding family history, we observed a high incidence of family history of menstrual disorders in women with PCOS, in accordance with the general view that PCOS has a strong familial component (10, 32, 33). Another observation was that hirsute women reported a strong family history of hirsutism; it seems that familiar and ethnic aspects should be taken into consideration. Additionally, women with PCOS reported a high, statistically significant incidence of family history of diabetes mellitus compared to normal and hirsute women. This observation may imply that the genetic trait of PCOS is associated with a diabetogene(s), and it should be further examined in large scale studies, focussing on the prevalence of a family history of diabetes mellitus in PCOS. Additionally, a family history of diabetes mellitus could have influenced the metabolic profile in the studied women with PCOS. However, the only supporting evidence on this matter has been provided by insulin secretory abnormalities in women with PCOS and a family history of diabetes mellitus, assessed by sophisticated methods in a study by Erhmann et al. (23). On the other hand, the presence of insulin resistance, which is a distinct feature of PCOS, seems to be independent of the family history of diabetes mellitus up to the third decade of life (34). In conclusion, in the Greek population studied, PCOS is considered to be a common endocrine disorder, with a prevalence of 6.77%. The metabolic abnormalities, in particular fasting hyperinsulinemia and FG:I ratio, seem to accompany the severity of the clinical phenotype, covering the spectrum of hyperandrogenic disorders in the studied groups of women, independently of obesity. These data also suggest that women with hirsutism and regular menses constitute a heterogeneous group as far as hormonal and metabolic parameters are concerned. Additionally, the incidence as well as the role of family history of diabetes mellitus in women with PCOS should be considered in terms of its possible implication in the pathogenesis of the syndrome. References 1. Dunaif A, Givens JR, Haseltine FP, Merriam GR Current issues in endocrinology and metabolism: polycystic ovary syndrome. Boston: Blackwell. 2. Diamanti-Kandarakis E, Dunaif A New perspectives in polycystic ovary syndrome. Trends Endocrinol Metab. 7: Dunaif A, Segal KR, Futterweit W, Dobrjansky A Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 38: Kiddy DS, Sharp PS, White DM, et al Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol (Oxf). 32: Givens JR Polycystic ovaries: a sign, not a diagnosis. Semin Reprod Endocrinol. 2: Polson DW, Adams J, Wadsworth J, Franks S Polycystic ovaries: a common finding in normal women. Lancet. 1: Clayton RN, Ogden V, Hodgkinson J, et al How common are polycystic ovaries in normal women and what is their significance for the fertility of the population. Clin Endocrinol (Oxf). 37: Farquhar CM, Birdsall M, Manning P, Mitchell JM, France JT The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust NZ Obstet Gynaecol. 34: Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab. 83: Legro RS The genetics of polycystic ovary syndrome. Am J Med. 98:9S 16S. 11. Norman RJ, Mahabeer S, Masters S Ethnic differences in insulin and glucose response to glucose between white and Indian women with polycystic ovary syndrome. Fertil Steril. 63: Kissebah A, Vydelingum N, Murray R, et al Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab. 54: Ferriman D, Gallwey J Clinical assessment of body hair growth in women. Clin Endocrinol (Oxf). 21: Legro RS, Finegood D, Dunaif A A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 83: Azziz R, Zacur HA Hydroxylase deficiency in female hyperandrogenism: screening and diagnosis. J Clin Endocrinol Metab. 69: Zawadzki JK, Dunaif A Diagnostic criteria for polycystic ovary syndrome: Towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Boston: Blackwell; Siegel S, Castellan NJ Nonparametric statistics for the behavioral sciences. 2 nd ed, New york: McGraw-Hill, p Swanson M, Sauerbrei EE, Cooperberg PL Medical implications of ultrasonocally detected polycystic ovaries. J Clin Ultrasound. 9: Orsini LF, Venturoli S, Lorusso R, Pluchinotta V, Paradisi R, Bovicelli L Ultrasonic findings in polycystic ovarian disease. Fertil Steril. 43: Pardridge WM Serum Bioavailability of sex steroid hormones. Clin Endocrinol Metab. 15: Wu CH Plasma free and protein-bound testosterone in hirsutism. Obstet Gynecol. 60: Oka K, Hirano T, Noguchi M Changes in the concentration of testosterone in serum during menstrual cycle, as determined by liquid chromatography. Clin Chem. 34: Ehrmann DA, Sturis J, Byrne MM, Karrison T, Rosenfield RL, Polonsky KS Insulin secretory defects in polycystic ovary syndrome. J Clin Invest. 96: xxx Consensus Development Conference on Insulin Resistance. ADA. Diabetes Care. 21: McKnight E The prevalence of hirsutism in young women. Lancet. 1: Weiss DJ, Richards C, Dunaif A Increased prevalence of polycystic ovarian disease in Hispanic women [Abstract]. Clin Res. 35:796A. 27. Dunaif A, Sorbara L, Delson R, Green G Ethnicity and polycystic ovary syndrome are associated with independent and additive decreases in insulin action in Caribbean-Hispanic women. Diabetes. 42: Bardin CW, Lipsett MB Testosterone and androstenedione blood production rates in normal women and women with idiopathic hirsutism or polycystic ovaries. J Clin Invest. 46: Hosseinian AH, Kim MH, Rosenfield RL Obesity and oligomenorrhea are associated with hyperandrogenism independent of hirsutism. J Clin Endocrinol Metab. 42: Allen SE, Potter HD, Azziz R Prevalence of hyperandrogenemia among nonhirsute oligo-ovulatory women. Fertil Steril. 67: Zimmerman S, Phillips RA, Dunaif A, et al Polycystic ovary syndrome: lack of hypertension despite profound insulin resistance. J Clin Endocrinol Metab. 75: Simpson JL Elucidating the genetics of polycystic ovary syndrome. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Boston: Blackwell; Hague WM, Adams J, Reeders ST, Peto TE, Jacobs HS Familiar polycystic ovaries: a genetic disease? Clin Endocrinol (Oxf). 29: Diamanti E, Tsianateli T, Kouli C, et al. Insulin resistance and hyperandrogenemia in the polycystic ovary syndrome: Influence of obesity, fat distribution and family history of diabetes mellitus. Proc of the 4th Eur Congr of Endocrinol. 1998; P3 35.