This review provides a strong, evidence-based counterpoint to prevailing narratives, shifting the focus from contentious benefits to documented harms. As the chapter on ethics from the recently-released HHS report made clear, the ethics of an intervention are very different when the benefits are very uncertain and the risks much less so. What this review shows beyond doubt is that, at least among males, cross-sex hormones make little sense, if a medical professional wants to practice ethics-informed medicine. For example, if adults want to smoke, claiming that it gives them relief, that is their choice. But that does not mean that doctors will have to prescribe tobacco just because someone wishes to get it. 

These are the key highlights of the study:

• Extensive Risk Profile: It details a wide range of significant risk signals, including severe cardiovascular issues (venous thromboembolism, ischemic stroke), fertility problems, autoimmune diseases (lupus, rheumatoid arthritis, systemic sclerosis), various cancers (testicular, breast, thyroid), pancreatitis, and even potential cognitive decline and depression.

• Substantial Risk Increases with long-term usage: These above-mentioned risks aren't minor issues. The review highlights data suggesting significant risk increases, some doubling, others potentially rising over 40-fold, especially with long-term use. For example, one large cohort study found that the risk of VTE became 5.1 times higher after two years, and the risk of ischemic stroke rose to nearly 10 times higher after six years. (Compare this to the pain medication Vioxx, which had an approximate relative risk of 1.84 for MI/stroke in the trial leading to its withdrawal, and Merck, its manufacturer, had to pay a nearly $5 billion in settlements.)

• Challenging the Benefit Narrative: The paper reinforces the lack of robust evidence for benefits, particularly noting studies (like Chen 2023 in the NEJM) showing no psychosocial improvement in male adolescents and even a re-analysis (of Turban's study in PLOS ONE by Michael Biggs) indicating increased suicidality in natal males on estrogen.

• Addressing Autonomy Arguments: Implicitly, it confronts the recent shift towards autonomy-based justifications, arguing that the sheer scope and severity of these lifelong systemic harms present a fundamentally different ethical challenge compared to procedures with well-established safety profiles. It underscores the medical principle of non-maleficence.

The following is a summary of key adverse outcomes and emerging safety signals from the medical literature.

Cardiovascular Risks Estrogen therapy is consistently linked to severe and escalating cardiovascular dangers.

• Blood Clots (VTE): A major, well-documented risk. One review concluded estrogen  therapy increases the risk of Venous Thromboembolism (VTE) over fivefold (Irwig,  2018). A large cohort study found that the VTE risk was 4.6 times higher than in other  men (Nota et al., 2019).

• Stroke: The risk of ischemic stroke is significantly elevated. One meta-analysis found a  30% higher incidence (van Zijverden et al., 2024), and another major study reported an  80% increased risk compared to other men (Nota et al., 2019).

• Escalating Long-Term Risk: The danger increases dramatically over time. One study  found that after 6 years of use, the risk of ischemic stroke rose to nearly 10 times higher  than in the non-estrogen-using male population. The VTE risk became 5.1 times higher  after 2 years (Getahun et al., 2018).

• Retinal Vein Occlusion: Case reports link estrogen therapy to branch retinal vein  occlusion (BRVO), a cause of sudden vision loss (Andzembe et al., 2023).  

Cancer Risks 

Evidence points to a substantially increased risk of several cancers.

• Breast Cancer: A meta-analysis found the standardized incidence ratio (SIR) for breast  cancer was over 40 times higher in individuals on estrogen compared to other men  (Corso et al., 2023).

• Testicular Cancer: Histopathological studies of removed testes have found rates of  germ cell neoplasms that are alarmingly high. One analysis calculated an annual  incidence 26.5 times higher than that of the general male population (Shanker et al., 2024).

• Meningioma (Brain Tumor): An analysis of the French pharmacovigilance database found that meningiomas were the principal adverse drug reaction reported for individuals on feminizing hormones (Yelehe et al., 2022).

• Thyroid Cancer: One study of US veterans found a higher prevalence of thyroid cancer compared to non-transgender men, with a higher incidence of the more aggressive Hürthle cell cancer subtype (Christensen et al., 2024).

  
  

Fertility & Reproductive Harms 

Estrogen causes profound and often permanent damage to the male reproductive system.

• Infertility & Testicular Atrophy: Estrogen therapy suppresses sperm production, leading to infertility. It causes atrophic changes in the testes, including smaller seminiferous tubules, hyalinization (tissue hardening), and fibrosis (De Roo et al., 2025).

• Abnormal Sperm & DNA Damage: The treatment results in higher proportions of sperm abnormalities, including low count, poor motility, and azoospermia (no sperm). Analysis of testicular tissue after orchiectomy revealed that 65% of cases showed cellular atypia mimicking germ cell neoplasia (a precursor to cancer) (Riva-Morales et al., 2025).

Neurological & Cognitive Risks 

Estrogen is associated with concerning structural and functional changes in the brain.

• Brain Volume Loss: Multiple studies show that estrogen use is associated with a decrease in total brain volume and an increase in ventricle size (Hulshoff Pol et al., 2006; Seiger et al., 2016). Animal studies suggest this may be due to a loss of water content in brain cells (Gómez et al., 2020).

• Cognitive Impairment: A long-term study found that older individuals who had been on estrogen for an average of 28.5 years had lower scores in information-processing speed and episodic memory compared to both male and female controls (van Heesewijk et al., 2023).

• Lowered BDNF: Estrogen use has been associated with reduced serum levels of Brain-Derived Neurotrophic Factor (BDNF), a protein crucial for brain health. Lower BDNF is linked to an increased risk of Major Depressive Disorder (Fuss et al., 2015).

Metabolic & Autoimmune Risks 

• Diabetes & Insulin Resistance: Estrogen therapy is associated with increased fat mass and worsened insulin resistance. One study found that HOMA-IR, a key marker of insulin resistance, increased by 72% within the first year of treatment (Colizzi et al., 2015).

• Pancreatitis: Case studies link estrogen use to both hypertriglyceridemia-induced and gallstone pancreatitis (Chaudhry et al., 2021; Freier et al., 2021).

• Autoimmune Disease: Case reports describe new onset or severe worsening of autoimmune conditions like Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (Salgado et al., 2022). One large study found a 6.6-fold increased rate of Multiple Sclerosis (MS) (Pakpoor et al., 2016).

Mortality 

• Increased All-Cause Mortality: A landmark five-decade Dutch cohort study found that individuals on feminizing hormones had a significantly higher overall mortality risk (SMR 1.8) compared to men in the general population. This gap in survival widened over time. The leading causes of death were cardiovascular disease (21%) and cancer (32%) (de Blok et al., 2021).

Conclusion: The use of feminizing hormones in natal males is linked to a wide array of life-altering and life-threatening harms. These include dramatically increased risks for cardiovascular events, various cancers, irreversible infertility, brain changes, and overall mortality. The severity and breadth of these safety signals underscore the need for extreme caution and transparent, comprehensive informed consent.

Schwartz, L., Lal, M., Cohn, J. et al. Emerging and accumulating safety signals for the use of estrogen among transgender women. Discov Ment Health 5, 88 (2025). https://doi.org/10.1007/s44192-025-00216-3

References

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