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

Abstract

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...

Polycystic ovarian syndrome

“…It was also noted that brothers of the patients with PCOS had increased levels of DHEAS when compared with age matched controls. [13] Fathers of adolescent girls have a very high incidence of obesity (94%) and metabolic syndrome (79%). Also, mothers of such patients tend to be obese (54.4%) or overweight (11.4%) with the incidence of metabolic syndrome being 34%.…”

Polycystic ovary syndrome: an ancient disorder?

“…Finally, affected male relatives, while demonstrating evidence of androgen excess (34) and insulin resistance (35), do not demonstrate obvious impairment in fertility or ability to attract a suitable partner and in ancient times would even have had the metabolic advantages of PCOS females, and thus were readily able to transmit susceptibility alleles. Consequently, the metabolic and physical advantages of affected women and their progeny, the rearing advantages of their family units, the heterogeneity of the phenotype and genotype, and ready transmissibility of the genotype by affected males could have potentially equalized any disadvantages arising from the overall lower number of children begotten by PCOS women.…”

Ovarian and Adrenal Hyperandrogenism

“…Brothers of women with PCOS have significantly higher DHEAS levels compared to controls suggesting an inherited abnormality in adrenal androgen secretion. 20 However, in PCOS, no genetic alterations of adrenal enzymatic activity have been found 21 and the most consistent abnormality is an increased adrenal androgen response to adrenocorticotropin hormone (ACTH). [22][23][24] Because circulating ACTH is normal, 22 it is probable that factors external to the adrenal gland are responsible for the increased adrenal androgen responsivity.…”