In a perimenopausal woman with a history of endometriosis who cannot use oral combined hormone therapy because she is on tirzepatide (Mounjaro), is a combined estrogen‑progestin transdermal patch preferable to a low‑dose estrogen‑only patch?

Combined Estrogen-Progestin Transdermal Patch is Strongly Preferred

For a perimenopausal woman with endometriosis history on tirzepatide (Mounjaro), a combined estrogen-progestin transdermal patch is the clear choice over estrogen-only therapy to prevent endometrial hyperplasia and reduce the risk of endometriosis reactivation. 1, 2, 3

Why Combined Therapy is Essential

Endometrial Protection is Non-Negotiable

• Any woman with an intact uterus requires progestin opposition when using estrogen therapy, regardless of endometriosis history, to prevent endometrial hyperplasia and cancer. 1, 2
• The FDA explicitly warns that unopposed estrogen increases endometrial cancer risk, and adding progestin reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 2
• This requirement applies even after hysterectomy for endometriosis, as residual endometriotic tissue can undergo malignant transformation with unopposed estrogen. 3, 4

Endometriosis-Specific Considerations

• Women with endometriosis history who receive unopposed estrogen face higher risk of disease reactivation and potential malignant transformation compared to combined preparations. 5, 3, 4
• The ESHRE guideline specifically states that for women with endometriosis who required oophorectomy, combined estrogen/progestogen therapy can be effective for treating vasomotor symptoms and may reduce the risk of disease reactivation. 1
• Multiple reviews confirm that continuous combined preparations are the optimal choice for women with endometriosis history, even after hysterectomy. 3, 4

Recommended Transdermal Regimen

Optimal Patch Formulation

• Use a combined estrogen-progestin transdermal patch delivering 50 mcg/day of 17β-estradiol with continuous progestin. 1, 6, 7
• Transdermal 17β-estradiol is explicitly preferred over oral formulations because it has lower cardiovascular and thrombotic risk, which is particularly important given this patient's metabolic medication use. 1, 7
• The transdermal route avoids first-pass hepatic metabolism, reducing venous thromboembolism and stroke risk compared to oral estrogen. 1, 7

Progestin Component Selection

• Micronized progesterone is the preferred progestin due to superior cardiovascular and metabolic safety profile compared to synthetic progestins like medroxyprogesterone acetate. 6, 7
• If a combined patch is not available, pair a 50-100 mcg/day transdermal estradiol patch with oral micronized progesterone 100-200 mg daily continuously. 6, 7
• Continuous combined regimens (daily progestin without interruption) are preferred over sequential regimens for women with endometriosis history, as they may further reduce disease reactivation risk. 3, 4

Why Estrogen-Only is Contraindicated

Absolute Contraindication with Intact Uterus

• Estrogen-only therapy in a woman with a uterus is medically inappropriate and carries unacceptable endometrial cancer risk. 2
• Even "minimum dose" estrogen-only patches require progestin opposition—there is no safe dose of unopposed estrogen for women with a uterus. 2

Endometriosis Reactivation Risk

• Unopposed estrogen carries higher risk of endometriosis recurrence than combined preparations, with case reports documenting malignant transformation of endometriomas in postmenopausal women using estrogen-only HRT. 5, 4
• One study found 4/115 women on combined HRT developed pain recurrence versus 0/57 in no-treatment controls, but unopposed estrogen would carry even higher risk. 8

Mounjaro (Tirzepatide) Interaction Clarification

No Contraindication to Transdermal Hormones

• There is no pharmacologic interaction between tirzepatide and transdermal hormone therapy that would contraindicate combined patches. The concern with oral combined pills relates to potential GI absorption issues with GLP-1 receptor agonists, which is completely bypassed with transdermal delivery. 1
• Transdermal estradiol avoids first-pass metabolism and GI absorption variability, making it ideal for patients on medications affecting gastric emptying. 1

Monitoring and Safety

Essential Follow-Up

• Perform baseline endometrial ultrasound to document endometrial thickness before initiating therapy. 6
• Annual clinical review focusing on bleeding patterns, symptom control, and any signs of endometriosis reactivation (pelvic pain, dyspareunia). 1, 7
• Instruct the patient to report any pelvic pain, abnormal bleeding, or dyspareunia immediately, as these may indicate disease reactivation. 3, 4

Duration of Therapy

• Use the lowest effective dose for symptom control, but continue therapy at least until the average age of natural menopause (50-51 years) if she has premature ovarian insufficiency. 1, 7
• After natural menopause age, reassess risks versus benefits annually, but do not automatically discontinue if symptoms persist and quality of life is significantly impaired. 7

Common Pitfalls to Avoid

• Never prescribe estrogen-only therapy to any woman with a uterus, regardless of dose—this is an absolute contraindication. 2
• Do not delay starting HRT after surgery for endometriosis—delay provides no benefit in reducing recurrence risk. 5
• Avoid oral estrogen formulations when transdermal options are available, especially in patients on metabolic medications like tirzepatide. 1
• Do not use sequential (cyclic) progestin regimens in women with endometriosis history—continuous combined therapy is preferred. 3, 4