AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Steroids are a general class of agents that all have the steroid ring in common. The steroid ring is comprised of three 6-carbon rings and one 5-carbon ring joined, of which cholesterol is the most basic form and, indeed, the precursor. Although the term steroid includes all agents derived from this ringed structure, this discussion includes only testosterone and the anabolic-androgenic steroids (AASs).

Testosterone is the principle hormone in humans that produces male secondary sex characteristics (androgenic) and is an important hormone in maintaining adequate nitrogen balance, thus aiding in tissue healing and maintenance of muscle mass (anabolic). Testosterone has a dual action and can be described in terms of its androgenic and anabolic capacity.

AASs are drugs derived from the modification of the testosterone molecule in order to augment or limit certain characteristics of testosterone. In general, testosterone has been altered to produce drugs that are either more or less anabolic, are more or less androgenic, have differing affinity for the testosterone receptor, have different metabolic breakdown pathways, are efficacious for oral use, or have any combination therein. Well over a thousand different compounds have been synthesized and studied since the 1950s with the hope of producing compounds that have superior anabolic or androgenic effect compared with testosterone. Biochemists quickly noted that additions or subtractions to the testosterone molecule at specific locations would have a somewhat predictable effect on the inherent qualities of said compound. Specifically, qualities including but not limited to anabolic/androgenic ratio, metabolism, receptor affinity, and oral efficacy were noted.

In general, the goal is to increase the anabolic and decrease the androgenic characteristics so that the desirable anabolic nitrogen-sparing effects would be multiplied while the generally undesirable androgenic virilizing effects would be minimized. Complete dissociation of the anabolic/androgenic effect has not been possible to date, however.

Clinically, anabolic-androgenic steroids have been used to treat a host of conditions, including the following:

• Many forms of anemia



• Acute and chronic wounds



• Protein-calorie malnutrition with associated weight loss



• Severe burns



• Short stature



• Osteoporosis



• Primary or secondary hypogonadism



• Prolonged catabolic state secondary to long-term use of corticosteroids



• More recent use in HIV wasting syndrome

Almost with their inception, testosterone and anabolic-androgenic analogues have been used and abused by those seeking to augment both anabolic and androgenic potential to improve physical performance in athletic endeavors or to improve physique. Stories of Eastern-bloc athletes receiving testosterone and anabolic-androgenic steroids as part of their training regimens as early as the 1950s abound. The Eastern-bloc weightlifters and track athletes subsequently ruled the athletic stage for decades. 

The degree to which anabolic-androgenic steroids  affect performance enhancement in healthy athletes is widely debated, as are the precise mechanisms of action. Certainly anecdotal evidence, including increases in strength and lean body mass (LBM), is reported, but steroid effect is difficult to study in a true placebo-controlled double-blind fashion. Most athletes would notice testicular atrophy if receiving anabolic-androgenic steroids, which interferes with the double-blind structure. Dosing, nutrition, and training parameters would need to be monitored extensively to completely satisfy the most critical review.

Certainly, the use of anabolic-androgenic steroids has become a worldwide phenomenon, slowly trickling down to collegiate, high school, and even junior high levels. The early assertion from the medical community that "anabolic steroids have not been shown to enhance athletic ability," still in print in the 2002 Physicians Desk Reference, contributed to this phenomenon. Technically, the statement is correct; however, people misusing and abusing these drugs quickly realized that the performance-enhancing effects were real and subsequently dismissed the rest of the medical community's contraindications, dosing recommendations, and warnings.

BIOPHARMACOLOGY OF TESTOSTERONE

Section 3 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Testosterone, the primary male sex hormone, is manufactured in the testes under the influence of luteinizing hormone (LH) in amounts of 2.5-11 mg/d¹. Testosterone is produced under a negative feedback loop between the hypothalamus, the anterior pituitary, and the testes. Testosterone, dihydrotestosterone, and estrogen all act at the hypothalamus to exert negative feedback inhibition upon gonadotropin-releasing hormone (GnRH). Since GnRH stimulates follicle-stimulating hormone (FSH) and LH release in the pituitary, this negative feedback can be seen to inhibit subsequent testosterone production and effect spermatogenesis.

