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Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: A controlled, population-based study
Relationship of the metabolic syndrome and obesity to polycystic ovary syndrome: A controlled, population-based study Seija Korhonen, MD,a Maritta Hippeläinen, MD, PhD,b Leo Niskanen, MD, PhD,c Mauno Vanhala, MD, PhD,d and Seppo Saarikoski, MD, PhDb Mikkeli, Kuopio, and Imatra, Finland OBJECTIVE: Although hyperinsulinemia seems to be an essential feature of polycystic ovary syndrome, the frequency of gynecologic disorders related to polycystic ovary syndrome at a population level in women with evident metabolic syndrome is not known. STUDY DESIGN: We conducted a cross-sectional, population-based study. Participants (N = 204) were recruited from a random sample of women in 5 age groups (range, 35-54 years) living in a defined area. Metabolic syndrome was considered to be present if 3 of the following 8 criteria were fulfilled: (1) first-degree relative with type II diabetes, (2) body mass index ≥30 kg/m2, (3) waist/hip ratio ≥0.88, (4) blood pressure ≥160/95 mm Hg or drug treatment for hypertension, (5) fasting serum triglyceride level ≥1.70 mmol/L, (6) high-density lipoprotein cholesterol value <1.20 mmol/L, (7) abnormal glucose metabolism, and (8) fasting insulin value ≥13.0 mU/L. The frequency of metabolic syndrome was 106 (19.5%) of 543 cases. The control group consisted of 62 overweight women without central obesity or metabolic syndrome and 53 healthy lean women (body mass index <27 kg/m2). RESULTS: The group with metabolic syndrome differed from the other women according to most of the selection criteria and also had the highest free testosterone concentration. However, there were no differences between the groups regarding parity, infertility problems, or obstetric outcome. However, oligomenorrhea appeared to be more common in women with metabolic syndrome, especially in those with more severe symptoms (46.2%), than in obese (25.4%) and lean (15.1%) control subjects. Polycystic-like ovaries were detected by vaginal ultrasonography with similar frequency (13.1%, 15.3%, and 13.2% in women with metabolic syndrome, obese women, and lean women, respectively). CONCLUSIONS: Surprisingly few women with metabolic syndrome had symptoms suggestive of polycystic ovary syndrome, in comparison with obese and lean women. Our results suggest that at the population level polycystic ovary syndrome only accounts for a distinct subgroup of a much wider problem, metabolic syndrome. (Am J Obstet Gynecol 2001;184:289-96.)
Key words: Insulin resistance, metabolic syndrome, obesity, polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity characterized by signs and symptoms of hyperandrogenism and anovulatory disorders often associated with infertility and obesity. The underlying pathogenesis remains uncertain, although key components in the syndrome may be insulin resistance and hyperinsulinemia.1-4 Chronic hyperinsulinemia is hypothesized to
From the Department of Obstetrics and Gynecology, Mikkeli Central Hospital,a the Department of Obstetrics and Gynecologyb and the Department of Medicine and Clinical Nutrition,c Kuopio University Hospital, and the Imatra District Health Centre.d Received for publication June 25, 1999; revised April 26, 2000; accepted June 20, 2000. Reprint requests: Maritta Hippeläinen, MD, Department of Obstetrics and Gynecology, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/109596 doi:10.1067/mob.2001.109596
act synergistically with luteinizing hormone on the ovaries to produce excessive quantities of androgens, resulting in anovulatory disorders. Further, hyperinsulinemia directly reduces serum levels of sex hormone– binding globulin (SHBG) in obese women with PCOS.5 Excess obesity itself has been associated with a variety of alterations in hormone production, metabolism, and action.6-8 In obese women there appears to be a high frequency of menstrual disturbances and hirsutism, suggesting possible abnormalities of androgen production.9 However, these abnormalities seem not to be associated with total fat mass per se but more so with central fat accumulation.10 It has been shown in several epidemiologic studies that risk factors for cardiovascular disease, such as central obesity, hypertension, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, abnormal glucose metabolism, and hyperinsulinemia, are related to 289
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insulin resistance.11 Furthermore, there is a tendency for these risk factors to cluster in the same individual with central or abdominal adiposity. Various names have been suggested for this cluster of metabolic risk factors and diseases. Reaven12 first called this cluster of phenomena syndrome X. Other authors have suggested terms such as insulin resistance syndrome, plurimetabolic syndrome, deadly quartet,13 and civilization syndrome.14 The term metabolic syndrome has been the most widely used15 and is also the term used in this study. Although the connection of hyperinsulinemia and PCOS has been shown beyond a doubt, no studies have assessed this association the other way around; that is, the frequency of gynecologic problems in female patients with evident metabolic syndrome. Our hypothesis was that on the population level there would be more PCOSlike symptoms (ie, ovulatory disorders, hyperandrogenism, and infertility problems) among women with metabolic syndrome than in lean women or obese women with more peripheral fat distribution. Subjects and methods Screening for metabolic syndrome. Participants (N = 204) were recruited from all female residents born in 1942, 1947, 1952, 1957, and 1962 in Pieksämäki, a town in central Finland. These women had been screened during the years 1993 and 1994 for the detection of the metabolic syndrome, as described earlier in detail.16 The sample members were drawn from an updated census register. The metabolic syndrome was considered to be present if the study participant met at least 3 of the following 8 criteria: (1) first-degree relative with type II diabetes, (2) obesity as defined by a body mass index (BMI) ≥30 kg/m2, (3) abdominal adiposity as defined by a waist/hip ratio ≥0.88, (4) hypertension as defined by systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg or drug treatment for hypertension, (5) fasting serum triglyceride value ≥1.70 mmol/L, (6) fasting HDL cholesterol value <1.20 mmol/L, (7) abnormal glucose metabolism according to the World Health Organization (WHO) criteria,17 and (8) hyperinsulinemia (fasting insulin value ≥13.0 mU/L). To illustrate how the diagnostic criteria may modify the results, we created a subgroup of women with metabolic syndrome by using stricter criteria—presence of both dyslipidemia (serum triglyceride values >1.7 nmol/L or HDL cholesterol values <1.20 nmol/L) and hyperinsulinemia (fasting insulin concentration >13 mU/L) or impaired glucose tolerance. A total of 543 (92.5%) of the 587 women born during these years participated in the screening. Metabolic syndrome according to the looser criteria was found in 106 women (19.5%), as follows: born in 1942, 18 (17%); born in 1947, 43 (41%); born in 1952, 17 (16%); born in 1957, 17 (16%); born in 1962, 11 (10%). Of these 106 women,
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34 (32.1%) met the standards of the stricter criteria for metabolic syndrome. Formation of the study population Group with metabolic syndrome. Of the 106 women considered to have metabolic syndrome, 92 (86.8%) answered the questionnaire and 84 (79.2%) agreed to participate in the clinical study and give new blood samples for the biochemical analyses. Of the remainder, 2 were excluded because they had disabilities, 2 had moved outside the catchment area, 1 was pregnant, and the rest refused to participate in the study. Endometrial evaluation was performed in 65 (77.4%) of 84 subjects. Obese control group. The obese group was formed from the original screening population. Exclusion criteria were abdominal adiposity (waist/hip ratio ≥0.88) and metabolic syndrome. The inclusion criterion was a BMI >27 kg/m2. These criteria were fulfilled by 62 women, as follows: born in 1942, 16 (29%); born in 1947, 18 (29%); born in 1952, 13 (21%); born in 1957, 8 (13%); born in 1962, 7 (11%). None of these women had more than one of the diagnostic criteria for metabolic syndrome (excluding obesity) at presentation. Of these 62 women, 59 (95.2%) volunteered to come for the clinical examination and 58 (93.5%) agreed to undergo further laboratory tests. Endometrial evaluation was performed in 38 (64.4%) of the 59 women. Lean control group. The lean control group was chosen from the original screening population having a BMI <27 kg/m2 and none of the risk factors mentioned earlier. They were invited to the screening in alphabetic order. This group comprised 53 women from the various age groups. Fifty women (94.3%) participated in the laboratory tests. Endometrial evaluation was performed in 28 (52.8%) of the 53 women. This study was approved by the local ethics committee. Informed consent was obtained from all participants. Patient history. A structured questionnaire soliciting the social and medical history was distributed to all participants in the study. Information about gynecologic history, smoking, use of alcohol, chronic diseases, and medication was obtained. Subjects who were smoking daily were recorded as smokers. Patient records were reviewed with respect to diseases and operations. An intermenstrual interval of >35 days was considered to be oligomenorrhea. Abnormal uterine bleeding outside the regular menstrual cycle (28 ± 7 days) was defined as metrorrhagia. Clinical examination. All 204 subjects from the 3 groups were examined and personally interviewed according the questionnaire by the same gynecologist (Seija Korhonen) in 1996 and 1997. The blood pressure was measured with the subject seated after she had rested for 15 minutes. For anthropometric measurements, subjects were examined wearing light clothes. BMI was calculated as Weight (kg)/Height (m2). Waist and hip cir-
