Anabolic Steroid Toxicity

Article Author:
Igor Middlebrook
Article Editor:
Benjamin Schoener
Updated:
7/31/2019 7:02:20 PM
PubMed Link:
Anabolic Steroid Toxicity

Introduction

Androgenic-anabolic steroids (AAS) are widely missed worldwide as performance-enhancing agents. The use of AAS started in competitive sports and spread to non-competitive athletes. The World Anti-Doping Agency banned AAS since the 1950s and has continued adding new methods and new variations of AAS. Currently, the CDC estimates that the majority of AAS users are adolescent males.[1]

The hypothalamus is the integrating center for the reproductive axis (HPG). It receives signals from the amygdala, olfactory, and visual cortex. Gonadotropin-releasing hormone (GnRH) then gets released into a venous portal system which carries it to adenohypophysis of the pituitary gland. In addition to signals from the CNS, humoral factors from the testes also play a role in modulating the release of GnRH. Gonadotropin-releasing hormone release is pulsatile, seasonal, and circadian. Levels of GnRH are highest during spring and in the morning with peaks occurring every 90 to 120 minutes. Once released, GnRH acts on the pituitary gland and promotes the production and release of luteinizing hormone (LH) and to a lesser extent, follicle stimulating hormone (FSH). Luteinizing hormone, in turn, acts on Leydig cells in the testes, which are the site of production of most of the endogenous androgens. Androgen production also occurs in the adrenal cortex and the conversion of androstenedione peripherally. Testosterone, in turn, inhibits the production of GnRH in the hypothalamus.

Testosterone is a 19-carbon steroid and is the most potent endogenous androgen. As such, it is the basis of most AAS. Addition of various functional groups to this basic 19-carbon structure changes androgenic, anabolic, and toxicity profiles of AAS.

Testosterone and other AAS act to increase muscle hypertrophy through modulating androgen receptor and its interaction with co-activators. It also increased muscle hypertrophy through modulation of receptor expression through intercellular metabolism, an anti-catabolic effect, by interfering with glucocorticoid receptor expression and various genomic and non-genomic pathways that act on the central nervous system.[2]

Studies of long term AAS users showed an increase in muscle fiber hypertrophy. Both Type I and Type II had significant hypertrophy. Even though Type II muscle fibers compose the majority of muscle mass in power-lifters, it was Type I fibers that enlarged the most with a 33% increase in size. Additionally, Type II fibers require a lesser dose of testosterone 300 mg vs. 600 mg for Type I to exhibit hypertrophy.[3]

One of the critical mechanisms by which AAS induces muscle hypertrophy is by increasing synthesis of contractile proteins. Injections (IM) of 200 mg of testosterone enanthate increased synthesis two-fold by increasing the rate at which amino acids underwent reuse, while protein turnover rate was unchanged. Each muscle fiber contains multiple myonuclei that can support a certain level of protein synthesis. With resistance training, these myonuclei increase in size and can support an increase in protein synthesis and cross-sectional area of a muscle fiber. On average, this increase is no more than 26% for Type II muscle fiber, which is termed “ceiling theory,” however, with AAS supplementation, researchers observed a significant increase of 36%.[4] This effect is even higher for Type I muscle fibers.

Short term administration of androgenic-anabolic steroids (300 mg per week for 20 weeks) increases the number of muscle satellite cells; this is thought to be because testosterone promotes satellite cell proliferation and entry into the cell cycle. As these cells enter the cell cycle, some daughter cells don’t differentiate and become quiescent cells. Other satellite cells while dividing may become new myonuclei or proceed to form new myotubules.[3]

While the exact mechanism remains unclear, murine models showed that testosterone-treated C3H 10T1/2 pluripotent mesenchymal cells showed increases in MyoD and myosin heavy chains. Testosterone supplementation is a potent regulator of lipolysis via influencing catecholamine signal transduction. Testosterone also inhibits adipocyte precursor cells from differentiation.[5]

Finally, there may be an androgen receptor-independent pathway through which testosterone may act. AAS may work on G-protein coupled receptor at the plasma membrane, which would increase Ca2+ concentration and activate ERK1/2 kinases, which then would phosphorylate transcription factors.