Testosterone activity is mediated via an androgen receptor that is present in various tissues throughout the human body. Testosterone binds to an intracellular receptor found in the cytosol of cells, forming a receptor complex that migrates into the nucleus where it binds to specific DNA segments. This, in turn, activates specific mRNA to increase transcription leading to an increased rate of protein synthesis, specifically actin and myosin in the case of muscle cells. After this process is complete, the receptor complex dissociates and is recycled along with the hormone to repeat this process multiple times prior to metabolism.

These anabolic actions of testosterone are thought to be primarily due to testosterone acting upon the androgen receptor in anabolic responsive tissues. Androgenic effects are likely mediated via the same androgen receptor in androgen responsive tissues under the influence of dihydrotestosterone (DHT), which is produced by the interaction of 5-alpha reductase (5AR) upon testosterone and the subsequent reduction of the C4-5 double bond. Additionally, DHT cannot undergo further reduction, nor is it a substrate for aromatase; thus, it is not converted to estrogenic metabolites. DHT has been shown to bind avidly to receptors in tissues, such as skin, scalp, and prostate, and exert 3-4 times the androgenic effect compared to testosterone. Thus, the primary hormone mediating the androgenic effects of testosterone is actually the 5-alpha reduced DHT.

Other mechanisms of direct and indirect anabolic effects include anti-glucocorticoid activity mediated by displacement of glucocorticoids from their receptor², increases in the creatine phosphokinase activity in skeletal muscle³, and increases in both circulating insulin-like growth factor (IGF)–1⁴ as well as up-regulation of IGF-1 receptors⁵. These mechanisms may play a much larger role in the anabolic/anticatabolic actions of anabolic-androgenic steroids (AASs) than once thought. At physiologic testosterone levels, nearly all androgen receptors are engaged. Therefore, supraphysiologic doses of testosterone or anabolic-androgenic steroids would have no increased anabolic effect in healthy athletes unless other mechanisms of action existed.

BIOCHEMISTRY AND PHARMACOLOGY

Section 4 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Because there are many agents in production and literally hundreds more that have been synthesized, this discussion focuses on the basics involving the steroid ring substitutions and how these substitutions affect the properties of the drug. Detailed analysis is limited to those agents that are available or have been approved for use in the United States.

Anabolic-androgenic steroid (AAS) development was centered on the need for agents that exhibited different characteristics than that of testosterone. In general, the goal was to develop agents that were more anabolic and less androgenic than testosterone, capable of being administered orally, and had less effect upon the hypothalamic-pituitary-gonadal axis. Most anabolic-androgenic steroids are derived from 3 compounds: testosterone, dihydrotestosterone, and 19-nortestosterone. The latter compound is structurally identical to testosterone except for the deletion of the 19th carbon, hence its name. These parent compounds offer different properties in regards to action and metabolism that are generally constant throughout the entire family of compounds.

One of the first changes made to the testosterone molecule was the addition of a methyl or ethyl group to the 17-carbon position. This addition was noted to inhibit the hepatic degradation of the molecule, greatly extending the half-life and making it active when administered orally. Prior to this, testosterone, dihydrotestosterone, and 19-nortestosterone all required parenteral administration due to hepatic metabolism to 17-ketosteroids, which occurred on the "first-pass," when the drugs were administered orally.

This change, however, did not render a drug with exact properties of the parent compound. The alteration of hepatic metabolism was noted to cause strain on the liver, and indeed all oral compounds with this C-17 addition were found to cause dose-related hepatotoxicity. This small change was also found to lower the interaction with aromatase⁶. Therefore, even small changes to these parent compounds cause multiple changes in the inherent nature of the anabolic-androgenic steroids.

TESTOSTERONE ESTERS AND DERIVATIVES

Section 5 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Testosterone esters have seen an increase in their use in replacement therapy and in their propensity for abuse. The testosterone esters all have the testosterone molecule with a carboxylic acid group (ester linkage) attached to the 17-beta hydroxyl group in common. These esters differ in structural shape and size and function only to determine the rate at which the testosterone is released from tissue. Generally, the shorter the ester chain, the shorter the half-life and quicker the drug enters circulation. Longer/larger esters usually have a longer half-life and are released into the circulation more slowly. Once in the circulation, the ester is cleaved, leaving free testosterone.

