Ancient cultures spread learning through spoken lore, as much of the population could not read. Given the literacy trends of the last decade or two, this educational style may return. A collection of such tales has iconic status, known as Aesop's Fables. [Aesop was a slave who lived in Greek society approximately 600 B. C.] One of his most well known is the race between the tortoise and the hare. After ridiculing the ponderous tortoise and challenging him to a race, the hare (a rabbit for those not familiar with the term) sprinted ahead but stopped for a rest. When he realized he had goofed off too long, he ran as fast as he could, only to see the tortoise crossing the line before him. The moral of the story is slow and steady wins the race.
Consider for a moment the typical use pattern of testosterone (and other anabolic-androgenic steroids, or AAS) it is hare-like. Bodybuilders have been programmed by gym lore to follow eight- to 12-week high-dosed AAS cycles to maximize muscle and strength gains. While it is unquestionable that most men do achieve considerable growth and strength enhancement during AAS cycles, it is also very common for these gains to be temporary, with long-term mass and strength retention that is much less than the peak experienced during the cycle. Further, in the rush to acquire maximal growth during a cycle, injuries are common and dosages are pushed into a range wherein adverse side effects occur. Some of these side effects can be mitigated with the use of adjunct drugs (e.g., aromatase inhibitors), but many could be avoided if lower doses were used. Also, these types of cycles can wreak havoc on the mental state and mood of the user/abuser. Lastly, it is nearly certain that such cycles will result in the suppression of natural testosterone (and sperm) production of variable duration. Some men recover from AAS cycles quickly, especially if they tapered correctly; others may suffer from months of depressed mood, loss of strength, sexual problems, etc. In rare cases, this can become permanent or require specialized medical treatment.
Rumors of bodybuilders who are "always on" have circulated since the 1980s, if not earlier. However, the practice is now spoken of more commonly. "On" does not mean these bodybuilders are on nonstop cycles, rather that they are "bridging" between cycles with replacement dosing of testosterone to avoid the setbacks that occur during the post-cycle recovery. Given the dosing and duration of the cycles used by some, it is possible that post-cycle recovery could take many months. Instead, they "bridge" for a month or two at most between supraphysiologic mass-gaining or competition cycles. It would be interesting to compare the rate of professional bodybuilders fathering children during their competitive years now versus 20 or 30 years ago. The increased prevalence of human chorionic gonadotropin (hCG) use during cycles to maintain testicular size and Leydig cell function offers little in maintaining fertility as the Sertoli cells, which are involved in sperm production, are stimulated by a different hormone (FSH); hCG mimics the Leydig cell-associated pituitary hormone, luteinizing hormone (LH).
SAFER TESTOSTERONE CYCLES
Fertility aside, one needs to look at the pattern of testosterone use with a more critical eye. Is it possible that the common cycles are less effective than alternate patterns? Is it possible that a long duration of testosterone exposure is necessary to obtain the maximum benefits? If this were the case, and it does appear to be so, then perhaps those abusing AAS could be convinced to accept relatively safer and more responsible cycles. Of course, there can never be an absolute guarantee of 100 percent safe drug use of any sort. Exogenous testosterone or AAS use of any concentration holds the potential to render a man infertile or affect mood. This discussion does not condone illicit AAS use or offer medical advice.
It is an indication of how retarded, meaning delayed, the state of clinical research relating to testosterone is when one considers that pharmaceutical companies and physicians do not have a firm grasp of the proper dosing or treatment course. So, it is with great interest that the review of Farid Saad and colleagues titled, "Onset of effects of treatment and time span until maximum effects are achieved," published in the European Journal of Endocrinology was received.1 It is underappreciated how many systems in the body depend upon a healthy testosterone status, much like insulin or cortisol. Too little testosterone and many tissues in the body do not function well; too much and different effects emerge that are equally unhealthy. In the established manner of erring on the side of caution, clinical medicine tends not to treat testosterone deficiency unless it has reached a concentration low enough to allow for the health of an individual to be threatened. Sadly, physicians are advised not to screen men for testosterone deficiency unless symptoms are present that are considered relevant by the established professional societies.2 Unfortunately, they focus on the sexual effects of testosterone and generally dismiss other systemic effects. The muscle-building effect of testosterone is considered to be non-therapeutic and representative of abuse unless treating a wasting condition.3
To fully benefit from the application of therapeutic testosterone replacement, one needs to encourage the patient to allow several months to years for the body to accommodate to the revised hormonal balance. Unfortunately, the primary signals monitored by the physician and patient are erectile function and libido. Again, problems in these areas may emerge while the testosterone concentration is still "normal." Or the problems may not emerge until testosterone concentrations are pathologically low, and respond rapidly to a minor increase— at times subphysiologic. Failing to appreciate the need for a longer duration of treatment, and more aggressive dosing, to meet the needs of other organs and tissue is a failure of current male hormone replacement therapy. It has been speculated that there are two separate dose-response curves— one at low concentrations, the other at higher concentrations; this would support considering elevating testosterone to high-normal concentrations rather than a minimal threshold. Let's look at the findings of Dr. Saad and colleagues.