Etiology

Androgenic-anabolic steroids are mainly used for their effects on athletic performance and muscle size. Increase in muscle mass and strength were seen after administration of testosterone for six weeks in young, healthy males, average 19 years old.[6] Similar effects were observed after administering 600 mg testosterone per week to both trained and untrained men for ten weeks. Interestingly, males that did not participate in resistance training also gained muscle mass, albeit at a slower rate than those with resistance training and testosterone supplementation.[7] Effects of testosterone supplementation have shown to be dose dependent and be associated with changes to muscle pennation angle. Fascicle length and muscle pennation angle increase are needed to increase muscle surface area and the subsequent rise of the force of contraction.[8]

Interestingly, low levels of testosterone in geriatric males correlate with an increased risk of atrial fibrillation (AF).[9] Low levels of testosterone also correlate to coronary artery disease. However, it is not clear whether CAD preceded low testosterone levels or followed; this is an inverse relationship between CAD and testosterone levels, suggesting that testosterone supplementation may decrease the severity of CAD. A similar relationship exists between mortality associated with CAD and level of testosterone. Testosterone has been used to treat angina since the 1930s. Multiple studies since then confirmed a significant reduction of angina, the frequency of attacks, and the increase of angina free periods. There is also a long-established association between type 2 diabetes mellitus (T2DM) and low testosterone. Recent studies have shown that not only total testosterone but also free testosterone and DHT levels also decrease in T2DM.

Additionally, studies have demonstrated that testosterone supplementation decreased the risk of developing T2DM.  Testosterone increased metabolism and lipolysis. Evidence from multiple cohort studies shows that reduced levels of testosterone are seen in patients with obesity. Testosterone supplementation of 3 intramuscular injections significantly decreased the patient’s BMI by 1.3 in 30 weeks. Data on testosterone effect on lipid balance is conflicted and needs to be studied further. Testosterone supplementation, however, has been shown to decrease prolonged QT and ST intervals, often seen with aging, and Cushing disease.

Patients with congestive heart failure (CHF), due to activation of endocrine and inflammatory pathways, also have low testosterone levels. Decreasing testosterone levels have been recently shown to be associated with progressive worsening of CHF. Administration of testosterone to CHF patients, however, did not change left ventricular ejection fraction. Levels of total testosterone and free testosterone remain a good predictor of CHF. Testosterone has also been shown to be effective in increasing exercise tolerance in a patient with CHF and chronic obstructive pulmonary disease (COPD). Testosterone supplementation improved the 6-minute walk distance in patients with COPD.  It is likely that testosterone causes the skeletal muscle to have more Type I fibers, thus increasing exercise tolerance.[10]

Low levels of testosterone correlate with chronic liver disease (CLD). Up to 90% of males considered for a liver transplant show marked a reduction in free testosterone. The severity of CLD has an inverse correlation to testosterone levels. Mortality secondary to CLD was also inversely tied to free testosterone levels. An 8% increase in mortality is associated with 1 nmol/L drop of free testosterone.[11]

Epidemiology

Conservative estimates are that around 1 to 3 million people misused AAS in the United States. This number is on the rise as more adolescents report using AAS as early as high school, and there is even higher prevalence in weight lifters, bodybuilders, military, law enforcement, and prison populations.[12] A meta-analysis of 187 studies in 2014 showed the use of AAS worldwide had become a serious public health problem. The lifetime prevalence of use of AAS is higher in men (6.4%) than women (1.6%).[13]

Pathophysiology

There are many androgen receptors in the brain; thus, there are many neural and behavioral effects associated with AAS misuse. Side effects include hyperexcitability, suicidal tendencies, and aggressive behavior. Neurotoxicity induced apoptosis of neuronal cells was comparable to features of Alzheimer disease and Huntington disease. Researchers observed increased levels of beta-amyloid in individuals with a lengthy history of AAS misuse. Murine models demonstrated that excitotoxic neuronal death, induced by N-methyl-d-aspartate (NMDA) underwent amplification in the presence of testosterone.[14] Methandienone and 17-alpha-methyltestosterone were shown to inhibit neurite networks, induce apoptosis in AR-expressing neurons, and modulate levels of apoptosis-related proteins ERK and caspase-3.[15] This evidence prompted a more in-depth look at the effects of androgenic-anabolic steroids on cognition and memory. Self-reported AAS users received five computerized tests of cognitive performance: paired associates learning, rapid visual information processing, choice reaction test, verbal recognition memory, and pattern recognition memory. There was no significant performance difference between AAS users and nonusers on sustained attention, response speed, and verbal memory. However, pattern recognition memory and performance testing showed a marked decrease of almost one standard deviation in scores of AAS users vs. nonusers.[16]

