Estrogen-Methyltestosterone Hormone Replacement Therapy
Recommended Dosage and Administration
For postmenopausal women with vasomotor symptoms inadequately controlled by estrogen alone, the FDA-approved regimen is esterified estrogens 1.25 mg combined with methyltestosterone 2.5 mg daily (Estratest), or the half-strength formulation of esterified estrogens 0.625 mg with methyltestosterone 1.25 mg daily (Estratest HS). 1
Standard Dosing Protocol
- Initial therapy: Start with esterified estrogens 0.625 mg + methyltestosterone 1.25 mg daily (Estratest HS) for most postmenopausal women 1
- Dose escalation: If symptoms persist after 3 months, increase to esterified estrogens 1.25 mg + methyltestosterone 2.5 mg daily (Estratest) 1, 2
- Administration: Take orally once daily, preferably at the same time each day 1
Clinical Context and Indications
This combination is FDA-approved specifically for moderate-to-severe vasomotor symptoms in postmenopausal women whose symptoms have not been adequately relieved by estrogen therapy alone. 1 The addition of methyltestosterone may particularly benefit women experiencing hypoactive sexual desire, as the androgen component significantly increases bioavailable testosterone levels and improves sexual interest scores compared to estrogen alone. 3
Important Clinical Considerations
Monitoring Requirements
- Baseline assessment: Measure intraocular pressure (IOP) before initiating therapy, as this combination significantly raises IOP from baseline 15.0 mm Hg to 18.2 mm Hg after a median of 11.3 months 4
- IOP monitoring: Recheck IOP at 3 months and every 6-12 months thereafter, as pressure elevations become statistically significant within 3 months and continue over 12 months 4
- Lipid monitoring: Check baseline lipid panel and repeat at 6 months, as the estrogen-androgen combination decreases HDL cholesterol (unlike estrogen alone which increases HDL) while also reducing total cholesterol and triglycerides 2, 5
- Bone density: The higher-dose combination (1.25/2.5 mg) increases spine and hip bone mineral density more than estrogen alone, with a 3.4% increase in spinal BMD at 2 years 2, 5
Common Adverse Effects
- Androgenic effects: Monitor for hirsutism, acne, and alopecia, though these occur at similar rates to estrogen-only therapy in clinical trials 6, 2
- Estrogenic effects: Weight gain, headache, nausea, and vasodilation are the most commonly reported adverse events 6
- Serious events: Cardiovascular disease, thromboembolic phenomena, hepatic dysfunction, and cancer reports were rare (4% of cases) and assessed as unrelated to therapy in postmarketing surveillance of over 1 million woman-years of exposure 6
Critical Pitfalls to Avoid
Never use this combination as first-line hormone replacement therapy. The FDA label explicitly states this is indicated only for women whose vasomotor symptoms have not been relieved by estrogens alone. 1 Always attempt estrogen monotherapy first, preferably using transdermal 17β-estradiol 50-100 μg daily, which has superior cardiovascular and thrombotic safety profiles compared to oral formulations. 7, 8
Discontinue immediately if IOP increases by >4 mm Hg, as pressures return to baseline after discontinuation. 4 This is particularly important in women with glaucoma risk factors or pre-existing ocular hypertension.
Do not prescribe in women with active liver disease or history of hormone-sensitive malignancies, as these are absolute contraindications. 8 The methyltestosterone component undergoes hepatic metabolism and may exacerbate liver dysfunction.
Alternative Approaches
For women requiring both estrogen and androgen supplementation, consider separating the components rather than using fixed-dose combinations:
- Estrogen component: Transdermal 17β-estradiol 50-100 μg daily via patch (changed twice weekly) provides superior cardiovascular safety 7, 8
- Androgen component: Testosterone gel or patch formulations allow more precise dose titration and avoid the supraphysiologic peaks associated with oral methyltestosterone 7
- Progestin addition: Women with intact uterus require endometrial protection with micronized progesterone 200 mg daily for 12-14 days per month or 100 mg daily continuously 7, 8
The fixed-dose estrogen-methyltestosterone combinations remain a reasonable option for carefully selected postmenopausal women with refractory vasomotor symptoms and hypoactive sexual desire who have failed estrogen monotherapy, provided they undergo appropriate monitoring for IOP elevation and lipid changes. 1, 6, 3