Harms of Cross-Sex Hormones: A Brief Review
Many claim that cross-sex hormone use is mostly harmless, yet a review of the scientific literature reveals a stark reality.
Both sexes require a healthy range of testosterone and estrogen for the functioning of bodily systems. From the womb, male and female bodies are organized differently thanks to these different hormone levels, and such differences grow even more striking during puberty.
Healthy testosterone levels
For men, the healthy range of testosterone is 254 to 890 nanograms per deciliter (ng/dL).
For women, the healthy range of testosterone is around 15 to 58 ng/dL (Clark et al. 2018).
Healthy estrogen levels
For men, the healthy range is around 1.0 to 5.5 (ng/dL).
For women, the healthy range is around 3.0 to 40 (ng/dL) [Haldeman-Englert et al. 2024; White 2019].
Cross-sex hormone use
When trans-identified males and females are given cross-sex hormones, the aim is to get their hormone range to opposite sex levels. Men will suppress their testosterone and raise their estrogen so that both hormone levels match women’s levels. And women will often suppress their estrogen and raise their testosterone so that both hormone levels match men’s levels.
Because these hormones are now unbalanced, well outside the healthy range for their sex, this can cause a host of negative side effects across the body. This article presents a brief review of the literature on the harms of these cross-sex hormone levels in males and females.
Harms of cross-sex hormone levels in females
The tissues of the female reproductive system are organized around specific levels of estrogen and testosterone. When high levels of T are introduced consistently, ovulation is suppressed, and periods stop; the ovaries develop pathological morphology associated with polycystic ovarian syndrome (Cheng et al. 2019); the vagina deteriorates through the loss of the epithelial structure and a complete loss of the intermediate and superficial layers; and estrogen receptors essential for vaginal maturation and maintenance are severely reduced (Baldassarre et al. 2013).
Researchers found that "at high dosage, T exerts a potent antiestrogenic effect also in vaginal epithelium, which results in morphological changes compatible with a lack of proliferation and tissue atrophy” (Baldassarre et al. 2013).
There is often a complete depletion of glycogen content (Baldassarre et al. 2013). Glycogen is essential for maintaining vaginal health, such as reducing unhealthy bacteria and regulating appropriate acidity levels (Navarro, Abla, & Delgado 2023). Depletion of glycogen means an increase in vaginal pH, allowing for fungal and bacterial growth.
Because of its antagonizing effects on estrogen, high testosterone use has detrimental, atrophying effects to other tissues as well, such as the uterine endometrium and the breast. This occurs even in the presence of low circulating E levels.
Outside of the reproductive system, high T dosing in females also causes inflammatory markers in the heart known to promote clotting and vasoconstriction, which may lead to cardiovascular disease (Alzahrani et al. 2019). Trans-identified females on T have a 2-to-4-fold increased risk of having a myocardial infarction, also known as a heart attack.
Not to mention the many detrimental effects to the reproductive system and the heart, T use in females permanently deepens the voice by changing the structure of the vocal cords. It can also lead to balding, fluid retention, and weight gain. In fact, in a study of over 8,000 women taking higher doses of T were at an increased risk of developing Type 2 Diabetes (Rasmussen, Selmer, & Frossing 2020).
Overall, cross-sex hormone use in females is damaging to a host of bodily tissues, and many of these effects are permanent. The female body is not developed to handle high doses of T anywhere close to male levels.
Trans-identified females interested in taking T should seriously consider these long-term side effects. But most of them are not being correctly informed by doctors.
Harms of cross-sex hormone levels in males
Like the female body, the male body is organized around specific levels of testosterone and estrogen across development. When these are altered to female levels, a disorder is induced. And the effects are seen across almost all body tissues.
Beginning in the reproductive system, high estrogen and low testosterone can result in severely impaired reduction of sperm levels to complete cessation of sperm production, full testicular regression with severe cellular damage, hyalinization of the testes (tissue degenerates into a translucent glass-like substance) [Cheng et al. 2019], 25% reduction in testicular volume by the first year due to depletion of germ cells (Schneider et al. 2017), and erectile dysfunction. The effects of this and the decreased testosterone causes decreased sexual interest.
