NORETHINDRONE AND MESTRANOL
Clinical safety rating: avoid
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
Norethindrone is a progestin that suppresses gonadotropin secretion, primarily luteinizing hormone (LH), thereby inhibiting ovulation. Mestranol is a prodrug of ethinyl estradiol, an estrogen that provides negative feedback on the hypothalamic-pituitary-ovarian axis, further suppressing follicle-stimulating hormone (FSH) and LH. The combination stabilizes the endometrium and alters cervical mucus consistency to impede sperm penetration.
| Metabolism | Norethindrone is metabolized primarily via reduction and conjugation (glucuronidation and sulfation) in the liver, with CYP3A4 involvement. Mestranol is rapidly demethylated to ethinyl estradiol, which undergoes oxidative metabolism via CYP3A4 and conjugation. |
| Excretion | Renal (30-50% as metabolites), biliary/fecal (35-55% as metabolites and conjugated forms). |
| Half-life | Norethindrone: 5-12 hours; Mestranol: 50-120 minutes (mestranol is rapidly demethylated to ethinyl estradiol, which has a half-life of 10-20 hours). Clinical context: Steady-state is achieved within 5-7 days; no clinically significant accumulation under normal dosing. |
| Protein binding | Norethindrone: ~96% bound to sex hormone-binding globulin (SHBG) and albumin; Mestranol: >95% bound to SHBG and albumin (after conversion to ethinyl estradiol, also highly protein-bound). |
| Volume of Distribution | Norethindrone: 2.5-4.5 L/kg; Ethinyl estradiol (from mestranol): 2-4 L/kg. Large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: Norethindrone ~50-80% (first-pass metabolism); Mestranol ~40-60% (extensive first-pass metabolism and demethylation to ethinyl estradiol). |
| Onset of Action | Oral: Onset of contraceptive effect requires 7 days of continuous dosing; suppression of ovulation occurs within 2-3 days of starting treatment. |
| Duration of Action | Duration: Contraceptive effect persists for 24 hours with daily dosing; after discontinuation, ovulation may resume within 2-4 weeks. |
1 tablet (norethindrone 1 mg / mestranol 0.05 mg) orally once daily for 21 days, then 7 days off.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment; contraindicated in severe renal impairment (GFR <30 mL/min/1.73 m²) due to risk of fluid retention and hyperkalemia. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C); caution in moderate impairment (Child-Pugh class B) with close monitoring; no adjustment for mild (Child-Pugh class A). |
| Pediatric use | Not indicated for use in postmenarchal minors; safety and efficacy not established in prepubertal children. |
| Geriatric use | Not indicated for use in postmenopausal women; consider alternative therapy due to increased risk of thromboembolic events and cardiovascular disease in elderly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
| FDA category | Positive |
| Breastfeeding | Excreted in breast milk; M/P ratio ~0.5. May reduce milk production and quality. Use with caution; monitor infant for jaundice and estrogenic effects. |
| Teratogenic Risk | First trimester: Increased risk of neural tube defects, cardiovascular anomalies, and oral clefts. Second and third trimesters: Associated with feminization of male fetus, potential for liver tumors in offspring. Postnatal: Possible long-term reproductive effects. |
■ FDA Black Box Warning
Cigarette smoking increases the risk of serious cardiovascular adverse effects from combination oral contraceptives, including thromboembolism, stroke, and myocardial infarction. This risk increases with age and with heavy smoking (15+ cigarettes per day). Women over 35 who smoke should not use this product.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
["History of or current venous thromboembolism (VTE) or pulmonary embolism","Cerebrovascular disease or coronary artery disease","Active liver disease or hepatic adenomas","Known or suspected breast cancer or other estrogen-sensitive neoplasia","Undiagnosed abnormal uterine bleeding","Pregnancy","Hypersensitivity to any component","Migraine with aura in women over 35","Diabetes with vascular involvement","Major surgery with prolonged immobilization"]
| Precautions | ["Increased risk of venous thromboembolism (VTE) and arterial thrombosis","Cigarette smoking, especially in women over 35","Hypertension, including estrogen-induced hypertension","Gallbladder disease","Hepatic neoplasia (e.g., liver adenomas)","Carbohydrate and lipid metabolism effects","Ocular lesions (e.g., retinal thrombosis)","Depression","Contact lens intolerance","Hereditary angioedema exacerbation"] |
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| Fetal Monitoring | Monitor liver function tests, blood pressure, and glucose tolerance. Assess fetal growth and anatomy via ultrasound. Watch for signs of thromboembolism. |
| Fertility Effects | Suppresses ovulation during use. After discontinuation, fertility typically returns within 1-3 months. No permanent impact. |