Common testosterone preparations include the following:

Testosterone esters

• Testosterone propionate



• Testosterone cypionate
  


• Testosterone enanthate

• Methyltestosterone
  • Methyltestosterone is a very basic anabolic-androgenic steroid (AAS) with the only addition being a methyl group addition at C-17. This eliminates first pass degradation in the liver, making oral dosing possible. It also causes dose-related hepatotoxicity.  
    
  
  
  • It is metabolized by aromatase to the potent estrogen 17-alpha methyl estradiol and is also reduced by 5AR to 17-alpha-methyl dihydrotestosterone.
    
  
  
  • This compound exhibits very strong androgenic and estrogenic side effects and is generally a poor choice for most, if not all, uses.


• Methandrostenolone
  • Methandrostenolone has an added cis-1 to cis-2 double bond that reduces both estrogenic and androgenic properties. However, it does undergo aromatization to the rather potent estrogen 17-alpha methyl estradiol, but curiously does not show the in vivo propensity for reduction by 5AR to alpha dihydromethandrostenolone to any large degree⁷.
    
  
  
  • This steroid was first commercially manufactured in 1960 by Ciba under the brand name Dianabol and quickly became the most used and abused steroid worldwide to date. It jokingly came to be known as "the breakfast of champions" in sports circles.
    
  
  
  • This agent is very anabolic with a half-life of approximately 4 hours. The methyl group at C-17 makes this anabolic-androgenic steroid an oral preparation and potentially hepatotoxic.
    
  
  
  • Both Ciba and generic firms in the United States discontinued methandrostenolone in the late 1980s, but over 15 countries worldwide still produce it in generic form. 


• Fluoxymesterone
  • Fluoxymesterone is a potent androgen that is produced under the brand name Halotestin. It is an excellent substrate for 5AR and conversion to DHT metabolites. With the addition of a 9-fluoro group, it is a very potent androgen with very little anabolic activity. An added 11-beta hydroxyl group inhibits its aromatization. Again, the C-17 methyl group makes oral administration possible, along with hepatic concerns.
    
  
  
  • This anabolic-androgenic steroid is not favored in clinical practice due to its poor anabolic effects, yet athletes abuse it for its androgenic nature and lack of peripheral aromatization.

• Nandrolone decanoate
  • Nandrolone decanoate is simply 19-nortestosterone with the addition of a 10-carbon decanoate ester added to the 17-beta hydroxyl group. This addition extends the half-life of the drug considerably. Nandrolone (19-nortestosterone) is a potent anabolic with a relatively favorable safety profile. Nandrolone is reduced by 5AR in target tissues to the less potent androgen dihydronandrolone. It also has a low affinity for aromatization to estrogen, thought to be 3-4 times less than that of testosterone⁸.
    
  
  
  • Nandrolone and its several esters (decanoate, phenylpropionate) differ only in their half-lives due to the difference in ester properties.
    
  
  
  • Nandrolone is a relatively safe drug with minimal androgenic concerns and ample anabolic action at therapeutic doses. Nandrolone decanoate is an IM preparation and lacks the hepatotoxic C-17 group; however, this agent is one of the most widely abused AASs due to its efficacy, safety profile, and worldwide manufacture.


• Ethylestrenol
  • Ethylestrenol is an oral 19-nortestosterone derivative and was marketed in the United States under the brand name Maxibolin, but it has since been discontinued.
    
  
  
  • It differs from nandrolone by the addition of a 17-alpha ethyl group added to reduce first pass metabolism as well as the deletion of the 3-keto group. This latter omission seems to reduce androgen receptor binding.
    
  
  
  • This was a very mild anabolic-androgenic steroid with very little anabolic or androgenic effect at therapeutic doses.


• Trenbolone
  • Trenbolone is a derivative of nandrolone with several additions. First, the addition of a cis-9 to cis-10 double bond inhibits aromatization and a cis-11 to cis-12 double bond greatly enhances androgen receptor binding.
    
  
  
  • This drug is both a potent androgen and anabolic. It is comparably more androgenic than nandrolone due to its lack of conversion to a weaker androgen by 5AR, as is seen with nandrolone.
    
  
  
  • Trenbolone is a European drug with a very high abuse record. In the United States, it is used in veterinary preparations as trenbolone acetate, and as such, has found its way into the hands of those who wish to exploit its androgenic/anabolic potential.

• Oxandrolone
  • Oxandrolone, a derivative of DHT, is C-17 methylated and, therefore, an oral preparation.
    
