The Selectivity of a New Progestin

Abstract

Norgestimate is a new progestin developed for use with ethinyl estradiol as a combination oral contraceptive. It binds to rabbit uterine progestational receptors and in the oral form stimulates a progestational endometrial effect in rabbits. Norgestimate also exerts a direct effect on target organs, stimulating the endometrium in rabbits when injected directly into the uterine horn and inhibiting luteinizing hormone release from rat pituitary cells in culture. Like other progestins, norgestimate inhibits ovulation in several species and estrogen-induced vaginal cornification in ovariectomized rats, but it is not estrogenic. Unlike other progestins, including levonorgestrel and gestodene, norgestimate is relatively free of androgenic activity. Norgestimate's affinity for the androgen receptor is very poor (0.003 x dihydrotestosterone [DHT]), even poorer than that of progesterone (0.005 x DHT). In sharp contrast are the marked affinities of levonorgestrel (0.220 x DHT) and gestodene (0.154 x DHT) for that receptor. The selectivity of norgestimate at receptor level is demonstrated clearly by its highly favorable androgen-to-progestin binding ratio. Norgestimate is similar to progesterone in not significantly stimulating ventral prostate growth in immature rats, whereas levonorgestrel, gestodene, and desogestrel are significantly androgenic in this model. Further evidence of norgestimate's minimal androgenicity is its lack of affinity for human sex hormone binding globulin in vitro. In conclusion, these preclinical studies, consistent with clinical studies, demonstrate the progestational efficacy and selectivity of norgestimate.