Ga. Dissen et al., Intraovarian excess of nerve growth factor increases androgen secretion and disrupts estrous cyclicity in the rat, ENDOCRINOL, 141(3), 2000, pp. 1073-1082
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.