Abstract
Hypogonadism can result following anabolic steroid abuse. The duration and degree of recovery from anabolic steroid-induced hypogonadism (ASIH) is immensely variable, and there is a paucity of prospective controlled data characterising the trajectory of natural recovery following cessation. This poses difficulties for users trying to stop androgen abuse, and clinicians wanting to assist them. The objective of this paper was to synthesise evidence on the physical, psychological and biochemical patterns of ASIH recovery. We present the pathophysiology of ASIH through a literature review of hypothalamic–pituitary–testosterone axis recovery in supraphysiological testosterone exposure. This is followed by a scoping review of relevant observational and interventional studies published on PubMed and finally, a conclusion that is an easy reference for clinicians helping patients that are recovering from AAS abuse. Results indicate that ASIH recovery depends on age and degree of androgen abuse, with physical changes like testicular atrophy expected to have near full recovery over months to years; spermatogenesis expected to achieve full recovery over months to years; libido returning to baseline over several months (typically less potent than during AAS use); and recovery from gynaecomastia being unlikely. For psychological recovery, data are insufficient and conflicting, indicating a transient withdrawal period which may be followed by persisting longer-term milder symptoms. For biochemical recovery, near complete recovery of testosterone is seen over months, and complete gonadotropin recovery is expected over 3–6 months. Further prospective studies are indicated to more closely describe patterns of recovery.
Introduction
Anabolic–androgenic steroid (AAS) use is illegal if not prescribed by a medical practitioner (1). Androgens are abused predominantly by young males trying to improve sporting performance or to increase muscle mass and decrease body fat (2). After a period of AAS abuse, cessation may result in anabolic steroid-induced hypogonadism (ASIH), a state of dysfunction that may involve a suppressed hypothalamic–pituitary–testicular (HPT) axis accompanied by physical, psychological and biochemical changes. Clinical management to assist patients and the complications that ensue from androgen abuse is complex (2).
In this paper, we present an overview of the pathophysiology of ASIH, and a scoping review to explore what is known about the recovery from ASIH following cessation of AAS.
The estimated prevalence of AAS abuse is 3.3% of the global population, making it likely that doctors are seeing patients who abuse androgens. Often, clinicians are unaware that they are encountering these patients in clinical practice, given that abuse of AAS is often kept secret from health practitioners even if presenting with complications of androgen abuse such as infertility or gynaecomastia (1). Disclosure is typically only made on specific questioning by healthcare professionals. Although this behaviour of secrecy is similar to that seen with drug addiction, in contrast to those abusing classical drugs, most AAS users do extensive research beforehand and have considerable forethought in their patterns of use (1).
Sequelae arising from AAS abuse are wide ranging, encompassing direct biological effects of the androgen such as thromboembolic disease, to indirect sequelae including infection of injection sites (3). In terms of the sequelae and management of ASIH, there are a wide range of recovery patterns of the HPT axis seen in AAS abuse (2, 4), which have been detailed recently by de Ronde and Smit (2). They range from spontaneous recovery, to needing medical assistance using selective estrogen receptor modulators (SERMs) that stimulate gonadotropins, LH and FSH and or human chorionic gonadotropin (HCG) which stimulates testicular function, to cases of permanent non-recovery of the HPT axis requiring physiological testosterone replacement therapy (5).
The severity of ASIH depends on the type, combination, timeframe and dosages of AAS being abused, which can vary considerably between abusers (6). Up to 90% may combine various forms of AAS, otherwise known as ‘stacking’, believed to achieve optimal results whilst minimising side effects (7). Stacked regimes may achieve supraphysiological testosterone levels that are beyond the detection limit of commercially available assays.
Users of AAS often utilise several ‘cycles’ of stacked testosterone regimens, including intervals between cycles that are free of AAS use. During these times, they often add in medications to help recovery, forming a post-cycle treatment with the rationale of minimising unwanted side effects of AAS abuse (Table 1). The stacking and cycling of these anabolic steroids make the pharmacodynamics difficult to predict compared to medical testosterone replacement therapy, which is given as single androgenic agent in a fixed dose to maintain serum testosterone in the physiological range.
Possible sequelae of AAS abuse (8).
| Physical | Psychological | Biochemical |
|---|---|---|
| Acne | Depression | Reduced testosterone |
| Alopecia | Increased anxiety | Increased haematocrit |
| Testicular atrophy | Psychosis | Erythrocytosis |
| Gynaecomastiaa | Alcohol and drug addiction | Increased LDL and decreased HDL cholesterol |
| Tendon rupture | Cognitive deficit | PSA elevation |
| Premature epiphyseal closure | Aggression | Azoospermia |
| Arrythmias | Eating disorders | Hepatotoxicity |
| Left ventricular hypertrophy | Mania | Rhabdomyolysis and focal segmental glomerulosclerosis |
| Decreased libido and erectile dysfunction | Anti-social behaviour | Infection |
aIf aromatisable AAS are used (see Table 2).
LDL, low-density lipoprotein; HDL, high-density lipoprotein; PSA, prostate-specific antigen.
Given the dangers of AAS abuse, advocating abstinence alone is frequently insufficient as the symptoms of withdrawal or hypogonadism that ensues can be challenging. Furthermore, some patients do not wish to cease use which means that a harm minimisation approach should be considered in reducing adverse events summarised by de Ronde & Smit (2). If patients can be persuaded to cease AAS abuse, there is considerable variability in terms of recovery of the hypothalamic–pituitary–testosterone (HPT) axis.
Our objective in this scoping review was to illustrate the breadth of recovery patterns observed and to synthesise the evidence on recovery patterns observed in existing studies to assist clinicians advising patients who wish to cease AAS abuse on what is to be expected. We first examine the pathophysiology of HPT axis recovery in supraphysiological testosterone exposure in a literature review, and then present a scoping review of cross-sectional and prospective studies (cohort and randomised trials) that examine the recovery of hypogonadism, categorising outcomes into physical recovery, psychological recovery and biochemical recovery.
