Endocrine therapy to restore endogenous T levels and alleviate ASIH symptoms in AAS dependent men

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ABSTRACT

Introduction


Long-term anabolic-androgenic steroid (AAS) use poses several health risks, including secondary hypogonadism. There is a knowledge gap on treatment targeting the hypothalamic-pituitary-gonadal (HPG) axis among men with anabolic steroid-induced hypogonadism (ASIH). This study aims to gain insights into the potential utility of endocrine therapy to restore endogenous testosterone levels and alleviate ASIH symptoms in AAS dependent men.


Methods

In this proof-of-concept, single-site, open longitudinal pilot study, AAS dependent men with continuous AAS use and a desire to permanently discontinue use, were given endocrine therapy. The treatment included 25mg clomiphene citrate (CC) every second day for 16 weeks, transdermal testosterone daily during the first four weeks, and if indicated, human chorionic gonadotropin (hCG) injections for a maximum of eight weeks. Physical exams including blood collection and online questionnaires were completed every four and two weeks,respectively.


Results

Ten participants, with median age 32 years (interquartile range 30–45), with mean ± standard deviation AAS use of 11 ± 4 years, completed the CC intervention. Seven participants received hCG as part of their treatment protocol. Mild adverse events included headaches, dizziness, and mood swings, and no serious adverse events occurred. During the intervention, there was a decrease in levels of hematocrit, hemoglobin and ALT (alanine aminotransferase), as well as an increase in serum FSH (follicle stimulating hormone), LH (luteinizing hormone) and SHBG (sex hormone binding globulin). Five of ten participants reached a total testosterone level within normal range (9–30 nmol/l). The HPG axis response varied greatly among participants, and was not aligned with the severity of ASIH related withdrawal symptoms.


Conclusions

The findings from this proof-of-concept study may guide future randomized controlled trials aiming to investigate potential endocrine therapeutic approaches to ASIH.




1. Introduction


Anabolic-androgenic steroids (AAS) constitute a subgroup of image and performance-enhancing drugs (IPEDs) including testosterone and synthetic androgens yielding similar chemical and biological effects (Kicman, 2008). Since the 1980s, non-prescribed AAS have predominantly been used by male recreational athletes in supraphysiological dosages (Handelsman, 2021), to enhance muscle mass,reduce body fat, and elevate athletic performance (Pope et al., 2017) .AAS are typically consumed in patterns of weeks-long cycles with breaks in between, a practice known as cycling (Sagoe et al., 2015). Alternatively, individuals may take AAS continuously with low doses, sometimes alternating periodically between higher doses - a regime known as cruise and blast. Moreover, some use multiple AAS simultaneously in an attempt to enhance their potential effects, a method referred to as stacking (Handelsman, 2021). It is estimated that the global lifetime AAS use rate is 3.3 %, with a higher prevalence among males (6.4 %) (Sagoe et al., 2014).

The use of AAS is linked with several health risks that among other affect the endocrine, metabolic and cardiovascular system (Abdullahet al., 2023; Grant et al., 2023a; Pope et al., 2014; Rasmussen et al.,2018, 2017). Physical outcomes include hypertension, cardiomyopathy, dyslipidemia, hepatotoxicity, gynecomastia, sexual dysfunction, and hypogonadism (Bond et al., 2022; Horwitz et al., 2019). Long-term AAS use inhibits the endogenous testosterone production by its negative feedback mechanisms on the hypothalamic-pituitary-gonadal (HPG) axis (Hohl et al., 2023), also known as anabolic steroid-induced hypogonadism (ASIH). ASIH is a form of central hypogonadism, wherein the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is reduced, and the pituitary gland’s output of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsible for regulating testicular testosterone production and spermatogenesis, becomes temporary diminished or absent (Vilar Neto et al., 2021). The“withdrawal” symptoms of ASIH are manifested when AAS usage is discontinued. They include fatigue, reduced libido, erectile dysfunction,and depression (Rahnema et al., 2014) that may involve elevated risk of suicide (Fox et al., 2018; Lindqvist et al., 2014; Sharma et al., 2022). As ASIH symptoms during or after AAS cessation are difficult to endure, many restart AAS use, suggesting that ASIH plays a significant role in the pathology of AAS dependence (Kanayama et al., 2009). It is estimated that one third of people who initiate AAS use develop dependence, marked by persistent AAS use despite enduring adverse physical and mental effects (Skauen et al., 2023). Among men who have engaged in AAS use in a cyclic pattern with breaks in between cycles or have accumulated fewer years of use, the normalization of the HPG axis is found to occur within 3–18 months after AAS discontinuation (Grantet al., 2023a; Shankara-Narayana et al., 2020; Smit et al., 2021a). However, this period might be extended and even lead to permanent hypogonadism in some, especially in people with longer duration of use (Kanayama et al., 2015; Rasmussen et al., 2016). There is a knowledge gap on treatment targeting the HPG axis among AAS dependent men with continuous long-term AAS use.

