Norethisterone: international spelling of norethisteron

Norethisterone is the international English spelling of the active substance. In English-language literature and in some brand names (e.g. Primolut N) this form appears. In Germany the German spelling norethisteron is used. Norethisterone is one of the oldest orally active progestogens, introduced in 1957 as the first available oral contraceptive (Enovid) and still in use today across many indications.

Pharmacologically, norethisterone is a 19-nortestosterone derivative with marked progestogenic and weak estrogenic and androgenic residual activity. A small fraction is metabolised in the body to ethinylestradiol, which explains the weak estrogenic effect.

Mechanism of action

Norethisterone binds to progesterone receptors in various target tissues:

• Endometrium: secretory transformation and stabilisation of the lining
• Hypothalamus and pituitary: negative feedback on GnRH, FSH and LH, suppressing ovulation
• Cervix: thickening of cervical mucus, impeding sperm passage
• Breast tissue: differentiation of glandular tissue

In addition there is weak androgenic residual activity via androgen receptor binding and estrogenic activity through partial metabolism to ethinylestradiol. These properties distinguish norethisterone from newer progestogens such as dienogest or drospirenone, which are pure or antiandrogenic.

Indications

• Hormone replacement therapy (HRT) in postmenopause: as endometrial protection in combination with an estrogen
• Period postponement: short-term cycle-shifting use before events such as travel, sport or surgery
• Dysfunctional uterine bleeding: stabilisation in heavy or prolonged bleeding
• Endometriosis: off-label, now largely replaced by dienogest or GnRH analogues
• Premenstrual syndrome (PMS): in selected patients
• Secondary amenorrhoea: as provocation test or as endometrial protection during estrogen substitution
• Combined oral contraceptive pill: as a component, increasingly replaced by other progestogens

Dosing and administration

Period postponement: 5 mg three times daily, starting 3 days before the expected period, continued until the desired bleeding date. Maximum 14 days at a stretch.

Dysfunctional bleeding: 5 mg two to three times daily for 10 days; after stopping a withdrawal bleed follows.

HRT progestogen component: usually 1 mg daily continuous or cyclic.

Off-label endometriosis: 5 mg twice daily for several months.

Take with food, ideally at the same time each day. Missed doses can cause spotting or early period when used short-term.

Side effects

Common: breast tenderness, nausea, headache, mood swings, acne, fluid retention, spotting, slight weight gain.

Uncommon: visual disturbance, dizziness, rash, pruritus, hirsutism, cholestasis, weight fluctuations, loss of libido, hypertension.

Rare and very rare: deep vein thrombosis, pulmonary embolism, stroke, breast cancer (long-term HRT), endometrial cancer (rare with monotherapy), liver tumours, erythema nodosum, worsening of hereditary angioedema.

Risk assessment:

• Thromboembolic risk is low at HRT doses of norethisterone but rises at higher doses or in combination with estrogens
• Weak androgenic residual activity can worsen acne or mood changes in sensitive patients
• In migraine with aura, the indication should be reviewed critically

Interactions

• Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort): reduced plasma levels, possible loss of efficacy, spotting or failure of cycle shifting
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin): raised levels, intensified side effects
• Anticoagulants (vitamin K antagonists): possible INR changes
• Tamoxifen, aromatase inhibitors: antagonistic action, avoid combination
• Lamotrigine: reduced levels via glucuronidation
• Antibiotics in general: contrary to earlier assumptions, current data show little clinically relevant influence on hormonal contraception; the exception is enzyme-inducing agents like rifampicin

Special considerations

Pregnancy: contraindicated. Stop therapy immediately on suspicion of pregnancy.

Breastfeeding: small amounts pass into milk, individual evaluation.

Before therapy: gynaecological examination, blood pressure, history for thrombosis, breast cancer, severe liver disease, migraine with aura, diabetes, hyperlipidaemia.

Contraindications: acute or past thrombosis, severe liver disease, hormone-sensitive tumours, vaginal bleeding of unknown cause, pregnancy.

Counselling on period postponement: this off-label use is widely used. In the consultation it helps to set expectations clearly: norethisterone usually shifts the period reliably, but spotting is possible, especially when ramp-up and stop fall awkwardly.

Surgery: because of slightly increased VTE risk, pause therapy 4 to 6 weeks before major elective surgery if possible.

Related substances

• Dienogest, modern progestogen with antiandrogenic action
• Estradiolvalerat, estrogen component in HRT and pill
• Ethinylestradiol, classic synthetic estrogen
• Cyproteronacetat, antiandrogenic progestogen

Frequently asked questions

Sources

• EMA European Medicines Agency
• BfArM Federal Institute for Drugs and Medical Devices
• AWMF guidelines hormone replacement therapy and endometriosis
• Gelbe Liste norethisteron monograph