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GHRP (growth hormone releasing peptide)
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Ligandrol (LGD-4033)
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Laxogenin 100

The effect of 6 days of Alpha-GPC on isometric strength


Ergogenic aides are widely used by fitness enthusiasts and athletes to increase performance. Alpha glycerylphosphorylcholine (A-GPC) has demonstrated some initial promise in changing explosive performance. The purpose of the present investigation was to determine if 6 days of supplementation with A-GPC would augment isometric force production compared to a placebo.

Thirteen college-aged males (Means ± SD; Age: 21.9 ± 2.2 years, Height: 180.3 ± 7.7 cm, Weight: 87.6 ± 15.6 kg; VO2 max: 40.08 ± 7.23 ml O2*Kg−1*min−1, Body Fat: 17.5 ± 4.6 %) gave written informed consent to participate in the study. The study was a double blind, placebo controlled, cross-over design. The participants reported to the lab for an initial visit where they were familiarized with the isometric mid thigh pull in a custom squat cage on a force platform and upper body isometric test against a high frequency load cell, and baseline measurements were taken for both. The participant then consumed either 600 mg per day of A-GPC or placebo and at the end of 6 days performed isometric mid thigh pulls and an upper body isometric test. A one-week washout period was used before the participants’ baseline was re-measured and crossed over to the other treatment.

The A-GPC treatment resulted in significantly greater isometric mid thigh pull peak force change from baseline (t = 1.76, p = 0.044) compared with placebo (A-GPC: 98.8. ± 236.9 N vs Placebo: −39.0 ± 170.9 N). For the upper body test the A-GPC treatment trended towards greater change from baseline force production (A-GPC: 50.9 ± 167.2 N Placebo: −14.9 ± 114.9 N) but failed to obtain statistical significance (t = 1.16, p = 0.127).

A-GPC is effective at increasing lower body force production after 6 days of supplementation. Sport performance coaches can consider adding A-GPC to the diet of speed and power athletes to enhance muscle performance.

Keywords: Alpha glycerylphosphorylcholine, Strength, Human performance, Sport supplements


Performance in sport is often determined by moments of extreme force production and power output [1]. While much of this can be attributed to muscular strength [23], some adaptations to training can be neural in nature [4]. A study by Pensini, Martin and Maffiuletti [5] demonstrated that increases in torque associated with 4 weeks of eccentric exercise were likely the result of central (or neural) adaptation. Based upon current knowledge it appears that both central and peripheral adaptations are necessary to enhance performance in athletes. Therefore, it is important to study nutritional interventions that have the potential to augment either potential site of adaptation.

α Glycerylphosphorylcholine (A-GPC) is a substance that could potentially augment human performance by facilitiating neuro-muscular interaction. A-GPC has been shown to augment acetylcholine levels in neurons in rat CNS [6], and has been shown to maintain reaction time in humans following exhaustive exercise [7]. Additionally A-GPC is generally considered safe for consumption in moderate to high doses [89]. Ingested A-GPC is converted to phosphatidylcholine, a source of choline [10]. Dietary choline levels are linked to the rate of biosynthesis of acetylcholine [11]. Given that cholinergic nerves trigger muscle contraction, and that choline availability is linked to acetylcholine synthesis substances that could augment choline availability might have the potential to influence muscular performance. To date some work has been done examining the ability of phospholipids to restore choline levels after exercise, but there is a dearth of information regarding the ability of compounds like A-GPC to acutely enhance performance [11]. The purpose of this study was to examine the effects of 6 days of supplementation with A-GPC on measures of isometric force production in the upper and lower body.


The Institutional Review Board at the University of Louisiana at Lafayette reviewed the present investigation for ethics. The study was a double-blind, placebo-controlled crossover with a 1-week washout period that included 13 healthy, college-aged males (Means ± SD; Age: 21.9 ± 2.2 years, Height: 180.3 ± 7.7 cm, Weight: 87.6 ± 15.6 kg; VO2 max: 40.08 ± 7.23 ml O2*Kg−1*min−1, Body Fat: 17.5 ± 4.6 %). Subjects reported to the lab and give informed consent, which included consent to publish, prior to baseline assessments which included height and weight, an assessment of maximum aerobic capacity via a COSMED CPET system (COSMED, Rome ITL) with integrated electronically braked cycle ergometer as outlined in previous studies [12], and body fat percentage via air displacement plethysmography (Bod Pod Gold Standard System, COSMED Rome, ITL) . The following week trial one (random order: either placebo or 600 mg of A-GPC) began. For the trials baseline performance testing was done and they were given an initial dose (placebo or A-GPC) while in the lab, 1 h later the performance testing (isometric mid thigh pull, upperbody isometric test) was repeated. The subjects were then given 6 days of additional pre-packaged supplement to take (morning and evening). The subjects reported back on day 6 of this period to repeat performance testing after the final dose of supplement. After a 1-week washout period, the subjects repeated the trial with the other treatment. (see Fig. 1).

Flowchart of Experimental Procedures

The treatments consisted of 600 mg daily of A-GPC (AlphaSize®, ChemiNutra, Austin, TX) or a placebo. Both treatments were administered in the same capsules (gel caps) and were the same color (white). The A-GPC capsules were supplied with a certificate of analysis from a third party lab confirming the amount of active ingredient. The placebo capsule consisted of microcrystalline cellulose and magnesium stearate (Nature’s Supplements, Carlsbad, CA USA). Both the participant and researcher were unaware of the identity of either treatment until the end of the study.

The participants were instructed to take doses in the morning and evening that would deliver a total of 600 mg of A-GPC per day and were given the pills in a non-distinct plastic bottle marked only with a code. The participants returned the bottles at the end of the study. The participants reported 100 % compliance with taking the required doses.

Upper body isometric test (UBIST)

The participants were positioned on three elevated platforms with the chest directly suspended over a load cell anchored into the concrete floor of the lab (iLoad Pro, Loadstar Sensors, Fremont CA). The load cell had a capacity of greater than 5000 N and a listed accuracy of 0.25 % for the full scale of measurement. The participants were placed in a push-up style position, with the hands at 150 % of biacromial width, and the elbows at 90° of extension (measured via a goniometer). A thick, non-elastic strap was run over one shoulder and under the opposite shoulder and connected with metal rings to a chain that was tethered to the load cell.

The participants were instructed to keep their backs flat, and push with their hands maximally until told to stop by the researcher. Prior to data capture the load cell was tared to ensure the weight of the load cell and apparatus were accounted for. The researcher started data collection and verbally instructed the participant to “push as hard as possible”. The participants were verbally encouraged during data collection, which was terminated when the force production declined by 50 N from the peak value registered. The load cell was set to capture data at maximum rate (150Hz) and the data was exported and analyzed in JMP 11.0 (SAS Institute Inc, Cary NC). Peak force values were isolated from the data and used for subsequent analysis. The test was performed three times with 5 min rest between assessments. The validity and reliability of this test have been reported in the literature [14].

Statistical analysis
Reliability was assessed for the isometric tests via Intra Class Correlation Coefficients (ICC). Repeated measures Ancovas were used to examine acute (baseline and 1 h post) and chronic (baseline and day 6) changes in performance between treatments. Order of administration (Placebo first, A-GPC first) was entered into the model as a covariate. G*Power software [15] was used to determine effect size (Cohen’s d), all other analyses were performed using a modern statistical software package (JMP, version 11.0 SAS Institute Inc., Cary, NC). Magnitude based inferences were calculated to assist with interpretation of results [16]. The use of magnitude based inference is an attempt to expand the interpretation of findings to include harmful, trivial and beneficial as interpretations, rather than just significant, non-significant [17]. This interpretations in not without controversy [18], as such the authors have chosen to include it alongside a more traditional statistical approach.


Reliability of isometric tests
The isometric tests demonstrated reliability when the triplicate measurements were examined via ICC (range: 0.969–0.984). Measurements were not different at any time points (p > 0.05). Therefore in subsequent analysis the peak value from the set of three measures was used.

Treatment effects—acute
Repeated measures Anova did not reveal any main effects (F = 0.003, p = 0.9584) nor interaction effects of treatment*time (F = 0.114, p = 0.738) for IMTP performance 1 h after the initial dose of A-GPC or Placebo. Similar results were revealed when UBIST performance was analyzed.

Treatment effects—chronic
Repeated measures Anova revealed a significant interaction effect for treatment (A-GPC vs Placebo) by time (baseline, day 6) for IMTP peak performance (F = 3.12, p = 0.04; change from baseline A-GPC: 98.8. ± 236.9 N vs Placebo: −39.0 ± 170.9 N, ES = 0.961). See Fig. 2.

Mean change in Isometric Mid Thigh Pull Peak force after 6 days of supplementation with A-GPC. Error bars represent +/− 1 SEM

For the upper body test the A-GPC treatment trended towards greater change from baseline force production (A-GPC: 50.9 ± 167.2 N Placebo: −14.9 ± 114.9 N) but the interaction effect of treatment by time failed to obtain statistical significance (F = 1.36, p = 0.127). However, this data (see Fig. 3) demonstrated a large effect size (ES = 0.714). This suggests that the variability of the subject’s upper body strength limited the statistical power, however, it if likely that a real effect exists in this data. Magnitude based inferences suggest that the A-GPC was 68.3 % likely beneficial for increasing upper body isometric force and 86.5 % likely beneficial for increasing lower body isometric force production.


The results of this study support the use of A-GPC to enhance strength, particularly in the lower body after 6 days of administration of a 600 mg dose. The literature does not contain controlled experimental data regarding the effects of A-GPC on aspects of human performance directly related to isometric strength, and thus this study represents a first step in the evaluation of this product for such use. The literature does contain some evidence that choline itself is important to consider in regard to endurance performance [1920]. The current literature does contain some information about A-GPC and performance measurements. Jagim et al. [21] reported that a multi-ingredient supplement that contained A-GPC enhanced mean power during a maximal effort sprint test on a non-motorized treadmill but did not produce any changes in counter movement jumping performance peak or mean power. Parker et al. [22] reported acute supplementation with 200 mg or 400 mg of A-GPC did not statistically enhance performance, thought the authors did note a non-significant trend in vertical jump peak power. Acute supplementation with 600 mg of A-GPC has been shown to augment bench press power in a small sample of men with 2 years of training experience [23]. This study is similar in finding to the present investigation in dose of A-GPC administered (600 mg) and suggests enhancements in performance. These previously reported studies on A-GPC vary greatly in design, measurements and administrations. The lack of consistency of doses (200–600 mg) and time of administration (30–90 min prior to activity) may explain the lack of consistent findings. Given the present evidence in the literature, further studies will be needed to confirm the results reported from this experiment, the data represent a promising start and suggest alternative uses for A-GPC.

