How the love of muscle can break a heart: Impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health

Abstract

It is estimated 6.4% of males and 1.6% of females globally use anabolic-androgenic steroids (AAS), mostly for appearance and performance enhancing reasons. In combination with resistance exercise, AAS use increases muscle protein synthesis resulting in skeletal muscle hypertrophy and increased performance. Primarily through binding to the androgen receptor, AAS exert their hypertrophic effects via genomic, non-genomic and anti-catabolic mechanisms. However, chronic AAS use also has a detrimental effect on metabolism ultimately increasing the risk of cardiovascular disease (CVD). Much research has focused on AAS effects on blood lipids and lipoproteins, with abnormal concentrations of these associated with insulin resistance, hypertension and increased visceral adipose tissue (VAT). This clustering of interconnected abnormalities is often referred as metabolic syndrome (MetS). Therefore, the aim of this review is to explore the impact of AAS use on mechanisms of muscle hypertrophy and markers of MetS. AAS use markedly decreases high-density lipoprotein cholesterol (HDL-C) and increases low-density lipoprotein cholesterol (LDL-C). Chronic AAS use also appears to cause higher fasting insulin levels and impaired glucose tolerance and possibly higher levels of VAT; however, research is currently lacking on the effects of AAS use on glucose metabolism. While cessation of AAS use can restore normal lipid levels, it may lead to withdrawal symptoms such as depression and hypogonadism that can increase CVD risk. Research is currently lacking on effective treatments for withdrawal symptoms and further long-term research is warranted on the effects of AAS use on metabolic health in males and females.

Keywords: Anabolic-androgenic steroids; Cardiovascular disease; High-density lipoprotein cholesterol; Insulin resistance; Low-density lipoprotein cholesterol; Metabolic syndrome.

Fig. 1

Genomic and non-genomic mechanisms of AAS induced skeletal muscle hypertrophy and mechanisms of insulin signalling and resistance. Genomic pathway: Androgen binding of the AR complex causes translocation to the nucleus following dissociation of heat shock proteins (HSP). The androgen/AR complex regulates gene transcription on the androgen response element (ARE) of DNA. Non-genomic pathway: In addition to the AR, androgens can activate other membrane-bound receptors such as EGFR and SHBGR. This causes an increase in intracellular calcium (Ca2+), activation of several second messenger signalling such as extracellular regulated kinases 1/2 (ERK 1/2), protein kinase A (PKA), calmodulin (CaM) and phosphatidylinositol-3-phosphate kinase (PI3K)/Akt/mTORc1 pathways and deactivation of myostatin pathway. Activation of these genomic and non-genomic pathways leads to skeletal muscle hypertrophy via upregulating gene transcription of anabolic genes, nutrient sensing, storage and transporting. While also upregulating satellite cell proliferation, differentiation, MPS and inhibiting muscle protein breakdown (MPB). Insulin/IGF-1 signalling pathway: Insulin/IGF-1 bind to the insulin/IGF-1 receptor on the cell membrane inflicting tyrosine phosphorylation. The now activated receptor causes phosphorylation of insulin receptor substrate-1/2 (IRS-1/2) activating the PI3K/Akt signalling cascade leading to satellite cell proliferation; MPS via mTORc1, 4E-binding protein 1 (4E BP1) and p70 S6 kinase 1 (S6K1) activation; glucose uptake via GLUT4 translocation and inhibition of forkhead O transcription factor (FOXO) leading to reduced MPB. Abnormal levels of circulating fatty acids and inflammatory cytokines result in serine/threonine phosphorylation of IRS-1 causing insulin resistance.

Fig. 2

The dose-response effect of testosterone on change in fat-free mass (FFM) and leg press strength after 20 weeks in combination with a resistance exercise protocol (redrawn from Bhasin et al.) [65]

Fig. 3

Normal and AAS-influenced lipoprotein metabolism. During normal lipoprotein metabolism, intestinally produced chylomicrons carrying dietary lipids are hydrolysed by lipoprotein lipase (LPL). FFA are liberated and taken up by the liver, muscle and adipose tissue. Resulting chylomicron remnants are taken up by the liver via low-density lipoprotein receptor (LDL-R) and the LDL receptor-related protein (LRP). Meanwhile, hepatically produced VLDL transport cholesterol esters (CE) and TG through blood vessels, during which they undergo hydrolysis, releasing FFA which are taken up by peripheral tissues. This loss of TG means VLDL particles decrease in size (and therefore density) and become cholesterol-enriched and known as idLDL. Due to the action of HGTL, IDL particles become even smaller and known as LDL. LDL particles have an increased propensity to deposit cholesterol in peripheral tissues; however, they primarily transport cholesterol to the liver, where they are taken up by the LDL-R. The intestine also produces precursors which contribute towards the production of HDL. Small HDL3 particles acquire CE and TG and form larger HDL2 particles which, with the assistance of lecithin–cholesterol acyltransferase (LCAT), subsequently exchange CE for even more TG with VLDL particles and chylomicrons, before travelling to the liver where they are taken up by scavenger receptor B1 (SR-B1) or LDL-R. During AAS-influenced lipoprotein metabolism HGTL is upregulated, resulting in a preponderance of more atherogenic small, dense LDL III and IV particles, as opposed the larger and more buoyant LDL I and II particles found in normal lipoprotein metabolism. There is also a severe decrease in the number of HDL 2 and 3 particles overall, which are generally regarded as being atheroprotective.

Fig. 4

Potential mechanisms of insulin resistance with chronic anabolic steroid use. Chronic upregulation of S6K1 via activation of PI3K/Akt signalling cascade by AAS may reduce insulin sensitivity due to inhibition of IRS-1 by S6K1 as seen with nutrient overload models. Furthermore, chronic AAS use may lead to an increase in VAT increasing circulating fatty acids and/or inflammatory cytokines causing inhibition of IRS-1 and reducing insulin sensitivity. Aromatisation of testosterone may lead to increasing levels of Estradiol causing IR by binding to insulin and the insulin receptor.