Prevalence of hyperprolactinaemia in female premenopausal blood donors.

OBJECTIVE: The prevalence of asymptomatic hyperprolactinaemia has been widely studied in certain populations such as antipsychotic drugs users, infertile women or patients with primary hypothyroidism, but data on the prevalence of hyperprolactinaemia and macroprolactinaemia in the healthy population are very scarce in the literature. We aimed to obtain an unbiased estimation of the prevalence in premenopausal women of: (i) hyperprolactinaemia and (ii) its aetiology, including macroprolactinaemia and stress-related hyperprolactinaemia, while considering simultaneously the use of hormonal contraceptives. DESIGN: Prevalence survey. SUBJECTS: Three-hundred and ninety-three consecutive premenopausal women reporting spontaneously for blood donation. MEASUREMENTS: We performed an exhaustive clinical history and physical examination, establishing the presence of hirsutism, acne, alopecia, menstrual dysfunction and reproductive history. We also measured serum prolactin (PRL) (ruling out macroprolactinaemia when indicated), thyrotrophin, total testosterone, androstendione, sex hormone binding globulin and dehydroepiandrosterone sulphate concentrations. RESULTS: Serum PRL concentrations were increased in 16 of 393 women (4·1% prevalence, 95% CI: 2·1-6·0). The prevalence of macroprolactinaemia was 0·6% (95% CI: 0-1) in the total female blood donor population and was 12·5% (95% CI: 6-31) among hyperprolactinaemic patients. The remaining hyperprolactinaemic women had stress-related hyperprolactinaemia as the more likely aetiology. Finally, the frequency of hyperprolactinaemia was similar in users and nonusers of hormonal contraceptives (4·5% and 3·9% respectively, P = 0·209). CONCLUSIONS: The prevalence of hyperprolactinaemia in healthy female blood donors is low and is not influenced by the use of hormonal contraceptives. Pathological causes are very rare with stress-related hyperprolactinaemia and macroprolactinaemia being the most frequent causes of hyperprolactinaemia in these women.

Sexual dimorphism in adipose tissue function as evidenced by circulating adipokine concentrations in the fasting state and after an oral glucose challenge.

STUDY QUESTION: Do the circulating levels of a panel of adipokines involved in glucose metabolism exhibit sexual dimorphism in the fasting state and after an oral glucose load? SUMMARY ANSWER: Our results indicate sexual dimorphism in the circulating concentrations of adipokines involved in intermediate metabolism in the fasting state and during an oral glucose load. This finding suggests an influence of sex steroids on adipose tissue function. WHAT IS KNOWN ALREADY: Sexual dimorphism in adipose tissue distribution fully develops after puberty and modulates the risk for cardiometabolic disorders. However, the possibility that adipose tissue function exhibits sexual dimorphism as well as its distribution is unproved. STUDY DESIGN, SIZE, DURATION: Cross-sectional case-control study including 32 subjects. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen subjects with weight excess (8 men and 8 women, including 4 overweight and 4 obese subjects in each group) and 16 normal weight healthy volunteers (8 men and 8 women) presenting with similar age were submitted to a 75-g oral glucose tolerance test (oGTT). We measured circulating concentrations of insulin, glucose, chemerin, lipocalin-2, omentin-1, leptin and adiponectin and calculated their areas under the oGTT curve (AUC). MAIN RESULTS AND THE ROLE OF CHANCE: Leptin and adiponectin concentrations were higher throughout the oGTT in women compared with men. Lipocalin-2 concentrations decreased during the oGTT in the whole group of study subjects. However, these levels remained higher in men with weight excess compared with normal weight men, whereas in women with weight excess lipocalin-2 levels at the end of the oGTT were lower compared with normal weight women. Sex was among the main determinants of the AUC of omentin-1 and leptin in linear regression models, and lower estradiol and testosterone concentrations were related to higher AUC of chemerin and omentin-1, respectively. Subjects with weight excess had higher AUC of chemerin and leptin and lower AUC of omentin-1 and adiponectin levels, independently of sex. LIMITATIONS, REASONS FOR CAUTION: We included a relatively small sample size and, because this was a cross-sectional study, we cannot infer causality to the associations between the changes in circulating adipokine concentrations and the variables studied here. WIDER IMPLICATIONS OF THE FINDINGS: Sexual dimorphism in adipose tissue function should be considered when studying adiposity and obesity, and also when designing strategies for their diagnosis and management.

