Testosterone, the main male sex hormone, plays a crucial role in the development of male reproductive organs and secondary sex characteristics. It is primarily produced in the testes and predominantly circulates in the blood bound to proteins and sex hormone-binding globulin. Only a small fraction, around 1%–2%, exists in a free form (14). Once testosterone binds to androgen receptors, it initiates gene transcription that influences different tissues downstream (15).

AAS encompass a diverse range of natural and synthetic androgens that are derived from testosterone. The term “anabolic” describes their ability to promote the synthesis of complex molecules from simpler ones, facilitating tissue-building in the body. On the other hand, “androgenic” refers to their masculinizing effects. Many AAS have been created by modifying the structure of testosterone derivatives to reduce androgenic effects while maximizing the anabolic advantages (16). The anabolic effects of various AAS have many medical applications including the FDA-approved uses of oxymetholone in the treatment of congenital and acquired aplastic anemia (17), danazol in hormone-receptive endometriosis (18, 19), and testosterone undecanoate in the treatment of primary hypogonadism (20). The same anabolic properties of AAS use in medical therapy also make them particularly attractive to athletes who seek to increase muscle mass for increased strength and speed, and in individuals who desire cosmetic muscular changes (21). Table 1 shows some of the commonly used AAS and their route of intake.

AAS abuse in the United States has been steadily increasing in the past 40 years (22). Although competitive athletes were among the first groups of people described to be abusing AAS for their purported performance-enhancing effects, AAS abuse spread to the general population at large by the 1970 s (23). Interest in AAS increased in the 1990 s due to improved awareness of the prevalence and adverse effects of AAS in the population, culminating in the Anabolic Steroids Control Act in 1990 which added anabolic steroids to the list of scheduled III substances (11). A 2013 study that pooled data from 10 previous studies estimated a total of 2.9–4.0 million individuals used AAS between the ages of 13–50 years (24), putting the overall lifetime prevalence at over 1% (25).

The diagnosis of AAS-associated cardiomyopathy involves a multistep approach, including a thorough history of AAS use, laboratory analysis of AAS levels where possible, and both imaging and invasive modalities to assess cardiac dysfunction. Figure 2 illustrates diagnostic and treatment algorithm for suspected AAS users. When there is a low threshold for suspected AAS misuse, the history should cover the drug type, dose, mode of consumption, and duration. While a strong therapeutic alliance is the ideal way to obtain information that patients may be reluctant to offer, proposed structured interview modules to assess AAS misuse have also been suggested, showing preliminary reliability and validity (62). Investigations into the use of other substances commonly abused in association with AAS, such as tobacco, alcohol, and recreational drugs, should also be performed when AAS misuse is suspected (26).

The use of AASs can be quantified in several ways. If AAS misuse is suspected but unconfirmed, laboratory analysis may be initiated with serum measurement of substances more readily testable than AAS, including testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), all of which are decreased in the setting of AAS use (63). While an “athlete biological passport” developed by the World Anti-Doping Agency for elite athletes measures levels of testosterone, testosterone products, and precursors from a baseline level, there is no standard method for measuring AAS in the general population. Various urine and serum assays can be performed to measure specific AAS levels using chromatography-mass spectrometry, enzyme-linked immunosorbent assays (ELISA), and other methods (64, 65). The conversion of known AAS drugs to testosterone equivalents can also be used to estimate AAS exposure over a given period of time (26).

Cardiac dysfunction associated with AAS, including ischemia, left ventricular hypertrophy, reduced EF, and right ventricular strain, is determined in various ways. Transthoracic echocardiography (TTE) is used to evaluate these parameters and assess biventricular size and function (12). Transesophageal echocardiography (TEE) is capable of more extensive measurements such as LV end-diastolic dimension and volume, end-systolic dimension and volume, global longitudinal strain, and myocardial performance index, among other indices (47).

Once cardiomyopathy is diagnosed, coronary computed tomography angiography (CCTA) and cardiac catheterization can help characterize the ischemic vs. non-ischemic nature of the pathology, analyzing coronary artery stenosis, and the degree of atherosclerotic plaque burden (26). Table 3 summarize used modalities in the diagnosis of AAS induced cardiomyopathy.

