Gonadotropin Gene Modulation by Steroids and Gonadotropin-Releasing Hormone1

Physiological gonadotropin levels are modulated by complex interrelationships between the sex steroids and the hypothalamic GnRH pulse generator, and the steroids and GnRH individually regulate gonadotropin subunit (alpha, LH beta, FSH beta) gene expression. Steroids may act directly at the pituitary level or indirectly at the hypothalamus to alter GnRH pulses, and they can have positive or negative actions, depending on the model system and physiological state. GnRH pulse frequency and amplitude have subunit-specific effects on the gonadotropin genes, and alteration of pulse frequency during the reproductive cycle can selectively favor LH or FSH synthesis. The cloning of the gonadotropin subunit genes and sensitive molecular approaches to the study of transcriptional 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 measurement 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 hormonal and tissue-specific control of gene expression. Recent studies in the rat model suggest that some steroid actions, such as estrogen stimulation of LH beta gene transcription and alteration of estrogen and GnRH receptor number, occur directly at the level of the pituitary, while suppressive effects of estrogen on gonadotropins may occur at least partly if not primarily via hypothalamic effects. Changes in GnRH pulses may also alter GnRH receptor number, thus modifying the potential signal received by the gonadotroph. Current and emerging molecular technologies will probably identify additional targets of steroid and GnRH action and allow greater insight into gonadotropin regulation and reproductive function.