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

Abstract

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: FSHbeta transcription is induced, whereas LHbeta is repressed. In this study, we investigated the mechanism of progesterone repression of LHbeta gene expression using immortalized gonadotrope-derived LbetaT2 cells. The progesterone suppression of both basal and GnRH-induced LHbeta 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 LHbeta 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 LHbeta promoter is distinct from FSHbeta, which involves direct PR binding to the promoter to produce activation. It also differs from androgen repression of LHbeta gene expression in that, rather than Sp1 or steroidogenic factor-1 elements, it requires elements within -300/-250 and -200/-150 that also contribute to basal expression of the LHbeta 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.

FOXO1 Transcription Factor Inhibits Luteinizing Hormone β Gene Expression in Pituitary Gonadotrope Cells

“…The Ϫ1800 rat Lhb-luc reporter in pGL3 was provided by Dr. Mark Lawson. Construction of 5Ј truncations of the Ϫ1800 Lhb-luc reporter plasmid (Ϫ500, Ϫ300, Ϫ150, Ϫ87) was previously described (63). The Ϫ1068/ϩ9 human LHB-luc reporter in pA3 was generously provided by Dr. Daniel Bernard.…”

Variation in Progesterone Receptors and GnRH Expression in the Hypothalamus of the Pregnant South American Plains Vizcacha, Lagostomus maximus (Mammalia, Rodentia)1

“…After ovulation, a progressive increase of P4 secretion from corpora lutea produces a negative feedback over GnRH secretion [3,4]. In addition, P4 also acts in the pituitary gland by repressing luteinizing hormone (LH) expression in a receptor-dependent manner [5]. If fertilization takes place following ovulation, P4 levels increase progressively, modulating blastocyst implantation, and remain elevated throughout the ensuing pregnancy [6][7][8].…”

Androgen Receptor Drives Transcription of Rat PACAP in Gonadotrope Cells

“…Because androgen stimulation in the presence of the endogenous L␤T2 AR is relatively weak, several of these studies have amplified the steroid hormone response by cotransfecting AR expression constructs, a method we have adopted in the current study. The same strategy has been employed to study ER, PR, and GR in L␤T2 cells (35,36,52,68,69). In the studies reported here, the rPACAP promoter was robustly activated by androgen in the context of the immortalized L␤T2 gonadotrope, with activation that is dependent on the presence of AR.…”