What is the first-line hormone therapy (HT) for menopausal symptoms?

First-Line Hormone Therapy for Menopause

For women with an intact uterus, the first-line hormone therapy is transdermal estradiol (50 μg/day patch applied twice weekly) combined with micronized progesterone (200 mg daily oral), which provides the most favorable safety profile for breast cancer and cardiovascular risk while effectively treating vasomotor symptoms. 1, 2

Regimen Selection Based on Uterine Status

Women WITH an Intact Uterus

• Combination therapy is mandatory to prevent endometrial cancer, which reduces endometrial cancer risk by approximately 90% 2
• Preferred regimen: Transdermal estradiol 50 μg/day (0.05 mg/day patch, applied twice weekly) PLUS micronized progesterone 200 mg daily oral 1, 2
• Why transdermal estradiol: Bypasses hepatic first-pass metabolism, resulting in lower cardiovascular and thromboembolic risks compared to oral formulations 2
• Why micronized progesterone: More favorable breast cancer risk profile and lower venous thromboembolism rates compared to synthetic progestins like medroxyprogesterone acetate 1, 3

Women WITHOUT a Uterus (Post-Hysterectomy)

• Estrogen-alone therapy is appropriate since endometrial protection is unnecessary 2
• Preferred regimen: Transdermal estradiol 50 μg/day (0.05 mg/day patch, applied twice weekly) 2
• Reduces vasomotor symptoms by approximately 75% 2

Critical Timing Considerations

The benefit-risk profile is most favorable for women under 60 years of age OR within 10 years of menopause onset 2, 4, 5

• Therapy can be initiated during perimenopause when symptoms begin; does not need to be delayed until postmenopause 2
• Do NOT initiate HT in women over 60 or more than 10 years past menopause unless severe symptoms warrant it, and only at the absolute lowest dose 2
• For women with premature ovarian insufficiency (from chemotherapy/radiation), initiate HT immediately at diagnosis 2

Dosing Principles

• Start with the lowest effective dose: Transdermal estradiol 50 μg/day is the standard starting dose 2
• Use for the shortest duration necessary 6, 7
• Reassess every 3-6 months to determine if treatment is still necessary 8
• Attempt to taper or discontinue at 3-6 month intervals 8

Alternative Progestin Options (If Micronized Progesterone Unavailable)

If micronized progesterone is not available or tolerated:

• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days every 28 days 2
• Dydrogesterone 10 mg daily for 12-14 days every 28 days 2
• Note: These synthetic progestins carry higher breast cancer and VTE risk compared to micronized progesterone 1, 3

Absolute Contraindications to Systemic HT

Do not prescribe HT if any of the following are present: 6, 2

• History of hormone-sensitive cancers (breast, endometrial)
• Active or recent thromboembolic events (DVT, PE, stroke)
• Coronary heart disease
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Unexplained abnormal vaginal bleeding
• Pregnancy

Expected Benefits and Risks

Benefits (per 10,000 women/year):

• 6 fewer colorectal cancers 6
• 5 fewer hip fractures 6
• 75% reduction in vasomotor symptom frequency 2

Risks (per 10,000 women/year with estrogen-progestin):

• 7 additional CHD events 6
• 8 additional strokes 6
• 8 additional pulmonary emboli 6
• 8 additional invasive breast cancers (with longer-term use) 6

Important caveat: These risks are primarily from studies using oral conjugated equine estrogen plus medroxyprogesterone acetate in older women. The transdermal estradiol plus micronized progesterone regimen recommended here has a more favorable risk profile 1, 2, 3

Common Pitfalls to Avoid

• Never initiate HT solely for chronic disease prevention (osteoporosis, cardiovascular disease) - this increases morbidity and mortality 6, 2
• Never use oral estrogen when transdermal is available - oral formulations increase cardiovascular and thrombotic risks due to hepatic first-pass metabolism 2, 4
• Never prescribe estrogen alone to women with an intact uterus - this dramatically increases endometrial cancer risk 6, 8
• Never continue HT indefinitely without reassessment - risks increase with duration, particularly breast cancer risk 6

Special Population: Cancer Survivors

• Contraindicated in hormone-sensitive cancer survivors (breast, endometrial, ovarian) 6, 1
• May be considered in non-hormone-sensitive cancer survivors (cervical, vaginal, vulvar) with severe vasomotor symptoms 6, 1
• For cancer survivors with vasomotor symptoms from treatment, consider HT until average age of menopause (51 years), then re-evaluate 2