Hormone Therapy Reshapes Cardiometabolic Risk in Distinct Ways for Transgender Women and Men

Gender-affirming hormone therapy (GAHT) is associated with measurable, domain-specific shifts in cardiometabolic risk, but the changes do not simply move transgender people toward the risk profile of the affirmed gender, according to a systematic review published in Cardiovascular Diabetology – Endocrinology Reports. The review, led by Mattia Fienga and Uwe J. F. Tietge, systematically searched PubMed for English-language primary human studies published through November 26, 2025. Of 346 screened records, 96 unique original investigations were included and synthesized narratively, because differences in study design, hormone regimens, comparator populations, follow-up duration and outcome definitions made quantitative pooling inappropriate.

The scope of the question is growing. The number of people seeking gender-affirming medical care and GAHT is increasing, and recent multi-country survey data suggest that roughly 3% of adults report a transgender or gender-diverse identity, with substantial variation by country and generation. Data from the Amsterdam Cohort of Gender Dysphoria Study show that the number of people presenting at a gender identity clinic increased substantially between 1972 and 2015, a pattern mirrored by other studies. The review’s authors note that these trends likely reflect improved awareness and greater access to care rather than a sudden change in underlying prevalence, which may still be underestimated because of stigma and structural barriers.

The biological rationale for metabolic effects is well grounded. Sex steroid hormones such as testosterone and estrogen act through nuclear receptors, modulating pathways that influence lipid metabolism, glucose homeostasis, vascular function, coagulation and inflammatory signaling. Feminizing GAHT in the included studies typically comprised estradiol, given orally, transdermally or intramuscularly, combined with anti-androgens such as cyproterone acetate or spironolactone. Masculinizing GAHT most commonly used testosterone esters or undecanoate by intramuscular or subcutaneous injection, or transdermal testosterone gel, with dosages individually adjusted to target hormone levels.

Body composition emerged as one of the most consistent findings. In transgender women, BMI was often reported as stable, yet total fat mass increased significantly, with documented gains of 9.8 kilograms and 4.0 kilograms in different cohorts, while lean mass fell by amounts ranging from 1.7 to 6.9 kilograms. One study recorded a 4% increase in muscle fat infiltration at five years. In transgender men, BMI increased or remained stable, lean mass rose, with gains of 7.8 and 4.7 kilograms reported, and fat mass changes were variable. Some long-term imaging data showed increases in visceral and liver fat: one study found a 14% increase in the visceral-to-total body fat ratio in transgender men, and at six years of follow-up visceral adipose tissue in transgender men exceeded reference values for healthy cisgender men. The authors stress that stable BMI can mask substantial metabolic remodeling, underscoring the value of imaging-based assessments over weight-based metrics alone.

Glucose metabolism showed a contrasting pattern between the two groups. In transgender women, insulin resistance tended to increase regardless of medication: one study of 179 participants using oral estradiol valerate or transdermal patches with cyproterone acetate found an average 47% increase in HOMA-IR at one year, an change that occurred independently of relative visceral fat mass. Another study found HOMA2-IR to be 1.5 times higher than in age-matched cisgender males. Yet fasting glucose and HbA1c were usually longitudinally stable, and one study reported a significant decrease in an NMR-based Diabetes Risk Score. In transgender men, glucose usually remained stable while insulin resistance findings were mixed, with some studies reporting significant decreases in HOMA-IR at one year and others finding no significant change over five years. The review’s authors caution that the available cohorts were predominantly young and metabolically healthy at baseline, so glycemic compensation may not persist as individuals age, and no hyperinsulinemic euglycemic clamp studies have yet been performed in this population.

Lipid changes diverged sharply. In transgender women, studies often showed favorable reductions in total cholesterol, low-density lipoprotein cholesterol and triglycerides, while high-density lipoprotein cholesterol changes depended heavily on regimen: increases appeared in spironolactone users, no significant change in cyproterone acetate combinations, and decreases in some cyproterone acetate cohorts. One study found dyslipidemia in 47% of transdermal estradiol users versus 3% of oral users. Two studies also documented decreased HDL cholesterol efflux capacity, a pro-atherogenic change in HDL function. In transgender men, the shift was consistently toward a more atherogenic profile: HDL cholesterol decreased in multiple studies, LDL cholesterol and triglycerides increased in most, and no study observed a decrease in triglycerides. NMR analyses additionally revealed lower large HDL particles and higher small LDL concentrations in transgender men. Notably, no differences in lipid alterations were found between different testosterone formulations.