The potential mechanism by which A-GPC could confer enhanced strength and power performance involves increased bio-available choline, which may result in augmented acetylcholine synthesis in neurons. A-GPC has been shown to augment acetylcholine levels in CNS neurons [6]. Evidence suggests that when administered intramuscularly A-GPC can increase plasma choline levels [24]. A-GPC has also been shown to increase growth hormone secretion though the action of acetylcholine stimulated catecholamine release [25]. This increase in cholinergic tone and associated increased growth hormone release was also reported in old and young subjects after administration of growth hormone releasing hormone in conjunction with A-GPC [26]. In the present investigation it is unlikely a moderate increase in growth hormone over the course of 7 days would have impacted maximum strength although this evidence suggests that longer chronic studies of A-GPC may be warranted as chronic elevations in growth hormone could potentially further augment performance.

While the present study presents positive preliminary findings for A-GPC augmenting strength, it is not without limitation. The present investigation is limited by sample size. The study will need to be replicated with larger study populations and alternative measures of human performance, likely those that have the capacity to measure power not just peak force. Additionally, different does of A-GPC need to be explored to determine any potential dose-response, or lower limit for meaningful effect. We suggest that in vitro studies may also be warranted to demonstrate that A-GPC has the potential to augment neurotransmitter levels in motor neurons. These studies can help to clarify the timing of A-GPC administration, which may in turn result in studies with a more targeted and informed dosing scheme.


The results of the study suggest that A-GPC is effective at increasing lower body force production after 6 days of supplementation. A similar trend was noted in upper body isometric strength, however; this failed to attain statistical significance. Given that in many sports it is understood that a very small change in performance, often times less than 2 %, can significantly affect outcomes it is important to note that the 6 days of A-GPC resulted in greater than a 3 % increase in lower body isometric strength. Sport performance coaches can consider adding A-GPC to the diet of speed and power athletes to potentially enhance muscle performance.


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Oxandrolone, sold under the brand names Oxandrin and Anavar, among others, is an androgen and anabolic steroid (AAS) medication which is used to help promote weight gain in various situations, to help offset protein catabolism caused by long-term corticosteroid therapy, to support recovery from severe burns, to treat bone pain associated with osteoporosis, to aid in the development of girls with Turner syndrome, and for other indications.[4][5][6] It is taken by mouth.[4]

DHT Derivative

Highly anabolic – Low Androgenic/Progesteronic effects
Doesn’t aromatize

FDA-approved for treating bone pain associated with osteoporosis, aiding weight gain following surgery or physical trauma, during chronic infection, or in the context of unexplained weight loss, and counteracting the catabolic effect of long-term corticosteroid therapy.[14][15

Not metabolized in the liver, mainly metabolized in the kidney, minimal liver toxicity

Men’s testosterone levels largely determined by where they grow up

Men who grow up in more challenging conditions where there is potential of exposure to infectious diseases, for example, are likely to have lower testosterone levels in later life than those who spend their childhood in healthier environments, according to new research.

Men’s testosterone levels are largely determined by their environment during childhood, according to new research.

The Durham University-led study suggests that men who grow up in more challenging conditions where there are lots of infectious diseases, for example, are likely to have lower testosterone levels in later life than those who spend their childhood in healthier environments.

The study, published in Nature Ecology and Evolution, challenges the theory that testosterone levels are controlled by genetics or race.

As high testosterone levels potentially lead to an increased risk of prostate enlargement and cancer, the researchers suggest that any screening for risk profiles may need to take a man’s childhood environment into account.

The study found that Bangladeshi men who grew up and lived as adults in the UK had significantly higher levels of testosterone compared to relatively well-off men who grew up and lived in Bangladesh as adults. Bangladeshis in Britain also reached puberty at a younger age and were taller than men who lived in Bangladesh throughout their childhood.

The researchers say the differences are linked to energy investment as it may only be possible to have high testosterone levels if there are not many other demands placed on the body such as fighting off infections.?In environments where people are more exposed to disease or poor nutrition, developing males direct energy towards survival at the cost of testosterone.

The researchers collected data from 359 men on height, weight, age of puberty and other health information along with saliva samples to examine their testosterone levels. They compared the following groups: men born and still resident in Bangladesh; Bangladeshi men who moved to the UK (London) as children; Bangladeshi men who moved to the UK as adults; second-generation, UK-born men whose parents were Bangladeshi migrants; and UK-born ethnic Europeans.

Lead author of the study, Dr Kesson Magid from Durham University’s Department of Anthropology (UK), said: “A man’s absolute levels of testosterone are unlikely to relate to their ethnicity or where they live as adults but instead reflect their surroundings when they were children.”

Men with higher levels of testosterone are at greater risk of potentially adverse effects of this hormone on health and ageing. Very high levels can mean increased muscle mass, increased risk of prostate diseases and have been linked to higher aggression. Very low testosterone levels in men can include lack of energy, loss of libido and erectile dysfunction. The testosterone levels of the men in the study were, however, all in a range that would unlikely have an impact on their fertility.

Co-author Professor Gillian Bentley from Durham University, commented: “Very high and very low testosterone levels can have implications for men’s health and it could be important to know more about men’s childhood circumstances to build a fuller picture of their risk factors for certain conditions or diseases.”

Aspects of male reproductive function remain changeable into adolescence, up to the age of 19 and are more flexible in early rather than late childhood, according to the research. However, the study suggests that, in adulthood, men’s testosterone levels are no longer heavily influenced by their surroundings.

Senior co-author Gillian Bentley and colleagues have also previously found that the environment in which girls grow up can affect their hormone levels, fertility and risk levels for reproductive cancers as adults.

The research was funded by the Economic and Social Research Council (ESRC), the Royal Society and Prostate Cancer UK, and involved researchers from the University of Chittagong (Bangladesh), Durham University (UK), and Northwestern University (USA).

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Materials provided by Durham UniversityNote: Content may be edited for style and length.


  1. Kesson Magid, Robert T. Chatterton, Farid Uddin Ahamed, Gillian R. Bentley. Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant menNature Ecology & Evolution, 2018; DOI: 10.1038/s41559-018-0567-6

Testosterone dose-response in healthy young men



Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18–35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk.

Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose.

We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.

Testosterone regulates many physiological processes, including muscle protein metabolism, some aspects of sexual and cognitive functions, secondary sex characteristics, erythropoiesis, plasma lipids, and bone metabolism. However, testosterone dose dependency of various androgen-dependent processes is not well understood. Administration of replacement doses of testosterone to hypogonadal men and of supraphysiological doses to eugonadal men increases fat-free mass, muscle size, and strength.

Conversely, suppression of endogenous testosterone concentrations is associated with loss of fat-free mass and a decrease in fractional muscle protein synthesis. However, not known are whether testosterone effects on the muscle are dose dependent, or the nature of the testosterone dose-response relationships. Androgen receptors in most tissues are either saturated or downregulated at physiological testosterone concentrations; this leads to speculation that there might be two separate dose-response curves: one in hypogonadal range, with maximal response at low normal testosterone concentrations, and a second in supraphysiological range, representing a separate mechanism of action. However, testosterone dose-response relationships for a range of androgen-dependent functions in humans have not been studied.

Animal studies suggest that different androgen-dependent processes have different androgen dose-response relationships. Sexual function in male mammals is maintained at serum testosterone concentrations that are at the lower end of the male range. However, it is not known whether the low normal testosterone levels that normalize sexual function are sufficient to maintain muscle mass and strength, or whether the higher testosterone concentrations required to maintain muscle mass and strength might adversely affect plasma lipids, hemoglobin levels, and the prostate.

This information is important for optimizing testosterone replacement regimens for treatment of hypogonadal men. Also, for the proposed use of testosterone in sarcopenia associated with ageing and chronic illness, it is important to know whether significant gains in muscle mass and strength can be achieved at testosterone doses that do not adversely affect plasma high-density lipoprotein (HDL) and prostate-specific antigen (PSA) levels.

Therefore, the primary objective of this study was to determine the dose dependency of testosterone’s effects on fat-free mass and muscle performance. We hypothesized that changes in circulating testosterone concentrations would be associated with dose-dependent changes in fat-free mass, muscle strength, and power in conformity with a single linear dose-response relationship and that the dose requirements for maintaining other androgen-dependent processes would be different.

We treated young men with a long-acting gonadotropin-releasing hormone (GnRH) agonist to suppress endogenous testosterone secretion, and concomitantly also with one of five testosterone-dose regimens to create different levels of serum testosterone concentrations extending from subphysiological to the supraphysiological range. The lowest testosterone dose, 25 mg weekly, was selected because this dose had been shown to maintain sexual function in GnRH antagonist-treated men. The selection of the 600-mg weekly dose was based on the consideration that this was the highest dose that had been safely administered to men in controlled studies.




This was a double-blind, randomized study consisting of a 4-wk control period, a 20-wk treatment period, and a 16-wk recovery period. Each participant provided informed consent, approved by the institutional review boards of Drew University and Harbor-UCLA Research and Education Institute.


The participants were healthy men, 18–35 yr of age, with prior weight-lifting experience and normal testosterone levels. These men had not used any anabolic agents and had not participated in competitive sports events in the preceding year, and they were not planning to participate in competitive events in the following year.


Sixty-one eligible men were randomly assigned to one of five groups. All received monthly injections of a long-acting GnRH agonist to suppress endogenous testosterone production. In addition, group 1 received 25 mg of testosterone enanthate intramuscularly weekly;group 2, 50 mg testosterone enanthate; group 3, 125 mg testosterone enanthate; group 4, 300 mg testosterone enanthate; and group 5, 600 mg testosterone enanthate. Twelve men were assigned to group 1, 12 to group 2, 12 to group 3, 12 to group 4, and 13 togroup 5. Testosterone and GnRH agonist injections were administered by the General Clinical Research Center staff to assure compliance.

Nutritional intake.

Energy and protein intakes were standardized at 36 kcal · kg−1 · day−1 and 1.2 g · kg−1 · day−1, respectively. The standardized diet was initiated 2 wk before treatment was started; dietary instructions were reinforced every 4 wk. The nutritional intake was verified by analysis of 3-day food records and 24-h food recalls every 4 wk by use of the Minnesota Nutritional Software.

