Anabolic steroid-induced hypogonadism – towards a unified hypothesis of anabolic steroid action

Anabolic steroid-induced hypogonadism – Towards a unified hypothesisof anabolic steroid action a HPT/Axis Inc., 1660 Beaconshire Road, Houston, TX 77077, USAb OPAL Medical Clinic, 5555 West Loop S., Suite 205, Houston, TX 77401, USA Anabolic steroid-induced hypogonadism (ASIH) is the functional incompetence of the testes with subnor- mal or impaired production of testosterone and/or spermatozoa due to administration of androgens or anabolic steroids. Anabolic–androgenic steroid (AAS), both prescription and nonprescription, use is a cause of ASIH. Current AAS use includes prescribing for wasting associated conditions. NonprescriptionAAS use is also believed to lead to AAS dependency or addiction. Together these two uses account formore than four million males taking AAS in one form or another for a limited duration. While both ofthese uses deal with the effects of AAS administration they do not account for the period after AAS ces-sation. The signs and symptoms of ASIH directly impact the observation of an increase in muscle massand muscle strength from AAS administration and also reflect what is believed to demonstrate AASdependency. More significantly, AAS prescribing after cessation adds the comorbid condition of hypogo-nadism to their already existing chronic illness. ASIH is critical towards any future planned use of AAS orsimilar compound to effect positive changes in muscle mass and muscle strength as well as an under-standing for what has been termed anabolic steroid dependency. The further understanding and treat-ments that mitigate or prevent ASIH could contribute to androgen therapies for wasting associateddiseases and stopping nonprescription AAS use. This paper proposes a unified hypothesis that the neteffects for anabolic steroid administration must necessarily include the period after their cessation orASIH.
Ó 2009 Elsevier Ltd. All rights reserved.
Another of the beliefs held by the medical community deals with the period after anabolic steroid cessation, not their adminis- The development of AAS compounds was originally for treat- tration. The prevailing medical opinion is that clinically significant ment of hypogonadal dysfunction and commencement of delayed ASIH occurs from nonprescription AAS use but not from clinically puberty in men and for growth promotion AAS have, however, prescribed AAS . The signs and symptoms of ASIH will neces- not always been used for pure medical purposes. Due to their ana- sarily impact upon our understanding for the clinical use of AAS.
bolic effects, AAS became vastly popular among athletes, body- Additionally, these very same signs and symptoms might be builders, and power lifters. Moreover, scientific and official court instrumental in what has been described as AAS dependency.
documents, including doctoral theses and scientific reports, dem-onstrate the positive effects of these and other hormonal drugs on Anabolic steroid-induced hypogonadism (ASIH) muscle strength and performance in elite sports, which was com-mon knowledge and had been in practice since the early 1960s .
Anabolic–androgenic steroids (AAS) are a class of compounds Controversy raged for decades over the effectiveness of AAS in that include any drug or hormonal substance, chemically and phar- promoting muscle mass and muscle strength. Despite the admitted macologically related to testosterone that stimulates the growth or illicit use of AAS by athletes, the record breaking in Olympic events, manufacturing of bone and muscle. It has long been held that non- and the obvious appearance in musculature enhancement, the prescription AAS use results in a functional type of hypogonadotro- medical and research community disputed and denied the AAS ef- pic hypogonadism. Boje was the first physician to suggest, in 1939, fects . After a considerable period of scientific controversy, it is that AAS might enhance athletic performance, but he was also the now clear that anabolic–androgenic steroid hormones are effective first to forewarn athletes of potential health effects of steroids.
in increasing both muscle mass and muscle strength .
For over a quarter century, publications demonstrate HPTA sup- pression after nonprescription anabolic steroid use. Consistently,there is found a dramatic suppression of serum gonadotropins * Corresponding author. Tel.: +1 281 493 4817; fax: +1 713 490 3543.
