What is the recommended dose of hormone therapy and what are the associated risks?

Hormone Therapy Dosing and Associated Risks

For postmenopausal women with bothersome vasomotor symptoms, start with low-dose estrogen therapy: 1-2 mg oral estradiol daily or 50-100 μg transdermal estradiol patches (changed twice weekly), using the lowest effective dose for the shortest duration necessary. 1, 2

Recommended Dosing by Indication

For Vasomotor Symptoms (Hot Flashes)

• Oral estradiol: Start with 1-2 mg daily, adjust to control symptoms, then titrate to minimal effective maintenance dose 1, 2
• Transdermal estradiol: 50-100 μg patches applied twice weekly or weekly depending on formulation 1
• Vaginal gel: 0.5-1 mg daily (alternative route) 1
• Administer cyclically (3 weeks on, 1 week off) or continuously based on patient preference 2

For Women with Intact Uterus

• Must add progestogen to prevent endometrial hyperplasia 2
• Sequential regimen: Micronized progesterone 200 mg orally for 12-14 days per 28-day cycle (preferred first choice due to lower cardiovascular and thromboembolism risk) 1
• Alternative sequential options: Medroxyprogesterone acetate (MPA) 10 mg for 12-14 days monthly, or dydrogesterone 10 mg for 12-14 days monthly 1
• Continuous combined regimen: Norethisterone 1 mg daily, MPA 2.5 mg daily, or dydrogesterone 5 mg daily 1
• Combined patches (estradiol + levonorgestrel) are recommended as first choice when available to improve compliance 1

For Women Without Uterus (Post-Hysterectomy)

• Estrogen-only therapy is appropriate and has more favorable risk/benefit profile 1, 3, 2
• No progestogen needed 3, 2
• Same estrogen dosing as above 2

For Vaginal Symptoms Only

• Low-dose vaginal estrogen is preferred over systemic therapy 1, 3
• Estradiol vaginal cream 0.003%: 0.5 g (15 μg estradiol) daily for 2 weeks, then twice weekly 3
• Estradiol vaginal tablets: 10 μg daily for 2 weeks, then twice weekly 3
• Vaginal rings: Simplest regimen, changed every 3 months 3
• No progestogen required even in women with intact uterus when using low-dose vaginal preparations 3

Major Risks by Therapy Type

Combined Estrogen-Progestin Therapy (Oral CEE 0.625 mg + MPA 2.5 mg)

• Increased breast cancer risk: Approximately 8 additional cases per 10,000 person-years with extended use 1
• Increased cardiovascular events: Trend toward increased cardiac events (HR 1.22) 1
• Increased stroke risk: Persistent small increased risk 1
• Increased venous thromboembolism (VTE): Significant risk elevation 1
• Increased gallbladder disease 1
• Increased urinary incontinence: New onset or worsening after 1 year 1
• Reduced colorectal cancer: Beneficial effect 1
• Reduced fractures: Significant benefit for all fracture types 1

Estrogen-Only Therapy (Oral CEE 0.625 mg)

• Reduced breast cancer risk: Approximately 8 fewer cases per 10,000 person-years 1
• Reduced breast cancer mortality: Approximately 2 fewer deaths per 10,000 person-years 1
• Increased stroke risk: Persistent elevation 1
• Increased VTE risk 1
• Increased gallbladder disease 1
• No effect on coronary heart disease: HR 0.95 1
• Reduced fractures: About 56 fractures prevented per 10,000 person-years 1

Route-Specific Considerations

Transdermal vs. Oral Estrogen

• Transdermal formulations preferred when possible due to lower rates of VTE and stroke compared to oral 1, 4
• Transdermal avoids hepatic first-pass metabolism, reducing coagulation activation 5, 6
• Use transdermal in women with: Coagulation disturbances, history of VTE, cardiovascular risk factors 1, 5
• Use oral in women with: Insulin resistance, metabolic syndrome, or diabetes (greater improvements in lipid profile) 5

Progestogen Selection

• Micronized progesterone is first choice due to lower cardiovascular disease and VTE risk compared to synthetic progestogens 1, 6
• Avoid progestogens with anti-androgenic effects in women with iatrogenic premature ovarian insufficiency (may worsen hypoandrogenism and sexual dysfunction) 1
• Natural progesterone preferred over MPA due to lower breast cancer risk 1, 6

Critical Timing and Duration Principles

Age and Timing of Initiation

• Most favorable benefit-risk ratio: Women <60 years old or within 10 years of menopause onset 1, 4
• Less favorable benefit-risk ratio: Women ≥60 years old or >10-20 years from menopause onset due to greater absolute risks of CHD, stroke, VTE, and dementia 1, 4
• Young women with premature menopause: Should continue HT until average age of natural menopause (45-55 years), then reassess 1, 7

Duration of Treatment

• Use lowest effective dose for shortest duration necessary 1, 2, 7
• Reassess every 3-6 months to determine if treatment still necessary 2, 7
• Attempt to discontinue or taper at 3-6 month intervals 2
• Longer durations acceptable only for documented persistent symptoms or bone loss with shared decision-making 4
• Risks increase with increasing age, time since menopause, and duration of use 7

Absolute Contraindications

• History of breast cancer (for systemic HT) 1, 7
• History of endometrial cancer (for systemic HT without adequate evaluation) 1
• Active or recent thromboembolic event 1, 7
• Active cardiovascular disease 7
• Active liver disease 1, 7
• Pregnancy 1
• Unexplained vaginal bleeding (until evaluated) 1, 2

Use with Caution In

• Coronary heart disease or hypertension 1
• Current smokers 1
• Increased genetic cancer risk 1
• History of hormone-sensitive cancers (individualize decision) 1

Special Populations

Cancer Survivors

• Contraindicated in breast cancer survivors for systemic HT 1
• Low-dose vaginal estrogen may be considered in breast cancer survivors with severe vaginal symptoms not responding to non-hormonal measures, only after thorough risk-benefit discussion 1
• Safe in early-stage endometrial cancer survivors based on retrospective data 1
• Women who received total body irradiation or survived Hodgkin lymphoma require strict breast cancer surveillance (annual imaging from age 25) 1

Premature Ovarian Insufficiency (Iatrogenic)

• Continue HT until average age of natural menopause (45-55 years) 1
• Use adult replacement doses, not contraceptive doses 1
• Avoid progestogens with anti-androgenic effects due to risk of worsening sexual dysfunction 1

Common Pitfalls to Avoid

• Do not use combined oral contraceptives instead of HRT in women with premature menopause—HRT provides more appropriate hormone levels 1
• Do not use systemic HT for isolated vaginal symptoms—low-dose vaginal estrogen is safer and more appropriate 1, 3
• Do not prescribe compounded bioidentical hormones—no FDA approval and no evidence they are safer or more effective than standard formulations 1
• Do not add progestogen in women without a uterus—increases risks without benefit 3, 2
• Do not use high-dose regimens when low doses are effective—risks increase with dose 1, 8
• Do not prescribe paroxetine or fluoxetine with tamoxifen—drug interaction reduces tamoxifen efficacy 1