The Role of Energy Balance in Gonadotrope and Reproductive Function

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PROJECT SUMMARY Polycystic Ovary Syndrome (PCOS) is the most common fertility disorder in reproductive-aged women. Women with PCOS have elevated gonadotropin luteinizing hormone (LH), androgens, glucose, and inflammatory cytokines. Concomitant increases in LH and testosterone in both women with PCOS and mouse models of PCOS counter the well-established paradigm that testosterone suppresses the neuroendocrine axis. Mechanisms behind this paradox are largely unexplored. LH translation and secretion are innately energy-dependent processes. Therefore, gonadotrope cellular metabolism may explain the counterintuitive relationship between androgens (anabolic steroids) and LH in PCOS. The overall goal of this proposal is to investigate the impact of gonadotrope glucose metabolism on LH secretion and fertility in both normal and PCOS-like conditions. The overarching hypothesis of this proposal is that factors associated with PCOS, including glucose, androgens, and inflammatory cytokines, perturb gonadotrope energy balance through GLUT1 and therefore alter LH synthesis. We have determined that glycolysis is the metabolic program required for normal gonadotrope function. Gonadotropes utilize glucose to support LH production and secretion through Glucose transporter 1 (GLUT1) at the exclusion of other members of the glucose transporter family. In Aim 1, we will determine the effects of gonadotrope specific glucose transporter 1 (GLUT1) knock out on female fertility in mice. Using this model, we will decipher how androgens increase gonadotrope glucose metabolism. We hypothesize that androgens increase gonadotrope utilization of glucose to drive LH secretion by pre- and post- translational regulation of GLUT1. We will assess the impact of androgen on glucose uptake after silencing GLUT1 in cell lines and use gonadotrope specific GLUT1 KO mice to determine the role of gonadotrope GLUT1 in PCOS. In Aim 2, we will elucidate the contribution of PCOS-induced inflammation to gonadotrope metabolism and function. We hypothesize that chronic inflammation directly modulates gonadotrope LH secretion and contributes to reproductive dysfunction in PCOS. Using complex bioinformatic approaches, we will identify the immunophenotype specific to PCOS and assess the contribution of immune cells to PCOS etiology using immune deficient transgenic mouse models. Together, these Aims will 1) outline a role for gonadotrope energy balance in reproduction and PCOS, 2) explain how androgens increase LH, and 3) identify specific inflammatory pathways as potential therapeutic targets in PCOS.