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.
Diagnosis of gender incongruence
Age 18 years or older at the start of therapy
Undergoing gender-affirming (replacement or suppressive) hormone therapy with testosterone or with estradiol plus anti-androgens for at least 12 months
Provision of informed consent for study participation and for the processing of personal and sensitive data
Any hormone therapy received before recruitment
History of cardiovascular events prior to the initiation of hormone therapy
Transgender AFAB and AMAB individuals diagnosed with gender incongruence who received medical therapy between January 2000 and December 2027 at the Gynecology and Reproductive Physiology Unit of the IRCCS AOU Bologna, Sant'Orsola University Hospital.
Cohort
Other
Feminizing GAHT
DrugBefore gender-affirming surgery, the regimen consists of an antiandrogen (cyproterone acetate or leuprorelin or triptorelin) plus estradiol (estradiol or estradiol valerate), whereas after an oophorectomy, estradiol/estradiol valerate can be administered alone.
Masculinizing GAHT
DrugBefore and after gender-affirming surgery, the regimen consists of the administration of testosterone or its esters (testosterone undecanoate, testosterone enanthate)
Modification of vital signs
Describe, in AFAB and AMAB transgender individuals who have been receiving gender-affirming hormone therapy (GAHT) for at least one year, changes in the following indicators of cardiovascular health: systolic BP (mmHg), diastolic BP (mmHg), mean arterial pressure (mmHg), heart rate (bpm).
Modifications in anthropometric parameters
Describe, in AFAB and AMAB transgender individuals who have been receiving gender-affirming hormone therapy (GAHT) for at least one year, changes in the following indicators of cardiovascular health: waist (cm), hip (cm) circumference.
Modifications in blood tests
Describe, in AFAB and AMAB transgender individuals who have been receiving gender-affirming hormone therapy (GAHT) for at least one year, changes in the following indicators of cardiovascular health:hemoglobin (g/dL), hematocrit (%), fibrinogen (mg/dL), PT (INR), aPTT (ratio), fasting glucose (mg/dL), insulin (µIU/mL), AST/ALT (U/L), total/LDL/HDL cholesterol (mg/dL), triglycerides (mg/dL), sodium/potassium (mmol/L), uric acid (mg/dL), creatinine (mg/dL), FSH/LH (IU/L), estradiol (pg/mL), testosterone (ng/dL), progesterone (ng/mL), TSH (mIU/L), SHBG (nmol/L).
Modifications in body composition
Describe, in AFAB and AMAB transgender individuals who have been receiving gender-affirming hormone therapy (GAHT) for at least one year, changes in the following indicators of cardiovascular health: Body composition (DXA): Change in fat mass (kg), body-fat % (%), lean mass (kg), lean mass + BMC (kg), total body mass (kg).
Presence/absence of cardiovascular disease
Calculate the incidence of conditions that increase cardiovascular risk-such as diabetes mellitus, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, and similar disorders-and determine whether specific medical treatments are required or whether gender-affirming hormone therapy should be discontinued.
Lifestyle habits of transgender individuals
Describe the lifestyle-including diet, physical activity, and related factors-in AFAB and AMAB transgender individuals undergoing gender-affirming hormone therapy. Specifically, the study will evaluate the following variables: smoking, quantified in pack-years; alcohol intake, reported as the number of standard alcohol units; use of other substances, recorded as present or absent based on participant self-report; physical activity, calculated using the Exercise Vital Sign metric; and dietary pattern, self-reported as unrestricted, vegetarian, vegan, ketogenic, or another specified regimen.
Changes in cardiovascular health parameters according to the various types of GAHT
Describe the changes in cardiovascular health parameters according to the type of gender-affirming hormone therapy administered-namely, transdermal testosterone versus injectable testosterone esters, or transdermal estradiol versus oral estradiol valerate combined with an anti-androgen.
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