AAS Induced Hypogonadism & PCT
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Anabolic Steroid Induced Hypogonadism (ASIH)
Micheal C. Scally, MD
The recurring controversy and politicization on the use of anabolic androgenic steroids (AAS) has been front and center in the news headlines. Within the last month the release of the book, “Wada MF, Williams, L. Game of Shadows: Barry Bonds, BALCO, and the Steroids Scandal that Rocked Professional Sports. Gotham Books; March 23, 2006,” precipitating Commissioner Bud Selig to name George J. Mitchell, former Senate majority leader, to lead an investigation into what appears to be the sport's long, and troubling, involvement with steroids. This falls almost exactly one year after publication of the book, “Canseco, J. Juiced: Wild Times, Rampant 'Roids, Smash Hits, and How Baseball Got Big. Regan Books; February 14, 2005.” Following within a month was the Government Reform Committee Hearing, United States House of Representatives, on March 17, 2005. The hearing was entitled "Restoring Faith in America's Pastime: Evaluating Major League Baseball's Efforts to Eradicate Steroid Use."[[1]] The hearing was the first in a series of hearings regarding steroid use in professional sports.
Since the introduction of steroids into mainstream culture, the media, sports organizations, medical community and public have all expressed their values and judgment of their ethical use outside of medical necessity. Within the medical establishment there is a pervasive atmosphere of fear and intimidation towards physicians who treat AAS users or prescribe AAS. This has created a vacuum or void in the proper use of AAS; an abandonment of basic scientific principles; and an ever increasing population of men at risk for significant health problems. For the greater part of 10 years I have found that the medical treatment provided for the condition termed anabolic steroid induced hypogonadism (ASIH), is nonexistent or ignored by the great majority of medical professionals. As predicted since my entry into this field in 1995 more and more cases of ASIH would appear due to this negligence. Clear and convincing evidence of this is demonstrated by recent articles in peer-reviewed medical literature affirming concerns for the long term effects of untreated ASIH [[2]], rapidity and severity of symptoms in ASIH [[3]], and inappropriate treatment with AAS based upon a flawed clinical study design [[4]].
An unproven and unfounded assumption has been made in the medical establishment that the treatment for an individual suffering from ASIH is to do nothing which is coined ‘watchful waiting’ and in time HPTA functioning will return to normal. This premise can be traced back to Knuth et al. (1989) [[5]] studying semen parameters in AAS users. He concluded, “Results suggest that even after prolonged use of extremely high doses of anabolic steroids, sperm production may return to normal.” The ability to create spermatozoa does not equate with a normal functioning HPTA. Hypogonadal males are known to have the ability to produce spermatozoa. There are no studies that demonstrate that serum testosterone levels sufficient for spermatozoa production are positively associated with the clinical effects of testosterone elsewhere within the individual. At the very same time members of the medical community announce an alert to suicide risk after AAS cessation. Kirk J. Brower, M.D. from the University of Michigan stated, “… whereas depressive episodes and suicide attempts are most likely to occur within three months of stopping AAS use.”[[6]] Shortly thereafter Texas HB 3563, “Use Of Anabolic Steroids By Public School Students,” was passed and signed into law June 18, 2005. Of particular importance is the bill analysis citing the problem of “clinical depression when steroid use is stopped.” [[7]] The obvious question is who are these astute physicians that are able to know the individual to attempt suicide during the treatment plan of ‘watchful waiting’ or do nothing?
AAS have proven beneficial in treating numerous medical conditions and symptoms in ailing populations. Currently HIV males account for an estimated 560,000 people in the U.S. reports the Centers for Disease Control and Prevention. Those experiencing lean muscle wasting greater than 10% will likely be administered a form of AAS therapy to help retain fat free tissue. According to the U.S. Food and Drug Administration, approximately 5 million men in the U.S. are considered hypogonadal with roughly 250,000 being treated with testosterone replacement. Finally, as of 2002 over 14 million men suffer with osteoporosis and low bone mass according to the National Osteoporosis Foundation. Cumulatively 810,000 people are possibly being treated with some type of androgen or AAS. Add to these patients the countless numbers of adolescents, young and middle aged men, and athletes using AAS for cosmetic and athletic enhancement the potential population of at risk men numbers well over one million.