  
  
  • The second carbon substitution with oxygen is thought to increase the stability of the 3-keto group and greatly increase its anabolic component. This AAS is very anabolic with little androgenic effect at a therapeutic dose. 5AR does not reduce oxandrolone to a more potent androgen, and, as a DHT derivative, it cannot be aromatized.
    
  
  
  • First marketed by Searle, it was discontinued in the mid 1990s. BTG remarketed this anabolic-androgenic steroid as Oxandrin, largely for the drug's use in HIV-related disease. 
    
  
  
  • Oxandrolone is one of a few agents to be routinely abused by female athletes due to its mild androgenic properties. Athletes, from weightlifters to boxers, use oxandrolone seeking to increase strength without additional weight gain.   


• Stanozolol
  • Stanozolol is an active anabolic-androgenic steroid due to the stability afforded by the 3,2 pyrazol group on the A-ring, which greatly enhances androgen receptor binding. The C-17 methyl group enhances oral availability.
    
  
  
  • Stanozolol is highly active in both androgen- and anabolic-sensitive tissue. It is a weaker androgen than DHT and exerts comparatively less androgenic effect. It will not aromatize to estrogenic metabolites.
    
  
  
  • This anabolic-androgenic steroid is marketed in the United States and abroad as Winstrol and comes in both oral and injectable forms.
    
  
  
  • Athletes, many in track and field, have abused it. Canadian sprinter Ben Johnson tested positive for stanozolol over a decade ago.  


• Oxymetholone
  • This quite potent anabolic-androgenic steroid is a unique agent. Oxymetholone is C-17 methylated and, thus, is an oral agent. The 3-keto stability added by the 2-hydroxymethylene group greatly enhances anabolic properties. The action of this agent in androgen-sensitive tissues is much like that of DHT and is quite androgenic.
    
  
  
  • It is the only anabolic-androgenic steroid to date to be considered a carcinogen (The Merck Manual of Diagnosis and Therapy, 15th edition, 1987).
    
  
  
  • Like this entire class, oxymetholone does not aromatize. It is thought to activate estrogen receptors via the 2-hydroxymethylene group, and it can exert many estrogenic side effects.
    
  
  
  • It is marketed in the United States as Anadrol-50 and has been abused the world over by weight lifters and strength athletes for both its strong anabolic and pronounced androgenic effects.

ADVERSE EFFECTS

Section 6 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Most of the adverse effects of AAS use are both dose dependent and reversible with cessation of the offending agent or agents. This overview of side effects and interactions is just that, an overview, and is not meant to represent the full spectrum of potential side effects that may be seen with this class of agents. Vital signs, including heart rate and blood pressure, and basic chemistries, such as sodium, potassium, hemoglobin, hematocrit, BUN, creatinine, hepatic, and lipid profiles, must be monitored carefully. Monitoring these parameters will help the clinician determine drug choice, treatment dose and duration, and help to alert the prescriber to potentially serious adverse effects necessitating discontinuation of therapy. 

Cardiovascular effects

The most common deleterious effects of anabolic-androgenic steroid (AAS) use on the cardiovascular system include increased heart rate, increased blood pressure, and changes in lipid metabolism including lowered high-density lipoprotein (HDL) and increased low-density lipoprotein (LDL). The increase in heart rate is thought to be more profound with the androgens, especially those resistant to aromatase, and is thought to be due to inhibition of monoamine oxidase (MAO). This effect, when combined with the increased renal recovery of ions such as sodium causing subsequent fluid retention, can lead to dramatic increases in blood pressure. Combine this with a tendency to lower HDL and raise LDL, and the stage is set for untoward atherogenic and cardiac effects.

Hepatic effects

The changes made to C-17 to inhibit hepatic degradation make nearly all oral preparations hepatotoxic. The alanine aminotransferase/aspartate aminotransferase (ALT/AST) can be seen to rise, usually in a dose-dependent fashion. levels approaching 2-3 times baseline are often set as upper limits of reference ranges when administering oral anabolic-androgenic steroids, but the risk-to-benefit ratio must be constantly evaluated. Anabolic-androgenic steroid use also results in suppression of clotting factors II, V, VII, and X and an increase in prothrombin time. Peliosis hepatitis, another rare but potentially life-threatening adverse effect that is seen in the liver and sometimes spleen, is the appearance of blood-filled cystic structures. These cysts may rupture and bleed profusely and have been found in both those with near normal liver function test (LFT) values and those in liver failure. Fortunately, drug cessation usually results in complete recovery.