Exercise stimulus.

The participants were asked not to undertake strength training or moderate-to-heavy endurance exercise during the study. These instructions were reinforced every 4 wk.

Outcome measures.

Body composition and muscle performance were assessed at baseline and during week 20. Fat-free mass and fat mass were measured by underwater weighing and dual-energy X-ray absorptiometry (DEXA, Hologic 4500, Waltham, MA). Total thigh muscle and quadriceps muscle volumes were measured by MRI scanning.

For estimation of total body water, the men ingested 10 g of2H2O, and plasma samples were drawn at −15, 0, 120, 180, and 240 min. We measured2H abundance in plasma by nuclear magnetic resonance spectroscopy, with a correction factor of 0.985 for exchangeable hydrogen. We measured bilateral leg press strength by use of the one-repetition maximum (1-RM) method. A seated leg press exercise with pneumatic resistance (Keiser Sport, Fresno, CA) was used for this purpose. Subjects performed 5–10 min of leg cycling and stretching warm-up and received instruction and practice in lifting mechanics before performing progressive warm-up lifts leading to the 1-RM. Seat position and the ensuing knee and hip angles, as well as foot placement, were measured and recorded for use in subsequent testing.

To ensure reliability in this highly effort-dependent test, the 1-RM score was reassessed within 7 days, but not sooner than 2 days, after the first evaluation. If duplicate scores were within 5%, the higher of the two values was accepted as the strength score. If the two tests differed by >5%, additional studies were conducted, ≥2 days apart but within 7 days, until the two highest scores were within 5%. No subject required >2 days of strength assessment.

We also measured leg power, because power in the lower extremity is strongly related to the performance of functional activities in the elderly. The sarcopenia that accompanies ageing is due in large part to a loss of the fast-twitch type II fibers and the coincident decrease in explosive force. Muscular power is important in performing such daily activities as rising from a chair, climbing stairs, and walking with speed. Leg power was measured with a previously validated Nottingham leg extensor power rig. Subjects performed 10–15 trials of the right leg and hip extension, attempting to generate as much force as possible by accelerating the leg rig’s weighted flywheel from rest.

The power score (in watts) was taken as the highest value observed during these trials with evidence of a plateau. As with the strength tests, power measurements were preceded by a 5- to 10-min warm-up, stretching, and practice. The power tests were repeated within 7 days, but not sooner than 2 days, after the first tests to reduce the effect of familiarization. To minimize test-retest variability, the angle of knee flexion and the seat position were recorded and maintained constant across tests.

Sexual function was assessed by daily logs of sexual activity and desire that were maintained for 7 consecutive days at baseline and during treatment by use of a published instrument. Spatial cognition was assessed by a computerized checkerboard test and mood by Hamilton’s depression and Young’s mania scales.

Adverse experiences, blood counts and chemistries, PSA, plasma lipids, total and free testosterone, luteinizing hormone (LH), sex steroid-binding globulin (SHBG), and insulin-like growth factor I (IGF-I) levels were measured periodically during control and treatment periods. Serum total testosterone was measured by an immunoassay; free testosterone by equilibrium dialysis; LH, SHBG, and PSA by immunoradiometric assays; and IGF-I by acid-ethanol extraction and immunoassay. The sensitivities and intra- and interassay coefficients of variation for hormone assays were as follows: total testosterone (0.6 ng/dl), 8.2 and 13.2%; free testosterone (0.22 pg/ml), 4.2 and 12.3%; LH (0.05 U/l), 10.7 and 13.0%; SHBG (6.25 nmol/l), 4 and 6%; PSA (0.01 ng/ml), 5.0 and 6.4%; and IGF-I (80 ng/ml), 4 and 6%, respectively. These assays have been validated previously.

Statistical analyses.

All variables were examined for their distribution characteristics. Variables not meeting the assumption of a normal distribution were log-transformed and retested. An ANOVA was used to compare change from baseline in outcome measures among the five groups. All outcome measures were analyzed using a paired t-test to detect a non-zero change from baseline within each group. P < 0.05 was considered statistically significant.

To describe the relationship between testosterone concentrations (T) and change in fat-free mass (Y) during testosterone administration, we tested three models: a linear model (Y = a +bT); a logarithmic model, Y = a +b · X, where X = log (T), and a and b represent the intercept and slope, respectively; and a growth model, Y = a/(1 +b · e−k · X). The logarithmic model provided the best fit for the data and was used to model the effects of testosterone concentrations on the change in other outcome variables. The correlations between testosterone concentrations and change in outcome variables are derived from this model. We also modelled the linear dependence of the change in outcome variables on testosterone dose by use of linear regression.




Participant characteristics.

Of 61 men enrolled, 54 completed the study: 12 in group 1, 8 in group 2, 11 in group 3, 10 in group 4, and 13 in group 5. One man discontinued treatment because of acne; other subjects were unable to meet the demands of the protocol. The five groups did not significantly differ with respect to their baseline characteristics (Table1).



All evaluable subjects received 100% of their GnRH agonist injections, and only one man in the 125-mg group missed one testosterone injection.

Nutritional intake.

Daily energy intake and proportion of calories derived from protein, carbohydrate, and fat were not significantly different among the five groups at baseline. There was no significant change in daily caloric, protein, carbohydrate, or fat intake in any group during treatment (data not shown).

Hormone levels.

Serum total and free testosterone levels (Table2), measured during week 16, 1 wk after the previous injection, were linearly dependent on the testosterone dose (P = 0.0001). Serum total and free testosterone concentrations decreased from baseline in men receiving the 25- and 50-mg doses and increased at 300- and 600-mg doses. Serum LH levels were suppressed in all groups. Serum SHBG levels decreased dose dependently at the 300- and 600-mg doses but did not change in other groups. Serum IGF-I concentrations increased dose dependently at the 300- and 600-mg doses (correlation between log testosterone level and change in IGF-I = 0.55, P = 0.0001). IGFBP-3 levels did not change significantly in any group.


Body composition.

Fat-free mass, measured by underwater weighing, did not change significantly in men receiving the 25- or 50-mg testosterone dose, but it increased dose dependently at higher doses (Table3). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log total testosterone concentrations during treatment (r = 0.73, P = 0.0001, see Fig. 2).


Changes in fat-free mass, measured by DEXA scan, were qualitatively similar to those obtained from underwater weighing (Table3, Fig. 1). The measurements of fat-free mass by DEXA were highly correlated with values obtained from underwater weighing (r = 0.94, P < 0.0001)


Fig. 1.

Change in fat-free mass (A), fat mass (B), leg press strength (C), thigh muscle volume (D), quadriceps muscle volume (E), sexual function (F), insulin-like growth factor I (G), and prostate-specific antigen (H). Data are means ± SE. *Significant differences from all other groups (P < 0.05); ❖significant difference from 25-, 50-, and 125-mg doses (P < 0.05); +significant difference from 25- and 50-mg doses (P < 0.05); and ✞significant difference from 25-mg dose (P < 0.05).

To determine whether the apparent changes in fat-free mass by DEXA scan and underwater weighing represented water retention, we measured total body water and compared the ratios of total body water to fat-free mass before and after treatment in each group. The ratios of total body water to fat-free mass by underwater weighing did not significantly change with treatment in any treatment group (Table 3), indicating that the apparent increase in fat-free mass measured by underwater weighing did not represent water retention in excess of that associated with protein accretion.

Fat mass, measured by underwater weighing, increased significantly in men receiving the 25- and 50-mg doses but did not change in men receiving the higher doses of testosterone (Table 3, Fig. 1). There was an inverse correlation between change in fat mass by underwater weighing and log testosterone concentrations (r = −0.60, P = 0.0001, Fig.2).


Fig. 2.

Relationship between serum testosterone concentrations (T) during treatment (week 16) and change in fat-free mass (A), fat mass (B), leg press strength (C), thigh muscle volume (D), quadriceps muscle volume (E), sexual function (F), insulin-like growth factor I (G), and prostate-specific antigen (H). The correlation coefficient, r, was calculated using the logarithmic model, Y = a +b · X, where X = log (T), and a and represent the intercept and slope.

Muscle size.

The thigh muscle volume and quadriceps muscle volume did not significantly change in men receiving the 25- or 50-mg doses but increased dose dependently at higher doses of testosterone (Table4, Fig. 1). The changes in thigh muscle and quadriceps muscle volumes correlated with log testosterone levels during treatment (r = 0.66, P = 0.0001, and r = 0.55, P = 0.0001, respectively, Fig. 2).


Muscle performance.

The leg press strength did not change significantly in the 25- and 125-mg-dose groups but increased significantly in those receiving the 50-, 300-, and 600-mg doses (Table 5). The changes in leg press strength correlated with log testosterone levels during treatment (r = 0.48, P = 0.0005, Fig. 2) and changes in muscle volume (r = 0.54,P = 0.003) and fat-free mass (r = 0.74,P < 0.0001).


Leg power, measured by the Nottingham leg rig, did not change significantly in men receiving the 25-, 50-, and 125-mg doses of testosterone weekly, but it increased significantly in those receiving the 300- and 600-mg doses. The increase in leg power correlated with log testosterone concentrations (r = 0.39,P = 0.0105, Fig. 2) and changes in fat-free mass (r = 0.30, P = 0.0392) and muscle strength (r = 0.42, P = 0.0020).

Behavioural measures.

The scores for sexual activity and sexual desire measured by daily logs did not change significantly at any dose. Similarly, visual-spatial cognition (Table 6) and mood, as assessed by Hamilton’s depression and Young’s manic scales (data not shown), did not change significantly in any group.


Adverse experiences and safety measures.

Hemoglobin levels decreased significantly in men receiving the 50-mg dose but increased at the 600-mg dose; the changes in hemoglobin were positively correlated with testosterone concentrations (r = 0.66, P = 0.0001) (Table7). Changes in plasma HDL cholesterol, in contrast, were negatively dependent on testosterone dose (P = 0.0049) and correlated with testosterone concentrations (r = −0.40, P = 0.0054). Total cholesterol, plasma low-density lipoprotein cholesterol, and triglyceride levels did not change significantly at any dose. Serum PSA, creatinine, bilirubin, alanine aminotransferase, and alkaline phosphatase did not change significantly in any group, but aspartate aminotransferase decreased significantly in the 25-mg group. Two men in the 25-mg group, five in the 50-mg group, three in the 125-mg group, seven in the 300-mg group, and two in the 600-mg group developed acne. One man receiving the 50-mg dose reported decreased ability to achieve erections.




