The use of supraphysiologic doses of testosterone in natal females to induce male secondary sex characteristics is associated with a range of significant health risks across multiple organ systems. This document summarizes key adverse outcomes and safety signals identified in the medical literature.

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Cardiovascular and Blood Risks

Testosterone therapy is consistently linked to a more dangerous cardiovascular profile.

• Heart Attack (Myocardial Infarction): Studies report a significantly increased risk. One analysis found nearly fivefold increased odds of a heart attack compared to other women not on hormones (Alzahrani et al., 2019). Another large cohort study found a 3.7-fold higher incidence (Nota et al., 2019).

• Adverse Lipid Profile: Testosterone consistently creates a more atherogenic lipid profile by significantly increasing "bad" cholesterol (LDL) and triglycerides while significantly decreasing "good" cholesterol (HDL). These changes are sustained over the long term (Gosiker et al., 2024).

• Erythrocytosis (Dangerously High Red Blood Cells): A well-established risk, occurring in 11% of individuals in one large study. The cumulative risk increases over time, reaching 38% at 10 years and 50% at 14 years. This condition thickens the blood, increasing the risk of blood clots, stroke, and heart attack (Madsen et al., 2021).

• Blood Clots (VTE): Evidence suggests an increased risk for Venous Thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism (van Zijverden et al., 2024; Yelehe et al., 2022).

• High Blood Pressure: Increased systolic blood pressure is a known effect (Banks et al., 2021).

• Subclinical Atherosclerosis: Testosterone is associated with an increased risk of early-stage atherosclerosis (hardening of the arteries), a precursor to major cardiovascular events (Allgayer et al., 2023).

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Gynecological and Reproductive Harms

Testosterone causes significant and potentially irreversible damage to the female reproductive system.

• Ovarian Damage: Testosterone exposure leads to poorer ovarian follicle health and increased DNA damage in oocytes. This suggests adverse effects on the primordial follicle pool and reduced egg viability, impacting future fertility (Bailie et al., 2023).

• Uterine and Endometrial Pathology: Despite stopping periods, the uterine lining often remains active. Pathologies are common, including endometrial polyps, fibroids, and hyperplasia. A multicenter study found active endometrium in 69% of individuals on testosterone who underwent hysterectomy (Grimstad et al., 2019).

• Infertility: The therapy suppresses ovarian function, leading to infertility. The reversibility of these effects is not guaranteed (Bailie et al., 2023; De Roo et al., 2025).

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Cancer Risks

Emerging data signals potential cancer risks in hormone-sensitive tissues.

• Endometrial Cancer: The presence of endometrial hyperplasia, a precursor to cancer, has been documented. A case of endometrial intraepithelial neoplasia was reported in a 32-year-old after four years of testosterone (O'Connor et al., 2022).

• Breast Cancer: Pharmacovigilance data have identified reports of breast cancer as an adverse drug reaction (Gomez-Lumbreras & Villa-Zapata, 2024).

• Liver Cancer: A case of androgen-receptor-positive hepatocellular carcinoma (HCC) was documented in a 17-year-old after just 14 months of testosterone therapy (Lin et al., 2020).

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Urogenital and Pelvic Issues

Symptoms impacting quality of life and long-term health are common.

• Vaginal Atrophy: Testosterone induces vaginal atrophy, leading to dryness, irritation, and painful intercourse (dyspareunia) (Baldassarre et al., 2013; Tordoff et al., 2023).

• Prostatic Metaplasia: In one study, 100% of individuals on testosterone developed prostatic metaplasia in their vaginal tissue—the growth of prostate-like glands. The long-term cancer risk of this change is unknown (Xu et al., 2022).

• Pelvic Pain: A high prevalence of pelvic pain is reported, with 72% of survey respondents experiencing it after starting testosterone (Zwickl et al., 2023).

• Pelvic Floor Dysfunction: A study found 94% of individuals on testosterone had symptoms of pelvic floor dysfunction, including urinary and bowel issues (da Silva et al., 2024).

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Neurological and Psychiatric Risks

• Idiopathic Intracranial Hypertension (IIH): This condition, characterized by high pressure around the brain, was the most predominant serious neurological adverse event found in an analysis of the FDA's reporting system. It can cause severe headaches and vision loss (Gomez-Lumbreras & Villa-Zapata, 2024).

• Psychiatric and Behavioral Risks: Reports include anxiety, depression, and suicidal ideation (Gomez-Lumbreras & Villa-Zapata, 2024).

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Surgical Complications

• Vaginal Cuff Dehiscence: Testosterone use is associated with more than double the risk of the vaginal cuff tearing open after a hysterectomy, a serious surgical complication (Wong et al., 2025).

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Bone Health and Mortality

• Reduced Bone Density: Individuals who undergo oophorectomy (removal of ovaries) can experience significant reductions in bone mineral density, with one study finding low bone density in 10.5% of a 10-year cohort (Sanna et al., 2024).

• Increased Mortality: A large, multi-decade study found that individuals on testosterone had an 80% increased overall mortality risk compared to other women, an increase primarily attributed to non-natural causes of death (de Blok et al., 2021).

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Conclusion

The administration of cross-sex testosterone to natal females is associated with a wide array of serious physiological harms, including increased risks of cardiovascular events, blood disorders, gynecological pathologies, cancer, and mortality. Many long-term consequences remain unknown, underscoring the need for caution and comprehensive, ethically sound informed consent.

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Learn more about “gender-affirming care.”

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References

Allgayer, R. M. C., Borba, G. S., Moraes, R. S., Ramos, R. B., & Spritzer, P. M. (2023). The Effect of Gender-Affirming Hormone Therapy on the Risk of Subclinical Atherosclerosis in the Transgender Population: A Systematic Review. Endocrine Practice, 29(6), 498-507.

