What is the recommended regimen for continuous combined Hormone Replacement Therapy (HRT)?

Continuous Combined HRT Regimen

For continuous combined hormone replacement therapy, use transdermal 17β-estradiol 50 μg daily (changed twice weekly) plus oral micronized progesterone 100-200 mg daily at bedtime. 1, 2, 3

Estrogen Component

• Start with transdermal 17β-estradiol 50 μg/day as first-line therapy because it bypasses hepatic first-pass metabolism, reducing cardiovascular and thromboembolic risks compared to oral formulations 2, 3
• Apply patches twice weekly (or weekly depending on brand) 3
• Transdermal delivery avoids the hepatic "first-pass effect" that increases clotting factors and inflammatory markers seen with oral estrogen 2

Progestogen Component for Endometrial Protection

The critical distinction in continuous combined regimens is that progestogen must be given DAILY (not cyclically) to maintain amenorrhea and endometrial protection. 1, 4

Recommended Daily Progestogen Doses:

• Micronized progesterone 100-200 mg orally at bedtime (preferred first-line due to lowest cardiovascular and breast cancer risk) 1, 2, 3
• Alternative: Medroxyprogesterone acetate 2.5 mg daily 1, 5
• Alternative: Dydrogesterone 5 mg daily 1
• Alternative: Norethisterone acetate 1 mg daily 1

Micronized progesterone is strongly preferred over synthetic progestins because it demonstrates lower rates of venous thromboembolism and breast cancer risk compared to medroxyprogesterone acetate 2

Why Continuous Combined vs Sequential?

• Continuous combined regimens are designed to eliminate withdrawal bleeding by providing daily progestogen, which increases long-term compliance 5, 6
• The daily progestogen maintains endometrial suppression continuously rather than allowing monthly proliferation and shedding 5
• Most women achieve amenorrhea within 6-12 months on continuous combined therapy 6

Critical Dosing Principles

Always use the lowest effective dose for the shortest duration consistent with treatment goals 2, 4, 7

• The FDA explicitly states that patients should be reevaluated every 3-6 months to determine if treatment is still necessary 4
• Starting with lower doses (such as 50 μg transdermal estradiol rather than 100 μg) reduces bleeding disturbances and breast tenderness while maintaining symptom control 6
• If symptoms are not adequately controlled on the lower dose, the estradiol can be increased to 100 μg daily after 6 months 6

Common Pitfalls to Avoid

Never use less than the recommended daily progestogen dose in continuous combined regimens - inadequate progestogen dosing has been associated with endometrial cancer cases even on "continuous" regimens 8

• The 2.5 mg daily dose of medroxyprogesterone acetate is the minimum effective dose; lower doses (1.5 mg) have been associated with endometrial cancer cases 8
• Poor compliance with daily progestogen intake eliminates endometrial protection - emphasize that the progestogen must be taken every single day without breaks 8
• Do not confuse continuous combined regimens with sequential regimens - they require different progestogen dosing schedules 1

Expected Bleeding Pattern

• Counsel patients that unscheduled spotting or bleeding is common during the first 3-6 months and generally decreases with continued use 9, 6
• This bleeding is not harmful and does not indicate treatment failure 9
• Most women achieve amenorrhea by 6-12 months on continuous combined therapy 6

When to Investigate Bleeding

If unscheduled bleeding persists beyond 6 months or becomes heavy, rule out:

• Poor medication compliance 8
• Drug interactions (particularly with medications that induce hepatic enzymes) 9
• Endometrial pathology (polyps, fibroids, hyperplasia, cancer) 9, 4
• Perform endometrial sampling if bleeding is persistent, heavy, or occurs after a period of amenorrhea 4

Monitoring Requirements

• Clinical reassessment every 3-6 months during the first year, then annually 2, 4
• No routine laboratory monitoring of hormone levels is required 2
• Continue mammography per standard screening guidelines 2
• Assess bone health with adequate calcium (1000 mg/day) and vitamin D (800-1000 IU/day) 2

Duration of Therapy

HRT should be used for the shortest duration necessary to control menopausal symptoms, not for chronic disease prevention 2, 4, 7

• Attempt to discontinue or taper every 3-6 months once symptoms are controlled 4
• Risk of breast cancer increases with duration beyond 5 years 2, 7
• The absolute risks remain modest but increase with prolonged use 7