UC San Diego

Reproductive function in mammals is primarily regulated by the production, release, and feedback actions of hormones in the hypothalamus and pituitary. Sex steroids such as androgens regulate the kisspeptin neurons, which activate the gonadotropin-releasing hormone (GnRH) neurons, stimulating luteinizing hormone (LH) and follicle- stimulating hormone (FSH) release from the pituitary. The work presented herein investigates the molecular mechanisms of the effects of kisspeptin and androgens on gene expression in the pituitary, as well as the reproductive consequences of early androgen exposure in female mice. Two models of androgen exposure in females are described: prenatal androgen (PNA) and prepubertal androgen (PPA). PNA caused advanced puberty, delayed fertility with concomitant cycling irregularities, and advanced reproductive senescence, while PPA caused early puberty with no lasting effects. Thus, both the late prenatal and prepubertal time frames represent windows of androgen sensitivity in females, but the PNA treatment has developmental influences that alter reproductive function throughout adulthood, while PPA only acts transiently to induce early puberty. The neuropeptide kisspeptin (and its receptor, Kiss1R) are required for puberty onset through their roles in the hypothalamus, but whether kisspeptin acts on the pituitary to regulate reproduction has not been extensively studied. In the pituitary gonadotrope cell line, LbT2, ligand-activated Kiss1R increased promoter activity of LHb and FSHb. This induction required the activation of the immediate early genes Egr-1 and cFos, and was dependent on protein kinase C (PKC). Furthermore, pituitary Kiss1R expression was induced in ovariectomized female mice undergoing the LH surge. This increase in pituitary Kiss1R, coupled with the kisspeptin-mediated gonadotropin induction, is strong evidence of a physiological role of Kiss1R in the pituitary to promote the reproductively important LH surge. Lastly, studies of androgen action in the pituitary showed that androgen receptor (AR) up-regulates the GnRH receptor (GnRHR) promoter through two proximal hormone response element (HRE) sites and direct binding of AR. Furthermore, a novel, pituitary-specific, AR-null mouse will yield valuable information on the reproductive role of AR in the pituitary. Overall, the research presented will further our understanding of the mechanisms by which the reproductive axis is regulated, under both normal and pathological conditions