What are the considerations for using norethisterone (a progestogen) in a female patient of reproductive age with a high risk of venous thromboembolism (VTE)?

Norethisterone Use in High-Risk VTE Patients

In female patients at high risk for venous thromboembolism, medroxyprogesterone acetate is preferred over norethisterone for menstruation suppression, as norethisterone has been associated with a nonsignificant trend toward increased thromboembolism risk at higher doses. 1

Primary Recommendation for Menstruation Suppression

Progestogen-only agents are strongly preferred over combined oral contraceptives in high VTE-risk patients, particularly during prothrombotic treatment periods. 1 The 2024 European LeukemiaNet guidelines specifically recommend:

• Medroxyprogesterone acetate is the preferable option in patients with high risk of venous embolism 1
• Norethisterone shows a nonsignificant association between higher dose exposure and thromboembolism risk 1
• Continuous administration of progestational agents should be used to suppress menorrhagia during thrombocytopenic periods 1

Critical Duration Limitation

All progestational agents should not be used for more than 6 months to prevent meningioma occurrence. 1 This represents a significant safety concern that must be monitored regardless of which progestogen is selected.

VTE Risk Stratification with Norethisterone

Combined Oral Contraceptive Formulations (Contraindicated in High VTE Risk)

When norethisterone is combined with ethinylestradiol in oral contraceptives:

• Second-generation combined oral contraceptives containing norethisterone (with ≤30 µg ethinylestradiol) have lower VTE risk than third/fourth-generation formulations 2, 3
• The adjusted hazard ratio for norethisterone acetate versus levonorgestrel is 0.73 (95% CI: 0.48-1.11), confirming similar safety profiles 2
• In women over 50 years, norethisterone-containing oral contraceptives carry a 5.4-fold increased VTE risk compared to non-users 4

However, any combined oral contraceptive is contraindicated in patients with high VTE risk or prior VTE history. 3, 5

Progestogen-Only Formulations (Acceptable in High VTE Risk)

• Progestogen-only contraceptive methods, including norethisterone alone, do not significantly increase VTE risk 3, 5
• These can be safely used in patients with VTE history or known thrombophilic defects 3, 5
• The mechanism of safety is the absence of estrogen, which is the primary component responsible for coagulation activation 5

Specific Clinical Context: Hormone Replacement Therapy

In postmenopausal hormone therapy formulations:

• Oral micronized estradiol combined with norethisterone acetate carries a 3.9-fold (95% CI: 1.5-10.7) increased VTE risk 4
• Non-oral (transdermal) hormone therapy does not increase VTE risk (OR 1.1; 95% CI: 0.6-1.8) 4
• Women with prior hormone-associated VTE who received estradiol plus norethisterone acetate had 10.7% recurrence rate versus 2.3% with placebo 6

Alternative Safer Options in High VTE-Risk Patients

For contraception in women with VTE history or high thrombotic risk:

• Levonorgestrel-only pills 3, 5
• Desogestrel-only pills 3
• Etonogestrel subdermal implants (do not induce prothrombotic state) 7, 3
• Levonorgestrel intrauterine devices 8, 3

These progestogen-only methods are the contraception of choice and should be offered despite VTE risk, given the much higher VTE risk in pregnancy (5-20 per 10,000 woman-years) and postpartum (40-65 per 10,000 woman-years). 1, 3

Key Clinical Pitfalls to Avoid

• Do not use any estrogen-containing formulation in patients with prior VTE or high thrombotic risk 1, 3, 5
• Do not continue progestational agents beyond 6 months due to meningioma risk 1
• Do not assume all progestogens carry equal VTE risk—medroxyprogesterone acetate is preferred over norethisterone in high-risk scenarios 1
• Depot medroxyprogesterone acetate is an exception among progestogen-only methods and is associated with increased VTE risk 3

Monitoring Considerations

For patients requiring norethisterone despite high VTE risk:

• Use the lowest effective dose 1
• Limit duration to less than 6 months 1
• Consider switching to medroxyprogesterone acetate if available 1
• Ensure thromboprophylaxis is optimized during high-risk periods (e.g., chemotherapy, immobilization) 1