SEXUALLY DIMORPHIC TRANSCRIPTIONAL RESPONSES TO GONADOTROPIN-RELEASING-HORMONE REQUIRE CHRONIC IN-VIVO EXPOSURE TO ESTRADIOL

GnRH regulates secretion of the gonadotropins, LH and FSH, in a sexual ly dimorphic manner. In the present study, we examined GnRH regulation of the gonadotropin alpha-subunit promoter to assess whether sex-depe ndent hormonal effects are manifest at the transcriptional level. Prim ary cultures of male or female rat pituitary cells were transfected wi th a reporter gene containing the alpha-promoter linked to luciferase (-420 alpha-LUC) and then subjected to treatment with GnRH for 24 h. B asal alpha-LUC expression was 4.2-fold greater in pituitary cells from males than those from females. alpha-LUC activity was stimulated 5.3- fold by GnRH in males, whereas GnRH responsiveness of the transfected alpha-promoter did not vary in pituitary cells isolated at different s tages of the female reproductive cycle, suggesting that acute changes in the hormonal milieu are not sufficient to alter transcriptional res ponses to GnRH. In males, orchidectomy minimally influenced alpha-LUC activity, indicating that testosterone does not exert a suppressive ef fect on GnRH responsiveness. In ovariectomized females, basal expressi on of alpha-LUC increased 3.7-fold, and GnRH stimulation was reduced f rom 165- to 11-fold, suggesting that an ovarian factor suppresses basa l activity and enhances GnRH stimulation. Treatment of ovariectomized females with estrogen suppressed activity and restored GnRH stimulatio n of alpha-LUC, but the estrogen effects required long term treatment (10 days). Addition of progesterone to estrogen or treatment with the progesterone antagonist. RU486, had little effect on GnRH responsivene ss. We conclude that estrogen exerts dual effects to suppress basal ex pression and to dramatically enhance GnRH responsiveness of the alpha- promoter. This model reveals potent actions of estrogen at the level o f transcription and should provide new insights into the mechanisms th at control estrogen priming of gonadotrope cells.