madman
Super Moderator
Abstract
Objective
Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation.
Methods
Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery.
Results
Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR 8.0-19.0) weeks, PCT; 26.0 (IQR 10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR 3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR 0.55), 3 (OR 0.46), or 4(OR 0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR 0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously.
Conclusion
Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation.
Introduction
Anabolic-androgenic steroids (AAS) are highly potent, illicit drugs used for their direct or indirect actions to increase muscle development. AAS use has been reported to increase the risk of death, cardiomyopathy, stroke, severe mental illness including psychosis, transmission of blood-borne viruses, and violent behavior.1-6 The Crime Survey of England and Wales estimated that 411 000 men (2% of the UK male population) admitted to recently using AAS; similar prevalence has been reported in the United States and other countries.7-10
Exogenous AAS suppress endogenous testosterone, and their cessation is associated with reduced testosterone and gonadotrophin secretion.2,11,12 Studies suggest that it may take months or years for some to recover testosterone secretion following cessation of AAS.2,11-14 As a result, men may experience diminished libido, poor erections, tiredness, weakness, depressive symptoms, and suicidal ideation.11-13,15-17 Unsurprisingly, men experiencing these severe withdrawal symptoms following cessation often resume AAS, leading to an increased risk of developing dependence.17-19 Other addictive substances such as heroin, benzodiazepines, alcohol, and nicotine have recommended drug treatments proven to reduce withdrawal symptoms.
There is currently no evidenced-based therapeutic approach to facilitate safe withdrawal from AAS. Some endocrinologists advise simple cessation of AAS. It is important to investigate whether alternative therapies can temporarily reduce withdrawal symptoms in men ceasing AAS use, without prolonging recovery of testicular function. Development of such therapies would allow men access to behavioral interventions to reduce risks of relapse.
Many men using AAS illicitly self-administer post-cycle therapy (PCT) to stimulate endogenous testicular function when transitioning from AAS use to cessation, in an attempt to prevent or relieve hypogonadal symptoms.2,20,21 PCT is a colloquial, non-medical term used by men using AAS to describe a heterogeneous group of non-prescribed substances used in varying regimes. PCT typically comprises a 2-to-12-week course of human chorionic gonadotrophin (hCG), and/or selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI).21 hCG directly stimulates endogenous testosterone secretion within the testes, while SERMs and AIs indirectly stimulate testosterone secretion by inhibiting estrogenic feedback on hypothalamus GnRH and pituitary gonadotropin secretion. hCG, SERMs, and AIs have been reported to potently stimulate endogenous testosterone and gonadotrophin secretion when treating men with infertility and/or hypogonadism.22-24 There is a growing literature on PCT, and user characteristics associated with PCT use, but there is limited data investigating the interactions of PCT with the recovery of testicular function following AAS cessation; such studies are important since PCT drugs have powerful effects either prolonging or promoting recovery from AAS.20,25-29
Glasgow is a city in Scotland with some of the highest rates of social deprivation, crime, and substance misuse rates within the UK.30 We conducted the largest ever retrospective study of PCT use, auditing clinical and biochemical parameters in over 600 users stopping AAS in Glasgow since 2015, attending a single harm reduction clinic providing drug awareness, health promotion, and blood-borne virus testing. All data was collected within the clinic using the same questionnaire. Our study aimed to investigate how many men stopping AAS achieve normalization of reproductive hormones with and without the use of PCT.
