Is estrogen prescribed alone in women with an intact uterus?

Is Estrogen Prescribed Alone in Women with an Intact Uterus?

No, estrogen should never be prescribed alone in women with an intact uterus—progestin must be added to prevent endometrial cancer. 1

The Fundamental Rule

When estrogen is prescribed for a woman with a uterus, progestin must also be initiated to reduce the risk of endometrial cancer. 1 This is not optional—it is mandatory to prevent endometrial hyperplasia and cancer. 2

Why Unopposed Estrogen is Dangerous

Unopposed estrogen dramatically increases endometrial cancer risk:

• Unopposed estrogen significantly increases endometrial cancer risk (RR 2.3,95% CI 2.1-2.5). 3
• The risk escalates dramatically with duration: relative risk reaches 9.5 after 10 years of unopposed estrogen use. 3
• The elevated risk persists for at least 5 years after discontinuation. 3
• This is precisely why estrogen without progestin has been restricted to women who have had a hysterectomy. 3

Evidence from Clinical Trials

The Women's Health Initiative enrolled 10,739 women who had undergone prior hysterectomy and randomized them to receive estrogen alone or placebo—notably, these women had no uterus. 4 The trial involving 16,608 women with intact uteri received estrogen plus progestin, not estrogen alone. 4

Multiple large observational studies confirm the danger:

• The Million Women Study found unopposed estrogen increased endometrial cancer risk (RR 1.45,95% CI 1.02-2.06). 5
• A Swedish population-based study showed 5 or more years of unopposed estrogen had an OR of 6.2 for estradiol and 6.6 for conjugated estrogens. 6

The Only Exception: Post-Hysterectomy

A woman without a uterus does not need progestin. 1 Women who have had a hysterectomy can use estrogen alone, which paradoxically reduces breast cancer risk but still carries DVT, stroke, and gallbladder disease risks. 3

How to Provide Endometrial Protection

For women with an intact uterus requiring estrogen therapy, progestin regimens include:

Cyclic Regimens:

• Micronized progesterone 200 mg daily for 12-14 days per month 2
• Medroxyprogesterone acetate 10 mg daily for 12-14 days per month 2
• Dydrogesterone 10 mg daily for 12-14 days per month 2

Continuous Regimens (preferred for endometrial protection):

• Minimum of 1 mg oral norethisterone daily 2
• 2.5 mg oral medroxyprogesterone acetate daily 2
• 5 mg oral dydrogesterone daily 2

Continuous combined therapy shows superior endometrial protection (RR 0.71,95% CI 0.56-0.90) compared to sequential regimens. 5, 7 Sequential progestin use (<15 days per month) for ≥10 years increases endometrial cancer risk (RR 1.88,95% CI 1.36-2.60), whereas continuous progestin use (>25 days per month) decreases risk (RR 0.64,95% CI 0.49-0.83). 8

Critical Pitfall to Avoid

Using unopposed estrogen in women with an intact uterus poses a risk of endometrial hyperplasia and cancer. 2 Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer, and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. 1

Special Consideration: Vaginal Estrogen

Even low-dose vaginal estrogen requires progestogen protection in women with an intact uterus. 2 The FDA warns that unopposed estrogens increase the risk of endometrial cancer in women with a uterus, and this risk applies to both systemic and topical estrogen formulations, though the risk may be lower with vaginal preparations. 2