What diagnoses in postmenopausal women are treated with progesterone-only therapy, such as medroxyprogesterone acetate (MPA) or norethindrone acetate?

Progesterone-Only Treatment in Postmenopausal Women

Progesterone-only therapy is NOT recommended as monotherapy for postmenopausal women. Progestins are used exclusively in combination with estrogen to protect the endometrium in women with an intact uterus, not as standalone treatment for any diagnosis in postmenopausal women 1.

Key Clinical Context

The FDA-approved indications for norethindrone acetate specifically state it is "not intended, recommended or approved to be used with concomitant estrogen therapy in postmenopausal women for endometrial protection" 1. This creates an important distinction between premenopausal and postmenopausal use.

Appropriate Uses of Progestins in Postmenopausal Women

Endometrial Protection (Combined Therapy Only)

Progestins must be combined with estrogen in postmenopausal women with an intact uterus to prevent endometrial hyperplasia and carcinoma 2, 3. The evidence demonstrates:

• Medroxyprogesterone acetate (MPA) at doses of 1.5-2.5 mg daily continuously or 5-10 mg for 14 days per cycle effectively prevents endometrial hyperplasia when combined with estrogen 4
• Norethindrone acetate at doses as low as 0.1 mg daily continuously combined with estradiol 1 mg reduces endometrial hyperplasia incidence to <1% compared to 14.6% with unopposed estrogen 5
• Unopposed estrogen at all doses increases endometrial hyperplasia risk at durations between 1-3 years 3

Special Population: Premature Ovarian Insufficiency

In younger women with chemotherapy or radiation-induced premature ovarian insufficiency (POI), progestins serve the same endometrial protective role when combined with estrogen replacement 2. MPA remains widely used despite cardiovascular concerns due to proven endometrial efficacy, though micronized progesterone is increasingly preferred for its superior safety profile regarding thrombotic and cardiovascular risk 2.

Diagnoses Where Progestins Are NOT Used Alone in Postmenopausal Women

Chronic Disease Prevention

The USPSTF recommends against hormone therapy (including progestin-containing regimens) for primary prevention of chronic conditions in postmenopausal women 2. Combined estrogen-progestin therapy increases risks of:

• Stroke, dementia, gallbladder disease, and urinary incontinence (moderate harms) 2
• Invasive breast cancer and breast cancer deaths (small to convincing increase) 2
• Deep venous thrombosis and pulmonary embolism (small increase) 2
• Coronary heart disease (no benefit, probable increased risk) 2

Contraception in Special Populations

Progesterone-only preparations (medroxyprogesterone acetate, etonogestrel) are recommended for contraception in women with pulmonary arterial hypertension, avoiding estrogen-related thrombotic risks 2. However, this applies to women of reproductive age, not typical postmenopausal women.

Clinical Algorithm for Progestin Use

For postmenopausal women with intact uterus receiving estrogen therapy:

• Prescribe continuous combined regimen: estrogen daily + progestin daily (prevents withdrawal bleeding) 2
• OR sequential regimen: estrogen daily + progestin 10-14 days per cycle (allows withdrawal bleeding for pregnancy detection if relevant) 2

Minimum effective doses for endometrial protection:

• MPA: 1.5 mg daily continuous or 5 mg for 14 days per cycle 3, 4
• Norethindrone acetate: 0.1 mg daily continuous 5
• Micronized progesterone: 45-90 mg vaginally every 48 hours (though oral formulations preferred per ESHRE) 2, 6

For postmenopausal women with hysterectomy:

• Estrogen alone without progestin 2
• No indication for progestin therapy

Critical Pitfalls to Avoid

• Never prescribe progestin monotherapy for postmenopausal hormone replacement - it provides no benefit and lacks evidence for any postmenopausal indication 1
• Do not use progestin-only therapy for osteoporosis prevention - only combined estrogen-progestin or estrogen alone (post-hysterectomy) reduces fracture risk 2
• Avoid confusing premenopausal indications (secondary amenorrhea, endometriosis, abnormal uterine bleeding) with postmenopausal use - these are distinct populations 1