madman
Super Moderator
Abstract
Introduction
Non-prescribed anabolic-androgenic steroid (AAS) use is widespread and may induce hypogonadism, and metabolic, cardiovascular and mental health risks. The study aims to explore feasibility and safety of off label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency,and to study changes in health risks after cessation.
Methods and analysis
This is a non-randomized proof of concept pilot study to test the feasibility of an off-label hormone intervention. In this open-labeled intervention study, we shall include males with AAS dependence intending to quit AAS use. Clomiphene citrate will be given for a period of 16 weeks to stimulate the endogenous testosterone production. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention period, and at follow-up 6- and 12-months post-cessation.
Change in self-reported symptoms of hypogonadism (fatigue, depression, anxiety, sexual dysfunction)and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without any medical intervention.
Discussion
This pilot study is the first study to test feasibility of off-label use of CC with the intention to restart endogenous testosterone production upon cessation of AAS among men with AAS-induced hypogonadism. The study may provide valuable clinical insights, enabling the exploration of whether adjustments are needed for the intervention. The results may be used to determine the sample size and informing the design of future RCTs or case comparison studies.
1 Introduction
Anabolic-androgenic steroids (AAS) include testosterone and synthetic derivatives, often used with an intent to build muscle mass, decrease body fat and improve overall athletic performance [1]. Non-prescribed AAS are predominantly utilized by male recreational athletes in cyclic patterns, withPage intermittent breaks or continuous administration where the ‘off-cycle’ includes AAS at a lower level [2].Global lifetime prevalence of AAS use among men is estimated to be 6.4%, but is found higher in subpopulations such as recreational athletes [3], prisoners [4] and patients in substance use disorder (SUD) treatment [5]. Associated health risks and behavioral outcomes make AAS use a public health concern [6–8]. As a substantial proportion of men who use AAS long term move into middle age, health professionals are likely to encounter an increasing number of patients who experience adverse effects from long term AAS use [8]
AAS use is associated with a wide range of adverse effects on mental [9, 10] and physical health [1, 11] including negative effects on the cardiovascular system such as left ventricle systolic dysfunction,myocardial hypertrophy, hypertension [12–14], severe biventricular cardiomyopathy [15], acute myocardial infarction [16] and sudden cardiac death [17]. Increased carotid intima-media thickness, reduced arterial elasticity and lower carotid artery compliance are early predictors of atherosclerosis and cardiovascular risk that are found among men with long term AAS use [18]. In addition, AAS use may lead to altered renal, hepatic and metabolic functions alongside increased total body fat percentage and visceral and subcutaneous adipose tissue, hypercholesterolemia and reduced insulin sensitivity [19]. High androgen levels might lead to gynecomastia and several dermatological conditions [20], and infertility during on-going use is common due to the disruption of hypothalamic-pituitary-gonadal (HPG) axis [21,22].
One in three people using AAS seem to develop a dependence syndrome, characterized by a pattern of escalating doses and reduced breaks between cycles, or continuous use with a stable dose or cyclic pattern with higher doses, despite experiencing adverse effects and a desire to cease use [23–25]. The neuroendocrine mechanism of AAS-dependence is linked to suppression of the hypothalamic-pituitary gonadal (HPG) axis leading to AAS-induced hypogonadism [21]. The features of androgen deficiency (fatigue, depression, anxiety and sexual dysfunction) will first occur weeks after AAS cessation. For most men, the endogenous testosterone production recovers after 3–12 months [25], but this phase is typically hard to endure [26], often resulting in restart of AAS use and development of a pattern of continuous use.When AAS use is ceased temporarily or permanently, some may self-initiate Post Cycle Therapy (PCT) with non-prescribed hormonal substances in various combinations and doses with the intention to restore the HPG-axis faster [27, 28].
Despite experiencing health problems associated with AAS use, many individuals fail to receive treatment [29]. According to a recent meta-analysis, only a third of people who use AAS seek medical support [30].In a recent study from our research group, more than half of the sample of men with AAS-related health issues did not seek health service [31]. This reluctance to engage with health services may be attributed to limited treatment options and insufficient awareness of AAS among clinicians. Many individuals who use AAS feel stigmatized, and fear being identified with or labelled as either drug users or sport cheats,with this acting as a further barrier to service engagement [32]. As one of few countries, Norway has integrated AAS and other performance and image enhancing drugs (PIEDs) in the national Drug Policy.The possession and use of AAS and other PIEDs became criminalized in 2013, and people with current or previous AAS use got access to SUD treatment in the specialist health service. Presently, there is no consensus, nationally or internationally, on whether endocrine treatment should be used in the treatment of AAS-induced hypogonadism [33]. Nonetheless, endocrinologists with extensive clinical experience witht his patient group have proposed potential interventions [34–36].