Many people who use AAS tend to self-monitor symptoms of androgen deficiency that follows AAS cessation through a practice called “post-cycle therapy” (PCT) (Bulut et al., 2023; Griffiths et al., 2017). PCT comprises hormonal agents such as selective estrogen receptor modulators (SERMs), human chorionic gonadotropin (hCG) and aromatase inhibitors (Rahnema et al., 2014). These drugs are normally prescribed for treatment of infertility or breast cancer in women (Bonnecaze et al.,2021). In men, hCG acts as a LH-analogue with longer half-life on Leydig cells in the testicles, by stimulating the synthesis and release of endogenous testosterone (Lee & Ramasamy, 2018). Clomiphene citrate (CC) belongs to the drug class SERM (Rahnema et al., 2014), and has previously been used in treating male hypogonadism unrelated to AAS use (Guo et al., 2020; Wheeler et al., 2019). CC‘s mechanism of action is to increase the release of pituitary LH and FSH, thus restoring and preserving testicular testosterone production and spermatogenesis, without further suppressing the HPG axis (Krzastek et al., 2019). While there has been limited research on the safety profile of CC use in men, previous literature has indicated mild side effects such as weight gain, mood changes, breast tenderness and hot flushes (Huijben et al., 2023; Huijbenet al., 2022; Krzastek et al., 2019). Moreover, there have been single case reports of more severe adverse events such as liver injury (Zhang et al.,2018), suicidal behavior and psychotic episodes (Knight et al., 2015), thromboembolic events (Solipuram et al., 2021), and visual disturbances (Purvin, 1995).


A combination of CC and hCG has previously demonstrated to be an effective therapeutic approach in promoting a sufficient HPG axis response to recover spermatogenesis after exogenous testosterone exposure (Wenker et al., 2015), and has been proposed as a treatment option among infertile men with former AAS use (Tatem et al., 2020). Additionally, the use of off-label PCT protocols has widespread accessibility among people who use AAS (Westerman et al., 2016). Despite this, no previous experimental study has evaluated their efficacies in treating or preventing the development of ASIH. There is an urgent need to gain more knowledge on the safety and usefulness of PCT and whether endocrine therapies of similar nature should be implemented during or after AAS discontinuation in clinical settings. In this pilot study, we aimed to obtain insights into the potential utility of endocrine therapy with CC, transdermal testosterone, and hCG for AAS dependent men withdrawing from prolonged continuous AAS use. A key aspect of AAS dependence involves the difficulty in discontinuing use due to substantial discomfort. Recognizing this challenge, we initiated this treatment to assess its feasibility in guiding individuals through the most challenging phase following AAS cessation.




