UC San Diego

Androgens and androgen receptor (AR) have important roles in both male and female reproductive physiology. In males, androgens are critical for sexual differentiation, the development of secondary sex characteristics, and spermatogenesis. While specific roles of AR within the testis have been studied, whether neuroendocrine AR directly contributes to male fertility remains to be elucidated. Androgens also contribute to female fertility, with global loss of AR in mice resulting in age-dependent subfertility similar to premature ovarian failure in humans. Conversely, excess androgens are a key factor driving the pathophysiology of polycystic ovary syndrome (PCOS), the most common reproductive endocrinopathy in women. In the work presented herein, we demonstrate that AR positively regulates the GnRH receptor (GnRH) by acting at two novel hormone response elements in the GnRHR proximal promoter. We also show that, while AR regulates Gnrhr mRNA in vivo, loss of AR from pituitary gonadotropes (GARKO) does not appear to impair downstream reproductive function. We further investigated neuroendocrine roles of AR by selectively deleting AR from kisspeptin neurons (KARKO) and evaluating effects on male and female fertility. We found that loss of AR from kisspeptin neurons advances puberty and increases pituitary expression of Lhb, suggesting dysregulation of the reproductive neuroendocrine axis. We also utilized the letrozole-induced (LET) mouse model of PCOS to investigate AR contributions to disease pathology in this model. We first demonstrated that treatment with the antiandrogen flutamide ameliorates or reverses many key reproductive and metabolic PCOS phenotypes in LET females. We next treated GARKO females with LET to determine whether selective loss of AR from pituitary gonadotropes affects PCOS phenotypes in this model. We found that deletion of AR from gonadotropes improved reproductive but not metabolic PCOS phenotypes in LET females. Altogether, this work furthers our understanding of the roles of AR in neuroendocrine tissues, both in normal reproductive physiology and in a murine model of PCOS.