What alternatives are available if norethindrone (a progestin) is not an option?

Alternatives to Norethindrone for Progestin-Only Contraception

If norethindrone is not an option, etonogestrel implant (Implanon/Nexplanon) or dienogest are the preferred alternatives, with medroxyprogesterone acetate (MPA) oral formulation as a third option—though depot MPA should be avoided due to thrombogenicity concerns. 1, 2

First-Line Alternative: Etonogestrel Implant

• Etonogestrel (the active metabolite of desogestrel) delivered via implant has been well tolerated in patients requiring progestin-only contraception, including those with contraindications to estrogen 1
• The implant provides consistent hormone delivery without requiring daily adherence, eliminating the strict 3-hour timing window required with traditional progestin-only pills 3
• This option is particularly valuable for patients who struggled with compliance on norethindrone 3

Second-Line Alternative: Dienogest

• Dienogest has become one of the most widely used progestins for long-term treatment, particularly in endometriosis management 2
• As a fourth-generation progestin, dienogest offers anti-androgenic properties with reduced off-target effects compared to first-generation progestins like norethindrone 1
• It provides systemic therapy for patients declining intrauterine devices 4

Third-Line Alternative: Oral Medroxyprogesterone Acetate (MPA)

• Oral MPA is available as an alternative for women with intolerance to other progestin-only pills, though it has limited cycle tolerance and some glucocorticoid/androgenic potency 1
• Critical caveat: Depot medroxyprogesterone acetate (DMPA) should be avoided due to significantly elevated VTE risk (RR 2.67,95% CI 1.29-5.53) and bone mineral density loss of up to 7.5% over 2 years 4
• DMPA is particularly contraindicated in women with antiphospholipid antibodies, history of VTE/stroke, cardiovascular disease, or osteoporosis risk 2, 4

Additional Progestin Options in Specific Contexts

High-Dose Normethyltestosterone Derivatives (10 mg daily):

• Lynestrenol has shown good tolerance and decreased attack frequency in some women, even permitting discontinuation of danazol in hereditary angioedema patients 1
• These agents have potent antigonadotropic effects with mild androgenic activity 1
• Avoid combining with tranexamic acid due to potentially greater VTE risk 1

Tibolone:

• Used successfully in 8 premenopausal and postmenopausal women with hereditary angioedema with good clinical results 1
• Important limitation: No data on contraceptive efficacy in premenopausal women 1

Key Safety Considerations

• All progestin-only options have lower VTE risk than combined hormonal contraceptives (RR 0.90,95% CI 0.57-1.45 in healthy women) 3
• Contraindications include active thromboembolism, history of VTE (though risk is lower than with estrogen-containing products), and pregnancy 2, 3
• Irregular bleeding is the most common side effect across all progestin-only formulations and should be counseled about upfront 3, 4

Clinical Algorithm for Selection

1. First choice: Etonogestrel implant for patients requiring reliable contraception without daily adherence requirements 1, 3
2. Second choice: Dienogest for patients needing systemic therapy who decline IUD or implant 2, 4
3. Third choice: Oral MPA only when other options are unavailable or not tolerated, and never use depot formulation 1, 2, 4
4. Consider high-dose lynestrenol specifically for hereditary angioedema patients, but avoid combination with tranexamic acid 1