Progesterone Treatment That either Blocks or Augments the Estradiol-Induced Gonadotropin-Releasing Hormone Surge Is Associated with Different Patterns of Hypothalamic Neural Activation

Abstract

Progesterone can either augment or inhibit the surge of gonadotropin-releasing hormone (GnRH) that drives the preovulatory luteinizing hormone (LH) surge. This study investigated the central mechanisms through which progesterone might achieve these divergent effects by examining the effects of exogenous steroids on the activation of GnRH neurons and non-GnRH-immunopositive cells in the preoptic area/anterior hypothalamus of steroid-treated ovariectomized ewes. Fos expression (an index of cellular activation) was examined during the estradiol-induced GnRH surge in ewes treated with progesterone using regimes that have been reported to either augment (progesterone pretreatment) or inhibit (progesterone treatment at the time of the surge-inducing estradiol increment) the GnRH surge. Control groups received either no progesterone pretreatment or no surge-inducing estradiol increment. Induction of an LH surge was associated with a significant (p < 0.0001) increase in the proportion of activated GnRH neurons, irrespective of whether ewes received progesterone pretreatment. However, the number of non-GnRH-immunopositive cells activated during the surge was significantly (p < 0.0001) increased in ewes that received the progesterone pretreatment. By contrast, the proportion of GnRH neurons and non-GnRH-immunopositive cells that expressed Fos was significantly (p < 0.0001) reduced in ewes in which the surge was inhibited by progesterone compared to ewes in which a surge was stimulated. These data indicate that (1) progesterone pretreatment increases the activation of non-GnRH cells during the estradiol-induced surge, but does not affect the proportion of GnRH neurons activated and (2) when administered concurrently with a surge-inducing estradiol increment, progesterone prevents the activation of GnRH neurons and non-GnRH cells that is normally associated with the estradiol-induced surge. Therefore, progesterone does not appear to augment the GnRH surge by increasing the proportion of GnRH neurons that are activated by estradiol, whereas inhibition of the GnRH surge involves prevention of the activation of GnRH neurons. Thus, the augmentation and inhibition of the GnRH surge by progesterone appear to be regulated via different effects on the GnRH neurosecretory system.

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

“…P blocks the E 2 -induced LH surge at both the early follicular phase and the early luteal phase in rhesus monkeys with gonadal-axes intact (19). 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).…”

Progesterone Blocks the Estradiol-Stimulated Luteinizing Hormone Surge by Disrupting Activation in Response to a Stimulatory Estradiol Signal in the Ewe1

“…In addition, studies of the effects of progesterone on estradiolinduced expression of the protein product of the immediateearly gene, c-fos, which is believed to be involved in the regulation of transcription in several neuronal systems [38], also support this idea. For example, the increase in Fos expression in GnRH and non-GnRH cells that is normally observed when a GnRH surge is induced by estradiol, is absent from rats and ewes that have been treated with progesterone to prevent activation of the surge [39,40].…”

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

“…Investigations of the neural mechanisms through which oestradiol acts within the hypothalamus to regulate reproduction in the ewe has led to differentiation of the GnRH/LH surge‐induction process into three stages, the absolute durations of which vary between breeds of sheep (3–6): (i) ‘activation’ (during which oestradiol concentrations must be elevated) is the stage during which oestradiol‐receptive neurones within the anteromedial hypothalamus are activated; (ii) ‘transmission’ (oestradiol‐independent) is the stage during which the activational oestradiol signal is transmitted from oestradiol‐receptive cells to GnRH‐releasing neurones; and (iii) ‘surge’ (oestradiol‐independent) is the stage during which the release of GnRH peptide into the pituitary portal vasculature increases dramatically (6, 7),…”

“…Oestradiol positive feedback, in the ewe, can be blocked by high circulating concentrations of progesterone (11), which normally occur during the luteal phase of the oestrous cycle. Investigations of the efficacy of progesterone to block the surge, relative to the three stages of the surge‐induction process outlined above, have demonstrated that progesterone can block the surge if it is administered either coincident with (6) or immediately after (4) the stimulatory oestradiol signal (i.e. during either the activation or transmission stages of the surge‐induction process).…”

“…Previous work has demonstrated that the administration of progesterone at the same time as the surge‐inducing oestradiol signal prevents the activation of GnRH neurones, as well as non‐GnRH‐immunoreactive cells, within the hypothalamus at the time of the LH surge (6), but where within the brain progesterone acts to block the oestradiol‐induced GnRH/LH surge is unclear. As is the case for oestradiol, the actions of progesterone on GnRH secretion are likely indirect in the ewe, because ovine GnRH neurones do not express progesterone receptors (12).…”