What are the risks associated with estradiol (Estrogen) and testosterone replacement therapy?

From the Guidelines

Hormone replacement therapy with estradiol and testosterone carries significant risks, including increased chances of blood clots, stroke, and heart attack, and should be approached with caution and personalized medical guidance. The risks associated with estradiol replacement include increased chances of blood clots, stroke, and heart attack, particularly in older patients or those who smoke, as well as a potential increased risk of breast cancer with long-term use, especially when combined with progestin 1. Additionally, gallbladder disease, elevated triglycerides, and worsening of migraines are concerns. For testosterone replacement, risks include polycythemia, acne and oily skin, male pattern baldness, and potential worsening of sleep apnea, as well as testicular shrinkage, reduced fertility, and mood changes including aggression or irritability 1.

In women, testosterone can cause unwanted hair growth, deepening voice, and clitoral enlargement. Both hormones can affect liver function and may worsen existing liver disease, highlighting the need for careful consideration in patients with liver conditions 1. The most recent and highest quality study, published in 2021, emphasizes the importance of personalized risk-benefit ratios and regular monitoring during hormone replacement therapy 1.

Key considerations for hormone replacement therapy include:

• Individual health factors, such as age, dosage, and administration method
• Potential interactions with existing medical conditions, such as liver disease
• Regular monitoring through blood tests, physical examinations, and appropriate cancer screenings
• Personalized medical guidance to weigh the benefits and risks of hormone replacement therapy.

Overall, while hormone replacement therapy can be beneficial for some patients, it is crucial to approach this treatment with caution and careful consideration of the potential risks and benefits, prioritizing personalized medical guidance and regular monitoring.

From the FDA Drug Label

In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women-years). In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer The most important randomized clinical trial providing information about breast cancer in estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg). After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA.

The risks of estradiol and testosterone replacement include:

• Cardiovascular events: increased risk of myocardial infarction, stroke, and venous thrombosis
• Venous thromboembolism (VTE): increased risk of deep venous thrombosis and pulmonary embolism
• Endometrial cancer: increased risk in women with intact uteri
• Breast cancer: increased risk in women taking estrogen plus progestin therapy However, there is no information about the risks of testosterone replacement in the provided drug labels. 2, 2, 3

From the Research

Risks of Estradiol and Testosterone Replacement

• The use of hepatotoxic androgens must be avoided in testosterone replacement therapy 4
• Testosterone treatment induces reversible suppression of spermatogenesis, which may be a concern for men who desire fertility in the near future 4
• Estradiol, a stronger estrogen, is associated with significant risks, but estriol, a weaker estrogen, may provide some protection without these risks 5
• However, continuous use of estriol in high doses may have a stimulatory effect on both breast and endometrial tissue 5
• Hormone replacement therapy, including estradiol, is associated with potential risks, and its use should be carefully considered and monitored 6

Considerations for Replacement Therapy

• Patients should meet criteria for hypogonadism, including a low testosterone level and signs or symptoms of hypogonadism, to receive exogenous testosterone replacement therapy 7
• Management discussions should be individualized to address patient needs and goals, and counseling before therapy should include shared decision-making regarding risks, benefits, and expectations 7
• The choice of testosterone formulation depends on factors such as cost and patient preference, and patients receiving this therapy require close monitoring 7
• The benefits and potential risks of hormone replacement therapy, including estradiol, should be carefully considered and discussed with patients 6

Guidelines and Recommendations

• The Society for Endocrinology has published guidelines for testosterone replacement therapy in male hypogonadism, which provide a multidisciplinary approach to treating patients with this condition 8
• Current recommendations for hormone replacement therapy use in menopausal women emphasize the importance of careful consideration and monitoring of potential risks and benefits 6