THE EFFECTS OF ESTROGEN
ON MALES
Although the psychological pain that boys feel from gender dysphoria is undoubtedly real, studies demonstrate no psychological relief from cross-sex hormone treatment or surgery.
Brain Structure
Cross-sex hormone treatment causes brain damage in males.
Cognitive Impairment
Long-term use of estrogen in males is associated with cognitive impairment.
Autoimmune Disease
Rates of autoimmune diseases increase after cross-sex hormone treatment.
Diabetes
Estrogen therapy increases insulin resistance in males.
Fertility & Genital Physiology
Cross-sex hormone treatment negatively affects fertility.
Adverse Reactions
Documented adverse drug reactions for patients on cross-sex hormones are extremely alarming.
Elevated estradiol levels in males are associated with depression.
Depression & Anxiety
Males on cross-sex hormones have an elevated risk of aggressive thyroid cancer.
Thyroid Cancer
Long-term cardiovascular risk goes up dramatically with cross-sex hormone treatment.
Cardiovascular Risk
Estrogen therapy is likely a risk factor for acute pancreatitis.
Pancreatitis
Medicalized transgender-identified males have a higher mortality risk.
Early Mortality
BRAIN STRUCTURE
Cross-sex hormone treatment causes brain damage in males.
A growing body of evidence suggests that the brains of transgender-identified people not on cross-sex hormone treatment (CSHT) are more similar in structure to those of their biological sex than to those of their preferred gender (Kiyar et al., 2020). However, after beginning hormonal treatment, the brain structure does seem to change in several ways. In transgender-identified males (TIMs), estradiol plus an antiandrogen was associated with significantly reduced right hippocampal volume and a corresponding increase in the size of the ventricular structures (Seiger et al., 2016). Additionally, progesterone levels decrease; this is correlated with a decrease in gray matter in the right hippocampus and right caudate. Another study found that after at least six months of estrogen and antiandrogens, there was a decrease in brain cortical thickness and subcortical volumetric measures, along with an increase in ventricular volume (Zubiaurre-Elorza et al., 2014). After twelve months of CSHT in natal males, their serum brain-derived neurotrophic factor (BDNF) levels were reduced (Fuss et al., 2015). BDNF is a protein found in the brain and spinal cord that helps neurons survive and develop new ones, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. Such changes have also been observed in adult male rats in more controlled settings. An experiment in adult male rats showed that pharmacologic doses of estradiol, with or without cyproterone acetate, caused a significant reduction in brain cortical volumes (in both hemispheres) compared with untreated control rats. It also led to an increased concentration of glutamate and glutamine in the hippocampus, the hypothalamus, the parietal cortex, and the frontal lobe (Gomez et al., 2020). The authors observed that these changes mimic those observed in human subjects in several other studies (Pol et al., 2006; Seiger et al., 2016; Zubiaurre-Elorza et al., 2014).
These changes have been associated with several psychological, neurological, and physiological disorders (although it is difficult to determine causality between brain changes and various associated medical conditions, the correlation is statistically significant). For example, reduced hippocampal volume has been shown to be associated with depression (Frodl et al., 2006). In this study, the patients with depression had significantly smaller hippocampal and frontal lobe volumes than the control subjects, along with lower gray and white matter volumes. Smaller hippocampal volumes were also linked to poorer performance in cognition tests. The smaller hippocampal white matter volumes were seen only among the patients diagnosed with major depression. Lower BDNF levels were also associated with an increased risk of developing major depressive disorder (Emon et al., 2020). Decreased levels of BDNF have been shown to be associated with neurodegenerative diseases involving neuronal loss, such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. It is also supposed to play an important role in the pathogenesis of obesity, type 2 diabetes, and metabolic syndrome (a collection of conditions that increases the risk of stroke, heart disease, and diabetes) (Bathina, 2015). In addition to depression, other medical conditions are associated with hormone-induced brain changes: gray matter damage is linked with memory loss, cognitive impairment, and motor movement issues (Cleveland Clinic, 2023); increased glutamate is associated with several brain- and non-brain-related diseases (Cleveland Clinic, 2023); and an increase in ventricle size is associated with degenerative brain disease and gait (Crook et al., 2020).