Limitations
This study’s large size compared with prior publications permitted multivariable analysis to determine factors associated with gonadal recovery. Furthermore, it summarizes clinical experience within a harm reduction service supporting men stopping AAS. However, it is important to fully consider the limitations of this study. This was an observational study of a convenience-based sample in which blood was drawn at widely varying intervals after steroid use. The use of AAS and the follow-up is subject to recall bias, the exact dose and composition of illicit AAS are largely unknown, and there is potential indication bias (for the use of PCT) and selection bias. The PCT and non-PCT groups were not matched so were different for many parameters, although this may have been mitigated by multivariable analysis. The duration, dose, and timing of PCT relative to the steroid regimen were highly variable and were not described. Tests for non-disclosed AAS use were not conducted. No information was collected on AAS cycles prior to the ones that users were ceasing at the time of their visit. Men using AAS may have other substance use disorders; we had no information about concomitant opioid use, which is known to cause hypogonadism.26,38 We were unable to verify the provenance of illicitly purchased PCT, some of which may not have contained any active hCG, SERM, or AI drug product.39 For this reason, the merit of studying doses of illicitly procured drugs may be limited. Fasting increases serum testosterone, and serum LH is not changed significantly during food ingestion.40,41 Therefore, the use of nonfasting samples may have enhanced the specificity of classifying men as having “biochemical gonadal recovery”; however, this would have also reduced the sensitivity of detecting “biochemical gonadal recovery”. Serum total testosterone was determined using a validated immunoassay. Mass spectrometry may be superior to immunoassay at low levels of serum total testosterone however our primary outcome only required determination if serum testosterone levels were within the adult male reference range (10-36 nmol/L); the accuracy at low levels of serum total testosterone is unlikely to have changed our conclusion. Our use of a joint endpoint to define normalization of gonadal hormones attempted to identify concurrent AAS or PCT use; specifically, elevated LH/FSH suggests current SERM exposure, low LH/FSH with raised testosterone suggests current testosterone-based AAS exposure and low LH/FSH with low testosterone suggest either current non-testosterone AAS exposure or post-AAS hypogonadism. In keeping with our study criteria, low serum LH has recently been shown to correlate with concealed AAS use detected on urine toxicology analysis.42 We also excluded anyone self-reporting AAS or PCT use within the last 1 week. However, it is important to consider whether individuals with hormone levels in the reference range can be considered “recovered”. The lack of contemporaneous toxicological AAS testing means we cannot exclude that some men had residual amounts of PCT in their circulations, which may have artificially increased testosterone to within reference levels; if reference range LH and FSH levels were also present, then the end-point of “biochemical recovery” would have been achieved, but it we would expect endogenous testosterone levels to quickly once PCT-induced testosterone secretion stopped. We therefore cannot exclude that recovery appeared quicker in the PCT group since some men had residual, circulating PCT during the blood test. Consistent with this observation, recovery levels were equally low in both groups 3 months after the last AAS use, when it can be assumed that none of the participants were still using PCT. It is therefore premature to interpret our study as evidence that PCT encourages hypothalamic-pituitary-gonadal axis recovery in men stopping AAS, although this is possible.
Conclusion
In summary, this study of real-world practice suggests several factors associated with an altered chance of normalization of reproductive hormones and recovery from post-AAS hypogonadism. Men should be advised that fewer AAS drugs used and AAS usage under 3 months are associated with endocrine recovery following their cessation. PCT remains an ill-defined and illicit drug category, but their association with normalized reproductive hormones following recent AAS use raises the important question of whether they have future therapeutic potential. Interventional studies are therefore warranted to determine the effects of PCT on endocrine recovery in men following AAS cessation.
Objective
Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation.
Methods
Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery.
Results
Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR 8.0-19.0) weeks, PCT; 26.0 (IQR 10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR 3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR 0.55), 3 (OR 0.46), or 4(OR 0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR 0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously.
Conclusion
Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation.
Introduction
Anabolic-androgenic steroids (AAS) are highly potent, illicit drugs used for their direct or indirect actions to increase muscle development. AAS use has been reported to increase the risk of death, cardiomyopathy, stroke, severe mental illness including psychosis, transmission of blood-borne viruses, and violent behavior.1-6 The Crime Survey of England and Wales estimated that 411 000 men (2% of the UK male population) admitted to recently using AAS; similar prevalence has been reported in the United States and other countries.7-10
Exogenous AAS suppress endogenous testosterone, and their cessation is associated with reduced testosterone and gonadotrophin secretion.2,11,12 Studies suggest that it may take months or years for some to recover testosterone secretion following cessation of AAS.2,11-14 As a result, men may experience diminished libido, poor erections, tiredness, weakness, depressive symptoms, and suicidal ideation.11-13,15-17 Unsurprisingly, men experiencing these severe withdrawal symptoms following cessation often resume AAS, leading to an increased risk of developing dependence.17-19 Other addictive substances such as heroin, benzodiazepines, alcohol, and nicotine have recommended drug treatments proven to reduce withdrawal symptoms.
There is currently no evidenced-based therapeutic approach to facilitate safe withdrawal from AAS. Some endocrinologists advise simple cessation of AAS. It is important to investigate whether alternative therapies can temporarily reduce withdrawal symptoms in men ceasing AAS use, without prolonging recovery of testicular function. Development of such therapies would allow men access to behavioral interventions to reduce risks of relapse.