Prevalence of functional disorders of androgen excess in unselected premenopausal women: a study in blood donors.

BACKGROUND: The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. On the contrary, the prevalences of other disorders of androgen excess such as idiopathic hyperandrogenism and idiopathic hirsutism remain unknown. We aimed to obtain an unbiased estimate of the prevalence in premenopausal women of (i) signs of androgen excess and (ii) PCOS, idiopathic hyperandrogenism and idiopathic hirsutism. METHODS: A multicenter prevalence survey included 592 consecutive premenopausal women (393 from Madrid, Spain and 199 from Bologna, Italy) reporting spontaneously for blood donation. Immediately before donation, we conducted clinical and biochemical phenotyping for androgen excess disorders. We determined the prevalence of (i) hirsutism, acne and alopecia as clinical signs of androgen excess and (ii) functional disorders of androgen excess, including PCOS, defined by the National Institute of Child Health and Human Development/National Institute of Health criteria, idiopathic hyperandrogenism and idiopathic hirsutism. RESULTS: Regarding clinical signs of hyperandrogenism, hirsutism and acne were equally frequent [12.2% prevalence; 95% confidence interval (CI): 9.5-14.8%], whereas alopecia was uncommon (1.7% prevalence, 95% CI: 0.7-2.7%). Regarding functional disorders of androgen excess, PCOS and idiopathic hirsutism were equally frequent (5.4% prevalence, 95% CI: 3.6-7.2) followed by idiopathic hyperandrogenism (3.9% prevalence, 95% CI: 2.3-5.4). CONCLUSIONS: Clinical signs of hyperandrogenism and functional disorders of androgen excess show a high prevalence in premenopausal women. The prevalences of idiopathic hyperandrogenism and idiopathic hirsutism are similar to that of PCOS, highlighting the need for further research on the pathophysiology, consequences for health and clinical implications of these functional forms of androgen excess.

Common variants in the sex hormone-binding globulin gene (SHBG) and polycystic ovary syndrome (PCOS) in Mediterranean women.

STUDY QUESTION: Is there an association between polycystic ovary syndrome (PCOS) and the sex hormone-binding globulin (SHBG) rs1799941, rs6257, rs6259 and rs727428 variants in a large series of Mediterranean women? SUMMARY ANSWER: The rs727428 and rs6259 variants are associated with PCOS in Mediterranean women. WHAT IS KNOWN ALREADY: The level of SHBG, the primary plasma transport protein for sex steroids, which regulates the bioavailability of these hormones to target tissues, is reduced in patients with PCOS. Single-nucleotide polymorphisms in the SHBG gene influence circulating SHBG levels in American patients with PCOS and may predict the development of type 2 diabetes. STUDY DESIGN, SIZE AND DURATION: This was a genetic case-control association study including 1004 premenopausal Mediterranean women. PARTICIPANTS/MATERIALS, SETTING AND METHODS: In an Academic setting, we genotyped a clinical cohort consisting of 281 patients with PCOS and 142 women without any evidence of androgen excess, and a population-based cohort comprised of 581 unselected female blood donors from Spain and Italy. The latter included 31 patients with PCOS and 550 controls, of whom 298 had no evidence of any androgen excess disorder and were considered hyper-normal controls. MAIN RESULTS AND THE ROLE OF CHANCE: Mutant alleles of the rs727428 variant were more frequent in patients with PCOS compared with controls and with hyper-normal controls. This association was independent of obesity. Carrying mutant alleles of rs727428 was found to be associated with a 1.29 odds ratio (OR) for PCOS, whereas carrying mutant alleles of rs6259 associated with a 0.68 OR for PCOS. The rs1799941 and rs6257 variants were not associated with PCOS. None of the SHBG variants influenced serum SHBG concentrations. LIMITATIONS AND REASONS FOR CAUTION: The associations found here were relatively weak and, arising from a case-control study, do not necessarily indicate a causative role of the SHBG variants in the development of PCOS. Also, we studied different patients and controls from different sources, making some of the interpretations difficult. Finally, the rs1799941 variant was not in Hardy-Weinberg equilibrium in the small group of patients with PCOS recruited from the general population, yet this variant was not associated with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: SHBG variants that influenced circulating SHBG levels in American patients with PCOS are also associated with this syndrome in Mediterranean women, pointing to SHBG as a candidate gene for PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants PI080944 and PI110357 from Instituto de Investigación Carlos III, Spanish Ministry of Economy and Competitiveness. CIBERDEM is also an initiative of Instituto de Investigación Carlos III. The Authors have no competing interests to declare.