Pathophysiology of ASIH
AAS abuse can have numerous potential sequelae, as summarised in Table 1. Most symptoms of ASIH can be understood through prolonged feedback inhibition (if not long-term suppression) of gonadotropin-releasing hormone (GnRH) and therefore luteinising hormone (LH) and follicle-stimulating hormone (FSH). The degree and duration of suppression of GnRH varies depending on several factors, as explored below with the mechanism of pathophysiology coming from animal studies due to paucity of human studies.
The process of inhibition of GnRH by androgens is via androgen and estrogen receptors (9), which are not actually found in GnRH neurons but rather in neurons located in the arcuate nucleus and preoptic area the hypothalamus (10). These neurons are known as kisspeptin neurons and it is kisspeptin neurons in the arcuate nucleus (often referred to as KNDy neurons, as they contain the neuropeptides kisspeptin, neurokinin B and dynorphin A (11)) that project to GnRH neurons and tightly regulate the tonic/pulsatile release of GnRH in both males and females (12).
Neurokinin B serves as an autoregulatory stimulatory signal for KNDy neurons whilst dynorphin A serves as an autoregulatory inhibitory signal (13). Both culminate in a pulsatile release of kisspeptin from the KNDy neurons. Kisspeptin then serves to generate GnRH pulses in GnRH neurons (see Fig. 1). In ASIH, the feedback inhibition of GnRH is believed to occur in KNDy cells as seen in animal models that use supraphysiological doses suppressing neurokinin, increasing dynorphin A, and decreasing kisspeptin (14).
Reinitiation of GnRH pulse by KNDy neurons and its regulation. Schematic representation of the signalling pathway responsible for the generation of gonadotropin-releasing hormone (GnRH) pulses. KNDy neurons (containing the neuropeptides kisspeptin, neurokinin B (NKB) and dynorphin (Dyn) in the arcuate nucleus (ARC)) of the hypothalamus receive autoregulatory input from NKB and Dyn, forming a local circuit. Kisspeptin release is enhanced by NKB and reduced by Dyn and this net effect increases GnRH pulses. The resultant production of sex steroids will feedback to KNDy neurons to facilitate homeostatic regulation of GnRH pulses. Higher neuronal centres, such as the suprachiasmatic nucleus as well as proopiomelanocortin (POMC) and neuropeptide Y (NPY)/Agouti-related protein (AgRP), feed into this circuitry. Peripheral hormones and potentially anabolic–androgenic steroids also regulate this system to govern fertility.
Citation: Endocrine Connections 12, 12; 10.1530/EC-23-0358
The suppression of gonadotropins is dose dependent and is also dependent on the type of androgen used. In other words, the feedback inhibition of androgens is not absolute (switching ‘on or off’) but that of degree. This can be shown in standard testosterone replacement therapy for hypogonadal men, for example, where testosterone replacement from 8 nmol/L to 14 nmol/L results in LH decreasing by 40%; testosterone replacement to 19 nmol/L results in LH decreasing by 60%; and testosterone replacement to 27 nmol/L results in LH decreasing by 80% (15). Different androgens also exert different degrees of suppression of the HPT axis. Dihydrotestosterone (DHT), a non-aromatisable testosterone, for example, shows dose-dependent lowering of LH in animal models (16) but not to the same extent as testosterone (17). Taken together, this suggests that abusers of AAS that often go 10–100 times above physiologic endogenous serum testosterone levels using multiple androgens (Table 2) will have significant variation in their HPT axis suppression. To date, these have not been specifically quantified in clinical studies, given (amongst other factors) the unreliability of what is acquired on the black market and of recall.
Commonly abused anabolic–androgenic steroids.
| Generic name | Trade names | Formula | Route | Half-life | Aromatisation | 5α-reduction | A/A ratio |
|---|---|---|---|---|---|---|---|
| 17α alkyl derivatives | |||||||
| Methandrostenolone/metandienone | Dianabol, Anabol, Refovit | C20H28O2 | PO | 3.2–4.5 h | ✓ | ✓ | |
| 17α-Methyltestosterone | Android, Testred, Methitest | C20H30O2 | PO | 150 min | – | ✓ | |
| Oxandrolone | Anavar, Oxandrin, Vasorome | C19H30O2 | PO | 9 h | – | ✓ | 10 |
| Oxymetholone | Anadrol, Roboral, Anasteron, Anapolon | C21H32O3 | PO | – | ✓ | 9 | |
| Stanozolol | Winstrol, Stromba, Winstrol V | C21H32N2O | PO/IM | 24 h | – | ✓ | 30 |
| Danazol | Danocrine | C22H27NO2 | PO | 24 h | |||
| Fluoxymesterone | Halotestin, Fluotestin, Ora-Testryl | C20H29O3 | PO | 9.2 h | – | ✓ | |
| 17β ester derivatives | |||||||
| Testosterone | Testavan, Androforte 5, AndroGel, Testim, Fortigel, Testoderm, Androderm | C19H28O2 | Transdermal | 10–100 min | ✓ | ✓ | 1 |
| Testosus, Aquaviron, Univet Uni-test | IM | ||||||
| Testosterone propionate | Testrex, Androgeston, Testogen | C22H32O3 | IM | 4.5 days | |||
| Testosterone enanthate | Delatestryl, Primotestone, Testinon | C26H40O3 | IM | 7–9 days | |||
| Testosterone cypionate | Depo-Testosterone, Durandro | C27H40O3 | IM | 8 days | |||
| Testosterone undecanoate | Reandron, Andriol, Undestor, Nebido | C30H48O3 | PO/IM | ||||
| Testosterone propionate + phenylpropionate + isocaproate + decanoate | Sustanon 250 | c | |||||
| Nandroloneb decanoate | Deca-Durabolin, Anabolin | C28H44O3 | IM | 6–8 days | – | ✓ | |
| Nandroloneb phenylpropionate | Deca Rapide | IM | – | ✓ | 10 | ||
| Boldenone undecylenate | Equipoise, Ganadol, Equigon | C30H44O3 | IM | 14 days | ✓ | ✓ | |
| Metenolone acetate | Primobolan | C22H32O3 | PO | – | ✓ | ||
| Metenolone enanthate | Primobolan Depot, Delapromor | C27H42O3 | IM | – | ✓ | ||
| Trenbolone acetate | Finaplix H, Finaplix S, Parabolan | C20H24O3 | PO, IM, pellets | – | ✓ | ||
| Drostanolone propionate | Masteron | C23H36O3 | IM | – | – | ||
Information sources: trade names (18), formula (18, 19), route (18), therapeutic dose (20), half-life (20, 21), aromatisation (22), 5α-reduction (22), anabolic–androgenic ratio (23).
