Cardiovascular Health of Transgender Individuals During the Gender-affirming Pathway

Gender incongruence, described in the eleventh revision of the International Classification of Diseases (ICD-11) as "a marked and persistent incongruence between an individual's experienced gender and the gender assigned at birth" , is usually managed in specialised, multidisciplinary centres where psychologists, endocrinologists, gynaecologists, urologists and other professionals guide each person through the process of gender affirmation. Central to this pathway is gender-affirming hormone therapy (GAHT). In individuals assigned female at birth (AFAB) who seek masculinisation, treatment relies primarily on testosterone, whereas in those assigned male at birth (AMAB) who desire feminisation or demasculinisation, androgen-lowering agents such as cyproterone acetate or gonadotropin-releasing-hormone analogues (triptorelin or leuprorelin acetate) are combined with oestradiol; when complete feminisation is requested, suppression of endogenous testosterone and administration of oestradiol proceed in tandem. Gender-affirming surgery (GAS) offers further individualised possibilities: chest masculinisation in AFAB people and breast augmentation in AMAB people, orchiectomy or vaginoplasty for AMAB individuals, and hysterectomy with or without salpingo-oophorectomy followed by phalloplasty or metoidioplasty for AFAB individuals. Ancillary procedures, including facial feminisation and thyroplasty, may refine the outcome for AMAB clients.

The physiological goal of GAHT is to suppress endogenous sex-hormone levels and associated secondary sexual characteristics of the birth sex while inducing and maintaining hormone levels, and thus features, congruent with the individual's affirmed gender. Although GAHT is widely used, robust data on its cardiovascular safety remain scarce. Sex-steroid receptors are ubiquitous in vascular tissues and help explain the sex-specific patterns of cardiovascular (CV) risk seen in cisgender populations; accordingly, GAHT is biologically plausible as a modulator of CV outcomes in transgender people, yet the evidence base is still limited. Current literature points to an increased composite CV risk-up to 2.66-fold-among AFAB individuals receiving testosterone compared with cisgender AFAB controls. The most frequently reported risk-factor shifts in this group include higher blood pressure and lower high-density lipoprotein cholesterol, whereas clinically significant polycythaemia remains uncommon and treatable. By contrast, studies have not shown a statistically significant overall CV risk elevation in AMAB individuals treated with feminising regimens when compared with cisgender AMAB peers, though findings are inconsistent. One observational investigation documented that within four months of starting GAHT systolic blood pressure rose by 2.6 mmHg in trans men but fell by 4 mmHg in trans women, with diastolic values remaining unchanged in both cohorts.

Interpretation of these data is hindered by small sample sizes, the paucity of large prospective cohorts, inadequate control populations and the predominance of surrogate biochemical markers in place of clinical CV end-points. Moreover, several published studies neglect to register GAHT exposure, despite its fundamental role in transgender health management, underscoring the need for further research into the therapy's effects and risks. Social determinants of health compound the picture: higher prevalences of mental-health disorders, substance misuse and structural healthcare inequities are increasingly recognised in transgender communities and likely contribute to the observed CV risk burden.

Many critical questions therefore remain unanswered. The long-term impact of GAHT on cardiovascular morbidity and mortality is unknown, as is the extent to which a person's age modifies GAHT-related shifts in blood pressure, lipid profile or other risk parameters. Clinicians lack evidence-based targets for blood pressure or surrogate CV markers in trans men and trans women, and the biological mechanisms that underlie GAHT-related alterations in CV risk factors are not fully understood. Addressing these uncertainties will demand rigorously designed, large-scale prospective studies, conducted with active involvement of transgender participants, that integrate biomedical outcomes with the broader social realities shaping transgender health.

In summary, although GAHT is indispensable for many individuals seeking gender affirmation, its cardiovascular implications-particularly the elevated risk signalled in AFAB people receiving testosterone-warrant cautious, evidence-based monitoring. Future work should clarify long-term outcomes, refine management protocols and ensure that clinical guidelines reflect both the physiological effects of hormone therapy and the social determinants that influence cardiovascular health in transgender populations.