Combined oral contraceptives plus spironolactone compared with metformin in women with polycystic ovary syndrome: a one-year randomized clinical trial.

OBJECTIVE: We aimed to compare a combined oral contraceptive (COC) plus the antiandrogen spironolactone with the insulin sensitizer metformin in women with polycystic ovary syndrome (PCOS). DESIGN: We conducted a randomized, parallel, open-label, clinical trial comparing COC (30 µg of ethinylestradiol and 150 µg of desogestrel) plus spironolactone (100 mg/day) with metformin (850 mg b.i.d.) for one year in women with PCOS (EudraCT2008-004531-38). METHODS: The composite primary outcome included efficacy (amelioration of hirsutism, androgen excess and menstrual dysfunction) and cardiometabolic safety (changes in the frequencies of disorders of glucose tolerance, dyslipidemia and hypertension). A complete anthropometric, biochemical, hormonal and metabolic evaluation was conducted every three months and data were submitted to intention-to-treat analyses. RESULTS: Twenty-four patients were assigned to COC plus spironolactone and 22 patients to metformin. Compared with metformin, COC plus spironolactone caused larger decreases in hirsutism score (mean difference 4.6 points, 95% CI: 2.6-6.7), total testosterone (1.1 nmol/L, 0.4-1.7), free testosterone (25 pmol/L, 12-39), androstenedione (5.5 nmol/L, 1.8-9.2) and dehydroepiandrosterone sulfate (2.7 µmol/L, 1.4-4.0). Menstrual dysfunction was less frequent with COC plus spironolactone (OR: 0.06, 95% CI: 0.02-0.23). No differences were found in frequencies of abnormal glucose tolerance (OR: 1.7, 95% CI: 0.7-4.4), dyslipidemia (OR: 0.6, 95% CI: 0.2-1.8) or hypertension (OR: 0.3, 95% CI: 0.5-2.0). No major adverse events occurred and biochemical markers were similarly safe with both treatments. CONCLUSIONS: COC plus spironolactone was more effective than metformin for symptoms of PCOS showing similar safety and overall neutral effects on cardiometabolic risk factors.

Association of TLR2 S450S and ICAM1 K469E polymorphisms with polycystic ovary syndrome (PCOS) and obesity.

Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P=0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P=0.014). K469 alleles were also related to increased body mass index (P=0.017) and diastolic blood pressure (P=0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P=0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P=0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women.

Referral bias in female functional hyperandrogenism and polycystic ovary syndrome.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) seeking health care in the United States may be more obese and hyperandrogenic than those present in the general population. We aimed to assess the impact of referral bias on European women with functional androgen excess disorders. DESIGN: Cross-sectional study. METHODS: We studied two groups of patients: i) 368 consecutive patients referred to our clinic for the study of functional hyperandrogenism (FH) (referral patients); ii) 57 consecutive premenopausal patients identified by screening during blood donation (unselected patients). We compared the anthropometric data from the groups of patients with those of two control populations: iii) a group of unselected premenopausal healthy female blood donors (unselected controls); and iv) data available from the local general premenopausal female population. RESULTS: Referral patients with FH were more hirsute, had a higher percentage of hyperandrogenemia, and fulfilled PCOS criteria more frequently than unselected patients. The prevalence of obesity in unselected controls was similar to that observed in the general population, whereas referral patients and unselected patients were more frequently obese. The prevalence of obesity was also higher among referral patients compared to unselected patients. CONCLUSION: Referral bias influences the phenotype of patients with FH. Patients studied at the clinical setting may show more severe hyperandrogenic and obese phenotypes than patients from the general population, even though PCOS appears to be associated with weight excess also in the general European population. This fact should be considered when establishing reference values and control populations for clinical and research purposes.

