Inhibitory Effect of a Highly Potent Antagonist of LH Releasing Hormone (SB-75) on the Pituitary Gonadal Axis in the Intact and Castrated Rat

Abstract

The biological potency of the new, highly potent antagonist [AC-D-Nal (2)¹, E-Phe(4Cl)², D-Pal(3)³, E > -Cit⁶, D-Ala¹⁰] LH-RH (SB-75) on the pituitary-gonadal system of female castrated and intact ovulating rats was tested. Administration of a single dose (50-100 µg/kg BW) of the antagonist SB-75 inhibited effectively the elevated gonadotrophin levels for 48 h. Pituitary LH and FSH content was not affected by SB-75 treatment. When administered in the early afternoon of the proestrus to intact cycling rats, SB-75 blocked the preovulatory LH surge as well as the primary and secondary FSH surges. However, the secondary FSH surge was not affected by SB-75 treatment when administered on the evening of proestrus suggesting its independence from the LH-RH mechanism. A group of ovariectomized rats was chronically treated with D-Trp⁶-LH-RH after having been pretreated by administration of a single dose of the antagonist. The initial stimulatory release of LH and FSH initiated by injection of the LH-RH agonist was significantly reduced by pretreatment with the LH-RH antagonist. We conclude that the LH-RH antagonist SB-75 may be used effectively in the field of reproductive dysfunction and endocrinological oncology and may become an invaluable physiological probe in studying the hormonal dynamics of the reproductive endocrine axis.