What are the potential risks associated with estrogen therapy for postmenopausal women?

Risks Associated with Estrogen Therapy in Postmenopausal Women

All four options listed are associated with estrogen therapy in postmenopausal women, but the specific risks vary critically based on whether estrogen is used alone or combined with progestin.

Thrombophlebitis/Deep Venous Thrombosis (Option A)

Both unopposed estrogen and combined estrogen-progestin therapy increase the risk of deep venous thrombosis (DVT) and pulmonary embolism. 1

• Estrogen-only therapy is associated with a small increase in DVT risk 1
• Combined estrogen-progestin therapy carries convincing evidence of a small increased risk for DVT and pulmonary embolism 1
• Oral estrogen formulations increase VTE risk approximately 4-fold (OR 4.2,95% CI 1.5-11.6), while transdermal estrogen shows no significant association (OR 0.9,95% CI 0.4-2.1) 2
• FDA labeling confirms a 2- to 4-fold increase in relative risk of post-operative thromboembolic complications with oral estrogen use 3

Hepatic Adenoma (Option B)

Benign hepatic adenomas are associated with oral estrogen use, though the incidence is rare. 3

• The attributable risk is estimated at 3.3 cases per 100,000 users, increasing after four or more years of use 3
• Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage 3
• Long-term use (>8 years) has shown increased risk of hepatocellular carcinoma, though these cancers are extremely rare in the U.S. with attributable risk approaching less than one per million users 3

Endometrial Cancer (Option C)

Unopposed estrogen therapy dramatically increases endometrial cancer risk, which is precisely why progestin must be added for women with an intact uterus. 1, 4

• Unopposed estrogen significantly increases endometrial cancer risk (RR 2.3,95% CI 2.1-2.5) 4
• Risk escalates dramatically with duration: relative risk reaches 9.5 after 10 years of unopposed estrogen use 4
• The elevated risk persists for at least 5 years after discontinuation 4
• This is the fundamental reason estrogen without progestin has been restricted to women who have had a hysterectomy 1
• Continuous combined estrogen-progestin therapy actually reduces endometrial cancer risk (RR 0.71,95% CI 0.56-0.90) compared to never users 5

Breast Cancer (Option D)

The relationship between estrogen therapy and breast cancer depends critically on whether progestin is added:

• Combined estrogen-progestin therapy increases invasive breast cancer risk (RR 1.26,95% CI 1.00-1.59) with convincing evidence of a small increase in breast cancer incidence and deaths 1, 4
• Estrogen-only therapy paradoxically shows a small reduction in invasive breast cancer risk (about 8 fewer cases per 10,000 person-years) and breast cancer deaths (about 2 fewer deaths per 10,000 person-years) 1
• The biological mechanism underlying this protective effect of estrogen alone versus the harmful effect of combined therapy remains unclear 1

Critical Clinical Distinctions

The formulation type fundamentally alters the risk profile:

• Women with an intact uterus require progestin addition to prevent endometrial cancer, but this increases breast cancer risk 1, 4
• 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 1
• Transdermal estrogen shows substantially lower thrombotic risk (OR 0.9) compared to oral formulations (OR 4.2) 2

Answer to the Multiple Choice Question

All four options (a, b, c, d) are correct associations, though the magnitude and context vary. The most clinically significant associations are:

• (a) Thrombophlebitis/DVT: Consistently increased with both formulations
• (c) Endometrial cancer: Dramatically increased with unopposed estrogen (the primary reason for adding progestin)
• (d) Breast cancer: Increased with combined therapy but paradoxically decreased with estrogen-only therapy

If forced to select a single answer, option (c) endometrial cancer with unopposed estrogen represents the most dramatic and clinically consequential risk, with relative risks reaching 9.5 after prolonged use 4, which fundamentally shapes prescribing practices for all postmenopausal women with an intact uterus.