Anabolic Steroid Toxicity

Etiology

Androgenic-anabolic steroids are mainly used for their effects on athletic performance and muscle size. An increase in muscle mass and strength was seen after administration of testosterone for 6 weeks in young, healthy males, averaging 19 years old.[6] Similar effects were observed after administering 600 mg testosterone per week to trained and untrained men for ten weeks. Interestingly, men who did not participate in resistance training also gained muscle mass, albeit at a slower rate than those with resistance training and testosterone supplementation.[7] The effects of testosterone supplementation have shown to be dose-dependent and associated with changes in muscle pennation angle. Fascicle length and muscle pennation angle increase is 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 coronary artery disease (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 the level of testosterone. Testosterone has been used to treat angina since the 1930s. Multiple studies since then confirmed a significant reduction in angina, the frequency of attacks, and the increase in 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 decreases the risk of developing T2DM.  Testosterone increases 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's 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 the left ventricular ejection fraction. Levels of total testosterone and free testosterone remain predictors 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 a 1 nmol/L drop of free testosterone.[11]

Epidemiology

Conservative estimates are that around 1 to 3 million people misuse 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 an 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 the 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 in terms of 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 non-users.[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 in 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 non-users. 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 include testosterone and other AAS-induced 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

• Hypertension secondary to elevated systemic vascular resistance 
• Hypercoagulative state 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 [19]

Hepatic System Signs of Anabolic Steroid Toxicity

• Cholestasis
• Nonalcoholic steatohepatitis (NASH)
• Direct liver toxicity
• Hepatic neoplasms
• Decreased SHBG
• Hepatomegaly
• Bile acid nephropathy [20]

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 the 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 a 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 vitamins B1, B6, B12, nicotinamide, and linoleic acid have been shown to protect hepatocytes from AAS-induced toxicity.[21](B2)

Differential Diagnosis

The differential diagnoses for anabolic steroid toxicity are broad, as AASs affect many organ systems.

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

Prognosis

Spermatogenesis is stimulated by LH and follicle-stimulating hormone (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 a marked decrease in levels of LH and FSH. Male androgenic-anabolic steroid users show severe to moderate oligozoospermia 5-20x106/mL. The 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 hypothalamic-pituitary axis (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

Complications of anabolic steroid toxicity include:

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