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Glucose Intolerance, Insulin Resistance, and Hyperandrogenemia in First Degree Relatives of Women with Polycystic Ovary Syndrome

Department of Internal Medicine, Division of Endocrinology and Metabolism (B.O.Y., M.B.); Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (H.Y.); and Department of Pediatrics, Endocrinology Unit (H.O.), Faculty of Medicine, Hacettepe University, 06100 Sihhiye, Ankara, Turkey

Address all correspondence and requests for reprints to: Dr. Bülent O. Yildiz, Emeklisubayevleri 2, C. 23 C Blok 15/3, 06580 Yucetepe, Ankara, Turkey. E-mail: yildizbo{at}yahoo.com.

Polycystic ovary syndrome (PCOS) is associated with hyperinsulinemia, insulin resistance (IR), increased risk of glucose intolerance, and type 2 diabetes. Family studies have indicated a genetic susceptibility to PCOS. The aims of this study were 1) to assess glucose tolerance status, gonadotropins, and androgens in first degree relatives of patients with PCOS; and 2) to assess IR in normal glucose tolerant (NGT) family members. One hundred two family members of 52 patients with PCOS [Mothers_PCOS (n = 34; mean age, 46.5 yr; mean body mass index (BMI), 28.8 kg/m²), Fathers_PCOS (n = 24; mean age, 50.4 yr; mean BMI, 27.5 kg/m²), Sisters_PCOS (n = 19; mean age, 25.1 yr; mean BMI, 22.9 kg/m²), and Brothers_PCOS (n = 25; mean age, 23.7 yr; mean BMI, 22.5 kg/m²)] and 82 unrelated healthy control subjects without a family history of diabetes or PCOS (4 age- and weight-matched subgroups, i.e. Control_MothersPCOS, Control_FathersPCOS, Control_SistersPCOS, and Control_BrothersPCOS) were studied. Glucose and insulin (at baseline and during a 75-g, 2-h oral glucose tolerance test) were measured. IR was assessed by fasting insulin (FI), fasting glucose to insulin ratio (FGI), homeostatic model assessment (HOMA IR), and area under the curve for insulin during the oral glucose tolerance test (AUC_insulin) in NGT Mothers_PCOS, Fathers_PCOS, Sisters_PCOS, Brothers_PCOS, and matched control subgroups. Including the prestudy-diagnosed 3 mothers and 2 fathers with diabetes, diabetes and impaired glucose tolerance (IGT) were noted in 16% and 30% of Mothers_PCOS and 27% and 31% of Fathers_PCOS, respectively. There was no diabetes in Sisters_PCOS and Brothers_PCOS. IGT was found in 5% of Sisters_PCOS. Impaired fasting glucose was found in 3% of Mothers_PCOS and 4% of Brothers_PCOS. The analysis of NGT family members showed that Mothers_PCOS had higher FI (P < 0.05), HOMA IR (P < 0.05), and AUC_insulin (P < 0.01) and lower FGI (P < 0.05) than Control_MothersPCOS, whereas all IR parameters were comparable between Fathers_PCOS and their matched control subgroup. Sisters_PCOS had higher FI (P < 0.05), HOMA IR (P < 0.01), and AUC_insulin (P < 0.05) and lower FGI (P < 0.01), and Brothers_PCOS had higher AUC_insulin (P < 0.01) than their matched control subgroups, respectively. Mothers_PCOS had higher testosterone levels than Control_MothersPCOS (P < 0.01 and P < 0.05 for pre- and postmenopausal women, respectively). Sisters_PCOS had higher LH (P < 0.01), testosterone (P < 0.001), androstenedione (P < 0.01), and dehydroepiandrosterone sulfate (P < 0.05) levels than Control_SistersPCOS. There was no difference in gonadotropin and androgen levels in Fathers_PCOS compared with Control_FathersPCOS or in Brothers_PCOS compared with Control_BrothersPCOS.

Our results suggest that 1) first degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance; 2) NGT female family members have insulin resistance; and 3) mothers and sisters of PCOS patients have higher androgen levels than control subjects. We propose that the high risks of these impairments warrant screening in first degree relatives of patients with PCOS.

This work was supported in part by a grant from the Scientific and Technical Research Council of Turkey.

Abbreviations: A, Androstenedione; AUC, area under the curve; BMI, body mass index; DHEAS, dehydroepiandrosterone; E₂, estradiol; FGI, fasting glucose to insulin ratio; FI, fasting insulin; HOMA, homeostatic model assessment; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IR, insulin resistance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; T, testosterone; WHR, waist to hip ratio.

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