ANDROGENIC ANABOLIC STEROIDS (AAS)
Testosterone and testosterone analogues, anabolic-androgenic steroids (AAS), have long been used in the athletic community for improving lean muscle tissue and strength. A positive correlation has been shown with testosterone to include: increased protein synthesis resulting in lean muscle tissue development [[8]], enhanced sexual desire (libido) [[9]], increased muscular strength [[10]], increased erythropoiesis [[11]], a possible positive effect on bone development [[12]], improved mental cognition and verbal fluency [[13]], and male masculinizing characteristics [[14]]. Recently, however, clinicians have recognized the potential benefits of their use in the treatment of various conditions and ailments. Numerous studies have discussed the use of AAS in the treatment of HIV-associated conditions [[15]], hypogonadism [[16]], impotence [[17]], burn victims [[18]], various anemia’s [[19]], deteriorated myocardium [[20]], glucose uptake [[21]], continuous ambulatory peritoneal dialysis (CAPD) [[22]], alcoholic hepatitis [[23]], hemochromatosis [[24]] and prevention of osteoporosis [[25]]. Since there has been such strong evidence for the medicinal use of AAS in the treatment of various conditions, these medications have become more prevalent in the medical community.
While the use of AAS by physicians has become more prevalent, this class of medicines is not without their inherent problems. AAS have been shown to induce hypogonadotropic hypogonadism [[26]]. This condition typically results from an abnormality in the normal functioning of the hypothalamic-pituitary-gonadal axis (HPTA), either from an over-or underproduction of one of the hormone secreting glands, causing a cascading unbalance in the rest of the axis. This condition may be the result of a physiological abnormality (i.e. mumps orchitis, Klinefelters syndrome, pituitary tumor) or as an acquired result of exogenous factors (i.e. androgen therapy, anabolic-androgenic steroid administration). Clerico et al found a dramatic suppression of serum gonadotropin levels in athletes given methandrostenolone, suggesting a direct action of AAS on the hypothalamus [[27]]. Similar results of suppressed gonadotropins have been found in patients supplementing solely testosterone [[28]]. Case report studies discussed a 36-year old male competitive bodybuilder and a 39-year old father, each using various AAS regimens over extended periods of time, who showed a blunted response to GnRH stimulation tests [[29]]. Bhasin et al showed a complete suppression of serum luteinizing hormone levels after administration of 600 mg testosterone enanthate over ten weeks [[30]]. A similar study administered 600 mg of nandrolone decanoate to 30 HIV-positive males over twelve weeks [[31]]. The results documented mild elevations in hemoglobin and alanine aminotransferase levels but no reference to LH or testosterone levels. The lack of gonadotropin response is puzzling as the data showed 12 of 30 subjects experienced testicular shrinkage, implying Leydig cell dysfunction and suppressed testosterone levels. A contraceptive investigation found that 6 of 9 men receiving 200mg of testosterone enanthate per week became azoospermic with suppressed gonadotropin levels after 16-20 weeks [[32]]. Other studies using AAS also showed no reference to LH or FSH levels but suppressed values are expected in each case [[33]]. Declining, or suppressed, circulating testosterone levels as a result of either pathophysiological or induced hypogonadal conditions can have many negative consequences in males. Declining levels of testosterone have been directly linked to a progressive decrease in muscle mass [[34]], loss of libido [[35]], decrease in muscular strength [[36]] impotence [[37]], oligospermia or azoospermia [[38]], increase in adiposity [[39]] and an increased risk of osteoporosis [[40]].