bor 19-nortestosterone; ctakes 21 days for plasma testosterone to return to lower normal range in males (3).
A/A ratio, anabolic–androgenic ratio; IM, intramuscular injection; PO, oral.
Another reason for the variation seen in recovery from ASIH is that KNDy neurons receive input from the hormonal milieu of the organism from leptin (24), CRH, cortisol (25) and prolactin (26), as well as being subject to higher neuronal regulation, such as the first-order metabolic neurons POMC and NPY/AgRP as well as neurons from the suprachiasmatic region (27). This suggests that individual factors and co-morbidities, as well as other factors such as concurrent anti-depressant use and psychological stress disorders (28) as well as adiposity (29) are highly relevant. Age is also an important variable, with the HPT axis known to recover more rapidly in younger than older men, although the mechanisms remain unknown (30).
Lastly, cessation of AAS abuse is commonly associated with burdensome psychological disorders, especially anxiety and depression (31). Whether these disorders predate and contribute to the abuse of AAS, or whether AAS abuse brings out or leads to anxiety and depression, is unclear. ASIH may cause psychological disturbances by directly and indirectly mediating several brain regions, primarily the amygdala, the hippocampus, and the bed nucleus of the striae terminalis (32). For example, the degree of amygdala activation in relation to fear has been found to have a positive correlation with testosterone levels in men (33). Furthermore, KNDy neuropeptides play an important role in regulating mood; for instance, in male mice hypogonadal from absent kisspeptin signalling (via transgenic kisspeptin receptor deletion) demonstrate anxiety-related behaviours independent of circulating levels of androgen replacement (34). This may explain the persistent mood disturbance when ceasing androgen abuse despite adequate testosterone replacement therapy.
Recovery from ASIH
To review the current evidence regarding recovery from ASIH, PubMed was searched from inception to 26 April 2022. The following search strategy (returning 811 results) was used on Title/Abstract: AND (Abuse* OR Recover* OR Cessation OR Former OR Previous) AND (Hypogonad* OR Reproduc* OR Testic* OR Sperm* OR Fertility).
Eligibility criteria included studies of human subjects who had taken (or were taking) AAS, in which physical, psychological or biochemical measurements were taken following AAS cessation. Male contraceptive trials of testosterone were also included, as these serve as simplistic models of AAS misuse. Excluded studies were those that were case studies or series, studies that were not in the English language, or studies of animal models. Articles were first assessed on title/abstract basis, with all potentially relevant articles assessed in full. In addition, the reference lists of all included articles were scanned for other relevant articles.
All included studies are summarised in Table 3. Studies described considerable variability in the substances abused, the amount abused, the length of abuse, and the duration of follow-up after cessation. As such, a meta-analysis was not feasible. Many studies were limited, with small sample sizes meaning that not all differences reached statistical significance. Only one study assessed different usage patterns (stacking, cyclical, continuous, etc.), finding this factor to have no impact on the recovery of any parameter (4).
Studies investigating recovery from ASIH following cessation of AASa.
