Anabolic-Androgenic Steroid Induced Hypogonadism ASIH): A Unique Type of Hypogonadism

Anabolic-Androgenic Steroids (AAS)– the Good News and the Bad News

It is estimated that the numbers of anabolic steroid (AAS) users has tripled–most notably among young users– from one to three million since these agents were declared illegal in 1991. In contrast to AAS use by the professional athletes of media headlines, the largest AAS using group are now middle-class men who do not compete in any sport: 75% of users state that their use is for purely cosmetic reasons, primarily a lean and muscular body. (Endocrine Review, Dec 2013) The development of AAS, including at least 100 synthetic relatives of testosterone and a reported 15-25% of AAS contaminated dietary supplements advertised as AAS free (Pope & Brower, 2008), has made it possible to enhance attempts to create this ideal body- to increase muscle mass and strength, and promote leanness, while decreasing recovery time and improving healing. However, as their hyphenated description indicates, AAS isn’t only about anabolism (muscle building). Users must also contend with their androgenic (male sex hormones) effects. Thus, there have been many attempts to pharmacologically dissociate the desired anabolic actions of AAS from the unwanted androgenic side effects–especially those accompanying high doses of these agents (Langenbucher….). Some of these androgenic effects include hepatotoxicity, cholestasis, renal failure, inhibition of reproductive function, oligiospermia/azoospermia which threaten fertility; hypogonadism–decreased production of natural testosterone, leading to lability in libido and mood; acne and loss of hair; physical feminization of males, e.g., gynecomastia which, when severe, can require surgery (Langenbucher et al, 2008; Sullivan, in Kuhn, 2010; Rahnema et al, 2015). Some of these side effects of AAS may be transient, resolving when AAS use is ended. However, they can also cause longlasting or permanent end organ damage. (Rahnema et al. 2015) For example, high doses of AAS, over long periods of time, have been shown to have multiple long lasting effects on the cardiovascular system. A prime example of such cardiovascular effects are bodybuilders who typically use AAS in doses up to one hundred times greater than the normal body amount, risking clumping platelets in the heart and potentially triggering strokes and heart attacks. Even after stopping AAS there may be a decrease in left ventricular function, leading to heart failure. (Sullivan, in Kuhn, 2010; mechanics)

Of these myriad effects which can affect users variably, the

condition believed to be ‘nearly universal’ in AAS users (Canavan, 2013), and the primary reason for which men who have used AAS come to see physicians, is Anabolic Steroid Induced Hypogonadism (ASIH), androgen deficiency denoting the shutting down of the hypothalamic pituitary/testicular system (HPT) due to AAS use.

ASIH A Unique Hypogonadism

Despite the fact that this hypogonadal state, the result of a complex and global endocrine disruption which accompanies long-term AAS use, stacking (use of several AAS products simultaneously), and cycling (on and off AAS, typically over 12 weeks), and multiple high doses of ancillary drugs, has been reported in a some well-known earlier studies, (Kashin & Kleber, 1989; Hochberg et al, 2003; Scally & Tan, 2009) ASIH has been under-focused in the medical literature. Thus, there has been little clinical guidance for physicians about AAS and concomitant medical conditions. Acknowledging this, Rahnema and colleagues cautioned that the ‘unique pharmacological milieu’ resulting from long term AAS use was such that ‘medical testosterone which is given for testosterone replacement therapy (TRT), at a fixed replacement dose, may not be a good model to describe the pharmacodynamics of AAS.’ In their systematic review of AAS, based on interviews with hypogonadal users as well as research and clinical experience reported between 1965 and 2013, these authors have provided insight into what is now known about ASIH, and about evidence-based treatments. Systematic reviews such as theirs are especially valuable because of the judgmental overlay which some believe has influenced under-treatment of AAS users. Such reviews ‘explicitly aim to limit systematic error (bias), mainly attempting to identify, appraise and synthesize all relevant studies (of whatever design) in order to answer a particular question (or set of questions)’ (Schlosser, J, 2006). The questions, which Rahnema and his colleagues sought to answer, concerned the pathophysiology of AAS, and safe, effective ways to treat related medical conditions in current and past users. Their findings validated what other experts had previously reported, i.e., that cyclical depletion of endogenous testosterone during long term self-dosing of supraphysiologic AAS (synthetic testosterone and other anabolic steroids), results in a unique form hypogonadism, an acquired inability of the HPT to produce the body’s natural testosterone–Anabolic Androgenic Steroid Induced Hypogonadism (ASIH).

