Hereditary factors in the Stein-Leventhal syndrome

Proc. Natl. Acad. Sci. U.S.A.

Driscoll

et al. 1999

451

284

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women, characterized by hyperandrogenism and chronic anovulation. It is a leading cause of female infertility and is associated with polycystic ovaries, hirsutism, obesity, and insulin resistance. We tested a carefully chosen collection of 37 candidate genes for linkage and association with PCOS or hyperandrogenemia in data from 150 families. The strongest evidence for linkage was with the follistatin gene, for which affected sisters showed increased identity by descent (72%; 2 ‫؍‬ 12.97; nominal P ‫؍‬ 3.2 ؋ 10 ؊4 ). After correction for multiple testing (33 tests), the follistatin findings were still highly significant (P c ‫؍‬ 0.01). Although the linkage results for CYP11A were also nominally significant (P ‫؍‬ 0.02), they were no longer significant after correction. In 11 candidate gene regions, at least one allele showed nominally significant evidence for population association with PCOS in the transmission͞disequilibrium test ( 2 > 3.84; nominal P < 0.05). The strongest effect in the transmission͞disequilibrium test was observed in the INSR region (D19S884; allele 5; 2 ‫؍‬ 8.53) but was not significant after correction. Our study shows how a systematic screen of candidate genes can provide strong evidence for genetic linkage in complex diseases and can identify those genes that should have high (or low) priority for further study.

supporting

confidence: 74%

Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin

Urbanek

Proc. Natl. Acad. Sci. U.S.A.

Driscoll

et al. 1999

451

284

“…Familial clustering of PCOS consistent with a genetic susceptibility to the disorder has been well documented (8)(9)(10)(11)(12). Recently, we have shown that there are two reproductive phenotypes in the sisters of women with PCOS: 1) chronic anovulation and HA consistent with typical PCOS, and 2) HA with regular menses and apparently normal fertility (13).…”

Section: Author Manuscriptmentioning

confidence: 76%

Insulin Resistance in the Sisters of Women with Polycystic Ovary Syndrome: Association with Hyperandrogenemia Rather Than Menstrual Irregularity

The Journal of Clinical Endocrinology & Metabolism

Bentley‐Lewis

Driscoll

et al. 2002

169

This study was performed to determine whether the sisters of women with polycystic ovary syndrome (PCOS) have evidence for insulin resistance. Three hundred and thirty-six women with PCOS, 307 sisters of these probands, and 47 control women were studied. The sisters were grouped by phenotypes: PCOS [hyperandrogenemia (HA) with chronic oligo-or amenorrhea, n = 39], HA with regular menses (n = 36), unaffected (UA; n = 122), and unknown (n = 110). The analyses were adjusted for age and body mass index. PCOS and HA sisters of women with PCOS had similar and significantly elevated fasting insulin levels (P = 0.001) as well as similar and significantly decreased fasting glucose/insulin ratios (P < 0.001) suggestive of insulin resistance compared with UA sisters and control women. Markers of insulin resistance were associated with hyperandrogenemia and not with menstrual irregularity. PCOS sisters also had decreased levels of SHBG (P = 0.02) suggestive of higher ambient insulin levels. PCOS sisters had increased levels of proinsulin (P = 0.04) compared with control women, which suggested pancreatic β-cell dysfunction in this group of sisters. The magnitude of obesity also differed significantly among the groups of sisters. The PCOS sisters were significantly more obese than all the other groups, and the HA sisters were more obese than the UA sisters. We conclude that markers of insulin resistance are associated with hyperandrogenemia rather than menstrual irregularity in the sisters of women with PCOS. Menstrual irregularity may be related to the magnitude of insulin sensitivity or insulin secretion or to other factors associated with obesity.POLYCYSTIC OVARY syndrome (PCOS) is a disorder of unknown etiology characterized by chronic anovulation and hyperandrogenism (1). It remains a diagnosis of exclusion of Copyright © 2002 HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript specific disorders of the ovaries, adrenals, and pituitary gland. PCOS is frequently associated with insulin resistance (2). There is now convincing evidence from studies in which insulin levels have been lowered by several modalities that hyperinsulinemia contributes to the hyperandrogenemia (HA) and anovulation (3-7).Familial clustering of PCOS consistent with a genetic susceptibility to the disorder has been well documented (8)(9)(10)(11)(12). Recently, we have shown that there are two reproductive phenotypes in the sisters of women with PCOS: 1) chronic anovulation and HA consistent with typical PCOS, and 2) HA with regular menses and apparently normal fertility (13). Previous studies have suggested that women with HA and regular cycles were not insulin resistant (14-16). Family studies have suggested that HA in PCOS sisters is common and may be a monogenic trait (13,17). A twin study of PCOS women showed high correlation within twin pairs for both circulating androgen and fasting insulin levels (18). Defects in insulin action persist in cultured skin fibroblasts, and increased androgen productio...

“…Premature male balding has been suggested to be a male phenotype in previous studies in PCOS families that ascertained the PCOS index case on the basis of ovarian morphology determined by ultrasonography rather than by endocrine criteria (6)(7)(8)(9)(10). No endocrinological marker of male affected status was noted.…”

Section: Discussionmentioning

confidence: 99%

“…Familial aggregation of PCOS consistent with a genetic etiology has been well documented (4,5). The male reproductive phenotypes that have been proposed in PCOS families include abnormalities in hair distribution, such as increased hair growth (6), and more commonly balding (7)(8)(9)(10). This latter phenotype has been further refined to premature male balding defined as balding onset with an age of less than 30 yr (9,10).…”

mentioning

confidence: 99%

Elevated Dehydroepiandrosterone Sulfate Levels as the Reproductive Phenotype in the Brothers of Women with Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology &Amp; Metabolism

Kunselman

Demers

et al. 2002

130

There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight-and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score ≥ V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 ± 1132 ng/ml (mean ± SD) vs. control men 2494 ± 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that we found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. We conclude that there is a biochemical reproductive endocrine phenotype in men in PCOS families.Polycystic Ovary Syndrome (PCOS) is among the most common endocrinopathies of premenopausal women, affecting 5-10% of this population (1, 2). The syndrome is characterized by hyperandrogenism and chronic anovulation in the absence of specific Copyright © 2002 HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript disorders of the pituitary, ovaries, or adrenal glands (3). Familial aggregation of PCOS consistent with a genetic etiology has been well documented (4, 5). The male reproductive phenotypes that have been proposed in PCOS families include abnormalities in hair distribution, such as increased hair growth (6), and more commonly balding (7-10). This latter phenotype has been further refined to premature male balding defined as balding onset with an age of less than 30 yr (9, 10). Others have noted abnormalities in LH levels in male members of PCOS kindreds (11).We recently reported elevated T and dehydroepiandrosterone levels in the sisters of women with PCOS (12). There was a bimodal distribution of biologically available T levels in these sisters consistent with a monogenic trait controlled by alleles of a gene at an autosomal locus (12). If there was variation in such a gene regulating steroidogenesis, it was our hypothesis that this should result in a reproductive phen...