Primary liver tumors have been reported, most of which are benign and androgen dependent and regress with discontinuation of anabolic-androgenic steroid therapy. Several case reports exist of young, healthy athletes who have died from primary malignant liver carcinoma with the only identifiable risk factor being oral anabolic-androgenic steroid use.

Endocrine effects

The endocrine system has a remarkable array of checks and balances that ensure the human body is at or near homeostasis at any point in time. Interruption of one feedback system has been shown to produce changes in other hormone feedback systems via direct receptor changes as well as competition for common enzymes and metabolic pathways. Studies have shown that anabolic-androgenic steroids bind to glucocorticoid, progesterone, and estrogen receptors and exert multiple effects. Discussions exist as to how the endogenous testosterone and spermatogenic functions of the testes are inhibited by the use of testosterone and anabolic-androgenic steroids. By suppressing FSH, spermatogenic function should be reduced.

Anabolic-androgenic steroids have also been shown to alter fasting blood sugar levels and decrease glucose tolerance, presumably due to either a hepatic effect or changes in the insulin receptor. Thyroxine-binding globulin (TBG) may also be lowered by AASs and result in lowered total T4 levels, with free T4 levels remaining normal. An up-regulation of sex-hormone binding globulin with concomitant decrease in TBG is thought to cause the changes in total T4 levels.

The aromatization of testosterone/ anabolic-androgenic steroids to estradiol and related compounds can render many adverse estrogenic effects. The most apparent and common adverse effect is the growth of tender estrogen-sensitive tissue under the male nipple. This unsightly growth is termed gynecomastia and can be treated medically or surgically.

Urologic effects

The male prostate is very sensitive to androgens, especially those that are reduced in prostatic tissue to DHT or DHT-analogues. In response to this stimulation, the prostate grows in size, potentially causing or exacerbating benign prostatic hyperplasia (BPH). Worsening BPH may indeed cause severe bladder and secondary renal damage. In addition, the use of anabolic-androgenic steroids in those with underlying carcinoma of the prostate is absolutely contraindicated due to the potential for hormone-sensitive tumor growth. However, a recent 3-year study of hypogonadal men on testosterone replacement therapy failed to show significant differences between the group and controls in urinary symptoms, urine flow rate, or urine postvoid residual⁹.

Hematologic effects

Direct clotting factors may be reduced with an increase in prothrombin time. In patients on concomitant anticoagulant therapy, this increase could cause bleeding. Anabolic-androgenic steroids cause increases in hemoglobin and hematocrit and are used in many cases of anemia, although the clinician must be aware of the potential for polycythemia.

Dermatologic effects

Skin, especially the face and scalp, has a high degree of both androgen receptors and 5AR. DHT is known to cause increases in sebum production, leading to clinical acne. Also, male-pattern baldness is related to both scalp DHT production and binding combined with genetic factors influencing hair growth. Male-pattern baldness is greatly exacerbated by most anabolic-androgenic steroids in susceptible individuals.

CLINICAL USES

Section 7 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

Clearly, hormone replacement therapy is the most common use of testosterone. Anabolic-androgenic steroids (AASs) have many other potential clinical uses. Most of these uses center on the anabolic nature of these drugs and their use in people with cachexia produced by such disease states as HIV, hepatic and renal failure, chronic obstructive pulmonary disease (COPD), some types of cancer, burns, and postoperative recovery. In most clinical scenarios, the association of protein-calorie malnutrition increases the morbidity and mortality of the primary disease state. By preventing this loss of LBM, the clinician can hope to prevent many of the adverse effects of the disease and perhaps even other treatments that have been enacted. In all clinical cases with the exception of cancer, anabolic-androgenic steroids have shown efficacy in weight gain.

In HIV infection, both testosterone replacement and anabolic-androgenic steroid use are generally considered. Commonly used anabolic-androgenic steroids  include oxandrolone, nandrolone, and oxymetholone. All 3 agents have been studied for increased LBM and weight gain^{10, 11, 12, 13}.

