LKB1 suppresses androgen synthesis in a mouse model of hyperandrogenism via IGF‐1 signaling

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.

Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms

“…An important role of AMPK-dependent mechanisms in the antiandrogenic action of MF in PCOS is supported by the data on the relationship between the androgen production and the activity of LKB1 in the ovaries of mice with experimental HA [ 199 ]. The LKB1 expression in the ovaries of hyperandrogenic mice is inhibited by high concentrations of androgens through activation of intracellular androgen receptors.…”

“…In opposite, LKB1 activation leads to a decrease in the androgens production by theca cells, but increases the estrogen production by granulosa cells. Transgenic mice overexpressing LKB1 are characterized by the increased resistance to the development of HA [ 199 ]. Mice with a functionally inactive ovarian gene Lkb1 have significantly enlarged ovaries and activated entire pool of primordial follicles, but without further maturation and ovulation, which results in the premature ovarian failure and severely reduced fertility [ 200 ].…”

The Association Between Polycystic Ovary Syndrome and Its Dermatological Manifestations

“…In another study, detailed research was carried on LKB1. It was observed that LKB1 has an inhibitory action on androgens in theca cells of the ovary, whereas the excess amount of androgens suppresses LKB1 activity [33]. This suggests a possible LKB1 link to PCOS disease.…”

“…IGFR is understood to have a negative impact on CYP17 and a positive one on CYP19. Thus, in PCOS, where androgen is on a higher level, there will be IGFR activity present and, consequently, high CYP19 and dysfunctioning CYP17 levels are recorded [33,34]. In a study among 198 Iranian patients diagnosed with acne vulgaris conducted to shed some light on the association between acne vulgaris and two genotypes of CYP 450 (CYP 17 and CYP 19), it was proved that both genotypes are connected to the occurrence of acne vulgaris [35].…”