Context: Previous studies showed that nerve growth factor (NGF) induces the expression of functional FSH receptors (FSHR) in preantral follicles of the developing rat ovary. Objective: The objective of this study was to determine whether NGF can affect granulosa cell (GC) function in human periovulatory follicles using intact human ovaries and isolated human GCs. Patients and Interventions: Human GCs were obtained from in vitro fertilization patients and normal ovaries from women with elective pelvic surgery for nonovarian indications. Results: In normal ovaries, NGF and trkA (NGF's high-affinity receptor) were detected by immunohistochemistry in GCs of preantral and antral follicles. NGF and trkA are also present in thecal cells of antral follicles. Both freshly collected and cultured GCs contained immunoreactive NGF and trkA in addition to their respective mRNAs. Human GCs respond to NGF with increased estradiol (E2) secretion and a reduction in progesterone output. Exposure of human GCs to NGF increased FSHR mRNA content within 18 h of treatment, and this effect was blocked by the trk tyrosine kinase blocker K-252a. Also, cells preexposed to NGF released significantly more E2 in response to hFSH than cells not pretreated with the neurotropin, showing that the NGF-induced increase in FSHR gene expression results in the formation of functional FSHRs. Conclusions: These results suggest that one of the functions of NGF in the preovulatory human ovary is to increase the secretion of E 2 while preventing early luteinization via an inhibitory effect on progesterone secretion. NGF stimulates E2 secretion both directly and by increasing the formation of FSHRs.