Norethindrone
Norethindrone
Generic Name
Norethindrone
Mechanism
Norethindrone is a synthetic progestin that mimics the activity of endogenous progesterone.
• Receptor binding: Selective agonist at the progesterone receptor (PR) in target tissues, particularly the endometrium, myometrium, and hypothalamic-pituitary axis.
• Antigonadotropic effect: Inhibits luteinizing hormone (LH) and follicle‑stimulating hormone (FSH) release, suppressing ovarian follicular development when used in oral contraceptives.
• Endometrial modulation: Induces secretory changes, stromal decidualization, and inhibits endometrial proliferation, thereby preventing implantation.
• Vascular effects: Has minimal estrogenic activity, preserving the menstrual cycle while reducing estrogen‑only side effects such as endometrial hyperplasia.
Pharmacokinetics
- Absorption: Oral bioavailability ~30–40 % due to first‑pass metabolism; peak plasma concentrations reached within 1–2 h post‑dose.
- Distribution: Highly protein‑bound (~85 % to albumin and sex hormone–binding globulin).
- Metabolism: Predominantly hepatic via 3β‑hydroxylation, 20β‑hydroxylation, and subsequent glucuronidation; minor CYP450 involvement (CYP3A4).
- Elimination: Renal (≈70 %) and fecal (~30 %) routes; mean elimination half‑life 12–15 h.
- Drug interactions: CYP3A4 inducers (rifampin, carbamazepine) ↓ plasma levels; inhibitors (ketoconazole, erythromycin) ↑ exposure.
- Special populations: Pregnancy, liver disease, or extreme obesity may alter pharmacokinetics; dose adjustment usually not required for mild obesity.
Indications
- Monophasic oral contraceptive (≤1 mg daily, 21 days on / 7 days off).
- Combination oral contraceptive (with estrogen, ≤2 mg).
- Endometrial protection: Adjunct to low‑dose estrogen in women with estrogen‑only therapy.
- Primary treatment of menorrhagia (≤5 mg daily).
- Post‑menopausal vaginal atrophy (when combined with local estrogen).
- Progestin‑only injectable: Not available in commercial form; some research uses intramuscular depot preparations.
Contraindications
- Contraindications:
- Pregnancy (risk of fetal harm).
- Known or suspected breast cancer, liver tumors, or thromboembolic disorders.
- Unexplained vaginal bleeding, active hepatic disease, uncontrolled hypertension.
- Known hypersensitivity to any component.
- Warnings:
- Venous thromboembolism (VTE) risk increased in smokers >35 yr, hypertension, or clotting disorders.
- Cardiovascular: May exacerbate hypertension or dyslipidemia.
- Hepatic: Rare hepatotoxicity (elevated transaminases).
- Bone health: Long‑term use can reduce BMD; combine with vitamin D & calcium.
Dosing
| Indication | Dose | Schedule | Notes |
| Oral contraceptive (monophasic) | 0.35 mg | 21 days on, 7 days off | Start at day 1 of menstrual cycle or any day for continuous use. |
| Combination oral contraceptive | 0.35–0.5 mg | 21 days on, 7 days off | Use with 0.03–0.05 mg estrogen. |
| Menorrhagia | 5 mg daily | Continuous | Monitor menstrual flow, adjust if excessive bleeding or amenorrhea. |
| Endometrial protection | 0.35 mg daily | As with contraception | Add when using estrogen only for menopause symptom relief. |
• Administration: Take with or without food; avoid alcohol to minimize GI upset.
• Missed dose: If ≥2 h late, take dose immediately; continue next usual dose. If >12 h late, use backup contraception within 48 h.
Adverse Effects
Common (≥10 %)
• Nausea, vomiting
• Headache, dizziness
• Breast tenderness, edema
• Menstrual irregularities (spotting, breakthrough bleeding)
• Acne, alopecia
Serious (≤1 %)
• Deep vein thrombosis (DVT) / pulmonary embolism (PE)
• Hepatic adenoma/carcinoma (rare)
• Severe cutaneous reactions (Stevens–Johnson syndrome)
• Severe hyperemesis or gastrointestinal ulceration
• Acute hepatic dysfunction (↑AST/ALT >5× ULN)
Monitoring
| Parameter | Targets | Frequency |
| CBC / Hemoglobin | Anemia, thrombocytopenia | Every 3–6 months in high‑risk groups |
| Lipid profile | ↑LDL, ↓HDL | Annually |
| Liver enzymes (AST/ALT, ALP, bilirubin) | >2× ULN | Baseline, then annually or if symptoms arise |
| Blood pressure | ≥140/90 mmHg | Every visit |
| Pregnancy test | Negative in contraceptive users | Prior to initiation; if pregnancy suspected |
| Bone mineral density | Decrease >3 % | Every 12–24 months in long‑term users |
| Adverse symptom diary | Mood changes, bleeding | As needed |
Clinical Pearls
- Low‑dose advantage: A 0.35 mg dose provides sufficient progestogenic activity while minimizing estrogen‑like side effects and VTE risk.
- Compliance tip: The “empty pillbox” (7‑day placebo pack) reduces missed‑dose anxiety and encourages adherence.
- Combination synergy: When paired with 35 yr or women with thrombotic history.
- Menorrhagia management: Starting a high dose (5 mg) for the first 14 days followed by a maintenance dose (0.5–1 mg) can reduce initial breakthrough bleeding.
- Endometrial safety: In estrogen‑only therapy, adding a progestin like norethindrone for 12 weeks cyclically prevents endometrial hyperplasia.
- Drug‑drug interaction: Inform patients that enzyme inducers like phenytoin or St. John’s wort can significantly lower norethindrone levels; alternative contraception may be needed.
- Patient education: Emphasize that breakthrough bleeding during the first 4–6 weeks is common and self‑limiting; reassure regarding VTE risk, especially in non‑smoker, low‑risk individuals.
Key Takeaway: Norethindrone is a versatile, low‑dose progestin that efficiently prevents pregnancy, treats heavy menstrual bleeding, and safeguards the endometrium, with a favorable safety profile when used appropriately.