On the overall body systems, cross-sex hormones in males causes redistribution of body fat mass and an increase in total body fat mass, muscle degeneration, oiliness of skin, abnormal breast tissue growth (gynecomastia), reduction of facial and body hair, weight gain, increase in blood pressure, and insulin resistance (Hembree et al. 2009).
Certain medical conditions like coronary artery disease and cerebrovascular disease (causing blood clots and strokes) can be exacerbated with a moderate to high risk of adverse outcomes, and in general, males taking high levels of estrogen are at an increased risk for cardiovascular events (Hembree et al. 2009; Judge et al. 2014).
The effects on the bones are particularly problematic, as the effects of low testosterone induce hypogonadism (where the gonads do not produce enough sex hormones), causing decreased bone turnover (lack of new bone generation) and loss of bone mineral density. This can eventually lead to osteoporosis (Kumar et al. 2010).
Psychologically, there is increased irritability and difficulty concentrating, along with lethargy and reduced energy (Kumar et al. 2010).
Finally, long term use of these drugs can result in decreased receptor responsiveness and an increase in drug resistance (Leavy et al. 2017).
Trans-identified males interested in taking cross-sex hormones should seriously consider these long-term side effects. But like their female counterparts, most of them are not being correctly informed by doctors.
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Alzahrani, T., et al. (2019). Cardiovascular disease risk factors and myocardial infarction in transgender population. Circulation: Cardiovascular Quality and Outcomes, 12.
Baldassarre, M., et al. (2013). Effects of long-term high dose testosterone administration on vaginal epithelium structure and estrogen receptor-a and -b expression of young women. International Journal of Impotence Research, 25, 172-177.
Cheng, P.J., Pastuszak, A.W., Myers, J.B., Goodwin, I.A. & Hotaling, J.M. (2019). Fertility concerns of the transgender patient. Transl Androl Urol, 8(3): 209-218.
Clark, R., Wald, J., Swerdloff, R., et al. (2018). Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex-specific competition in sports, a narrative review. Clinical Endocrinology, 90(1).
Haldeman-Englert, C., Turley, R., Novick, T. (2024). Estradiol (blood). Health Encyclopedia, University of Rochester Medical Center.
Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer WJ 3rd, Spack NP, et al. (2009). Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 94(9).
Judge C, O'Donovan C, Callaghan G, Gaoatswe G & O'Shea D. (2014) Gender dysphoria - prevalence and co-morbidities in an Irish adult population. Front Endocrinol (Lausanne) 5, 87.
Kumar, P., Kumar, N., Thakur, D., Patidar, A. (2010). Male hypogonadism: symptoms and treatment. J Adv Pharm Technol Res, 1(3).
Leavy, M., Trottmann, M., Liedl, B., et al. (2017). Effects of Elevated β-Estradiol Levels on the Functional Morphology of the Testis - New Insights. Scientific Reports, 7.
Meriggiola MC & Berra M. (2013) Safety of hormonal treatment in transgenders. Curr Opin Endocrinol Diabetes Obes 20, 565–569.
Navarro, S., Abla, H., Delgado, B. (2023). Glycogen availability and pH variation in a medium simulating vaginal fluid influence the growth of vaginal Lactobacillus species and Gardnerella vaginalis. BMC Microbiology, 23(186).
Rasmussen, J., Selmer, C., Frossing, S., et al. (2020). Androgens and type 2 diabetes in women. Journal of the Endocrine Society, 4(6).
Schneider, F., Kliesch, S., Schlatt, S., et al. (2017). Andrology of male-to-female transsexuals: influence of cross-sex hormone therapy on testicular function. Andrology, 5(5).
White, W. (2019). The importance of estrogen (estradiol) in men’s health. Testosterone Centers of Texas.