Gingival fibroblasts contain a significant number of androgenic receptors. Testosterone converts to DHT in peripheral tissues such as gingival tissues; this is especially evident if the tissue is inflamed, as the number of ARs and amount of DHT rises. Wound healing positively correlates to systemic sex hormones. Young males with above average amounts of testosterone showed impaired wound healing, whereas elderly females with low amounts of free testosterone in the blood showed improved wound healing. A study of 42 AAS users and 50 nonuser controls was performed to see how AAS affects periodontal health. Both participant groups were 19 to 40 years old. Periodontitis was present in a more significant percentage of AAS users (32%) vs. controls (16.7%). Dental plaque was also present more frequently in AAS users than controls. Clinical attachment loss was seen almost 2.4 times more often in AAS users than control nonusers. Researchers also examined the microbiota in AAS users vs. controls. Infection with P. intermedia was 4.9 times more likely in AAS users vs. nonusers. Similarly, AAS users were 3.5 times more likely to be infected with A. actinomycetemcomitans than the control group. Finally, fungal cultures showed that AAS users were more likely to have Candida pocketing than nonusers.[17]

Histopathology

Myocyte histopathological changes:

Testosterone and other AAS induce reactive oxygen species (ROS) generation. They, in turn, induce cell apoptosis. Testosterone also increased Bax (apoptosis promoter) to Bcl-2 (apoptosis inhibitor) ratio.[18]

History and Physical

Cardiovascular signs of anabolic steroid toxicity[19]:

  • Hypertension secondary to elevated systemic vascular resistance 
  • Hypercoagulative state which may result in intracardiac thromboses, venous thromboses
  • Direct myocardial toxicity and pro-inflammatory biomarker profile, which may result in non-ischemic cardiomyopathy, myocardial infarction, heart failure
  • Dyslipidemia
  • Erythrocythemia
  • Accelerated coronary atherosclerosis

Hepatic system signs of anabolic steroid toxicity[20]:

  • Cholestasis
  • NASH
  • Direct liver toxicity
  • Hepatic neoplasms
  • Decreased SHBG
  • Hepatomegaly
  • Bile acid nephropathy

Endocrine system signs of anabolic steroid toxicity:

  • Acne
  • Gynecomastia (males)
  • Virilization (females)
  • Irregular menses (females)
  • Hypogonadism
  • Decreased levels of HDL
  • Premature epiphyseal closure

Neuropsychiatric symptoms of anabolic steroid toxicity:

  • Major depression
  • Body dysmorphic syndrome
  • Narcissistic personality disorder
  • Aggression
  • Dependence
  • Anxiety
  • Bipolar depressive disorder
  • Suicidal tendencies
  • Decreased pattern recognition

Evaluation

Evaluation begins with a thorough patient history and a physical exam. It is essential to establish a temporal relationship between a chief complaint, presenting symptoms, and use of the anabolic steroid. It is equally important to determine which specific agent is in use as that information can aid the clinician in obtaining the proper workup. Laboratory testing remains a challenge for clinicians as there are over 170 variants of anabolic steroids and no single rapid test to identify every agent. However, even when there is high suspicion of the presence of a specific agent, confirmatory analysis is generally gas chromatography. Testing may take a considerable amount of time, depending on the institutional capabilities.

Treatment / Management

Initial treatment of suspected acute anabolic steroid toxicity starts with discontinuing the offending agent followed by largely supportive measures while awaiting the results of the diagnostic workup.

The provider should tailor further treatment to the underlying pathology caused by the anabolic steroid use as signs of toxicity may manifest in multiple organ systems.

Multivitamins consisting mostly of vitamin B1, B6, B12, nicotinamide, and linoleic acid have been shown to protect hepatocytes from AAS induced toxicity.[21]

Differential Diagnosis

The differential diagnoses for anabolic steroid toxicity are broad as AAS's affect many organ systems.

  • Adrenal neoplasm
  • Ovarian cancer
  • Precocious puberty
  • Drug-induced hirsutism
  • Drug-induced jaundice
  • Hepatitis
  • Cirrhosis
  • Hepatic malignancy
  • Viral myocarditis
  • Conn syndrome
  • Hemolytic anemia
  • Anorexia
  • Vasculopathy
  • Thromboembolic state

Prognosis

Spermatogenesis is stimulated by LH and FSH release from the anterior pituitary, and inhibited by the negative feedback of testosterone and inhibin. AAS mimics testosterone, which creates an increase of inhibition of spermatogenesis and marked decrease in levels of LH and FSH. Male androgenic-anabolic steroid users show severe to moderate oligozoospermia 5-20x106/mL. Percentage of motile sperm is also significantly impaired in AAS users. Those users who stopped taking AAS for more than four months showed sperm levels return to normal, even after years of taking AAS.[22] Gynecomastia is another often reported side-effect of AAS misuse. Gynecomastia is a benign proliferation of breast tissue driven by the increased estrogen receptor expression secondary to alteration in HPA axis function. Estradiol nuclear and cellular receptor concentrations were similarly elevated in AAS users with pre-malignant soft tissue proliferation of the breast and patients with benign breast tissue proliferation, not due to AAS use.[23] The only definitive way to treat gynecomastia is the cessation of steroid use and surgical excision.