Alzahrani, T., Nguyen, T., Ryan, A., Dwairy, A., McCaffrey, J., Yunus, R., Forgione, J., Krepp, J., & Salami, J. (2019). Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population. Circulation: Cardiovascular Quality and Outcomes, 12(4), e005597.

Bailie, E., Maidarti, M., Jack, S., Hawthorn, R., Watson, N., Telfer, E., & Anderson, R. A. (2023). The ovaries of transgender men indicate effects of high-dose testosterone on the primordial and early growing follicle pool. Reproduction and Fertility, 4(2), e220102.

Baldassarre, M., Giannone, F. A., Foschini, M. P., Battaglia, C., Busacchi, P., Meriggiola, M. C., & Venturoli, S. (2013). Effects of long-term high dose testosterone administration on vaginal epithelium structure and estrogen receptor-α and -β expression of young women. International Journal of Impotence Research, 25(5), 172-177.

Banks, K., Kyinn, M., Leo, L. M., Wagner, J. K., & Irwig, M. S. (2021). Cardiovascular morbidity in transgender individuals. Reviews in Endocrine & Metabolic Disorders, 22(3), 611-624.

da Silva, L. M. B., Freire, S. N. D., Moretti, E., & Barbosa, L. (2024). Pelvic Floor Dysfunction in Transgender Men on Gender-affirming Hormone Therapy: A Descriptive Cross-sectional Study. Urology, 184, 171-177.

de Blok, C. J. M., Wiepjes, C. M., van Velzen, D. M., Staphorsius, A. S., Nota, N. M., Gooren, L. J. G., Kreukels, B. P. C., & den Heijer, M. (2021). Mortality trends over five decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria. The Lancet Diabetes & Endocrinology, 9(10), 663-670.

De Roo, C., Schneider, F., Stolk, T. H. R., van Vugt, W. L. J., Stoop, D., & van Mello, N. M. (2025). Fertility in transgender and gender diverse people: systematic review of the effects of gender-affirming hormones on reproductive organs and fertility. Human Reproduction Update, 31(3), 183-217.

Gomez-Lumbreras, A., & Villa-Zapata, L. (2024). Exploring Safety in Gender-Affirming Hormonal Treatments: An Observational Study on Adverse Drug Events Using the Food and Drug Administration Adverse Event Reporting System Database. Annals of Pharmacotherapy, 10600280241231612.

Gosiker, B., Moutchia, J., Nguyen, N., Getahun, D., & Goodman, M. (2024). Changes in Blood Lipids Following Initiation of Gender Affirming Hormone Therapy: A Systematic Review and Meta-Analysis. Journal of Clinical & Translational Endocrinology, 36, 100349.

Grimstad, F. W., Fowler, K. G., New, E. P., Ferrando, C. A., Pollard, R. R., Chapman, G., Gomez-Lobo, V., & Gray, M. (2019). Uterine pathology in transmasculine persons on testosterone: a retrospective multicenter case series. American Journal of Obstetrics and Gynecology, 220(3), 257.e1-257.e7.

Lin, A. J., Baranski, T., Chaterjee, D., Chapman, W., Foltz, G., & Kim, H. (2020). Androgen-receptor-positive hepatocellular carcinoma in a transgender teenager taking exogenous testosterone. New England Journal of Medicine, 383(1), 95-96.

Madsen, M. C., van Dijk, D., Wiepjes, C. M., et al. (2021). Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years. The Journal of Clinical Endocrinology & Metabolism, 106(6), 1710-1718.

Nota, N. M., Wiepjes, C. M., de Blok, C. J. M., et al. (2019). Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy. Circulation, 139(11), 1461-1462.

O'Connor, R. M., Scott, M. E., Bakkar, R., & Rimel, B. J. (2022). A case of endometrial intraepithelial neoplasia in a transgender man on testosterone therapy. Gynecologic Oncology Reports, 40, 100949.

Sanna, E., Lami, A., Giacomelli, G., et al. (2024). Bone health in transgender assigned female at birth people: effects of gender-affirming hormone therapy and gonadectomy. Journal of Endocrinological Investigation, 47(1), 153-161.

Tordoff, D. M., Lunn, M. R., Chen, B., et al. (2023). Testosterone use and sexual function among transgender men and gender diverse people assigned female at birth. The Journal of Sexual Medicine, 20(7), 950-960.

van Zijverden, L. M., Wiepjes, C. M., Van Diemen, J. J., Thijs, A., & den Heijer, M. (2024). Cardiovascular disease in transgender people: a systematic review and meta-analysis. European Journal of Endocrinology, 190(2), S13-S24.

Wong, J. W. H., Xu, R. H., Stephens, J., et al. (2025). Increased Vaginal Cuff Dehiscence among Gender Diverse People on Testosterone. American Journal of Obstetrics and Gynecology.

Xu, R., Diamond, D. A., Borer, J. G., et al. (2022). Prostatic metaplasia of the vagina in transmasculine individuals. World Journal of Urology, 40(3), 849-855.

Yelehe, M., Klein, M., El Aridi, L., Maurier, A., Gillet, P., & Feigerlova, E. (2022). Adverse effects of gender-affirming hormonal therapy in transgender persons: Assessing reports in the French pharmacovigilance database. Fundamental & Clinical Pharmacology, 36(6), 1116-1124.

Zwickl, S., Burchill, L., Wong, A. F. Q., et al. (2023). Pelvic Pain in Transgender People Using Testosterone Therapy. The Journal of Sexual Medicine, 20(1), 85-94.