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cumferences were measured to the nearest centimeter with a tape measure while the subject was standing. The waist was measured at the smallest girth midway between the lowest rib margin and the iliac crest, and the hip circumference was measured at the level of the greater trochanter to calculate the waist/hip ratio. The clinical features of acanthosis nigricans and androgenic alopecia were assessed. Hirsutism was classified according to the Ferriman-Gallwey score.18 During the routine gynecologic examination, transvaginal ultrasonography was performed (5.0-MHz transvaginal transducer, ALOKA Echo Camera SSD-500; Aloka Company, Tokyo, Japan). The form and the dimensions of the uterus and the thickness of the endometrium were assessed. The morphologic features and dimensions of the ovaries were determined. Ovaries were considered as polycystic if there were >10 small (<10 mm) subcapsular follicles in either ovary. Endometrial evaluation was carried out by taking an endometrial sample with a special brush (Ori endometrial brush; Medical AB, Malmö, Sweden). Whenever possible, both histologic and cytologic evaluation were performed by a pathologist in the Kuopio University Hospital Department of Pathology. Biochemical tests. Total cholesterol, HDL cholesterol, and triglyceride levels were measured after an overnight fast. The 2-hour oral glucose tolerance test was performed with 75 g glucose (Nutricia Nederland BV, Zoetermeer, The Netherlands) according to the WHO recommendations. Blood was drawn at baseline and at 120 minutes for the measurement of blood glucose and plasma insulin. The samples for serum testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHBG were collected in the early follicular phase for the premenopausal women. All hormone treatments were stopped for 1 month before blood tests. A 1-mg overnight dexamethasone suppression test was performed to exclude Cushing syndrome. Additionally, serum prolactin and thyrotropin concentrations were determined to exclude hyperprolactinemia, hyperthyroidism, and hypothyroidism. Analytic methods. Serum cholesterol and triglycerides were analyzed by enzymatic colorimetric methods in the Department of Clinical Chemistry, Kuopio University Hospital. Serum HDL cholesterol was measured by the same method after the precipitation of low-density lipoprotein and very low-density lipoprotein cholesterol by dextran sulfate and magnesium chloride. Insulin and glucose values were determined from plasma that had been separated by centrifugation and frozen at –20°C. Glucose values were determined by an ion-selective electrode system (YSI 2000; YSI, Yellow Springs, Ohio), and insulin values were determined by the Phadeseph Insulin RIA (Pharmacia Diagnostics AB, Uppsala, Sweden) in the Department of Medicine laboratory, University of Kuopio. The serum testosterone concentration was deter-
mined after extraction by the DPC Coat-a-Count (radioimmunoassay kit; Diagnostic Products Corporation, Los Angeles, Calif) method. The SHBG measurement was determined with an immunoradiometric assay (Organon Teknika, Boxtel, The Netherlands). The unbound testosterone concentration in serum was calculated by use of testosterone and SHBG concentrations according to Anderson et al.18a The free androgen index was calculated as the following quotient: Testosterone/ SHBG × 1000, with both testosterone and SHBG being measured in nanomoles per liter. Dehydroepiandrosterone sulfate (DHEAS) was measured with a radioimmunoassay (Coat–a-Count). Statistical methods. Statistical analyses were performed with the SPSS for Windows, version 8.0 (SPSS, Chicago, Ill). Data are shown as the mean ± SEM. A normal distribution of the variables was tested with the KolmogorovSmirnov test. Log transformation was used if variables were not normally distributed. To test differences among the 3 study groups, we used 1-way analysis of variance and the Scheffé test. Homogeneity of variances was tested with the Levene test. If variances were not homogeneous, the Tamhane test was used instead of the Scheffé test. The χ2 test or, in the case of small expected frequencies, the Fisher exact test was used for nominal scale clinical variables. The differences between the 2 groups were determined by the Fisher exact test with the Bonferroni correction. Results Table I shows clinical and biochemical characteristics of the study population, including all 8 criteria used in screening women for the metabolic syndrome diagnosis. Although only 3 criteria were required for including women in the group with metabolic syndrome, this group differed significantly from the lean control group according to all 8 screening characteristics and also from the obese group except for HDL cholesterol. Thus abdominal adiposity, high blood pressure, high serum triglyceride levels, and high plasma insulin levels, as well as abnormal glucose tolerance, were significantly more common findings in the group with metabolic syndrome than in the other 2 groups. In a comparison of the simple obese and lean control groups, blood pressure and fasting glucose, insulin, and triglyceride levels were higher in obese women. There were also differences among the groups in androgen levels (Table I). Obesity per se and especially central obesity were associated with low SHBG concentrations. Similarly, the highest free testosterone concentration and androgen indexes were found in the group with metabolic syndrome. Nineteen women (22.6%) in the group with metabolic syndrome were treated for hypertension, in comparison with 2 subjects (3.4%) in the group with simple obesity.
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Table I. Clinical characteristics of study population Study group Metabolic syndrome (n = 84) Age (y, mean ± SEM) 46 ± 1 BMI (kg/m2, mean ± SEM) 31.5 ± 0.7*, † Waist circumference (cm, mean ± SEM) 99.2 ± 1.4*, † Waist/hip ratio (mean ± SEM) 0.91 ± 0.01*, † Current smokers (No.) 20 (23.8%) Non–insulin-dependent diabetes mellitus in first-degree relative (No.) 39 (46.4%)*, † Systolic blood pressure (mm Hg, mean ± SEM)) 144.0 ± 2*, † Diastolic blood pressure (mm Hg, mean ± SEM) 87.8 ± 1*, † Total cholesterol (mmol/L, mean ± SEM) 5.5 ± 0.1* HDL cholesterol (mmol/L, mean ± SEM) 1.28 ± 0.04* Triglycerides (mmol/L, mean ± SEM) 1.7 ± 0.09*, † Fasting glucose (mmol/L, mean ± SEM) 5.5 ± 0.1* Glucose, 2 h (mmol/L, mean ± SEM) 6.2 ± 0.2*, † Fasting plasma insulin (mU/L, mean ± SEM) 11.9 ± 0.8*, † SHBG (nmol/L, mean ± SEM) 38.7 ± 2.7*, † DHEAS (nmol/L, mean ± SEM) 4.44 ± 0.3* Free testosterone (mean ± SEM) 20.4 ± 1.0*, † Free androgen index (mean ± SEM) 48.2 ± 5*, †
Obese (n = 58)
Lean (n = 50)
Statistical significance
46 ± 1 44 ± 1 28.8 ± 0.3‡ 22.6 ± 0.3 88.3 ± 0.9‡ 74.5 ± 0.8 0.82 ± 0.001‡ 0.78 ± 0.01 11 (19.0%) 20 (40.0%)* 18 (31.0%) 2 (4.0%) 135 ± 2‡ 125 ± 2 83.8 ± 1‡ 76.6 ± 1 5.6 ± 0.1 5.1 ± 0.1 1.36 ± 0.03 1.43 ± 0.05 1.3 ± 0.09‡ 0.9 ± 0.07 5.3 ± 0.1‡ 5.0 ± 0.1 5.4 ± 0.2‡ 4.7 ± 0.2 9.2 ± 0.5‡ 6.7 ± 0.3 46.6 ± 2.5‡ 60.9 ± 3.6 3.90 ± 0.2 3.62 ± 0.18 16.95 ± 0.8 15.28 ± 0.97 30.6 ± 2.0 24.3 ± 2.1
P < .001 P < .001 P < .001 P = .01 P < .001 P < .001 P < .001 P < .05 P < .05 P < .001 P < .001 P < .001 P < .001 P < 0.001 P = .026 P = .001 P < .001
*P < .05, significant difference between metabolic syndrome and lean groups. †P < .05, significant difference between metabolic syndrome and obese groups. ‡P < .05, significant difference between obese and lean groups.
Table II. Gynecologic history of study groups Study group Metabolic syndrome (n = 92)
Obese (n = 59)
Lean (n = 53)
13.1 ± 0.1 7 (7.6%)
13.2 ± 0.2 7 (11.9%)
13.3 ± 0.2 6 (11.3%)
32 (34.8%)* 20 (21.7%) 35 (38.0%)*, † 12 (13.0%)
15 (25.4%) 8 (13.6%) 9 (15.3%) 11 (18.6%)
8 (15.1%) 9 (17.0%) 6 (11.3%) 8 (15.1%)
18 (19.6%) 1 (1.1%)
9 (15.3%) 2 (3.4%)
7 (13.2%) 1 (1.9%)
54 (58.7%) 25 (27.2%) 19 (20.7%) 46.9 ± 0.7
38 (64.4%) 15 (25.4%) 17 (28.8%) 47.6 ± 0.6
32 (60.4%) 17 (32.1%) 10 (18.9%) 47.4 ± 0.8
Menarche (y, mean ± SEM) Irregular menstrual cycles before age 20 y (No.) Irregular menstrual cycles after age 20 y (No.) Oligomenorrhea Metrorrhagia Hypermenorrhea Infertility problems (No.) Miscarriages (No.) 1-2 >3 Parity (No.) 1-2 >3 Postmenopausal (No.) Menopause (y, mean ± SEM)
Statistical significance
P = .03 P = .001
*P < .05, significant difference between metabolic syndrome and lean groups. †P < .05, significant difference between metabolic syndrome and obese groups.
