Safety of Estrogen-Based Feminizing Gender-Affirming Hormone Therapy: A Practical Endocrine Approach to Risk Stratification and Monitoring

Abstract

Estrogen-based feminizing hormone therapy is a cornerstone of care for transfeminine and gender-diverse individuals. Its benefits are well established, including improvements in gender dysphoria, mental health, and overall quality of life, with meaningful downstream effects on social functioning and long-term well-being.

Much of the historical concern regarding safety largely reflects earlier use of ethinyl estradiol, which was associated with substantially increased risks of venous thromboembolism (VTE) and cardiovascular events. Contemporary practice has shifted toward the use of 17β-estradiol delivered orally, transdermally, or by injection, alongside more individualized dosing, and attention to baseline risk. This transition has materially improved the safety profile of therapy.

The primary safety concern remains VTE, alongside evolving considerations related to cardiovascular risk and malignancy screening. Contemporary data suggest that these risks are both predictable and modifiable, allowing clinicians to individualize therapy without compromising gender-affirming outcomes.

This review provides a clinically focused framework for risk stratification, route selection, and monitoring of estrogen-based feminizing therapy.