Influence of adrenal hyperandrogenism on the clinical and metabolic phenotype of women with polycystic ovary syndrome.

OBJECTIVE: To study the impact of adrenal hyperandrogenism (AH; defined as DHEAS concentration >95th percentile of a healthy female control population) on cardiometabolic risk factors associated with polycystic ovary syndrome (PCOS). DESIGN: Cross-sectional study. SETTING: Academic hospital. PATIENT(S): Two-hundred ninety-eight consecutive women with PCOS, of whom 120 were obese (body mass index [BMI] ≥30 kg/m(2)) and 178 nonobese (BMI <30 kg/m(2)). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Comprehensive evaluation of cardiovascular risk factors, including 75-g oral glucose tolerance test, office blood pressure, lipid profile, and low-grade inflammatory markers. RESULT(S): Patients with AH (AH-PCOS) had higher insulin circulating levels and lower insulin sensitivity than their counterparts without AH (non-AH-PCOS). Obesity, but not AH, was the main contributor to the presence of glucose tolerance disorders. Both obesity and AH increased the prevalence of prehypertension and hypertension. AH diminished high-density lipoprotein (HDL) levels in nonobese PCOS women in parallel with a decrease in total cholesterol levels, leading to a total to HDL cholesterol ratio similar to that of nonobese non-AH-PCOS patients. Furthermore, AH blunted the deleterious effect of obesity on the total cholesterol/HDL ratio, with the ratio of obese AH-PCOS patients being similar to that of nonobese PCOS patients with or without AH. CONCLUSION(S): The presence of AH in women with PCOS is associated with reduced insulin sensitivity and increased blood pressure but may have beneficial impact on the lipid profile. Obesity is the main determinant of the clustering of cardiovascular risk factors in PCOS women.

Office blood pressure, ambulatory blood pressure monitoring, and echocardiographic abnormalities in women with polycystic ovary syndrome: role of obesity and androgen excess.

Whether or not blood pressure (BP) and heart function of women with polycystic ovary syndrome (PCOS) are altered remains unclear, albeit subtle abnormalities in the regulation of BP observed in these women might suggest a mild masculinization of their cardiovascular system. To study the influence of obesity and androgen excess on BP and echocardiographic profiles of women with the syndrome, we conducted a cross-sectional case-control study comparing office and ambulatory BP monitoring, as well as echocardiographic assessments, in 63 premenopausal women with the classic phenotype, 33 nonhyperandrogenic women with regular menses, and 25 young men. Forty-nine subjects were lean and 72 had weight excess (body mass index ≥25 kg/m(2)). Participants had no previous history of hypertension and were nonsmokers. Men showed the highest BP readings, and the lowest readings were observed in control women, whereas women with PCOS had intermediate values. Undiagnosed hypertension was more common in subjects with weight excess irrespective of sex and hyperandrogenism. Women with PCOS and weight excess showed frequencies of previously undiagnosed hypertension that were similar to those of men with weight excess and higher than those observed in nonhyperandrogenic women. Lastly, male sex, weight excess and hypertension, the latter in men as well as in women with PCOS, increased left ventricular wall thickness. In summary, our results show that patients with classic PCOS and weight excess frequently have undiagnosed BP abnormalities, leading to target organ damage.

Surrogate markers of visceral adiposity in young adults: waist circumference and body mass index are more accurate than waist hip ratio, model of adipose distribution and visceral adiposity index.

