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

Abstract

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/m(2)), Fathers(PCOS) (n = 24; mean age, 50.4 yr; mean BMI, 27.5 kg/m(2)), Sisters(PCOS) (n = 19; mean age, 25.1 yr; mean BMI, 22.9 kg/m(2)), and Brothers(PCOS) (n = 25; mean age, 23.7 yr; mean BMI, 22.5 kg/m(2))] 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 leve...

Brothers of women with polycystic ovary syndrome are characterised by impaired glucose tolerance, reduced insulin sensitivity and related metabolic defects

“…A large study by Legro et al [13] confirmed that fasting insulin levels were elevated in 307 sisters of PCOS women, compared with 47 control participants. Two other studies [20,22] have also found that sisters and brothers of women with PCOS have significantly higher insulin levels (fasting or during OGTT) and homeostasis model assessment insulin resistance compared with control individuals. Finally, a recent study demonstrated that sisters of PCOS women have increased prevalence of the metabolic syndrome [24].…”

“…To the best of our knowledge, nine studies have previously assessed the metabolic phenotypes of relatives of women with PCOS [13,[19][20][21][22][23][24][25]39]. The first of these studies concluded that glucose-stimulated hyperinsulinaemia was frequent in sisters (n=24) and brothers (n=5) of PCOS probands [19].…”

“…Few studies have assessed the metabolic phenotype of relatives of women with PCOS [13,[19][20][21][22][23][24][25], and only four of these assessed brothers [19][20][21][22]. These studies showed hyperinsulinaemia or altered indirect indices of insulin resistance in brothers, sisters, mothers or fathers of women with PCOS.…”

Retinol-binding protein 4 levels are elevated in polycystic ovary syndrome women with obesity and impaired glucose metabolism

“…Insulin resistance increases with increasing body mass index (BMI) and waist circumference as a clinical sign of central obesity (7). Whilst a family history of obesity, insulin resistance, and T2DM appears to be more prevalent in affected women (8), it is unclear whether this association is due to environmental or inherited factors, thus implicating a genetic background. Several T2DM candidate genes, including those for insulin, the insulin receptor, and insulin receptor substrates, have been investigated in this context, indicating evidence for a genetic contribution to PCOS susceptibility (9,10).…”

SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients

“…PCOS is characterized by the presence of hyperandrogenism, menstrual irregularities and, in a significant portion of patients, insulin resistance (2)(3)(4). The familial aggregation of PCOS, hyperandrogenism and associated metabolic abnormalities indicates a genetic origin for PCOS (5). Heterogeneous clinical manifestations influenced by ethnic factors indicate the involvement of environmental factors (6).…”