Androgen Receptor and Cardiovascular Disease: A Potential Risk for the Abuse of Supplements Containing Selective Androgen Receptor Modulators

Abstract

The androgen receptor (AR) is a member of the family of ligand-activated transcription factors. Selective androgen receptor modulators (SARMs) exert their biological function through complex interactions with the AR. It has been speculated that overexertion of AR signaling cascades as a result of SARM abuse can be a risk factor for the development of various cardiovascular diseases. The present literature review explores the implications of the interaction between SARMs and the AR on cardiovascular health by focusing on the AR structure, function, and mechanisms of action, as well as the current clinical literature on various SARMs. It is shown that SARMs may increase the risk of cardiovascular diseases through implications on the renin-angiotensin system, smooth muscle cells, sympathetic nervous system, lipid profile, inflammation, platelet activity, and various other factors. More research on this topic is necessary as SARM abuse is becoming increasingly common. There is a noticeable lack of clinical trials and literature on the relationship between SARMs, cardiovascular diseases, and the AR. Future in vivo and in vitro studies within this field are vital to understand the mechanisms that underpin these complex interactions and risk factors.

Keywords: SARMs; androgen receptor; androgen receptor signaling; atherosclerosis; cardiovascular disease; hypertension; myocardial hypertrophy; stroke.

Figure 1

Structural domains of AR-A and AR-B.

Figure 2

Genomic action of the AR consisting of eight different steps that ultimately lead to nuclear translocation of the AR, followed by the activation of gene transcription of androgen-responsive genes and the proteosomal breakdown of the AR. A detailed description of the pathway is given in Section 2.3.

Figure 3

The non-genomic action of the AR consists of 11 steps, including the interaction of the AR with signaling molecules within the membrane of the cell, which starts a cascade of reactions that regulate separate cytoplasmic targets, as well as nuclear receptors and transcription factors within the cytoplasm. A detailed description of the pathway is given in Section 2.4.

Figure 4

SARMs mechanism of action on the AR.

Figure 5

The potential effects of high levels of AR signaling on the risk of hypertension. There is evidence that AR signaling increases renin, ACE, AT1R, and aldosterone (hence increasing sodium retention) and decreases AT2R, with implications for the RAAS, resulting in Ang II-induced hypertension. As well as this, AR signaling may have implications on the SNS, increasing neuropeptide Y and norepinephrine levels, as well as increased smooth-muscle-cell proliferation, leading to hypertension. ACE: angiotensin-converting enzyme, Ang II: angiotensin II, AR: androgen receptor, AT1R: angiotensin 2 receptor type 1, AT2R: angiotensin 2 receptor type 2, RAAS: renin–angiotensin–aldosterone system, SNS: sympathetic nervous sytem.

Figure 6

Potential effects of high levels of AR signaling on the risk of atherosclerosis. The specific factors include changes in blood lipid profiles (HDL, LDL) in the body, increased inflammation (IL-1α) in endothelial cells, increased muscle cell proliferation, as well as changes in platelet activity. ERK: extracellular signal-regulated kinase; LTCCs: L-type calcium channels; mTOR: mammalian target of rapamycin, SERCA: sarcoplasmic reticulum calcium ATPase.

Figure 7

Potential effects of high levels of AR signaling on the risk of myocardial hypertrophy. The specific involved mechanisms are around increased muscle cell proliferation and decreased breakdown, as well as increases in muscle protein synthesis pathways (mTOR, ERK) and changes in calcium homeostasis (LTCC, SERCA) within cardiac muscle cells.

Figure 8

Potential effects of high levels of AR signaling on the risk of stroke. Hypertension and atherosclerosis are the main factors that cause stroke, but there is also evidence that endothelial dysfunction (altered eNOS, NO, oxidative capacity, inflammation and aldosterone) can contribute to stroke development [65], with there being evidence that high levels of AR signaling can lead to endothelial dysfunction. eNOS: endothelial NO synthase; NO: nitric oxide.