Anabolic-androgenic steroids have recently been studied in COPD-associated cachexia. Stanozolol (12 mg/d), after initial 250 mg IM testosterone injection, has shown significant improvement in a patient's weight, BMI, and strength compared to controls at 26 weeks¹⁴. A study of 217 COPD patients randomized to nandrolone plus nutrition and exercise, or nutrition and exercise alone, for a total of 8 weeks showed that the nandrolone group had significant increases in both LBM and maximum inspiratory pressure¹⁵. Studies of oxandrolone (20 mg/d) in tetraplegic patients also showed significant gains in weight and inspiratory parameters¹⁶.

Hepatic failure is also associated with protein-calorie malnutrition and wasting. In a study of 273 patients with moderate weight loss due to alcoholic hepatitis, oxandrolone (80 mg/d) improved hepatic function, improved nutrition parameters, and increased 6-month survival when compared to controls¹⁷. Although this is considered a preliminary study, it does show that the use of anabolic-androgenic steroids, even oral agents, can be useful even in some types of liver failure with associated weight loss. 

Wound and burn healing have been treated with anabolic-androgenic steroids including testosterone esters, stanozolol, oxandrolone, and nandrolone. These agents increased collagen synthesis and activity of dermal fibroblasts¹⁸, as well as having a positive effect upon healing rates in previously nonhealing wounds¹⁹.

Cancer-associated cachexia and anemia are both very common. Anabolic-androgenic steroids have been proposed for use in cancer-associated weight loss and treatment of the hypogonadal state that often accompanies such severe cachexia. Anabolic-androgenic steroids have also been used for their erythropoietic effects, usually in leukemia treatment.

Anabolic-androgenic steroids use with renal failure, especially those on hemodialysis, has recently been studied. A double-blind, placebo-controlled study of 29 dialysis patients receiving either nandrolone (100 mg/wk) or placebo for 6 months showed significant gains in both LBM and functional parameters²⁰. Studies also indicate that the erythropoietic effect of anabolic-androgenic steroids (nandrolone decanoate) is useful in chronic renal disease, and when used in combination with recombinant human erythropoietin, the gains in hematocrit are greater than when either of the two is used alone²¹.

These are just a sample of the many disease states that anabolic-androgenic steroids are used to treat. In most cases in which the anabolic properties are desired, an increase in protein and calories ingested must accompany their use. Other uses of anabolic-androgenic steroids, not explored in this article, include hormone replacement therapy and the general use of androgenic agents as such. Indeed androgens are used clinically, in cases such as endometriosis and fibrocystic breast disease, to negatively affect the hypothalamic-pituitary-gonadal axis and to limit disease symptoms or progression.

ANABOLIC-ANDROGENIC STEROID ABUSE

Section 8 of 9  

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

The topic of drug abuse of any kind is very complex and often difficult to assess accurately and objectively. The abuse of anabolic-androgenic steroids (AASs) is no different. The complex myriad of neurological effects of anabolic-androgenic steroids is still being studied. Relating this biopharmacology to the individual abusing  anabolic-androgenic steroids is a particularly difficult task because of several factors. For one, many individuals abusing anabolic-androgenic steroids have done so in relative secrecy, and many have been reluctant to engage in valid medical research. The lack of a standard when performing research because of the vast numbers of agents that are sold worldwide on the black market and their relative potency, or complete lack thereof, is another problem. Many counterfeit products are sold and used, which complicates the study of abuse.

In more than a few cases, contradictory data exist, especially concerning psychological effects. One must remember that the interaction of forces, which ultimately influences the abuser, is vast and multidimensional, a complex web of presumed gain and reward, which exists due to conditioning and related psychosocial issues. The use of performance-enhancing substances is not a novel idea and can be dated back to the Greeks. The use of anabolic-androgenic steroids for performance enhancement began in the 1950s with elite athletes, and the use has slowly trickled down to include the high school and junior high levels. With a "win at all cost" mentality and the high regard our society has for successful athletes, it is easy to see how this has occurred. Anabolic-androgenic steroid use in teenage years can prematurely fuse epiphyseal plates and stunt growth, as well as cause psychological problems.

When testosterone, anabolic-androgenic steroids, or both are used in the nonclinical setting, many problems arise. Athletes' self-prescribing habits are usually excessive and many times based more on fiction than fact. It is very common for the anabolic-androgenic steroid abuser to "stack" drugs, or to use multiple drugs at the same time. Surveys of weightlifters have documented the concurrent use of multiple drugs used in a cyclic fashion for a period of 12-16 weeks, usually with a dose of 2-8 times therapeutic range. The use of multiple drugs greatly increases side effects and risks to the user. Coupled with decreased medical surveillance, the anabolic-androgenic steroid abuser is at high risk for serious complications.

