Progesterone Can Block the Preovulatory Gonadotropin‐Releasing Hormone/Luteinising Hormone Surge in the Ewe by a Direct Inhibitory Action on Oestradiol‐Responsive Cells within the Hypothalamus

Abstract

Elevated oestradiol concentrations during the follicular phase stimulate a surge in gonadotropin-releasing hormone (GnRH) and luteinising hormone (LH) concentrations, which leads to ovulation. Progesterone can block the oestradiol-induced GnRH/LH surge, but the mechanism that is involved is unclear. We examined the effect of progesterone on oestradiol-induced activation of cells within the ovine hypothalamus/preoptic area (POA) to determine: (i) in which regions progesterone acts to block the GnRH/LH surge and (ii) whether progesterone directly or indirectly prevents activation of oestradiol-responsive cells. Cellular activation was assessed by measuring the number of cells that expressed Fos (an immediate early gene). Exposure to increased oestradiol concentrations in the absence of progesterone (which normally stimulates a LH surge) did not cause any region-specific changes in hypothalamic Fos expression during the activation stage of the LH surge-induction process (Experiment 1). The same treatment significantly increased cellular activation within the POA, lateral septum (LS), and arcuate nucleus at the time of surge onset (Experiment 2). Concurrent exposure to increased oestradiol and progesterone concentrations during the activation stage of the surge-induction process (which normally blocks the LH surge) was associated with significantly reduced cellular activation within the ventromedial hypothalamus and anterior hypothalamic area, relative to the positive controls (oestradiol increment alone) and arcuate nucleus relative to the negative controls (no increment in oestradiol) during the activation stage (Experiment 1). At the time of surge onset (Experiment 2), exposure to progesterone during the activation period prevented the oestradiol-induced increase in cellular activation that occurred in the POA, LS and arcuate nucleus of the positive controls. These results demonstrated that oestradiol and progesterone induced differential region- and time-specific effects on cellular activation within the regions of the ovine brain that generate the preovulatory GnRH/LH surge. Moreover, the lack of cellular activation within the POA, LS and arcuate nucleus at the time of surge onset in animals exposed to progesterone during the activation stage is consistent with the hypothesis that progesterone can block the preovulatory surge by direct inhibition of oestradiol-induced cellular activation in these areas.

Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization

“…The mechanisms of action of P in its stimulatory and inhibitory effects on pituitary LH and FSH discharges are mediated by the interactions among E 2 , P, and the GnRH neurosecretory system (20,21). P administration timing was critical in determining whether it would stimulate or inhibit an ovulatory LH surge in animal studies of rhesus monkeys and ewes (20,22,23). Harris et al demonstrated that the surge can be blocked in ewes only if P is applied immediately after the E 2 signal.…”

Progesterone Receptor A (PRA) and PRB-Independent Effects of Progesterone on Gonadotropin-Releasing Hormone Release

“…In rodents, the major release of P4 occurs on the afternoon and evening of proestrus and is responsible for the suppression of both GnRH pulsatility (11) and release of successive GnRH surges on subsequent days (24). The elevation of P4 secretion during pregnancy in female mammals also contributes to the suppression of basal GnRH pulsatility (55) and prevents release of preovulatory LH surges (56), presumably by blocking neurosecretion of GnRH surges (57,58). Ovarian P4 additionally appears to inhibit GnRH neurosecretion during suckling in rats (59).…”

Differential Estradiol Requirement for the Induction of Estrus Behavior and the Luteinizing Hormone Surge in Two Breeds of Sheep1

“…In this respect, it must be pointed out that the time lag between the onset of estrus behavior and the GnRH/ LH surge in the Romanov ewe (approximately 8 h) strongly suggests that there are more steps in the induction of the former than the latter. E enhances neuronal activation within the POA in time-and region-dependent manners [39]. This finding led these authors to suggest that neurons within the POA may participate in the GnRH surge-induction process even if they are not the primary site of E action but are downstream of this.…”