Effects of a novel gonadotropin-releasing hormone antagonist (ORG 30850) on gonadotropin and prolactin secretion by rat pituitary cells in culture

Abstract

The effect of a new GnRH antagonist (ORG 30850 ANT) on FSH, LH, and PRL secretion was studied using male rat pituitary cells in monolayer cell culture. In the absence of GnRH, ORG 30850 ANT did not alter spontaneous FSH and LH secretion into culture medium or the cell content of these hormones. In the presence of GnRH (10\m=-\8mol/l), ORG 30850 ANT significantly and dose-dependently inhibited FSH and LH secretion into culture medium while increasing their cell content. Conversely, in the presence of a single dose of ORG 30850 ANT, FSH and LH secretion rose significantly when subjected to increasing amounts of GnRH, whereas the hormonal cell content diminished. Furthermore, inhibition of GnRH-induced FSH and LH release by ORG 30850 ANT was not changed by pre-incubation with the GnRH antagonist regardless of the pre-incubation time. The inhibitory effect of the GnRH antagonist was observed early, with its peak occurring within 6 h of culture. These short-term studies indicate that ORG 30850 ANT specifically inhibits GnRH-induced gonadotropin release into culture medium, exerts no effect on the rate of gonadotropin production in the presence or absence of GnRH, competitively and reversibly inhibits the binding of natural GnRH to its receptors, and does not lead to any modifications in PRL secretion.The use of GnRH agonists and antagonists consti¬ tutes a new therapeutic approach in the manage¬ ment of conditions and diseases for which FSH and LH inhibition is desirable, such as precocious pu¬ berty, endometriosis, menopause and, most important, hormone-dependent neoplasias, including prostate, mammary, ovarian, and testicular carci¬ nomas. These nonsteroidal hormonal compounds have also been proposed as a new means of con¬ traception. GnRH agonists are known to inhibit FSH and LH secretion after a more or less pro¬ longed period of time during which hyperstimulation of gonadotropins may lead to a flair up of disease symptoms (1-3). Furthermore, inhibition of spermatogenesis obtained with GnRH agonists in male subjects is incomplete (4,5). By contrast, GnRH antagonists, which directly inhibit gonado¬ tropin secretion without an initial period of stim¬ ulation, appear to be a better alternative.Several substances were proposed, including the Nal-Lys and the Nal-Glu GnRH antagonist (6-8). These compounds were able to suppress serum LH release to undetectable levels and induce azoospermia in both rats and primates (9-11). However, the potency and tolerance of these substances could be improved. In this study, we therefore investigate the action of a new GnRH antagonist (ORG 30850 ANT: Oss, The Netherlands) on gonadotropin and PRL secretion by rat pituitary cells in monolayer culture. The latter hormone was investigated to assess the spec¬ ificity of the antagonist at the gonadotropin level.