PROJECT 2 - GnRH-Gonadotrophe Responses - Steroid-Metabolic Interactions

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Temporally regulated secretion of the pituitary gonadotropins luteinizing hormone (LH) and folliclestimulating hormone (FSH) is critical for steroidogenesis and fertility. LH and FSH are tightly controlled by hypothalamic gonadotropin-releasing hormone (GnRH) pulses, and directly and indirectly by ovarian steroids. GnRH pulse amplitude and frequency are regulated physiologically by estrogen (E), progesterone (P) and testosterone (T). High-frequency GnRH pulses occur with E stimulation and favor LH secretion and LH subunit gene transcription, whereas low-frequency pulses occur with P plus E and preferentially stimulate FSH secretion and the FSHbeta gene. Polycystic ovarian syndrome (PCOS) conservatively affects between 6-8% of women of reproductive age, and is characterized by hyper-androgenism, erratic menstrual cycles, and infertility. Many women also have insulin resistance and hyper-insulinemia, with or without obesity. Between 30-90% of PCOS patients have increased LH/FSH ratios, and P is less effective in reducing GnRH pulse frequency and altering gonadotropin secretion in these women. P sensitivity can be partially restored by antiandrogens in some women. Treatment with the insulin sensitizing drug, metformin, can also restore fertility in some subjects, but sites and mechanism of action of insulin or this drug on the reproductive axis are unclear. Understanding mechanisms underlying GnRH gonadotrope regulation is critical to develop treatments for PCOS. Proposed studies will use the prenatal androgenized (PNA) mouse model that mimics many symptoms of PCOS, including elevated LH and T, erratic reproductive cycles and glucose intolerance. We will examine regulated gonadotropin expression, and responses to GnRH and P feedback in PNA and control gonadotropes. Treatment of mice with antiandrogen and metformin will test potential contributions of elevated T or insulin insensitivity to PNA responses. The role of androgen receptor CAG repeat length in influencing T responses will be evaluated in vitro and in transgenic mice. We will also examine the pulsatile GnRH stimulation of gonadotropin gene transcription requirement for proteasome activity, and if insulin or T modulate this process and may thus contribute to dysregulated LH/FSH ratios seen in PCOS.