What are the side effects of bioidentical hormone replacement therapy (HRT)?

Side Effects of Bioidentical Hormone Replacement Therapy

Bioidentical hormone replacement therapy (HRT) carries significant risks including increased risk of stroke, venous thromboembolism, breast cancer, and gallbladder disease, with risks often outweighing benefits for chronic disease prevention in most women. 1

Cardiovascular and Thrombotic Risks

• Bioidentical HRT increases the risk of stroke, with a relative risk of 1.12 (95% CI, 1.01 to 1.23) according to meta-analyses of observational studies 1
• Venous thromboembolism risk is significantly increased with HRT use (RR, 2.14 [95% CI, 1.64 to 2.81]), with highest risk occurring within the first year of use (RR, 3.49 [95% CI, 2.33 to 5.59]) 1
• HRT may increase the risk of coronary heart disease rather than decrease it, as was previously thought 1
• Transdermal administration of estrogen is associated with lower thrombotic risk compared to oral routes (odds ratio for venous thromboembolism of 0.9 compared to 4.2 for oral preparations) 2

Cancer Risks

• Unopposed estrogen therapy significantly increases the risk of endometrial cancer (RR, 2.3 [95% CI, 2.1 to 2.5]), with risk increasing with duration of use (RR, 9.5 for 10 years of use) 1
• Combined estrogen-progestin therapy has shown increased breast cancer incidence (RH, 1.26 [95% CI, 1.00 to 1.59]) in the Women's Health Initiative study 1, 3
• Data on ovarian cancer risk are inconsistent, but some cohort studies report increased risks (RR, 1.8 to 2.2) for women who have taken HRT for 10 years or more 1
• Women with BRCA gene mutations should be particularly cautious about HRT use due to potential breast cancer risk 1

Gastrointestinal Side Effects

• Increased risk of cholecystitis has been reported among current HRT users (RR, 1.8 [95% CI, 1.6 to 2.0]) and long-term users (>5 years) (RR, 2.5 [95% CI, 2.0 to 2.9]) 1
• Common gastrointestinal side effects include nausea, bloating, and abdominal discomfort 4, 5
• In surveys of women using bioidentical HRT, bloating was reported in 23.1% of users 6

Common Short-term Side Effects

• Weight gain (37.2%), breast tenderness (19.2%), and bloating (23.1%) are commonly reported with bioidentical HRT 6
• Headache, vaginal bleeding, and skin reactions are more common in women using bioidentical HRT compared to placebo 7
• Mood alterations may occur and can sometimes be managed by adjusting dosage or changing preparations 5

Considerations for Different Formulations

• 17-β estradiol is preferred to ethinylestradiol or conjugated equine estrogens for estrogen replacement 1
• Transdermal estradiol is the preferred method of delivery for women with hypertension 1, 2
• Higher doses of bioidentical HRT may be associated with greater effectiveness but also higher risk of adverse effects 7

Important Clinical Considerations

• Women with an intact uterus must use progestogen in combination with estrogen to protect the endometrium from hyperplasia and cancer 1, 7
• The FDA drug label for estradiol warns of serious side effects including breast cancer, heart attack, stroke, blood clots, dementia, and gallbladder disease 4
• Warning signs requiring immediate medical attention include unusual vaginal bleeding, chest pain, severe headaches, shortness of breath, leg pain, vision changes, and vomiting 4
• Risk of venous thromboembolism is highest within the first year of HRT use 1

Monitoring and Management

• Annual clinical reviews are recommended for women using bioidentical HRT, with particular attention to compliance 1
• Side effects can often be managed by changing the dose, using another preparation, or altering the route of administration 5
• Irregular bleeding warrants endometrial biopsy to rule out hyperplasia 5
• Women should be informed that while bioidentical hormones are chemically identical to those produced by the human body, they still carry significant risks 7