Rahnema and his colleagues also provided support for treatment protocols which have been endorsed by other experts, and which will be described later in this article.

The Unique AAS milieu and ASIH: It’s About Sex

As a physician who has spent years researching medical issues related to AAS in both the ivory tower and the iron gym, always maintaining a non-judgmental attitude toward users, I have had the good fortune to treat thousands of men who are completely open with me about their use. For 90% of these men who seek out my medical services regarding a specific health issue related to using AAS, there is something related to sex in their motivation. It’s axiomatic that, after years of AAS use, a man’s testosterone will be low. Their low testosterone state, in most AAS users’ cases related to ASIH, leads to a lower threshold for symptoms, e.g., poor libido, which is more severe than in a man with ‘organic’ low testosterone. (Kelleher, 2004) The mechanism-of-action (MOA) for this difference is unknown. We do know that injecting esters of testosterone in higher doses than standard testosterone replacement doses, for prolonged periods, leads to chronic higher free testosterone states in the central nervous system (CNS). These chronic high levels of free testosterone cause changes in parts of the CNS that may lead to dependency on super physiologic testosterone doses for optimal sexual experience. “Chronically consumed high doses of AAS are postulated to stimulate brain reward systems in humans, and to result in neuroadaptations in other brain systems that manifest as withdrawal symptoms (e.g., poor libido) upon discontinuation’. (Wood, 2004). Over time, it is also likely that there will be permanent damage in these and other areas, contributing to severe low libido states when AAS are stopped. (Kanayama, 2015)

When the Music Stops

Men, even young men with normal testosterone levels, experience increased libido on steroids. However, the operant word here is “on”; any experienced steroid user learns quickly that sex ‘on’ steroids vs. ‘off”, is very different. In the beginning, most steroid users, with/without Post Cycle Therapy (drugs taken to counteract the androgenic effects of AAS) experience only minimal side effects regarding sex. Over time, however– whether in cycling or in attempts to stop using- the hypogonadal state created by AAS can cause poor libido, impotence, infertility, severe depression, and even suicidality during withdrawal. (Brower, 2009)

To try to understand the relationship between AAS and the sexual issues which are paramount in ASIH, we must understand the dynamics of some of the most widely

used agents. In addition to a variety of testosterone based agents, e.g., Testosterone Cypionate, Enanthate. Propionate, there are testosterone derived drugs like Dianabol and Boldenone. There are also Dihydrotestosterone DHT derived agents like Anadrol and Anavar, and the 19-nortestosterone (19nor) AAS agents like Deca-Durabolin and Trenbolone. Each of these agents has chemical effects specific to its mechanisms, which affect a man’s sexual function. However, they ALL share one effect, mediated by the HPT: They will ALL shut down a man’s natural testosterone production while taking the drug. Specific drugs, doses and individual user profile will influence the severity of this inevitable hypogonadal outcome. For example, drugs like Trenbolone and DecaDurabolin are known to be very suppressive to the HPT– hence, the classic term since the 1970’s, “Deca Dick’.

