Cardiovascular Health of Transgender Individuals During the Gender-affirming Pathway

NCT07187947 | Recruiting FDA Drug

• 1 other identifier: CV-TGD
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Gender Incongruence; Cardiovascular (CV) Risk; Cardiovascular Disease Risk Factor; Cardiovascular Disease Acute; Cardiovascular Health Status; Cardiovascular Disease (CVD); Cardiovascular Disease Prevention

Keywords

cardiovascular risk; transgender; GAHT; GAS; hormones

Outcome Measures

Primary Outcomes (5)

• 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).

  From baseline through study completion, estimated to be in 2035.

• 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.

  From baseline through study completion, estimated to be in 2035.

• 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).

  From baseline through study completion, estimated to be in 2035.

• 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).

  From baseline through study completion, estimated to be in 2035.

• Changes in insulin resistance

  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: Insulin resistance indices: HOMA-IR (unitless), TyG index (unitless).

  From baseline through study completion, estimated to be in 2035.

Secondary Outcomes (3)

• Presence/absence of cardiovascular disease

  From baseline through study completion, estimated to be in 2035.

• Lifestyle habits of transgender individuals

  From baseline through study completion, estimated to be in 2035.

• Changes in cardiovascular health parameters according to the various types of GAHT

  From baseline through study completion, estimated to be in 2035.

Study Arms (2)

AMAB

Individuals assigned male at birth, who will take on feminising gender-affirming care (i.e. cyproterone acetate/leuprorelin/triptorelin + estradiol/estradiol valerate, or estradiol/estradiol valerate alone after undergoing orchiectomy).

Drug: Feminizing GAHT

AFAB

Individuals assigned male at birth, who will take on masculinizing gender-affirming care (i.e. testosterone, either before and after the hysterectomy with our without oophorectomy, if desired).

Drug: Masculinizing GAHT

Interventions

Feminizing GAHT DRUG

Before 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.

AMAB

Masculinizing GAHT DRUG

Before and after gender-affirming surgery, the regimen consists of the administration of testosterone or its esters (testosterone undecanoate, testosterone enanthate)

AFAB

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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

You may not qualify if:

• Any hormone therapy received before recruitment
• History of cardiovascular events prior to the initiation of hormone therapy

Sponsors & Collaborators

• IRCCS Azienda Ospedaliero-Universitaria di Bologna: lead

Study Sites (1)

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola

Bologna, BO, 40138, Italy

RECRUITING

MeSH Terms

Conditions

Gender Dysphoria; Cardiovascular Diseases

Condition Hierarchy (Ancestors)

Sexual Dysfunctions, Psychological; Mental Disorders

Central Study Contacts

Maria Cristina Meriggiola, MD, PhD

CONTACT

+390512144394; cristina.meriggiola@unibo.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: August 29, 2025
• First Posted: September 23, 2025
• Study Start: July 18, 2025
• Primary Completion (Estimated): December 31, 2035
• Study Completion (Estimated): December 31, 2035
• Last Updated: September 23, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR

Locations

IT (1)