and testosterone levels that continues for an indefinite period after 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2008.12.042 Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a unified hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042 R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx AAS cessation . In 2003, a retrospective study examined the ure to AAS, with the signs and symptoms after AAS cessation indi- effects of illicit AAS on a population in which the mean time off ste- cations of AAS withdrawal . Upon nonprescription AAS roids was 43 months with the minimum length of time 1 year and cessation, psychological disturbances include aggressiveness, the maximum 10 years. The study found 13/15 ex-AAS users were depression, anxiousness, potency problems (libido), sleep disor- in the lower 20 percent of the normal reference range for testoster- ders, violent behavior, rage, and suicidal ideation one and 2/15 were below the normal range . Another well-de- The two most widely-accepted standards for defining, classify- scribed event are reports citing long periods for the return of ing and diagnosing drug abuse and dependence are the Diagnostic spermatogenesis after nonprescription AAS use, include continuing Statistical Manual IV (DSM-IV) and the International Classification azoospermia . Contrary to the belief that nonprescription of Diseases, Volume 10 (ICD-10). The Diagnostic Statistical Manual AAS doses are 10–100-fold greater than those clinically prescribed, IV (DSM-IV) and the International Classification of Diseases, Vol- reports include doses approximately twice that for replacement ume 10 (ICD-10) differ in the way they regard anabolic–androgenic steroids’ (AAS) potential for producing dependence . DSM-IV Similarly, during the same timeframe documentation in peer- regards AAS as potentially dependence producing and ICD 10 re- reviewed literature shows AAS prescribing with clinical doses gards them as non-dependence producing.
and durations to cause both gonadotropin suppression and de- This difference in approach towards AAS prompts debate as to creased serum testosterone after AAS cessation The whether or not AAS are dependence-producing substances. The authors went so far as to warn that anabolic steroid administration main work in this area has been conducted by Brower et al.
is a possible cause for hypogonadism Birth control studies who investigated the existence of a ‘‘steroid with testosterone administration in physiological as well as sub- dependency syndrome” and classified subjects as dependent on physiological doses demonstrate HPTA suppression and continuing AAS using an adaptation of the DSM-III-R criteria for depen- infertility . More recent studies and reviews on androgen dence on psychoactive substances, which differ only slightly from and androgen/progestin male contraceptives confirm the offset of reliable contraception and of resumption of normal male fertility In 2002, Brower summarizes the literature on AAS abuse and to baseline values can be up to 2 years Finally, even the dependence and reports of at least 165 cases of addiction or depen- FDA approved labeling PDR for AAS contain the adverse effects of dence in the medical literature Brower also concludes no cases HPTA suppression, inhibition of testicular function, testicular atro- of dependence have been associated with legitimate prescriptions phy, oligospermia, impotence, and more.
of AAS used at therapeutic doses for medical purposes. According Published literature uniformly finds AAS administration, both to Brower, individuals who use high doses of AAS over prolonged prescription and nonprescription, induces a state of hypogonadism periods may develop withdrawal symptoms that include fatigue, after AAS cessation. All compounds classified as anabolic–andro- depressed mood, restlessness, anhedonia, impaired concentration, genic steroids cause a negative feedback inhibition of the hypotha- increased aggression, anorexia, insomnia, decreased libido, self-im- lamic pituitary testicular axis, suppress endogenous gonadotropin age dissatisfaction, androgen desire, headaches, suicidal ideation, secretion, and as a consequence endogenous testosterone produc- decrease in size/weight/strength, and feeling depressed/down/un- tion. After AAS administration, HPTA suppression follows, with the happy due to size loss when they stop taking AAS and these with- variables being the duration and severity.
drawal effects may contribute to a syndrome of dependence. As the ASIH, as a form of hypogonadism, is a real disease with poten- table shows below, the patient with hypogonadism may experi- tially serious consequences. Declining, or suppressed, circulating ence almost all of these above symptoms . Rather than diag- testosterone levels because of either pathophysiological or induced nosing substance abuse or dependence the criteria in use by hypogonadal conditions can have many negative consequences in these investigators for addiction is the patient examination for males. There is an association between hypogonadism (decreased levels of testosterone) and a number of signs and symptoms, mostnotably body composition changes (decrease in muscle mass and Symptoms of hypogonadism vs. dependence.
increase in fat mass), decreased muscle strength, bone loss, in-creased cardiovascular risk, sexual dysfunction (decreased libido, decreased spontaneous erections, decreased ejaculate, erection dysfunction, decreased sexual fantasies, and anorgasmia), de- creased cognitive abilities (memory and concentration), sleep dis- turbances, adverse psychological effects (depression, low-self esteem, guilt, increased stress, and anhedonia), and constitutional symptoms (general fatigue, agitation/motor dyskinesia, and de- creased appetite) . These adverse effects have importance in an understanding for what has been called AAS dependency and the clinical use in wasting associated conditions of AAS for positive changes in muscle mass and muscle strength.