The method of action (MOA) for this severe shutdown may be related not only to the suppression of endogenous testosterone, but also to the fact that Deca Durabolin is reduced to dihydronandrolone (DHN) as opposed to dihydrotestosterone (DHT) which, along with endogenous testosterone, binds with androgen receptors in the brain to support libido in a naturally intact male. When DHN then crosses the blood-brain-barrier, interacting with androgen receptors in the brain, it may either compete with DHT and testosterone or act as a direct antagonist, causing inhibitory actions, resulting in a low libido state. We also know that 19-nor drugs like Deca Durobolin and Trenbolone, which are synthetic progestins, can cause increased prolactin production, which can lead to diminished libido and non-optimal CNS dopaminergic states. (Web MD) The ‘Bro Science” remedy for this, widely published on AAS websites and forums, has been to take greater parts of testosterone-to-nandrolone doses; most experienced users recommend 1.5 to 2/1 ratio. And this works-for a time. Men almost never take a nandrolone agent like Deca or Tren without testosterone. And when they are ‘on’ these drugs, sexual performance is usually not only preserved, but most men say they are hypersexual during this time. It appears that the combination of a 19-nor drug and testosterone esters provides ‘over stimulation’ to the sexual areas of the brain; at least for a period of time. Then things can come crashing down! The CNS, which is dynamic, always in flux, tries to maintain balance in reaction to continuous stimulation, including various and changing hormonal chemistry(s). Thus, as AAS provide initial stimulation of the androgen receptors in the brain there is an upswing in libido, only to be followed by a crash as the body reacts to restore balance in the face of these artificial forces. Although it is true that some men can live on fixed doses of testosterone/nandrolone for prolonged periods and maintain a good libido, as we have discussed in this article,

the likely health consequences of living on two AAS’s must be considered. The same is true for using net super-physiologic doses of androgen over prolonged periods, the effects of which are known to cause serious health issues.

In addition to the suppressive nature of AAS on HPT, related imbalances in other hormones also play a role in the pathophysiology of how AAS affect sex. These hormones/ratios include estrogen/androgen, prolactin (as discussed above in the case of the nandrolone based AAS) DHT, and other CNS neurotransmitters like serotonin, dopamine, norepinephrine and GABA. ‘… the potential variability of molecular and cellular effects of the AAS in the brain and suggest that the range of actions of these steroids will be highly complex, depending not only upon the chemical signatures and concentrations of the different AAS taken, but also upon region-specific differences in AR (Androgen receptors), ERalpha, ERbeta, and aromatase expression and changes in the endogenous steroid environment that occur as a function of sex, age and hormonal state.’ (Penatti et al, 2009)

This complexity is demonstrated anecdotally by the thousands of interviews I have had with men who use AAS and/or who are on testosterone replacement. When I attempted to assess their sexual response to these agents, I was amazed at the variability, and the sometimes-paradoxical responses. Some men told me that they feel best on 1,500 mg of AAS a week, while others reported that just 2 days after a physiological replacement dose of 100 mg testosterone Cypionate, their libido is poor, and they feel best just prior to the next injection nadir. Clearly, sexual response to these agents is no simple formula.

Many men, who use AAS chronically, also use a drug called Dostinex to block the effects of elevated prolactin levels secondary to AAS, and to improve libido. However, the side effects of this drug which is a dopamine promoter used for hyperprolactinemic disorders either from unknown medical conditions or from pituitary growths, can be serious and can lead to other medical conditions, e.g., hypotension, nausea, vomiting, shortness of breath, ankle swelling, fertility issues and severe mood disorders (Web MD). Is it worth it? A drug for a drug, for yet another drug?

In my clinical practice, I have also observed that men living on AAS and even on physiologic testosterone have poor erections at times, despite a perfectly balanced hormonal milieu. Kanayama et al (2015) found a subset of AAS users treated for ASIH showed continued loss of sexual desire and erectile dysfunction even when normal testosterone levels were restored. ‘Such cases may possibly represent end organ resistance–reflecting a possibly irreversible down-regulation of androgen receptors or androgen receptor signaling mechanisms.’ Since almost 100 % of men on chronic AAS and testosterone replacement have atrophied testicles, they can suffer from a venous leak state that can lead to poor quality erections. A urologist colleague explained it to me like this, ‘The testicles are like dampers at the base of the penis, when the testicle is shrunken and atrophied, the ability to hold back blood in the erect engorged penis may be reduced, leading to a leak-like situation and poor sustained quality erections’.