Table III. Endometrial status and hysterectomies in 3 study groups Study group Metabolic syndrome (n = 92) Hyperplasia in history (No.) Hysterectomy (No.) Uterine myomas Hyperplasia Endometriosis Hypermenorrhea
Obese (n = 59)
Lean (n = 53)
4 (4.3%) 4 (6.8%) 4 (7.5%) 9 (9.8%) 5 (8.5%) 6 (11.3%) 8 2 2 1 1 1 2 1 2
The number of current smokers was highest in the lean control group (40.0%), compared with both the metabolic syndrome group and the group with simple obesity (22% and 19%, respectively; P < .05). Light to moderate consumption of alcohol (1-50 portions per month) was reported by 55 women (65.5%) in the group with metabolic syndrome, 43 (74.1%) in the obese group, and 47 (94.0%) in the lean group. The frequency of high alcohol consumption (51-100 portions per month) was uncommon (5%, 0%, and 0% in the metabolic syndrome group and the obese and lean control groups, respectively).
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Table IV. Current clinical findings in 3 study groups Study group Metabolic syndrome (n = 84) Hirsutism* No. Mean ± SD Acanthosis nigricans (No.) Alopecia areata (No.) Acne (No.) Ultrasonography findings (No.) Uterine myomas§ Ovaries Normalll Polycystic
17 (20.2%) 3.7 ± 4.1 5 (6.0%)†, ‡ 6 (7.1%)†, ‡ 13 (15.5%)
Obese (n = 59)
Lean (n = 53)
10 (16.9%) 2.8 ± 3.8 0 0 10 (16.9%)
5 (9.4%) 2.6 ± 3.8 0 0 5 (9.4%)
17/75 (22.7%)
11/53 (20.8%)
11/44 (25%)
65 (77.4%) 11 (13.1%)
44 (75.9%) 9 (15.3%)
Statistical significance
P = .044 P = .03
41 (82.0%) 7 (13.2%)
*Ferriman-Gallway18 score >7. †P < .05, significant difference between metabolic syndrome and lean groups. ‡P < .05, significant difference between metabolic syndrome and obese groups. §Different case number because of hysterectomies. llCorresponding to the cycle.
There were no differences in the mean age at menarche among the 3 groups (Table II). The occurrence of irregular cycles in late adolescence also did not differ among groups. In adulthood, however, oligomenorrhea was a more common disorder in the group with metabolic syndrome than in the lean control group. Only every third woman in the group with metabolic syndrome with oligomenorrhea at presentation had sought hormonal treatment. Furthermore, hypermenorrhea was a more common complaint in the group with metabolic syndrome. In addition, metrorrhagia tended to be more common in the group with metabolic syndrome than in other groups, but the difference did not reach statistical significance. Most of the women in each group had a stable sexual partnership (80%, 88%, and 83% in the metabolic syndrome group and the obese and lean control groups, respectively). Overall, ~90% of the women had children. Infertility problems tended to be more frequent in obese (18.6%) and lean (15.1%) control subjects than in the group with metabolic syndrome (13.0%), but the difference did not reach statistical significance (Table II). About half of the women with infertility problems (14/30 altogether) were treated for this problem, and 13 had become pregnant. There tended to be more miscarriages in the group with metabolic syndrome than in other groups. The number of postmenopausal women was comparable among the 3 groups. The onset of climacteric symptoms occurred at a similar age (mean, 47 years) (Table II). Only some of the postmenopausal women in the metabolic syndrome group (7/19) and the obese group (7/17) used hormone replacement therapy for climacteric symptoms, whereas the use of hormones tended to be more common among lean control subjects (7/10). Evaluation of the patients’ records showed that the frequencies of previous endometrial hyperplasia were simi-
lar (P = .73) among study groups (Table III). In addition, there were no differences in the frequency of hysterectomy. In about every tenth woman the uterus had been removed for the reasons shown in Table III. Additionally, there was 1 case of ovarian cancer in the obese group (1.7%) and 2 cases of breast cancer in the group with metabolic syndrome (2.2%). Endometrial samples obtained with an endocervical brush appeared to be representative in 122 (93.2%) of 131 cases, and histologic evaluation was possible in 104 (85.2%) of 122 samples. In about every third case in the metabolic syndrome group (32%) and the obese group (29%), the histologic findings in the endometrium did not correspond to the cycle, whereas such discordance was a rare finding among lean control subjects (14%). Hyperplasia was not detected in any of the 122 representative endometrial samples evaluated. In 1 case there were atypical cells (class II Papanicolaou smear), and in 2 cases a decidual reaction to an intrauterine contraceptive device was present. Transvaginal ultrasonographic evaluation showed that the frequency of myomas was comparable among the 3 groups. It is of interest that polycystic-like ovaries on ultrasonography were not more common in the group with metabolic syndrome than in the other groups (P = .9; Table IV). Clinical features for hyperandrogenism and also cutaneous markers of insulin resistance, such as androgenic alopecia and acanthosis nigricans, were detected only in the group with metabolic syndrome. On the other hand, although hirsutism and acne tended to be more common in the metabolic syndrome and obese groups than among lean women, the differences were not statistically significant (Table IV). None of the women in the group with metabolic syndrome and only 1 woman in the obese group and 2 women in the lean group had received hor-
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Table V. Group with metabolic syndrome, divided into those with severe form and those with nonsevere form
Age (y, mean ± SEM) Waist circumference (cm, mean ± SEM) Waist/hip ratio (mean ± SEM) BMI (kg/m2, mean ± SEM) Free androgen index (mean ± SEM) Oligomenorrhea (No.) Polycystic ovaries (No.) Hirsutism (No.) Acanthosis nigricans (No.) Alopecia areata (No.) Infertility problems (No.)
Severe form (n = 26)*
Nonsevere form (n = 58)
46 ± 1 103.8 ± 2.7† 0.93 ± 0.01 34.3 ± 1.2† 56.3 ± 10.4 12 (46.2%) 6 (23.1%) 6 (23.1%) 2 (7.7%) 3 (11.5%) 5 (19.2%)
46 ± 1 97.2 ± 1.5 0.90 ± 0.01 30.3 ± 0.7 44.5 ± 5.6 17 (29.3%) 5 (8.6%) 11 (18.9%) 3 (5.2%) 3 (5.2%) 7 (12.1%)
Statistical significance
P = .03 P = .004
*The severe form of metabolic syndrome is distinguished from the nonsevere form by strict criteria—dyslipidemia and hyperinsulinemia are present in the severe form. †P < .05, significant difference between groups.