GnRH agonist administration suppressed endogenous LH and testosterone secretion; therefore, circulating testosterone concentrations during treatment were proportional to the administered dose of testosterone enanthate. This strategy of combined administration of GnRH agonist and graded doses of testosterone enanthate was effective in establishing different levels of serum testosterone concentrations among the five treatment groups. The different levels of circulating testosterone concentrations created by this regimen were associated with dose- and concentration-dependent changes in fat-free mass, fat mass, thigh and quadriceps muscle volume, muscle strength, leg power, hemoglobin, circulating IGF-I, and plasma HDL cholesterol. Serum PSA levels, sexual desire and activity, and spatial cognition did not change significantly at any dose. The changes in fat-free mass, muscle volume, leg press strength and power, hemoglobin, and IGF-I were positively correlated, whereas changes in plasma HDL cholesterol and fat mass were negatively correlated with testosterone dose and total and free testosterone concentrations during treatment.

The compliance with the treatment regimen was high. The participants received 100% of their scheduled GnRH agonist and 99% of testosterone injections. Serum LH levels were suppressed in all men, demonstrating the effectiveness of GnRH agonist treatment. The treatment regimen was well tolerated. There were no significant changes in PSA or liver enzymes at any dose. However, long-term effects of androgen administration on the prostate, cardiovascular risk, and behaviour are unknown.

Serum testosterone levels were measured 7 days after the previous injection; they reflect the lowest testosterone levels after an injection. Testosterone concentrations were higher at other time points. Weekly injections of testosterone enanthate are associated with fluctuations in testosterone levels. Although nadir testosterone concentrations were highly correlated with testosterone enanthate dose, it is possible that sustained testosterone delivery by a patch or gel might reveal different dose-response relationships, particularly with respect to hemoglobin and HDL cholesterol.

There were no significant changes in overall sexual activity or sexual desire in any group, including those receiving the 25-mg dose. Testosterone replacement of hypogonadal men improves the frequency of sexual acts and fantasies, sexual desire, and response to visual erotic stimuli. Our data demonstrate that serum testosterone concentration at the lower end of the male range can maintain some aspects of sexual function. Testosterone has been shown to regulate nitric oxide synthase activity in the cavernosal smooth muscle, and it is possible that optimum penile rigidity might require higher testosterone levels than those produced by the 25-mg dose.

This study demonstrates that an increase in circulating testosterone concentrations results in dose-dependent increases in fat-free mass, muscle size, strength, and power. The relationships between circulating testosterone concentrations and changes in fat-free mass and muscle size conform to a single log-linear dose-response curve. Our data do not support the notion of two separate dose-response curves reflecting two independent mechanisms of testosterone action on the muscle. Forbes et al. predicted 25 years ago that the muscle mass accretion during androgen administration is related to the cumulative androgen dose, the product of daily dose and treatment duration. Our data are consistent with Forbes’s hypothesis of a linear relationship between testosterone dose and lean mass accretion; however, we do not know whether increasing the treatment duration would lead to further gains in muscle mass.

In addition, we do not know whether responsiveness to testosterone is attenuated in older men. Testosterone dose-response relationships might be modulated by other muscle growth regulators, such as nutritional status, exercise and activity level, glucocorticoids, thyroid hormones, and endogenous growth hormone secretory status.

Serum PSA levels decrease after androgen withdrawal, and testosterone replacement of hypogonadal men increases PSA levels into the normal range. We did not find significant changes in PSA at any dose, indicating that the lowest dose of testosterone maintained PSA levels. We did not measure prostate volume in this study; therefore, we do not know whether prostate volume exhibits the same relationship with testosterone dose as PSA levels.

Hemoglobin levels changed significantly in relation to testosterone dose and concentration. Testosterone regulates erythropoiesis through its effects on erythropoietin and stem cell proliferation (1. Although modest increments in hemoglobin might be beneficial in androgen-deficient men with chronic illness who are anemic, marked increases in hemoglobin levels could increase the risk of cerebrovascular events and hypertension.

Although men, on average, perform better on tests of spatial cognition than women, testosterone replacement has not been consistently shown to improve spatial cognition in hypogonadal men. We did not find changes in spatial cognition at any dose. The effect size of gender differences in spatial cognition is small; it is possible that our study did not have sufficient power to detect small differences. We cannot exclude the possibility that gender differences in spatial cognition might be due to organizational effects of testosterone and might not respond to changes in testosterone levels in adult men.

Although the mean change in fat-free mass and muscle size correlated with testosterone dose and concentration, there was considerable heterogeneity in response to testosterone administration within each group. These individual differences in response to androgen administration might reflect differences in activity level, testosterone metabolism, nutrition, or polymorphisms in androgen receptor, myostatin, 5-α-reductase, or other muscle growth regulators.

Our data demonstrate that different androgen-dependent processes have different testosterone dose-response relationships. Some aspects of sexual function and spatial cognition, and PSA levels, were maintained by relatively low doses of testosterone in GnRH agonist-treated men and did not increase further with administration of higher doses of testosterone. In contrast, graded doses of testosterone were associated with dose and testosterone concentration-dependent changes in fat-free mass, fat mass, muscle volume, leg press strength and power, hemoglobin, IGF-I, and plasma HDL cholesterol. The precise mechanisms for the tissue- and function-specific differences in testosterone dose dependence are not well understood. Although only a single androgen receptor protein is expressed in all androgen-responsive tissues, tissue specificity of androgen action might be mediated through combinatorial recruitment of tissue-specific coactivators and corepressors.

Testosterone doses associated with significant gains in fat-free mass, muscle size, and strength were associated with significant reductions in plasma HDL concentrations. Further studies are needed to determine whether clinically significant anabolic effects of testosterone can be achieved without adversely affecting cardiovascular risk. Selective androgen receptor modulators that preferentially augment muscle mass and strength, but only minimally affect prostate and cardiovascular risk factors, are desirable.

This study was supported primarily by National Institutes of Health (NIH) Grant 1RO1-AG-14369; additional support was provided by Grants 1RO1-DK-49296, 1RO1-DK-59297–01, Federal Drug Administration Grant ODP 1397, a General Clinical Research Center Grant MO-00425, NIH-National Center for Research Resources-00954, RCMI Grants P20-RR-11145–01 (RCMI Clinical Research Initiative) and G12-RR-03026. BioTechnology General (Iselin, NJ) provided testosterone enanthate, and R. P. Debio (Martigny, Switzerland) provided the GnRH agonist (Decapeptyl)





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Authors – Shalender Bhasin,  Linda Woodhouse, Richard Casaburi, Atam B. Singh, Dimple Bhasin, Nancy Berman, Xianghong Chen, Kevin E. Yarasheski, Lynne Magliano, Connie Dzekov, Jeanne Dzekov, Rachelle Bross, Jeffrey Phillips, Indrani Sinha-Hikim. Ruoquing Shen and Thomas W.

Cardiovascular Toxicity of Illicit Anabolic-Androgenic Steroid Use

Image result for heart anatomy


Background: Millions of individuals have used illicit anabolic-androgenic steroids (AAS), but the long-term cardiovascular associations of these drugs remain incompletely understood.

Methods: Using a cross-sectional cohort design, we recruited 140 experienced male weightlifters 34 to 54 years of age, comprising 86 men reporting ≥2 years of cumulative lifetime AAS use and 54 nonusing men. Using transthoracic echocardiography and coronary computed tomography angiography, we assessed 3 primary outcome measures: left ventricular (LV) systolic function (left ventricular ejection fraction), LV diastolic function (early relaxation velocity), and coronary atherosclerosis (coronary artery plaque volume).

Results: Compared with nonusers, AAS users demonstrated relatively reduced LV systolic function (mean±SD left ventricular ejection fraction = 52±11% versus 63±8%; P<0.001) and diastolic function (early relaxation velocity = 9.3±2.4 cm/second versus 11.1±2.0 cm/second; P<0.001). Users currently taking AAS at the time of evaluation (N=58) showed significantly reduced LV systolic (left ventricular ejection fraction = 49±10% versus 58±10%; P<0.001) and diastolic function (early relaxation velocity = 8.9±2.4 cm/second versus 10.1±2.4 cm/second; P=0.035) compared with users currently off-drug (N=28). In addition, AAS users demonstrated higher coronary artery plaque volume than nonusers (median [interquartile range] 3 [0, 174] mL3 versus 0 [0, 69] mL3P=0.012). Lifetime AAS dose was strongly associated with coronary atherosclerotic burden (increase [95% confidence interval] in rank of plaque volume for each 10-year increase in cumulative duration of AAS use: 0.60 SD units [0.16–1.03 SD units]; P=0.008).

Conclusions: Long-term AAS use appears to be associated with myocardial dysfunction and accelerated coronary atherosclerosis. These forms of AAS-associated adverse cardiovascular phenotypes may represent a previously underrecognized public-health problem.



An estimated 2.9 to 4.0 million Americans have used supraphysiologic doses of illicit anabolic-androgenic steroids (AAS), including testosterone and its synthetic relatives, to gain muscle mass for athletics or personal appearance.1 About 1 million of these individuals, almost all of whom are male, have developed AAS dependence, often leading to years of chronic AAS exposure.2 Illicit AAS use did not become widespread in the general US population until the 1980s.3 Thus, the oldest AAS users, who initiated AAS as youths in the 1980s, are only now reaching middle age, when the adverse effects of long-term use may become apparent. Therefore, these effects remain incompletely understood.

Previous studies have suggested an association between AAS use and cardiovascular disease, with a pathophysiologic link first proposed by early case reports of sudden cardiac death or ischemic stroke among young AAS-using men.46 Subsequently, preclinical studies have shown that AAS exposure at supraphysiologic doses causes dyslipidemia,79stimulates cardiomyocyte hypertrophy,10,11 impairs coronary arterial function,12,13 reduces cardiac β-adrenoreceptor sensitivity,14 potentiates oxidative cardiac stress,15 lowers arrhythmic thresholds,16 and induces myocyte apoptosis.17 Most recently, investigations utilizing noninvasive cardiac imaging in human users have demonstrated preliminary evidence of AAS cardiotoxicity in the forms of myocardial dysfunction,1822 myocardial fibrosis,23 and increased coronary artery calcification.24

In aggregate, data from these earlier studies suggest that illicit AAS use may cause a form of cardiomyopathy characterized by decreased left ventricular (LV) function18,19,2123,25,26 and may increase the risk of atherosclerotic disease.1,7,8,24 To date, definitive associations between AAS exposure and either myocardial or coronary artery disease have yet to be demonstrated in a large human study. To address this issue, we conducted comprehensive cardiovascular evaluations of 86 long-term AAS users and 54 nonusers.