Kiyar, M., Collet, S., T’Sjoen, G., & Mueller, S. C. (2020). Neuroscience in transgender people: An update. Neuroforum, 26(2), 85–92. https://doi.org/10.1515/nf-2020-0007
Seiger, R., Hahn, A., Hummer, A., Kranz, G. S., Ganger, S., Woletz, M., Kraus, C., Sladky, R., Kautzky, A., Kasper, S., Windischberger, C., & Lanzenberger, R. (2016). Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration. Psychoneuroendocrinology, 74, 371–379.
https://doi.org/10.1016/j.psyneuen.2016.09.028
Zubiaurre-Elorza, L., Junque, C., Gómez-Gil, E., & Guillamon, A. (2014). Effects of cross-sex hormone treatment on cortical thickness in transsexual individuals.The Journal of Sexual Medicine, 11(5), 1248–1261.
https://doi.org/10.1111/jsm.12491
Fuss, J., Hellweg, R., Van Caenegem, E., Briken, P., Stalla, G. K., T’Sjoen, G., & Auer, M. K. (2015). Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF). European Neuropsychopharmacology, 25(1), 95–99.
https://doi.org/10.1016/j.euroneuro.2014.11.019
Gómez, Á., Cerdán, S., Pérez-Laso, C., Ortega, E., Pásaro, E., Fernández, R., Gómez-Gil, E., Mora, M., Marcos, A., del Cerro, M. C. R., & Guillamon, A. (2020). Effects of adult male rat feminization treatments on brain morphology and metabolomic profile. Hormones and Behavior, 125, 104839.
https://doi.org/10.1016/j.yhbeh.2020.104839
Pol, H. E. H., Cohen-Kettenis, P. T., Van Haren, N. E. M., Peper, J. S., Brans, R. G. H., Cahn, W., Schnack, H. G., Gooren, L. J. G., & Kahn, R. S. (2006). Changing your sex changes your brain: Influences of testosterone and estrogen on adult human brain structure European Journal of Endocrinology, 155(Supplement_1), S107–S114. https://doi.org/10.1530/eje.1.02248
Frodl, T., Schaub, A., Banac, S., Charypar, M., Jäger, M., Kümmler, P., Bottlender, R., Zetzsche, T., Born, C., Leinsinger, G., Reiser, M., Möller, H.-J., & Meisenzahl, E. M. (2006). Reduced hippocampal volume correlates with executive dysfunctioning in major depression. Journal of Psychiatry and Neuroscience, 31(5), 316–325. PMID: 16951734; PMCID: PMC1557684. https://www.jpn.ca/content/31/5/316
Emon, Md. P. Z., Das, R., Nishuty, N. L., Shalahuddin Qusar, M. M. A., Bhuiyan, M. A., & Islam, Md. R. (2020). Reduced serum BDNF levels are associated with the increased risk for developing MDD: A case–control study with or without antidepressant therapy. BMC Research Notes, 13(1), 83.
https://doi.org/10.1186/s13104-020-04952-3
Bathina, S., & Das, U. N. (2015). Brain-derived neurotrophic factor and its clinical implications. Archives of Medical Science: AMS, 11(6). 1164-1178. https://www.archivesofmedicalscience.com/Brain-derived-neurotrophic-factor-and-its-clinical-implications,53477,0,2.html
Crook, J. E., Gunter, J. L., Ball, C. T., Jones, D. T., Graff-Radford, J., Knopman, D. S., Boeve, B. F., Petersen, R. C., Jack, C. R., & Graff-Radford, N. R. (2020). Linear vs volume measures of ventricle size: Relation to present and future gait and cognition. Neurology, 94(5), e549–e556.
DEPRESSION & ANXIETY
Elevated estradiol levels in males are associated with depression.
A recent highly publicized 4-center study (Chen et al., 2023) failed to observe any psychological benefits for natal male youths who take estrogen. There was no improvement in depression, anxiety symptoms, or life satisfaction. In fact, elevated levels of estradiol and lower levels of testosterone have been associated with depression among natal males younger than 60 (but not for men over 60) (Stanikova et al., 2018). This association of elevated serum estradiol levels with elevated depression was also found in adolescent boys (age range 11–17 years) (Chronister et al., 2021).
Mortality statistics also show an elevated risk of suicide among transgender-identified males (TIMs) receiving cross-sex hormone treatment (CSHT) (de Blok et al., 2021). A recent Danish population-based cohort study of medicalized transgender people spanning more than four decades found a total of 12 cases of suicide. All of these were medicalized TIMs (Erlangsen et al., 2023), with an adjusted incidence ratio of 4.5 (95% confidence interval [CI] of 2.6–8.0) as compared to biological males not on hormone treatment (i.e., the number of suicides is 4.5 times the expected number of suicides in the larger population). Although a minority stress argument has been hypothesized for this observed increase in suicide, its contribution has not been studied and so remains unknown. TIM patients have more than double the rate of mental disorder diagnoses (including anxiety, depression, and psychosis) as compared to neither transgender nor non-binary patients (TGNB) (Hanna et al., 2019). This is based on seven years of psychiatric encounters recorded in the largest publicly available all-payer inpatient care database in the United States, the NIS Database (this database is not limited by sample variations or survey responses).