Withdrawal Syndrome

Inseparable from the issue of ASIH, the shutdown of a man’s HPT when he is on steroids, is the issue of what happens when he comes off them, during cycling or in a cessation attempt. For most men, being on AAS leads to either ok or great sex, but remember, as discussed above, the specific user hormonal profile, the type of AAS and ancillary drugs, the specific combinations and doses of these, all play a role in one’s sexual experience on AAS. It’s when a man stops AAS that everything falls apart– regardless of what agents were used. This is what the average user does not know or understand–or consider when making the choice to use.

What is going on here? The HPT, which has been dormant while on AAS, has to start back up again when AAS is removed from the system. This takes time; and for men who have been on AAS for prolonged periods or have used high doses, or very suppressive AAS, the restoration of the HPT may be delayed for months or years, or as noted earlier, in some circumstances may never return, despite medical intervention.(Rahnema et al, 2014; Kanayama et al, 2015) The most distressing symptoms of the withdrawal state– poor libido and mood, impotence, severe depression and suicidality– can be so severe as to create a state of dependency in users who are compelled by these to resume use. When severe, withdrawal symptoms caused by ASIH can not only compromise attempts to end AAS use as they prompt reuse, but they have also been shown to cause the palliative use of other illegal substances, e.g., opiates as well. (Kanayama G et al, 2010). The gravest danger during the AAS withdrawal period is severe depression and suicidality, with 12% of users in withdrawal experiencing severe depression, and 5% attempting suicide. (Brower 2009) It is not only the severity of withdrawal symptoms, notably in libido and mod, but also the fear of these which compel re-use, hence, the cycle of dependency. (Brower, 2009; Rahnema et al, 2014) Dependency is believed to affect between 1530% of AAS users (JAMA, 2013), with AAS considered to be more addictive than cocaine. (Phillips, 2010) Because of these high rates of dependence, several experts proposed including AAS among the addictive/dependence substances in the Diagnostic Standard Manual. (Kanayama et al, 2009). The take home message here is that withdrawal syndrome is the MOST COMMON REASON WHY MEN DO NOT AND CANNOT STOP USING STEROIDS; why they are compelled to stay on steroids for prolonged periods, and even for life

The mechanism of operation regarding the pathophysiology of AAS withdrawal state is not fully understood, but may relate to the fact that during use the hypothalamus and pituitary go into a dormant state called apoptosis (programmed cell death) (Hartgen & Kuipers, 2004), so that their production of gonadotropins, e.g, LH and FSH is either inadequate or qualitatively deficient to produce sustained testicular testosterone. To counter this disease process which lies somewhere between the hypothalamus, the pituitary and cells that produce testosterone in the testicles, AAS users have used a treatment protocol called Post Cycle Therapy (PCT) over the past 3 decades in an attempt to hasten the restoration of the HPT and to minimize the devastating physiological and psychological effects of ASIH in the post- use period.

Post-Cycle Therapy (PCT)

The medical agents used for PCT are fertility medications of the class Selective Estrogen Receptor Modulator (SERM), e.g, Tamoxifen and Clomid, Human Chorionic Gonadotropin (HCG) and various anti-estrogen medications, e.g, Arimidex and Letrozole. There is impressive support from experts for the medical use of these agents to support cessation by ameliorating withdrawal symptoms during treatment focused on restoring HPT and production of endogenous testosterone. (Talih, F et al,/Cleveland Clinic, 2007; Hochberg et al, 2003; Spratt, 2012; Pope & Brower, 2008; Rahnema et al, 2014). However, it should be stated that although it is ethical for a physician to use these agents to assist any man coming off AAS, neither medical use nor various PCT regimens, has been shown to produce sustainable endogenous testosterone levels or quality libido states in men who have used AAS chronically. Again, while medical PCT is 100% ethical, it may not work in blocking the effects of AAS used over long periods of time. I have had a number of men who have used AAS say to me, ‘Doc, I did my PCT, but now I feel terrible and my testosterone and sex is down! What happened? Why didn’t the PCT work? ‘The answer is, we just don’t know.

