In Vivo and In Vitro Investigation of the Extrapituitary Antireproductive Effects of a Potent LHRH Agonist in Immature and Adult Male Rats

¹ Endocrinology Section, Wyeth Laboratories, Inc., Philadelphia, Pennsylvania

Co-incubation with a potent LHRH agonist, D-Ala⁶-Des-Gly¹⁰-Pro⁹-NHEt-LHRH (Wy-18,481), did not affect testosterone or progesterone production by adult intact rat testes in vitro. Prior administration to adult intact rats in vivo (100 µg/rat/day, subcutaneously) reduced subsequent basal and hCG-stimulated testosterone production in vitro and dramatically increased progesterone production. Similar chronic administration of the agonist in vivo to adult hypophysectomized (hypx) rats also depressed testosterone production in vitro but had no effect on that of progesterone. Using dosages which produce marked inhibition of the weights of the testes and of accessory reproductive glands in both immature and adult intact rats, long-term (up to 28 days) treatment with Wy-18,481 slightly potentiated the atrophy of the testes and of the seminal vesicles due to hypophysectomy in the immature rat but had no apparent effect in the hypx adult. Concurrent administration of Wy-18,481 did not affect the support provided to the reproductive organs by dihydrotestosterone replacement in either immature or adult hypx rats. These results suggest that extended exposure is required to elicit direct effects of the agonist on testicular function and that these effects, which involve interference with steroidogenesis and not steroid action, differ qualitatively in the hypx animals from those occurring in the presence of the pituitary. Moreover, there appears to be an age-related difference in sensitivity to the direct effect of the agonist.

     Key words: LHRH agonist, extrapituitary reproductive effects, age-dependency, hypophysectomy, testicular function in vitro and in vivo, dihydrotestosterone, male contraception

Submitted on September 3, 1980
Revised on October 28, 1980
Accepted on November 10, 1980