Surrogate indexes of visceral adiposity, a major risk factor for metabolic and cardiovascular disorders, are routinely used in clinical practice because objective measurements of visceral adiposity are expensive, may involve exposure to radiation, and their availability is limited. We compared several surrogate indexes of visceral adiposity with ultrasound assessment of subcutaneous and visceral adipose tissue depots in 99 young Caucasian adults, including 20 women without androgen excess, 53 women with polycystic ovary syndrome, and 26 men. Obesity was present in 7, 21, and 7 subjects, respectively. We obtained body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), model of adipose distribution (MOAD), visceral adiposity index (VAI), and ultrasound measurements of subcutaneous and visceral adipose tissue depots and hepatic steatosis. WC and BMI showed the strongest correlations with ultrasound measurements of visceral adiposity. Only WHR correlated with sex hormones. Linear stepwise regression models including VAI were only slightly stronger than models including BMI or WC in explaining the variability in the insulin sensitivity index (yet BMI and WC had higher individual standardized coefficients of regression), and these models were superior to those including WHR and MOAD. WC showed 0.94 (95% confidence interval 0.88-0.99) and BMI showed 0.91 (0.85-0.98) probability of identifying the presence of hepatic steatosis according to receiver operating characteristic curve analysis. In conclusion, WC and BMI not only the simplest to obtain, but are also the most accurate surrogate markers of visceral adiposity in young adults, and are good indicators of insulin resistance and powerful predictors of the presence of hepatic steatosis.

Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS).

CONTEXT: Sexual dimorphism suggests a role for androgens in body fat distribution. Women with polycystic ovary syndrome (PCOS), a mainly androgen excess disorder, often present with abdominal obesity and visceral adiposity. OBJECTIVE: We hypothesized that women with PCOS have a masculinized body fat distribution favoring the deposition of fat in visceral and organ-specific adipose tissue depots. DESIGN: This was a case-control study. SETTING: The study was conducted at an academic hospital. PARTICIPANTS: Women with PCOS (n = 55), women without androgen excess (n = 25), and men (n = 26) presenting with similar body mass index participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Ultrasound measurements of adipose tissue depots including sc (minimum and maximum), preperitoneal, ip, mesenteric, epicardial, and perirenal fat thickness were obtained and total body fat mass was estimated using a body fat monitor. RESULTS: Men and patients with PCOS had increased amounts of total body fat compared with control women. Men had increased thickness of intraabdominal adipose tissue depots compared with the control women, with the women with PCOS showing intermediate values that were also higher than those of control women in the case of ip and mesenteric fat thickness and was close to reaching statistical significance in the case of epicardial fat thickness. Women with PCOS also showed increased minimum sc fat thickness compared with the control women. Obesity increased the thickness of all of the adipose tissue depots in the 3 groups of subjects. CONCLUSIONS: Women with PCOS have higher global adiposity and increased amounts of visceral adipose tissue compared with control women, especially in the ip and mesenteric depots.

Androgens and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a mainly hyperandrogenic disorder and is possibly the most frequent endocrinopathy in premenopausal women. Androgen excess is the primary defect in PCOS, because ovarian theca cells secrete increased amounts of androgens even after several passes in primary culture. Excessive androgen amounts might favor the visceral deposition of body fat in affected women, resulting in insulin resistance, compensatory hyperinsulinism and further androgen excess. This vicious circle starts early during life in women with PCOS, even during fetal development, manifests clinically during puberty and does not end after menopause. All the steps in the vicious circle contribute to the association of PCOS with metabolic dysfunction and cardiovascular risk factors. Fortunately, most, if not all, of the therapeutic strategies currently in use for the management of PCOS, including lifestyle modification and diet, oral contraceptives, antiandrogens and insulin sensitizers, may ameliorate androgen excess and its long-term consequences.

Management of postmenopausal virilization.

CONTEXT: Mild clinical signs of hyperandrogenism such as hirsutism may appear during the menopausal transition as part of the normal aging process, but the development of frank virilization suggests a specific source of androgen excess, including androgen-secreting tumors. PATIENT AND METHODS: A 68-yr-old postmenopausal woman was referred because of a history of progressive development of hirsutism and frontal balding for the previous 8 yr, together with moderate hyperandrogenemia. Initial imaging procedures depicted a 2-cm solid nodule in the right adrenal gland and normal appearance of both ovaries. To confirm the source of androgen excess, we conducted simultaneous selective venous sampling of adrenals and ovaries. Sampling was consistent with an ovarian source. After bilateral laparoscopic salpingo-oophorectomy, the patient was diagnosed with bilateral ovarian hyperthecosis. Three weeks after surgery, her androgen levels had decreased to the normal female range. CONCLUSION: Diagnosis of hyperandrogenism in postmenopausal women is challenging. Postmenopausal virilization may be associated with adrenal or ovarian androgen-secreting tumors or with benign conditions. A detailed clinical history is critical to differentiate the progressive development of virilization that characterizes benign causes from the rapid progression that characterizes malignant tumors. Imaging techniques do not always reveal the cause of hyperandrogenism and may even be misleading. Although technically difficult, combined adrenal and ovarian venous sampling may be required to confirm the source of androgen excess before the best surgical approach is determined.

