A Comprehensive Monograph on Norethisterone (DB00717)

Executive Summary

Norethisterone, also known as norethindrone, is a synthetic small molecule progestin that has served as a cornerstone of gynecological and endocrine pharmacotherapy for over seven decades. First synthesized in 1951, its development marked a pivotal moment in medicine by providing the first orally active and potent progestational agent, a critical step that enabled the creation of hormonal contraceptives. Chemically classified as a second-generation, 19-nortestosterone (estrane) derivative, its structure confers high progestational activity and oral bioavailability, but also accounts for its secondary hormonal effects.

The primary mechanism of action of Norethisterone is potent agonism of the progesterone receptor (PR), with a binding affinity approximately 150% that of endogenous progesterone. This activity underlies its therapeutic effects, including ovulation inhibition, endometrial transformation, and stabilization of the uterine lining. Pharmacodynamically, Norethisterone exhibits a complex profile; it is also a weak agonist of the androgen receptor (AR) and possesses indirect estrogenic activity through hepatic metabolism to the potent estrogen, ethinylestradiol. This metabolic conversion is a key determinant of its dose-dependent effects, with the drug acting as a pure progestin at low contraceptive doses and as a de facto combination hormone therapy at higher therapeutic doses, a distinction with significant clinical implications for its safety profile.

Pharmacokinetically, Norethisterone is characterized by rapid oral absorption and extensive hepatic metabolism, with a mean elimination half-life of approximately 8 hours. Notably, there is significant inter-individual variability in its bioavailability and clearance, which can influence both efficacy and the incidence of side effects.