What this Trial Is About

Gender incongruence, now classified in ICD-11 as a "marked and persistent incongruence between an individual's experienced gender and the gender assigned at birth," is managed in dedicated, multidisciplinary centres that coordinate psychological support with medical-surgical care. Gender-affirming hormone therapy (GAHT) is central to this care pathway. In particular, masculinising GAHT for people assigned female at birth (AFAB) relies mainly on testosterone, and feminising or demasculinising GAHT for people assigned male at birth (AMAB) combines oestradiol with androgen-lowering agents such as cyproterone acetate or GnRH analogues (triptorelin, leuprorelin). In addition, Gender-affirming surgery (GAS) offers further individualised options: "Top" procedures- chest masculinisation for AFAB or breast augmentation for AMAB, and "Bottom" procedures\*\* such as hysterectomy with or without oophorectomy, phalloplasty or metoidioplasty for AFAB; orchiectomy or vaginoplasty for AMAB. Other ancillary interventions include facial feminisation or voice surgery. GAHT aims to suppress endogenous sex-hormone levels and secondary sex characteristics while inducing those consistent with the affirmed gender. Despite its widespread use, cardiovascular (CV) safety data are scant and largely observational. Sex-steroid receptors are ubiquitous in the vasculature and contribute to the sex-dimorphic patterns of CV risk seen in cisgender populations; GAHT is therefore biologically plausible as a modifier of CV outcomes in transgender people, yet robust evidence remains limited. Current literature suggests that AFAB individuals on testosterone exhibit an up to 2.66-fold higher composite CV risk than cisgender AFAB comparators. The most consistent changes are higher blood pressure and lower HDL cholesterol; clinically significant polycythaemia is uncommon and treatable. Instead, AMAB individuals on feminising therapy do not show a clearly increased overall CV risk compared with cisgender AMAB peers, though data are inconsistent. An observational study reported that within four months of GAHT initiation, systolic blood pressure rose by 2.6 mmHg in trans men and fell by 4 mmHg in trans women, with no diastolic change in either group. The current evidence base is weakened by small cohorts, inadequate control groups, and reliance on surrogate biochemical markers rather than hard clinical endpoints. Many studies also overlook GAHT exposure altogether, hampering meaningful interpretation. Moreover, social determinants-mental-health burden, substance use, and healthcare inequities-compound CV risk but are seldom accounted for. Key unanswered questions include the long-term CV effects of GAHT, age-specific interactions with blood pressure and lipids, optimal therapeutic targets, and underlying mechanisms. Addressing these gaps demands rigorously designed, large-scale, prospective studies that actively involve transgender participants. In summary, while GAHT is indispensable for gender affirmation, its cardiovascular implications-especially for AFAB individuals-warrant caution and systematic monitoring. Future evidence should inform tailored protocols that balance gender-affirming benefits against potential CV risks and integrate biomedical parameters with the broader social context impacting transgender health.

Cardiovascular Health of Transgender Individuals During the Gender-affirming Pathway