Anabolic-androgenic steroids have been shown to alter moods by a number of mechanisms. Studies show that testosterone and anabolic-androgenic steroids may act as a central monamine oxidase (MAO) inhibitor. Indeed anabolic-androgenic steroids are mood elevators and have been studied in depressed individuals. Vogel et al (1985) compared the antidepressant effects of amitriptyline (75 mg/d, up to a maximum of 300 mg/d) with mesterolone (100 mg/d, up to a maximum of 550 mg/d) in a double-blind design with 34 depressed male outpatients. The study found that the 2 drugs were equally effective in reducing depressive symptoms and that mesterolone produced significantly fewer adverse effects than amitriptyline²².

Another study combined methyltestosterone (15 mg/d) with imipramine (25-50 mg/d) and found a prompt paranoid response in 4 of 5 men treated. This paranoid response was quickly abated by the discontinuation of methyltestosterone²³. This was likely due to the central MAO inhibition by methyltestosterone combined with the known effects of imipramine.

Other studies indicate that testosterone, particularly in the prenatal period but also during puberty and adulthood, is important in establishing a biological readiness for normal aggressive behavior and in facilitating the expression of aggression in appropriate social settings. They also indicate that both social factors and learning significantly influence the actual expression of aggression in adulthood²⁴. In a 1983 study of 32 weightlifters using anabolic-androgenic steroids, 56% reported a temporary increase in self-defined irritability and aggressive behavior. When these psychoactive effects combine with strong positive reinforcement from weight and strength gains as well as improved self-image, anabolic-androgenic steroids can have addictive features.

Anabolic-androgenic steroid addiction is generally held as a psychic addiction, but the occurrence of withdrawal effects upon cessation of use clearly indicates an element of physical addiction as well. Multiple studies have shown that the withdrawal symptoms include depression, fatigue, paranoia, and suicidal thoughts and feelings. Furthermore, a strong desire to continue abusing anabolic-androgenic steroids exists even in the face of negative consequences; thus, the drugs are continued in order to provide continued perceived positive effects and inhibit withdrawal effects.

Finally, a 1989 review suggests the psychoactive effects, withdrawal symptoms, and underlying biological mechanisms of anabolic-androgenic steroids appear similar to the mechanisms and complications accompanying cocaine, alcohol, or opioid abuse. The review also proposes that a proportion of anabolic-androgenic steroid  abusers may develop a sex-steroid hormone dependence disorder.

The abuse of anabolic-androgenic steroids, especially over the past 20 years, has had a deleterious effect upon the clinical use of these compounds. These drugs are now considered controlled substances in the United States (schedule 2 and 3), and this, along with excessive negative media attention, has resulted in a steep decline in their appropriate clinical use.

Indeed, many anabolic-androgenic steroid agents have been withdrawn from the US market; however, clinical interest in the beneficial effects of these drugs has once again come to the forefront over the past few years. With recent increases in use (estimated at 400%),  anabolic-androgenic steroids are once again being prescribed for known uses and ongoing research will continue to uncover novel uses and further define the mechanisms of action. Physicians should be aware of both the clinical and underground worlds of anabolic-androgenic steroids and not allow the abuse of these drugs to limit their appropriate therapeutic use, just as with opioids or other potential drugs of abuse. Indeed, a particular agent is not inherently good or evil but depends upon the end use of said agent. Thus, it is the job of the physician to help ensure these compounds are used appropriately and not abused.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Biopharmacology of Testosterone
• Biochemistry and Pharmacology
• Testosterone Esters and Derivatives
• Adverse Effects
• Clinical Uses
• Anabolic-Androgenic Steroid Abuse
• References

1. Rosenfeld RL. Role of androgens in growth and development of the fetus, child, and adolescent. Adv Pediatr. 1972;19.
2. Danhaive PA, Rousseau GG. Binding of glucocorticoid antagonists to androgen and glucocorticoid hormone receptors in rat skeletal muscle. J Steroid Biochem. Feb 1986;24(2):481-7. [Medline].
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Article Last Updated: Mar 5, 2007