Testosterone synthesis is regulated by the hypothalamus and pituitary gland (Fig. 4.2). A neuropeptide hormone called gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus. GnRH then passes through the hypothalamo-hypophyseal portal circulation to the anterior pituitary where it stimulates the production of the glycoprotein hormones: luteinizing hormone (LH) and follicle stimulating hormone (FSH). FSH and LH are consequently secreted into the circulation to carry stimulatory actions to the testes. FSH acts on Sertoli cells triggering spermatogenesis and hormone synthesis, essentially inhibin. LH on the other hand binds to LH receptors on Leydig cells stimulating steroidogenesis and testosterone production. There is some evidence suggesting that FSH may stimulate testosterone production by Leydig cells secondary to release of activating hormones from Sertoli cells [3]. GnRH is secreted in a pulsatile manner leading to a similar response in LH and consequently testosterone synthesis giving rise to a circadian rhythm that is essential for human health and well being [8].

Testosterone is then aromatized to estradiol, which exerts a negative feedback on the hypothalamus and pituitary gland resulting in decreased production of GnRH, FSH, and LH consequently maintaining testosterone in its optimal range. Inhibin also exerts a negative feedback on the pituitary gland decreasing LH and FSH production [3].

Several nonhormonal factors were proven to regulate testosterone production including insulin-like growth factor 1 and 3, leptin, gherlin, and tumor necrosis factor B. However, their exact effect on testosterone regulation is still not fully established [9].

Testosterone replacement can be considered in patients experiencing symptoms of hypogonadism along with biochemical evidence of low serum testosterone levels. It is typically prescribed for patients complaining of decreased libido, erectile dysfunction, fatigue, decreased muscle mass, depression, lack of concentration, and a low sense of wellbeing.

Exogenous administration of testosterone or its synthesis derivatives induces feedback inhibition on the hypothalamic–pituitary axis resulting in reduction of FSH and LH synthesis and consequently a decrease of intratesticular T levels. Infertility after AAS abuse commonly presents as oligozoospermia or azoospermia, associated with abnormalities in sperm motility and morphology [19].

Histopathologic evaluation on testicular tissue in AAS abusers revealed Leydig cell alterations mainly [20]. Moreover, impairment of spermatogenesis with a picture of maturation arrest has been described [21]. After AAS discontinuation, Leydig cells tend to proliferate but remain below the regular counts, even after longer periods. Clearly, long-lasting, or possibly persistent effects of AAS use cannot be ruled out. Apoptosis has been reported to play an important role in the regulation of germ cell populations in the adult testis. Recently, the correlation between apoptosis and high AAS doses and exercise has been experimentally assessed in animal models. Shokri et al. [22] report a significant increase in the rate of apoptosis of spermatogenic cells after nandrolone administration—an increase clearly amplified by physical exercise.

Erectile dysfunction (ED) is common in patients receiving AAS. It usually starts 5–6 weeks after the initiation of treatment and is most notable with nandrolone and trenbolone. Possible reasons for this consequence include excessive estrogen levels or reduction of DHT levels. Estrogen is commonly elevated secondary to unopposed aromatization of exogenous T. Kwan et al. [23] confirmed existence of inhibited sexual activity, spontaneous erections, and nocturnal penile tumescence in men receiving estrogen. In addition to its negative feedback effects on gonadotropin secretion by the hypothalamus and pituitary gland, estrogen competes with testosterone on binding to ARs throughout the body. As estrogen levels increase, testosterone cell stimulation may be locked in the “off” position, thus reducing sexual arousal and causing loss of libido. DHT is essential for erectile function. Again, inhibition of the hypothalamo–pituitary–gonadal axis results in reduction of endogenous T and consequently DHT causing ED.