| Study and design | Subjects | AAS used | Duration of use | Duration of follow-up after cessation | Parameters measured | Outcome at follow-upb |
|---|---|---|---|---|---|---|
| Analyses of previous studies | ||||||
| Christou et al. 2017 (30) Meta-analysis |
For serum testosterone: 27 athletes (from 5 studies) For FSH and LH: 17 athletes (from 3 studies) For semen, numerous subjects from 8 studies |
Variable | Variable | Variable | Serum testosterone, FSH, LH Sperm features |
|
| Liu et al. 2006 (35) Meta-analysis | 1549 healthy eugonadal men aged 31.8 (6.1) years (from 30 studies) | Testosterone + (in 58% of subjects) progestogen Sensitivity analysis found no difference in recovery rate with +/− progestogen |
9.45 (4) months (up to 18) | Variable | Sperm concentration, motility, and morphology |
|
| Ly et al. 2005 (36) Secondary analysis | 532 healthy fertile men aged 21–45 years (from two prospective studies) | Testosterone enanthate 200 mg/week IM | Until azoospermic (up to 6 months) | Until sperm recovery to ≥20 × 106/mL | Sperm concentration |
|
| Interventional (including male contraception) studies | ||||||
| Handelsman et al. 2022 (37) Randomised controlled trial |
Men aged mean 60.1 years with impaired glucose tolerance or newly diagnosed type 2 diabetes mellitus, randomised to receive testosterone or placebo | Testosterone undecanoate 1000 mg IM | 2 years (dose at baseline, 6 weeks, then every 3 months) | 12 months | Testosterone, FSH, LH Psychosexual quality of life |
|
| Garevik et al. 2016 (38) Prospective study | 11 healthy Caucasian men aged 29–46 years, medically screened for illicit drug use | Nandrolone decanoate 150 mg IM | Single dose | 14 days | Serum testosterone, FSH, LH |
|
| Garevik et al. 2014 (39) Prospective study | 25 healthy men aged 27–43 years, medically screened for illicit drug use and other health issues | Testosterone enanthate 500 mg, then 250 mg, then 125 mg IM | Three doses 6–8 weeks apart | 14 days (after each dose) | Testosterone, FSH, LH |
|
| Gu et al. 2009 (40) Multicenter phase III contraceptive efficacy clinical trial | 733 healthy Chinese men aged 20–45 years | Testosterone undecanoate 500 mg/month | 30 months | 12–15 months | Total testicular volume Serum testosterone, FSH, LH Sperm concentration, morphology, and semen volume |
|
| Wang et al. 2007 (41) Randomised controlled trial | 18 Chinese men aged 27–48 years | Testosterone undecanoate 1000 mg followed by 500 mg every 6 weeks IM | 18 weeks | 12 weeks | Serum testosterone, FSH, LH Sperm concentration, motility and morphology |
|
| Yates et al. 1999 (42) Randomised controlled trial | 31 healthy men aged 21–40 years | Testosterone cypionate 100 mg, 250 mg, or 500 mg/week IM | 14 weeks | 12 weeks | Psychosexual (aggression, libido, mood, psychopathology) Serum testosterone |
|
| MacIndoe et al. 1997 (43) Randomised controlled trial |
31 men aged 18–40 years | Testosterone cypionate 100, 250, or 500 mg/week IM | 14 weeks | 12 weeks | Serum testosterone, FSH, LH Sperm concentration and motility |
|
| Small et al. 1984 (44) Prospective study | Nine healthy men aged 19–35 years | Stanozolol 10 mg/day PO | 2 weeks | 2 weeks | Serum testosterone, LH, FSH |
|
| Bijlsma et al. 1982 (45) Prospective study | 11 men with rheumatoid arthritisc aged 44–62 years | Nandrolone decanoate 25mg/week for 6 weeks, then 50 mg/week for 6 weeks IM | 12 weeks | 12 weeks | Serum testosterone, FSH, LH |
|
| Clerico et al. 1981 (46) Prospective study | Nine male athletes aged 20–36 years, who were AAS-free for ≥50 days | Methandrostenolone 20–35 mg/day | 14 days | 7 days | Serum testosterone, FSH, LH |
|
| Remes et al. 1977 (47) Randomised controlled trial | 12 male athletes aged 20–28 years, randomised into two experiments | Methandienone 5 mg/day (phase I) → 10 mg/day (phase II) PO DHEAS 20 mg/day (phase I) → 40 mg/day (phase II) PO |
3-5 months per phase | 6 weeks | Serum testosterone, FSH, LH |
|
| Caminos-Torres et al. 1977 (48) Prospective study |
12 healthy men aged 20–27 years | Testosterone enanthate 50 mg/week or 200 mg/week IM | 8 weeks | 5 weeks | Serum testosterone FSH and LH (normal and GnRH-stimulated) |
|
| Mauss et al. 1975 (49) Prospective study | Seven healthy men aged 20–27 years | Testosterone oenanthate 250 mg/week IM | 21 weeks | 18 weeks | Libido, sexual frequency, hair growth, acne Testicular volume Serum testosterone, FSH, LH Sperm concentration, motility and morphology |
|
| Observational studies: prospective | ||||||
| Smit et al. 2021 (50) Prospective study | 100 male amateur athletes aged 19–67 years, who intended to start androgen cycle in the next 2 weeks | Variable (number of AAS used: median 5, range 1–11) Median dose 901 mg/week (range 250–3382) |
Median 13 weeks (range 2–52 weeks) | Median 9.4 months (range 3.7–12.1) |
Serum testosterone, FSH, LH Testicular volume Semen volume and sperm concentration, count, progressive motility, motile sperm count |
|
| Windfeld-Mathiasen et al. 2021 (51) Prospective study |
545 males aged 26.2 (6.3) years attending fitness centers with positive AAS in urine sample, compared to age-matched controls from population registry | Variable | Unknown | Mean 7.3 years | Fertility rate |
|
| Garevik et al. 2011 (52) Prospective study | 35 AAS-abusing men aged 26.4 (7.2) years, recruited through anti-doping hotline | Testosterone IM, Nandrolone IM | <5 weeks for testosterone | 6 months | FSH, LH |
|
| Karila et al. 2004 (53) Prospective study | 21 male power athletes aged 24–42 years, undergoing medical assessment to rule out chronic diseases and medication use ‘Major users’ are those with cumulative lifetime dose > median value |
Variable 17–167 mg/day |
5.4–38.3 weeks | 6 months | Serum testosterone, FSH, LH Sperm concentration and morphology |
|
| Alen et al. 1987 (54) Prospective study | Seven power athletes in training aged 24–34 years | Testosterone IM, Methandienone PO, Nandrolone IM, Stanozolol IM (variable doses) | 12 weeks | 13 weeks | Serum testosterone, LH, FSH |
