Abstract

PIP: The numerous studies of norethisterone, alone or combined with ethinyl estradiol, conducted since it came into use in the 1st oral contraceptives (OCs) over 2 decades ago, are described. Inhibition of ovulation is the principal mechanism of action of all current OCs. Administered orally, norethisterone has an ovulation blocking effect 11 to 25 times more potent than levonorgestrel and medroxyprogesterone acetate respectively. Norethisterone and progesterone have equal antiovulatory potency intramuscularly. The cervical mucus of women using OCs containing norethisterone resembles the luteal phase mucus which is hostile to the penetration of sperm. Norethisterone binds to progesterone receptors as readily as doses progesterone, and is active in the classic in vivo assay which measures progestational activity by endometrial stimulation in prepubertal rabbits. Norethisterone, like natural progesterone, maintains pregnancy in ovariectomized rats. It has been agreed for some time that the risk of deleterious effects on lipid metabolism, acne, and other undesirable effects of progestins is proportional to their androgenic activity. The androgenic potency of norethisterone is .008 and that of levonorgestrel is .12 times that of the standard, methyltestosterone. Norethisterone doses required to produce an androgenic reaction in laboratory testing are very high. It can be concluded that at clinical doses, norethisterone has hardly any androgenic effect. Standard bioassays at use levels indicate that norethisterone lacks estrogenic activity, and the same result is obtained in in vitro tests of binding to estrogen receptors. Norethisterone apparently does not modify the serum levels of sex hormone binding globulin (SHBG). In vitro studies have shown that the capacity of norethisterone to bind to SHBG is greater than that of progesterone but less than that of levonorgestrel. In vitro tests in rats demonstrate that norethisterone has an antiestrogenic action 5 times greater than that of progesterone. Norethisterone passes rapidly into the general circulation, attaining maximum plasma concentrations in 1-2 hours. Plasma concentrations vary depending on dose. Oral administration of 1 mg of norethisterone gives plasma levels of 7-30 mcg/ml. About 70% of the dose is abosrbed. 40-50% of the norethisterone administered is excreted in the urine, principally in the form of metabolites, and 20-40% is excreted in the bowel movements. Norethisterone alone or combined with estrogens has been found in longterm studies to have minimal toxic effect.