Effects of modifying gonadotrophin-releasing hormone input before and after the oestrogen-induced LH surge in ovariectomized ewes with hypothalamo-pituitary disconnection

Abstract

The patterns of gonadotrophin-releasing hormone (GnRH) input to the pituitary gland that affect the expression of a positive-feedback event by oestrogen on LH secretion were investigated in ovariectomized ewes with hypothalamo-pituitary disconnection (HPD). In experiment 1, ovariectomized HPD ewes were given hourly i.v. pulses of 250 ng GnRH and an i.m. injection of 50 micrograms oestradiol benzoate (OB). The ewes were given a bolus pulse of 2.25 micrograms GnRH 16 h after injection of OB, followed by half-hourly pulses of 250 ng GnRH for 14 h (treatment A). The LH surge response was significantly (P less than 0.05) greater in these ewes compared with that in ewes given a continuous infusion of GnRH (250 ng/h) after the OB injection, followed by a continuous infusion of 500 ng GnRH/h after the bolus pulse of GnRH (treatment B). When no GnRH was administered after the OB injection, except for the bolus pulse of GnRH (treatment C), the surge response was significantly (P less than 0.05) reduced compared with that in treatment A, and was reduced compared with treatment B. These data suggest that GnRH pulses are important in the generation of the OB-induced LH surge, but that a baseline secretory component can prime the pituitary to some extent. In experiment 2, a doubling of the continuous infusion dose of GnRH used in treatment B to 500 ng/h before the bolus pulse of GnRH and to 1 micrograms/h afterwards (treatment D) gave a similar response compared with treatment A, suggesting that if the baseline input of GnRH is of sufficient magnitude, it can overcome the lack of pulsatile input. In experiment 3, halving the GnRH pulse amplitude used in treatment A from 250 to 125 ng (treatment E) did not reduce the LH surge response, implying that when the GnRH input is in a pulsatile mode, the amplitude of GnRH pulses is less important than the pulsatile nature per se. In experiment 4, removal of GnRH input after the bolus pulse of GnRH (treatment F) significantly (P less than 0.05) reduced the surge response compared with when pulses were maintained (treatment A), indicating that GnRH input is still required once the LH surge has been initiated. Collectively, these experiments show that several forms of GnRH delivery, both pulsatile and baseline, can result in the full expression of a positive-feedback response in ovariectomized ewes treated with oestrogen.

Gonadotropin-Releasing Hormone Requirements for Ovulation1

“…This study, and others using complementary approaches [47,[50][51][52], suggest that the hypothalamic signal for the LH surge in the ewe consists of a sudden increase in GnRH secretion. Combining these observations with results of the GnRH antagonist study (Fig.…”

“…Numerous studies have addressed the amount of GnRH needed to produce an LH surge in sheep [27,47,[50][51][52].…”

“…Blockade of the endogenous GnRH stimulus was achieved in one of a number of ways including surgical disconnection of the hypothalamus from the pituitary [50,51], immunoneutralization of GnRH [47], and hormonal [27] or pharmacological [52] inhibition of GnRH release. A common theme has emerged from all of these studies: an abrupt and sustained increase is an essential component of the GnRH signal for the LH surge.…”

Is GnRH Reduced at the Midcycle Surge in the Human?

“…This approach is possible because GnRH is the only known secretagogue for LH, GnRH and its antagonist bind to a single receptor type, and there has been no demonstration of changes in GnRH receptor affinity over a wide range of physiological and pharmacological conditions [38]. It is been shown in animal models that the GnRH receptor density is increased at the time of the midcycle surge [39, 40, 41], and it is also hypothesized that there is postreceptor amplification of the GnRH signal [4]. Any such changes in the human which are not accounted for by expression of the data in relation to baseline would be expected to result in less LH inhibition at the surge in contrast to the increased inhibition demonstrated [28].…”

A Transient Effect of Estrogen on Calcium Currents and Electrophysiological Responses to Gonadotropin-Releasing Hormone in Ovine Gonadotropes

“…In this model, a single intramuscular injection of E2 resulted in an initial inhibition of the response to GnRH, followed by a period of enhanced response. Appropriate manipulation of the GnRH input can produce a full LH surge in this model [19,20], The time-delayed increase in responsiveness to GnRH following E2 injection is thought to represent part of the mechanism of the preovulatory LH surge. Although the change in GnRH-induced LH release is biphasic, a simple increase in GnRH receptor number occurs throughout the response to E2, even when LH secretion in response to GnRH is reduced [21], These data suggest that the action of E2 to cause enhanced responsivity to GnRH at the start of the LH surge is due to modification of the transduction pathways distal to the GnRH receptor.…”