Study Design

We conducted an observational study using a cross-sectional cohort design. We have previously presented the formal properties of this design,27 which has been used both explicitly2831 and implicitly32,33 in many earlier studies. This method identifies a dynamic cohort of individuals drawn from a given source population who in principle could have been enumerated in the past and followed to the present (termed the conceptual cohort). Instead of sampling from the conceptual cohort, one samples in the present from those currently available (the study cohort). With this design, estimates of effects derived from the study cohort are valid with respect to the conceptual cohort, subject to similar conditions for validity as other retrospective designs (eg, retrospective cohort and case-control studies).27 We chose the cross-sectional cohort design because it can efficiently assess the association of outcomes with an uncommon exposure (eg, AAS use) in the same manner that a case-control design can efficiently assess the association of exposures with an uncommon outcome.

For the present study, we sampled from a source population of men who lift weights in gymnasiums and then compared exposed (ie, AAS-using) and nonexposed (ie, non-AAS-using) men from this group. We chose this source population because almost all long-term AAS users are male2 and lift weights regularly.1,34 We did not recruit from sporting venues because most AAS users are not competitive athletes but simply recreational weightlifters.1,35,36

Although this approach minimized the effects of confounding variables inherent to weightlifting, we considered that weightlifting or its associated lifestyle might be associated with specific cardiovascular characteristics. Therefore, in an ancillary study, we recruited a group of nonweightlifting and non-AAS-using men (frequency-matched in age to the weightlifters but never weightlifting >30 minutes per week at any time since 18 years of age), drawn from a roster of potential study volunteers maintained by Massachusetts General Hospital, and compared these nonweightlifters to the subgroup of non-AAS-using weightlifters from the primary study. These 2 groups (AAS nonusers and nonweightlifting and non-AAS-using men) exhibited no scientifically important or statistically significant differences on measures of cardiovascular physiology or pathology (Tables I–III in the online-only Data Supplement), indicating that weightlifting per se, of the duration and intensity selected by our recruitment techniques, was associated with little or no cardiovascular adaptation or pathology.


As described in our previous cross-sectional cohort studies involving AAS,28,29 we advertised in gymnasiums for men 34 to 54 years of age who could bench-press 275 pounds for at least one repetition, currently or in the past to recruit AAS users and nonusers. On telephone screening, advertisement respondents were invited to participate without inquiring about AAS use to minimize selection bias that might arise if they knew in advance the exposure variable of interest. It is notable that AAS are typically ingested in courses or cycles, with deliberate intervening off-drug intervals.1 Thus, our design anticipated that the AAS-using weightlifters would include 2 subgroups: those on-drug and those off-drug at the time of evaluation. We excluded AAS users reporting <2 years of cumulative lifetime AAS exposure. We imposed no specific exclusions for medical or psychiatric history.


Qualifying participants were evaluated at a screening interview, where they provided written informed consent for the study as approved by the McLean Hospital Institutional Review Board. We then obtained demographic data, lifetime exercise history (ie, exercise modalities, duration, intensity, and consistency), and fat-free mass index, a validated measure of muscularity.29,37,38 Psychiatric and substance-use histories were obtained using the Structured Clinical Interview for DSM-IV.39 We next assessed history of AAS use, including age at onset of use, maximum weekly dose of AAS (calculated as mg of testosterone equivalent),40 cumulative lifetime years of use, lifetime dose ingested, time of most recent use, and types and doses of AAS taken during most recent (or current) use. We also assessed use of other performance-enhancing substances, including over-the-counter substances (eg, creatine) and illicit drugs (eg, human growth hormone, clenbuterol). Participants then provided urine samples to be tested for AAS29,38 and head or axillary hair to be tested for opiates, cannabis, phencyclidine, amphetamines, and cocaine.29,38 Men showing urine or hair findings inconsistent with their reported substance-use history were excluded from further evaluation. We also excluded men denying AAS use but exhibiting a fat-free mass index >26 kg/m2 together with body fat <10% based on previous work showing that a combination of leanness and muscularity beyond these limits strongly suggests surreptitious AAS use.37,41

Men found to qualify after the screening interviews were then referred for a cardiovascular evaluation performed by investigators blinded to AAS status to characterize LV structure, LV function, and coronary atherosclerosis. Two-dimensional transthoracic echocardiography (iE33, Philips Medical Systems) was used to develop profiles of LV structure and function as previously detailed by our group.42 The primary outcome variables for LV systolic and diastolic function were left ventricular ejection fraction (LVEF) as measured using the modified biplane method of disks43 and early LV relaxation velocity (E´; average of basal septum and lateral wall values44), respectively. Second, coronary computerized tomography angiography (CTA) was performed using a dual-source 128-slice CT scanner (Definition Flash, Siemens Medical Systems), with a primary outcome variable of total coronary artery plaque volume.45 Secondary CTA measures included number of atherosclerotic coronary segments, degree of stenosis of the worst segment, and Agatston calcium score.46 Detailed echocardiographic and CTA methods are provided in the online-only Data Supplement.

Statistical Analysis

Based on our pilot data18 and those of others,1,24 our primary hypotheses were that AAS users would exhibit: (1) decreased LVEF, (2) decreased E´, and (3) increased coronary plaque volume compared with non-AAS-using weightlifters. We further hypothesized that within the AAS-user group, greater pathology on these variables would be associated with currency of AAS use (ie, on-drug versus off-drug status at the time of evaluation) and with cumulative lifetime duration of AAS exposure.

Using linear regression, we estimated the mean difference between groups on the outcome measures (technically, the estimated mean difference was the estimated beta coefficient corresponding to group status in a linear model that also included a set of covariates and was fitted using ordinary least-squares linear regression). To control for confounding, our primary analysis adjusted for a set of plausible confounding variables including: age; race/ethnicity (modeled as black versus all others); history of tobacco use, cocaine dependence, and alcohol dependence; weekly hours of aerobic activity in the last 10 years (modeled in tertiles of the distribution); and reported family history of coronary artery disease as defined by the presence of angina, myocardial infarction, angioplasty/stent, or coronary bypass surgery in a first-degree relative. For echocardiographic measures, we additionally adjusted for body surface area as calculated by the Mosteller formula. To explore the relationship between LV mass, a potentially important mechanistic mediator of LV functional impairment, and our primary functional outcome variables, we performed post hoc analyses examining the association of LV mass index with LVEF and E´ among AAS users and nonusers. Specifically, we used linear regression with the same set of potential confounding variables and the addition of a term for AAS-user versus nonuser group status to examine the relationships between LV mass index (LV mass in g/body surface area in m2) and the primary cardiac function outcomes. Also, because resting heart rate could influence cardiac functional outcomes, we performed additional analyses of the primary cardiac functional outcomes by adding resting heart rate as a covariate. Note that heart rate may influence functional outcomes and also might be affected by current AAS use. In the latter eventuality, the estimated mean difference between groups adjusted for resting heart rate would likely be biased toward the null (ie, would potentially represent an overadjustment), thus producing an underestimate of the effect of AAS use.

In subsequent sensitivity analyses assessing the influence of adjustments using alternative sets of potential confounders, we repeated all comparisons (1) with no adjustment for any covariates, (2) with the adjustment covariates reduced to only age and race (plus body surface area for echocardiographic measures), and (3) with the adjustment covariates augmented to include hypertension and dyslipidemia (as defined in Tables X-X in the online-only Data Supplement). It is important to note that the augmented set of covariates would be expected to yield underestimates of the effect of AAS use because hypertension and dyslipidemia are often effects of AAS use,1,7,9,47 and adjustment for these variables would consequently adjust out effects of AAS mediated by these variables.

Because the distributions of coronary CTA measures contained many zero values (ie, no measurable coronary artery disease), we used ranked data for these analyses. Within the AAS-user group, we evaluated the association of all outcome measures with duration of use and currency of use (ie, on-drug versus off-drug) using linear regression with adjustment for the same set of covariates. To aid in interpretation of comparisons between groups and associations within groups involving rank-transformed data, we used standard deviation (SD) units to express the estimated difference in ranks for binary predictor variables and the estimated change in ranks for each 1-unit increase in continuous predictor variables. The SD units were calculated by dividing the estimated beta coefficient for the predictor variable from the linear regression model by the SD of the ranks for the entire sample used for a given model.

All models were fitted using Stata 14.1 software (StataCorp). We set α=0.05, 2-tailed. We did not perform corrections for multiple comparisons, so that the statistical significance of P-values for secondary outcomes, particularly those between 0.01 and 0.05, should be interpreted with caution.





We screened 165 men, of whom 25 were excluded from medical evaluation as follows: 10 qualified for participation but withdrew before medical evaluation (9 AAS users, 1 nonuser), 12 reported AAS use of <2 years duration, and 3 showed findings on drug testing or fat-free mass index inconsistent with their self-reports. The remaining sample comprised 86 AAS users and 54 nonusers. Among the AAS users, 58 (67%) were on-drug and 28 (33%) off-drug at evaluation. The off-drug users had last used AAS a median (interquartile range) of 15 (5, 70) months before evaluation.


AAS users and nonusers were similar on most characteristics (Table 1), but users showed higher body mass index and fat-free mass index, consistent with known effects of AAS.



Cardiometabolic Features

Compared with nonusers, AAS users displayed higher blood pressure (mean±SD systolic, 118±11 versus 115±10 mm Hg; diastolic, 76±9 versus 72±9 mm Hg) and a higher prevalence of dyslipidemia (N [%] with low-density lipoprotein cholesterol >160 mg/dL: 20 [23%] versus 7 [13%]).