The following comment, which appeared on a highly regarded anabolic steroids blog regarding PCT, indicates the persistence of an overly sanguine view of the pathway back to normal following AAS use:

‘Once the use of the AAS is complete and all of the exogenous steroidal hormones have cleared your system, natural testosterone recovery will begin again. Natural recovery assumes no prior low testosterone condition. It also assumes no damage was done to the HPTA (HPT) due to improper AAS use. While natural recovery will occur on its own, it will be slow. For this reason, most are encouraged to implement a PCT plan after AAS use. Such a plan will commonly include the SERM’s Nolvadex and Clomid, and often-additional HCG. This will greatly speed up the recovery process, as well as its overall efficiency. It will not return your natural testosterone levels to normal on its own. If this is something you’ve been told, (know that) it is a myth. However, it will ensure you have testosterone for proper bodily function while your levels continue to naturally rise. Total recovery will still take months, but this will cut the total time down dramatically and ensure a smooth recovery.’

Such views do not consider what we now know about the potentially ravaging long term and even permanent effects of ASIH in patients suffering the consequences of long term, high dose AAS use. It’s important to discourage such unsupported notions about an automatic restart button after AAS use– especially since a significant number of high school students–the fastest growing group of users– do not believe these agents (AAS) are harmful (DOJ, 2004).

ASIH: Threat to Cessation

While a complete explanation for AAS dependency/addiction is not yet fully understood, similarities to the neurological pathway of opioid addiction have been reported. (Wood, 2008; Caraci et al, 2007) Sexual and other physiological symptoms of withdrawal, e.g., flu, mood, whether in cycling or in attempts to end use, were described some time ago by experts who noted that these were probably an endocrine effect of the episodic nature of use and discontinuance (cycling). (Kashkin & Kleben, 1989; Hochberg, 2003). A component part of the explanation of dependency is the psychological explanation that when steroid use stops, muscle development is limited, and related feelings of power and self-esteem are impacted. Co-morbid conditions such as pre-existing depression and Body Dysmorphia are also thought to contribute to dependency. (Leone et al, 2005) This complex symptom profile causes AAS dependency to differ significantly from that of other addictive drugs which are valued primarily for the ‘high’ they produce. Thus, it is clear that, while education is seen by some as an important component in prevention/cessation efforts, as with other addictive drugs, it is not sufficient for safe and effective AAS withdrawal when a man is seeking cessation. This complex and well characterized AAS withdrawal syndrome has now been described as a major factor in the development of AAS dependence, as dysphoric withdrawal effects lead to resumption of AAS use for relief. (Kanayama et al, 2009; Bhasin et al, 2013; Brower, 2009) Brower (2009) notes that the physiological nature of dependency on AAS can be diagnosed by asking what happens when a patient tries to stop using AAS. He cautions, ‘Conventional methods of treating substance abuse are usually inappropriate unless modified specifically for AAS users’. Despite such cautions, treatment for AAS dependence continues to be modelled after other substance dependence: a recent description of treatment offered for Steroids Addiction at a wellknown, and expensive residential treatment center stated, “(Our) Steroids addiction treatment is largely psychological in nature to deal with the user’s psychological dependence on the drug..(therefore) the primary treatment is behavioral therapy’. Completely misses the boat.

A parallel criticism could be leveled at physicians who, because of their lack of understanding of ASIH, rely on unrepresentative studies of other hypogonadic populations to inform their treatment of AAS users. The supraphysiologic doses required for anabolic effect (muscle building), which are widely available on the Internet without prescriptions, along with advice on how to use them for maximum effect, far exceed the recommended physiological dose that ethical physicians administer for hypogonadism. Thus, the results of studies in which, for ethical reasons, AAS subjects received only physiologic dose of testosterone over short periods of time do not provide useful guides for treating AAS related conditions such as ASIH. Clearly, such studies are not representative of men who have used AAS- -of all kinds, including neurotoxic substances–in doses 10-100 times greater than those given to study samples, cycling these substances over years, not weeks or months, and presenting with serious AAS related co- morbid medical conditions. (Mechanics., 2016) Yet, because of the lack of prospective studies using supraphysiological doses– which would be unethical– many physicians continue to base their treatments on these. Extrapolating from such studies to men presenting with ASIH is not only inappropriate, but one could also reasonably say unethical inasmuch as we now have available therapeutic agents shown to be safe and effective for relieving the severest symptoms of ASIH. ‘Cold turkey’ prescriptions like ‘stop the drugs immediately and await recovery in patience” which astonishingly appeared in an major Journal article as recently as 2016,(Mechanic et al, 2016) are now neither appropriate nor necessary as they do not tally with either compassion nor evidence based medicine. Because of the potential severity of symptoms accompanying withdrawal, ‘cold turkey’ cessation is not recommended, as abrupt cessation of AAS and waiting until natural testosterone levels return, unaided by medication, leaves the body ‘wide open to hormonal collapse’ (Turek, 2015). No physician should risk a patient’s health in this way.