|
| Alen et al. 1985 (55) Prospective pilot study | Five power athletes aged 27 (5.5) years | Testosterone IM, Methandienone PO, Stanozolol IM, Nandrolone IM (variable doses) | 26 weeks | 12 weeks | Serum testosterone, FSH, LH |
|
| Ruokonen et al. 1985 (56) Prospective study |
Four power athletes | Methandienone PO, Nandrolone IM, Stanozolol IM, Testosterone IM (variable doses) | 26 weeks | 16 weeks | Serum testosterone |
|
| Observational studies: cross-sectional | ||||||
| Shankara-Narayana et al. 2020 (4) Cross-sectional |
31 previous users aged 33 (2) years, compared with 21 healthy controls aged 32 (2) years All were males regularly involved in recreational exercise (≥3 times/week) |
Variable Median 5 compounds used |
Lifetime median 115 weeks | Median 42.9 weeks since cessation | Gynaecomastia, acne, temporal hair loss Testicular volume Sperm output, concentration and motility Serum testosterone, FSH, LH |
|
| Lindqvist Bagge et al. 2017 (57) Cross-sectional |
143 male elite athletes reporting a history of AAS abuse, compared with 540 who reported none | Not stated | Not stated | 30 years after ceasing their active sports career | Lifetime prevalence of physical/mental health issues where professional help was sought |
|
| Rasmussen et al. 2017 (58) and Rasmussen et al. 2016 (59) Cross-sectional |
33 previous users aged 34.8 (1.2) years, compared with 30 healthy controls aged 31.5 (1.2) years All were males in recreational strength training |
Not stated Median 6 different compounds used |
Lifetime mean 111.8 weeks | At least 3 months since cessation | Psychosexual features Testicular volume Serum testosterone, FSH, LH |
|
| Kanayama et al. 2015 (60) Cross-sectional |
19 previous users aged 42.7 (3.8) years, compared with 36 weightlifting controls aged 42.9 (5.8) years | Not stated | 6.9 (4.5) years over lifetime | Mean 4.9 (6.6) years since cessation (range 0.25-21.2 years) | Psychosexual factors Testicular volume Serum testosterone, FSH, LH |
|
| Graham 2006 (61) Cross-sectional | Ten previous users aged 41.7 (3) years, compared with 10 bodybuilding controls aged 43.1 (4.6) years | Not stated | 20.7 (2.8) years over lifetime | Single point in time, at least 3 months after cessation | Testosterone |
|
| Urhausen et al. 2003 (62) Cross-sectional | 15 male bodybuilding/powerlifting previous users | Variable | Mean 720 mg/week for 26 weeks yearly, over 9 years | At least 12 months since cessation (median 24 months, mean 43 months) | Gynaecomastia Serum testosterone, LH, FSH |
|
| Lemcke et al. 1996 (63) Cross-sectional | 47 men aged 21–30 years previously treated for idiopathic tall stature, compared with 123 healthy controls without idiopathic tall stature | Testosterone enanthate 250 mg/week IM | 12.1 (5.2) months | 10.6 (2.5) years | Testicular volume Sperm count, concentration, progressive motility and morphology Serum testosterone, FSH, LH |
|
| Bond et al. 1995 (64) Cross-sectional | 16 previous users aged 24.4 (2.6) years, compared with 14 controls aged 23.5 (4.4) years, all of whom had lifted weights for ≥2 years | Variable | Previous cycles lasting 8–11 weeks | Single point in time, at least 1 week (for PO) or 1 month (for IM) after cessation | Psychological factors, aggression |
|
| Malone et al. 1995 (65) Cross-sectional | 46 previous powerlifting/bodybuilding users aged 27.5 years (including 3 females), compared with 87 controls aged 26.7 years (including 11 females) | Not stated | Lifetime mean 5.3 years | Not stated | Prevalence of psychiatric diagnoses (ever) Current recreational drug use/dependence |
|
| Pope & Katz 1994 (66) Cross-sectional | 51 previous users aged 25.5 (7) years, compared to 68 controls aged 28.3 (10) years, all of whom had lifted weights for ≥2 years All were weightlifting males |
Not stated | Variable (1–28 cycles over lifetime) | At least 1 week (PO) or 1 month (IM) since cessation | Gynaecomastia, acne, hair loss (physical examination) Testicular length (calipers) Psychiatric diagnoses |
|
| O'Connor & Baldini 1990 (67) Cross-sectional | Five retired powerlifting previous users aged 40 (1.2) years | Not stated, mean 233 mg/week | 3–4 cycles yearly, each lasting 9.8 (1.3) weeks | At least 5 years since cessation | Serum testosterone |
|
| Knuth et al. 1989 (68) Cross-sectional | 11 bodybuilding previous users, compared with 41 controls Aged 26.7 (0.7) years |
Variable | Not stated | Single point in time, at least 4 months after cessation | Sperm concentration, motility and morphology Serum testosterone, FSH, LH |
|
| Shephard et al. 1977(69) Cross-sectional |
Four bodybuilding previous users aged 23–52 years | Methandrostenolone 10–15 mg/day | 7–10 months | 2 weeks–7 months since cessation | Sexual function Serum testosterone, LH, FSH |
|
Parameters reported as mean (SD) or a range (minimum–maximum) unless otherwise stated. Differences reported were all statistically significant. A parameter ‘recovered’ when it had no statistically significant difference to baseline.
aSubjects, parameters and outcomes not relevant to the research question (e.g. data on current AAS users) omitted; bUnless otherwise stated, refers to measurement at the endpoint of the study, compared to baseline (i.e. individual levels before AAS use, or controls who had never used AAS); cRheumatoid arthritis treatment, comprising of non-steroidal anti-inflammatory drugs (8 subjects) or chloroquine (3 subjects) was continued throughout the study period.
AAS, anabolic androgenic steroid; CI, confidence interval; FSH, follicle-stimulating hormone; IM, intramuscular; LH, luteinising hormone; PO, oral; RR, relative risk.
To aid interpretability of results, the physical, psychological and biochemical changes measured across these studies will be reviewed in turn. A broad summary table of conclusions is provided at the end of this paper (Table 4).
