Presence of metabolic risk factors in non-obese PCOS sisters: evidence of heritability of insulin resistance.

This study was performed to determine whether phenotypically healthy sisters of women with polycystic ovary syndrome (PCOS) have evidence of insulin resistance. We studied 54 women: 17 with PCOS, 17 sisters of these probands and 20 control women with similar age, body mass index (BMI) and waist-to-hip ratio (WHR). The PCOS sisters had neither clinical nor laboratory evidence of hyperandrogenism. However, estimated insulin resistance indices indicated decreased insulin sensitivity in PCOS sisters compared with the controls. No difference of insulin resistance indices was detected between the PCOS and their sisters. This finding provides additional evidence that there is a hereditary trait regarding insulin resistance in the PCOS families.

The influence of obesity on hyperandrogenism and infertility in the female.

Although a critical mass of adipose tissue is essential for the normal development of female reproductive function, obesity has been shown to produce menstrual disturbances and subfertility. The severity of obesity and the distribution of fat tissue are important factors that influence the female reproductive system. The pathogenetic mechanistic links between them aren't clearly elucidated. Obese women, especially those with upper body obesity, have insulin resistance and hyperinsulinaemia, hyperandrogenaemia, increased peripheral aromatization of androgens to oestrogens, altered gonadotrophin secretion, decreased sex hormone binding globulin, decreased growth hormone (GH) and insulin like growth factor binding proteins (IGFBPs), increased leptin levels and altered neuroregulation of the hypothalamic-pituitary-gonadal axis. These have been considered as some of the links in the sequence of events of the disrupted ovulatory process. The mechanisms of these actions and their influence on female reproductive function are discussed below.

Microsatellite polymorphism (tttta)(n) at -528 base pairs of gene CYP11alpha influences hyperandrogenemia in patients with polycystic ovary syndrome.

OBJECTIVE: To investigate the functional significance of CYP11alpha microsatellite polymorphism (tttta)(n) (-528 base pairs) in patients with polycystic ovary syndrome. DESIGN: Follow-up study. SETTING: Academic research center. PATIENT(S): Eighty patients and 90 controls. INTERVENTION(S): Body mass indices and waist-to-hip ratios were determined. Blood samples were obtained for DNA analysis and hormone measurements. MAIN OUTCOME MEASURE(S): CYP11alpha marker (tttta)(n) genotyping and serum total testosterone levels. RESULT(S): All the women were assigned to one of two genotype groups: 216+ (for women who had at least one copy of high frequency allele 216 with four repeat units) or 216- (for women who did not have allele 216). Fifty-nine patients (73.75%) had genotype 216+; their mean (+/-SD) total testosterone level was 78.0 +/- 19.8 ng/dL. Twenty-one patients (26.25%) had genotype 216-; their mean (+/-SD) total testosterone level was 100.0 +/- 23.3 ng/dL. The difference in total testosterone levels was statistically significant. Seventy-eight controls (86.67%) had genotype 216+ and 12 controls (13.33%) had genotype 216-; the total testosterone levels of these two groups were similar (38.6 +/- 15.5 vs. 40.3 +/- 12.1 ng/dL). The difference in genotype distribution between the women with polycystic ovary syndrome and the controls (26.25% vs. 13.33% with genotype 216-) was statistically significant. CONCLUSION(S): CYP11alpha (tttta)(n) allelic variants were associated with both polycystic ovary syndrome and total testosterone levels in women with polycystic ovary syndrome, suggesting the existence of an epistasis phenomenon.

