What type of endometrial protection should be provided for a postmenopausal woman with an intact uterus who wishes to use hormonal replacement therapy (HRT) patches?

Endometrial Protection for HRT Patch Users with Intact Uterus

Any postmenopausal woman with an intact uterus using estrogen patches must receive concurrent progestogen therapy to prevent endometrial hyperplasia and cancer, with oral micronized progesterone 200 mg daily for 12-14 days per month (sequential regimen) or 100 mg daily continuously being the preferred first-line option due to superior cardiovascular and breast safety profiles. 1, 2

Mandatory Progestogen Requirement

• Progestogen must be given in combination with estrogen therapy to protect the endometrium in women with an intact uterus. 1
• The use of unopposed estrogen increases endometrial cancer risk 2- to 12-fold, with the greatest risk (15- to 24-fold) occurring with prolonged use of 5-10 years or more. 1
• The FDA explicitly states: "When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer." 3

First-Line Recommendation: Micronized Progesterone

Oral micronized progesterone is the preferred progestogen choice due to its neutral effects on breast tissue and superior cardiovascular safety compared to synthetic progestins. 2, 4

Sequential Regimen (Preferred for Most Women)

• Micronized progesterone 200 mg orally daily for 12-14 days per 28-day cycle paired with transdermal estradiol patches. 1, 2
• This regimen provides proven endometrial protection while inducing predictable withdrawal bleeding. 1, 2
• The 12-14 day duration is critical—shorter durations provide inadequate endometrial protection. 1, 2

Continuous Combined Regimen (For Women Preferring Amenorrhea)

• Micronized progesterone 100 mg orally daily without interruption when paired with continuous estradiol patches. 2
• This avoids withdrawal bleeding but may take 6-12 months to achieve amenorrhea. 2

Alternative Route: Vaginal Administration

• Vaginal micronized progesterone 200 mg daily for 12-14 days per month provides good endometrial protection with fewer systemic side effects. 2
• This route is particularly useful for women experiencing systemic progestogen side effects. 2

Second-Line Options: Synthetic Progestins

While the strongest evidence for endometrial protection exists for oral cyclical combined treatment with synthetic progestins, micronized progesterone remains preferred due to better overall safety. 1

Norethisterone Acetate (Preferred Synthetic Option)

• 1 mg orally daily (continuous regimen) provides adequate endometrial protection with better cardiovascular and metabolic profiles than medroxyprogesterone acetate. 2, 5
• For sequential regimens: 5 mg daily for 12-14 days per month. 5

Medroxyprogesterone Acetate (MPA)

• 10 mg orally daily for 12-14 days per month (sequential regimen) has the most extensive safety data for endometrial protection. 1, 2, 6
• 2.5-5 mg orally daily (continuous regimen) is an alternative. 2
• Important caveat: MPA has documented adverse effects on lipid profiles, vasomotion, and carbohydrate metabolism compared to natural progesterone. 5, 4

Dydrogesterone

• 10 mg orally daily for 12-14 days per month (sequential regimen) or 5 mg daily (continuous regimen). 2
• This is considered a second-choice progestin with less robust safety data than micronized progesterone. 2, 5

Third-Line Option: Levonorgestrel Intrauterine System (LNG-IUS)

The levonorgestrel IUD (Mirena) delivers progestogen directly to the uterus, providing reliable endometrial protection with minimal systemic effects. 5, 7

• Particularly useful for women experiencing systemic progestogen side effects (mood changes, bloating, breast tenderness). 5
• Requires annual clinical review with attention to IUD string presence. 7
• Typically reduces menstrual bleeding and cramping. 7

Critical Dosing Principles and Pitfalls

Duration Requirements

• Progestogen must be delivered for at least 12-14 days monthly in sequential regimens—this mimics the luteal phase duration necessary for complete endometrial maturation. 1, 2
• Shorter durations (e.g., 10 days or less) provide inadequate endometrial protection and should be avoided. 2

Continuous vs. Sequential Regimens

• Continuous combined regimens (progestogen given daily) provide superior endometrial protection compared to sequential regimens. 4, 8
• Sequential regimens induce predictable withdrawal bleeding, which many women prefer initially. 1, 2
• Continuous regimens eventually lead to amenorrhea but may cause irregular bleeding during the first 6-12 months. 2

Breast Cancer Considerations

• Micronized progesterone does not increase breast cell proliferation, unlike synthetic progestins such as MPA. 4
• All estrogen-progestin combinations show a small increased risk of invasive breast cancer (8 additional cases per 10,000 women-years), but this risk appears lower with micronized progesterone. 1, 4
• The protective effect of progestogens seen in the endometrium is not replicated in the breast. 4

Monitoring and Follow-Up

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control. 1, 7
• No routine laboratory monitoring is required unless specific symptoms or concerns arise. 1, 7
• In cases of undiagnosed persistent or recurrent abnormal vaginal bleeding, endometrial sampling must be undertaken to rule out malignancy. 3, 6
• Baseline endometrial ultrasound should be considered, especially if using off-label vaginal regimens. 5

Estrogen Patch Pairing Recommendations

• Transdermal 17β-estradiol 50-100 μg daily is the preferred estrogen to pair with progestogen due to lower cardiovascular and thrombotic risk compared to oral formulations. 1, 2
• 17β-estradiol is explicitly preferred over ethinylestradiol or conjugated equine estrogens. 1
• Patches are typically changed twice weekly or weekly depending on the brand. 2

Special Populations

Women with Premature Ovarian Insufficiency (POI)

• Begin cyclic progestogen after at least 2 years of estrogen therapy alone, or when breakthrough bleeding occurs. 2
• Continue treatment until the average age of natural menopause (45-55 years). 2, 5

Women with Cardiovascular Risk Factors

• Transdermal estradiol paired with micronized progesterone is strongly preferred due to lower thrombotic risk. 1, 2
• Hypertension should not be considered a contraindication to HRT use. 1

Women with History of Endometriosis

• Combined estrogen/progestogen therapy can be effective for vasomotor symptoms and may reduce the risk of disease reactivation. 1

Absolute Contraindications to Progestogen Therapy

• Active liver disease. 5
• Current or history of breast cancer or other hormone-sensitive malignancies. 5
• Undiagnosed abnormal vaginal bleeding (until malignancy is ruled out). 3, 6