monal treatment for hirsutism. The use of hormonal contraception was comparable among the groups (3%-4%). Finally, we used more stringent criteria for metabolic syndrome (ie, simultaneous presence of dyslipidemia and either hyperinsulinemia or abnormal glucose tolerance). By this definition, oligomenorrhea and polycystic ovarian structure seemed to be more common findings in this “core” subgroup of women with metabolic syndrome than in control women (Table V). Comment Our a priori hypothesis was that disorders that were similar to PCOS would be concentrated, especially in women with metabolic syndrome, because emerging evidence suggests that insulin resistance may have a primary etiologic role in PCOS.19 However, this connection was unclear at the population level. Therefore metabolic syndrome and PCOS should not be considered synonymous entities, although overlap seems to be evident. The definition of metabolic syndrome in this study was based on the simultaneous presence of at least 3 of 8 clinical and metabolic markers of insulin resistance. According to these criteria, about one fifth of the women (19.5%) fulfilled the criteria for metabolic syndrome, the prevalence increasing with age. This corresponds to previous findings, in which one fourth to one third of healthy women or men had some degree of insulin resistance.20 However, although only 3 criteria were required, the group with metabolic syndrome differed from the lean control group according to all 8 characteristics and also from the group with simple obesity. Similar significant differences were also detected between subjects with simple obesity and lean control subjects. When these 3 female groups were compared according to menstrual and fertility history, however, surprisingly few differences were found. In regard to the definition of metabolic syndrome, we acknowledge that this is a matter of dispute, because there are no internationally accepted criteria for meta-
bolic syndrome. The recent Provisional Report of a WHO Consultation21 is perhaps the most important in this respect. As those authors acknowledged, this definition was not based on causal relationships and is suggested to be regarded more as a working definition. The criteria proposed by WHO were as follows: impaired glucose regulation or diabetes, insulin resistance as measured by the hyperinsulinemic-euglycemic clamp, raised arterial blood pressure, elevated plasma triglyceride levels (≥1.7 mmol/L) or low HDL cholesterol level (≤1.0 mmol/L in women), central obesity (for female patients, a waist/hip ratio >0.85 or a BMI of ≥30 kg/m2), and microalbuminuria. The relative importance of each component is unclear at present. According to the WHO definition, 2 of these criteria should be present for the patient’s condition to qualify as metabolic syndrome. Note that in this study all women with any 3 of the 8 criteria were included in the group with metabolic syndrome. Obese control women were required to have a BMI >27 kg/m2 but a waist/hip ratio <0.88, because the exclusion criteria were abdominal obesity and the metabolic syndrome. Thus, besides obesity, only 1 feature of metabolic syndrome was allowed for inclusion in the control group with simple obesity. Obesity itself causes insulin resistance and characteristics associated with it, but the risk seems to be especially associated with central obesity.15 The group with metabolic syndrome differed significantly from the obese control group according to all screening characteristics except HDL cholesterol concentrations. However, it is evident that metabolic syndrome is a very heterogeneous condition and that various subgroups are to be found within this population. When interpreting the findings of this study, one should bear in mind 3 important points. First, this study was population based, in contrast to nearly all previous studies assessing the connection between PCOS and hyperinsulinemia or insulin resistance. Second, we first identified subjects with metabolic syndrome by using an increased waist/hip ratio as a surrogate marker, whereas
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the previous studies first identified women with symptoms and findings similar to those of PCOS and then evaluated the connection with insulin resistance. Third, we also controlled for the effects of obesity per se by including a group with a predominantly peripheral fat distribution. According to recent data, diagnostic and clinical features of PCOS also vary greatly. Commonly used current diagnostic criteria include clinical signs and symptoms of hyperandrogenism and ovulatory dysfunction, with the exclusion of a well-defined underlying cause of androgen excess. Although we did not explicitly state PCOS criteria in particular, pertinent features previously associated with PCOS were evaluated in this study (ie, clinical signs and symptoms of hyperandrogenism, androgen levels, menstrual disorders [especially oligomenorrhea], infertility, and ovarian structure on vaginal ultrasonography). Thyroid dysfunction, hyperprolactinemia, and abnormal cortisol secretion were excluded. The onset of PCOS, which often occurs at menarche, is characterized by a failure to establish a regular pattern of menses.22 In this population-based study there were no differences between the metabolic syndrome group and the control groups for menarche and irregular menstrual periods before the age of 20 years. On the other hand, during later life the common menstrual disorders evaluated in this study tended to be more frequent among women in the group with metabolic syndrome. Oligomenorrhea with anovulatory periods seemed to be especially associated with central obesity, because there was no difference between women with peripheral obesity and lean control subjects. It is of interest that the complaint of heavy menstrual bleeding with regular menstrual periods was also more common in the group with metabolic syndrome than in the other groups. Hypermenorrhea in metabolic syndrome may be caused by endocrinologic or local endometrial factors, because myomas or other endometrial pathologic changes were not more common on vaginal ultrasonography. It is notable that abnormal endometrial ripening seemed to be associated with obesity itself, which supports the idea that obesity is a risk factor for endometrial hyperplasia and malignancies.23 However, there were no differences regarding fertility or obstetric outcome among the groups. Clinical features of possible hyperandrogenism (hirsutism and acne) were not associated with metabolic syndrome and were equally as common among women with simple obesity and lean control women. However, cutaneous markers of hyperinsulinemia (alopecia areata and acanthosis nigricans) were detected, although seldom, only in the group with metabolic syndrome. As hypothesized, the highest free testosterone levels were found in the group with metabolic syndrome. More generally, obesity also was associated with low SHBG concentrations.
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Ultrasonographic examination revealed polycystic-like ovaries in a similar frequency in every group (~14%). This corresponds to earlier reports. Even though polycystic ovaries have been the cornerstone of the diagnosis of PCOS, up to 20% of women may have changes in ovarian morphologic features without symptoms.24 As mentioned earlier, metabolic syndrome is an entity without a clear-cut definition. It consists of various cardiovascular risk factors, all of which are connected with a decreased sensitivity of target tissues to the action of insulin (ie, insulin resistance). The full-blown syndrome, including all factors, seldom occurs. Although central obesity was not included in the original definition of metabolic syndrome, later studies have emphasized its key role.25 The impaired suppression of lipolysis by insulin in central obesity leads to increased production of fatty acids, which by competition impair glucose uptake in skeletal muscle.14 Accordingly, in our study the levels of glucose, insulin, and triglyceride were higher in the group with central obesity than in the group with obesity in which the fat distribution was more peripheral. To evaluate how the diagnostic criteria may influence the results in this study, we analyzed the subgroups using more stringent criteria. In our analysis the so-called core of metabolic syndrome included the most severe form of this syndrome (ie, hyperinsulinemia associated with dyslipidemia). Clearly, among women with this form of the syndrome, the PCOS-like symptoms were more pronounced. It must be stressed, however, that even when stricter criteria were used >70% of the women with metabolic syndrome did not show any clinical or ovarian findings traditionally associated with PCOS, with the exception of oligomenorrhea (46%). However, the subgroup analysis should be interpreted with great caution. The important message of this study is that, although PCOS and the metabolic syndrome are clearly closely interwoven pathophysiologically, PCOS only accounts for a distinct subgroup of a much wider problem, metabolic syndrome. Actually, although the connection of insulin resistance to PCOS is largely accepted, the heterogeneous nature of PCOS has recently been emphasized.26 According to our results, insulin resistance is associated only partly with the expressions of this common endocrinopathy, possibly on the basis of different causes. Women who seek help for infertility and who have a more classical picture of PCOS (ie, oligomenorrhea or amenorrhea since puberty, hirsutism, and especially central obesity) most probably represent the group with the highest degree of insulin resistance, in combination with another pathogenesis that is, so far, poorly defined. In conclusion, although metabolic syndrome and PCOS are two different although overlapping entities, both have important implications for the gynecologist. The implications of PCOS are evident. However, because a gynecologist may be the only physician that a woman of
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reproductive age and with metabolic syndrome encounters, it is important to suspect metabolic syndrome and to perform adequate examination. The woman should be informed about the most notable clinical implication of metabolic syndrome (ie, the markedly increased risk of cardiovascular disease and type II diabetes) and should be told about the importance of prevention (ie, avoiding both obesity and smoking). REFERENCES
1. Burghen G, Givens J, Kitabchi A. Correlation of hyperandrogenism with hyper-insulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113-6. 2. Barbieri R, Ryan K. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983; 147:90-6. 3. Dunaif A, Segal K, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-72. 4. Dunaif A. Insulin resistance and the polycystic ovarian syndrome: mechanisms and implications for pathogenesis. Endocr Rev 1997;18:774-800. 5. Nestler J, Powers L, Matt D, Steingold K, Plymate S, Rittmaster R, et al. A direct effect of hyperinsulinemia on serum sex hormone–binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:83-9. 6. Hartz A, Barboriak P, Wong A, Katayama K, Rimm A. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obesity 1979;3:57-73. 7. Kirschner M, Schneider G, Ertel N, Worton E. Obesity, androgens, estrogens and cancer risk. Cancer Res 1982;42:3281-5. 8. Glass A, Burman K, Dahms W. Endocrine function in human obesity. Metabolism 1981;30:89-104. 9. Samojlik E, Kirschner M, Silber D, Schneider G, Ertel N. Elevated production and metabolic clearance rates of androgens in morbidly obese women. J Clin Endocrinol Metab 1984;59: 949-54. 10. Evans D, Hoffmann R, Kalkhoff R, Kissebach A. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 1983;57:304–10.
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11. Reaven G, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-81. 12. Reaven G. Role of insulin resistance in human disease [Banting Lecture 1988]. Diabetes 1988;37:1595-607. 13. Kaplan N. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989;149:1514–20. 14. Björntorp P. Visceral obesity: “a civilization syndrome.” Obes Res 1993;1:206-22. 15. Björntorp P. Abdominal obesity and the metabolic syndrome. Ann Med 1992;24:465-8. 16. Vanhala M, Kumpusalo E, Pitkäjärvi T, Takala J. Metabolic syndrome in a middle–aged Finnish population. Cardiovasc Risk Factors 1997;4:291-5. 17. World Health Organization. Report of WHO Study Group on Diabetes Mellitus. Geneva: World Health Organization; 1985. Technical Report Series No.: 727. 18. Ferriman D, Gallwey J. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440-7. 18a. Anderson DC. Sex hormone binding globulin. Clin Endocrinol 1974;3:69-96. 19. Nestler J. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997;15:581-6. 20. Zavaroni J, Bonini L, Fantuzzi A. Hyperinsulinemia, obesity and syndrome X. J Intern Med 1994;235:51-6. 21. Alberti K, Zimmet P, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus. [Provisional Report of a WHO Consultation.] Diabet Med 1998;15: 539-53. 22. Conway G. Polycystic ovary syndrome: clinical aspects. Baillieres Clin Endocrinol Metab 1996;10:263-79. 23. Levi F, La Vecchia C, Negri E, Parazzini F, Franceschi S. Body mass at different ages and subsequent endometrial cancer risk. Int J Cancer 1992;50:567-71. 24. Polson D, Wadsworth J, Adams J, Franks S. Polycystic ovaries: a common finding in normal women. Lancet 1988;1:870-2. 25. Lapidus L, Bengtsson C, Björntorp P. The quantitative relationship between “the metabolic syndrome” and abdominal obesity in women. Obes Res 1994;2:372-7. 26. Hopkinson Z, Sattar N, Fleming R. Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ 1998;317: 329-32.
