What is the recommended regimen for progesterone-only hormone replacement therapy (HRT)?

Progesterone-Only Hormone Replacement Therapy

Critical Decision Point: Progesterone-Only HRT is NOT Recommended

Progesterone-only HRT should not be prescribed as standard hormone replacement therapy because it provides no therapeutic advantage for menopausal symptom management or chronic disease prevention, and women with an intact uterus require combined estrogen-progesterone therapy to prevent endometrial cancer. 1

When Progesterone-Only Therapy May Be Considered

Limited Evidence for Vasomotor Symptoms

• Progesterone monotherapy has been used in women with contraindications to estrogen, but the evidence is weak and inconsistent 2
• Oral micronized progesterone 300 mg daily demonstrated 58.9% improvement in vasomotor symptoms versus 23.5% in placebo (n=133), but this was the only formulation showing benefit 2
• Transdermal progesterone showed no improvement in the largest study (n=230) 2
• Side effects including headaches and vaginal bleeding were significant, leading to treatment discontinuation in 6-21% of patients 2

No Benefit for Mood Symptoms

• No studies reported improvement in mood symptoms with progesterone-only therapy 2

Standard Recommendation: Combined Estrogen-Progesterone Therapy

For Women with Intact Uterus

Women with an intact uterus must receive progestogen combined with estrogen therapy to prevent endometrial hyperplasia and carcinoma—progesterone alone provides no benefit and exposes women to unnecessary risks. 1

• Unopposed estrogen increases endometrial cancer risk (relative risk 2.3,95% CI 2.1-2.5), with risk increasing to 9.5-fold after 10 years of use 3
• Adding progesterone for 12-14 days per month reduces hyperplasia incidence from 64% (estrogen alone) to 6% (combined therapy) over 36 months 4

Recommended Combined Regimen

• Transdermal 17β-estradiol 50-100 μg daily PLUS oral micronized progesterone 200 mg daily for 12-14 days per 28-day cycle (sequential regimen) 5
• Transdermal estradiol is preferred because it avoids hepatic first-pass effect, minimizes impact on hemostatic factors, and has more beneficial effects on lipids and blood pressure compared to oral formulations 3
• The 12-14 day duration of progesterone is critical—shorter durations provide inadequate endometrial protection 5

Alternative Progestogen Options

• Medroxyprogesterone acetate 10 mg daily for 12-14 days per month 5
• Dydrogesterone 10 mg daily for 12-14 days per month 5
• Micronized progesterone is preferred over synthetic progestins due to lower cardiovascular and thrombotic risk 5

For Women After Hysterectomy

Women who have had a hysterectomy should receive estrogen-only therapy—there is no therapeutic advantage in prescribing progestins to this population, with the possible exception of women with residual intra-peritoneal endometriosis. 3, 1

Critical Safety Considerations

Cardiovascular and Thrombotic Risks

• Combined estrogen-progestin therapy increases risk of venous thromboembolism (RR 2.11,95% CI 1.26-3.55), with highest risk in the first year of use (RR 3.49,95% CI 2.33-5.59) 3
• Per 10,000 women taking estrogen-progestin for 1 year: expect 7 additional CHD events, 8 more strokes, 10 more pulmonary emboli, and 8 more invasive breast cancers 4

Duration and Dosing Principles

• Use the lowest effective dose for the shortest duration consistent with treatment goals 3
• HRT should be limited to women younger than age of expected natural menopause (approximately 51 years) when used for menopausal symptoms 3
• For women with premature ovarian insufficiency, continue treatment until average age of natural menopause (45-55 years) 5

Monitoring Requirements

• Annual clinical review focusing on compliance, bleeding patterns, symptom control, and reassessment of risks versus benefits 5
• No routine laboratory monitoring required unless specific symptoms or concerns arise 5
• Adjust dose according to tolerance and wellbeing 5

Common Pitfalls to Avoid

• Never prescribe progesterone alone for standard menopausal HRT—it lacks efficacy for symptom relief and provides no benefit for chronic disease prevention 1, 2
• Never use progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 5
• Never prescribe progestogen to hysterectomized women unless residual endometriosis is present—it adds unnecessary risks without benefit 3, 1