Gonadotropin releasing hormone (GnRH) neurons play a central role in the control of mammalian reproductive function. Changes in the pulsatile secretion of GnRH and luteinizing hormone (LH) are critical for the regulation of events leading to ovulation, as well as to the inhibition of ovulation prior to puberty and during other physiological periods of infertility. Based on recent data, we have developed a working hypothesis for the control of pulsatile GnRH/LH secretion by endogenous opioid peptides (EOP). This hypothesis suggests that one of the EOP systems in the brain, the dynorphin-kappa receptor system, acts in the mediobasal hypothalamus (MBH) to mediate the inhibitory effect of progesterone on GnRH pulse frequency during the luteal phase of the ovine estrous cycle. In the first aim, we will test this hypothesis by determining if dynorphin neurons contain progesterone receptors; progesterone treatment increases dynorphin mRNA and/or peptide levels; and removal of dynorphin blocks the ability of progesterone to inhibit LH pulse frequency. In the second aim, we will delineate the anatomical substrates of these interactions by determining whether GnRH neurons express kappa receptors, and whether dynorphin cells that project to the median eminence contain progesterone receptors and form axo- axonic contacts with GnRH terminals. Finally, in the third aim, we test the hypothesis that dynorphin neurons, acting via kappa receptors, are involved in the generation of GnRH pulses by determining whether kappa receptor antagonists or dynorphin antisera alter the shape of GnRH pulses. These questions will be explored using the sheep as an animal model because of advantages which include the similarity of its estrous cycle to the human menstrual cycle and the ability to directly monitor GnRH pulses without anesthesia. In addition, EOP have been shown to play a major role in mediating progesterone negative feedback during the luteal phase in humans as well as sheep. Thus, these studies may lay the foundation for the development of better treatments for pathological disruptions of reproductive function, may lead to better clinical management of follicular development, increasing the efficiency of assisted reproductive technologies, and may provide the basis for the design of novel contraceptive techniques.
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