There is a high prevalence of psychiatric comorbidities among adolescents with gender dysphoria (Kaltiala-Heino et al., 2018). In fact, psychiatric symptoms that are present before gender dysphoria occurs do not abate with hormonal treatment (Bechard et al., 2017; Kaltiala et al., 2020; Kaltiala-Heino et al., 2015; Kaltiala et al., 2023; Kozlowska et al., 2020). For example, in a register-based study in Finland with patients who contacted the national centralized gender identity services from 1996 to 2019, those who sought gender treatment had an equal risk of needing subsequent psychiatric treatment compared with the control group, regardless of whether or not they proceeded to medicalization (Kaltiala et al., 2023). Not only do psychiatric symptoms not lessen after beginning CSHT, studies show that these symptoms can worsen. A recent nationwide cohort study in Denmark found that the probability of any psychiatric diagnosis among TIMs compared to control males was five times higher before initiating CSHT (Glintborg et al., 2023). The odds ratio for any psychiatric diagnosis for TIMs from 2 years before beginning GAHT to 1, 5, and 10 years after was 1.5 (i.e., the odds of a psychiatric diagnosis after initiating CSHT were significantly higher than the odds before starting treatment; it also worsened relative to controls). Not surprisingly, the odds ratios for the prescription of psychopharmacological medication increased by 30%, 100%, and 80% after 1, 5, and 10 years respectively (also remaining elevated with respect to controls). Another retrospective cohort study using military healthcare data from 2010–2018 of transgender-identified youths found that their mental health did not significantly change while their psychotropic medications increased significantly following the initiation of hormone treatment (Hisle-Gorman et al., 2021).
Chen, D., Berona, J., Chan, Y.-M., Ehrensaft, D., Garofalo, R., Hidalgo, M. A., Rosenthal, S. M., Tishelman, A. C., & Olson-Kennedy, J. (2023). Psychosocial Functioning in Transgender Youth after 2 Years of Hormones. New England Journal of Medicine, 388(3), 240–250. https://doi.org/10.1056/NEJMoa2206297
Stanikova, D., Luck, T., Bae, Y. J., Thiery, J., Ceglarek, U., Engel, C., Enzenbach, C., Wirkner, K., Stanik, J., Kratzsch, J., & Riedel-Heller, S. G. (2018). Increased estrogen level can be associated with depression in males. Psychoneuroendocrinology, 87, 196–203. https://doi.org/10.1016/j.psyneuen.2017.10.025
Chronister, B. N., Gonzalez, E., Lopez-Paredes, D., Suarez-Torres, J., Gahagan, S., Martinez, D., Barros, J., Jacobs, D. R., Checkoway, H., & Suarez-Lopez, J. R. (2021). Testosterone, estradiol, DHEA and cortisol in relation to anxiety and depression scores in adolescents. Journal of Affective Disorders, 294, 838–846. https://doi.org/10.1016/j.jad.2021.07.026
de Blok, C. J. de, Wiepjes, C. M., Velzen, D. M. van, Staphorsius, A. S., Nota, N. M., Gooren, L. J., Kreukels, B. P., & Heijer, M. den. (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. https://doi.org/10.1016/S2213-8587(21)00185-6
Erlangsen, A., Jacobsen, A. L., Ranning, A., Delamare, A. L., Nordentoft, M., & Frisch, M. (2023). Transgender Identity and Suicide Attempts and Mortality in Denmark. JAMA, 329(24), 2145–2153.
https://doi.org/10.1001/jama.2023.8627
Hanna, B., Desai, R., Parekh, T., Guirguis, E., Kumar, G., & Sachdeva, R. (2019). Psychiatric disorders in the U.S. transgender population. Annals of Epidemiology, 39, 1-7.e1.
https://doi.org/10.1016/j.annepidem.2019.09.009
Kaltiala-Heino, R., Bergman, H., Työläjärvi, M., & Frisén, L. (2018). Gender dysphoria in adolescence: Current perspectives. Adolescent Health, Medicine and Therapeutics, 9, 31–41.
