Intraovarian excess of nerve growth factor increases androgen secretion and disrupts estrous cyclicity in the rat

A single injection of estradiol valerate induces a form of cystic ovary res embling some aspects of the human polycystic ovarian syndrome. Preceding th e development of follicular cysts, there is an increase in intraovarian syn thesis of nerve growth factor (NGF) and the low affinity NGF receptor (p75 NGFR). Selective blockade of NGF actions and p75 NGFR synthesis in the ovar y restored estrous cyclicity and ovulatory capacity in estradiol valerate-t reated rats, suggesting that an increase in NGF-dependent, p75 NGFR-mediate d actions within the ovary contributes to the development of cystic ovarian disease. We have tested this hypothesis by grafting NGF-producing neural p rogenitor cells into the ovary of juvenile rats that have been induced to o vulate precociously by a single injection of PMSG. The NGF-producing cells, detected by their content of immunoreactive p75 NGFR material, were found scattered throughout the ovary with some of them infiltrating the granulosa cell compartment of large, precystic follicles. Ovarian NGF content was a- fold higher than in the ovary of rats receiving control cells. Estrous cycl icity was disrupted, with the animals showing prolonged periods of persiste nt estrus, and an almost continuous background of vaginal cornified cells a t other phases of the estrous cycle. Morphometric analysis revealed that th e presence of NGF-producing cells neither reduced the total number of corpo ra lutea per ovary nor significantly increased the formation of follicular cysts. However, the ovaries receiving these cells showed an increased incid ence of precystic, type III follicles, accompanied by a reduced number of h ealthy antral follicles, and an increased size of both healthy and atretic follicles. These changes in follicular dynamics were accompanied by a selec tive increase in serum androstenedione levels. The results show that an abn ormally elevated production of NGF within the ovary suffices to initiate se veral of the structural and functional alterations associated with the deve lopment of follicular cysts in the rat ovary.