Blood pressure and vascular findings were heterogeneous. In transgender women, no included study reported an increase in blood pressure; most described no significant or clinically meaningful change, while several cohorts showed decreases in systolic pressure, and one found significant decreases in both systolic and diastolic pressure in a cohort largely treated with sublingual micronized 17-beta estradiol. One coronary CT angiography study of 29 transgender women found a lower prevalence of coronary plaques of any type compared with cisgender males, with estradiol levels moderately and negatively correlated with plaque prevalence, though the study was not sufficiently powered. In transgender men, findings were mixed: several studies showed no significant blood pressure change, while others recorded significant systolic increases. Long-term data raised concern about arterial aging, with one study finding that transgender men exposed to testosterone for a cohort average of 14 years had higher carotid-femoral pulse wave velocity, indicating greater aortic stiffening, than both cisgender male and female controls.

Clinical event data, the most consequential endpoint, remain limited and comparator-dependent. In transgender women, venous thromboembolism incidence was consistently and significantly elevated compared with both cisgender men and women across multiple cohorts. Myocardial infarction incidence was significantly higher than in cisgender women, exemplified by a standardized incidence ratio of 1.57, but typically comparable to or lower than in cisgender men. Ischemic stroke and cerebrovascular accident risks were higher than in cisgender women but often aligned with cisgender men, particularly after adjustment for socioeconomic factors. One study reported higher cardiovascular mortality in transgender women than both cisgender men, with a standardized mortality ratio of 1.4, and cisgender women, with a ratio of 2.6. The authors note that long retrospective cohorts may include exposure to older estrogen formulations such as ethinyl estradiol, which as a contraceptive was associated with significantly higher myocardial infarction and thrombotic stroke risk, posing potential interpretation bias.

In transgender men, testosterone therapy did not appear to significantly increase composite cardiovascular disease risk compared with untreated individuals. Myocardial infarction and cerebrovascular accident risks were significantly higher than in cisgender women, with one study reporting a four times higher myocardial infarction risk, but generally not higher than in cisgender men, and outcomes often aligned with cisgender male rates. Evidence for other cardiovascular outcomes was limited and inconsistent, and venous thromboembolism findings were often similar to cisgender comparators or lacked statistical significance in smaller cohorts because of low event frequency. Transgender men also exhibited an increased risk of conduction disorders in one study.

The review concludes that GAHT is associated with quantifiable cardiometabolic changes whose magnitude and clinical relevance vary by regimen, population, baseline risk and follow-up duration, and that heterogeneous regimens, study methods and confounding contribute to mixed findings. Evidence on systemic inflammation, renal and hepatic outcomes is sparse. On kidney function, the authors highlight that creatinine-based eGFR estimates are particularly vulnerable in this population because creatinine generation tracks lean mass, which shifts in opposite directions during GAHT; one longitudinal study found cystatin C changes corresponding to an approximate 7 ml/min/1.73 m² increase in eGFR in transgender women and a 6 ml/min/1.73 m² decrease in transgender men, likely reflecting body composition change rather than true filtration change. Major gaps persist, including limited long-term prospective data, sparse mechanistic insight, underrepresentation of adolescents and non-European ancestry populations, and insufficient information on cardiometabolic outcomes with ageing. The authors call for large, well-characterized prospective cohorts and registries with standardized phenotyping and structured long-term follow-up to optimize evidence-based care.

Subject of Research: Cardiometabolic effects of gender-affirming hormone therapy in transgender populations

Article Title: Cardiometabolic diseases in transgender populations

Article References: Fienga, M., & Tietge, U. J. F. (2026). Cardiometabolic diseases in transgender populations. Cardiovascular Diabetology – Endocrinology Reports, 12(1), Article 64. https://doi.org/10.1186/s40842-026-00336-x

Image Credits: AI Generated

DOI: 10.1186/s40842-026-00336-x

Keywords: gender-affirming hormone therapy, transgender health, cardiometabolic risk, insulin resistance, lipid profile, venous thromboembolism, body composition, blood pressure, myocardial infarction, systematic review, estrogen, testosterone