Effect of prolonged exposure to oestradiol on subsequent LH secretion in ewes

Abnormal follicles can produce oestradiol continuously for up to 20 days and this inhibits the hypothalamic-pituitary axis. The present experimental series was designed to determine the minimum exposure to high or low follicular phase concentrations of oestradiol that were required to exert inhibitory effects on LH surge secretion induced by additional oestradiol administered at the end of continuous exposure to oestradiol. Experiments were also included to establish whether the inhibitory effects of prolonged oestradiol were mediated at the pituitary, and whether the failure of response to the oestradiol challenge could be corrected by exposure to normal luteal phase patterns of progesterone. Treatment of ewes between 2 and 12 days with 1, 2 or 4 oestradiol implants (3 cm) totally blocked the subsequent normal LH surge in response to an oestradiol challenge in 45 of 52 ewes pretreated with oestradiol. In the seven ewes that did have an increase in LH, the response occurred at the expected time but was greatly reduced (14 versus 40 ng ml-1), and occurred only in ewes pretreated with oestradiol implants for 2 or 4 days. We were unable to establish a robust linear time-dose relationship, i.e., when ewes were treated with lower doses of oestradiol (one or two implants) for a reduced time (2, 4 or 8 days), there was random distribution of the 7 of 32 animals that had a reduced LH surge after oestradiol challenge (with four implants or 50 micrograms injection). The present study is the first to show that exposure for only 2-4 days to continuous oestradiol at late follicular phase concentrations can disrupt LH surge release. However, in oestradiol-treated ewes, LH secretion was provoked by high or low doses (0.5 mg or 0.5 microgram) of GnRH, although it was reduced by 50%, and a GnRH self-priming effect was still evident. All of these results suggest that inhibitory effects occur at the pituitary and hypothalamus. It remains to be confirmed whether the major effect is at the pituitary by reducing GnRH receptor or LH synthesis, or at the hypothalamus via inhibition of GnRH secretion.