Growth of the mammalian ovary is regulated by both the endocrine and nervous systems. During the past year of support we have gathered additional evidence in support of the concept that ovarian development is subjected to the regulatory influence of a """"""""neuroendocrinotrophic"""""""" complex. This complex consists of three basic components the extrinsic innervation to the gland, an intragonadal source of catecholamines, and growth factors of the neurotrophin family. Neonatal rat ovaries, which are unresponsive to gonadotropins, respond in vitro to isoproterenol, a -adrenergic agonist, or vasoactive intestinal peptide (VIP) -- which, like norepinephrine (NE), is contained in ovarian nerves -- with an increase in FSH receptor gene expression and the formation of biologically active FSH receptors. Thus, neurotransmitters may contribute to the early differentiation of newly formed follicles by facilitating formation of FSH receptors. The nonhuman primate gland contains an intrinsic network of neuron-like cells, some of which contain catecholamines and express tyrosine hydroxylase (TH) and dopamine -hydroxylase (DBH), the two key enzymes in catecholamine biosynthesis. In addition, monkey oocytes are able to uptake dopamine (DA) via a DA transporter and convert it into NE via DBH. In turn, NE activates -adrenoreceptors in adjacent granulosa cells, which respond with cAMP formation. Since cAMP inhibits oocyte maturation, oocyte-derived catecholamines may represent one of the cell-to-cell mechanisms involved in the autoregulation of oocyte maturation. Neurotrophins are important for development of the innervation, but they also exert direct actions on ovarian cells. The expression of trkA, the tyrosine kinase receptor for nerve growth factor (NGF), increases dramatically in cells of the follicular wall during the preovulatory surge of gonadotropins. The increase in trkA mRNA is LH-dependent and is accompanied by an increase in NGF gene expression. Blockade of NGF action inhibits ovulation, suggesting an involvement of trkA receptors in the ovulatory process. Purified bovine thecal cells, transfected with a trkA expression vector to simulate a periovulatory condition, respond rapidly to NGF with connexin-43 serine phosphorylation and a reduction in gap junction-mediated cell-cell communication. These immediate changes are followed by increased cell proliferation. Thus, NGF may contribute to the ovulatory process by first disrupting cell-cell communication and then facilitating the cytomorphogenic transformation of thecal cells into their luteal counterparts.
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