Cardiac Structure and Function

For the primary outcome variables of LVEF and E´, AAS users showed significant deficits compared with nonusers (Table 2). In models further adjusted for resting heart rate, the estimated mean differences between groups were reduced by 15%, and this change had no impact on the statistical significance of these findings (P<0.001 for both). On other measures, AAS users exhibited higher LV mass index, thicker LV walls, and more concentric LV geometry than nonusers. On subsequent analyses examining the association of outcomes with duration and currency of AAS use, currency of use was strongly associated with greater pathology (Figure 1 and Table IV in the online-only Data Supplement). Specifically, 41 (71%) of the 58 on-drug users showed LVEFs falling below the normal threshold of 52%,43 whereas off-drug users showed largely normal LVEFs. Twenty-nine (50%) on-drug users fell below the normal E´ threshold of 8.5 cm/second,44 with off-drug users showing only partially normalized E´. Similar associations with currency of AAS use were found across other echocardiographic measures (Table IV in the online-only Data Supplement). In contrast, we found no significant associations between duration of AAS use and the primary outcome variables (for each additional 10 years of AAS exposure, the estimated mean change [95% confidence interval] in LVEF was −3.3% [−8.3 to 1.6], P=0.19; and the estimated mean change in E´ was 0.1 cm/second [−1.0 to 1.2 cm/second], P=0.90).


Left ventricular systolic and diastolic function in anabolic-androgenic steroid users and comparison nonusers. A, Boxplots of left ventricular ejection fraction in anabolic-androgenic steroid (AAS) users (N=86), shown as an entire group (Left) and as subgroups of individuals who were on-drug (N=58) and off-drug (N=28) at the time of evaluation (Middle); and nonusers (N=54) (Right). On this variable, the estimated mean difference (95% confidence interval) between on-drug and off-drug AAS users, adjusted for covariates as described in the text, is −9.5% (−13.8 to −5.2), P<0.001; for on-drug AAS users versus nonusers, the difference is −13.6% (−17.3 to −9.8), P<0.001; and for off-drug AAS users versus nonusers, the difference is −4.1% (−8.6 to 0.3), P=0.072. B, Left ventricular early relaxation velocity in the same 4 groups. On this variable, the mean difference between on-drug and off-drug AAS users is −1.1 (−2.1 to −0.1) cm/second, P=0.035; for on-drug AAS users versus nonusers, the difference is −2.2 (−3.1 to −1.4) cm/second, P<0.001; and for off-drug AAS users versus nonusers, the difference is −1.1 (−2.2 to −0.1) cm/second, P=0.035.

Because LVEF and E´ differed by group (ie, AAS user versus nonuser) and by subgroup based on currency of use (ie, current versus past AAS users), we further tested for interactions of group and subgroup status with LV mass index for each of these associations and found evidence for a significant interaction with AAS user group status (P=0.046 and P=0.016 for LVEF and E´, respectively) but not for currency of use among AAS users (P=0.21 and P=0.86, respectively). Therefore, we assessed the associations separately for AAS users and nonusers. Examining LVEF, among AAS users, a significant association occurred between increased LV mass index and decreased LVEF (estimated mean change [95% confidence interval] in LVEF for each 10 g increase in LV mass index −1.6% [−2.4 to −0.8], P<0.001). In contrast, among the nonusers, no significant association occurred between LV mass index and LVEF (estimated mean change in LVEF for each 10 g increase in LV mass index –0.2% [–1.5 to 1.2], P=0.80). Examining E´, among AAS users, a significant association occurred between increased LV mass index and reduced E´ (estimated mean change in E´ for each 10 g increase in LV mass index −0.31 cm/second [−0.49 to −0.13 cm/second], P<0.001). Among nonusers, the relationship was of approximately equal magnitude but in the opposite direction, with a significant association between increased LV mass index and increased E´ (estimated mean change in E´ for each 10 g increase in LV mass index 0.36 cm/second [0.04–0.68 cm/second], P<0.001).

Coronary Artery Atherosclerosis

AAS users showed significantly higher coronary plaque volume than nonusers (Table 3 and Figure 2). On examining the association of CTA measures with currency and duration of AAS use, we found strong associations between lifetime duration of use on all angiographic measures of coronary pathology (Table 4 and Figure 3). However, we found no significant association between currency of use and plaque volume (estimated mean difference between on-drug and off-drug users in ranks: −0.07 SD units [−0.56 to 0.41], P=0.76). It is notable that 3 (3%) AAS users had experienced earlier myocardial infarctions because of underlying atherosclerotic disease, documented by cardiac catheterization, occurring at 38 years of age (ST-segment myocardial infarction with complete occlusion of left anterior descending artery), 43 years of age (non-ST-segment myocardial infarction with 99% occlusion of both the right coronary and left circumflex coronary arteries), and 46 years of age (ST-elevation myocardial infarction with complete occlusion of a second obtuse marginal artery) and after 17, 11, and 5 years of cumulative lifetime AAS exposure, respectively. In addition, 1 AAS user had presented at 42 years of age after 20 years of cumulative lifetime AAS exposure with congestive heart failure and underwent stenting of the left circumflex and first obtuse marginal arteries. None of the 54 nonusers had a history of myocardial infarction or stenting.


Figure 2.

Distribution of computed tomography coronary angiography measures in anabolic-androgenic steroid users and nonusers. Histograms displaying distribution of coronary artery plaque volume, degree of stenosis for most severe stenosis, number of diseased coronary artery segments, and coronary artery calcium for anabolic-androgenic steroid (AAS) users (N=84) and nonusers (N=53). The histograms for plaque volume and calcium score include for men with imputed values, as described in the footnote to Table 3.



Figure 3.

Relationship between coronary artery plaque volume and cumulative lifetime duration of anabolic-androgenic steroid exposure. Scatter plot displaying coronary artery plaque volume and cumulative years of lifetime anabolic-androgenic steroid (AAS) exposure, with a median spline (red line) fitted to the data to aid in the visualization of the relationship between these variables. Because of the highly right-skewed distributions, the data are presented on a transformed scale (square root transformation for coronary artery plaque volume; logarithmic transformation for cumulative years of AAS use).

Sensitivity Analyses

Assessing the influence of alternative sets of potential confounders, using models with both reduced and augmented sets of covariates, we obtained results similar to those of the primary analysis, with <15% change in the estimates for the primary outcomes and preservation of statistical significance for all results identified as such in the primary analysis (Tables V–VII in the online-only Data Supplement). We also reanalyzed the echocardiographic findings while omitting the 3 men with previous myocardial infarctions. This analysis produced negligible changes in the findings, with the estimated mean differences between users and nonusers on the 2 primary outcome variables changing by <2% when these 3 men were excluded.



Illicit AAS use is widespread, but its long-term adverse effects remain poorly understood. A growing literature, largely comprised of case reports and small observational studies, suggests that AAS use may cause cardiovascular disease. We undertook the present study to examine cardiovascular health measures among long-term AAS users and otherwise similar nonusers with the following 4 key findings. First, AAS users demonstrated substantial impairment of LV systolic function as assessed by LVEF and longitudinal strain. This finding was driven almost entirely by those AAS users who were on-drug at the time of evaluation, suggesting that LV dysfunction may be a dynamically related to AAS-use patterns. Second, AAS users also showed impaired LV diastolic dysfunction, both relative to nonusers and also as defined by current diagnostic criteria.44 In contrast to systolic function, which appeared largely normal among off-drug AAS users, LV diastolic function was impaired in both on-drug and off-drug users, suggesting a more permanent form of acquired pathology. Third, AAS users had significantly more LV hypertrophy, as reflected by LV mass index, than nonusers, suggesting an anabolic effect on cardiac muscle mass. In addition, the magnitude of LV hypertrophy among AAS users was directly related to the degrees of both systolic and diastolic function, suggesting a mechanistic link between LV hypertrophy and functional deterioration. Fourth, AAS use was associated with increased coronary atherosclerosis, and the severity of atherosclerotic disease was strongly associated with cumulative lifetime duration of AAS use. In aggregate, our findings suggest that long-term AAS use is associated with adverse cardiovascular phenotypes characterized by both myocardial pathology and coronary artery pathology, which may represent a clinically substantial and largely unrecognized public health problem.

Several scientific and clinical implications emerge from this study. First, improved identification of the adverse cardiovascular associations of AAS use may deter potential future users. Second, clinicians may be better informed about the potential adverse cardiovascular effects of AAS. It is important to note that participants in the present study were not elite or professional athletes, the small subset of the general population most commonly tied to AAS exposure, but rather a sample of middle-age men representing a reasonably broad socioeconomic and racial/ethnic distribution. Thus, when comparable men are found to have impaired LV function or premature coronary artery disease, it seems prudent for clinicians to now include AAS use on the differential diagnosis of possible causes. Third, data derived from the present cross-sectional study provide a foundation for critical future work. The hypothesis that some cardiovascular phenotypes associated with AAS use may wax and wane with drug exposure (eg, LV systolic dysfunction) while others may be more permanent, perhaps irreversible (eg, LV diastolic dysfunction and coronary atherosclerosis), deserves rigorous assessment. Longitudinal studies of illicit AAS users with hard clinical end points, and with interventions to impact drug exposure patterns and treat detected disease, are also of importance.


Several threats regarding the internal validity of this study, as previously delineated in general for cross-sectional cohort studies,27,29 deserve consideration. First, bias might arise through exiting from the underlying conceptual cohort (ie, becoming unavailable for study in the present) that is differential with respect to exposure status. For example, AAS users might be more likely than nonusers to develop cardiovascular morbidity, stop weightlifting, and hence be unavailable for recruitment. Any resulting bias, however, would likely underestimate the effects of AAS use. Second, as in all observational studies, we cannot exclude residual confounding. However, given the lack of confounding seen with our measured potential confounders—as evidenced by similar estimates in sensitivity analyses using both reduced and augmented sets of potential confounders—it is unlikely that substantial residual bias remains because of unmeasured confounders. Third, because both AAS users and nonusers were weightlifters, the effects of AAS might be clouded if weightlifting contributed to cardiovascular pathology. However, our ancillary study comparing non-AAS-using weightlifters with nonweightlifters demonstrated that weightlifting alone (of the duration and intensity exhibited by our sample) had little effect on cardiac adaptation or pathology. Fourth, bias could arise from measurement error, particularly in the exposure variables (eg, misclassifying surreptitious AAS users as nonusers or inaccurately assessing the type, duration, dose, and currency of use). In particular, AAS users provided retrospective accounts, often spanning many years of time, of the use of illicit drugs of uncertain potency or authenticity. As such, estimates of participants’ lifetime duration of AAS use and total lifetime AAS dose were only approximations. The effect of these various sources of measurement error would be expected to be differential for between-group comparisons (because of the potential for inclusion of surreptitious AAS users in the nonuser group and the much less likely inclusion of individuals falsely reporting AAS use in the user group) and random for within-group comparisons among AAS users (because of the low likelihood of an association between cardiac outcomes and error in the predictor variables). Both of these sources would likely bias results toward the null, thereby yielding an underestimate of the effects of AAS use.

