Biology of Reproduction, Vol 24, 889-901, Copyright © 1981 by Society for the Study of Reproduction

Relative Importance of the Adenohypophyseal and Gonadal Sites of Inhibitory Action of LHRH Agonists

¹ Medical Research Council Group in Molecular Endocrinology, Le Centre Hospitalier de l'Université Laval, Québec G1V 4G2, Canada

Assessment of the role of endogenous LH release and direct gonadal action of LHRH agonists in the loss of gonadal LH receptors induced by treatment with gonadotropin-releasing peptides was first made by comparing the effect of single administration of 1 µg of [D-Ala⁶, des-Gly-NH₂¹⁰]-LHRH ethylamide, [D-Ala⁶] LHRH-EA, 12 h before or immediately after hypophysectomy (HYPOX) on LH receptor levels measured 48 h after surgery in male and female adult rats. While administration of the LHRH agonist before HYPOX leads to a 50% loss of testicular LH receptors, only a 20% decrease is seen in HYPOX animals, thus suggesting a predominant role of endogenous LH release in the desensitization process in male animals. Treatment with increasing doses (1 to 100 ng/day) of another LHRH agonist, [D-Ser(TBU)⁴] LHRH-EA, causes a 90% loss of testicular LH receptors in intact rats at the highest dose used (100 ng daily for 9 days) while the same treatment decreases LH receptors by only 35% in HYPOX animals. As measured by the steroidogenic response to 10 µg oLH in vivo, while treatment of intact animals with [D-Ser(TBU)⁶] LHRH-EA leads to a marked blockage of the testicular steroidogenic pathway at the level of 17-hydroxylase and 17,20-desmolase activities with a corresponding increase of 5-reductase activity, minimal or no signs of changes of enzymatic activity are seen after identical treatment in HYPOX animals. Chronic treatment (1 month) with the LHRH agonist in intact rats leads to degenerative changes of the seminiferous tubules, while no effect is observed in HYPOX animals, thus suggesting the essential role of the pituitary gland. Moreover, adrenalectomy does not influence the inhibitory effect of treatment with LHRH agonists on the loss of testicular LH receptors in HYPOX animals, thus eliminating the role of the adrenals in the action of LHRH agonists. Contrary to the results obtained in male animals, single administration of the LHRH agonist in female rats has similar inhibitory effects on ovarian gonadotropin receptors when administered either before or after hypophysectomy. Moreover, treatment with increasing doses of [D-Ser(TBU)⁶] LHRH-EA leads to a similar inhibition of ovarian LH receptor levels in intact and HYPOX female animals. The present data show that LHRH agonist-induced endogenous LH release plays a predominant role in the desensitizing effect of treatment with LHRH agonists on testicular LH receptors and steroidogenesis as well as on inhibition of spermatogenesis; in the female, the direct gonadal effect, at least on LH and FSH receptors, appears to play a more important role than in male animals.

Note:
ACKNOWLEDGMENTS F. L. is an associate of the Medical Research Council of Canada. This study was supported by a grant from the Medical Research Council of Canada.