Anabolic steroids comprise a group of compounds that are structurally similar to testosterone and have similar actions when administered in an appropriate dose. Administration of androgens in a supraphysiological dose and combined with an adequate diet and strength training, is very effective to increase muscle mass and strength in men and women. As a result, androgens are by far the most popular performance and image-enhancing drugs among both elite and amateur athletes.

Over the past 40 years, the use of anabolic steroids has spread from use for performance enhancement by a relatively small group of elite athletes to widespread use among young men to obtain a more muscular physique. Indeed, androgen abuse has been called ‘a hidden epidemic’ [1].

Male hypogonadism remains by far the most important indication for testosterone therapy. Because testosterone has a high first-pass effect after oral ingestion, the molecule has been modified in an attempt to improve its bioavailability. Alkylation of the 17th carbon atom significantly prevents metabolism in the liver. However, it was quickly apparent that these oral androgens can be hepatotoxic [2]. For that reason, its application has been largely abandoned. Testosterone is currently mainly prescribed in the form of injectable depots or dermal gels.

The term ‘anabolic androgenic steroids’ refers to the anabolic (muscle building) and androgenic (virilising) effects of these compounds. In the past, several attempts have been made to manipulate the parent testosterone molecule in order to increase the desired anabolic effects and reduce the virilising effects, for instance to make these androgens better applicable for use in women. Although this concept is still widely acclaimed among androgen abusers, it has been criticised by experts and deemed obsolete since all compounds included in this group bind and activate the androgen receptor, making them basically androgens, which, by definition, have muscle building and virilising effects [3]. In clinical practice, these synthetic derivatives have been largely abandoned, however, among body builders, these obsolete androgens are still in full use [4].

The mode of androgen abuse is mainly driven by myth and bro-science. There is no doubt that administration of supraphysiological doses in combination with strength training and proper nutrition leads to a significant increase in muscle mass and strength [5]. There is an indelible belief among androgen abusers that there is an essential difference between androgens, and that the risk-benefit ratio can be improved by combining androgens. As a result, most administration schedules consist of a collection of different agents. While there are some common principles, virtually every user uses a different dosing schedule and it is common practice that an individual uses a large number of different androgens in different combinations throughout his career.

In most countries, anabolic steroids, such as testosterone, can only be obtained via a pharmacy with a doctor's prescription. However, illegal androgens are cheap and easily obtained via internet or local suppliers. The typical user of anabolic steroids is male, aged between 20 and 40 and engaged in weight lifting, bodybuilding, strongman competitions or martial arts. Anabolic steroids are mostly used in cycles with a duration between 6 and 18 weeks in doses up to 30 times the male substitution dose. Most cycles contain an injectable testosterone ester, mostly combined with nandrolone, trenbolone, drostanolone and/or boldenone esters. Although anabolic steroids are by far the most abused drugs, a variety of other performance and image-enhancing drugs are commonly used such as human growth hormone, insulin, human chorionic gonadotrophin, selective oestrogen receptor modulators, aromatase inhibitors and thyroid hormone [4].

All users of anabolic steroids, assuming a significant exposure, have side effects, although the majority of these side effects is mild and transient and some go unnoticed. Common signs of androgen abuse are gynaecomastia, acne, suppression of high density lipoprotein cholesterol, suppression of sex hormone binding globulin, erythrocytosis and thrombocytosis [6]. Although reliable data are lacking, there is sufficient evidence that links the use of anabolic steroids with serious and potentially lethal side effects, including heart failure and premature death [7, 8, 9]. An inevitable side effect of steroid abuse in men is suppression of gonadotrophins and subsequent inhibition of gonadal function. Clinical signs of gonadal dysfunction become evident after exogenous androgen levels start to decay following the last injection. Due to the sharp decline of androgen levels, this may result in anhedonia, erectile dysfunction, loss of libido, mood swings and agitation.

The inevitable suppression of the hypothalamus–pituitary–gonad (HPG) axis is a major concern for users. Not only does it lead to symptoms of androgen deficiency after finishing the androgen cycle, it is also causes a decrease in the much desired muscle mass and muscle strength. This post-steroid dip is believed to be partly responsible for the addiction effects of anabolic steroids. It can lead to users starting a new course of anabolic steroids earlier than planned. It also appears that users are increasingly deciding not to stop using altogether. It goes without saying that a longer exposure to these substances is potentially more detrimental to the health of the user.

Until a few years ago, most of the knowledge about the recovery of the HPG axis after using exogenous androgens came from male contraception research. These studies showed that testosterone, administered at a physiological or mildly supraphysiological dose, does not completely suppress spermatogenesis in many men and is therefore unsuitable as a contraceptive. After cessation of testosterone administration, endogenous testosterone production and spermatogenesis are restored, although only after many months [10].

The results of these studies have limited applicability to the group of androgen abusers. First, androgen abusers often use other types of androgens, the effect of which on spermatogenesis and HPG axis activity has hardly been studied, if at all. Second, they generally use highly supraphysiological doses, sometimes as much as 20 times the dose recommended for the treatment of hypogonadal men. Most cycles contain one or more injectable androgen esters. The type of ester varies; proprionate, acetate, enanthate, decanoate or undecylenate. Typically, the rate of diffusion form the oil depot is proportionate to the length of the ester, leading to plasma half-lives ranging from several days to several months. Theoretically, the speed of recovery of the HPG axis depends primarily on the decay of exogenous androgens which, on its turn, is dependent on the half-life and dose of the anabolic steroids used in the last phase of the cycle. Also, since oestrogens have a strong suppressive effect on gonadotrophin secretion, aromatisable androgens are expected to be more suppressive [11].