The association of AAS with adverse psychological and behav- ioral effects is extensive . Historically, researchers went so far as to categorically state that AAS are without any evidence upon muscle going so far as to argue that there is saturation of the androgen receptor with eugonadal levels of testosterone. This attitude spurned the concept that the large doses commonly used by illicit AAS users indicate that the drug use is for actions other than their normal physiological effects, implying an addictive nat- Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a unified hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042 R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx verse muscle wasting and augment muscle function may reduce the burden of disease, improve quality of life, and reduce utiliza- tion of health care resources. Because of the effects of testoster- one in enhancing lean body mass (LBM), muscle strength, and decreased adiposity studies investigate the possible role for tes- tosterone or anabolic–androgenic steroids (AAS) in catabolic states. Anabolic–androgenic steroids have received particular attention with regard to improving body composition in those The current prescribing of AAS, including testosterone, is for sarcopenia (loss of muscle mass and muscle strength with ageing),chronic kidney disease (hemodialysis), HIV+ males, chronic In 1990, the National Institute of Drug Abuse (NIDA) published an obstructive pulmonary disease (COPD), osteoporosis, and long- extensive monograph on anabolic steroid abuse This mono- term glucocorticoid treatment The anabolic steroid re- graph represents a ‘‘state-of-the-art” information resource concern- search concludes that anabolic steroid administration results in- ing anabolic steroid abuse. ‘‘It must be concluded at this time that creases in muscle mass and muscle strength. Based on these the use of steroids by humans does not meet the criteria necessary conclusions, the physician-investigators recommend their use as to establish that steroids have significant abuse liability as defined a possible means of decreasing morbidity and mortality. These in pharmacological terms”. The conclusion from this monograph is studies are indicative of the developing trend in using aggressive anabolic steroids do not satisfy the criteria for abuse potential.
pharmacological therapy with anabolic steroids to reverse declines Echoing this opinion is a report from President’s Council on Physical in lean body mass and muscle strength. On close inspection of Fitness. In 1994, evidence review of the published literature states, these investigations where there is measurement of sex hormones ‘‘Despite increasing clinical descriptive data on anabolic steroid or documentation of side-effects there is the universal finding of withdrawal, dependence, and abuse, there are insufficient substan- tial basic or clinical research data to support the inclusion of these In all of the studies that include muscle mass and muscle syndromes in DSM-IV” . In the intervening 18 years since the strength measurements both during and after AAS administration, original findings, there is nothing in the published scientific litera- the positive effects of AAS during their administration disappear in ture to change these conclusions. There are few, if any, well-con- the period after stopping AAS . In 2004, after years of pub- trolled investigations or studies on the dependence potential of lished studies reporting on the positive benefits of AAS administra- tion but with no follow-up for the period of hypogonadism after In the future, studies on AAS dependency must include for the AAS cessation a randomized controlled study reported on the body monitoring of hypogonadism. This paper proposes that these trials composition changes during administration and after a 12-week will support and affirm the hypothesis that the signs and symp- follow-up period after AAS cessation The study found that toms previously attributed to dependency will be due to ASIH. Fur- the positive body composition changes in lean body mass, muscle ther, treatments aimed at preventing or mitigating ASIH will prove area, and strength produced by the androgen in the study had com- pletely disappeared 12 weeks after AAS cessation. Rather than rec-ognize anabolic–androgenic steroid-induced hypogonadism as thecritical factor for the loss of muscle mass and strength, these inves-tigators suggest, ‘‘However, the benefits were lost within 12 weeks after oxandrolone was discontinued, suggesting that prolongedandrogen treatment would be needed to maintain these anabolic The idea that secretions of the testis might regulate body composition is as old as humanity itself. For decades, testoster- Each of the aforementioned studies examined the effects of AAS one and testosterone analogues, anabolic–androgenic steroids during their administration. Upon discontinuation of AAS, these (AAS), have long been used in the athletic community for patients would develop anabolic steroid-induced hypogonadism improving muscle mass and muscle strength. Despite the obvi- (ASIH), which negates the positive body composition changes ous changes in musculature and appearance to even the most and potentially leave them in a state of health worse than when uninitiated, the academic community steadfastly refused to ad- first prescribed AAS. These studies utilizing AAS therapy have not mit to any association. The scientific evidence shows the con- identified what should be done to restore normal endocrine status post-treatment. The most significant concern is that marginally In 1996, Bhasin et al. reported testosterone administration healthy individuals placed on AAS for this goal may be placing causes an increase in muscle mass and muscle strength .
