Polycystic ovarian syndrome (PCOS) is the most common ovarian pathology affecting women of reproductive age. Numerous factors, including abnormal gonadotropin secretion, alterations in adrenal function and faulty cell- cell interactive processes within the ovarian microenvironment, have been invoked as primary responsibles for the etiology of the syndrome. While it is clear that the progression of PCOS depends on multiple interactive dysfunctions, no consensus has been reached as to the primary factors that may initiate the abnormal process. This disagreement stems, to a significant extent, from the lack of an adequate nonhuman primate model. Rhesus monkeys do not appear to develop PCOS spontaneously and, thus, their usefulness as an animal model for the study of PCOS has not been pursued. A form of PCOS can be induced in rodents by the administration of a single dose of estradiol valerate (EV), a long-acting estrogen. Utilizing this paradigm, we have recently provided evidence for a direct involvement of the nervous system in the maintenance and progression of PCOS. We have shown that the ovaries of animals with EV-induced PCOS are subjected to increased noradrenergic tone via the extrinsic innervation of the ovary, and have suggested that this augmented tone results from an upregulation of the genes encoding nerve growth factor (NGF) and one of its receptors (p75 NGFR) in the ovary itself. Though potentially significant, direct extrapolation of these findings to the human is not possible until an adequate primate model is developed. We propose to do so by relying on the existing expertise in primate ovarian physiology and neuroendocrinology at the ORPRC, the knowledge of the neural control of the ovary gathered from studies in rodents, and the availability of new neuroendocrine and molecular tools recently developed by ORPRC scientists that can now be directly applied to research with nonhuman primates. We propose to test the hypotheses that PCOS can be induced in the nonhuman primate ovary by selectively altering the noradrenergic input to the gland, and that such an alteration can be brought about by the selective intra-ovarian upregulation Of the gene encoding NGF, the neurotrophic factor involved in determining the survival, activity and density of the sympathetic innervation. To this end, the following Aims are proposed: 1. To induce PCOS in rhesus monkeys via chronic, but intermittent infusion of a beta-adrenergic agonist to the ovary. A sequential treatment protocol will be used wherein each animal serves as its own control. First, the vehicle will be delivered to one of the ovaries via a catheter connected to a peristaltic pump. Following a 90-day interval, the vehicle is substituted by isoproterenol and the intermittent infusion is continued for several more weeks. It is anticipated that this procedure will result in selective, unilateral activation of ovarian beta-adrenergic receptors. 2. To induce PCOS in rhesus monkeys by autologous intraovarian implantation of fibroblasts genetically engineered to overexpress a human NGF cDNA under the control of a metallothionein promoter. Activation of the transgenic via systemic administration of a heavy metal (zinc chloride) to the animal should result in enhanced NGF production, which would then increase sympathetic fiber outgrowth and nerve activity in the gland.
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