https://doi.org/10.2147/AHMT.S135432
Bechard, M., VanderLaan, D. P., Wood, H., Wasserman, L., & Zucker, K. J. (2017). Psychosocial and Psychological Vulnerability in Adolescents with Gender Dysphoria: A “Proof of Principle” Study. Journal of Sex & Marital Therapy, 43(7), 678–688. https://doi.org/10.1080/0092623X.2016.1232325
Kaltiala, R., Heino, E., Työläjärvi, M., & Suomalainen, L. (2020). Adolescent development and psychosocial functioning after starting cross-sex hormones for gender dysphoria. Nordic Journal of Psychiatry, 74(3), 213–219. https://doi.org/10.1080/08039488.2019.1691260
Kaltiala-Heino, R., Sumia, M., Työläjärvi, M., & Lindberg, N. (2015). Two years of gender identity service for minors: Overrepresentation of natal girls with severe problems in adolescent development. Child and Adolescent Psychiatry and Mental Health, 9(1), 9. https://doi.org/10.1186/s13034-015-0042-y
Kaltiala, R., Holttinen, T., & Tuisku, K. Have the psychiatric needs of people seeking gender reassignment changed as their numbers increase? A register study in Finland. European Psychiatry. 2023;66(1):e93. https://doi:10.1192/j.eurpsy.2023.2471
Glintborg, D., Møller, J. K., Rubin, K. H., Lidegaard, Ø., T'Sjoen, G., Larsen, M. J. Ø., Hilden, M., & Andersen, M. S. (2023). Gender-affirming treatment and mental health diagnoses in Danish transgender persons: a nationwide register-based cohort study. European journal of endocrinology, 189(3), 336–345.
https://doi.org/10.1093/ejendo/lvad119
Hisle-Gorman, E., Schvey, N. A., Adirim, T. A., Rayne, A. K., Susi, A., Roberts, T. A., & Klein, D. A. (2021). Mental healthcare utilization of transgender youth before and after affirming treatment. The Journal of Sexual Medicine, 18(8), 1444–1454. https://doi.org/10.1016/j.jsxm.2021.05.014
COGNITIVE IMPAIRMENT
Long-term use of estrogen in males is associated with cognitive impairment.
In a recent case-control study (van Heesewijk et al., 2023), transgender-identified males (TIMs) who had been on long-term cross-sex hormone therapy (CSHT) had lower scores than both biological males and females in information-processing speed and episodic memory (this study, from researchers at the Amsterdam University Medical Center, was presented at the 2023 EPATH [the European arm of WPATH] conference in Killarney, Ireland). Furthermore, based on data from the Behavioral Risk Factor Surveillance System (BRFSS) survey between 2016–2018, Lambrou et al. found that 14% of transgender-identified and 17% of nonbinary adults over the age of 45 in the US reported subjective cognitive decline (or SCD)—an early symptom that may indicate Alzheimer’s dementia—as compared with 10% for non-transgender-identifiying men and women (the study could not identify how many of those identifying as transgender or gender nonbinary were taking hormones) (Lambrou et al., 2020). There are known associations between the observed brain changes after estrogen therapy with various medical conditions (see above, under “Brain Structure”). For example, gray matter damage is associated with memory loss, cognitive impairment, and motor movement issues (Cleveland Clinic, 2023).
van Heesewijk, J., Dreijerink, K., Wiepjes, C., Kok, A., Geurtsen, G., van Schoor, N., Huisman, M., den Heijer, M., & Kreukels, B. (2023, April 26–28). Cognitive functioning after long-term gender-affirming hormone therapy—A study in older transgender individuals [Paper presentation]. EPATH 2023: Killarney, Ireland. 233–234. https://epath2023.exordo.com/programme/presentation/98
Lambrou, N. H., Gleason, C. E., Cicero, E., & Flatt, J. D. (2020, July 30). Prevalence of subjective cognitive decline higher among transgender and gender nonbinary adults in the U.S., 2016–2018. 2020 Alzheimer’s Association International Conference.
https://alz.confex.com/alz/20amsterdam/meetingapp.cgi/Paper/44298
THYROID CANCER
Males on cross-sex hormones have an elevated risk of aggressive thyroid cancer.
Thyroid cancer occurs in medicalized transgender-identified males (TIMs) about 3.5 times more than in biological women, and experimental studies indicate that estrogen probably has a role in the pathogenesis (Derwahl & Nicula, 2014; Liu et al., 2021). A study of thyroid cancer in military veteran TIMs between 2017–2022 found that it was 75% higher than that of non-TIMs. Significantly, there was a higher incidence of follicular and oncocytic (Hürthle-cell) thyroid cancer (which have lower survival rates than papillary thyroid cancer) as compared to women in the general population (Christensen et al., 2023).
Derwahl, M., & Nicula, D. (2014). Estrogen and its role in thyroid cancer. Endocrine-related Cancer, 21(5), T273–T283. https://doi.org/10.1530/ERC-14-0053
Liu, J., Xu, T., Ma, L., & Chang, W. (2021). Signal pathway of estrogen and estrogen receptor in the development of thyroid cancer. Frontiers in oncology, 11, Article 593479.
https://doi.org/10.3389/fonc.2021.593479
Christensen, J., Hiba Basheer, H., Lado‐Abeal, J. (2023). Thyroid cancer is more common among transgender female veterans. [Late Breaking Poster 490]. [Late Breaking Abstracts].Thyroid, 23(S1), A–125–A–171. https://doi.org/10.1089/thy.2023.29161.lb.abstracts
AUTOIMMUNE DISEASE
Rates of autoimmune diseases increase after cross-sex hormone treatment.
