PROGESTERONE/ANDROGEN FEEDBACK CONTROL OF GNRH NEURONS

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Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway regulating reproduction. Pulsatile release of GnRH stimulates secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from pituitary gonadotropes and is absolutely required for fertility. In female mammals, shifts in GnRH pulse frequencies help drive the preferential release of LH or FSH at specific times of the cycle to create appropriate hormone milieux for ovarian follicle maturation. GnRH pulse patterns are largely regulated by negative feedback from the ovarian steroids progesterone and estradiol. Although this feedback is well characterized in vivo, the underlying cellular mechanisms and neural pathways have yet to be elucidated. This has precluded understanding the neural components of common forms of hypothalamic infertility, such as polycystic ovarian syndrome (PCOS), in which elevated circulating androgen levels are accompanied by a persistent high frequency of LH (and presumably GnRH) release. The latter appears to be due in part to androgens interfering with the efficacy of progesterone feedback. Considerable evidence suggests one mechanism of steroid feedback regulation of GnRH release is transsynaptic. In particular, anatomical and physiological data support a role for gamma-aminobutyric acid (GABA)- and opiate peptide-producing neurons in this communication. Four Specific Aims are proposed to investigate the cellular mechanisms of progesterone feedback, and how androgens might alter the efficacy of progesterone feedback. The primary methodology will be electrophysiological recordings of green-fluorescent protein-identified GnRH neurons in acute brain slices. Aim 1 will investigate the effects of steroid and neurotransmitter milieux on the firing properties and firing patterns of GnRH neurons. Aim 2 will examine how steroids and neurotransmitters alter GABAergic drive to GnRH neurons. Aims 3 and 4 will study the effects of steroids and neurotransmitters on potassium and calcium currents, respectively, as these play major roles in setting firing properties of neurons as well as their ability to respond to synaptic input. These studies will help us understand GnRH neuron physiology in both healthy and diseased states, knowledge paramount for improving treatments for hypothalamic fertility disorders, developing novel contraceptive methods, ensuring effective reproduction in endangered and food-producing species, and understanding other similar neuronal systems.