A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, chronic anovulation, and oligomenorrhea (O/M). PCOS has variable clinical phenotypes, biochemical features, and metabolic abnormalities. To determine the prevalence of PCOS in the Greek population as well as the metabolic parameters, we performed a cross-sectional study of 192 women of reproductive age (17-45 yr), living on the Greek island of Lesbos. They were divided into 4 groups according to the presence of hirsutism (defined as a Ferriman-Gallwey score > or = 6) and O/M: group N (n = 108), regular menses and absence of hirsutism; group 1 (n = 56), regular menses and hirsutism; group 2 (n = 10), O/M and absence of hirsutism; and group 3 (n = 18), O/M and hirsutism. Body mass index, waist to hip ratio, and mean blood pressure did not differ among the studied groups. Hormonal profile was assessed by measuring free testosterone (FT). The prevalence of PCOS, defined by the presence of O/M and biochemical hyperandrogenism (FT > or = 95th percentile of the normal women), was estimated to be 6.77% (13 women of 192). Higher FT levels were observed in group 3 (O/M and hirsutism) compared with groups N (P < 0.00001) and 1 (P < 0.0001) and in groups 1 (hirsutism) and 2 (O/M) compared with group N (P < 0.0001 and P < 0.005, respectively). Sex hormone-binding globulin levels were lower in women with PCOS and in groups 1 and 3 than those in group N (P < 0.002, P < 0.02, and P < 0.002, respectively) independently of the body mass index. The metabolic profile was investigated by measurements of fasting glucose (FG), fasting insulin (FI), and estimation of the fasting glucose to insulin ratio (FG:I ratio). After covariance adjusted for the BMI, FI levels were higher in group 3 and in women with PCOS than in the normal (P < 0.005 and P < 0.002, respectively) and the hirsute (P < 0.05 and P < 0.02, respectively) women, whereas FG levels did not differ among the studied groups. The FG:I ratio was lower in group 3, group 1, and in women with PCOS than in normal women (P < 0.05). Finally, a high incidence of family history of diabetes mellitus (P = 0.001) and menstrual disorders (P = 0.01) was observed in women with PCOS, in contrast to the normal and hirsute women. In conclusion, PCOS appears to be a particularly common endocrine disorder in the Greek population under study (prevalence, 6.77%); furthermore, it is associated with certain metabolic abnormalities. These data also suggest that the severity of the fasting hyperinsulinemia is associated with the severity of the clinical phenotype of hyperandrogenism independently of obesity.

Polymorphism T-->C (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome.

OBJECTIVE: To investigate the frequency of T-->C substitution (-34 bp) of gene CYP17 promoter in Greek patients with polycystic ovary syndrome (PCOS) and to elucidate its role in the pathogenesis of the syndrome. DESIGN: Follow-up study. SETTING: Academic research setting. PATIENT(S): Fifty patients with PCOS and 50 healthy women. INTERVENTION(S): Body mass index and the waist-hip ratio were determined for each woman. Blood samples were obtained for DNA analysis and hormone estimates. MAIN OUTCOME MEASURE(S): Serum total T levels. RESULT(S): Seventeen patients (34%) did not carry the base pair substitution (genotype A1A1) and their mean (+/- SD) total T level was 75.7+/-32.2 ngl/dL, 29 patients (58%) were heterozygous carriers of the A2 allele (genotype A1A2) and their mean total T level was 77.8+/-29.9 ng/dL, and 4 patients (8%) carried the A2 allele in homozygosity (genotype A2A2) and their mean total T level was 87.0+/-2.8 ngl/dL. Twenty-two controls had the genotype A1A1 (44%) and their mean total T level was 39.1+/-15.5 ng/dL, whereas 28 (56%) had the genotype A1A2 and their mean total T level was 44.9+/-22.1 ng/dL. Homozygosity of the polymorphic A2 allele was not observed in controls, and this difference (8% versus 0%) was statistically significant. CONCLUSION(S): Although this base pair substitution is not the primary genetic defect in PCOS, it may aggravate the clinical picture of hyperandrogenemia, particularly when homozygosity exists.

Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome.

Evidence suggests that insulin resistance and hyperinsulinaemia are associated with ovarian hyperandrogenism and menstrual irregularities in polycystic ovary syndrome (PCOS). Sixteen obese women with PCOS on a weight-maintaining diet were studied before and after 6 months of therapy with the insulin-sensitizing antidiabetic agent metformin at a dose of 1700 mg per day. Compared with baseline values, glucose utilization was markedly enhanced at 6 months using the two-step euglycaemic-hyperinsulinaemic clamp to measure changes in insulin sensitivity (2.56 +/- 0.32 vs 4.68 +/- 0.49 mg/kg per min, P = 0.0001, when 40 mU insulin/m2 per min was infused, and 6.48 +/- 0.58 vs 9.84 +/- 0.72 mg/kg per min, P = 0.0002, when 400 mU insulin insulin/m2 per min was infused). The improvement in insulin action was accompanied by significant increases in the levels of sex hormone-binding globulin (24.5 +/- 7.2 vs 39.8 +/- 16.2 nmol/l, P = 0.003) and decreases in free testosterone (12.8 +/- 5.8 vs 9.0 +/- 3.0 pmol/l, P = 0.03) and androstenedione (12.9 +/- 5.6 vs 7.3 +/- 1.7 nmol/l, P = 0.003). No significant changes were recorded in body weight. Seven subjects resumed normal menstruation and two cases of spontaneous pregnancy occurred during treatment. Metformin was well tolerated except for one case of flatulence. These results confirm that metformin treatment can lead to improvements in insulin resistance and ovarian hyperandrogenism.