Most patients with autoimmune diseases are biologically female (Cooper & Stroehla, 2003). This prevalence is also seen in transgender-identified males (TIMs) who are on cross-sex hormone treatment (CSHT). Case studies are observing increased immune-mediated rheumatic diseases (IMRD) among TIMs, such as rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus (SLE), and vasculitis, as well as the onset of other autoimmune diseases (Salgado et al., 2022; White et al., 2022). Chan and Mok report that a TIM developed SLE 20 years after sex-reassignment surgery (SRS) and prolonged estrogen therapy (Chan & Mok, 2013). Another study describes a TIM with previously limited and contained skin-related systemic sclerosis (SSc) whose condition suddenly became acute after starting estrogen and then developed into scleroderma renal crisis (a life-threatening complication with the abrupt onset of severe hypertension accompanied by rapidly progressive renal failure) (Arneson & Varga, 2021). The authors concluded that “estrogen supplementation could play a pathogenic role in SSc and its diverse complications.” A retrospective cohort study of Hospital Episode Statistics (HES) from 1999 through 2012 in English hospitals found a strong association between gender identity disorder (GID) and multiple sclerosis (MS) and “a potential role for low testosterone and/or feminizing hormones on MS risk” among natal males (Pakpoor et al., 2016). For natal males (but not natal females) with GIDs, the adjusted rate ratio of MS was 6.63 (95% CI of 1.81-17.01).
Cooper, G. S., & Stroehla, B. C. (2003). The epidemiology of autoimmune diseases. Autoimmunity reviews, 2(3), 119–125. https://doi.org/10.1016/s1568-9972(03)00006-5
Salgado, E., Romera-Baurés, M., Beltran-Catalan, E., Naredo, E., Carreira, P. E., Garcia-Vivar, M., Moreno-Muelas, J. V., Boteanu, A., Calvo-Penades, I., Sellas-Fernandez, A., Valero, M., & Gomez-Reino, J. J. (2022). Immune-mediated inflammatory rheumatic diseases in transgender people: A scoping review. Seminars in Arthritis and Rheumatism, 52, 151920.
https://www.sciencedirect.com/science/article/abs/pii/S0049017221001931
White, A. A., Lin, A., Bickendorf, X., Cavve, B. S., Moore, J. K., Siafarikas, A., Strickland, D. H., & Leffler, J. (2022). Potential immunological effects of gender-affirming hormone therapy in transgender people – an unexplored area of research. Therapeutic Advances in Endocrinology and Metabolism, 13, Article 20420188221139612. https://doi.org/10.1177/20420188221139612
Chan, K., & Mok, C. (2013). Development of systemic lupus erythematosus in a male-to-female transsexual: The role of sex hormones revisited. Lupus, 22(13), 1399–1402. https://doi.org/10.1177/0961203313500550
Arneson, L. C., & Varga, J. (2021). Scleroderma renal crisis complicating male-to-female transgender hormonal therapy in a patient with long-standing and stable limited cutaneous systemic sclerosis. JCR: Journal of Clinical Rheumatology, 27(8S), S355. https://doi.org/10.1097/RHU.0000000000001579
Pakpoor, J., Wotton, C. J., Schmierer, K., Giovannoni, G., & Goldacre, M. J. (2016). Gender identity disorders and multiple sclerosis risk: A national record-linkage study. Multiple Sclerosis Journal, 22(13). https://doi.org/10.1177/1352458515627205
CARDIOVASCULAR RISK
Long-term cardiovascular risk goes up dramatically with cross-sex hormone treatment.
A recent systematic review includes a meta-analysis of different cardiovascular diseases among medicalized transgender-identified males (TIMs) as compared to natal males not on estrogen therapy (van Zijverden et al., 2024). The results indicated a 30% increase in the incidence of stroke, a similar increase in myocardial infarction, and a 220% increase in the incidence of venous thromboembolism (VTE) among those on feminizing hormones. Another systematic review that focused only on VTE did not make a direct comparison between TIMs on cross-sex hormone treatment (CSHT) and natal males not on CSHT; instead, it compared the incidence rate of the former (2.7%) with that of natal males on other hormone therapy (VTE 0.4%): a nearly seven-fold increase among TIMs on CSHT (Kotamarti et al., 2021). The authors also mention “some reports suggesting a 20-fold increase” when comparing TIMs on CSHT to natal males who are not on any hormonal treatment (Nakatsuka, 2010).
