Progesterone Inhibits Basal and Gonadotropin-Releasing Hormone Induction of Luteinizing Hormone β-Subunit Gene Expression

LH and FSH play critical roles in mammalian reproduction by mediating steroidogenesis and gametogenesis in the gonad. Gonadal steroid hormone feedback to the hypothalamus and pituitary influences production of the gonadotropins. We previously demonstrated that progesterone differentially regulates the expression of the LH and FSH beta-subunits at the level of the gonadotrope: FSH beta transcription is induced, whereas LH beta is repressed. In this study, we investigated the mechanism of progesterone repression of LH beta gene expression using immortalized gonadotrope-derived L beta 2 cells. The progesterone suppression of both basal and GnRH-induced LH beta gene expression occurs in a hormone- and receptor-dependent manner. Chromatin immunoprecipitation demonstrates that the hormone- bound progesterone receptor (PR) is recruited to the endogenous mouse LH beta promoter. In addition, suppression requires both the amino-terminal and DNA-binding regions of PR. Furthermore, progesterone suppression does not require direct PR binding to the promoter, and, thus, PR is likely recruited to the promoter via indirect binding through other transcription factors. These data demonstrate that the molecular mechanism for progesterone action on the LH beta promoter is distinct from FSH beta, which involves direct PR binding to the promoter to produce activation. It also differs from androgen repression of LH beta gene expression in that, rather than Sp1 or steroidogenic factor-1 elements, it requires elements within -300/-50 and -200/-150 that also contribute to basal expression of the LH beta promoter. Altogether, our data indicate that progesterone feedback at the level of the pituitary gonadotrope is likely to play a key role in differential production of the gonadotropin genes. (Endocrinology 150: 2395-2403, 2009)