Key words: Insulin resistance, metabolic syndrome, obesity, polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity characterized by signs and symptoms of hyperandrogenism and anovulatory disorders often associated with infertility and obesity. The underlying pathogenesis remains uncertain, although key components in the syndrome may be insulin resistance and hyperinsulinemia.1-4 Chronic hyperinsulinemia is hypothesized to
From the Department of Obstetrics and Gynecology, Mikkeli Central Hospital,a the Department of Obstetrics and Gynecologyb and the Department of Medicine and Clinical Nutrition,c Kuopio University Hospital, and the Imatra District Health Centre.d Received for publication June 25, 1999; revised April 26, 2000; accepted June 20, 2000. Reprint requests: Maritta Hippeläinen, MD, Department of Obstetrics and Gynecology, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland. Copyright © 2001 by Mosby, Inc. 0002-9378/2001 $35.00 + 0 6/1/109596 doi:10.1067/mob.2001.109596
act synergistically with luteinizing hormone on the ovaries to produce excessive quantities of androgens, resulting in anovulatory disorders. Further, hyperinsulinemia directly reduces serum levels of sex hormone– binding globulin (SHBG) in obese women with PCOS.5 Excess obesity itself has been associated with a variety of alterations in hormone production, metabolism, and action.6-8 In obese women there appears to be a high frequency of menstrual disturbances and hirsutism, suggesting possible abnormalities of androgen production.9 However, these abnormalities seem not to be associated with total fat mass per se but more so with central fat accumulation.10 It has been shown in several epidemiologic studies that risk factors for cardiovascular disease, such as central obesity, hypertension, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, abnormal glucose metabolism, and hyperinsulinemia, are related to 289
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insulin resistance.11 Furthermore, there is a tendency for these risk factors to cluster in the same individual with central or abdominal adiposity. Various names have been suggested for this cluster of metabolic risk factors and diseases. Reaven12 first called this cluster of phenomena syndrome X. Other authors have suggested terms such as insulin resistance syndrome, plurimetabolic syndrome, deadly quartet,13 and civilization syndrome.14 The term metabolic syndrome has been the most widely used15 and is also the term used in this study. Although the connection of hyperinsulinemia and PCOS has been shown beyond a doubt, no studies have assessed this association the other way around; that is, the frequency of gynecologic problems in female patients with evident metabolic syndrome. Our hypothesis was that on the population level there would be more PCOSlike symptoms (ie, ovulatory disorders, hyperandrogenism, and infertility problems) among women with metabolic syndrome than in lean women or obese women with more peripheral fat distribution. Subjects and methods Screening for metabolic syndrome. Participants (N = 204) were recruited from all female residents born in 1942, 1947, 1952, 1957, and 1962 in Pieksämäki, a town in central Finland. These women had been screened during the years 1993 and 1994 for the detection of the metabolic syndrome, as described earlier in detail.16 The sample members were drawn from an updated census register. The metabolic syndrome was considered to be present if the study participant met at least 3 of the following 8 criteria: (1) first-degree relative with type II diabetes, (2) obesity as defined by a body mass index (BMI) ≥30 kg/m2, (3) abdominal adiposity as defined by a waist/hip ratio ≥0.88, (4) hypertension as defined by systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg or drug treatment for hypertension, (5) fasting serum triglyceride value ≥1.70 mmol/L, (6) fasting HDL cholesterol value <1.20 mmol/L, (7) abnormal glucose metabolism according to the World Health Organization (WHO) criteria,17 and (8) hyperinsulinemia (fasting insulin value ≥13.0 mU/L). To illustrate how the diagnostic criteria may modify the results, we created a subgroup of women with metabolic syndrome by using stricter criteria—presence of both dyslipidemia (serum triglyceride values >1.7 nmol/L or HDL cholesterol values <1.20 nmol/L) and hyperinsulinemia (fasting insulin concentration >13 mU/L) or impaired glucose tolerance. A total of 543 (92.5%) of the 587 women born during these years participated in the screening. Metabolic syndrome according to the looser criteria was found in 106 women (19.5%), as follows: born in 1942, 18 (17%); born in 1947, 43 (41%); born in 1952, 17 (16%); born in 1957, 17 (16%); born in 1962, 11 (10%). Of these 106 women,
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34 (32.1%) met the standards of the stricter criteria for metabolic syndrome. Formation of the study population Group with metabolic syndrome. Of the 106 women considered to have metabolic syndrome, 92 (86.8%) answered the questionnaire and 84 (79.2%) agreed to participate in the clinical study and give new blood samples for the biochemical analyses. Of the remainder, 2 were excluded because they had disabilities, 2 had moved outside the catchment area, 1 was pregnant, and the rest refused to participate in the study. Endometrial evaluation was performed in 65 (77.4%) of 84 subjects. Obese control group. The obese group was formed from the original screening population. Exclusion criteria were abdominal adiposity (waist/hip ratio ≥0.88) and metabolic syndrome. The inclusion criterion was a BMI >27 kg/m2. These criteria were fulfilled by 62 women, as follows: born in 1942, 16 (29%); born in 1947, 18 (29%); born in 1952, 13 (21%); born in 1957, 8 (13%); born in 1962, 7 (11%). None of these women had more than one of the diagnostic criteria for metabolic syndrome (excluding obesity) at presentation. Of these 62 women, 59 (95.2%) volunteered to come for the clinical examination and 58 (93.5%) agreed to undergo further laboratory tests. Endometrial evaluation was performed in 38 (64.4%) of the 59 women. Lean control group. The lean control group was chosen from the original screening population having a BMI <27 kg/m2 and none of the risk factors mentioned earlier. They were invited to the screening in alphabetic order. This group comprised 53 women from the various age groups. Fifty women (94.3%) participated in the laboratory tests. Endometrial evaluation was performed in 28 (52.8%) of the 53 women. This study was approved by the local ethics committee. Informed consent was obtained from all participants. Patient history. A structured questionnaire soliciting the social and medical history was distributed to all participants in the study. Information about gynecologic history, smoking, use of alcohol, chronic diseases, and medication was obtained. Subjects who were smoking daily were recorded as smokers. Patient records were reviewed with respect to diseases and operations. An intermenstrual interval of >35 days was considered to be oligomenorrhea. Abnormal uterine bleeding outside the regular menstrual cycle (28 ± 7 days) was defined as metrorrhagia. Clinical examination. All 204 subjects from the 3 groups were examined and personally interviewed according the questionnaire by the same gynecologist (Seija Korhonen) in 1996 and 1997. The blood pressure was measured with the subject seated after she had rested for 15 minutes. For anthropometric measurements, subjects were examined wearing light clothes. BMI was calculated as Weight (kg)/Height (m2). Waist and hip cir-
