GONADOTROPIN GENE MODULATION BY STEROIDS AND GONADOTROPIN-RELEASING-HORMONE

Physiological gonadotropin levels are modulated by complex interrelati onships between the sex steroids and the hypothalamic GnRH pulse gener ator, and the steroids and GnRH individually regulate gonadotropin sub unit (alpha, LH beta, FSH beta) gene expression. Steroids may act dire ctly at the pituitary level or indirectly at the hypothalamus to alter GnRH pulses, and they can have positive or negative actions, dependin g on the model system and physiological state. GnRH pulse frequency an d amplitude have subunit-specific effects on the gonadotropin genes, a nd alteration of pulse frequency during the reproductive cycle can sel ectively favor LH or FSH synthesis. The cloning of the gonadotropin su bunit genes and sensitive molecular approaches to the study of transcr iptional regulation have permitted insights into the sites of steroid and GnRH action and into the mechanisms by which such hormonal effects occur. This review describes several such approaches including the me asurement of endogenous gene transcription by nuclear run-off assays, definition of hormone-sensitive gene regions by transient transfection analysis, and the use of transgenic animal technology to verify hormo nal and tissue-specific control of gene expression. Recent studies in the rat model suggest that some steroid actions, such as estrogen stim ulation of LH beta gene transcription and alteration of estrogen and G nRH receptor number, occur directly at the level of the pituitary, whi le suppressive effects of estrogen on gonadotropins may occur at least partly if not primarily via hypothalamic effects. Changes in GnRH pul ses may also alter GnRH receptor number, thus modifying the potential signal received by the gonadotroph. Current and emerging molecular tec hnologies will probably identify additional targets of steroid and GnR H action and allow greater insight into gonadotropin regulation and re productive function.