Complications

  • Depression may persist for years
  • Gynecomastia may require surgical excision
  • Hirsutism may be irreversible
  • Hepatic tumors
  • If the route of administration was an intramuscular injection, there is a risk of contracting HIV or hepatitis C virus
  • Cardiomyopathy

Deterrence and Patient Education

Various public safety campaigns exist to educate aspiring athletes about the dangers of using anabolic steroids. Most major sports associations continuously test their athletes for banned substances, which include AAS. It is essential to acknowledge that testing will never catch up to cover every single anabolic compound, but new compounds are added to the list of banned substances regularly. Primary care physicians should suspect AAS misuse if any of the following are present:

  • Participation in sports in which an increase in physical strength, speed, and agility is advantageous
  • Males
  • Increased musculature or accelerated rate of muscle gain
  • Increase in acne
  • Oligospermia
  • Gynecomastia
  • Early puberty
  • High hematocrit
  • Hirsutism in females

Clinicians should educate the patients regarding the use of AAS and advise them that possession of AAS is a criminal offense as well as a violation of anti-doping rules of most sports organizations.

Enhancing Healthcare Team Outcomes

Androgen abuse is a very common problem among athletes. While most sporting organizations do conduct random screening checks, there are newer analogs being introduced every year; hence discovering people who abuse these agents is not always easy. Various public safety campaigns exist to educate aspiring athletes about the dangers of using anabolic steroids. Most major sports associations continuously test their athletes for banned substances, which include AAS. In fact, many sporting organizations now employ clinicians including physicians and nurses to educate athletes about the harms of androgen abuse.

A five-year study funded by WADA (World Anti-Doping Agency) published in 2016 highlighted the strategy to reduce AAS misuse. The results of the study were predictable in that the areas of focus should be on prevention and education. Coaches, athletic trainers, and team physicians are not appropriately trained to identify athletes at risk (Evidence level III).

WADA has multiple educational programs and many resources available on its website for each discipline. Prevention is the best strategy to reduce AAS misuse and sequelae resulting from it. WADA maintains that each athlete is responsible for every chemical in his or her body. Sports organizations can issue severe penalties if they find any of the banned substances. Physicians and nurse practitioners treating athletes need to be aware of medical exception rules that are available on WADA's website. Most importantly, clinicians should be mindful of the risk factors for AAS misuse, clinical presentations, complications of use, and other conditions which may mimic AAS misuse.

In summary, AAS misuse and toxicity requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. The nurses often assist with patient education and report to the clinical team individuals they believe are at risk. Pharmacists trained in toxicology may assist the interprofessional team in managing patients that have untoward complications. The pharmacist can also assist in drug reconciliation and assist the team in avoiding drug interaction. Coaches and athletic trainers should be included in addressing the dangers of androgen use and be taught to identify potentially concerning athletes. [Level V]


