Abstract
Polycystic ovary syndrome (PCOS), characterized by ovarian androgen excess, is the commonest endocrine disorder in women. Obesity increases androgen synthesis, a phenomenon attributed to the accompanying hyperinsulinemia. Our hypothesis was that adipokines, fat cell-derived hormones, play a direct role in modulating ovarian androgen secretion. Therefore, the aims of this study were to explore the effects of adipokines (in particular, adiponectin) on ovarian steroidogenesis and compare the expression of adiponectin receptors in ovaries from women with and without PCO. Sections of archived human ovaries (nine from women with normal ovaries and 16 with PCOS, classified histologically, with reference to menstrual history and ultrasound) were analysed by quantitative morphometry and the proportion of positive-labelling cells compared. In addition, studies of androgen production in relation to adipokine function in primary bovine theca cell culture were also performed. A significantly lower proportion of theca cells expressed adiponectin receptors 1 and 2 (AdipoR1, AdipoR2) in polycystic ovaries than in normal ovaries. In cultured theca cells, adiponectin suppressed androstenedione production and gene expression of LH receptor and key enzymes in the androgen synthesis pathway. Moreover, knockdown of genes for AdipoR1 and AdipoR2 was associated with increased androstenedione secretion by bovine theca cells. These results provide evidence for a direct link between fat cell metabolism and ovarian steroidogenesis, suggesting that disruption of adiponectin and/or its receptors plays a key role in pathogenesis of hyperandrogenism in PCOS.
Highlights
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women, affecting 5-10% of females of reproductive age [1,2]
We show by means of suppression of gene expression by small interfering RNA, that adiponectin, the principal adipokine in humans, decreases the production of androgens in theca cells in vitro
The most abundant secreted adipokine in humans, caused a decrease of about 40% in androgen secretion in a theca cells
Summary
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women, affecting 5-10% of females of reproductive age [1,2]. Androgen production is markedly increased in PCOS in the presence of obesity, which has been attributed, at least in part, to the effect of higher than normal insulin levels on theca cell function [7]. A possible role for cytokine products of fat (adipokines) as a link between reproductive and metabolic abnormalities has been mooted [8] In this regard, quantitatively and functionally, adiponectin (a 30kd protein) is considered to be one of the most important adipokines in human physiology [9]. Quantitatively and functionally, adiponectin (a 30kd protein) is considered to be one of the most important adipokines in human physiology [9] It differs from most other adipokines by having what appears to be a protective effect on development of obesity. Abnormal serum levels of various adipokines in PCOS have been reported [12,13,14,15,16,17,18,19] few studies have addressed the effects of adipokines on reproductive tissues [20,21]
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