Post-Coital Contraceptive Effects of an Agonistic Analogue of Luteinizing Hormone Releasing Hormone

Abstract

An analogue of synthetic hypothalamic LRH, D-[ALA]6-DES-[GLY]10-PRO9-ethylamide-LRH (Wy-18,481) was evaluated for agonistic (in vivo LH-releasing and ovulation-inducing), post-coital contraceptive and reproductive target organ effects. Both LRH and the analogue terminated pregnancy; there appeared to be a direct relationship between agonistic and post-coital contraceptive potency and activity. The analogue proved to be a potent agonist and both a pre-and post-implantational post-coital anti-fertility agent. In contrast to LRH, the congener did not produce a uterotrophic effect in the hypophysectomized rat. The data suggest that agonist analogue(s) of LRH can terminate pregnancy via hyperstimulation of the pituitary-ovarian-reproductive complex and the use of members of this neurohormonal class as potential clinical pro-fertility agents should be weighted with caution.

Peptide Contraception: Antifertility Properties of LH‐RH Analogues

“…Other studies revealed that if such agonist-treated animals with identifiable resorption sites are permitted to term (day [22][23][24], total resorption will have occurred (15). The collective data herein reported, reinforced by studies employing other agonists (14), clearly attest to the antipregnancy properties of this peptide class, fortify the agonist/postcoital contraceptive relationship, and stress that the greater the agonist property, the greater the antifertility property.…”

“…There was much aspiration for its potential value in correcting gynec o p a t h y and andropathic states, thus stimulating an ambitious endeavor to synthesize more potent and longer acting congeners (26,27). In spite of the considerable success achieved in generating these highly potent LH-releasing analogues, additional testing undoubtedly confirmed the antireproductive nature of this class of compounds, and further corroborated the direct relationship to their agonist properties (14,15). T h e various hormonal and receptor studies begin to explain the mechanisms by which the excessive and inappropriate hypophysial stimulation fraught by the "super" analogues is injurious to the reproductive integrity of the animal, be it female or male, immature or mature, and why, in a considerable number of clinical studies, the analogues are truly incapable of significantly ameliorating or reversing the infertile or hypogonadal state (15).…”

“…Fig. 9 shows the structure of two highly potent agonists (Wy-18,481 and Wy-40,972) which have received our considerable attention in establishing the reproductive pharmacologic profile of this class of peptides (14)(15)(16). Preliminary testing established the standard agonist properties of these compounds: ovulation induction via various routes of administration in the nembutalized, proestrous rat (Figs.…”

“…More importantly, this report will review studies supporting the antireproductive profile of the "super" agonists, as a special class of L H -R H derivatives, exemplified by the analogues, Wy-18,481 (D-Ala 6 des-Gly 10 -Pro 9 -LH-RH ethylamide) (16,17) and Wy-40,972 (D-Trp 6 -N-Me-Leu 7 -des-Gly 10 -Pro 9 -L H -R H ethylamide) (15) and the clinical relevance of this genre of peptide. A generalized scheme is presented in Fig.…”

Vaginal Absorption of a Potent Luteinizing Hormone-Releasing Hormone Analogue (Leuprolide) in Rats IV: Evaluation of the Vaginal Absorption and Gonadotropin Responses by Radioimmunoassay

“…Recently, multiple high doses of leuprolide were found to effect regression of hormone-dependent mammary tumors (3,4) and to have birth control potential in both sexes (5)(6)(7)(8).…”