References

[1] Parkinson AB,Evans NA, Anabolic androgenic steroids: a survey of 500 users. Medicine and science in sports and exercise. 2006 Apr;     [PubMed PMID: 16679978]
[2] Kicman AT, Pharmacology of anabolic steroids. British journal of pharmacology. 2008 Jun;     [PubMed PMID: 18500378]
[3] Kadi F, Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle. A basis for illegal performance enhancement. British journal of pharmacology. 2008 Jun;     [PubMed PMID: 18414389]
[4] Wolfe R,Ferrando A,Sheffield-Moore M,Urban R, Testosterone and muscle protein metabolism. Mayo Clinic proceedings. 2000 Jan;     [PubMed PMID: 10959218]
[5] Singh R,Artaza JN,Taylor WE,Gonzalez-Cadavid NF,Bhasin S, Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway. Endocrinology. 2003 Nov;     [PubMed PMID: 12960001]
[6] Friedl KE,Dettori JR,Hannan CJ Jr,Patience TH,Plymate SR, Comparison of the effects of high dose testosterone and 19-nortestosterone to a replacement dose of testosterone on strength and body composition in normal men. The Journal of steroid biochemistry and molecular biology. 1991;     [PubMed PMID: 1958561]
[7] Tricker R,Casaburi R,Storer TW,Clevenger B,Berman N,Shirazi A,Bhasin S, The effects of supraphysiological doses of testosterone on angry behavior in healthy eugonadal men--a clinical research center study. The Journal of clinical endocrinology and metabolism. 1996 Oct;     [PubMed PMID: 8855834]
[8] Blazevich AJ,Giorgi A, Effect of testosterone administration and weight training on muscle architecture. Medicine and science in sports and exercise. 2001 Oct;     [PubMed PMID: 11581553]
[9] Magnani JW,Moser CB,Murabito JM,Sullivan LM,Wang N,Ellinor PT,Vasan RS,Benjamin EJ,Coviello AD, Association of sex hormones, aging, and atrial fibrillation in men: the Framingham Heart Study. Circulation. Arrhythmia and electrophysiology. 2014 Apr;     [PubMed PMID: 24610804]
[10] Oskui PM,French WJ,Herring MJ,Mayeda GS,Burstein S,Kloner RA, Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. 2013 Nov 15;     [PubMed PMID: 24242682]
[11] Sinclair M,Angus PW,Grossmann M,Gow PJ, Muscle mass and mortality in chronic liver disease: the impact of testosterone. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2014 Apr;     [PubMed PMID: 24357579]
[12] Sjöqvist F,Garle M,Rane A, Use of doping agents, particularly anabolic steroids, in sports and society. Lancet (London, England). 2008 May 31;     [PubMed PMID: 18514731]
[13] Sagoe D,Molde H,Andreassen CS,Torsheim T,Pallesen S, The global epidemiology of anabolic-androgenic steroid use: a meta-analysis and meta-regression analysis. Annals of epidemiology. 2014 May;     [PubMed PMID: 24582699]
[14] Caraci F,Pistarà V,Corsaro A,Tomasello F,Giuffrida ML,Sortino MA,Nicoletti F,Copani A, Neurotoxic properties of the anabolic androgenic steroids nandrolone and methandrostenolone in primary neuronal cultures. Journal of neuroscience research. 2011 Apr;     [PubMed PMID: 21290409]
[15] Basile JR,Binmadi NO,Zhou H,Yang YH,Paoli A,Proia P, Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells. Frontiers in cellular neuroscience. 2013;     [PubMed PMID: 23675320]
[16] Kanayama G,Kean J,Hudson JI,Pope HG Jr, Cognitive deficits in long-term anabolic-androgenic steroid users. Drug and alcohol dependence. 2013 Jun 1;     [PubMed PMID: 23253252]
[17] Brusca MI,Verdugo F,Amighini C,Albaina O,Moragues MD, Anabolic steroids affect human periodontal health and microbiota. Clinical oral investigations. 2014 Jul;     [PubMed PMID: 24221579]
[18] Lopes RA,Neves KB,Pestana CR,Queiroz AL,Zanotto CZ,Chignalia AZ,Valim YM,Silveira LR,Curti C,Tostes RC, Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement. American journal of physiology. Heart and circulatory physiology. 2014 Jun 1;     [PubMed PMID: 24658017]
[19] Baggish AL,Weiner RB,Kanayama G,Hudson JI,Lu MT,Hoffmann U,Pope HG Jr, Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use. Circulation. 2017 May 23;     [PubMed PMID: 28533317]
[20] Luciano RL,Castano E,Moeckel G,Perazella MA, Bile acid nephropathy in a bodybuilder abusing an anabolic androgenic steroid. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2014 Sep;     [PubMed PMID: 24953892]
[21] Pagonis TA,Koukoulis GN,Hadjichristodoulou CS,Toli PN,Angelopoulos NV, Multivitamins and phospholipids complex protects the hepatic cells from androgenic-anabolic-steroids-induced toxicity. Clinical toxicology (Philadelphia, Pa.). 2008 Jan;     [PubMed PMID: 17852158]
[22] Knuth UA,Maniera H,Nieschlag E, Anabolic steroids and semen parameters in bodybuilders. Fertility and sterility. 1989 Dec;     [PubMed PMID: 2512180]
[23] Salazar EL,Torres JA,Avila A,Andrade A, Hyperplastic changes and receptor status in the breast tissue of bodybuilders under anabolic-androgenic steroid stimulation. Archives of andrology. 2000 Jul-Aug;     [PubMed PMID: 10959495]