Progesterone Priming Is Essential for the Full Expression of the Positive Feedback Effect of Estradiol in Inducing the Preovulatory Gonadotropin-Releasing Hormone Surge in the Ewe

Abstract

The luteal phase elevation in circulating progesterone (P) powerfully inhibits GnRH and, consequently, LH release, thereby preventing premature preovulatory LH surges in the ewe. Whether luteal phase P modulates the response of the GnRH system to the positive feedback effect of estradiol is unknown. To investigate this possibility, two experiments were conducted during the anestrous season using an artificial model of the follicular phase in ovariectomized ewes bearing 10-mm s.c. 17beta-estradiol SILASTIC brand implants (Dow Coming Corp.). In Exp 1, ewes (n = 10) were run through four successive artificial cycles during which a luteal phase level of P was either replaced (cycles 1 and 3) or not replaced (cycles 2 and 4). GnRH and LH secretions were monitored by sampling cerebrospinal fluid (CSF) and jugular blood from 10-35 h after four 30-mm 17beta-estradiol SILASTIC implants were inserted sc. CSF could be collected from only four ewes over the four cycles. There was no P-dependent difference in the onset of the GnRH and LH surges, which may have been due to a progressive delay in the surge onsets over the four cycles (by ANOVA, P < 0.05). Due to this delay, it was not possible to obtain an accurate estimate of the duration of the GnRH and LH surges in all ewes, but the size of the GnRH surge was always greater when animals had been treated with P, resulting in a significant increase in the maximum (P < 0.01) and mean (P < 0.05) levels during the surge. In contrast, there was no effect on any parameter of LH secretion. In Exp 2, ewes (n = 10) were run through two artificial estrous cycles during which luteal phase P was either replaced or not replaced, using a cross-over experimental design. CSF was collected from seven ewes over the two cycles. GnRH and LH secretions were monitored from 10-53 h after estradiol administration. As in Exp 1, a clear significant increase in the maximal and mean GnRH levels (P < 0.05 for both) was observed during the surge when ewes had been pretreated with P. Again, no changes were observed in LH release during the surge. P priming did, however, delay the onsets of the GnRH (P < 0.01) and LH surges (P < 0.01). Our data show that the increase in P during the luteal phase of the estrous cycle is essential for the full expression of the positive feedback effect of estradiol in inducing the preovulatory GnRH surge in the ewe.

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

“…A fourth group (NC; n = 7) was pretreated with progesterone, but did not receive an estradiol increment. Based on previous reports [1, 13], GnRH surges were expected in the –P (normal amplitude) and +P (enhanced amplitude) groups but were not expected in the PB (activation of the surge blocked) and NC (no stimulatory estradiol signal) groups. The experimental protocol is summarized in figure 1.…”

“…Therefore, the onset of the LH surge was used as a marker of the start of the GnRH surge. Treating ewes with luteal phase concentrations of progesterone prior to the stimulation of a GnRH/LH surge with estradiol enhances the amplitude and delays the onset of the GnRH surge [13, 36]. We used the delay of the LH surge onset to indicate that the stimulatory progesterone treatment was effective.…”

“…The first aim was to determine how activation of GnRH neurons is affected by a progesterone treatment regime that has been reported to increase the amplitude of the GnRH surge [13]. Therefore, the levels of cellular activation in the hypothalami of the NC, –P and +P groups were compared.…”

“…By contrast, elevations in peripheral estradiol concentrations that accompany follicular growth during the luteal phase are unable to stimulate a GnRH/LH surge, despite being of sufficient magnitude, due to the presence of elevated progesterone concentrations [10, 11, 12]. However, exposure to progesterone prior to an independent increase in estradiol, such as occurs during the natural follicular phase, has been reported to augment the GnRH surge in ewes [13]. …”

Progesterone improves the maturation of male-induced preovulatory follicles in anoestrous ewes

“…Besides, hormonal assay in blood samples clearly indicated that progesterone had completely cleared before male introduction. Secondly, the differences found in our study might be due to exposure of the gonadotrophin-releasing hormone (GnRH) system to powerful inhibitory effect of progesterone (Caraty & Skinner 1999). According to this hypothesis, following CIDR removal, the response of the hypothalamuspituitary axis to the stimulatory signals of males might be delayed, resulting in a slow follicular growth rate and a late LH surge.…”