Norethisterone

Norethisterone is a progestogen medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological conditions. The drug is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or by injection into the muscle.

Pharmacodynamics

Progestins act by binding to progesterone receptors on the cell membrane or inside the cell (intracellular). The intracellular receptors bind to the DNA of the cell after contact with a progestin and thus regulate protein expression. Norethisterone binds mainly to receptors in the uterus. Binding to these receptors slows the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This process leads to suppression of the normal physiological rise in luteinizing hormone (LH) that precedes ovulation. It inhibits follicular rupture and the release of viable eggs from the ovaries.

Pharmacokinetics

Norethisterone is rapidly absorbed and reaches maximum plasma concentration after 1-2 hours. Plasma protein binding is 99%. Metabolism occurs in the liver by the enzymes α- and 3β-hydroxysteroid dehydrogenase and 5α- and 5β-reductase and also to some extent by the enzymes of the CYP450 system. Excretion is 50% in the urine and 50% in the stool. The half-life is 8-10 hours.

Interactions

5α-Reductase inhibitors such as finasteride and dutasteride may inhibit the metabolism of norethisterone. Norethisterone is metabolized in part via hydroxylation by CYP3A4, and inhibitors and inducers of CYP3A4 may significantly alter circulating levels of norethisterone. The CYP3A4 inhibitors rifampicin and bosentan slow the breakdown of norethisterone, while the CYP3A4 inducers carbamazepine and St. John's wort accelerate norethisterone clearance.

Side effects

Side effects of Norethisterone include menstrual irregularities, headache, nausea, breast tenderness, mood swings, acne, and increased hair growth. It has weak androgenic and estrogenic activity, especially at high doses.

Toxicological data

LD50 (mouse, oral): > 6000 mg-kg-1