Pharmacodynamics of gonadotropin-releasing hormone. 1. Effects of gonadotropin-releasing hormone pulse contour on pituitary luteinizing hormone secretion in vivo in sheep

The gonadotropin-releasing hormone (GnRH) waveform arrives at the pituitary gonadotropes via the pituitary portal blood and provides the immediate suprapituitary stimulus to luteinizing hormone (LH) secretion. Despite their importance, nature and influence of the physiological GnRH waveform in vivo have been difficult to study. Recent pharmacological and in vitro studies have suggested the potential importance of the wave contour as a specific and independent factor in the pharmacodynamic effects of GnRH on pituitary gonadotrope LH secretion in vivo, and it has been hypothesized that the steepness of the rising edge of the GnRH wave contour is a specific determinant of pituitary LH secretion. In order to investigate the pharmacodynamic influence of GnRH pulse wave contour on pituitary LH secretion in vivo, variations in plasma LH responses to alterations in GnRH wave contour were measured in chronic ovariectomized, hypothalamopituitary-disconnected sheep undergoing physiological pulsatile GnRH maintenance regimen at a fixed dose (250 ng/pulse) and frequency (interpulse interval 120 min). Variable wave contours were then generated by administration of the same total GnRH pulse dose over various lengths of time from near-instantaneous bolus to increasing lengths of constant-rate infusion time up to 8 min. This model allowed specific examination of pulse wave contour in the absence of concurrent changes in endogenous GnRH or sex steroid secretion and holding constant GnRH pulse dose, frequency, and route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)