Davinia White

DIFFERENCES IN CLINICAL AND ENDOCRINE FEATURES BETWEEN OBESE AND NON‐OBESE SUBJECTS WITH POLYCYSTIC OVARY SYNDROME: AN ANALYSIS OF 263 CONSECUTIVE CASES

Two hundred and sixty‐three women with ultrasound‐diagnosed polycystic ovary syndrome were studied of whom 91 (35%) were obese (BMI > 25 kg/m2‐). Obese women with PCOS had a greater prevalence of hirsutism (73% compared with 56%) and menstrual disorders than non‐obese subjects. Total testosterone and androstenedione concentrations in serum were similar in the two subgroups but SHBG concentrations were significantly lower, and free testosterone levels higher, in obese compared with lean subjects. In addition, concentrations of androsterone glucuronide, a marker of peripheral 5α‐reductase activity, were higher in obese than in non‐obese women with PCOS. There were no significant correlations of either SHBG or free testosterone with androsterone glucuronide suggesting that obesity has independent effects on transport and on metabolism of androgen. There were no significant differences between the subgroups in either baseline gonadotrophin concentrations or the pulsatile pattern of LH and FSH secretion studied over an 8‐h period. There was, however, an inverse correlation of FSH with BMI, but only in the obese subgroup. In conclusion, the increased frequency of hirsutism in obese compared with lean women with PCOS is associated with increased bio‐availability of androgens to peripheral tissues and enhanced activity of 5α‐reductase in obese subjects. The mechanism underlying the higher prevalence of anovulation in obese women remains unexplained.

Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 10% of women of reproductive age. Women with anovulatory PCOS have hyperinsulinaemia, insulin resistance, and dyslipidaemia, and the syndrome is associated with greatly increased risks of non-insulin-dependent diabetes mellitus and cardiovascular disease and it often clusters in families. The VNTR (variable number of tandem repeats) locus upstream of the insulin gene (INS) regulates insulin expression. We have studied INS VNTR as a candidate genetic locus for susceptibility to PCOS. METHODS We evaluated linkage of PCOS to the INS VNTR locus on chromosome 11p15.5 in 17 families with several cases, and looked for an association between VNTR and PCOS in two additional clinic populations. VNTR genotypes were designated I/I, I/III, and III/III and linkage disequilibrium mapping was used to test the primary role of the VNTR. FINDINGS In a group of PCOS/male pattern baldness families, we obtained positive evidence for linkage to 11p15.5 (p = 0.002). The INS VNTR III/III genotype was associated with an increased risk of PCOS in two independent case-control studies (odds ratios 8.20 [p = 0.005] and 5.70 [p = 0.043]). Multilocus linkage disequilibrium mapping suggests that VNTR itself is the predisposing locus. INTERPRETATION Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production. The data suggest a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.

Evidence for a single gene effect causing polycystic ovaries and male pattern baldness

OBJECTIVE Polycystic ovary syndrome is one of the most common endocrine disorders but its aetiology remains unknown. It is highly prevalent within families, suggesting a genetic basic for the syndrome, but the mode of inheritance is unclear. The purpose of this study was to determine the mode of inheritance of polycystic ovary syndrome, within the families of affected individuals, by classic segregation analysis.

The prevalence of polycystic ovaries in women with a history of gestational diabetes

Women with a history of gestational diabetes mellitus (GDM) and women with polycystic ovary syndrome (PCOS) both demonstrate abnormalities in insulin action and secretion, and both are at increased risk of developing type 2 diabetes. To determine whether these similarities reflect a common pathophysiological basis, we examined the prevalence of ultrasound‐based polycystic ovarian morphology in a large multiethnic group of women with a history of GDM and a group of women who had normal glucose tolerance during pregnancy.

