How should I give norethisterone to induce a withdrawal bleed in a non‑pregnant, non‑breastfeeding woman of reproductive age, and what are the contraindications and side effects?

Norethisterone for Inducing Withdrawal Bleeding

Administer norethisterone 5 mg orally twice daily for 10–14 days to induce a withdrawal bleed in a non-pregnant, non-breastfeeding woman of reproductive age; bleeding typically occurs 2–3 days after completing the course. 1, 2

Dosing Regimen

• Standard dose: Norethisterone 5 mg orally twice daily (total 10 mg/day) for 10–14 days 1, 3
• Alternative dose: Norethisterone 5–10 mg three times daily may be used for dysfunctional uterine bleeding, though this higher dose carries increased thrombotic risk 3
• Withdrawal bleeding onset: Expect bleeding to begin 2–3 days after the final dose 1, 2
• Duration of progestogen exposure: A minimum of 10–12 days is required; shorter courses (< 10 days) are associated with a 1.8-fold increase in endometrial cancer risk if used repeatedly for endometrial protection 1

Mechanism and Expected Outcome

• Norethisterone transforms proliferative endometrium into secretory endometrium during the treatment period 3
• Upon withdrawal of the progestogen, the endometrial lining destabilizes and sheds, producing a predictable withdrawal bleed 1, 2
• This regimen effectively reduces menstrual blood loss volume and duration in women with dysfunctional uterine bleeding 3

Absolute Contraindications

Before prescribing norethisterone, confirm the absence of:

• Active or history of venous thromboembolism or pulmonary embolism 1
• History of stroke or transient ischemic attack 1
• Coronary heart disease or myocardial infarction 1
• Active liver disease 1
• Known or suspected breast cancer 1
• Undiagnosed abnormal vaginal bleeding (pregnancy must be excluded first) 1
• Antiphospholipid syndrome or positive antiphospholipid antibodies 1

Relative Contraindications and Risk Factors

• Smoking in women over age 35: Norethisterone at therapeutic doses may increase venous thromboembolism risk; smoking amplifies this risk through shared thrombotic mechanisms 1
• Thrombophilic disorders: Screen for inherited or acquired thrombophilia before initiating therapy 1
• Hypertension: Monitor blood pressure, as progestogens can elevate systolic and diastolic values 1
• Obesity (BMI ≥ 30 kg/m²): Obesity confers a 2–3-fold baseline increase in VTE risk, which may be further amplified by high-dose norethisterone 1

Common Side Effects

• Menstrual pattern changes: Breakthrough bleeding or spotting may occur during treatment 4, 5
• Mood changes: Drowsiness, irritability, or mood swings are reported with progestogen therapy 1
• Breast tenderness 1
• Headache: May improve with transdermal estrogen if norethisterone is used as part of combined hormone therapy 1
• Nausea or bloating: Less common with norethisterone than with oral estrogen 1

Clinical Considerations and Monitoring

• Pregnancy exclusion is mandatory: Confirm the patient is not pregnant before initiating norethisterone, as progestogens are Category X in pregnancy 1
• No routine laboratory monitoring required: Management is symptom-based; hormone levels (FSH, estradiol) do not guide dosing 1
• Baseline blood pressure measurement: Obtain BP before treatment and at follow-up (6–12 weeks) because progestogens can raise blood pressure 1
• Endometrial assessment if indicated: If the patient has a history of prolonged amenorrhea or risk factors for endometrial hyperplasia, consider baseline transvaginal ultrasound to document endometrial thickness 1, 2

Special Populations

Women with Thrombotic Risk

• For patients with elevated VTE risk (obesity, thrombophilia, smoking), consider medroxyprogesterone acetate depot injection or a levonorgestrel intrauterine system as safer alternatives to high-dose oral norethisterone 1

Women Requiring Menstrual Suppression

• For patients needing continuous menstrual suppression (e.g., during chemotherapy or thrombocytopenia), norethisterone 5–15 mg daily continuously may be used, but limit continuous use to < 6 months to prevent meningioma risk 1
• In patients with high VTE risk, medroxyprogesterone acetate is preferable to norethisterone for continuous suppression 1

Breastfeeding Women

• Norethisterone is generally compatible with breastfeeding; transfer to the newborn through breast milk is negligible, with undetectable plasma levels in breastfed infants even when maternal levels are maximal 6
• Lactation is not inhibited by norethisterone 6

Common Pitfalls to Avoid

• Inadequate duration: Prescribing norethisterone for fewer than 10 days may fail to produce a withdrawal bleed and does not provide sufficient endometrial protection if used repeatedly 1, 2
• Failure to exclude pregnancy: Always confirm non-pregnancy status before initiating progestogen therapy 1
• Ignoring thrombotic risk factors: High-dose norethisterone (> 10 mg/day) carries thrombotic risk; screen for VTE risk factors (smoking, obesity, thrombophilia) and consider alternative progestogens in high-risk patients 1
• Using norethisterone as sole endometrial protection with estrogen: If the patient is on estrogen therapy and has an intact uterus, norethisterone must be given for at least 12–14 days per month to prevent endometrial hyperplasia; shorter durations are unsafe 1, 2

Alternative Progestogens for Withdrawal Bleeding

If norethisterone is contraindicated or not tolerated:

• Medroxyprogesterone acetate: 10 mg orally daily for 10–14 days induces withdrawal bleeding with extensive safety data, though it has a less favorable metabolic profile than norethisterone 1
• Micronized progesterone: 200 mg orally at bedtime for 12–14 days offers superior cardiovascular and breast safety compared to synthetic progestins, though it is primarily used for endometrial protection in hormone therapy rather than isolated withdrawal bleeding 1, 2

Emergency Warning Signs

Instruct the patient to seek immediate medical attention for:

• Sudden chest pain or severe shortness of breath (possible pulmonary embolism) 1
• Acute neurological deficits: Severe headache, visual changes, speech difficulty, or weakness (possible stroke) 1
• Leg pain, swelling, warmth, or redness (possible deep vein thrombosis) 1
• Heavy vaginal bleeding that soaks through a pad per hour for > 2 hours 1