Two recent large studies exemplify these risks. There is a dramatic increase in acute cardiovascular events among TIMs after the first few years of estrogen therapy. A large US cohort study including 2,842 TIMs found a 50% higher VTE incidence within the first two years of hormone treatment compared to natal males not on CSHT. After two years on feminizing hormones, this rate rose 5.1 times higher (Getahun et al., 2018). Within six years, the incidence of ischemic stroke went up by 30%, and beyond six years, it went up nearly ten times higher (9.9). These findings highlight the importance of long-term follow-up: the risks seem manageable at the two-year mark but go up dramatically afterward. In a similarly large Dutch cohort study including 2,517 TIMs, the mean standardized incidence ratio (SIR) of stroke among TIMs was 1.80 (95% CI 1.23–2.56), and that of VTE was 4.55 (95% CI 3.55–5.69) after an average follow-up time of about nine years (Nota et al., 2019).
A related issue is the increased risk for ophthalmic disorders. One study discusses the case of a TIM on transdermal estradiol gel hormone replacement therapy who experienced sudden loss of vision and metamorphopsia (Andzembe et al., 2023). The authors conclude that as “estrogen increases cardiovascular risk when used in hormone replacement therapy, RVO [retinal vein occlusion] is a complication that must be taken into account . . . especially in transgender women who are more at risk.”
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. https://doi.org/10.1093/ejendo/lvad170
Getahun, D., Nash, R., Flanders, W. D., Baird, T. C., Becerra-Culqui, T. A., Cromwell, L., Hunkeler, E., Lash, T. L., Millman, A., Quinn, V. P., Robinson, B., Roblin, D., Silverberg, M. J., Safer, J., Slovis, J., Tangpricha, V., & Goodman, M. (2018). Cross-sex hormones and acute cardiovascular events in transgender persons.Annals of Internal Medicine, 169(4), 205–213. https://doi.org/10.7326/M17-2785
Nota, N. M., Wiepjes, C. M., de Blok, C. J. M., Gooren, L. J. G., Kreukels, B. P. C., & den Heijer, M. (2019). Occurrence of acute cardiovascular events in transgender individuals receiving hormone therapy.Circulation, 139(11), 1461–1462. https://doi.org/10.1161/CIRCULATIONAHA.118.038584
Andzembe, V., Miere, A., Zambrowski, O., Glacet-Bernard, A., & Souied, E. H. (2023). Branch retinal vein occlusion secondary to hormone replacement therapy in a transgender woman. Journal francais d'ophtalmologie, 46(2), 148–151. https://doi.org/10.1016/j.jfo.2022.07.024
DIABETES
Estrogen therapy increases insulin resistance in males.
Several studies have been done on the effects of estrogen on natal males as it relates to insulin resistance. The smaller studies of shorter duration did not record any change in insulin resistance, but longer-running studies with more participants did. A systematic review of the literature indicated body fat distribution with a decrease in waist-to-hip ratio and a rise in gynoid fat, visceral adipose tissue, and subcutaneous fat (Spanos et al., 2020). Measurements of the body composition and oral glucose tolerance tests among 55 transgender-identified males (TIMs) from the European Network for the Investigation of Gender Incongruence (ENIGI) study (Cocchetti et al, 2022) were made before and after one year of cross-sex hormone treatment (CSHT) (Shadid et al., 2020). At one year, TIMs experienced significant increases in body mass index and body fat content, and a female-typical fat distribution (increasing hip-to-waist ratio). Compared to their baseline at the beginning of CSHT, during an oral glucose tolerance test, they showed higher fasting insulin levels and higher values of HOMA-IR (Homeostatic Model Assessment of Insulin Resistance, an index that incorporates interacting glucose and insulin levels) and decreased incretin response to glucose—all signs the body is having difficulty metabolizing glucose. This was consistent with the fat gained by the subjects during CSHT.
An earlier study followed 79 (at baseline) healthy subjects for two years (Colizzi et al., 2015). They experienced an increase of 72% in their HOMA-IR values in their first year of treatment and a further 9% increase in their second year, which suggests that the initial 12 months are important in the progression of the disease (in the same study, the 43 TIMs showed slight increases in the HOMA-IR values, but the changes were not statistically significant).
