Norethisterone (Norethindrone) — Drug Profile
Class: Synthetic progestogen; a 19-nortestosterone (estrane) derivative. Related compounds (norethisterone acetate, lynestrenol, ethynodiol diacetate, norethynodrel) are all metabolized to norethisterone before becoming biologically active - Park's Textbook of Preventive and Social Medicine, p. (Gonadal steroids section).
Mechanism of action
- Binds progesterone receptors -> suppresses the LH surge and inhibits ovulation
- Thickens cervical mucus (impairs sperm penetration)
- Induces endometrial changes unfavorable to implantation
- Also carries notable intrinsic androgenic activity and weak estrogenic/anabolic activity, which accounts for several of its side effects - Langman's Medical Embryology.
Formulations and uses
- Oral contraceptives: combined with ethinylestradiol (e.g., 0.035 mg EE + 1 mg norethisterone) or as norethisterone acetate in various combined pill brands (e.g., Loestrin) - Park's Textbook, Table 20.
- Progestogen-only tablets: 5 mg tablets used for contraception and for menstrual disorders.
- Injectable depot: Norethisterone enantate (NET-EN), 200 mg IM every 60 days - a progestogen-only injectable contraceptive in use since 1966, though less widely used than DMPA - Park's Textbook, "NET-EN" section.
- Menstrual disorders: dysfunctional/heavy uterine bleeding, endometriosis-related pain (often combined with an aromatase inhibitor such as letrozole), dysmenorrhea, and to delay menstruation.
- Hormone replacement therapy: combined with estrogen (e.g., estradiol) in postmenopausal women to provide endometrial protection against unopposed estrogen.
Adverse effects
- Androgenic effects: acne, hirsutism, weight gain, voice changes
- Risk of masculinization of a female fetus if taken inadvertently in early pregnancy (clitoromegaly, labial fusion) due to androgenic potency - Langman's Medical Embryology
- Breakthrough bleeding/spotting, headache, mood changes, breast tenderness
- Mild adverse lipid profile changes; small increase in venous thromboembolism risk (lower than estrogen-containing preparations)
Contraindications
- Confirmed or suspected pregnancy
- Undiagnosed abnormal vaginal bleeding
- Active or past hormone-sensitive breast cancer
- Active thromboembolic disease or severe liver disease
Recent evidence check: A 2025 meta-analysis of RCTs found that 17β-estradiol plus norethisterone acetate therapy in postmenopausal women alters estradiol, testosterone, IGF-1, and SHBG levels compared with estradiol alone (Qian et al., Hormone and Metabolic Research, 2025, PMID: 40049226) - relevant if you're using norethisterone in an HRT context, as it may modestly affect androgen/SHBG balance. This doesn't contradict standard textbook teaching but adds a quantitative dimension worth noting for HRT counseling.
Let me know if you'd like a deeper dive into any specific angle - e.g., contraceptive regimens, use in endometriosis, or comparison with other progestins.