Understanding the regulation of pituitary progesterone receptor expression and phosphorylation

Abstract

Administration of human FSH (hFSH) during the diestrus phase in cyclic rats is followed by a reduction in the preovulatory LH surge. This inhibitory action of FSH involves a decrease in the stimulatory effect of gonadotrope progesterone receptor (PR) activation, in a ligand-dependent (progesterone) and -independent (GNRH) manner. PR activation and action are mandatory for LH surge, and are dependent on the phosphorylation of serine (Ser) residues. Together with this post-translational modification, PR is marked for downregulation by proteasome machinery. These experiments used the western blotting technique to measure pituitary expression of PR-A and PR-B isoforms and phosphorylation levels of Ser294 and Ser400 PR-B in rats bearing i) hFSH treatment or ii) PR downregulation. Treatment with hFSH reduced LH secretion and increased that of estradiol in proestrus afternoon. hFSH injections, without altering PR-A and PR-B content or ratio, caused a reduction in phosphorylation of Ser294 and Ser400 but only when pituitaries were previously challenged with progesterone or GNRH for 2 h. However, while pSer294 levels increased after 2 h of pituitary incubation with progesterone or GNRH, those of pSer400 were not modified by these in vitro treatments. Finally, progesterone had a biphasic effect: in 2-h incubations increased pituitary PR-A and PR-B content, but after 8 h caused downregulation and altered PR-A:PR-B ratio. The results provide a potential mechanism through which LH levels are decreased by hFSH administration and better understanding of the control of PR expression and phosphorylation in rat pituitaries.

Efficacy of Different Progestins in Women With Advanced Endometriosis Undergoing Controlled Ovarian Hyperstimulation for in vitro Fertilization-A Single-Center Non-inferiority Randomized Controlled Trial

“…In the multivariate analysis, the baseline FSH levels were independently associated with pituitary LH levels. No association was found with baseline LH values, which is not in agreement with previous findings (29,30). The inhibitory effects in the progesterone and dydrogesterone groups were weaker than in the MPA group, but were nonetheless statistically significant.…”

Use of medroxyprogesterone acetate in women with ovarian endometriosis undergoing controlled ovarian hyperstimulation for in vitro fertilization

“…Progestin can block estradiol-induced LH surges by preventing the activation of the GnRH surge induction system by estradiol. The mechanisms of action of progestin on pituitary LH and FSH discharges are mediated by the interaction of estradiol, progestin, and GnRH neurosecretory system 41 , 42 . There was a trend toward progressively deeper serum LH suppression during the hMG and MPA protocol.…”

Use of progestins to inhibit spontaneous ovulation during ovarian stimulation: the beginning of a new era?

“…The biological activities of progesterone receptors A and B are distinct: in most cells, progesterone receptor B mediates the stimulatory activities of progesterone; progesterone receptor A strongly inhibits this action and is also a transcriptional inhibitor of other steroid receptors. Current data, from a study in rats, suggest that co-activators and co-repressors interact differentially with the two receptors, and this may account, at least in part, for the differential activities of the two isoforms (Gordon et al, 2015) . One of the essential requirements of any compound with progesterone-like activity is that it is able to bind to the progesterone receptors.…”