Ovarian Morphology Is a Marker of Heritable Biochemical Traits in Sisters with Polycystic Ovaries

CONTEXT Polycystic ovary syndrome (PCOS) is a common endocrinopathy of uncertain etiology but with strong evidence for a genetic contribution. OBJECTIVE The objective of the study was to test the hypothesis that the typical polycystic ovarian morphology is a marker of inherited biochemical features in families of women with PCOS. DESIGN A study of probands with PCOS and their sisters. PATIENTS Patients included 125 probands and 214 sisters. All probands had PCOS, defined by symptoms of anovulation and/or hyperandrogenism with polycystic ovaries on ultrasound. Affected sisters were defined by polycystic ovaries, regardless of symptoms, and unaffected sisters defined by normal ovarian morphology. SETTING This was a clinic-based study. MAIN OUTCOME MEASURES Clinical, endocrine, and metabolic features in the various groups were compared, and estimates of broad-sense heritability were obtained using the quantitative transmission disequilibrium test. RESULTS Although affected sisters had fewer symptoms than probands (30% had no symptoms of PCOS), serum testosterone, androstenedione, LH, and fasting insulin and insulin sensitivity were similar in the two groups with polycystic ovaries but significantly different from those in unaffected sisters or controls. We observed moderate to high heritabilities for all traits studied in affected sister pairs, whereas heritabilities calculated from discordant siblings were substantially lower. CONCLUSIONS These data provide further evidence for a genetic basis of PCOS. The high heritability of biochemical features in probands and affected sisters, despite wide variation in symptoms, shows that not only are these biochemical traits strongly influenced by genetic factors but also, importantly, that polycystic ovarian morphology is an index of inherited traits in families with PCOS.

Gonadotrophin and gonadal steroid response to a single dose of a long‐acting agonist of gonadotrophin‐releasing hormone in ovulatory and anovulatory women with polycystic ovary syndrome

OBJECTIVE A previously published study has identified that anovulatory women with PCOS have an increased response of 17α‐hydroxyprogesterone (170HP) and androstenedione to a GnRH analogue suggesting dys‐regulation of cytochrome P450c17α. The object of this study was to compare the responses of the pituitary‐ovarian axis to a single dose of a long‐acting GnRH agonist (GnRHa) in both ovulatory and anovulatory women with PCOS with those in normal subjects.

Infertility in Polycystic Ovary Syndrome Focus on Low-Dose Gonadotropin Treatment

Polycystic ovary, syndrome accounts for more than 75% of cases of anovulatory infertility. The mechanism of anovulation is uncertain but there is evidence that arrested antral follicle development is associated with the abnormal endocrine profile, in particular the interaction of insulin and LH on granulosa cell differentiation. In terms of management, induction of ovulation can be achieved in most cases by the use of antiestrogens. Treatment of clomiphene-resistant subjects is difficult; conventional doses of gonadotropins are associated with high rates of ovarian hyperstimulation syndrome and multiple pregnancy. On the other hand, low-dose gonadotropin therapy has proven effective in inducing unifollicular ovulation and, in this review, we present, in detail, a recent analysis the results from this center. The cumulative conception rate after six cycles was more than 50% and, importantly, the multiple pregnancy rate was only 3%. Weight reduction in obese subjects with PCOS not only increases the chance of fertility but may also improve the long-term prognosis with regard to development of diabetes. Insulin-sensitizing drugs such as metformin may also have a place in treatment of PCOS.

Etiology of anovulation in polycystic ovary syndrome.

Various endocrine factors may contribute to the phenomenon of arrested follicular development, which is the hallmark of anovulatory infertility in polycystic ovary syndrome. Hypersecretion of luteinizing hormone and/or insulin, together with high intrafollicular concentrations of androgens, can interact to produce supraphysiological levels of cyclic AMP in granulosa cells, resulting in premature activation of terminal differentiation and, hence, arrest of follicle growth.

Genetics of polycystic ovary syndrome.

We have found evidence for the involvement of two major genes in the aetiology of PCOS. The results of both linkage and association studies suggest that CYP11a (coding for P450 cholesterol side chain cleavage) and the insulin VNTR regulatory polymorphism are important genes in the aetiology of PCOS and may explain, in part, the heterogeneity of the syndrome. Differences in expression of CYP11a could account for variation in androgen production in women who have polycystic ovaries and those subjects who are homozygous for III alleles at the insulin gene VNTR locus are more likely to be hyperinsulinaemic. It is likely that other genes are involved in the aetiology of PCOS. Recent results lend weight to the idea that PCOS represents a complex trait in which several genes--but perhaps a relatively small number of key genes--contribute, in conjunction with nutritional factors, to the observed clinical and biochemical heterogeneity.

Hepcidin levels in diabetes mellitus and polycystic ovary syndrome

Increased body iron is associated with insulin resistance. Hepcidin is the key hormone that negatively regulates iron homeostasis. We hypothesized that individuals with insulin resistance have inadequate hepcidin levels for their iron load.