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cumferences were measured to the nearest centimeter with a tape measure while the subject was standing. The waist was measured at the smallest girth midway between the lowest rib margin and the iliac crest, and the hip circumference was measured at the level of the greater trochanter to calculate the waist/hip ratio. The clinical features of acanthosis nigricans and androgenic alopecia were assessed. Hirsutism was classified according to the Ferriman-Gallwey score.18 During the routine gynecologic examination, transvaginal ultrasonography was performed (5.0-MHz transvaginal transducer, ALOKA Echo Camera SSD-500; Aloka Company, Tokyo, Japan). The form and the dimensions of the uterus and the thickness of the endometrium were assessed. The morphologic features and dimensions of the ovaries were determined. Ovaries were considered as polycystic if there were >10 small (<10 mm) subcapsular follicles in either ovary. Endometrial evaluation was carried out by taking an endometrial sample with a special brush (Ori endometrial brush; Medical AB, Malmö, Sweden). Whenever possible, both histologic and cytologic evaluation were performed by a pathologist in the Kuopio University Hospital Department of Pathology. Biochemical tests. Total cholesterol, HDL cholesterol, and triglyceride levels were measured after an overnight fast. The 2-hour oral glucose tolerance test was performed with 75 g glucose (Nutricia Nederland BV, Zoetermeer, The Netherlands) according to the WHO recommendations. Blood was drawn at baseline and at 120 minutes for the measurement of blood glucose and plasma insulin. The samples for serum testosterone, dehydroepiandrosterone sulfate (DHEAS), and SHBG were collected in the early follicular phase for the premenopausal women. All hormone treatments were stopped for 1 month before blood tests. A 1-mg overnight dexamethasone suppression test was performed to exclude Cushing syndrome. Additionally, serum prolactin and thyrotropin concentrations were determined to exclude hyperprolactinemia, hyperthyroidism, and hypothyroidism. Analytic methods. Serum cholesterol and triglycerides were analyzed by enzymatic colorimetric methods in the Department of Clinical Chemistry, Kuopio University Hospital. Serum HDL cholesterol was measured by the same method after the precipitation of low-density lipoprotein and very low-density lipoprotein cholesterol by dextran sulfate and magnesium chloride. Insulin and glucose values were determined from plasma that had been separated by centrifugation and frozen at –20°C. Glucose values were determined by an ion-selective electrode system (YSI 2000; YSI, Yellow Springs, Ohio), and insulin values were determined by the Phadeseph Insulin RIA (Pharmacia Diagnostics AB, Uppsala, Sweden) in the Department of Medicine laboratory, University of Kuopio. The serum testosterone concentration was deter-
mined after extraction by the DPC Coat-a-Count (radioimmunoassay kit; Diagnostic Products Corporation, Los Angeles, Calif) method. The SHBG measurement was determined with an immunoradiometric assay (Organon Teknika, Boxtel, The Netherlands). The unbound testosterone concentration in serum was calculated by use of testosterone and SHBG concentrations according to Anderson et al.18a The free androgen index was calculated as the following quotient: Testosterone/ SHBG × 1000, with both testosterone and SHBG being measured in nanomoles per liter. Dehydroepiandrosterone sulfate (DHEAS) was measured with a radioimmunoassay (Coat–a-Count). Statistical methods. Statistical analyses were performed with the SPSS for Windows, version 8.0 (SPSS, Chicago, Ill). Data are shown as the mean ± SEM. A normal distribution of the variables was tested with the KolmogorovSmirnov test. Log transformation was used if variables were not normally distributed. To test differences among the 3 study groups, we used 1-way analysis of variance and the Scheffé test. Homogeneity of variances was tested with the Levene test. If variances were not homogeneous, the Tamhane test was used instead of the Scheffé test. The χ2 test or, in the case of small expected frequencies, the Fisher exact test was used for nominal scale clinical variables. The differences between the 2 groups were determined by the Fisher exact test with the Bonferroni correction. Results Table I shows clinical and biochemical characteristics of the study population, including all 8 criteria used in screening women for the metabolic syndrome diagnosis. Although only 3 criteria were required for including women in the group with metabolic syndrome, this group differed significantly from the lean control group according to all 8 screening characteristics and also from the obese group except for HDL cholesterol. Thus abdominal adiposity, high blood pressure, high serum triglyceride levels, and high plasma insulin levels, as well as abnormal glucose tolerance, were significantly more common findings in the group with metabolic syndrome than in the other 2 groups. In a comparison of the simple obese and lean control groups, blood pressure and fasting glucose, insulin, and triglyceride levels were higher in obese women. There were also differences among the groups in androgen levels (Table I). Obesity per se and especially central obesity were associated with low SHBG concentrations. Similarly, the highest free testosterone concentration and androgen indexes were found in the group with metabolic syndrome. Nineteen women (22.6%) in the group with metabolic syndrome were treated for hypertension, in comparison with 2 subjects (3.4%) in the group with simple obesity.
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Table I. Clinical characteristics of study population Study group Metabolic syndrome (n = 84) Age (y, mean ± SEM) 46 ± 1 BMI (kg/m2, mean ± SEM) 31.5 ± 0.7*, † Waist circumference (cm, mean ± SEM) 99.2 ± 1.4*, † Waist/hip ratio (mean ± SEM) 0.91 ± 0.01*, † Current smokers (No.) 20 (23.8%) Non–insulin-dependent diabetes mellitus in first-degree relative (No.) 39 (46.4%)*, † Systolic blood pressure (mm Hg, mean ± SEM)) 144.0 ± 2*, † Diastolic blood pressure (mm Hg, mean ± SEM) 87.8 ± 1*, † Total cholesterol (mmol/L, mean ± SEM) 5.5 ± 0.1* HDL cholesterol (mmol/L, mean ± SEM) 1.28 ± 0.04* Triglycerides (mmol/L, mean ± SEM) 1.7 ± 0.09*, † Fasting glucose (mmol/L, mean ± SEM) 5.5 ± 0.1* Glucose, 2 h (mmol/L, mean ± SEM) 6.2 ± 0.2*, † Fasting plasma insulin (mU/L, mean ± SEM) 11.9 ± 0.8*, † SHBG (nmol/L, mean ± SEM) 38.7 ± 2.7*, † DHEAS (nmol/L, mean ± SEM) 4.44 ± 0.3* Free testosterone (mean ± SEM) 20.4 ± 1.0*, † Free androgen index (mean ± SEM) 48.2 ± 5*, †
Obese (n = 58)
Lean (n = 50)
Statistical significance
46 ± 1 44 ± 1 28.8 ± 0.3‡ 22.6 ± 0.3 88.3 ± 0.9‡ 74.5 ± 0.8 0.82 ± 0.001‡ 0.78 ± 0.01 11 (19.0%) 20 (40.0%)* 18 (31.0%) 2 (4.0%) 135 ± 2‡ 125 ± 2 83.8 ± 1‡ 76.6 ± 1 5.6 ± 0.1 5.1 ± 0.1 1.36 ± 0.03 1.43 ± 0.05 1.3 ± 0.09‡ 0.9 ± 0.07 5.3 ± 0.1‡ 5.0 ± 0.1 5.4 ± 0.2‡ 4.7 ± 0.2 9.2 ± 0.5‡ 6.7 ± 0.3 46.6 ± 2.5‡ 60.9 ± 3.6 3.90 ± 0.2 3.62 ± 0.18 16.95 ± 0.8 15.28 ± 0.97 30.6 ± 2.0 24.3 ± 2.1
P < .001 P < .001 P < .001 P = .01 P < .001 P < .001 P < .001 P < .05 P < .05 P < .001 P < .001 P < .001 P < .001 P < 0.001 P = .026 P = .001 P < .001
*P < .05, significant difference between metabolic syndrome and lean groups. †P < .05, significant difference between metabolic syndrome and obese groups. ‡P < .05, significant difference between obese and lean groups.
Table II. Gynecologic history of study groups Study group Metabolic syndrome (n = 92)
Obese (n = 59)
Lean (n = 53)
13.1 ± 0.1 7 (7.6%)
13.2 ± 0.2 7 (11.9%)
13.3 ± 0.2 6 (11.3%)
32 (34.8%)* 20 (21.7%) 35 (38.0%)*, † 12 (13.0%)
15 (25.4%) 8 (13.6%) 9 (15.3%) 11 (18.6%)
8 (15.1%) 9 (17.0%) 6 (11.3%) 8 (15.1%)
18 (19.6%) 1 (1.1%)
9 (15.3%) 2 (3.4%)
7 (13.2%) 1 (1.9%)
54 (58.7%) 25 (27.2%) 19 (20.7%) 46.9 ± 0.7
38 (64.4%) 15 (25.4%) 17 (28.8%) 47.6 ± 0.6
32 (60.4%) 17 (32.1%) 10 (18.9%) 47.4 ± 0.8
Menarche (y, mean ± SEM) Irregular menstrual cycles before age 20 y (No.) Irregular menstrual cycles after age 20 y (No.) Oligomenorrhea Metrorrhagia Hypermenorrhea Infertility problems (No.) Miscarriages (No.) 1-2 >3 Parity (No.) 1-2 >3 Postmenopausal (No.) Menopause (y, mean ± SEM)
Statistical significance
P = .03 P = .001
*P < .05, significant difference between metabolic syndrome and lean groups. †P < .05, significant difference between metabolic syndrome and obese groups.
Table III. Endometrial status and hysterectomies in 3 study groups Study group Metabolic syndrome (n = 92) Hyperplasia in history (No.) Hysterectomy (No.) Uterine myomas Hyperplasia Endometriosis Hypermenorrhea
Obese (n = 59)
Lean (n = 53)
4 (4.3%) 4 (6.8%) 4 (7.5%) 9 (9.8%) 5 (8.5%) 6 (11.3%) 8 2 2 1 1 1 2 1 2
The number of current smokers was highest in the lean control group (40.0%), compared with both the metabolic syndrome group and the group with simple obesity (22% and 19%, respectively; P < .05). Light to moderate consumption of alcohol (1-50 portions per month) was reported by 55 women (65.5%) in the group with metabolic syndrome, 43 (74.1%) in the obese group, and 47 (94.0%) in the lean group. The frequency of high alcohol consumption (51-100 portions per month) was uncommon (5%, 0%, and 0% in the metabolic syndrome group and the obese and lean control groups, respectively).