It is difficult to conduct high-quality research on the effects of androgen abuse on the male HPG axis. Most of the abused androgens, such as trenbolone, boldenone and drostanolone, are not registered for human use and the effects on gonadal function are therefore not well studied. Because of this, exposing individuals to these agents in the extreme doses typically used by androgen abusers is considered unethical. Moreover, abused androgens are typically obtained and manufactured illegally, making the quality and label information notoriously inaccurate. As stated above, type, dose and duration of administration are highly variable. Therefore, most of the current evidence derives from case reports, retrospective studies and cross-sectional investigations [12].

Recently, a number of studies have appeared that, each in a different way, provide new insights into the short- and long-term effects of androgen abuse on the male HPG axis. Winfeld-Mathiasen et al. [13] took advantage of the unique situation in Denmark where, as part of a nationwide anti-doping program, amateur athletes are forced to participate in a doping test. Male strength athletes who tested positive for androgens were compared with age-matched controls. The data from these men were paired with data from various national health databases. This made it possible to compare the probability of offspring, the probability of being diagnosed with infertility and the use of assisted fertility in a time frame 10 years prior to the positive doping tests and up to 17 years thereafter. In the period prior to the positive test, the chances of offspring among androgen abusers was 26% lower compared to matched controls. It may be speculated that a considerable proportion of the cases had been using androgens for an extended time span prior to their positive doping test. The lower fertility rate therefore likely reflects the suppressive effects of exogenous androgens on spermatogenesis. However, in the years after the doping test, the fertility rate more than doubled. At the end of follow up, the difference in fertility rate was no longer significantly different between cases and controls. Although the chances of being diagnosed with infertility was higher in cases, the frequency of needing assisted reproduction techniques was not different. These observations indicate that this doping program is effective in reducing androgen abuse among those that test positive. It also shows that the deleterious effects of androgen abuse on fertility can be reversed in most and probably all subjects.

Rasmussen et al. [14] conducted a cross sectional study among current steroid users, past users and never users. Inhibin B, a marker of Sertoli-cell function, was suppressed in current users, but reached normal levels approximately 21 months after last androgen use. Former androgen users exhibited decreased serum total testosterone and calculated free testosterone levels compared with controls. The authors were unable to note full recovery of free or total testosterone levels, Also, INSL3, a marker for functional Leydig cells in adult men was lower in former users, and was inversely associated with longer cumulative androgen abuse. The authors conclude that these results suggest that steroid abuse may result in persistent or even permanent Leydig cell dysfunction.

Shankara-Narayana et al. [15] used a similar design to investigate the rate, extent and determinants of recovery from androgen abuse-induced reproductive dysfunction after cessation of androgen intake. In this study, also semen quality was analysed. The average time to recovery was faster for endocrine parameters (7–10 months) than for sperm variables (10–14 months). The authors conclude that suppression of testicular function due to androgen abuse by young men appears to be fully but slowly reversible although testicular size remained significantly smaller in former users compared with controls.

Finally, Smit et al. [16] studied testicular function and recovery in a cohort of 100 male androgen abusers. Hormonal and semen parameters were evaluated prospectively before and during a cycle of androgens. Tests were repeated twice after androgen abuse up to 17 months after cessation. Androgen exposure resulted in complete suppression of the HPG axis, as demonstrated by undetectable LH and FSH concentrations in nearly all subjects. Furthermore, testicular volume declined during androgen abuse and spermatogenesis decreased, with two-thirds of subjects having oligo- or azoospermia by the end of the androgen cycle. When the pre-exposure gonadal function was normal, there was a 90% chance of having a normal total testosterone concentration after 3 months of recovery and a 100% chance at the end of follow-up. These data suggest that full recovery of endogenous testosterone production takes place for the majority of androgen abusers. In contrast to this observation, 37 individuals had signs of abnormal gonadal function at baseline. To be included in the study, subjects were not allowed to use androgens in the 3 months prior to inclusion, which was verified by interview when subjects were screened for eligibility. Of these 37 individuals, 35 had used androgens in the past, indicating past androgen abuse as a determinant of gonadal insufficiency. These subjects had a significantly higher cumulative past exposure to androgens, having abused androgens twice as long in their lifetime compared to the group with normal baseline gonadal function. Also, the pattern of gonadal dysfunction, i.e. hypogonadotropic hypogonadism, found in this subgroup was concordant with previous androgen use. In addition, a subgroup of nine subjects failed to achieve normal total testosterone concentrations at the end of follow-up, without signs of recovery.

In this study, the recovery of spermatogenesis took longer than the recovery of endogenous testosterone production. Mean sperm count was still significantly lower compared to baseline 3 months after the end of the androgen cycle. The estimated mean time of total sperm count to recover to baseline values was 48–69 weeks, depending on which group was taken as the reference (own control vs. non-user control group). Recovery was somewhat faster in the subgroup of subjects with normal gonadal function at baseline, with a calculated recovery time of 47–56 weeks.

Some attention needs to be addressed to the so-called ‘post cycle therapy (PCT)’. This is a popular, albeit unproven strategy that aims to restore endogenous testosterone production as soon as possible after a cycle of androgens. Selective oestrogen receptor modulators (SERMs), such as tamoxifen and clomiphene citrate, and aromatase inhibitors are frequently used for this purpose. Oestrogens, although present in much smaller concentrations compared to androgens, have strong suppressive effects on gonadotrophin production [11]. Anti-oestrogens, have been shown to stimulate gonadotrophin and testosterone production moderately in eugonadal men. Consequently, these substances are frequently used as PCT, based on the unproven assumption that they will speed up recovery of the male ––HPG axis.

However, the studies by Shankara-Narayana et al. [15] and Smit et al. [16] did not show any beneficial impact of PCT on rate of recovery for sperm variables, testis volume or hormones.