Although ischemic cardiomyopathy is more common than non-ischemic cardiomyopathy, which includes AAS-induced cardiomyopathy, guideline-directed medical therapy (GDMT) for both etiologies is fairly similar (66). First-line GDMT agents fall into four main classes: beta-adrenergic receptor blockers (beta-blockers), renin-angiotensin system inhibitors, including angiotensin receptor neprilysin inhibitors (ARNi), angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i).

All patients with LV dysfunction, regardless of etiology, should receive beta-blockers and ACE-I/ARBs, except those with contraindications or intolerance due to the mortality-reducing benefit provided by both agents (67). Beta-blockers have been used for decades in the management of LV dysfunction because of their ability to inhibit sympathetic nervous system stimulation of myocardial tissue (68, 69). ACE-I/ARBs cause peripheral vasodilation, leading to decreased afterload on the heart and prevention of cardiac remodeling. In particular, ARBs have been shown to decrease the harmful effects of angiotensin II on the cardiovascular system, including vasoconstriction and myocardial fibrosis (67, 70). While previous guidelines recommend ACE-I/ARBs as the mainstay of therapy, the latest HF guidelines include ARNis as the first-line therapy equivalent to ACE-I/ARBs (71). ARNis inhibit neprilysin, an enzyme involved in the degradation of natriuretic peptides and bradykinin, among other peptides. The PARADIGM-HF study compared the ARNi sacubitril/valsartan to enalapril, which showed a 20% reduction in mortality and hospitalizations due to HF with the use of the ARNi compared to the ACE-I (72, 73). MRAs act as antagonists of aldosterone receptors, including spironolactone and eplerenone, both of which confer benefits to morbidity and mortality in HF and are highly economical for patients (72). Additionally, Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) (74) and Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial (75) demonstrated a decrease in hospitalization and all-cause mortality in patients with HF who used SGLT2i. Therefore, the latest guidelines recommend SGLT2is for all patients with symptomatic chronic HF, irrespective of the presence of diabetes (72). Vasodilator combination drugs, such as hydralazine and isosorbide dinitrate, have been shown to improve survival in patients with HF compared to placebo, particularly in self-identified African-American patients who remain refractory to optimal therapy (72, 76). Additional therapies are indicated for patients who present with prior or current symptoms of clinical HF (77, 78).

The reversibility of AAS toxicity varies and can depend on user factors, the type, strength, and duration of AAS used, and the organ system involved (21). The effects of AAS on the hypothalamic pituitary adrenal (HPA) axis, for example, have shown reversibility in terms of recovery from oligospermia in many but not all patients (67). In terms of cardiac sequelae of AAS, various studies have shown opposing findings, with some demonstrating reversibility, while others do not. The HAARLEM study followed men aged ≥18 years who intended to use AAS and performed 3D echocardiography before, during, and one year after complete discontinuation of use, demonstrating reversibility in multiple measured parameters. Following a median recovery period of approximately 8 months, the measures of LV function, including LV mass, intraventricular end-diastolic septal thickness, and left ventricular end-diastolic posterior wall thickness, returned to baseline. Additionally, the left atrial volume and ratio of peak velocity of early to late diastolic waves, which had also been aberrant during the period of AAS use, also returned to within the normal range (43). Multiple individual cases have reported improvement in reduced EF as a consequence of AAS use following treatment with GDMT and non-pharmacologic strategies together with medication, such as the placement of left ventricular assist devices (LVAD) (68).

Conversely, other studies have reported contradictory findings indicating the irreversibility of AAS-induced cardiomyopathy. One study of athletes, comparing active users of AAS, former users who had been steroid-free for at least one year, and lifetime non-users, found that even after years of being steroid-free, former users still had slightly concentric left ventricular hypertrophy compared to lifetime non-users (65). However, other studies have reported mixed results regarding reversibility. One retrospective study that reviewed a group of patients with AAS-induced HF over the course of 4 years found that some patients had recovered EF with GDMT within the first six months of diagnosis, whereas others required referrals to cardiac transplantation and had LVAD placement with no improvement in EF (70). Further investigations are needed to evaluate whether reversibility is possible and the underlying mechanism.