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Table IV. Current clinical findings in 3 study groups Study group Metabolic syndrome (n = 84) Hirsutism* No. Mean ± SD Acanthosis nigricans (No.) Alopecia areata (No.) Acne (No.) Ultrasonography findings (No.) Uterine myomas§ Ovaries Normalll Polycystic
17 (20.2%) 3.7 ± 4.1 5 (6.0%)†, ‡ 6 (7.1%)†, ‡ 13 (15.5%)
Obese (n = 59)
Lean (n = 53)
10 (16.9%) 2.8 ± 3.8 0 0 10 (16.9%)
5 (9.4%) 2.6 ± 3.8 0 0 5 (9.4%)
17/75 (22.7%)
11/53 (20.8%)
11/44 (25%)
65 (77.4%) 11 (13.1%)
44 (75.9%) 9 (15.3%)
Statistical significance
P = .044 P = .03
41 (82.0%) 7 (13.2%)
*Ferriman-Gallway18 score >7. †P < .05, significant difference between metabolic syndrome and lean groups. ‡P < .05, significant difference between metabolic syndrome and obese groups. §Different case number because of hysterectomies. llCorresponding to the cycle.
There were no differences in the mean age at menarche among the 3 groups (Table II). The occurrence of irregular cycles in late adolescence also did not differ among groups. In adulthood, however, oligomenorrhea was a more common disorder in the group with metabolic syndrome than in the lean control group. Only every third woman in the group with metabolic syndrome with oligomenorrhea at presentation had sought hormonal treatment. Furthermore, hypermenorrhea was a more common complaint in the group with metabolic syndrome. In addition, metrorrhagia tended to be more common in the group with metabolic syndrome than in other groups, but the difference did not reach statistical significance. Most of the women in each group had a stable sexual partnership (80%, 88%, and 83% in the metabolic syndrome group and the obese and lean control groups, respectively). Overall, ~90% of the women had children. Infertility problems tended to be more frequent in obese (18.6%) and lean (15.1%) control subjects than in the group with metabolic syndrome (13.0%), but the difference did not reach statistical significance (Table II). About half of the women with infertility problems (14/30 altogether) were treated for this problem, and 13 had become pregnant. There tended to be more miscarriages in the group with metabolic syndrome than in other groups. The number of postmenopausal women was comparable among the 3 groups. The onset of climacteric symptoms occurred at a similar age (mean, 47 years) (Table II). Only some of the postmenopausal women in the metabolic syndrome group (7/19) and the obese group (7/17) used hormone replacement therapy for climacteric symptoms, whereas the use of hormones tended to be more common among lean control subjects (7/10). Evaluation of the patients’ records showed that the frequencies of previous endometrial hyperplasia were simi-
lar (P = .73) among study groups (Table III). In addition, there were no differences in the frequency of hysterectomy. In about every tenth woman the uterus had been removed for the reasons shown in Table III. Additionally, there was 1 case of ovarian cancer in the obese group (1.7%) and 2 cases of breast cancer in the group with metabolic syndrome (2.2%). Endometrial samples obtained with an endocervical brush appeared to be representative in 122 (93.2%) of 131 cases, and histologic evaluation was possible in 104 (85.2%) of 122 samples. In about every third case in the metabolic syndrome group (32%) and the obese group (29%), the histologic findings in the endometrium did not correspond to the cycle, whereas such discordance was a rare finding among lean control subjects (14%). Hyperplasia was not detected in any of the 122 representative endometrial samples evaluated. In 1 case there were atypical cells (class II Papanicolaou smear), and in 2 cases a decidual reaction to an intrauterine contraceptive device was present. Transvaginal ultrasonographic evaluation showed that the frequency of myomas was comparable among the 3 groups. It is of interest that polycystic-like ovaries on ultrasonography were not more common in the group with metabolic syndrome than in the other groups (P = .9; Table IV). Clinical features for hyperandrogenism and also cutaneous markers of insulin resistance, such as androgenic alopecia and acanthosis nigricans, were detected only in the group with metabolic syndrome. On the other hand, although hirsutism and acne tended to be more common in the metabolic syndrome and obese groups than among lean women, the differences were not statistically significant (Table IV). None of the women in the group with metabolic syndrome and only 1 woman in the obese group and 2 women in the lean group had received hor-
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Table V. Group with metabolic syndrome, divided into those with severe form and those with nonsevere form
Age (y, mean ± SEM) Waist circumference (cm, mean ± SEM) Waist/hip ratio (mean ± SEM) BMI (kg/m2, mean ± SEM) Free androgen index (mean ± SEM) Oligomenorrhea (No.) Polycystic ovaries (No.) Hirsutism (No.) Acanthosis nigricans (No.) Alopecia areata (No.) Infertility problems (No.)
Severe form (n = 26)*
Nonsevere form (n = 58)
46 ± 1 103.8 ± 2.7† 0.93 ± 0.01 34.3 ± 1.2† 56.3 ± 10.4 12 (46.2%) 6 (23.1%) 6 (23.1%) 2 (7.7%) 3 (11.5%) 5 (19.2%)
46 ± 1 97.2 ± 1.5 0.90 ± 0.01 30.3 ± 0.7 44.5 ± 5.6 17 (29.3%) 5 (8.6%) 11 (18.9%) 3 (5.2%) 3 (5.2%) 7 (12.1%)
Statistical significance
P = .03 P = .004
*The severe form of metabolic syndrome is distinguished from the nonsevere form by strict criteria—dyslipidemia and hyperinsulinemia are present in the severe form. †P < .05, significant difference between groups.
monal treatment for hirsutism. The use of hormonal contraception was comparable among the groups (3%-4%). Finally, we used more stringent criteria for metabolic syndrome (ie, simultaneous presence of dyslipidemia and either hyperinsulinemia or abnormal glucose tolerance). By this definition, oligomenorrhea and polycystic ovarian structure seemed to be more common findings in this “core” subgroup of women with metabolic syndrome than in control women (Table V). Comment Our a priori hypothesis was that disorders that were similar to PCOS would be concentrated, especially in women with metabolic syndrome, because emerging evidence suggests that insulin resistance may have a primary etiologic role in PCOS.19 However, this connection was unclear at the population level. Therefore metabolic syndrome and PCOS should not be considered synonymous entities, although overlap seems to be evident. The definition of metabolic syndrome in this study was based on the simultaneous presence of at least 3 of 8 clinical and metabolic markers of insulin resistance. According to these criteria, about one fifth of the women (19.5%) fulfilled the criteria for metabolic syndrome, the prevalence increasing with age. This corresponds to previous findings, in which one fourth to one third of healthy women or men had some degree of insulin resistance.20 However, although only 3 criteria were required, the group with metabolic syndrome differed from the lean control group according to all 8 characteristics and also from the group with simple obesity. Similar significant differences were also detected between subjects with simple obesity and lean control subjects. When these 3 female groups were compared according to menstrual and fertility history, however, surprisingly few differences were found. In regard to the definition of metabolic syndrome, we acknowledge that this is a matter of dispute, because there are no internationally accepted criteria for meta-
bolic syndrome. The recent Provisional Report of a WHO Consultation21 is perhaps the most important in this respect. As those authors acknowledged, this definition was not based on causal relationships and is suggested to be regarded more as a working definition. The criteria proposed by WHO were as follows: impaired glucose regulation or diabetes, insulin resistance as measured by the hyperinsulinemic-euglycemic clamp, raised arterial blood pressure, elevated plasma triglyceride levels (≥1.7 mmol/L) or low HDL cholesterol level (≤1.0 mmol/L in women), central obesity (for female patients, a waist/hip ratio >0.85 or a BMI of ≥30 kg/m2), and microalbuminuria. The relative importance of each component is unclear at present. According to the WHO definition, 2 of these criteria should be present for the patient’s condition to qualify as metabolic syndrome. Note that in this study all women with any 3 of the 8 criteria were included in the group with metabolic syndrome. Obese control women were required to have a BMI >27 kg/m2 but a waist/hip ratio <0.88, because the exclusion criteria were abdominal obesity and the metabolic syndrome. Thus, besides obesity, only 1 feature of metabolic syndrome was allowed for inclusion in the control group with simple obesity. Obesity itself causes insulin resistance and characteristics associated with it, but the risk seems to be especially associated with central obesity.15 The group with metabolic syndrome differed significantly from the obese control group according to all screening characteristics except HDL cholesterol concentrations. However, it is evident that metabolic syndrome is a very heterogeneous condition and that various subgroups are to be found within this population. When interpreting the findings of this study, one should bear in mind 3 important points. First, this study was population based, in contrast to nearly all previous studies assessing the connection between PCOS and hyperinsulinemia or insulin resistance. Second, we first identified subjects with metabolic syndrome by using an increased waist/hip ratio as a surrogate marker, whereas
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the previous studies first identified women with symptoms and findings similar to those of PCOS and then evaluated the connection with insulin resistance. Third, we also controlled for the effects of obesity per se by including a group with a predominantly peripheral fat distribution. According to recent data, diagnostic and clinical features of PCOS also vary greatly. Commonly used current diagnostic criteria include clinical signs and symptoms of hyperandrogenism and ovulatory dysfunction, with the exclusion of a well-defined underlying cause of androgen excess. Although we did not explicitly state PCOS criteria in particular, pertinent features previously associated with PCOS were evaluated in this study (ie, clinical signs and symptoms of hyperandrogenism, androgen levels, menstrual disorders [especially oligomenorrhea], infertility, and ovarian structure on vaginal ultrasonography). Thyroid dysfunction, hyperprolactinemia, and abnormal cortisol secretion were excluded. The onset of PCOS, which often occurs at menarche, is characterized by a failure to establish a regular pattern of menses.22 In this population-based study there were no differences between the metabolic syndrome group and the control groups for menarche and irregular menstrual periods before the age of 20 years. On the other hand, during later life the common menstrual disorders evaluated in this study tended to be more frequent among women in the group with metabolic syndrome. Oligomenorrhea with anovulatory periods seemed to be especially associated with central obesity, because there was no difference between women with peripheral obesity and lean control subjects. It is of interest that the complaint of heavy menstrual bleeding with regular menstrual periods was also more common in the group with metabolic syndrome than in the other groups. Hypermenorrhea in metabolic syndrome may be caused by endocrinologic or local endometrial factors, because myomas or other endometrial pathologic changes were not more common on vaginal ultrasonography. It is notable that abnormal endometrial ripening seemed to be associated with obesity itself, which supports the idea that obesity is a risk factor for endometrial hyperplasia and malignancies.23 However, there were no differences regarding fertility or obstetric outcome among the groups. Clinical features of possible hyperandrogenism (hirsutism and acne) were not associated with metabolic syndrome and were equally as common among women with simple obesity and lean control women. However, cutaneous markers of hyperinsulinemia (alopecia areata and acanthosis nigricans) were detected, although seldom, only in the group with metabolic syndrome. As hypothesized, the highest free testosterone levels were found in the group with metabolic syndrome. More generally, obesity also was associated with low SHBG concentrations.
