norethisterone
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norethisterone norethindrone clinical use
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norethisterone clinical uses doses pharmacology 2024 2025
Here is a comprehensive overview of norethisterone (norethindrone):
Norethisterone (Norethindrone)
Class and Structure
Norethisterone is a synthetic progestogen of the oestrane (19-nortestosterone) group. Related agents - norethisterone acetate, lynestrenol, ethynodiol diacetate, and norethynodrel - are all prodrugs that are metabolised to norethisterone before becoming active. It is structurally derived from testosterone, which accounts for its residual androgenic activity.
- Park's Textbook of Preventive and Social Medicine
Mechanism of Action
- Progesterone receptor agonist - inhibits ovulation by suppressing LH surge, thickens cervical mucus (impairs sperm penetration), and induces endometrial decidualisation/atrophy
- Androgenic activity - moderate; due to its 19-nortestosterone backbone
- Partial conversion to ethinylestradiol - small amounts undergo aromatisation, giving weak estrogenic effects
- Anti-estrogenic effects on the endometrium - causes secretory transformation, then atrophy with prolonged use
Clinical Uses and Doses
| Indication | Formulation | Dose |
|---|---|---|
| Combined oral contraceptive | + ethinylestradiol 35 mcg | Norethisterone 1 mg (cyclic) |
| Progestogen-only pill (POP / "mini-pill") | Norethisterone 350 mcg | Daily continuously |
| Injectable contraceptive (NET-EN) | Norethisterone enantate | 200 mg IM every 60 days |
| Heavy menstrual bleeding (AUB) | Norethisterone 5 mg tablets | 5 mg TDS (15 mg/day) or 10 mg OD for 3 weeks |
| Endometriosis | Norethisterone | 10-15 mg/day in 2-3 divided doses |
| GnRH agonist add-back therapy | Norethisterone acetate | 1-5 mg/day combined with estrogen |
| Delay of menstruation | Norethisterone 5 mg | 5 mg TDS from 3 days before expected period |
NET-EN (Noristerat/Norigest) has been used as a contraceptive since 1966. It works by inhibiting ovulation and exerting progesterogenic effects on cervical mucus. Its pregnancy (failure) rate is slightly higher than DMPA (0.4 per 100 woman-years).
- Park's Textbook of Preventive and Social Medicine; Berek & Novak's Gynecology
Use in Endometriosis / GnRH Add-back
When GnRH agonists are used for endometriosis, prolonged use causes hypoestrogenic state with bone loss and vasomotor symptoms. Add-back therapy with norethisterone 1.2 mg/day or norethisterone acetate 5 mg/day is effective at preventing vasomotor symptoms. However, progestogen-only add-back does not fully prevent bone loss - combined estrogen-progestogen add-back (e.g., estradiol 2 mg + norethisterone acetate 1 mg) is more effective for bone protection, and is safe for up to 2 years.
- Berek & Novak's Gynecology
Androgenic Effects and Teratogenicity
Norethisterone and ethisterone have considerable androgenic activity. When used in pregnancy (historically, to prevent miscarriage), cases of masculinisation of female embryo genitalia were reported - specifically:
- Enlarged clitoris
- Varying degrees of fusion of labioscrotal folds
This use in pregnancy has been abandoned.
- Langman's Medical Embryology
Side Effects
| System | Effect |
|---|---|
| Menstrual | Breakthrough bleeding, spotting, amenorrhoea |
| Androgenic | Acne, hirsutism, weight gain |
| CNS | Mood changes, depression |
| Metabolic | Mild adverse lipid changes (raises LDL, lowers HDL) |
| VTE | Small increased risk (lower than combined OCP) |
Contraindications
- Pregnancy (teratogenic androgenic effects)
- Undiagnosed vaginal bleeding
- Severe hepatic disease
- Hormone-sensitive tumours
- History of arterial disease (with estrogen combinations)
Key Formulations Summary
| Trade Name | Formulation |
|---|---|
| Noristerat/Norigest | NET-EN 200 mg IM injection (2-monthly) |
| Micronor / Noriday | Norethisterone 350 mcg POP tablet |
| Primolut N | Norethisterone 5 mg oral tablet |
| Various COCs | + ethinylestradiol (e.g., Orthonovin 1/50) |
Recent Evidence (PubMed 2024-2026)
- A 2024 network meta-analysis (PMID 39312359) examined drug efficacy in endometrial hyperplasia - relevant to norethisterone's role as a progestin.
- A 2025 systematic review (PMID 39987087) assessed the impact of progestogens (including norethisterone) on the renin-angiotensin-aldosterone system (RAAS), highlighting metabolic and cardiovascular nuances of different progestins.
Sources: Park's Textbook of Preventive and Social Medicine; Berek & Novak's Gynecology; Langman's Medical Embryology; MIMS Singapore drug monograph; PMC/PubMed 2024-2025.
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