What is the recommended first‑line hormone replacement therapy for a menopausal woman with vasomotor symptoms (hot flashes and night sweats)?

First-Line Hormone Replacement Therapy for Menopausal Vasomotor Symptoms

For a menopausal woman with bothersome hot flashes and night sweats who is younger than 60 years and within 10 years of menopause onset, transdermal estradiol 50–100 µg daily is the recommended first-line hormonal therapy, combined with a progestin if she has an intact uterus. 1

Candidate Selection and Contraindication Screening

Before prescribing hormone therapy, you must verify the patient meets eligibility criteria and has no absolute contraindications:

Ideal candidates:

• Age < 60 years 1
• Within 10 years of menopause onset 1, 2
• No elevated cardiovascular disease, stroke, or breast cancer risk 1
• Moderate to severe vasomotor symptoms affecting quality of life 3

Absolute contraindications to screen for:

• History of breast cancer or hormone-dependent malignancies 1, 4
• Active or recent venous thromboembolism 1
• Prior stroke or myocardial infarction 1
• Active liver disease 1, 3
• Unexplained vaginal bleeding 1, 4
• Pregnancy 1

Relative contraindications requiring caution:

• Coronary heart disease 5
• Hypertension 5
• Current smoking (heightened cardiovascular risk) 1
• Increased genetic cancer risk 5

Specific Prescribing Recommendations

Route of administration: Transdermal estrogen formulations are strongly preferred over oral preparations because they carry markedly lower rates of venous thromboembolism and stroke. 1 Oral estrogen-containing hormone therapy increases stroke risk, especially in women aged ≥60 years or >10 years after menopause. 1

Dosing strategy:

• Start with the lowest effective dose (transdermal estradiol 50–100 µg daily) 1
• Use for the shortest duration necessary 1, 4
• Reevaluate periodically at 3–6 month intervals to determine if treatment is still necessary 4
• Attempt to discontinue or taper at 3–6 month intervals 4

Progestin requirement: All women with an intact uterus require a progestin combined with estrogen to prevent endometrial hyperplasia and cancer. 1, 4 Micronized progestin may be preferred over medroxyprogesterone acetate due to lower rates of venous thromboembolism and breast cancer risk. 1

Women who have undergone hysterectomy should receive estrogen-alone therapy without progestin, which is associated with lower long-term cardiovascular and breast cancer risks compared to combined therapy. 1

Expected Efficacy

Menopausal hormone therapy is the most effective treatment for vasomotor symptoms, reducing hot flashes by approximately 75% compared to placebo. 1, 2 This represents a mean reduction of 2–3 hot flashes per day. 1

Risk Profile and Monitoring

Breast cancer risk: Combined estrogen-progestogen therapy increases breast cancer risk when used for more than 3–5 years. 1, 3 Low-dose conjugated equine estrogens plus bazedoxifene is not associated with increased breast cancer risk (0.25%/year vs 0.23%/year with placebo). 2

Cardiovascular and thromboembolic risk: The increased risk of stroke and venous thromboembolism with conjugated equine estrogens (with or without medroxyprogesterone acetate) is approximately 1 excess event per 1,000 person-years compared to placebo. 2 Low-dose transdermal estrogen does not show increased stroke risk compared to higher-dose preparations. 1

Monitoring requirements: For women with an intact uterus, adequate diagnostic measures such as endometrial sampling should be undertaken when indicated to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. 4

Special Population Considerations

Gynecologic cancer survivors: There are few formal contraindications for hormone therapy among gynecologic cancer survivors. There is no evidence to contraindicate systemic or topical hormone therapy for women with cervical, vaginal, or vulvar cancers, as these tumors are not hormone-dependent. 5 The risk-benefit profile is favorable for most non-epithelial and epithelial ovarian cancers (high-grade, clear cell, mucinous) and early-stage endometrial cancer. 5

Contraindicated in specific cancer types: Hormone therapy is contraindicated in patients with low-grade serous epithelial ovarian cancer, granulosa cell tumors, certain sarcomas (leiomyosarcoma and stromal sarcoma), and advanced endometrioid uterine adenocarcinoma. 5

Early or premature menopause: In women with early or premature menopause without other contraindications, hormone replacement therapy is recommended at least until the average age of natural menopause (approximately age 51). 5, 1

Common Pitfalls to Avoid

• Do not prescribe oral estrogen when transdermal formulations are available, as oral preparations carry higher thrombotic and stroke risk 1
• Do not omit progestin in women with an intact uterus, as this dramatically increases endometrial cancer risk 1, 4
• Do not initiate hormone therapy in women ≥60 years or >10 years post-menopause, as cardiovascular and stroke risks outweigh benefits 1
• Do not continue therapy indefinitely without periodic reassessment; attempt tapering at 3–6 month intervals 4
• Do not use hormone therapy for cardiovascular disease prevention, as current evidence does not support this indication 2, 6