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Ultrasonographic examination revealed polycystic-like ovaries in a similar frequency in every group (~14%). This corresponds to earlier reports. Even though polycystic ovaries have been the cornerstone of the diagnosis of PCOS, up to 20% of women may have changes in ovarian morphologic features without symptoms.24 As mentioned earlier, metabolic syndrome is an entity without a clear-cut definition. It consists of various cardiovascular risk factors, all of which are connected with a decreased sensitivity of target tissues to the action of insulin (ie, insulin resistance). The full-blown syndrome, including all factors, seldom occurs. Although central obesity was not included in the original definition of metabolic syndrome, later studies have emphasized its key role.25 The impaired suppression of lipolysis by insulin in central obesity leads to increased production of fatty acids, which by competition impair glucose uptake in skeletal muscle.14 Accordingly, in our study the levels of glucose, insulin, and triglyceride were higher in the group with central obesity than in the group with obesity in which the fat distribution was more peripheral. To evaluate how the diagnostic criteria may influence the results in this study, we analyzed the subgroups using more stringent criteria. In our analysis the so-called core of metabolic syndrome included the most severe form of this syndrome (ie, hyperinsulinemia associated with dyslipidemia). Clearly, among women with this form of the syndrome, the PCOS-like symptoms were more pronounced. It must be stressed, however, that even when stricter criteria were used >70% of the women with metabolic syndrome did not show any clinical or ovarian findings traditionally associated with PCOS, with the exception of oligomenorrhea (46%). However, the subgroup analysis should be interpreted with great caution. The important message of this study is that, although PCOS and the metabolic syndrome are clearly closely interwoven pathophysiologically, PCOS only accounts for a distinct subgroup of a much wider problem, metabolic syndrome. Actually, although the connection of insulin resistance to PCOS is largely accepted, the heterogeneous nature of PCOS has recently been emphasized.26 According to our results, insulin resistance is associated only partly with the expressions of this common endocrinopathy, possibly on the basis of different causes. Women who seek help for infertility and who have a more classical picture of PCOS (ie, oligomenorrhea or amenorrhea since puberty, hirsutism, and especially central obesity) most probably represent the group with the highest degree of insulin resistance, in combination with another pathogenesis that is, so far, poorly defined. In conclusion, although metabolic syndrome and PCOS are two different although overlapping entities, both have important implications for the gynecologist. The implications of PCOS are evident. However, because a gynecologist may be the only physician that a woman of
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reproductive age and with metabolic syndrome encounters, it is important to suspect metabolic syndrome and to perform adequate examination. The woman should be informed about the most notable clinical implication of metabolic syndrome (ie, the markedly increased risk of cardiovascular disease and type II diabetes) and should be told about the importance of prevention (ie, avoiding both obesity and smoking). REFERENCES
1. Burghen G, Givens J, Kitabchi A. Correlation of hyperandrogenism with hyper-insulinism in polycystic ovarian disease. J Clin Endocrinol Metab 1980;50:113-6. 2. Barbieri R, Ryan K. Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features. Am J Obstet Gynecol 1983; 147:90-6. 3. Dunaif A, Segal K, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989;38:1165-72. 4. Dunaif A. Insulin resistance and the polycystic ovarian syndrome: mechanisms and implications for pathogenesis. Endocr Rev 1997;18:774-800. 5. Nestler J, Powers L, Matt D, Steingold K, Plymate S, Rittmaster R, et al. A direct effect of hyperinsulinemia on serum sex hormone–binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 1991;72:83-9. 6. Hartz A, Barboriak P, Wong A, Katayama K, Rimm A. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obesity 1979;3:57-73. 7. Kirschner M, Schneider G, Ertel N, Worton E. Obesity, androgens, estrogens and cancer risk. Cancer Res 1982;42:3281-5. 8. Glass A, Burman K, Dahms W. Endocrine function in human obesity. Metabolism 1981;30:89-104. 9. Samojlik E, Kirschner M, Silber D, Schneider G, Ertel N. Elevated production and metabolic clearance rates of androgens in morbidly obese women. J Clin Endocrinol Metab 1984;59: 949-54. 10. Evans D, Hoffmann R, Kalkhoff R, Kissebach A. Relationship of androgenic activity to body fat topography, fat cell morphology, and metabolic aberrations in premenopausal women. J Clin Endocrinol Metab 1983;57:304–10.
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11. Reaven G, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-81. 12. Reaven G. Role of insulin resistance in human disease [Banting Lecture 1988]. Diabetes 1988;37:1595-607. 13. Kaplan N. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989;149:1514–20. 14. Björntorp P. Visceral obesity: “a civilization syndrome.” Obes Res 1993;1:206-22. 15. Björntorp P. Abdominal obesity and the metabolic syndrome. Ann Med 1992;24:465-8. 16. Vanhala M, Kumpusalo E, Pitkäjärvi T, Takala J. Metabolic syndrome in a middle–aged Finnish population. Cardiovasc Risk Factors 1997;4:291-5. 17. World Health Organization. Report of WHO Study Group on Diabetes Mellitus. Geneva: World Health Organization; 1985. Technical Report Series No.: 727. 18. Ferriman D, Gallwey J. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440-7. 18a. Anderson DC. Sex hormone binding globulin. Clin Endocrinol 1974;3:69-96. 19. Nestler J. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997;15:581-6. 20. Zavaroni J, Bonini L, Fantuzzi A. Hyperinsulinemia, obesity and syndrome X. J Intern Med 1994;235:51-6. 21. Alberti K, Zimmet P, for the WHO Consultation. Definition, diagnosis and classification of diabetes mellitus and its complications. I. Diagnosis and classification of diabetes mellitus. [Provisional Report of a WHO Consultation.] Diabet Med 1998;15: 539-53. 22. Conway G. Polycystic ovary syndrome: clinical aspects. Baillieres Clin Endocrinol Metab 1996;10:263-79. 23. Levi F, La Vecchia C, Negri E, Parazzini F, Franceschi S. Body mass at different ages and subsequent endometrial cancer risk. Int J Cancer 1992;50:567-71. 24. Polson D, Wadsworth J, Adams J, Franks S. Polycystic ovaries: a common finding in normal women. Lancet 1988;1:870-2. 25. Lapidus L, Bengtsson C, Björntorp P. The quantitative relationship between “the metabolic syndrome” and abdominal obesity in women. Obes Res 1994;2:372-7. 26. Hopkinson Z, Sattar N, Fleming R. Polycystic ovarian syndrome: the metabolic syndrome comes to gynaecology. BMJ 1998;317: 329-32.