Rahnema and colleagues presented a treatment model to prevent severe symptoms of hypogonadism during cessation of AAS including use of clomiphene citrate (CC), a Selective Estrogen Receptor Modulator (SERM), to restart the HPG-axis [21]. CC selectively binds to estrogen receptors and acts as a receptor antagonist with week estrogen activity in the hypothalamus which leads to blocked negative feedback inhibition. This leads to increased gonadotropin-releasing hormone (GnRH) pulsation in the hypothalamus, increased release of luteinizing hormone (LH) from the pituitary gland and finally increased levels of endogenous testicular testosterone. CC is approved for short-term treatment of female infertility. CC as off-label treatment has been found safe, tolerable and effective to improve serum levels of testosterone, symptoms of hypogonadism and infertility in men with hypogonadism of other causes than AAS use [37–40]. In the reviewed studies, dosages of 25 mg daily for up to 12 months, 50 mg daily for up to 6 months, and 25–50 mg every second day for 1, 2 and 3 years or more were administered. The majority of these investigations reported no occurrence of major side effects. Side effects reported were: headache, dizziness, mood changes, blurred vision/visual change, breast tenderness/gynecomastia,secondary polycythemia without need for phlebotomy and a few cases of elevated liver enzymes [38, 40].Two case reports of psychotic episodes and one case of suicide attempts have been published [41]. Deep vein thrombosis risk is found lower among men treated with CC when compared with testosterone replacement therapy (TRT) [42]. Despite these findings, more knowledge is needed on feasibility of a model with CC among men with a desire to cease long term continuous AAS. The primary aim of the present study is to explore whether the 16 weeks therapy model with CC leads to stimulation of endogenous LH and testosterone production, if the treatment model is safe, and if the model is more effective in reducing AAS-withdrawal symptoms compared to no intervention. The secondary aims are to detect health risks during ongoing AAS use in the intervention group only and assess whether and to what extent the health risks are reduced 12 months after cessation of AAS.
3 Discussion
This non-randomized proof of concept pilot study with a small number of participants, is the first study to test off-label use of CC with the intention to restart endogenous testosterone production upon cessation of AAS use among men with AAS-induced hypogonadism. It is also the first longitudinal study to compare changes in health risks in a sample of men with AAS dependence that withdraw from long term continuous AAS use.
The study will compare symptoms of AAS-induced hypogonadism and other AAS-related side effects between the group receiving CC and a group of male AAS users not receiving the intervention. The comparison group differs from the intervention group as the participants may have less serious AAS use and may have less symptom burden during use as they mostly use AAS as cycles with an intention to cease use only temporarily
Detailed and frequent monitoring using objective biological measures is a strength and the study may provide valuable clinical insights, enabling the exploration of whether adjustments are needed for the intervention. Furthermore, the results may be used to determine the sample size and informing the design of future RCT or case comparison studies.
Introduction
Non-prescribed anabolic-androgenic steroid (AAS) use is widespread and may induce hypogonadism, and metabolic, cardiovascular and mental health risks. The study aims to explore feasibility and safety of off label clomiphene citrate therapy, whether the treatment will reduce the symptoms of androgen deficiency,and to study changes in health risks after cessation.
Methods and analysis
This is a non-randomized proof of concept pilot study to test the feasibility of an off-label hormone intervention. In this open-labeled intervention study, we shall include males with AAS dependence intending to quit AAS use. Clomiphene citrate will be given for a period of 16 weeks to stimulate the endogenous testosterone production. Measures of physical and mental health will be examined from ongoing AAS use, during the intervention period, and at follow-up 6- and 12-months post-cessation.
Change in self-reported symptoms of hypogonadism (fatigue, depression, anxiety, sexual dysfunction)and other withdrawal symptoms will be compared with data from a group of men who ended AAS use temporarily without any medical intervention.
Discussion
This pilot study is the first study to test feasibility of off-label use of CC with the intention to restart endogenous testosterone production upon cessation of AAS among men with AAS-induced hypogonadism. The study may provide valuable clinical insights, enabling the exploration of whether adjustments are needed for the intervention. The results may be used to determine the sample size and informing the design of future RCTs or case comparison studies.
1 Introduction
Anabolic-androgenic steroids (AAS) include testosterone and synthetic derivatives, often used with an intent to build muscle mass, decrease body fat and improve overall athletic performance [1]. Non-prescribed AAS are predominantly utilized by male recreational athletes in cyclic patterns, withPage intermittent breaks or continuous administration where the ‘off-cycle’ includes AAS at a lower level [2].Global lifetime prevalence of AAS use among men is estimated to be 6.4%, but is found higher in subpopulations such as recreational athletes [3], prisoners [4] and patients in substance use disorder (SUD) treatment [5]. Associated health risks and behavioral outcomes make AAS use a public health concern [6–8]. As a substantial proportion of men who use AAS long term move into middle age, health professionals are likely to encounter an increasing number of patients who experience adverse effects from long term AAS use [8]
AAS use is associated with a wide range of adverse effects on mental [9, 10] and physical health [1, 11] including negative effects on the cardiovascular system such as left ventricle systolic dysfunction,myocardial hypertrophy, hypertension [12–14], severe biventricular cardiomyopathy [15], acute myocardial infarction [16] and sudden cardiac death [17]. Increased carotid intima-media thickness, reduced arterial elasticity and lower carotid artery compliance are early predictors of atherosclerosis and cardiovascular risk that are found among men with long term AAS use [18]. In addition, AAS use may lead to altered renal, hepatic and metabolic functions alongside increased total body fat percentage and visceral and subcutaneous adipose tissue, hypercholesterolemia and reduced insulin sensitivity [19]. High androgen levels might lead to gynecomastia and several dermatological conditions [20], and infertility during on-going use is common due to the disruption of hypothalamic-pituitary-gonadal (HPG) axis [21,22].