Potential threats to external validity (generalizability) also require consideration. First, we recruited AAS users from gymnasiums. Thus, our results might not generalize to other AAS-using groups (eg, elite athletes). However, most AAS users are recreational weightlifters, and thus our results likely generalize to the population of AAS users of greatest public health importance. Second, despite the demographic diversity of our sample, white non-Hispanic men were overrepresented, and therefore our results might not generalize to the full racial/ethnic spectrum of AAS users. Overall, however, these potential threats to internal and external validity appear modest. Thus, our findings likely represent reasonably unbiased estimates of the associations of AAS exposure with adverse cardiovascular phenotypes.



Our findings suggest that AAS use is associated with LV dysfunction and premature coronary artery disease. These findings may inform public health initiatives to curb drug exposure and provide clinicians with information that will translate into improved patient care.


Sources of Funding

This study was supported by grant R01 DA-029141 from the National Institute on Drug Abuse (to Drs Pope, Kanayama, Hudson, Baggish, Weiner, and Hoffmann).



Drs Pope, Kanayama, Hudson, Baggish, Weiner, and Hoffmann have received grant support for this study from the National Institute on Drug Abuse. Dr Hoffmann has received grants from HeartFlow and KOWA. Dr Pope has received expert witness fees for cases involving anabolic-androgenic steroids from the McNeil, Leddy, & Sheahan Law Firm and the US District Attorney for Eastern New York. Drs Kanayama and Weiner report no additional conflicts of interest. Dr Lu reports no conflicts of interest.



Clinical Perspective

What Is New?

  • Millions of individuals have used anabolic-androgenic steroids (AAS) to gain muscle for athletic purposes or personal appearance.

  • Preliminary findings have suggested that long-term AAS exposure may lead to both cardiomyopathy and atherosclerotic disease, but previous studies have been small or methodologically limited.

  • Here, in the first large controlled study of its type, we demonstrate that long-term AAS use is associated with both systolic and diastolic myocardial dysfunction, as well as coronary atherosclerosis.

  • Systolic functional deficits appear to recover after AAS discontinuation, whereas diastolic dysfunction appears less reversible.

  • Atherosclerotic disease appears strongly associated with lifetime duration of AAS exposure.

What Are the Clinical Implications?

  • Widespread illicit AAS use first appeared in the general population in the 1980s, and thus most AAS users are still young or middle-aged today.

  • Thus, when clinicians encounter young or middle-age men who exhibit evidence of unexplained left ventricular dysfunction or premature coronary artery disease, the possibility of cardiotoxicity because of long-term AAS use should be considered in the differential diagnosis.

  • It is notable that ≈80% of contemporary AAS users are simply recreational weightlifters rather than competitive athletes, and thus the possibility of AAS use should be considered even in individuals who do not identify themselves as athletes.

The Effects of Mild Cycles



Note: I’m not an advocate of steroid use. The average guy should be able to get really good results with intelligently designed, drug-free training. The risks, including legal problems, usually aren’t worth it unless you’re an actor or professional athlete, where millions of dollars are at stake.

Original article

The Debate

The mainstream media propogates some incredibly ignorant hype and hysteria regarding anabolic steroids. They’d have you believe a single dianabol tablet will turn you into a roid-raged zombie. T Nation readers probably have more informed views. You probably know that “roid rage” is largely a myth, and you know that there’s a big difference between use and abuse.

Still, the debates rage on, even if the users do not. What is a “mild,” “moderate,” or “intelligent” cycle of steroids? What effects does it really have? Some say that the effects are profound. Others will say that mild usage produces minimal results. The answer? Let’s look to science.


The Study

A study from 2007 seems to have slipped under the radar, and it provides insights to many of our questions.

The primary intent of the study was to see if a steroid cycle could make measurable changes in size and strength in less than 6 weeks. The answer seems like an obvious “yes,” and there’s a plethora of anecdotal evidence to confirm this. But this double-blind, placebo-controlled study answers the question more objectively.

Sixteen men were match-paired, with one group receiving testosterone enanthate injections and the other receiving a placebo. Their strength and lean mass were tested after training for three, then six weeks. Here are some of the things we can learn from it:


1 – Even a modest steroid cycle will produce results.

The subjects who received steroids did get a supraphysiologic dose of testosterone, meaning the dose was higher than what the body would normally produce or higher than what one would receive from testosterone replacement therapy. For comparison:

  • A male receiving TRT from his doctor may get around 100 mg. per week to bring his T levels up to “high normal.”
  • A competitive bodybuilder may use 1000 to 3000 mg. of testosterone or testosterone analogs per week.
  • In this study, participants not in the placebo group received 275-315 mg. per week depending on body weight, which is about three times the normal or natural production. This is however less than the dosage of a typical “beginner” steroid cycle, which might be around 500-600 mg/week.

There are two schools of thought when it comes to first-time steroid cycles. One is to go ahead and do a full-fledged, higher dose cycle in order to maximize gains and take advantage of “virgin” receptor sites. The other is to do a more moderate dosage (like the one used in this study) in order to make gains while minimizing side effects.

This study shows that you can make gains on a more moderate cycle if that’s the route you want to take. There’s quite a bit of anecdotal evidence of guys getting good results from a 250 mg/week cycle.


2 – Steroids work, and they work quickly.

The primary purpose of the study was to see if anything significant happened within the first 3-6 weeks of a cycle compared to a placebo. The answer was a resounding “yes.”

Those who were taking testosterone enanthate saw their bench press increase beyond their placebo-using peers at week three and week six. But what was remarkable was the increase in body mass: the steroid users were over TEN pounds heavier than the placebo group after just six weeks.

Based on this evidence, it’s amusing to hear people minimize the benefit of these drugs. Use whatever you want, but let’s be honest about the difference between natural and “enhanced” trainees.


3 – Lower dosage steroid/testosterone cycles are not always easily detected.

Here’s another really intriguing finding from this study: 4 out of 9 testosterone-using subjects tested negative for steroid use under the WADA urinary testosterone/epitestosterone (T/E) ratio tests.

Remember, none of these guys were doing anything to try to “beat” the urine test. They weren’t even sure if they were getting testosterone or a placebo. It makes you wonder just how many professional athletes have used these kind of cycles in order to gain an advantage in competition while avoiding detection.


A Little Beyond Natural

You may have considered doing a steroid cycle in order to get faster results in the gym, to go beyond your natural genetic potential, or to offset the effects of aging. A lower dose cycle (250-300 mg of testosterone a week) may give you the best of both worlds: significant results with lower risks of side effects. It’s always good to know your options.

As always, the best advice is to see what you can accomplish naturally before making a decision about steroids. Find a solid workout program and spend a few years building your foundation before you even think about taking your body beyond its natural potential.





  1. J Strength Cond Res. 2007 May;21(2):354-61. The effect of short-term use of testosterone enanthate on muscular strength and power in healthy young men. Rogerson S1, Weatherby RP, Deakin GB, Meir RA, Coutts RA, Zhou S, Marshall-Gradisnik SM.


Anabolic Overview 3 – Free vs. Bound Testosterone

A very small amount of testosterone actually exists in a free state, where interaction with cellular receptors is possible. The majority will be bound to the proteins SHBG (sex hormone binding globulin, also referred to as sex steroid binding globulin and testosterone-estradiol binding globulin) and albumin, which temporarily prevent the hormone from exerting activity. Steroid hormones actually bind much more avidly to SHBG than albumin (with approximately 1,000 times greater affinity), however albumin is present in a level 1,000 times greater than SHBG. Therefore, the activity of both binding proteins in the body is relatively equal. The distribution of testosterone in men is typically 45% of testosterone bound to SHBG, and about 53% bound to albumin. The remaining 2% of the average blood concentration exists in a free, unbound state. In women, the percentage of free testosterone is lower, measured to be approximately 1%. A binding protein called ABP (androgen binding protein) also helps to mediate androgen activity in the reproductive system, although since it is found exclusively in these tissues, it is not relevant to muscle growth. The level of free testosterone available in the blood is likewise an important factor mediating its activity, as only a small percentage is really active at any given time. It must also be noted that as we alter testosterone to form new anabolic/androgenic steroids, we also typically alter the affinity in which the steroid will bind to plasma proteins. This is an important consideration, as the higher percentage we have of free hormone, the more active the compound should be on a milligram for milligram basis. And the variance can be substantial between different compounds.

For example, Proviron® (1-methyl dihydrotestosterone) binds with SHBG many times more avidly than testosterone,19 while mibolerone (7,17 dimethyl-nandrolone) and bolasterone (7,17 dimethyl- testosterone) show virtually no affinity for this protein at all (clearly the reason these steroids are such potent androgens). The level of SHBG present in the body is also variable, and can be altered by a number of factors. The most prominent seems to be the concentration of estrogen and thyroid hormones present in the blood. We generally see a reduction in the amount of this plasma binding protein as estrogen and thyroid content decreases, and a rise in SHBG as they increase. A heightened androgen level due to the administration of anabolic/androgenic steroids has also been shown to lower levels of this protein considerably. This is clearly supported by a 1989 German study, which noted a strong tendency for SHBG reduction with the oral anabolic steroid stanozolol (Winstrol®).20 After only 3 days of administering a daily dose of .2mg/kg body-weight (about 18mg for a 200lb man), SHBG was lowered nearly 50% in normal subjects. Similar results have been obtained with the use of injectable testosterone enanthate; however, milligram for milligram, the effect of stanozolol was much greater in comparison. The form of administration may have been important in reaching this level of response. Although the injectable was not tried in the German study, we can refer to others comparing the effect of oral vs. transdermal estrogen.21 These show a much greater response in SHBG levels when the drug is given orally. This is perhaps explained by the fact that SHBG is produced in the liver. Therefore, we cannot assume that injectable Winstrol® (or injectable steroids in general) will display the same level of potency in this regard. Lowering the level of plasma binding proteins is also not the only mechanism that allows for an increased level of free testosterone. Steroids that display a high affinity for these proteins may also increase the level of free testosterone by competing with it for binding. Obviously if testosterone finds it more difficult to locate available plasma proteins in the presence of the additional compound, more will be left in an unbound state. A number of steroids including dihydrotestosterone, Proviron®, and Oral-Turinabol (chlorodehydromethyltestosterone) display a strong tendency for this effect. If the level of free-testosterone can be altered by the use of different anabolic/androgenic steroids, the possibility also exists that one steroid can increase the potency of another through these same mechanisms. For\ example, Proviron® is a poor anabolic, but its extremely high affinity for SHBG might make it useful by allowing the displacement of other steroids that are more active in these tissues. We must not let this discussion lead us into thinking that binding proteins serve no valuable function. In fact they play a vital role in the transport and functioning of endogenous androgens. Binding proteins act to protect the steroid against rapid metabolism, ensure a more stable blood hormone concentration, and facilitate an even distribution of hormone to various body organs. The recent discovery of a specific receptor for Sex Hormone Binding Globulin (SHBG-R) located on the membrane surface of steroid responsive body cells also suggests a much more complicated role for this protein than solely hormone transport. However, it remains clear that manipulating the tendency of a hormone to exist in an unbound state is an effective way to alter drug potency.


