An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovaryin the rat
He. Lara et al., An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovaryin the rat, ENDOCRINOL, 141(3), 2000, pp. 1059-1072
A form of polycystic ovary (PCO) resembling some aspects of the human PCO s
yndrome 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 w
as 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 for
mation 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 eleva
tion in sympathetic tone to the ovary and preceding the appearance of folli
cular cysts. Intraovarian injections of the retrograde tracer fluorogold co
mbined with in situ hybridization to detect tyrosine hydroxylase (TH) messe
nger RNA-containing neurons in the celiac ganglion revealed that these chan
ges in NGF/p75 NGFR synthesis are accompanied by selective activation of no
radrenergic neurons projecting to the ovary. The levels of RBT2 messenger R
NA, which encodes a beta-tubulin presumably involved in slow axonal transpo
rt, were markedly elevated, indicating that EV-induced formation of ovarian
cysts is preceded by functional activation of celiac ganglion neurons, inc
luding those innervating the ovary. Intraovarian administration of a neutra
lizing antiserum to NGF in conjunction with an antisense oligodeoxynucleoti
de to p75 NGFR, via Alzet osmotic minipumps, restored estrous cyclicity and
ovulatory capacity in a majority of EV-treated rats. These functional chan
ges were accompanied by restoration of the number of antral follicles per o
vary that had been depleted by EV and a significant reduction in the number
of both precystic follicles and follicular cysts. The results indicate tha
t 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 r
egulatory loop is a component of the pathological process by which EV induc
es cyst formation and anovulation in rodents. The possibility exists that a
similar alteration in neurotrophic input to the ovary contributes to the e
tiology and/or maintenance of the PCO syndrome in humans.