One in three people using AAS seem to develop a dependence syndrome, characterized by a pattern of escalating doses and reduced breaks between cycles, or continuous use with a stable dose or cyclic pattern with higher doses, despite experiencing adverse effects and a desire to cease use [23–25]. The neuroendocrine mechanism of AAS-dependence is linked to suppression of the hypothalamic-pituitary gonadal (HPG) axis leading to AAS-induced hypogonadism [21]. The features of androgen deficiency (fatigue, depression, anxiety and sexual dysfunction) will first occur weeks after AAS cessation. For most men, the endogenous testosterone production recovers after 3–12 months [25], but this phase is typically hard to endure [26], often resulting in restart of AAS use and development of a pattern of continuous use.When AAS use is ceased temporarily or permanently, some may self-initiate Post Cycle Therapy (PCT) with non-prescribed hormonal substances in various combinations and doses with the intention to restore the HPG-axis faster [27, 28].
Despite experiencing health problems associated with AAS use, many individuals fail to receive treatment [29]. According to a recent meta-analysis, only a third of people who use AAS seek medical support [30].In a recent study from our research group, more than half of the sample of men with AAS-related health issues did not seek health service [31]. This reluctance to engage with health services may be attributed to limited treatment options and insufficient awareness of AAS among clinicians. Many individuals who use AAS feel stigmatized, and fear being identified with or labelled as either drug users or sport cheats,with this acting as a further barrier to service engagement [32]. As one of few countries, Norway has integrated AAS and other performance and image enhancing drugs (PIEDs) in the national Drug Policy.The possession and use of AAS and other PIEDs became criminalized in 2013, and people with current or previous AAS use got access to SUD treatment in the specialist health service. Presently, there is no consensus, nationally or internationally, on whether endocrine treatment should be used in the treatment of AAS-induced hypogonadism [33]. Nonetheless, endocrinologists with extensive clinical experience witht his patient group have proposed potential interventions [34–36].
Rahnema and colleagues presented a treatment model to prevent severe symptoms of hypogonadism during cessation of AAS including use of clomiphene citrate (CC), a Selective Estrogen Receptor Modulator (SERM), to restart the HPG-axis [21]. CC selectively binds to estrogen receptors and acts as a receptor antagonist with week estrogen activity in the hypothalamus which leads to blocked negative feedback inhibition. This leads to increased gonadotropin-releasing hormone (GnRH) pulsation in the hypothalamus, increased release of luteinizing hormone (LH) from the pituitary gland and finally increased levels of endogenous testicular testosterone. CC is approved for short-term treatment of female infertility. CC as off-label treatment has been found safe, tolerable and effective to improve serum levels of testosterone, symptoms of hypogonadism and infertility in men with hypogonadism of other causes than AAS use [37–40]. In the reviewed studies, dosages of 25 mg daily for up to 12 months, 50 mg daily for up to 6 months, and 25–50 mg every second day for 1, 2 and 3 years or more were administered. The majority of these investigations reported no occurrence of major side effects. Side effects reported were: headache, dizziness, mood changes, blurred vision/visual change, breast tenderness/gynecomastia,secondary polycythemia without need for phlebotomy and a few cases of elevated liver enzymes [38, 40].Two case reports of psychotic episodes and one case of suicide attempts have been published [41]. Deep vein thrombosis risk is found lower among men treated with CC when compared with testosterone replacement therapy (TRT) [42]. Despite these findings, more knowledge is needed on feasibility of a model with CC among men with a desire to cease long term continuous AAS. The primary aim of the present study is to explore whether the 16 weeks therapy model with CC leads to stimulation of endogenous LH and testosterone production, if the treatment model is safe, and if the model is more effective in reducing AAS-withdrawal symptoms compared to no intervention. The secondary aims are to detect health risks during ongoing AAS use in the intervention group only and assess whether and to what extent the health risks are reduced 12 months after cessation of AAS.
3 Discussion
This non-randomized proof of concept pilot study with a small number of participants, is the first study to test off-label use of CC with the intention to restart endogenous testosterone production upon cessation of AAS use among men with AAS-induced hypogonadism. It is also the first longitudinal study to compare changes in health risks in a sample of men with AAS dependence that withdraw from long term continuous AAS use.
The study will compare symptoms of AAS-induced hypogonadism and other AAS-related side effects between the group receiving CC and a group of male AAS users not receiving the intervention. The comparison group differs from the intervention group as the participants may have less serious AAS use and may have less symptom burden during use as they mostly use AAS as cycles with an intention to cease use only temporarily
Detailed and frequent monitoring using objective biological measures is a strength and the study may provide valuable clinical insights, enabling the exploration of whether adjustments are needed for the intervention. Furthermore, the results may be used to determine the sample size and informing the design of future RCT or case comparison studies.