2.4. The intervention

In this proof-of-concept study, we tested an adapted version of a 16-week hormone therapy model with CC as main component, as initially proposed by Rahnema et al. (2014). Based on previous clinical and user experience with AAS dependence, we considered it highly likely that men with years-long continuous use would become symptomatically hypogonadal shortly after discontinuing AAS, even with a total testosterone (TT) levels within the normal reference (range 9–30 nmol/l) due to accustomed supraphysiological endogenous androgen levels over many years. Therefore, we chose to initiate treatment when TT levels dropped below 25 nmol/l, which according to our observations occurred relatively quickly after they had ceased AAS, depending on their recent cycle interval. Subsequently, 25 mg CC were administered every second day for a continuous period of 16 weeks, and 50 mg transdermal testosterone gel were added daily during the first four weeks to avoid symptoms of ASIH. Upon cessation of gel treatment, serum testosterone concentrations typically start to decline after 24 h, returning to baseline levels within 48 h following the administration of the final dose (Marbury et al., 2003). Consequently, to ensure that the recent dermal application did not interfere with blood tests, participants were instructed to abstain from using testosterone gel for 48 h before undergoing the first blood test during the intervention phase, which occurred after four weeks of CC treatment. hCG injections (Ovitrelle 250µg/0.5 ml prefilled pen = choriogonadotropin alfa/recombinant hCG equivalent to approximately 6500 international units (IU)) were then added in the treatment scheme in cases of inadequate endogenous TT response below 10 nmol/l. An initial dose of 1500 IU hCG was given twice per week during week 4–8, and if insufficient testicular response persisted at week 8, the dosages were increased to 1500 IU 3x per week during week 8–12 (i.e. maximum eight weeks of hCG injections). Of note, participants presenting with low levels of both TT and sex hormone binding globulin (SHBG), giving a concurrent high free testosterone index (FTI or also called free androgen index), were not given hCG. See Fig. 1 for a detailed illustration of the treatment model. The original treatment protocol as proposed in Rahnema et al. (2014) suggested to halve the CC dose from 25 to 12.5 mg in weeks 10–16. However, drawing from the existing literature concerning the safety and efficacy of treatments for men with hypogonadism not stemming from ASIH (Huijben et al., 2022), the lowest dose of CC used was 25 mg every other day. Hence, we regarded a dosage of 25 mg every second day for a duration of 16 weeks as a safe and feasible alternative option. Nonetheless, since this intervention had not been scientifically tested previously, we were still uncertain about the outcomes. All modifications to the original endocrine model, as well as the decision on whether to include hCG in the individual protocol or terminate the intervention,were made after thorough evaluations among a team of three physicians,including a senior endocrinologist. Furthermore, Rahnema et al. (2014) did not specify a particular target TT level. However, we presumed that achieving a TT level of 20 nmol/l during the intervention or a TT level within the normal physiological TT range (9–30 nmol/l) at the conclusion of intervention would be a reasonable target. The midrange TT level of 20 nmol/l during intervention was specifically chosen to avoid setting it too low, which might have lead participants to experience symptoms of hypogonadism before the HPG axis was normalized. Consequently, participants reaching TT levels of ≥20 nmol/l before week 16 would conclude the intervention. The treatment would be considered potentially low-responsive if the target was not reached or in cases of TT levels below 9 nmol/l by week 16.




6. Conclusions

This proof-of-concept study obtained crucial insights into a less explored research field, particularly the feasibility of CC application to restore endogenous testosterone levels and alleviate symptoms of ASIH in men with prolonged AAS use. Treatment with CC could potentially be considered a safer and better alternative to the standard TRT for menwith ASIH, especially in young men with a future fertility aspect. Future studies may target men with less severe AAS use who intend to discontinue usage, potentially yielding more favorable outcomes to prevent long-term continuous use. Ultimately, studies randomizing more subjects and controls to different treatment regimens should be performed before this novel treatment for men with AAS dependence is established as a routine.
 
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Fig. 1. The endocrine therapy model with 16 weeks intervention. Note that treatment with hCG was only given on indication, between weeks 4–12. hCG = human chorionic gonadotropin, TT = total testosterone.
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