Dose response effects of pulsatile GnRH administration on restoration of pituitary GnRH receptors and pulsatile LH secretion during lactation

Ovariectomized (OVX) rats suckling 8 pups have a complete suppression of pulsatile LH secretion and a decrease in pituitary GnRH receptor (GnRH-R) content. Removing the suckling stimulus for 24 h results in a sharp increase in GnRH-R and a restoration of pulsatile LH secretion. These findings suggest that the suckling stimulus induces a suppression of GnRH secretion, and removal of the suckling stimulus permits the restoration of GnRH secretion. Indeed, if GnRH antiserum is injected at the time of pup removal, the restoration of pituitary GnRH-R and LH secretion is prevented. The present studies were designed to test our hypothesis that the deficits in pituitary gonadotroph function observed during lactation are due to suckling-induced suppression of GnRH. Exogenous GnRH was administered in a pulsatile regimen to OVX lactating rats on days 10 and 11 postpartum, and the effects on pituitary GnRH-R levels, pituitary sensitivity to GnRH, and pulsatile LH secretion were assessed. GnRH doses of 0, 0.5, 2.0 or 5.0 ng/pulse were administered every 50 min for 24 h beginning on day 10. Administration of 0.5 ng GnRH/pulse for 24 h increased GnRH-R from 35 ± 3 to 63 ± 8 fmol/pituitary. There was a clear GnRH dose-related upregulation of GnRH-R to approach nonsuckling levels (140-160 fmol/pituitary) with the 5 ng GnRH dose. At the beginning of GnRH administration, the pituitary was very unresponsive to GnRH. Consistent LH pulses were only observed with 5 ng GnRH/pulse. However, after 24 h of exposure to pulsatile GnRH, pituitary sensitivity was greatly enhanced; i.e. 2 ng GnRH/pulse, LH peak height increased from 9 ± 2 on day 10 to 27 ± 3 ng/ml on day 11; 5 ng GnRH/pulse, LH peak height increased from 29 ± 3 on day 10 to 69 ± 7 ng/ml on day 11. We conclude from these studies that (1) upregulation of GnRH-R occurs in response to small doses (0.5 ng/pulse) of GnRH which are not sufficient to stimulate LH secretion, (2) the increment of GnRH-R shows a proportional relationship to the GnRH dose given, (3) upregulation of GnRH-R increases pituitary sensitivity to GnRH, and (4) administration of pulsatile GnRH in the presence of the suckling stimulus and hyperprolactinemia can restore GnRH-R and pulsatile LH secretion. Furthermore, the present results support the hypothesis that the suckling stimulus induces a suppression in GnRH secretion which in turn decreases pituitary GnRH-R content, and, hence, decreases pituitary sensitivity to GnRH, so that plasma LH concentration is suppressed.