Conclusions from scoping review.
| Change associated with ASIH | Recovery pattern after cessation of AAS |
|---|---|
| Physical changes | |
| Testicular atrophy | Near-complete recovery expected over months to years, with difference in volume in one year being minimal |
| Gynaecomastia | Recovery is not likely |
| Libido and erectile dysfunction | Recovery to baseline is expected over months, but ‘baseline’ is typically not as potent or active as during AAS abuse |
| Spermatogenesis | Complete recovery in months likely |
| Psychological changes | |
| Mood disorder | Insufficient and conflicting data; depressive and anxious symptoms are common on cessation of AAS and improvement after initial withdrawal period is likely, but incomplete |
| Quality-of-life measures | Insufficient and conflicting data, but symptoms like fatigue often remain, perhaps normalised over years but not as good as during AAS abuse |
| Biochemical changes | |
| Testosterone | Near-complete recovery in 3–6 months is likely, but full recovery is uncertain. |
| Gonadotropins (FSH, LH) | Full recovery in 3–6 months is highly likely |
Physical changes
Testicular volume
For many individuals, testicular volume is not fully reversible after AAS cessation. Amongst AAS abusers, Smit et al. found mean testicular volume to be a mean 0.7 mL lower than baseline 3 months after AAS cessation, although most individuals recovered to their baseline at 9 months (50). Prospective trials investigating testosterone’s contraceptive potential have found that mean testicular volume, compared to individuals’ pre-use baseline, remains 15% lower (3 mL reduction in testicular volume) 18 weeks after cessation of testosterone enanthate (49), but only 4% lower (1.5 mL reduction in total testicular volume) 12 months after cessation of testosterone undecanoate (with only 28% of these subjects having a smaller total testis volume than their baseline) (40). Over longer time periods however, testicular volume may recover fully with men treated with testosterone for idiopathic tall stature having no significant difference in testicular volume after a mean of 10.6 years compared to controls who had never used testosterone (63). However, data from male contraceptive cohorts may not be applicable to AAS abuse, as patterns of AAS abuse typically involve more complex regimes of testosterone involving supraphysiological doses.
In AAS abusers, the cross-sectional study by Rasmussen et al. demonstrate a negative correlation between accumulated weeks of AAS abuse and testicular volume (59). The control group in this study had an average testicular volume measured by orchidometer of 22.3 mL compared with a volume of 17.4 mL of past abusers who had not used AAS for over 2 years. Current abusers in the study had the lowest volume of 12.2 mL, as expected.
These findings are supported by a more recent case control study by Shankara-Narayana et al. using ultrasound to measure testicular volume. In this study, those who had ceased use for a median 10.7 months had a reduction of 32% (9 mL) compared with healthy controls (4). In terms of longest duration since AAS abuse and testicular volume change, another cross-sectional study by Kanayama et al. supports a reduced testicular volume of 10% (2.3 mL) up to a mean of 4.9 years of previous AAS abuse compared with controls (60).
Taken together, the evidence suggests that most testicular volume lost does recover after ceasing AAS use, but it may take years and often is not complete. A limitation of these studies is the use of orchidometry, with the exceptions of Shankara-Narayana et al. and Lemcke et al., which measured testicular volume with ultrasonography (4, 63).
Gynaecomastia
Gynaecomastia is a consequence of increased oestradiol from aromatisation of excessively high levels of testosterone, as well as imbalance of the estrogen-to-testosterone ratio after AAS abuse. To avoid this outcome, tamoxifen or other estrogen receptor blockers are often used concomitant with AAS. Unfortunately, tamoxifen use in males can be associated with side effects of nausea, loss of libido, and mood deterioration, as well as an increased risk of thromboembolism (70).
Gynaecomastia ‘in the past’ is reported by two-thirds of former AAS abusers (62), and is known to persist after AAS cessation. Compared to controls who had never used AAS, former AAS abusers who had ceased use for at least 1–4 weeks (having used up to 28 cycles over their lifetime) were significantly more likely to have gynaecomastia on physical examination (31% vs 3%) (66). Moreover, former AAS abusers who had ceased use for a mean 10.7 months reported gynaecomastia at greater rates than controls (23% vs 0%), but this difference did not reach statistical significance (4). Beyond this timeframe, evidence is lacking.
Libido/erectile dysfunction
Using psychometric questionnaires, a cross-sectional study of former AAS abusers who had ceased use for at least 3 months found more had erectile dysfunction (27% vs 7%) or low libido (40% vs 10%) compared to controls (59). Similarly, another study of AAS abusers with a mean 6.9 years of abuse who had ceased use for a mean 4.9 years finding reduced sexual desire compared to controls (60).
This is, however, not universal. There were studies that found no differences in libido amongst former AAS abusers (42, 49, 69) but most of these measured libido and erectile dysfunction via self-reported history rather than psychometric questionnaires.
A prospective controlled study of 3-monthly testosterone undecanoate vs placebo amongst eugonadal men with insulin resistance found that sexual satisfaction (in terms of erectile function and sexual desire) was increased in the testosterone-supplemented group compared with controls. Once testosterone use was ceased, sexual satisfaction returned to baseline control levels beyond 18 weeks (37). Although not a study of AAS abuse, this study does support anecdotal reports of lower libido and erectile function after AAS cessation, but suggests that this reduction is merely a return to baseline.
However, some individuals have lower libido and erectile function during AAS abuse, depending on the type of androgen used. If the androgen is non-aromatisable (resists aromatisation to oestradiol despite a supraphysiological testosterone), this would lead to lowering of libido and erectile function as both testosterone and oestradiol are needed for libido and erectile function (71). Examples of synthetic non-aromatisable androgens include Nandralone and stanazolol (Table 1). Stanzolol bears a 17α-alkyl substitution rendering it resistant to degradation and despite anabolic activity, involves reduced reproductive function (reported anecdotally and observed in animal studies) (72).