CHRONOLOGY
In 1982, more than two decades ago, it was shown that nandrolone decanoate caused a suppression of the HPTA in males. [[41]] A 1989 study demonstrated the period of hypogonadism after androgenic-anabolic steroid cessation in male hemodialysis patients.[[42]] The authors warned that the cessation of anabolic steroids caused hypogonadism stating: "Nandrolone decanoate are anabolic steroids prescribed for uremic anemia and those may possibly exacerbate uremic gonadal damage. This clinical study suggests that some anabolic steroids play a role in uremic hypogonadism.”
The sequence of changes in body composition induced by testosterone and reversal of changes after cessation was studied in 1992. Testosterone treatment produced a progressive increase in lean body mass and a progressive decrease in body fat. After the testosterone was stopped a period of hypogonadism ensued and the body composition reverted slowly back to normal. [[43]]
Each of the studies done prior to 1995 is designed correctly taking into consideration the characteristics of life. The characteristics of life are to physiology as Newton's Laws of Motion and Gravity are to physics. If one was to disregard or fail to consider the Law of Gravity in a physics experiment the conclusions drawn from such a study would be erroneous and wrong. The Characteristics of life are the following: All living things follow the tenets of cell theory; Living things acquire and use energy and produce wastes; Living things reproduce, grow, and develop; Living things evolve;. Living things respond to stimuli; Living things maintain a state of homeostasis; All living things are made up of some kind of atoms and molecules. The scientific method is a method of collecting evidence through observation, questioning, hypothesis formation, and hypothesis testing. Similarly, if one was to disregard or fail to consider the characteristics of life in a physiology experiment their conclusions would be erroneous and wrong.
Ironically it was not until 1996 and the publication by Bhasin [[44]] that the medical community finally came to recognize that androgens do enhance the ability of the body to manufacture muscle. Bhasin failed to document and report the effects for the period following cessation of testosterone. Since its publication, the same experimental protocol with no follow up has been used in many patient populations by many different researchers. Uniformly publications have reported positive body composition changes with AAS administration but neglect to include any follow-up on duration and severity of ASIH after AAS cessation. [[45]]
That it took over 60 years since the discovery of the hormone testosterone and countless years of unsupported comments by the pundits of the exact opposite nature of testosterone is a clear indication of medicine’s lack of intellectual and clinical curiosity in the face of a highly politicized and rhetoric laden class of drugs. This lack of rigor and adherence to scientific principles persisted and researchers made conclusions which were erroneous, flawed, and simply wrong. This could not have been better displayed than by researchers studying AAS in hemodialysis patients.
Navarro JF et al. (1998) concluded androgen administration had beneficial effects on erythropoiesis, as well as positive anabolic actions in patients under peritoneal dialysis. [[46]] Gascon A et al. (1999) concluded, "The use of Nandrolone decanoate will allow us an acceptable treatment of anemia, as well as a better nutritional condition in elderly patients on dialysis." [[47]] Lastly, Johansen KL et al. (1999) concluded, “Treatment with Nandrolone for six months resulted in a significant increase in lean body mass associated with functional improvement in patients undergoing dialysis." If you look at testosterone and luteinizing hormone values at baseline, each decreased significantly at three months. [[48]] None of these published studies noted or referenced the previous work cited above that studied AAS in hemodialysis patients.
ADVERSE EVENTS
In the paper by Pena et al. many of the adverse events associated with ASIH are displayed. But even more remarkable is that the ignorance and unfamiliarity with AAS is there for all to see in a Board certified endocrinologist and urologist.
The patient was an HIV+ married male discovered to be azoospermic when the couple was exploring artificial insemination as an option to have children. His medications included testosterone enanthate and oxandrolone. To restore spermatogenesis the urologist discontinued only the testosterone and allowed the patient to remain on oxandrolone. Within months of this action the patient's testosterone level was 30 nanograms per deciliter, with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) both below normal range, and suffering from notable depression and irritability that necessitated antidepressant medication. A repeat semen analysis continued to demonstrate azoospermia.
