Cancer Risk with Hormone Replacement Therapy

Breast Cancer Risk

The Women's Health Initiative study found that combined estrogen-progestin HRT increases the risk of invasive breast cancer (relative risk 1.26, 95% CI 1.00-1.59) 1

Unopposed estrogen therapy significantly increases endometrial cancer risk (relative risk 2.3, 95% CI 2.1-2.5) according to the American Academy of Family Physicians 2, 1
Risk increases dramatically with duration of use, reaching a relative risk of 9.5 for 10 years of use, as reported by the American Academy of Family Physicians 2, 3
The elevated risk remains for at least 5 years after discontinuation of unopposed estrogen therapy, as found by the American Academy of Family Physicians 2

Long-term HRT use (10+ years) is associated with increased risks of ovarian cancer mortality (RR 1.8-2.2) according to the American Academy of Family Physicians 2, 3

HRT appears to reduce the risk of colorectal cancer, as reported by the American College of Physicians 4
Transdermal routes show lower thrombotic risk (odds ratio 0.9 vs 4.2 for oral) according to the American College of Physicians 1, 5

For women with an intact uterus, progestogen must be used in combination with estrogen to protect against endometrial hyperplasia and cancer, as recommended by the American College of Obstetricians and Gynecologists 1
Transdermal estradiol is preferred over oral formulations, particularly for women with hypertension or elevated thrombotic risk, according to the American Heart Association 1, 5
Annual clinical reviews with mammography are recommended for women using HRT, as suggested by the American College of Radiology 1

Limit duration of HRT use to the shortest period needed for symptom control, as recommended by the American Academy of Family Physicians 2, 3
Consider transdermal rather than oral administration to reduce thrombotic risk, according to the American Heart Association 1, 5
Women with BRCA gene mutations should be particularly cautious about HRT use due to potential breast cancer risk, as advised by the American College of Medical Genetics and Genomics 1

Unopposed systemic estrogen therapy increases endometrial cancer risk 10-30 fold if treatment continues for 5 years or more, according to the American Society of Clinical Oncology 6

The American Urological Association guidelines state that data do not show an increased risk of recurrence of breast cancer, endometrial hyperplasia or carcinoma in women who use vaginal estrogen for urogenital symptoms, with minimal systemic absorption and no associated increase in serum estrogen 7
Women with a history of breast cancer who are experiencing severe genitourinary symptoms may use vaginal estrogen with caution, as data do not show an increased risk of breast cancer recurrence, as recommended by the American Urological Association 7

The American Family Physician reports that progesterone, when used in combination with estrogen, increases the risk of stroke by approximately 41% (RH 1.41, 95% CI 0.86-2.31) 8
The American Family Physician also found that venous thromboembolism risk is doubled (RR 2.14, 95% CI 1.64-2.81) with hormone therapy containing progesterone, with highest risk in the first year of use 8
The Women's Health Initiative study, as reported by the American Family Physician, found that estrogen plus progestin therapy was associated with a 29% increased risk of coronary heart disease (RH 1.29, 95% CI 1.02-1.63) 8
The BMJ recommends that cardiovascular risks, which are particularly elevated in women with pre-existing risk factors such as hypertension, smoking, or age over 35, should be carefully considered when prescribing progesterone hormone therapy 9

The American Family Physician suggests that when used alone (unopposed), progesterone does not appear to increase endometrial cancer risk and may be protective compared to unopposed estrogen 8
The American Family Physician also found that long-term hormone therapy containing progesterone (10+ years) has been associated with increased risks of ovarian cancer mortality (RR 1.8-2.2) 8

The BMJ recommends considering alternative treatments for symptoms if cardiovascular risk factors are present 9