Because of the unique pathophysiology of ASIH which distinguishes hypogonadic AAS users from other substance abusers, as well as from other hypogonadic populations, treatment protocols used by physicians familiar with this condition differ significantly from those used by physicians who are not as informed. It is generally recommended that withdrawal from AAS be supported by hormonal replacement therapy, tapering hormones down over time, and continuing until recovery of the hypothalmic-pituitary-gonadal axis. Management strategies that are recommended include testosterone replacement therapy (TRT), human chorionic gonadotropin (hCG), and selective estrogen receptor modulators (SERMs) to restore the HPT axis and its ability to produce endogenous testosterone. (Talih et al, Cleveland Clinic, 2007; Hochberg et al, 2003; Spratt, 2012; Pope & Brower, 2008; Rahnema et al, 2014) However, there is no guarantee, even with medical assistance, of when–or if–the HPT axis will recover. Persistence of hypogonadism even after drug cessation is ‘probably the result of long term adaptation to hormones which may involve relatively persistent changes in molecular switches.’ (Hochberg, 2003) Recovery can take place in months, or can be quite prolonged, with ASIH persisting years after cessation, or it can be irreversible, depending on the damage done to the HPT during use (Kanayama et al, 2010; Borogowda et al, 2001). Rahnema et al (2014) have warned that failure to treat ASIH could result in permanently failed HPT axis. Such a case has been described by Stephens et al (2011).

Medications such as those listed above to relieve withdrawal symptoms and assist HPT recovery have been found to be both effective and safe in physiologic doses. McLaren et al (2008) found that short-term (up to 5 years) TRT resulted in minimal prostatic growth or development of lower urinary tract obstructive symptoms. Morgantaler (2010) has reported that the use of physiological dose of testosterone to restore the body to hormonal balance presents no significant medical risks: ‘While side effects of physiological dose testosterone can include some elevation of red blood count, with no reported stroke or other adverse effects; and some minor swelling and some acne breakouts, these effects go away as soon as treatment is stopped.’

When ASIH Requires Long-Term Testosterone Replacement

Almost all AAS related sexual issues will be related to libido. I find it puzzling that so many doctors give AAS users Viagra for their sexual issues, when it is 100% useless! A AAS user’s poor libido is not a failure of the man’s penis to produce nitric oxide. In most cases, a user’s poor libido will be the result of ASIH as his CNS has adapted to higher levels of androgen while on AAS. As discussed above, the HPT is the main player here, and even with PCT, the shortest amount of time a man can expect to gain full restoration of the HPT is 3-6 months. If he still has a poor libido at that point he should consider the possibility of more severe ASIH, and seek a medical expert for diagnosis and treatment.

