Norgestimate. From the laboratory to three clinical indications

This review of preclinical studies and clinical trials of efficacy and safety examines the relation between structure and function in the norgestimate (NGM) molecule, describes the pharmacologic characteristics of NGM and evaluates clinical experience with NGM in oral contraception (OC), treatment of hyperandrogenism in women and hormonal replacement therapy (HRT). NGM is a progestin of the 19-norsteroid series with an oxime group on C-3. In women, only low serum levels of NGM can be detected for five hours after ingestion. NGM is swiftly converted into its main metabolite, the 17-deacetylated norgestimate (norelgestromin), which carries the progestogenic properties of NGM. The metabolite reaches a mean peak concentration of 3,500 pg/mL 1.5 hours after intake and has a half-life of > 24 hours. The progestogenic potency of NGM and its main metabolite is comparable to that of progesterone. The doses of NGM in OCs effectively inhibit ovulation and control uterine bleeding. In the triphasic NGM/ethinyl estradiol (EE) OC, the total monthly load of progestin is only 4.5 mg. NGM has a low androgenic impact and does not interfere with the positive metabolic actions of estrogens, notably the estrogen-induced increase in high-density lipoprotein levels. OCs with NGM and EE increase the serum concentration of sex hormone binding globulin threefold, augmenting the binding of circulating testosterone and reducing free testosterone levels by 50%. Consequently, OCs with NGM are therapeutic for hyperandrogenic symptoms, such as acne. In a new type of HRT three-day dosing with 17 beta-estradiol (E2) alone is followed by three-day dosing with E2 plus NGM. This regimen treats vasomotor symptoms, protects the endometrium from hyperproliferation and is associated with a favorable lipid profile. NGM is a versatile progestin suitable for medical use from adolescence through the reproductive years to menopause.