At this point the patient was referred to a medical endocrinologist for the evaluation of central hypogonadism. Pituitary and thyroid disorders were ruled out by normal serum prolactin and thyroid hormone levels, respectively. Magnetic resonance imaging of the brain and pituitary were normal. Finally, a decision was made that the patient’s continued hypogonadism after testosterone cessation was due to the oxandrolone. After discontinuing both testosterone enanthate and oxandrolone for three months the patient’s serum testosterone rose to 134ng/dL which was sufficient for the production of spermatozoa. The patient was then encouraged to restart his androgen supplementation to improve both physical and emotional well-being.[[49]]
The evaluation and management of this patient was extraordinarily poor and inept. First, it is incredulous that these physicians are apparently unfamiliar with oxandrolone. Despite this they continued to treat him and order test which are costly and unnecessary. The MRI was without any medical indication, particularly in the face of the known medications testosterone and oxandrolone. It is fortuitous that the MRI was negative since ~10% of the general populations have asymptomatic pituitary adenomas.
This patient demonstrates the pervasive effect upon the health and welfare those AAS studies which failed to account for homeostasis. Clinicians across the USA and beyond are using these studies as a basis for the clinical care of patients. That neither of these physicians even knew the most rudimentary AAS knowledge and was unaware as to ASIH after AAS cessation is horrific and shocking. But what is particularly disheartening is no one displayed any sense on what to do regarding the patient’s HPTA. There are literally tens of thousands of patients in the United States who are receiving similar androgen treatment as the patient in Pena et al., each is potentially being left in the state of HPTA dysfunction.
LONG-TERM EFFECTS
Urhausen et al. (2003) studied serum parameters in 15 AAS users. The mean time after steroid cessation was 43 months with the minimum length of time 1 year and the maximum 10 years in the study. The average amount of medication used was a mean of 700 milligrams for 26 weeks, half a year, for 9 years. [[50]] The long-term side-effects of anabolic steroid use were demonstrated to be most pronounced on the HPTA. It was found A13/15 ex-AAS users were found in the lower 20 percent of the normal reference range for testosterone, 2/15 ex-AAS users were found below the normal range with values of 6.6 and 9.0 nanomoles per liter. VanBreda et al. (2003) presents a case study in a 37y male who after AAS cessation had persistent HPTA dysfunction. [[51]] Restoration of HPTA dysfunction was achieved with the use of LH-RH.
DURABILITY
In 2004, Schroeder et al. included an equivalent amount of time for follow-up after AAS cessation as AAS administration. The study found that the positive body composition changes produced by the androgen in the study had completely disappeared after cessation. This was due to the state of hypogonadism induced by the administration of androgens (ASIH). Anabolic improvements were lost 12 weeks after discontinuing the androgen.[[52]] The publication and timing of the study by Schroeder et al. is strongly suspect. This study may have never possibly been done if not for a formal complaint filed against the researchers through the Office of Human Research Protection (OHRP).[[53]] Also, documents received from researchers through the Freedom of Information Act (FOIA) conflict with data observed in the published study. Over 200+ pages were clearly missing in the materials sent.
HPTA NORMALIZATION & RESTORATION - TREATMENT
There are vast differences between the health of an individual with frank hypogonadism (primary hypogonadism or testicular failure; secondary hypogonadism – hemochromatosis, Kleinfelters, etc.) and the individual with Andropause or PADAM (Partial Androgen Deficiency in Aging Male). The morbidity observed with true hypogonadism have been documented. While there are clinical indicators that are improved with AAS administration in Andropause there are no studies to show that these are factors for increased morbidity or an overall decreased quality of life. Until these studies are done care should be taken regarding the continuous long term administration of AAS.