Several reports have linked AAS abuse to cardiovascular morbidity and even mortality [24]. These dreadful events tend to occur in young men without any previous cardiac history, and are secondary to atherogenic changes, thrombogenic effects, vasospasm effects, and direct myocardial toxicity that is often seen in AAS abusers [25]. Autopsy studies revealed the presence of hypercontracted, deeply eosinophilic cardiac myocytes [24], likely representing exposure to increased sympathetic activity. Certainly, this exaggeration of sympathetic activity has been found in few animal studies to be triggered by androgens [26]. AAS abuse results in left ventricular (LV) concentric hypertrophy that seems to persist years after discontinuation [27]. Atrial fibrillation, ventricular arrhythmia, diastolic dysfunction, and sudden cardiac death are all linked with this concentric remodeling of LV hypertrophy. Recent echocardiographic studies showed that both systolic and diastolic dysfunctions were directly proportional to the dose and duration of AAS use [28]. The utilization of AAS has been associated with polycythemia and adverse alterations in clotting factors [29]. A few reports have demonstrated that nonaromatizable androgens, such as stanozolol, can reduce plasma high-density lipoprotein by more than 30% [30]. AAS additionally increase hepatic lipase activity, subsequently worsening the dyslipidemia. All these factors place AAS abusers in real danger of life-changing cardiovascular incidents.

AAS use has been associated with elevations of various liver functions tests such as alkaline phosphatase, aminotransferases, conjugated bilirubin, and plasma proteins [31]. In the majority of cases, this elevation of liver enzymes is transient, with levels normalizing about 2 weeks after sensation of AAS use. Jaundice has been reported to occur following 2–5 months of treatment. Moreover, 17-alpha alkylated agents were particularly associated with cholestasis [32]. Breakdown of skeletal muscles amid extreme training may bring about an elevation of transaminases and hence should be assessed with caution in competitive athletes. Peliosis hepatis and hepatocellular adenomas have been also seen with the utilization of 17-alpha alkylated AAS [33]. Strong evidence linking hepatocellular carcinoma with AAS is lacking [34].

Estrogen produced by excessive aromatization of testosterone may result in premature epiphyseal plate closure. Androgens can have a paradoxical catabolic effect on tendons and ligaments characterized by an increased risk of rupture of biceps and quadriceps tendons [35]. Ultrastructural analysis of tendons in rodents treated with anabolic steroids shows dysplasia of collagen fibrils [36].

Acne fulminans and acne conglobate are the two most common forms of acne seen in almost half of AAS abusers [37]. Sebaceous gland hypertrophy, cysts, increased skin surface fatty acids, and increased cutaneous populations of propionibacterium acnes are all contributing factors to acne formation in this population. Anecdotal evidence shows that acne associated with AAS can get worse with vitamin B supplements [37]; hence, subjects using AAS should be warned about this consequence.

Balding is another consequence resulting from continued steroid use. It is believed to be secondary to androgen receptor-mediated gradual transformation of active large scalp epithelial hair follicles into smaller dermal villus follicules [38].

Several case reports of adverse central nervous system effects for AAS have been described. Negative feedback inhibition of the pituitary gland may result in secondary empty sella syndrome [38]. Persistent hiccups were also reported in an elite bodybuilder abusing AAS, suggesting a brain stem locus of involvement [38]. Permanent central vertigo and insomnia are other symptoms that have been linked to AAS abuse [38].

AAS use has been associated with a variety of psychiatric disturbances such as aggression, dysthymia, psychosis, and criminal behavior. The severity of these symptoms appears to be dose-dependent. Twenty-three percent of medium- and high-dose abusers (more than 300 mg AAS/week) did meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for a major mood syndrome (mania, hypomania, and major depression) and up to 12% of them developed psychotic symptoms [39]. In a double-blind, randomized, placebo-controlled crossover study, eight men received increasing doses of testosterone cypionate (150 mg/week for 2 weeks, 300 mg/week for 2 weeks, and 600 mg/week for 2 weeks). The subjects’ aggressive responses were experimentally evaluated and were found to be significantly higher among patients receiving supraphysiologic doses of T [40]. Another placebo-controlled study showed that manic symptoms are more prevalent among men receiving 600 mg per week testosterone cypionate than men receiving lower doses or placebo [41]. Moreover, delusions of grandiosity, elation, criminal behavior, and acute confusional states has also been associated with AAS abuse [42]. Interestingly, AAS abusers exhibited dependency on other substances with approximately 70% of them meeting criteria for alcohol dependence [43], followed by opioid dependence [44].