SERMS such as those mentioned earlier may help a man suffering with AAS related sexual issues. However, if these do not work, a man who has been living on AAS for years and finds that he cannot get off AAS due to lack of libido, may have to be considered for life- long physiologic testosterone replacement therapy. The seriousness of this choice of treatment for ASIH cannot be overstated. If the therapy choice is physiologic testosterone replacement (TRT), this may be for life, with not only considerable expense and inconvenience, but also with potential implications for cardiovascular and prostate health, and other medical issues, such as the following, which have been associated with testosterone:

Cardiovascular Disease: How testosterone is connected to heart disease is complex and multifactorial, but very real! Focusing on this is an important part of TRT treatment and also for men using AAS. AAS (including testosterone) have been shown to worsen existing heart disease risk factors such as hypertension, poor lipid ratios–higher LDL and low HDL, and to cause obstructive sleep apnea, which can lead an enlarged heart and heart failure. Other risks include increasing red blood cell indices, hypercoagulable states and direct adverse effect on the heart muscle itself (cardiomyopathy), and damage to the endothelial aspect of the artery(s)–leading to plaque progression and the potential for a heart attack. (Morgantaler et al (2015). Since beginning my medical practice in 2005, I have seen many men with premature heart disease secondary to AAS use. This disease state can take decades to progress, and men with poor family histories associated with early and severe heart disease are especially at risk. Identifying these risk factors early is very important because, in addition to supporting safe and effective AAS discontinuation, physicians can play a very important role in providing protective medicines while someone is going through a dangerous period of use. Treating hypertension, lipid abnormalities, polycythemia, sleep apnea, and other medical issues related to AAS use is the ethically right thing to do, and many physicians will do this. Give a man time to make the right decision, and prevent him from having a heart attack, has always been my perspective.

Prostate Disease: While the debate about a connection between prostate disease and the cumulative effects of long term testosterone treatment, no conclusion has been reached. Following the FDA warning regarding these, Nam & Wallis (2016) presented the findings of their own study which involved over 38,000 men, both treated and untreated, and which not only found no increase in prostate risk in treated men over 5 years, but found that risk decreased with long term exposure. However, the design of the study has been criticized by other experts who continue to advise caution. Since there are no longterm studies of men on testosterone treatment, it is reasonable to exercise caution in providing testosterone treatment of men with family history of prostate disease or preexisting malignancy. Current recommendations are to exclude prostate cancer before initiating TRT in men over age 40 and to closely monitor men in the first year of testosterone replacement, followed by observation in subsequent years. (Barqawi, 2006)

Challenges to Diagnosing ASIH

To provide safe and effective treatments for ASIH, physicians must first be able to interpret signs and symptoms in the context of AAS use, and not reflexively by lab numbers. ASIH is evidenced by both clinical symptoms such as those cited earlier, and somewhat less reliably by laboratory levels of testosterone, as is standard practice when treating hypogonadism. Lab levels, generally, have been challenged on both validity and reliability in diagnosing hypogonadism. As a result, attempts are being made to improve reliability by standardizing lab procedures (Wartofsky & Handelsmann, 2012). Validity of lab numbers in individual cases, however, remains a strongly debated issue. Several experts assert that while what constitutes a functionally’normal’ testosterone level is consistent within a particular man, ‘normal’ levels differ ‘significantly’ between men.( Kelleher et al, 2004) Just as there is now broad consensus on medications required to assist in recovery of HPT system in ASIH patients, there is also growing support for evaluating recovery of the HP axis on the basis of symptom recovery, and not solely on lab levels of testosterone. Zitzmann and Nieschlag (2000) have defined recovery of HPT axis as return to sexual health, which they define as ‘..restoration of libido, increase in sexual fantasies, and the frequency erections were considered signs of adequate therapy while symptoms such as lethargy, inactivity and depressed mood indicated less than adequate therapy. A five-year study by Kelleher et al. (2004) of the variability of testosterone thresholds in hypogonadal men receiving TRT provides objective evidence to support ‘…the common clinical practice of monitoring adequacy of androgen replacement therapy by observing how well the presenting symptoms are rectified.’ An essential implication of such studies, which validate the importance of symptoms as indicators of ideal testosterone levels –of adequate restoration of HPT axis– underscores the important role of clinical judgment as a guide to treatment. Morgantaler & Conners (2013) concur: ‘Since there is no serum testosterone value that reliably identifies men who will respond to treatment from those who will not, healthcare providers must exercise clinical judgment in making the diagnosis of testosterone deficiency..’ These authors caution that assuming a certain number indicates normal testosterone level can cause a physician to falsely assume that the problem lies elsewhere. Finkelstein et al (2013) have recommended a continuum, rather than a rigid threshold above, which clinical measures are normal and below which adverse change occurs. Clearly, diagnosis and recovery of androgen deficiency, ASIH, are not simple matters of recording ‘low’ or ‘high’ lab testosterone levels, but are more validly inferred from individual symptom report/response, i.e., subjective as well as objective.

