In a postmenopausal woman with an intact uterus who has been on estrogen therapy alone for one year and has no contraindications, should progesterone be added?

Yes—Progesterone Must Be Added Immediately

A postmenopausal woman with an intact uterus who has been on estrogen therapy alone for one year should have progesterone added immediately to prevent endometrial hyperplasia and cancer. Unopposed estrogen dramatically increases endometrial cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5), escalating to 9.5-fold after 10 years of use, and this patient has already accumulated one year of unopposed exposure 1, 2.

Critical Endometrial Protection Requirement

The FDA explicitly mandates that 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. This is not optional—it is a fundamental safety requirement.

Magnitude of Risk Without Progesterone

• Unopposed estrogen increases endometrial cancer risk 10- to 30-fold if continued for 5 years or more 2, 4
• The risk persists for 5 or more years even after discontinuing unopposed estrogen 2
• Adding progestogen reduces endometrial cancer risk by approximately 90% compared to unopposed estrogen 1, 2

Recommended Progesterone Regimen

Start micronized progesterone 200 mg orally at bedtime as the preferred progestin due to its superior breast safety profile compared to synthetic progestins while maintaining adequate endometrial protection 2, 5, 6.

Dosing Options

• Continuous regimen: 200 mg daily without interruption (preferred for simplicity and compliance) 2
• Sequential regimen: 200 mg daily for 12-14 days per 28-day cycle 2

Alternative Progestins (if micronized progesterone unavailable)

• Medroxyprogesterone acetate (MPA) 2.5 mg daily (continuous) or 10 mg daily for 12-14 days per month (sequential) 2, 7
• Dydrogesterone 10 mg daily for 12-14 days per month 2
• Norethisterone acetate (NETA) 1 mg daily (continuous) 7

Why Micronized Progesterone Is Preferred

Micronized progesterone does not increase cell proliferation in breast tissue compared to synthetic MPA, and observational studies suggest natural progesterone is associated with lower breast cancer risk compared to other progestins 5, 6. However, recent data suggest micronized progesterone may be slightly less efficient than synthetic progestins for endometrial protection, though it remains adequate when dosed appropriately 8.

Immediate Clinical Actions

Before Adding Progesterone

Perform endometrial assessment immediately given one year of unopposed estrogen exposure 3:

• Transvaginal ultrasound to measure endometrial thickness
• If endometrial thickness >4-5 mm or any abnormal bleeding has occurred, perform endometrial biopsy to rule out hyperplasia or malignancy 3

After Initiating Progesterone

• Continue the current estrogen dose (do not discontinue) while adding progesterone 2
• Use the lowest effective estrogen dose for symptom control 1, 3
• Transdermal estradiol 50 μg patch twice weekly is preferred over oral formulations due to lower cardiovascular and thromboembolic risks 2

Monitoring Requirements

• Annual clinical review with attention to compliance and ongoing symptom burden 1, 2
• Investigate any undiagnosed persistent or recurring abnormal vaginal bleeding with endometrial sampling 3
• No routine laboratory monitoring (estradiol levels, FSH) is required—management is symptom-based 2

Critical Pitfall to Avoid

Never prescribe estrogen-alone therapy to women with an intact uterus beyond the initial evaluation period—this dramatically increases endometrial cancer risk and represents a fundamental prescribing error 2. The only exception is women who have undergone hysterectomy, for whom estrogen-alone therapy is appropriate and actually shows reduced breast cancer risk 1, 4.

Duration of Combined Therapy

• Use the lowest effective dose for the shortest duration consistent with treatment goals 1, 3
• Reassess necessity every 3-6 months and attempt discontinuation or dose reduction once symptoms are controlled 3
• For women under 60 or within 10 years of menopause, the risk-benefit profile is most favorable 2
• For women over 60 or more than 10 years past menopause, use the absolute lowest dose possible and strongly consider discontinuation 2