19. Endocrinology 114(6):2100-06 1984 June,“Relative Binding Affinity of Anabolic-
Androgenic Steroids…”, Saartok T; Dahlberg E; Gustafsson JA
20. Sex Hormone-Binding Globulin Response to the Anabolic Steroid Stanozolol: Evidence
for Its Suitability as a Biological Androgen Sensitivity Test. J Clin Endocrinol Metab
21. Twenty two weeks of transdermal estradiol increases sex hormone-binding globulin in
surgical menopausal women. Eur J Obstet Gynecol Reprod Biol 73: 149-52,1997

Anabolic Overview 2 – Direct and Indirect Anabolic Effects

Although testosterone has been isolated, synthesized, and actively experimented with for many decades now, there is still some debate today as to exactly how steroids affect muscle mass. At this point in time, the primary mode of anabolic action with all anabolic/androgenic steroids is understood to be direct activation of the cellular androgen receptor and increases in protein synthesis. As follows, if we are able to increase our androgen level from an external source by supplementing testosterone or a similar anabolic steroid, we can greatly enhance the rate in which protein is retained by the muscles. This is clearly the primary cause for muscle growth with all anabolic/androgenic steroids. As our hormone levels increase, so does androgen receptor activation, and ultimately the rate of protein synthesis. But other indirect mechanisms could possibly affect muscle growth outside of the normally understood androgen action on protein synthesis. An indirect mechanism is one that is not brought about by activation of the androgen receptor, but the affect androgens might have on other hormones, or even the release of locally acting hormones or growth promoters inside cells (perhaps mediated by other membrane bound receptors). We must remember also that muscle mass disposition involves not only protein synthesis, but also other factors such as tissue nutrient transport and protein breakdown. We need to look at androgenic interaction with these factors as well to get a complete picture. Concerning the first possibility, we note that studies with testosterone suggest that this hormone does not increase tissue amino acid transport.9 This fact probably explains the profound synergy bodybuilders have noted in recent years with insulin, a hormone that strongly increases transport of nutrients into muscle cells. But regarding protein breakdown, we do see a second important pathway in which androgens might affect muscle growth.

Anti-Glucocorticoid Effect of Testosterone

Testosterone (and synthetic anabolic/androgenic steroids) may help to increase mass and strength by having an anti-catabolic effect on muscle cells. Considered one of the most important indirect mechanisms of androgen action, these hormones are shown to affect the actions of another type of steroid hormone in the body, glucocorticoids (cortisol is the primary representative of this group).10 Glucocorticoid hormones actually have the exact opposite effect on the muscle cell than androgens, namely sending an order to release stored protein. This process is referred to as catabolism, and represents a breaking down of muscle tissue. Muscle growth is achieved when the anabolic effects of testosterone are more pronounced overall than the degenerative effects of cortisol. With intense training and a proper diet, the body will typically store more protein than it removes, but this underlying battle is always constant. When administering anabolic steroids, however, a much higher androgen level can place glucocorticoids at a notable disadvantage. With their effect reduced, fewer cells will be given a message to release protein, and more will be accumulated in the long run. The primarily mechanism believed to bring this effect out is androgen displacement of glucocorticoids bound to the glucocorticoid receptor. In fact, in-vitro studies have supported this notion by demonstrating that testosterone has a very high affinity for this receptor,11 and further suggesting that some of its anabolic activity is directly mediated through this action.12 It is also suggested that androgens may indirectly interfere with DNA binding to the glucocorticoid response element.13 Although the exact underlying mechanism is still in debate, what is clear is that steroid administration inhibits protein breakdown, even in the fasted state, which seems clearly indicative of an anti-catabolic effect.

Testosterone and Creatine

In addition to protein synthesis, a rise in androgen levels should also enhance the synthesis of creatine in skeletal muscle tissues.14 Creatine, as creatine phosphate (CP), plays a crucial role in the manufacture of ATP (adenosine triphosphate), which is a main store of energy for the muscles. As the muscle cells are stimulated to contract, ATP molecules are broken down into ADP (adenosine diphosphate), which releases energy. The cells will then undergo a process using creatine phosphate to rapidly restore ADP to its original structure, in order to replenish ATP concentrations. During periods of intense activity, however, this process will not be fast enough to compensate and ATP levels will become lowered. This will cause the muscles to become fatigued and less able to effort a strenuous contraction. With increased levels of CP available to the cells, ATP is replenished at an enhanced rate and the muscle is both stronger and more enduring. This effect will account for some portion of the early strength increases seen during steroid therapy. Although perhaps not technically considered an anabolic effect as tissue hypertrophy is not a direct result, androgen support of creatine synthesis is certainly still looked at as a positive and growth-supporting result in the mind of the bodybuilder.

Testosterone and IGF-1

It has also been suggested that there is an indirect mechanism of testosterone action on muscle mass mediated by Insulin-Like Growth Factor. To be more specific, studies note a clear link between androgens and tissue release of,15 and responsiveness to, this anabolic hormone. For example, it has been demonstrated that increases in IGF-1 receptor concentrations in skeletal muscle are noted when elderly men are given replacement doses of testosterone.16 In essence, the cells are becoming primed for the actions of IGF-1, by testosterone. Alternately we see marked decreases in IGF-1 receptor protein levels with androgen deficiency in young men. It also appears that androgens are necessary for the local production and function of IGF-1 in skeletal muscle cells, independent of circulating growth hormone, and IGF-1 levels.17 Since we do know for certain that IGF-1 is at least a minor anabolic hormone in muscle tissue, it seems reasonable to conclude that this factor, at least at some level, is involved in the muscle growth noted with steroid therapy.

Direct and Indirect Steroids?

In looking over the proposed indirect effects of testosterone, and pondering the effectiveness of the synthetic anabolic/androgenic steroids, we must resist the temptation to believe we can categorize steroids as those which directly, and those which indirectly, promote muscle growth. The belief that there are two dichotomous groups or classes of steroids ignores the fact that all commercial steroids promote not only muscle growth but also androgenic effects. There is no complete separation of these traits at this time, making clear that all activate the cellular androgen receptor. I believe the theory behind direct and indirect steroid classifications originated when some noted the low receptor binding affinity of seemingly strong anabolic steroids like oxymetholone and methandrostenolone.18 If they bind poorly, yet work well, something else must be at work. This type of thinking fails to recognize other factors in the potency of these compounds, such as their long half-lives, estrogenic activity, and weak interaction with restrictive binding proteins (see: Free vs. Bound Testosterone). While there may possibly be differences in the way various compounds could foster growth indirectly, such that advantages way various compounds could foster growth indirectly, such that advantages might even be found with certain synergistic drug combinations, the primary mode of action with all of these compounds is the androgen receptor. The notion that steroid X and Y must never be stacked together because they both compete for the same receptor when stimulating growth, while X and Z should be combined because they work via different mechanisms, should likewise not be taken too seriously. Such classifications are based on speculation only, and upon reasonable investigation are clearly invalid.

test2MECHANISM OF ACTION DIAGRAM: The mechanism of anabolic
action due to the administration of anabolic/androgenic steroids. AAS
causes not only direct stimulation of the androgen receptor, but also
supports muscle growth by increasing the levels of free androgens,
increasing androgen receptor density, inhibiting corticosteroid action,
increasing GH/IGF-1, and suppressing IGF-1 binding proteins.

9. Testosterone injection stimulates net protein synthesis but not tissue amino acid transport.
Fernando A, Tipton K, Doyle D et al. Am J. Physiol (Endocrinology and Metabolism)
10. Glucorticoid antagonism by exercise and androgenic-anabolic steroids. Hickson RC,
Czerwinski SM, Falduto MT, Young AP. Med Sci Sports Exerc 22 (1990) 331-40
11. Binding of glucorticoid antagonists to androgen and glucorticoid hormone receptors in rat
skeletal muscle. Danhaive PA, Rousseau GG. J Steroid Biochem Mol Biol 24 (1986) 481-
12. Evidence for a sex-dependent anabolic response to androgenic steroids mediated by
muscle glucorticoid receptors in the rat. Danhaive PA, Rousseau GG. J. Steroid Biochem
Mol Biol. 29 (1988) 575-81
13. Glucorticoid antagonism by exercise and androgenic-anabolic steroids. Hickson RC,
Czerwinski SM, Falduto MT, Young AP. Med Sci Sports Exerc 22 (1990) 331-40
14. The source of excess creatine following methyl testosterone. Samuels L. T., Sellers D.
M., McCaulay C. J. J. Clin. Endocrinol. Metab. 6 (1946) 655-63
15. Ontogeny of growth hormone, insulin-like growth factor, estradiol and cortisol in the
growing lamb: effect of testosterone. Arnold AM, Peralta JM,Tonney MI. J Endocrinol 150
(1996) 391-9 12.Jun;130(6):3677-83. 81, 2001.
16. Testosterone administration to elderly men increases skeletal muscle strength and protein
16. Testosterone administration to elderly men increases skeletal muscle strength and protein
synthesis. Am J Physiol 269 (1995) E820-6
17. Testosterone deficiency in young men: marked alterations in whole body protein kinetics,
strength, and adiposity. Mausas N, Hayes V, Welch S et al. J Clin Endocrin Metab 83
(1998) 1886-92
18. Endocrinology 114(6):2100-06 1984 June,“Relative Binding Affinity of Anabolic-
Androgenic Steroids…”, Saartok T; Dahlberg E; Gustafsson JA