Looking Ahead

Because of the multi-system side effects of AAS, its unique pathophysiology, and the added complication of patient-specific use patterns, it is important for physicians to ask patient directly about use in order to provide appropriate treatment, and to counsel about cessation. 56% of AAS users have never disclosed their use to doctors; their reasons include not believing doctors are informed on AAS, fear of possible legal consequences of acknowledging use, and the belief by some users that these agents are not harmful. (Pope & Brower, 2004) Failing to ask patients directly about use can lead to masking the underlying cause of many health problems, including hypogonadism and infertility. Asking about AAS use should be part of the routine medical workup of all hypogonadal men. Specific questions should include: dates of first and last use; the names and doses of AAS used; sources of drugs (legal or prescription); routes of administration, e.g., needle sharing; patterns of use, e.g., stacking, cycling. Also of interest should be other drug combinations used to: augment AAS effects (human growth hormone, insulin, Selective Androgen Receptor Modulators (SARMS), peptides and clenbuterol); to reduce unwanted side effects–post cycle therapy PCT (clomid, human chorionic gonadotropin HCG, tamoxifen, and various anti-estrogens); to mask urine testing (probenicid, diuretics); and use of other illicit drugs, e.g., opiods (Pope & Brower, 2008).

When physicians do not inquire about AAS in cases of infertility, despite the fact that male infertility has been linked to prior or current steroid use, a couple may be unnecessarily led into an expensive–between fifteen and thirty thousand dollars out of pocket–and potentially frustrating course(s) of fertility treatment. (Kirby EW, et al, 2016) AAS related male infertility which can sometimes be long-term, or even irreversible, has also caused a significant number of men who have used AAS to later express regret because they had not known that elevated serum testosterone levels obtained from AAS result in oligospermia and azoospermia. (Kovac, JR et al, 2014) It’s not clear that enough physicians know that either, or know that the main cause of severe hypogonadism in young men is previous AAS use. (Crosnoe-Shipley et al, 2015)

A database study of 6,033 men of varying ages who sought treatment for hypogonadism from 2005 to 2010 found that prior anabolic steroid use is common in young men who seek treatment for hypogonadism, with hypogonadal men younger than 50 years more than 10 times more likely to have prior AAS exposure than men 50 years or older. Further, in men with profound hypogonadism, AAS use was the most common etiology. (Coward, et al 2015.) Inasmuch as neither the role of AAS in hypogonadism nor the issue of AAS use generally been discussed adequately in mainstream medicine, such findings make it clear that we need to refocus the approach to evaluation and treatment of hypogonadism which has heretofore been focused on aging men, by recognizing ASIH as a unique form of hypogonadism affecting increasing numbers of young men.

The Medical Profession: New Directions in ASIH

In the most recent Endocrine Society Guidelines (2010) formulated to provide evidence based decision-making assistance to clinicians treating hypogonadism, AAS or ASIH were not mentioned in either the text, references, nor illustrative tables. However, in 2013, an Endocrine Society Expert Panel was convened, presumably to address this deficit, in the face of what one member has called a ‘cultural tsunami at the corner gym’, and increasing reports of AAS use with adverse events. (Canavan, 2013) The final report issues a call for physicians to become better informed about AAS and related conditions like ASIH, to understand and respond to the motivations of users in a non-judgmental way, and to study the mechanisms of action of AAS. Despite the panel’s acknowledgement that there is much yet to discover about the effects of AAS, one author has noted that one side effect is ‘nearly universal’ in users—the suppression of testicular function… The effect, which has been labeled ASIH by the experts cited in this article.

References: ASIH

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