Role of decreased circulating hepcidin concentrations in the iron excess of women with the polycystic ovary syndrome.

CONTEXT: Hepcidin inhibits the intestinal absorption of iron and its deficiency causes juvenile hemochromatosis. OBJECTIVE: The objective of the investigation was to study the involvement of hepcidin in the iron overload of patients with polycystic ovary syndrome (PCOS). DESIGN: This was a case-control study followed by a randomized clinical trial. SETTING: The study was conducted at an academic hospital. PATIENTS: Thirty-four patients with PCOS and 30 women without hyperandrogenism, matched for age and body mass index, participated in the study. INTERVENTION: Patients with PCOS were randomly allocated to treatment with either an antiandrogenic oral contraceptive or metformin for 24 wk. MAIN OUTCOME MEASURES: Serum hepcidin levels and ferritin to hepcidin molar ratios were measured. RESULTS: Patients with PCOS showed decreased circulating hepcidin levels and increased ferritin to hepcidin molar ratios compared with controls. Patients with PCOS presenting with chronic oligoamenorrhea (an iron sparing mechanism) showed a paradoxical decrease in serum hepcidin levels and an increase in ferritin to hepcidin molar ratios compared with the patients who had regular anovulatory menstrual cycles and with the controls. The major predictor of circulating hepcidin concentrations was the presence of PCOS, whereas the main determinants of the ferritin to hepcidin molar ratio were the insulin sensitivity index and menstrual dysfunction. Serum hepcidin levels did not change during treatment with either metformin or the antiandrogenic oral contraceptive pill, yet patients treated with the oral contraceptive pill normalized the ferritin to hepcidin molar ratio. CONCLUSIONS: Patients with PCOS had reduced serum hepcidin concentrations that might contribute to their iron overload by favoring the intestinal absorption of iron. The imbalance between increased iron stores and reduced hepcidin levels was related to the insulin resistance and androgen excess characteristic of this syndrome.

The determinants of insulin sensitivity, ß-cell function, and glucose tolerance are different in patients with polycystic ovary syndrome than in women who do not have hyperandrogenism.

OBJECTIVE: To evaluate the pathogenetic mechanisms underlying abnormal glucose tolerance in polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SETTING: Academic hospital. PATIENT(S): One hundred twelve patients with PCOS and 86 nonhyperandrogenic control women of similar age and body mass index (BMI). INTERVENTION(S): An oral glucose tolerance test (OGTT) served to explore glucose tolerance and to calculate insulin sensitivity, insulin secretion, and insulin disposition indexes. MAIN OUTCOME MEASURE(S): Frequency of abnormal glucose tolerance, indexes of insulin sensitivity, secretion and disposition, and markers of inflammation, androgen excess, and iron stores. RESULT(S): Obesity and age, but not PCOS, were associated with an increased frequency of abnormal glucose tolerance and diabetes. An imbalance between insulin resistance and secretion--translated into decreased insulin disposition index--predicted abnormal glucose tolerance in patients with PCOS and controls, yet these women differed in the factors associated with decreased insulin disposition. In patients with PCOS, hyperandrogenism, chronic inflammation, and family history of diabetes contributed to insulin resistance as the main pathogenetic mechanism. In nonhyperandrogenic women, familial aggregation of defective insulin secretion, adiposity, and increased body iron stores explained most of the decrease in insulin disposition. CONCLUSION(S): In addition to a major influence of obesity and age, the mechanisms underlying abnormal glucose tolerance are different in patients with PCOS compared with women who do not have hyperandrogenism.