themselves at an even greater morbidity and mortality risk upon The investigation is not a clinical study for AAS treatment, but a study to separate out the effects of progressive resistance exer- Interestingly, nonsteroidal androgen or selective androgen cise and AAS on muscle mass and strength. Significantly, the re- receptor modulators (SARM) administration is currently in the re- search did not include the period after anabolic steroid search and investigational stages for the same purposes as ana- administration. In spite of the known effects of AAS upon the bolic steroids. These studies indicate that their clinical use will HPTA, the evolution of AAS treatments for their ability to in- result in induced hypogonadism after cessation by their effects crease muscle mass and improve muscle strength began in ear- on gonadotropin levels This same opinion was voiced by investigators that, ‘‘Selectivity with regard to gonadotropin sup- In many chronic illnesses, we can now achieve disease stability pression represents a significant barrier to the clinical use of but not cure. In these chronic disorders, loss of muscle occurs fre- quently and is associated with debility, impaired quality of life, This does not mean that the use of androgens to promote posi- and poor disease outcome. Similarly, as men grow older, their tive changes in muscle mass and muscle strength needs to be aban- muscle mass decreases and fat mass increases in association with doned. The better approach is to develop combinatorial therapies a decline in testosterone levels. Therefore, strategies that can re- of androgens for an improvement in muscle mass and muscle Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a unified hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042 R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx strength followed by a treatment to prevent or minimize ASIH, thereby sustaining those positive changes.
There are reports of the use of anabolic steroids by athletes since the 1950s to increase muscle size and strength to improve performance. Anabolic steroids use became more prominent inthe athletic world, but use by the lay public has also increased.
A treatment goal of HPTA restoration will have its basis in the Long confined to bodybuilding and professional sports, the use of regulation and control of testosterone production. The HPTA has AAS is nowadays a problem that involves a wider population. In two components, both spermatogenesis and testosterone produc- 2006, a report demonstrates that AAS use is common among males tion. In males, luteinizing hormone (LH) secretion by the pituitary over 18 years In the United States, prevalence estimates are positively stimulates testicular testosterone (T) production; folli- between 4% and 12% among adolescent males . Current esti- cle-stimulating hormone (FSH) stimulates testicular spermatozoa mates from 2000 indicate that there are as many as three million production. The pulsatile secretion of gonadotropin-releasing hor- AAS users in the United States and that 2.7–2.9% of adults have ta- mone (GnRH) from the hypothalamus stimulates LH and FSH ken AAS at least once in their lives According to surveys secretion. In general, absent FSH, there is no spermatozoa produc- and media reports, the illegal use of these drugs to increase muscle tion; absent LH, there is no testosterone production. Regulation of the secretion of GnRH, FSH, and LH occurs partially by the negative Anabolic–androgenic steroids are now commonly a prescribed feedback of testosterone and estradiol at the level of the hypothal- drug for chronic illnesses, with estimates in the millions amo-pituitary. Estradiol has a much larger, inhibitory effect than . AAS treatment for these conditions is towards disease-asso- testosterone, being 200-fold more effective in suppressing LH ciated morbidity, decreased muscle mass and decreased muscle strength, not treatment for the underlying disease cause. The treat- In the case of ASIH, where the individual suffers from functional ment for these conditions is of a limited duration. In addition, ad- hypogonadism and the belief for eventual return of function, treat- verse effects necessitate and require the discontinuation of these ment is directed at HPTA restoration. A medical quandary for phy- drugs. While the anecdotal and research reports of AAS benefits sicians presented with hypogonadal patients secondary to AAS are inarguable, there is the real problem for failure to consider the administration is there is currently no FDA approved drug to re- period after their cessation, anabolic steroid-induced hypogonadism store HPTA function. Standard treatment to this point has been tes- Clinical application of published study results is dependent gonadotropin (hCG), conservative therapy (‘‘watchful waiting” or upon sound research design. In these studies, the intervention, ‘‘do nothing”), or off-label prescribing of aromatase inhibitors or AAS, causes a change in the prognosis in the treatment group. This selective estrogen receptor modulators (SERM).
