Abstract
Polycystic ovary syndrome (PCOS) is a major cause of anovulatory sterility in women, and most PCOS patients exhibit hyperandrogenism (HA). Liver kinase b1 (LKB1) is a tumor suppressor that has recently been reported to be involved in PCOS. However, the mechanism by which LKB1 affects HA has not previously been elucidated. We report here that ovarian LKB1 levels are significantly decreased in a female mouse model of HA. Moreover, we report that LKB1 expression is inhibited by elevated androgens via activation of androgen receptors. In addition, LKB1 treatment was observed to suppress androgen synthesis in theca cells and promote estrogen production in granulosa cells by regulating steroidogenic enzyme expression. As expected, LKB1 knockdown inhibited estrogen levels and enhanced androgen levels, and LKB1‐transgenic mice were protected against HA. The effect of LKB1 appears to be mediated via IGF‐1 signaling. In summary, we describe here a key role for LKB1 in controlling sex hormone levels.
Highlights
Polycystic ovary syndrome (PCOS) is a major cause of anovulatory sterility in women, and most PCOS patients exhibit hyperandrogenism (HA)
Ovarian theca cells (TCs) were separated and supplemented with DHEA. qPCR analysis showed that DHEA decreased Liver kinase b1 (LKB1) expression in TCs
Because androgens acted via the stimulation of Androgen receptor (AR), we examined whether AR modulated LKB1 expression, which was inhibited using a siRNA particular to LKB1 (Fig. 1E,F)
Summary
Polycystic ovary syndrome (PCOS) is a major cause of anovulatory sterility in women, and most PCOS patients exhibit hyperandrogenism (HA). As a prevalent endocrine disease, polycystic ovary syndrome (PCOS) usually manifests as menstrual malfunction and hyperandrogenism (HA) in women in puberty [1,2,3,4]. In PCOS, androgen generation by the ovaries is disturbed, and increased generation of testosterone occurs, compared to estrogen [5,6]. Androgen generation occurs in the adrenal glands as well as ovaries. With regard to ovaries, luteinizing hormone (LH) activates the theca cells (TCs) to trigger the transformation of cholesterol to androstenedione, which serves as the main precursor of estrogen and testosterone. Abbreviations AR, androgen receptor; GCs, granulosa cells; HA, hyperandrogenism; LH, luteinizing hormone; LKB1, liver kinase b1; PCOS, polycystic ovary syndrome; TCs, theca cells.
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