Spermatogenesis
In interventional contraceptive studies of healthy young men, spermatogenesis recovers after cessation of testosterone. A meta-analysis of interventional contraceptive studies of testosterone found sperm concentration to recover to ≥20 × 106/mL at a mean 4.6 months (19 weeks) after cessation of testosterone. However, many took longer to recover, with 67% recovering by 6 months, 90% by 12 months, and 100% by 24 months. When sperm concentration recovered to individuals’ baseline values, sperm motility and morphology were significantly lower than pre-interventional values by 1.6% and 3.4%, respectively. This suggests that sperm concentration may be the first parameter to recover, followed by sperm motility, then sperm morphology. However, findings could not be extrapolated beyond the maximum usage duration of 18 months, and only 60% of individuals were followed up long enough for sperm concentration to recover to pre-interventional values (35). In another interventional study, it was found that by 15 months of ceasing testosterone use, sperm concentration recovered to individuals’ pre-interventional values in 99.7% of cases (40).
A prospective study of AAS abusers found that 3 months after AAS cessation, individuals had lower semen volume (mean difference 0.4 mL), sperm concentration (mean difference 10.4 × 106/mL), sperm count (mean difference 57.1 × 106/mL) and motile sperm count (mean difference 34.1 × 106/mL) than baseline, with only sperm progressive motility recovering to baseline. However, 9 months after AAS cessation, all variables recovered to baseline, with the exception of semen volume (mean difference 0.4 mL) and sperm count (mean difference 25 × 106/mL) remaining lower than baseline (50).
In contrast, cross-sectional studies of those abusing multiple AAS substances have found signs of impaired spermatogenesis up to at least 7.5 months after AAS cessation (30). Former AAS abusers who had ceased use for at least 4 months were found to have significantly lower sperm motility and morphology (but not concentration) than controls who had never used AAS (68), whereas sperm parameters amongst those who had ceased use for a median 11 months had recovered to those of controls (4). Regression analyses in the latter study found the duration of recovery to be positively associated with the duration of AAS abuse, with recovery time being a mean 10 months for sperm concentration and a mean 38 months for sperm motility (4). Encouragingly, a prospective controlled study following participants detected for abusing androgens in an antidoping program in Denmark showed that though fertility rate is significantly lower in the group of androgen users at baseline, catch up is achieved in the 2–3 years following (51).
Psychological changes
Former AAS abusers are at higher risk of psychopathology during the immediate period of AAS cessation as well as longer term. The earliest case control study performed in 2015 showed that following AAS abuse cessation, there is an increased risk of 29% of major depression compared with control of 5% (60). This was assessed by structured interview based on DSM-IV criteria and included suicidal ideation being observed. Following withdrawal, the rate of major depression equalised to rates of control but in a subsequent study by Rasmussen et al. a year later in 2016 showed that in the longer term, former AAS abusers still had significantly higher rates of depressive symptoms as measured by SF-36 questionnaire (24% vs 3%) and more severe fatigue than controls who had never used AAS (59).
Overall, former AAS abusers are significantly more likely to have had a psychiatric diagnosis (37% vs 12%) or experienced suicide ideation (13% vs 1%) (65), and significantly more likely to have experienced self-reported depression (13% vs 5%) or anxiety (13% vs 6%) than controls who had never used AAS (57). It is not clear, however, whether those who are prone to symptoms of depression and anxiety seek out AAS, or whether depression and anxiety is a consequence of AAS abuse. It would be reasonable to hypothesise that both are possible but the latter seems more significant contributing to the higher rates of psychopathology, given that former AAS abusers who had used cycles lasting more than 2 years were found to be significantly more likely to self-report having experienced anxiety (24.5% vs 6.7%) or any psychiatric illness (28.3% vs 12.4%) than former AAS abusers who had not used cycles lasting more than 2 years (57). In the absence of prospective studies, this remains a hypothesis.
There are, however, studies that show no differences in depression and anxiety between AAS past abusers and controls. In former AAS abusers ceasing use for at least 1–4 weeks, cross-sectional studies found no significant differences (according to a self-rated aggression scale) in aggression, mood or other psychopathology (except for lower self-rated affability) (64), and no significant differences in psychiatric diagnoses as per the Structured Clinical Interview for DSM-III-R (66). Similarly, a prospective laboratory study found no significant differences in psychopathology (as per the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Modified Mania Rating Scale and Buss–Durkee Hostility Inventory) 12 weeks after cessation of testosterone cypionate compared to pre-interventional baseline, and no evidence for a dose–response relationship (42).
This apparent lack of differences could mean no psychological difference or psychological impact from past AAS abuse but this is to be interpreted with the following caveats. First, recruitment bias is likely in these studies, which were recruiting through advertisements in gyms, which could exclude those that suffer from lethargy, anhedonia or individuals prone to paranoia. Second, psychopathology was not measured consistently and methods used are hard to compare between studies which include psychometric questionnaires (42), clinical history (57, 60, 65) or self-rating scales (64). Third, differences may not have been detected due to the small sample sizes of studies (42).
In summary, psychological disturbances affect many former AAS abusers, but long -erm symptoms are mild in most cases. Evidence to indicate a specific timeframe for recovery and the predictors of recovery is lacking. Further studies that can quantify and take into account the bidirectional relationship between the psychopathology of AAS abuse and the effect of AAS abuse on psychopathology are needed (31).
