What is the optimal hormone replacement therapy regimen for someone taking progesterone/bi-estrogen B/testosterone sublingually in the AM and progesterone/bi-estrogen B in the PM?

Optimal Hormone Replacement Therapy Regimen

Direct Recommendation

Your current sublingual compounded hormone regimen is not evidence-based and should be replaced with transdermal 17β-estradiol patches (50-100 μg daily) combined with oral micronized progesterone 200 mg daily for 12-14 days every 28 days. 1

Why Your Current Regimen Is Suboptimal

Problems with Sublingual Administration

• Sublingual bi-estrogen and testosterone formulations lack FDA approval and have no quality evidence supporting their use for hormone replacement therapy. 1
• The Endocrine Society specifically recommends transdermal 17β-estradiol over other routes because it avoids first-pass hepatic metabolism, provides a better cardiovascular risk profile, improves bone mass accrual, and carries lower risk of venous thromboembolism. 1
• Your AM testosterone dosing is not addressed in standard HRT guidelines for typical menopausal women, though it may be considered only in specific cases of documented androgen deficiency with sexual dysfunction. 2

Problems with Twice-Daily Dosing

• Standard HRT does not require split AM/PM dosing—this adds unnecessary complexity without clinical benefit. 1
• Transdermal patches provide continuous 24-hour hormone delivery, eliminating the need for multiple daily doses. 2

Evidence-Based Alternative Regimen

First-Line Recommendation

Transdermal 17β-estradiol patch 50-100 μg daily (changed twice weekly) PLUS oral micronized progesterone 200 mg daily for 12-14 days every 28 days. 1, 3

Why This Regimen Is Superior:

• Micronized progesterone (MP) is the preferred progestin because it has lower risk of cardiovascular disease and venous thromboembolism compared to synthetic progestins while providing complete endometrial protection. 2
• The sequential dosing (12-14 days per month) provides adequate endometrial protection with 200 mg daily dosing, as demonstrated in FDA-approved trials showing only 6% hyperplasia risk versus 64% with estrogen alone. 4
• The American College of Cardiology recommends micronized progesterone over medroxyprogesterone acetate (MPA) for women with cardiovascular risk factors. 5

Alternative if Sequential Bleeding Is Unacceptable

Continuous combined regimen: Transdermal 17β-estradiol patch 50-100 μg daily PLUS oral micronized progesterone 100 mg daily (every day without breaks). 2

• This avoids withdrawal bleeding but requires daily progesterone rather than cyclical dosing. 2
• Continuous regimens require minimum 5 mg dydrogesterone or 2.5 mg MPA daily if MP is not used, but MP remains preferred. 2

Critical Monitoring Requirements

Before Starting

• Measure blood pressure (required before HRT initiation). 5
• Rule out pregnancy if any uncertainty exists. 5
• Baseline transvaginal ultrasound to confirm appropriate endometrial thickness. 3

During Treatment

• Expect withdrawal bleeding within 7 days after each progesterone cycle (occurs in 73-80% of women). 4, 3
• If withdrawal bleeding does not occur within 3 weeks, perform pregnancy testing. 5
• Annual breast imaging starting at age 25 if you have history of chest radiation or other high-risk factors. 2
• Adjust estradiol dose based on symptom control and tolerance. 1

Important Caveats

Progestins to Avoid

• Avoid progestins with anti-androgenic effects if you have low testosterone symptoms (diminished libido, impaired sexual function), as they will worsen hypoandrogenism. 2
• This includes cyproterone acetate and certain combined oral contraceptives. 2

Duration of Therapy

• Continue HRT until the average age of natural menopause (45-55 years) if you have premature ovarian insufficiency. 2, 1
• After age 55, reassess continuation based on individual risks, family history, and symptom severity. 2

Common Pitfalls

• Do not use oral estrogen if transdermal is available—oral formulations have worse cardiovascular and thrombotic profiles. 1
• Do not omit progesterone if you have an intact uterus—endometrial cancer risk increases dramatically (64% hyperplasia rate with estrogen alone versus 6% with combined therapy). 4
• Do not use compounded "bioidentical" hormones—they lack quality control, standardized dosing, and safety data. 1

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