There are also clinical situations which would necessitate AAS cessation for health concerns. With increasing AAS use these clinical conditions are sure to become increasingly prevalent. Compliance in taking medication is not 100% for a number of reasons. This would lead to ASIH and potentially adverse events. A clinical situation would be elevation of LFTs (liver function tests) and impending liver dysfunction. Pens et. al. was a clear example of the adverse consequences with AAS cessation. AAS cessation was required in the treatment of polycythemia brought upon by continuous AAS administration.
A medical quandary for many physicians presented with hypogonadal patients, standard treatment to this point has been testosterone replacement therapy, human chorionic gonadotropin (hCG), or conservative therapy (i.e. nothing). The primary drawback of testosterone replacement is that this therapy is infinite in nature. Exogenous testosterone serves only to remedy the symptoms of suppressed testicular/gonadotropin production. While it may transiently combat the lean muscle atrophy, declining muscular strength, decreased libido, erection dysfunction, and depression associated with hypogonadism, it will not stimulate endogenous testosterone production. Administered testosterone will only suppress testicular function further. It is important to understand that the use of a treatment for HPTA restoration at this time would only be effective in those individuals who had a normal HPTA functionality prior to AAS administration. This is not to say that there may be developed something in the future that will be effective for other causes of HPTA dysfunction. The regulation of the HPTA is an active area of investigation. There are other factors that interact with the HPTA which may show promise in their ability to restore HPTA health. The influences of other hormones within the endocrine system and the HPTA have only partially been explored.
The normal operation of both the testicular and hypothalamic-pituitary regions is crucial in returning HPTA function to normal. Returning one component of the axis to normal without concurrently returning the other would sabotage and inhibit the operation of the entire HPTA. The ability to produce a cure whereby there is no longer a need for medication is small. Discounting costs and focusing strictly on medicine reasons for this include inadequate stimulation for a critical part of the HPTA for full restoration, secondary inhibition of the HPTA, inadequate follow up and monitoring, and compliance due to the length of time the medicines are prescribed.
HISTORY
History has not been kind to AAS users whether illicit or prescribed. Undoubtedly, heavy politicization of AAS, constant media and press coverage, and the total failure of the medical community to properly investigate this class of medications have lead to ignorance among the public and professional, alike. The hysteria surrounding AAS is unprecedented as demonstrated by the draconian measures the government has applied to illicit AAS users. A considerable amount of the fault lies at the door of the medical profession who has capitulated lock, stock, and barrel to the pundits who barely are able to pronounce AAS never mind name on other than testosterone.
But what is the most horrific in the history of AAS is the mind warp that the medical/ research establishment took after 1995. While finally admitting that there is a positive relationship between androgens and muscle the medical community has managed at the same time to have sentenced countless individuals to harm. One would have to been blind, deaf, and dumb and possibly dead to not recognize the relationship between androgens ands muscle. Apparently, the medical community was in a coma. The observational idea from association between androgens and muscle, of course, came from bodybuilders. Had any of the “white coats” ever come down from their Ivory Towers and bothered to ask the bodybuilders they would have been told about ASIH. It would not have been called that but there is no doubt they would have been told of post cycle signs and symptoms. But they did not ask, decided to ignore the principles of life, and in turn revealed once again their ability to make mistakes on a grand scale.
FUTURE DIRECTIONS
It is time for the medical community to act responsibly, intelligently, and forcefully and take control of the medical care for individuals. At the very minimum the:
I. Uniform definition and diagnosis of ASIH.
II. Investigations on a more accurate estimate of ASIH prevalence.
III. A does-response study on AAS and HPTA normalization. Clinical investigations regarding AAS (type, dose, duration, etc) to development of ASIH (severity of signs & symptoms, duration, HPTA normalization).
IV. Clinical investigations on medical treatments (prevent, eliminate, or minimize) for ASIH.
V. Investigations on the development of protocols or programs to effect positive body composition changes without the attendant consequences of ASIH.
VI. Collaborative clinical investigations regarding dependence, abuse, and addiction of androgens in relation to ASIH.