introduces bias, making the conclusions invalid. Biased research The primary drawback of testosterone replacement and hCG results open the door for harm to patients extending far beyond administration is that this therapy is infinite in nature. These treat- those subjects involved in the clinical trial. These results may lead ments will remedy the signs and symptoms associated with hypo- to erroneous conclusions about the safety or the efficacy of drugs.
gonadism, but do not alleviate the need for a life-long commitment Researchers working on the next generation of research, creating a to therapy. Further, administration serves to further HPTA suppres- domino effect of error, will also use them. Once disseminated in sion. Conservative therapy (‘‘watchful waiting” or ‘‘do nothing”) is the market, end user physicians and patients will pay the price the probably worst case option as this does nothing to treat the pa- for bad science in dollars, poor outcomes, and adverse events .
tient with ASIH. Also, conservative therapy will have the undesir- Importantly, a ‘‘good question” can be approached by good or able result of the nonprescription AAS user to return to AAS use bad research techniques; bad research methods do not render as a means to avoid ASIH signs and symptoms.
the question valueless. Thus, the significance of a hypothesis can The aromatase inhibitors demonstrate the ability to cause an and should be assessed prior to and independent of the specific re- elevation of the gonadotropins and secondarily serum testosterone search methods. Reviewers should not dismiss a proposal that uses . The administration of SERMs is a common treatment in at- inadequate methods without first considering whether adjust- tempts to restore the HPTA because they increase LH secretion ments could make the proposal scientifically valid.
from the pituitary that leads to increased local testosterone pro- Without definitive studies demonstrating there is no clinical con- sequence to ASIH after both prescription and nonprescription use, Guay has used clomiphene citrate as therapy for erection dys- the understanding of AAS actions will be incomplete. Any hypothesis function and secondary hypogonadism. Patients received clomi- on AAS in health and disease requires a thorough understanding for phene citrate 50 mg per day for 4 months in an attempt to raise the action not only during administration but also after their cessa- their testosterone level . Clomiphene has been reported in a tion. This paper proposes that clinically significant anabolic steroid- case study to reverse andropause secondary to anabolic–andro- induced hypogonadism (ASIH) ensues for both illicit and licit AAS genic steroid use The patient received clomiphene citrate use after AAS cessation with the severity and duration unknown.
50 mg twice per day in an attempt to raise his testosterone level.
Moreover, treatments that mitigate or prevent ASIH will be use- The patient when followed up after two months had a relapse, ful not only in the treatment for the adverse psychological effects tiredness and loss of libido, after discontinuing clomiphene citrate.
after stopping AAS, but also when used in combination with andro- There are case study reports demonstrating the effectiveness of gens to aid in the maintenance or sustaining of anabolic improve- the combination of clomiphene and tamoxifen in HPTA restoration ments sought in disorders marked by wasting. Finally, ASIH after stopping AAS administration Clomiphene is a mix- treatments might prove beneficial in mitigation of future post male ture of the trans (enclomiphene) and cis (zuclomiphene) enantio- contraceptive infertility. These need to be followed up with well- mers, which have opposite effects upon the estradiol receptor . Enclomiphene is an estradiol antagonist, while zuclomipheneis an estradiol agonist. The addition of tamoxifen to clomiphene might be expected to increase the overall antagonism of the estra- [1] Basaria S, Wahlstrom JT, Dobs AS. Clinical review 138: anabolic–androgenic diol receptor. Enclomiphene alone might be a good candidate to re- steroid therapy in the treatment of chronic diseases. J Clin Endocrinol Metab Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a unified hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042 R.S. Tan, M.C. Scally / Medical Hypotheses xxx (2009) xxx–xxx [2] Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a [34] Brower KJ, Eliopulos GA, Blow FC, Catlin DH, Beresford TP. Evidence for secret program of the German Democratic Republic Government. Clin Chem physical and psychological dependence on anabolic androgenic steroids in eight weight lifters. Am J Psychiatry 1990;147(4):510–2.
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Please cite this article in press as: Tan RS, Scally MC. Anabolic steroid-induced hypogonadism – Towards a unified hypothesis . Med Hy-potheses (2009), doi:10.1016/j.mehy.2008.12.042

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