Spanos, C., Bretherton, I., Zajac, J. D., & Cheung, A. S. (2020). Effects of gender-affirming hormone therapy on insulin resistance and body composition in transgender individuals: A systematic review. World Journal of Diabetes, 11(3), 66–77. https://doi.org/10.4239/wjd.v11.i3.66
Cocchetti, C., Romani, A., Collet, S., Greenman, Y., Schreiner, T., Wiepjes, C., den Heijer, M., T’Sjoen, G., & Fisher, A. D. (2022). The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of acquired endocrine knowledge and future perspectives. Journal of Clinical Medicine, 11(7), Article 7. https://doi.org/10.3390/jcm11071784
Shadid, S., Abosi-Appeadu, K., De Maertelaere, A. S., Defreyne, J., Veldeman, L., Holst, J. J., Lapauw, B., Vilsbøll, T., & T'Sjoen, G. (2020). Effects of gender-affirming hormone therapy on insulin sensitivity and incretin responses in transgender people. Diabetes care, 43(2), 411–417. https://doi.org/10.2337/dc19-1061
Colizzi, M., Costa, R., Scaramuzzi, F., Palumbo, C., Tyropani, M., Pace, V., Quagliarella, L., Brescia, F., Natilla, L. C., Loverro, G., & Todarello, O. (2015). Concomitant psychiatric problems and hormonal treatment induced metabolic syndrome in gender dysphoria individuals: A 2 year follow-up study. Journal of Psychosomatic Research, 78(4), 399-406. https://doi.org/10.1016/j.jpsychores.2015.02.001
PANCREATITIS
Estrogen therapy is likely a risk factor for acute pancreatitis.
Estrogen therapy in transgender-identified males (TIMs) can be an under-recognized cause of elevated triglyceride levels that may put this group at a higher risk for severe pancreatitis, which is a known precursor to pancreatic cancer (Chaudhry et al., 2021). A recent case study concluded that estrogen therapy among TIMs is also a “likely risk factor for the development of gallstone pancreatitis” (Freier et al., 2021).
More concerning, a 2024 study did a retrospective analysis of TIMs and gender nonconforming people who were taking cross-sex hormones (CSHT) and found a nearly seven-fold risk (6.96, with a 95% CI of 2.76 to 848.78) for developing pancreatitis after CSHT (Podboy, et al., 2024). Notably, none of the patients who were not exposed to CSHT developed pancreatitis. The risk was enhanced for both sexes. The authors state: “The incidence rate of pancreatitis in this patient population is alarming…this increased rate of pancreatitis could represent a significant unaddressed cause of morbidity and even mortality.”
Chaudhry, A., Yelisetti, R., Millet, C., Biggiani, C., Upadhyay, S., Chaudhry, A., Yelisetti, R., Millet, C., Biggiani, C., & Upadhyay, S. (2021). Acute pancreatitis in the transgender population. Cureus, 13(7).
https://doi.org/10.7759/cureus.16140
Freier, E., Kassel, L., Rand, J., & Chinnakotla, B. (2021). Estrogen-induced gallstone pancreatitis in a transgender female. American Journal of Health-System Pharmacy, 78(18), 1674–1680.
Podboy, A., Casey, C., Buerlein, R.C.D., Strand, D., Shami, V., & Wang, A. (2024). Increased rate of pancreatitis in gender diverse and transgender patients on hormone therapy: A case series study BMJ Open Gastroenterology 11(1). https://bmjopengastro.bmj.com/content/11/1/e001312
FERTILITY & GENITAL PHYSIOLOGY
Cross-sex hormone treatment negatively affects fertility.
The effects of estrogen on testicular morphology vary widely, and studies that report outcomes may have patients receiving antiandrogens (testosterone blockers) along with estrogen. The true effect on sperm production (spermatogenesis) is unknown, with several studies reporting that some fraction of patients have preserved spermatogenesis (e.g., 24% [Schneider et al., 2017]), while other studies say that they have "complete cessation of spermatogenesis with testicular atrophy, hyalinization, and fibrosis” (Cheng et al., 2019). Further studies need to be done to understand the actual effect on a natal male’s ability to produce sperm after beginning cross-sex hormone treatment (CSHT).
Schneider, F., Kliesch, S., Schlatt, S., & Neuhaus, N. (2017). Andrology of male-to-female transsexuals: Influence of cross-sex hormone therapy on testicular function. Andrology, 5(5), 873–880.
https://doi.org/10.1111/andr.12405
Cheng, P. J., Pastuszak, A. W., Myers, J. B., Goodwin, I. A., & Hotaling, J. M. (2019). Fertility concerns of the transgender patient. Translational Andrology and Urology, 8(3), Article 3.
EARLY MORTALITY
Medicalized transgender-identified males have a higher mortality risk.