Biochemical changes
Testosterone
The recovery of serum testosterone levels after AAS cessation is variable and controversial. The first meta-analysis examining the changes to testosterone was published in 2017 by Christou et al. (30). It showed that testosterone did not recover fully by 16 weeks, with a weighted mean difference in testosterone between abusers and non-abusers of 9.4 nmol/L. This is supported by the case control study by Rasmussen et al. in 2016 (not included in the meta-analysis), that showed that a longer duration of abstinence from AAS abuse up to 2 years still did not equalise the median testosterone level (59). The control group median was 18.8 nmol/L, whilst the past AAS abusers group had a median of 14 nmol/L. By contrast, Shankara-Narayana et al. showed no statistically significant difference between mean testosterone levels of abusers and non-abusers with the average of 300 days of AAS cessation (4). However, in Handelsman et al., following 2 years of blinded testosterone treatment, testosterone levels remained 11% lower than the placebo group after 1 year of follow-up (37).
In more controlled studies examining supraphysiological dosing of AAS use, results are similarly mixed. Testosterone levels are reported to recover to baseline anywhere between 10 days (47), 14 days (44), 5 weeks (48), 8 weeks (42), 10–14 weeks (43), 12 weeks (41, 45, 50), 16 weeks (56), 18 weeks (49) or 12–15 months (40) after AAS cessation, which is in contrast to studies that show a persistent reduction in testosterone between 4.5 and 11 nmol/L lower than baseline anywhere between 7 days (46), 14 days (38), 12 weeks (55) and 13 weeks (54) after AAS cessation.
Factors such as the type/s of AAS used, the pattern and duration of usage make it difficult to pool these findings together into an overall conclusion. Pattern and duration of usage is difficult to quantify accurately in studies but where it is attempted, those with a cumulative lifetime dose of AAS exceeding the median as in Karila et al. showed significantly lower serum testosterone 6 months after cessation (mean 6.1 vs 12.3 nmol/L) (53). Similarly, in Caminos-Torres et al., at 5 weeks after cessation of testosterone, the 50 mg group had recovered to pre-interventional baseline, but the 200 mg group was at a mean 6.1 nmol/L lower than baseline (48). However, this potential dose–response relationship was not universal, as in MacIndoe et al., where recovery of serum testosterone to pre-interventional baseline took 10 weeks in the 100 mg/week group, 14 weeks in the 250 mg/week group, but 10 weeks in the 500 mg/week group (43). This suggests that individual factors play a significant role (as outlined in the pathophysiology earlier; Figure 1), highlighting the need for prospective controlled studies.
Finally, it should be noted that studies that show former AAS abusers recover testosterone to the normal range often recover to only the lower limit of the reference interval. In Rasmussen et al., most AAS abusers had testosterone in the lower normal range (with only 3.3% below the lower reference range limit) (59), and all but 2 former AAS abusers in Urhausen et al. had serum testosterone in the lower 20% of the normal reference range (62). Even case control studies that show no statistically significant difference between past AAS abusers and controls show that past abusers have a mean serum testosterone lower than controls (as in Shankara-Narayana et al.; 6.2 ng/mL vs 8.7 ng/mL, respectively).
Taken together, testosterone recovery is expected but likely to be incomplete despite months or years of AAS cessation.
Gonadotropins
In most studies, FSH and LH recovered to baseline values (or were not significantly different to controls) 2–16 weeks after cessation (41, 44, 48, 49, 54, 55). However, a few studies described reduced gonadotropin levels when measured at 2 weeks (38, 39), 6 weeks (47) or 12 weeks (45, 50) after AAS cessation.
In Handelsman et al., following a 2-year blinded treatment with testosterone in hypogonadal men with diabetes, it took a median 33.9 weeks for individuals’ FSH and LH to recover to their own pre-treatment baselines (37). In Shankara-Narayana et al., the projected time taken for FSH and LH to recover was 19.6 and 10.7 months, respectively (4). Like testosterone recovery, the degree of AAS abuse is also likely to impact on recovery of gonadotropin levels, with those having a cumulative lifetime dose of AAS exceeding the median in Karila et al. demonstrating significantly lower FSH (mean 0.9 vs 2.9 IU/L) and LH (mean 1.5 vs 3.4 IU/L) than other study participants 6 months after cessation (53).
Conclusion
Amongst those who abuse AAS, cessation often results in the wide-ranging sequelae of anabolic steroid-induced hypogonadism. These sequelae encompass physical, psychological and biochemical changes, which in some cases may be irreversible. In this scoping review, we found that recovery from the sequelae of ASIH was immensely variable, depending on the type of AAS used (‘stacking’ if multiple), the dosages used, the duration of use, the patterns (‘cycles’) of use, and comorbid conditions.
Our scoping review demonstrated broad conclusions across some of the changes associated with ASIH, as summarised in Table 4. Recovery usually does occur in relation to gonadotropin levels whilst testosterone has near to complete recovery over the weeks to months of follow-up depending on duration and dose of AAS abuse. Spermatogenesis is usually completely recovered over months to years with sperm concentration typically recovering first, followed by sperm motility, then sperm morphology, with fertility rates eventually normalising over years.
Similar to recovery of spermatogenesis, the recovery of testicular volume takes months to years; however, the volume difference is still present up to a year, be it minimal in reduction in AAS abusers. Gynaecomastia is more common in AAS abusers and can persist despite years of follow-up, potentially warranting surgical intervention.
Owing to the paucity of data, the recovery patterns for libido and erectile dysfunction, and psychological changes remain less clear. There is an initial increase in depressive and anxious symptoms with recovery seen over months to years, however, some studies do not find any significant differences. The variability in duration of recovery and depth of symptoms ranging from mild to potential suicidality warrants further study in terms of helping patients avoid these dire outcomes, and helping those that are willing to abstain from returning to AAS abuse.
The secrecy, stigma and illegality associated with AAS abuse has long made recruitment for research a challenge prone to selection bias. Nonetheless, there is a need for controlled prospective studies and quantification of the abused regimes used rather than just considering the cohort homogenously. In the absence of these fine-grained studies, the evidence base for managing abusers of AAS will continue to be challenging.
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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