A form of polycystic ovary (PCO) resembling some aspects of the human PCO syndrome can be induced in rats by a single injection of
estradiol valerate (EV). An increase in sympathetic outflow to the ovary precedes, by several weeks, the appearance of
cysts, suggesting the involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was carried out to test the hypotheses that this change in sympathetic tone is related to an augmented production of ovarian
nerve growth factor (
NGF), and that this abnormally elevated production of
NGF contributes to the formation of
ovarian cysts induced by EV. Injection of the
steroid resulted in increased intraovarian synthesis of
NGF and its low affinity receptor, p75 NGFR. The increase was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding the appearance of
follicular cysts. Intraovarian
injections of the retrograde tracer
fluorogold combined with in situ hybridization to detect
tyrosine hydroxylase (TH)
messenger RNA-containing neurons in the celiac ganglion revealed that these changes in
NGF/p75 NGFR synthesis are accompanied by selective activation of noradrenergic neurons projecting to the ovary. The levels of RBT2
messenger RNA, which encodes a
beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that EV-induced formation of
ovarian cysts is preceded by functional activation ofceliac
ganglion neurons, including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to
NGF in conjunction with an antisense
oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These functional changes were accompanied by restoration of the number of
antral follicles per ovary that had been depleted by EV and a significant reduction in the number of both precystic follicles and
follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in EV-induced PCO is related to an overproduction of
NGF and its low affinity receptor in the gland. They also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the pathological process by which EV induces
cyst formation and
anovulation in rodents. The possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology and/or maintenance of the PCO syndrome in humans.