The all-cause mortality risks of transgender-identified males (TIMs) on cross-sex hormone treatment (CSHT) were found to be much higher than the general population. In a retrospective population cohort study of transgender-identified people in the Netherlands, among patients who visited the gender identity clinic of Amsterdam University Medical Centre over five decades, the overall survival odds of TIMs started to deviate from general population men or women within a few years of beginning CSHT, and the difference increased monotonically over time (de Blok et al., 2021). The authors noted that since 90% of the transgender-identified population in the Netherlands is treated at this clinic, these are reliable estimates. The overall mortality risk for medicalized TIMs was 80% higher compared to non-medicalized males in the general population (standard mortality rate [SMR] 1.8, 95% CI 1.6-2.0). (It was also higher than biological females in the general population [SMR 2.8, 95% CI 2.5-3.1].) Some of the major causes of death include cardiovascular disease (21%), cancer (32%), infection-related disease (5%), and suicide (7.5%).
Within the United States, private insurance data between 2011 and 2019 showed that American TIMs die much earlier than their neither transgender nor non-binary (TGNB) counterparts (Hughes et al., 2022), a deviation that begins after age 30. For example, while the probability of dying before 60 for a non-TGNB man in the United States is 7.7% (or about 1-in-13), that risk increases to nearly 19.5% (or 1-in-5) for a TIM.
From 2013–2017, there was a higher incidence of suicide among TIMs compared to the general Dutch population: three times higher than for non-medicalized men and over six times higher than for biological women (Wiepjes et al., 2020). In addition to increased suicide rates, transgender-identified Mediclaim beneficiaries in the US had a much higher incidence of chronic conditions (including asthma, autism spectrum disorder, chronic obstructive pulmonary disease, depression, hepatitis, HIV, schizophrenia, and substance use disorders) than the non-TGNB beneficiaries (Dragon et al., 2017). The transgender-identified Mediclaim beneficiaries also had higher observed rates of “potentially disabling mental health and neurological/chronic pain conditions, as well as obesity and other liver conditions.”
de Blok, C. J. de, Wiepjes, C. M., Velzen, D. M. van, Staphorsius, A. S., Nota, N. M., Gooren, L. J., Kreukels, B. P., & Heijer, M. den. (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. https://doi.org/10.1016/S2213-8587(21)00185-6
Hughes, L. D., King, W. M., Gamarel, K. E., Geronimus, A. T., Panagiotou, O. A., & Hughto, J. M. W. (2022). Differences in all-cause mortality among transgender and non-transgender people enrolled in private insurance. Demography, 59(3), 1023–1043. https://doi.org/10.1215/00703370-9942002
Wiepjes, C. M., Bremmer, M. A., Nota, N. M., G. Coumou, B. J., & Steensma, T. D. (2020). Trends in suicide death risk in transgender people: Results from the Amsterdam Cohort of Gender Dysphoria study (1972–2017). Acta Psychiatrica Scandinavica, 141(6), 486–491. https://doi.org/10.1111/acps.13164
Dragon, C. N., Guerino, P., Ewald, E., & Laffan, A. M. (2017). Transgender Medicare beneficiaries and chronic conditions: Exploring fee-for-service claims data. LGBT Health, 4, 404–411. https://doi.org/10.1089/lgbt.2016.0208
ADVERSE REACTIONS
Documented adverse drug reactions for patients on cross-sex hormones are extremely alarming.
Males and females have very different efficacy and safety patterns as it relates to adverse drug reactions (ADRs) (e.g., the ADRs associated with sexual dysfunction vary significantly between the sexes for antidepressants and antihypertensives). Recent research is showing that the same is true when it comes to cross-sex hormone treatment (CSHT).
Using the US FDA Adverse Event Reporting System (FAERS) database, a recent observational study on ADRs among transgender-identified males (TIMs) found that CSHT was associated with 58% of the reports, and more than half of them (53.6%) were classified as serious ADRs. The results among TIMs were even more striking: CSHT was associated with 72% of the reports, and 88% of those reports were deemed serious (Gomez-Lumbreras & Villa-Zapata, 2024). The two most-used “preferred terms” (as per MedDRA [Medical Dictionary for Regulatory Activities] terminology) were “off-label use” and “neoplasms (benign, malignant, and unspecified, including cysts and polyps).” These results, the authors concluded, show the importance of databases like FAERS that track “off-label ADRs, urging health care providers to approach hormone therapies with informed caution.”
Adverse effects from CSHT were also seen in a study that investigated the French pharmacovigilance database. In the cases with estrogens, 77% were in association with progestin or cyproterone acetate, and 68% involved antiandrogens (mainly cyproterone acetate). The principal ADRs were meningiomas, followed by cardiovascular events (CVE), with a median time to onset of 5.3 months (Yelehe et al., 2022).
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, 0(0), https://doi.org/10.1177/10600280241231612
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. Fundam Clin Pharmacol, 36(6), 1115–1124. https://doi.org/10.1111/fcp.12806