Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity

Abstract

Norgestimate is a novel progestin with highly selective progestational activity and minimal androgenicity. In rabbits, norgestimate binds to uterine progestin receptors, stimulates the endometrium, and inhibits ovulation. Norgestimate acts directly on target organs, stimulating rabbit endometrium when injected into the uterine cavity and inhibiting luteinizing hormone-releasing hormone-stimulated luteinizing hormone release in dispersed rat pituitary cells in culture. Norgestimate has no estrogenic activity, and like other progestins, it suppresses the action of estrogen. Unlike some other progestins, it is relatively free of androgenic activity. Norgestimate and its 17-deacetylated metabolite demonstrate very poor affinity for androgen receptors compared with levonorgestrel and gestodene and do not exhibit androgenic activity when measured as the stimulation of prostatic growth in immature rats. Norgestimate's lack of affinity for human sex hormone-binding globulin is further evidence of its minimal androgenicity.

PIP: The androgenic activity of progestins used in oral contraceptives (OCs) may be responsible for the adverse changes in lipid and lipoprotein metabolism, so researchers are continuing to work on developing progestins that reduce androgenicity. They have developed norgestimate (NGM) which is a progestin with improved selectivity. i.e., extent of maximization of progestational potency and minimization of androgenic potency. The receptor binding affinities of ngm and its major metabolite, 17-deacetylated norgestimate for the progestin receptor are on par with progesterone. Their binding affinities are only 0.003 and 0.013 times that of dihydrotestosterone, respectively, while the affinities for levonorgestrel and gestodene are 0.220 and 0.154 times that of dihydrotestosterone, respectively. They have almost no affinity for human sex hormone binding globulin (SHBG) in vitro. clinical research of 40 women using combined OCs with NGM and ethinyl estradiol over 4 cycles shows that NGM does not prevent estrogen-induced rises in SHBG levels indicating its minimal androgenicity. In addition, NGM successfully suppresses ovulation in rabbits, rats, hamsters, and mice by preventing the preovulatory rise of luteinizing hormone and, in rats, by targeting the hypothalamic/pituitary axis. NGM also allows rats and rabbits to effectively maintain pregnancy by stimulating the endometrium. It also has no estrogenic activity in vivo and does not bind to estrogen receptors in vitro. Specifically NGM prevents estrogen-induced vaginal cornification. These findings from various preclinical research and 1 clinical study demonstrate NGM to be a selective progestin which reduces androgenicity.