What is the recommended approach for prescribing hormone replacement therapy (HRT)?

How to Prescribe Hormone Replacement Therapy

For postmenopausal women with vasomotor symptoms who are under 60 years old or within 10 years of menopause, initiate transdermal 17β-estradiol 50 μg daily via patch (changed twice weekly) combined with micronized progesterone 200 mg orally for 12-14 days every 28 days if the uterus is intact, or estradiol alone if post-hysterectomy. 1, 2

Patient Selection and Timing

When to Initiate HRT

• Start HRT at symptom onset during perimenopause or early menopause—do not delay until postmenopause 2
• The optimal window is age <60 years or within 10 years of menopause onset, when the benefit-risk profile is most favorable 1, 2
• For women with premature ovarian insufficiency (POI) from chemotherapy or radiation, initiate HRT immediately at diagnosis and continue until age 45-55 years 1

Absolute Contraindications

Do not prescribe HRT if the patient has: 1, 2

• History of breast cancer
• Coronary heart disease
• Previous venous thromboembolism or stroke
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies

Estrogen Component Selection

First-Line: Transdermal 17β-Estradiol

Transdermal estradiol is superior to oral formulations because it bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks while maintaining physiological estradiol levels 1, 2, 3

Starting dose: 1, 3

• Patches releasing 50-100 μg of 17β-estradiol per 24 hours
• Change patches twice weekly or weekly depending on brand
• Apply to clean, dry skin of shoulders and upper arms

Dose adjustment: 1

• Titrate based on symptom control and patient tolerance
• Range: 50-100 μg/day for most women
• Women with hypertension should preferentially receive transdermal estradiol 1, 3

Second-Line: Oral 17β-Estradiol

If transdermal administration is contraindicated (diffuse skin disorders, chronic GVHD) or refused: 1

• Oral 17β-estradiol 1-2 mg daily
• 17β-estradiol is preferred over ethinylestradiol or conjugated equine estrogens 1, 3

Alternative: Vaginal Estradiol Gel

For women with POI or specific indications: 1

• Estradiol vaginal gel 0.5-1 mg daily

Progestogen Component (For Women with Intact Uterus)

Progestogen must be added to protect the endometrium from hyperplasia and reduce endometrial cancer risk by approximately 90%. 1, 2

First-Choice: Micronized Progesterone (MP)

MP 200 mg orally (or vaginally) for 12-14 days every 28 days is the preferred progestogen because it has the lowest risk of cardiovascular disease and venous thromboembolism 1, 3

Alternative Progestogens (Sequential Regimens)

If MP is not available or tolerated: 1, 3

• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month
• Dydrogesterone 10 mg daily for 12-14 days per month
• Norethisterone 1 mg daily for 12-14 days per month

Avoid progestogens with anti-androgenic effects in women with iatrogenic POI who may have diminished libido from low testosterone 1

Continuous Combined Regimens (For Avoiding Withdrawal Bleeding)

If the patient requests amenorrhea: 1, 3

• Combined patches: 50 μg estradiol + 7-10 μg levonorgestrel daily continuously
• Oral tablets: 1-2 mg estradiol + 5 mg dydrogesterone (or 2 mg dienogest) daily continuously
• Continuous progestogen minimum doses: norethisterone 1 mg, MPA 2.5 mg, or dydrogesterone 5 mg daily 1

Prescribing Algorithm

Step 1: Confirm Indication and Screen for Contraindications

• Vasomotor symptoms (hot flashes, night sweats) or genitourinary symptoms 2
• Rule out absolute contraindications (breast cancer, CVD, VTE, liver disease, APS) 1, 2
• Assess timing: age <60 or <10 years from menopause 2

Step 2: Choose Estrogen Route and Dose

• First choice: Transdermal 17β-estradiol 50 μg/day patch 1, 2, 3
• Second choice: Oral 17β-estradiol 1-2 mg/day if transdermal contraindicated 1

Step 3: Add Progestogen (If Uterus Present)

• First choice: Micronized progesterone 200 mg for 12-14 days/month 1, 3
• Alternative: MPA 10 mg or dydrogesterone 10 mg for 12-14 days/month 1
• For amenorrhea: Use continuous combined patch or oral formulation 1

Step 4: Provide Patient Instructions

• Apply transdermal patches to shoulders/upper arms on clean, dry skin 1
• Cover application site with clothing after gel dries 4
• Wash hands immediately after application 4
• Avoid swimming/showering for 2 hours after gel application 4
• Children and women should avoid contact with unwashed application sites 4

Step 5: Monitoring and Duration

• Annual clinical review focusing on compliance and symptom control 1
• No routine monitoring tests required unless prompted by specific symptoms 1
• Continue until age 45-55 years (average age of natural menopause) 1
• After age 51, reassess necessity and consider lowest effective dose for shortest duration 1, 2

Special Populations

Women Over Age 60 or >10 Years Post-Menopause

Do not initiate HRT for chronic disease prevention in this population—it increases morbidity and mortality 1, 2

If severe symptoms persist: 2

• Use the absolute lowest effective dose
• Plan for shortest possible duration
• Prefer transdermal over oral routes
• Reassess necessity regularly and attempt discontinuation

Women with Premature Ovarian Insufficiency

• Higher doses may be needed: patches releasing 50-100 μg/day 1
• Continue until age 45-55 years (not just until age 51) 1
• Use sequential regimens to allow withdrawal bleeding, which enables earlier pregnancy recognition since spontaneous ovulation can occur 1, 3

Women Requiring Contraception

If contraception is needed in addition to HRT: 1

• First choice: 17β-estradiol-based combined oral contraceptives (estradiol + nomegestrol acetate or estradiol + dienogest)
• Second choice: Ethinylestradiol-based combined oral contraceptives

Common Pitfalls to Avoid

• Do not initiate HRT solely for prevention of osteoporosis or cardiovascular disease—the risks outweigh benefits for primary prevention 1, 2
• Do not use oral estrogen in women with hypertension—transdermal is strongly preferred 1, 3
• Do not omit progestogen in women with intact uterus—this dramatically increases endometrial cancer risk 1, 2
• Do not start with high doses—begin with lowest effective dose (50 μg transdermal or 1 mg oral) and titrate up only if needed 1, 5, 6
• Do not prescribe combined estrogen-progestin for women >10 years post-menopause or age >60 for new initiation 1, 2
• Do not use ethinylestradiol or conjugated equine estrogens when 17β-estradiol is available 1, 3

Risk-Benefit Context

For every 10,000 women taking combined estrogen-progestin for 1 year: 1, 2

• Harms: 7 additional CHD events, 8 more strokes, 8 more pulmonary emboli, 8 more invasive breast cancers
• Benefits: 6 fewer colorectal cancers, 5 fewer hip fractures

HRT has not been found to increase breast cancer risk before the age of natural menopause in women with POI 1