Compromised Endothelial Function in Transgender Men Taking Testosterone

Barbara I. Gulanski; Clare A. Flannery; Patricia R. Peter; Cheryl A. Leone; Nina S. Stachenfeld

Disclosures

Clin Endocrinol. 2020;92(2):138-144. 

In This Article

Abstract and Introduction

Abstract

Context: Transgender men (TGM) are persons assigned female gender at birth with a male gender identity and are routinely treated with testosterone. Androgen excess is associated with endothelial dysfunction among cisgender females (CGF) and is an early sign of atherosclerosis and hypertension.

Objective: To determine the effect of testosterone treatment on endothelial function in TGM.

Setting: The John B. Pierce Laboratory and Yale School of Medicine.

Subjects: Eleven TGM (age 27 ± 5 years; BMI 24.4 ± 3.7 kg/m2) receiving testosterone (T) and 20 CGF (28 ± 5 years; BMI 26.0 ± 5.1 kg/m2) during the early follicular phase of their menstrual cycle.

Design and Outcome Measures: We evaluated brachial vasodilatory responses following stimuli designed to elicit shear stress using 5-minute occlusion to determine endothelial function (flow-mediated vasodilation, FMD).

Results: Total T was greater in the TGM compared to CGF (484.6 ± 122.5 vs 1.5 ± 0.7 ng/dL), as was free T (83.9 ± 32.4 vs 1.9 ± 0.8 pg/dL). FMD was markedly lower in the TGM (4.5 ± 2.7%) compared to the CGF (8.1 ± 2.9%, P = .002) indicating significantly diminished endothelial function in TGM.

Conclusions: We have shown for the first time that in TGM the androgen-dominant hormonal milieu was associated with impaired endothelial function. Endothelial dysfunction precedes clinically detectable atherosclerotic plaque in the coronary arteries, so is an important marker for clinical cardiovascular risk. Therefore, attention to cardiovascular risk factors should be integral to the care of transgender men.

Introduction

Approximately 0.6% or 1.4 million people in the US identify as transgender,[1] or having a current gender identity that differs from the sex assigned at birth. Cisgender individuals have a gender identity the same as the sex assigned at birth, thus cisgender women are persons assigned female at birth with a female gender identity. Transgender men are persons assigned female at birth with a male gender identity. It is common for TGM to undergo gender-affirming hormone therapy (HT), including both reducing ovarian hormones and increasing testosterone. Gender-affirming hormone therapy for TGM can include continuous, lifelong androgen exposure.

While the impact of chronic androgen exposure in TGM has not been well studied, testosterone is associated with increased cardiovascular risk in women.[2–4] In general, the engagement of androgen and the androgen receptor (AR) results in impaired agonist-triggered endothelial nitric oxide (NO) release in women[5,6] and testosterone exposure is characterized by endothelial dysfunction.[7,8] Excess free plasma testosterone in women is also a predictor of sympathetic nervous system-mediated increases in blood pressure and renal sympathetic activation. For example, in women with androgen excess-polycystic ovary syndrome (AE-PCOS), peripheral vascular sympathetic nervous system activity is increased independent of other comorbidities associated with PCOS.[9] The complete aetiology of AE-PCOS remains unknown, but is a complex condition characterized by disordered ovarian oestradiol, disrupted ovarian progesterone and excess ovarian androgen secretion, in addition to compensatory hyperinsulinaemia and menstrual irregularities.[10] Women with AE-PCOS are a corollary to TGM due to their chronic, lifelong androgen exposure, and young women with AE-PCOS have a number of cardiovascular comorbidities, including mild hypertension, enhanced sympathetic activity and endothelial dysfunction.[9,11] It is therefore logical that the HT for TGM may increase their cardiovascular risk, and these risks may be compounded by other medical or surgical interventions. Even in young TGM cohorts, testosterone therapy consistently increases systolic blood pressure,[12–16] triglycerides[15,16] LDL-cholesterol and decreases HDL-cholesterol.[14,17]

Testosterone exposure can begin in many TGM at an age when the overall risk for cardiovascular events is still low. It is therefore important to evaluate biomarkers and risk factors that can predict cardiovascular dysfunction and disease later in life. Endothelial dysfunction precedes clinically detectable atherosclerotic plaques in the coronary arteries, so is an important marker for cardiovascular risk. In this study, we evaluated the impact of physiological doses of testosterone as part of HT on endothelial dysfunction in TGM. We hypothesized that endothelial function would be impaired in TGM taking HT compared to CGF of similar age and health parameters.

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