Menstrual cyclicity, ovulation, and pubertal maturation of normal adult reproductive function are dependent upon the pulsatile pattern of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. Although the neural components comprising the GnRH """"""""pulse generator"""""""" are not only resident within the mediobasal hypothalamus (MBH) but capable of functioning independent of neural innervation from the remainder of the brain, this pulsatile GnRH secretion appears to be modulated by the multifactorial interactions of gonadal steroids, neuropeptides, and neuroamines. In particular, interactions between the prominent mediobasohypothalamic dopaminergic and Beta-endorphinergic neuronal systems appear to play a critical central role in this regulation. Accordingly, the proposed studies will utilize a recently developed in vitro method of characterizing pulsatile GnRH secretory frequency and amplitude from both rat and human hypothalami to investigate 1) the site of pulsatile GnRH secretion, assessed by isolating the essential GnRH pulse generator tissue in vitro; 2) the mechanism of pulsatile GnRH secretion, assessed by characterizing the pulsatile GnRH secretory activity of this tissue during pharmacologic manipulation of neuroamine/neuropeptide receptor activation/blockade and synthesis inhibition; 3) interactions between dopamine, endogenous opiates such as Beta-endorphin, and gonadal steroids in regulation of the amplitude and frequency of pulsatile GnRH secretion in vitro; 4) the role of prolactin, oxytocin, corticotrophin releasing factor, adrenocorticotropic hormone, and cortisol in the regulation of pulsatile GnRH secretion, as well as the ovarian steroid dependency and dopaminergic/Beta-endorphinergic mediation of these responses, also assessed in vitro. These mechanisms will be evaluated in both the rat and human hypothalamus. These studies will provide critical information regarding the complex multifactorial hypothalamic interactions which regulate gonadotropin secretion during not only the normal menstrual cycle but also during suckling, lactation, hyperprolactinemia, and stress.
