Testosterone is crucial in regulating secondary male characteristics and contributes to masculine traits. These include male hair distribution, changes in the voice by deepening the vocal tone. It also promotes anabolic effects, such as growth spurts during puberty via stimulating tissue growth at the epiphyseal plate and later closure, and the development of skeletal muscle through increased protein synthesis. Additionally, testosterone enhances erythropoiesis, leading to a higher hematocrit in males compared to females. As testosterone levels decline with age, men may consequently experience reduced testicular size, decreased libido, lower bone density, muscle mass loss, increased fat accumulation, and reduced erythropoiesis, which can result in anemia [10]. In circulation, testosterone is mainly bound to sex hormone binding globulin (SHBG), which modulates the delivery of testosterone to tissues. The abundance of SHBG and testosterone are highly related and can affect the ability to measure testosterone levels in the body [11]. In MLH, SHBG are elevated when compared to men without HIV and therefore highlights the importance of measuring SHBG together with a complete hormonal profile to properly diagnose and classify hypogonadism in MLH complaining about sexual symptoms [12, 13].

What is the Relation of Testosterone and Cardiovascular Disease Risk?

Testosterone influences cardiovascular disease (CVD) risk and all-cause mortality in men. Lower levels of testosterone are associated with an increased risk of both all-cause mortality and cardiovascular mortality. Men with baseline testosterone concentrations below 7.4 nmol/L (213 ng/dL) demonstrated a higher risk of all-cause mortality, and those with levels below 5.3 nmol/L (153 ng/dL) have been shown to be at increased risk of CVD mortality [14]. Additionally, when accounting for confounding variables, men with TD have been shown to have an increased risk of stroke, and venous thromboembolism at 1 and 5 years [15]. Testosterone deficiency is hypothesized to contribute as a risk factor for CVD in men, partly due to its contribution to increased large artery stiffness [16]. This arterial stiffness is believed to arise from elevated oxidative stress, which leads to reduced production of nitric oxide, degradation of elastin, and an increase in collagen deposition [16, 17]. Additionally, TD is reported to increase levels of low-density lipoprotein and total cholesterol and decrease high-density lipoprotein, all well-established risk factors for atherosclerosis [18, 19]. See Fig. 1.

Fig. 1

Proposed mechanism of testosterone and HIV on the systemic vasculature. This figure exemplifies the similarities of both TD and HIV on the vascular system and therefore the potential to enhance CVD risk. Both conditions lead to vessel injury and endothelial dysfunction, which increase the CVD risk in this population and emphasize the importance of early treatment for people with these comorbidities

What is Known About Testosterone Replacement Therapy and Cardiovascular Risk?

The controversy surrounding testosterone replacement therapy (TRT) and its cardiovascular safety has been debated for many years. Early randomized controlled trials of TRT yielded conflicting results and had limitations that hindered the generalizability of their findings. For instance, studies such as the Copenhagen Study and the Testosterone in Older Men with Mobility Limitations (TOM) trial suggested an increased risk of mortality or cardiovascular events with TRT [20, 21]. In contrast, the Testosterone's Effects on Atherosclerosis Progression in Aging Men (TEAAM) trial found no significant differences in the progression of subclinical atherosclerosis markers, like carotid intima-media thickness and coronary artery calcium scores, or in cardiovascular events over three years between the TRT and placebo groups [21]. Similarly, the cardiovascular arm of the Testosterone Trials noted greater increases in non-calcified and total plaque volumes over 12 months in the TRT group compared to placebo, though there were no differences in CAC scores or cardiovascular events [22]. The clinical significance of these plaque changes remains unclear, but they highlight the complexity of TRT’s effects and the potential implications for cardiovascular risk.

Building on previous meta-analyses of RCTs, which did not find a link between TRT and major adverse cardiovascular events, a more recent comprehensive meta-analysis conducted by Jaiswal et al. provides crucial insights into the cardiovascular implications of TRT. By analyzing data from 30 RCTs, including 11,502 patients, they report no significant differences in the rates of myocardial infarction, stroke, or cardiovascular mortality between the TRT and placebo groups [23]. Additionally, The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, demonstrated that in men with hypogonadism and preexisting or a high risk of cardiovascular disease, TRT was noninferior to placebo with respect to the incidence of major adverse cardiac events. However, patients on TRT did have a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism [20].

HIV-Associated Cardiovascular Disease is Currently an Established Risk for People Living with HIV

People living with HIV have an increased relative risk of 1.4 to 2.1 for myocardial infarction [23]. HIV infection has been established to create a pro-inflammatory state in the systemic vessels. The inflammatory state and immune system activation contribute to altered vessel biology, accelerated atherogenesis, plaque formation, and plaque instability. Despite antiretroviral therapy (ART), persistent activation of CD8 + T cells may be fueled in people living with HIV by ongoing anti-HIV responses and stimulation from poorly controlled opportunistic pathogens, such as cytomegalovirus. The clinical significance of these persistent T-cell abnormalities is underscored by their association with increased ischemic heart disease risk, characterized by low CD4 + T cell counts, elevated CD8 + T cell counts, and a low CD4 ratio. These findings highlight the importance of early HIV diagnosis and prompt ART initiation to optimize recovery of T-cell homeostasis. HIV-associated CVD has also been attributed to the metabolic effects of ARTs. Although newer ART regimens, including integrase strand transfer inhibitors, exhibit a more favorable lipid profile and potentially lower CVD risk, they are also associated with increased weight gain, leaving the overall impact on cardiometabolic risk uncertain [24, 25]. Consequently, contemporary studies continue to demonstrate an excess CVD risk in people living with HIV, attributable in part to persistent inflammation despite viral suppression.