What is norethindrone?

What is Norethindrone?

Norethindrone (also known as norethisterone or norethindrone acetate) is a first-generation synthetic progestin used primarily for contraception, treatment of abnormal uterine bleeding, endometriosis, and acne in women who also desire contraception. 1, 2

Chemical Structure and Classification

• Norethindrone is chemically designated as 17-Hydroxy-19-Nor-17-alpha-pregn-4-en-20-yn-3-one, a normethyltestosterone derivative with mild androgenic activity. 1, 2
• As a first-generation progestin, it has potent off-target effects on androgen and glucocorticoid receptors, which distinguishes it from newer generation progestins with lower androgenic properties. 1, 3

Mechanism of Action

Norethindrone works through multiple mechanisms depending on the dose and formulation used:

As a Contraceptive (Low Dose: 0.35 mg)

• Suppresses ovulation in approximately half of users. 2
• Thickens cervical mucus to inhibit sperm penetration. 2
• Lowers mid-cycle LH and FSH peaks. 2
• Slows ovum movement through fallopian tubes and alters the endometrium. 2

At Higher Therapeutic Doses (≥10 mg)

• Exerts potent antigonadotropic effects with mild androgenic activity. 1
• Produces pronounced endometrial antiproliferative effects, making it particularly effective for treating abnormal uterine bleeding and endometriosis. 4, 5

Unique Pharmacological Property

A critical distinguishing feature of norethindrone is its partial conversion to ethinyl estradiol (EE), which sets it apart from other progestins. 4

• 10-20 mg of norethindrone converts to approximately 20-30 µg of ethinyl estradiol. 4
• This estrogenic activity provides beneficial effects on bone mineral density and vasomotor symptoms. 4, 5
• However, this conversion means norethindrone carries estrogen-related risks including increased venous thromboembolism risk at therapeutic doses and potential concerns for women with migraine with aura. 4

Pharmacokinetics

• Rapidly absorbed with peak plasma concentrations occurring within 1-2 hours after oral administration (mean Tmax 1.2 hours). 2
• Absolute bioavailability is approximately 65% due to first-pass metabolism. 2
• 36% bound to sex hormone-binding globulin (SHBG) and 61% bound to albumin. 2
• Mean terminal elimination half-life is approximately 8 hours. 2
• Undergoes extensive biotransformation primarily via reduction, followed by sulfate and glucuronide conjugation. 2

FDA-Approved Indications

When combined with ethinyl estradiol, norethindrone acetate is FDA-approved for:

• Oral contraception. 6, 2
• Treatment of acne vulgaris in women who also desire contraception. 1, 6

As monotherapy or in other combinations:

• Management of abnormal uterine bleeding. 7
• Treatment of endometriosis. 4, 5
• Management of moderate to severe symptoms of uterine fibroids (when combined with relugolix/estradiol). 8

Available Formulations

• Progestin-only pills (POPs) containing 0.35 mg norethindrone for contraception. 1, 2
• Combined oral contraceptives with ethinyl estradiol (various doses). 1
• Higher dose formulations (10 mg) for therapeutic purposes. 1, 6
• Fixed-dose combinations with other agents (e.g., relugolix/estradiol/norethindrone acetate). 8

Clinical Considerations and Side Effects

Androgenic Effects

• May worsen acne in some women due to mild androgenic activity. 3
• Can lower high-density lipoprotein levels. 1, 5
• May cause breakthrough bleeding, pelvic discomfort, and mastalgia, particularly with progestin-only formulations. 1, 3

Cardiovascular Risks

• Contraceptive doses (0.35 mg) carry no increased VTE risk. 4
• Therapeutic doses (≥10 mg) may be associated with moderately increased venous thromboembolism risk due to conversion to ethinyl estradiol. 4
• Long-term use is associated with slightly increased breast cancer risk. 4

Monitoring Requirements

• Baseline pregnancy status and blood pressure assessment required. 6
• Ongoing blood pressure monitoring and health status changes. 6
• Liver function tests should be monitored periodically for patients on higher doses (≥10 mg daily), with consideration of monitoring every 3-6 months initially, then annually if stable. 6
• Annual clinical review for stable patients, with more frequent monitoring during initial therapy. 6

Contraindications

• Pregnancy (Category X). 6
• History of breast cancer. 6
• Caution in women with migraine with aura due to estrogen conversion, though specific risk data for therapeutic norethindrone use are lacking. 4

Drug Interactions

• Reduced effectiveness when combined with hepatic enzyme inducers including rifampin, griseofulvin, and some anticonvulsants. 3