Many men using AAS illicitly self-administer post-cycle therapy (PCT) to stimulate endogenous testicular function when transitioning from AAS use to cessation, in an attempt to prevent or relieve hypogonadal symptoms.2,20,21 PCT is a colloquial, non-medical term used by men using AAS to describe a heterogeneous group of non-prescribed substances used in varying regimes. PCT typically comprises a 2-to-12-week course of human chorionic gonadotrophin (hCG), and/or selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI).21 hCG directly stimulates endogenous testosterone secretion within the testes, while SERMs and AIs indirectly stimulate testosterone secretion by inhibiting estrogenic feedback on hypothalamus GnRH and pituitary gonadotropin secretion. hCG, SERMs, and AIs have been reported to potently stimulate endogenous testosterone and gonadotrophin secretion when treating men with infertility and/or hypogonadism.22-24 There is a growing literature on PCT, and user characteristics associated with PCT use, but there is limited data investigating the interactions of PCT with the recovery of testicular function following AAS cessation; such studies are important since PCT drugs have powerful effects either prolonging or promoting recovery from AAS.20,25-29
Glasgow is a city in Scotland with some of the highest rates of social deprivation, crime, and substance misuse rates within the UK.30 We conducted the largest ever retrospective study of PCT use, auditing clinical and biochemical parameters in over 600 users stopping AAS in Glasgow since 2015, attending a single harm reduction clinic providing drug awareness, health promotion, and blood-borne virus testing. All data was collected within the clinic using the same questionnaire. Our study aimed to investigate how many men stopping AAS achieve normalization of reproductive hormones with and without the use of PCT.
Limitations
This study’s large size compared with prior publications permitted multivariable analysis to determine factors associated with gonadal recovery. Furthermore, it summarizes clinical experience within a harm reduction service supporting men stopping AAS. However, it is important to fully consider the limitations of this study. This was an observational study of a convenience-based sample in which blood was drawn at widely varying intervals after steroid use. The use of AAS and the follow-up is subject to recall bias, the exact dose and composition of illicit AAS are largely unknown, and there is potential indication bias (for the use of PCT) and selection bias. The PCT and non-PCT groups were not matched so were different for many parameters, although this may have been mitigated by multivariable analysis. The duration, dose, and timing of PCT relative to the steroid regimen were highly variable and were not described. Tests for non-disclosed AAS use were not conducted. No information was collected on AAS cycles prior to the ones that users were ceasing at the time of their visit. Men using AAS may have other substance use disorders; we had no information about concomitant opioid use, which is known to cause hypogonadism.26,38 We were unable to verify the provenance of illicitly purchased PCT, some of which may not have contained any active hCG, SERM, or AI drug product.39 For this reason, the merit of studying doses of illicitly procured drugs may be limited. Fasting increases serum testosterone, and serum LH is not changed significantly during food ingestion.40,41 Therefore, the use of nonfasting samples may have enhanced the specificity of classifying men as having “biochemical gonadal recovery”; however, this would have also reduced the sensitivity of detecting “biochemical gonadal recovery”. Serum total testosterone was determined using a validated immunoassay. Mass spectrometry may be superior to immunoassay at low levels of serum total testosterone however our primary outcome only required determination if serum testosterone levels were within the adult male reference range (10-36 nmol/L); the accuracy at low levels of serum total testosterone is unlikely to have changed our conclusion. Our use of a joint endpoint to define normalization of gonadal hormones attempted to identify concurrent AAS or PCT use; specifically, elevated LH/FSH suggests current SERM exposure, low LH/FSH with raised testosterone suggests current testosterone-based AAS exposure and low LH/FSH with low testosterone suggest either current non-testosterone AAS exposure or post-AAS hypogonadism. In keeping with our study criteria, low serum LH has recently been shown to correlate with concealed AAS use detected on urine toxicology analysis.42 We also excluded anyone self-reporting AAS or PCT use within the last 1 week. However, it is important to consider whether individuals with hormone levels in the reference range can be considered “recovered”. The lack of contemporaneous toxicological AAS testing means we cannot exclude that some men had residual amounts of PCT in their circulations, which may have artificially increased testosterone to within reference levels; if reference range LH and FSH levels were also present, then the end-point of “biochemical recovery” would have been achieved, but it we would expect endogenous testosterone levels to quickly once PCT-induced testosterone secretion stopped. We therefore cannot exclude that recovery appeared quicker in the PCT group since some men had residual, circulating PCT during the blood test. Consistent with this observation, recovery levels were equally low in both groups 3 months after the last AAS use, when it can be assumed that none of the participants were still using PCT. It is therefore premature to interpret our study as evidence that PCT encourages hypothalamic-pituitary-gonadal axis recovery in men stopping AAS, although this is possible.
Conclusion
In summary, this study of real-world practice suggests several factors associated with an altered chance of normalization of reproductive hormones and recovery from post-AAS hypogonadism. Men should be advised that fewer AAS drugs used and AAS usage under 3 months are associated with endocrine recovery following their cessation. PCT remains an ill-defined and illicit drug category, but their association with normalized reproductive hormones following recent AAS use raises the important question of whether they have future therapeutic potential. Interventional studies are therefore warranted to determine the effects of PCT on endocrine recovery in men following AAS cessation.
