What are the best current hormone replacement therapy (HRT) options for a peri- or post-menopausal woman with moderate to severe menopausal symptoms?

Best Current HRT Options for Menopausal Symptoms

For symptomatic peri- or postmenopausal women under age 60 or within 10 years of menopause, transdermal estradiol 50 μg daily (0.05 mg patch changed twice weekly) is the first-line choice, combined with micronized progesterone 200 mg orally at bedtime for women with an intact uterus, or estradiol alone for women after hysterectomy. 1

Route and Formulation Selection

Transdermal estradiol is superior to oral formulations because it bypasses hepatic first-pass metabolism, resulting in lower rates of venous thromboembolism, stroke, and cardiovascular events compared to oral conjugated equine estrogens 1. This route maintains more physiological estradiol levels and avoids the hepatic effects that increase clotting factors 1.

For Women WITH an Intact Uterus:

• Start with transdermal estradiol 50 μg daily patch (changed twice weekly) 1
• Add micronized progesterone 200 mg orally at bedtime for endometrial protection 1, 2
• Micronized progesterone is preferred over medroxyprogesterone acetate (MPA) due to lower rates of venous thromboembolism and breast cancer risk 1
• Combined estrogen-progestin therapy reduces endometrial cancer risk by approximately 90% 1

For Women WITHOUT a Uterus (Post-Hysterectomy):

• Use transdermal estradiol 50 μg daily alone without progestin 1, 3
• Estrogen-alone therapy shows no increased breast cancer risk and may even be protective (HR 0.80) 1, 4
• This eliminates the breast cancer risk associated with synthetic progestins 1

Dosing Strategy

Use the lowest effective dose for the shortest duration necessary 1, 3. The FDA explicitly mandates this approach, with medication discontinued as promptly as possible once symptoms are controlled 3.

• Standard starting dose: Transdermal estradiol 50 μg daily (0.05 mg) 1
• Ultra-low dose option if standard dose causes side effects: Transdermal estradiol 14 μg daily 1
• Reassess every 3-6 months to determine if treatment is still necessary 3
• Attempt dose reduction or discontinuation at 3-6 month intervals 3

Timing Considerations

The benefit-risk profile is most favorable for women under 60 years or within 10 years of menopause onset 1. Starting HRT more than 10 years after menopause significantly worsens the risk profile, particularly for cardiovascular events 1.

Special Populations:

• Surgical menopause before age 45-50: Start HRT immediately post-surgery and continue at least until age 51, then reassess 1
• Chemotherapy/radiation-induced premature ovarian insufficiency: Initiate HRT immediately at diagnosis to prevent long-term cardiovascular, bone, and cognitive consequences 1
• Women over 60 or >10 years post-menopause: HRT initiation is explicitly contraindicated for chronic disease prevention and should only be considered for severe symptoms at the absolute lowest dose 1

Risk-Benefit Profile

For every 10,000 women taking combined estrogen-progestin for 1 year 1:

Benefits:

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

Harms:

• 8 additional strokes
• 8 additional pulmonary emboli
• 8 additional invasive breast cancers
• 7 additional coronary heart disease events

For estrogen-alone therapy (post-hysterectomy), the breast cancer risk is eliminated and may even be protective, while fracture benefits remain 4, 1.

Absolute Contraindications

Do not prescribe HRT if any of the following are present 1:

• Personal history of breast cancer
• History of venous thromboembolism or pulmonary embolism
• History of stroke
• Active or history of coronary heart disease/myocardial infarction
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Thrombophilic disorders
• Smoking in women over age 35 (relative contraindication with significantly amplified risks) 1

Alternative Formulations

Newer FDA-Approved Options:

• Conjugated estrogens/bazedoxifene (TSEC): Approved for moderate-to-severe vasomotor symptoms and osteoporosis prevention, with the bazedoxifene component providing endometrial protection without progestin 5, 6
• Bioidentical estradiol/progesterone combination capsule (Bijuva): FDA-approved 1 mg/100 mg dose for women with uterus, taken as single daily capsule 2

Vaginal-Only Therapy:

• Low-dose vaginal estrogen (rings, suppositories, creams) for genitourinary symptoms alone, without systemic progestin, improves symptom severity by 60-80% with minimal systemic absorption 1

Critical Pitfalls to Avoid

• Never initiate HRT solely for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women—this carries a Grade D recommendation (recommends against) from USPSTF 4, 1
• Never prescribe estrogen-alone to women with an intact uterus—this dramatically increases endometrial cancer risk 1
• Do not use compounded bioidentical hormones—these lack FDA approval and have no safety/efficacy data 4, 1
• Avoid oral estrogen when transdermal is available—oral formulations have higher thrombotic and cardiovascular risks 1
• Do not continue HRT beyond symptom management needs—breast cancer risk increases significantly beyond 5 years of use 1

Monitoring Protocol

• Annual clinical review assessing compliance, ongoing symptom burden, and need for continuation 1
• Attempt dose reduction to lowest effective level at 1 year 1
• No routine laboratory monitoring required unless prompted by specific symptoms or concerns 1
• Mammography per standard screening guidelines 1