The use of feminizing hormones (estrogen and/or anti-androgens) in males is linked to extensive, life-threatening risks—including cardiovascular events, various cancers, irreversible infertility, and brain changes. It is now emerging that males who use these substances for prolonged periods die much sooner than males who do not. Estrogen therapy causes systemic harm spanning vascular, endocrine, reproductive, neurological, metabolic, and immune pathways. Of even greater concern, affirming studies like Chen et al. (2023) in the New England Journal of Medicine show no psychosocial benefits of opposite-sex hormone therapy in males to offset these significant health risks. For males who traditionally transitioned in their 40s or 50s, the risks from opposite-sex hormones was naturally limited by the competing mortality risks of old age. For the current cohort who start taking feminizing hormones as adolescents or young adults, these risks start compounding from a very early age. This might explain their startlingly higher risk of death compared to their peers in their 50s and beyond. 

 

For a full review of risks from over 50 studies through early 2025, refer to this open-access paper, available freely to download and share: Emerging and accumulating safety signals for the use of estrogen among transgender women, Schwartz et al., June 2025, Discover Mental Health, Volume 5, Article 88. (Summary tables appear on pages 7–11; references on pages 13–17.)

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Cardiovascular and Blood Risks

• Increased risk of venous thromboembolism (VTE): potentially >5× higher after two years, escalating over time  (Getahun et al., 2018; Nota et al., 2019; Van Zijverden et al., 2024; Asscheman et al., 2011)

• Increased risk of stroke: potentially 10× higher after six years, escalating over time (Getahun et al., 2018; Nota et al., 2019; Van Zijverden et al., 2024)

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Reproductive System Harms

• Likely permanent testicular atrophy (Cheng et al., 2019; Schneider F et al., 2017)

• Abnormal sperm production, including cessation of spermatogenesis (azoospermia) (De Roo et al., 2025)

• Atypical germ cells mimicking germ cell neoplasia (an abnormal growth that develops from reproductive cells) (Shanker et al., 2024; Riva‑Morales et al., 2025)

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Brain Health and Neurological Risks

• Structural brain changes: decreased cortical volume, decreased gray matter, increased ventricle size (Hulshoff Pol et al., 2006; Seiger et al., 2016; Gómez et al., 2020)

• Cognitive decline: long term estrogen use associated with lower information processing speed and episodic memory (van Heesewijk et al., 2025)

• Reduced BDNF and increased depression risk: lower BDNF (Brain-Derived Neurotrophic Factor, a vital neuropeptide primarily synthesized in the central nervous system, it functions as a potent growth factor that supports the survival, maturation, and differentiation of neurons) linked to major depressive disorder and reduced hippocampal volume (Fuss et al., 2015; Emon et al., 2020; Frodl et al., 2006)

• Elevated estradiol associated with increased depressive symptoms in adult men and adolescent boys (Stanikova et al., 2017; Chronister et al., 2021)

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Autoimmune Risks

• Severe autoimmune reactions, including scleroderma renal crisis (Arneson & Varga, 2021)

• Immune mediated inflammatory diseases: lupus, rheumatoid arthritis, systemic sclerosis (Salgado et al., 2022)

• Increased multiple sclerosis risk: MS rate ratio 6.63× higher (Pakpoor et al., 2016)

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Metabolic Risks

• Increased insulin resistance: HOMA IR (a score that estimates how well your body handles insulin) increased 72% in first year, additional rise in second year (Spanos et al., 2020; Colizzi et al., 2015; Glintborg et al., 2024; Panday et al., 2024)

• Pancreatitis risk, including severe gallstone pancreatitis (Freier et al., 2021; Chaudhry et al., 2021)

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Cancer Risks

• Breast cancer: Standardized Incidence Ratio 22.5–40.7× higher vs men in the general population (Corso et al., 2023; Brinton et al., 2015)

• Testicular cancer/germ cell neoplasms: incidence potentially 26.5× higher (Riva Morales et al., 2025; Shanker et al., 2024; Bonapace-Potvin et al., 2022; de Nie et al., 2022)

• Thyroid cancer, including aggressive Hürthle cell type (Derwahl & Nicula, 2014; Christensen et al., 2024)

• Meningiomas and other neoplasms: principal adverse drug reaction in French pharmacovigilance, the branch of medicine that identifies potential adverse events after the introduction of a medical intervention (Yelehe et al., 2022; Gomez Lumbreras & Villa Zapata, 2024)

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Premature Death

Perhaps the most objective marker of increased risk is the dramatically higher mortality in this demographic, which deviates increasingly with age from both men and women in the general population.

• Overall mortality dramatically higher: SMR 1.8× higher vs men in the general population (de Blok et al., 2021)

• Estradiol use associated with 3× increased cardiovascular mortality (Asscheman et al., 2011)

• Earlier mortality and higher chronic disease burden: in U.S. and U.K. cohorts (Hughes et al., 2022; Jackson et al., 2023); the U.S. data shows that by age 50, the risk of death among trans-identifying men is 3.1x higher than men in the general population and 4.6x higher than women in the general population.

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Learn more about the risks of “gender-affirming care.”