TESTOSTERONE DEFICIENCY A COMPLEX PICTURE
There has been no concerted effort to delineate the timeline of testosterone's action, forcing Saad's group to combine numerous studies with a preference toward randomized, double-blind, placebo-controlled trials. In addition to sexual function, testosterone's effects on the following were reviewed: red blood cells, prostate, cholesterol and triglycerides, insulin sensitivity, fat mass, lean mass, strength, bone density, quality of life and mood. As the authors astutely noted, there is no specific threshold for symptoms of testosterone deficiency; some symptoms show up before others are affected. This is further compounded by the fact that many testosterone-related symptoms are affected by other factors as well. One example— erections are not solely dependent upon testosterone concentration, but also vascular function, nerves, psychological state and social relationships. In fact, erectile function is not affected by testosterone deficiency until it reaches a concentration of 8 nmol/L, (230 ng/dL).4 This is very low. In contrast, the libido is affected when testosterone drops below 15 nmol/L (430 ng/dL). The anabolic effects of testosterone may not be realized until the concentration reaches 700 ng/ml.3 These numbers can vary widely among individuals, confusing matters even more so.
It is interesting that the use of "percentage rise" dosing is suggested in the review.1,3 In plain English, this is basing the target testosterone concentration on the concentration at which the patient reports symptoms. If a person has low testosterone symptoms at a level of 250, he may be dosed to reach a concentration of 350-400; another person with symptoms at a level of 400 may need to be dosed to maintain a concentration of 600 before experiencing benefit. Age of onset may be an issue as well.
Looking in more detail into the findings of Saad et al., they note that certain variables affect an individual's response to testosterone replacement— the pharmacodynamics of the type of testosterone used and the pharmacogenomics of the patient. The first refers to how quickly testosterone is released to the bloodstream, how high a peak concentration is reached and how long an elevated concentration can be maintained. The second relates to how the individual responds to testosterone based on his unique DNA. This is critical for the physician to keep in mind, but for the reader it is beyond the scope of the article.
It is easiest to summarize the time course of effects in a table, as presented herein.
What is clear from the pattern is that testosterone's effects on mental functions and mood, as well as vascular effects, are rapid. Increases in libido, quality of life, depressive mood, cholesterol and triglycerides occur within three to four weeks, though additional benefits can be gained for months before the maximum benefit is reached. This suggests that the effects of testosterone in these areas are related to non-genomic effects.5 This means that certain cell types are able to respond to testosterone immediately, much like the heart begins racing as soon as the shock of adrenalin kicks in. Most other effects related to testosterone take longer to be realized and the maximum benefit may not be realized for months to years. This includes the anabolic effects of testosterone on muscle and bone, increase strength and red blood cell mass, as well as reduction in body fat (especially abdominal fat). Improvements in insulin sensitivity are initially rapid, but continue over time as related changes improve (e.g., reduced liver fat, lower inflammation, increase in muscle mass). These slower changes are dependent on testosterone activating beneficial genes and suppressing adverse (harmful) genes that slowly change the functional status of the specific tissue types involved (e.g., muscle, bone, fat).
For a man experiencing changes associated with declining testosterone, this is valuable information as it provides guidance as to how long it may take to see improvements with replacement therapy. An unintended benefit of this review may be in persuading men who have chosen to misuse testosterone or AAS to build muscle or increase strength to dose moderately, achieving equivalent or greater response over a longer period of time.
Before diving in, there are differences between the population of healthy young men with normal testosterone and aging men with low testosterone. Healthy young men might benefit slightly from a physiologic replacement dose of testosterone, but it would be like selling snow to Eskimos. Appreciable changes, particularly in muscle mass and strength, do require supraphysiologic dosing in young, healthy men. However, it does not require the exaggerated doses commonly reported.
TAKING EXERCISE OUT OF THE EQUATION
An interesting series of studies was reported in the last decade from the UCLA-affiliated Charles R. Drew University of Medicine and Science, headed by Shalender Bhasin, M.D.6 It looked at the effect of various doses of testosterone enanthate for 20 weeks on a variety of parameters, including muscle size and strength. Note, the young men in this study (18-35 years old) all had normal testosterone at the start of the study. They were instructed not to exercise other than light aerobic activity. Thus, the effect of testosterone on muscle size and strength is solely based on the change in that hormone, not heavier lifting. Obviously, combining the effect noted with the training response to weightlifting would amplify the increases seen.
In this study, men receiving less than the replacement dose of testosterone (resulting in lower blood testosterone concentration), maintained muscle size and strength. Those receiving supraphysiologic testosterone (300 mg/ week and 600 mg/week) experienced significant increases in size and strength, in a dose-dependent manner. Though no claims of safe use can be made, no significant adverse effects were noted, though HDL (good) cholesterol did drop. The authors noted that the doses were chosen based upon prior clinical studies, with 600 milligrams per week having been used safely previously. It was noted that certain functions (e.g., libido, erections, prostate) were maintained even at the lowest (below normal) testosterone dose, while muscle changes were only seen at the higher doses.
In closing, the hormonal yo-yo of eight-week cycles may result in temporary changes in size and strength, but requires aggressive dosing that is associated with many harmful effects. It appears that appreciable gains are delivered using more moderate dosing that has been safely administered for 20 weeks in small clinical studies, even in subjects who do not exercise. Bodybuilding and gym AAS use has been dominated by the "more is better" crowd needing immediate gratification. Safer and longer cycles, that are more effective, less risky and offer persisting results, may be the more intelligent approach. Again, this is not medical advice, nor does it condone illicit drug use. Instead, for those making the choice to use AAS, this may provide for a more informed decision.
By Daniel Gwartney, M.D. From Muscular Development
1. Saad F, Aversa A, et al. Onset of effects of testosterone treatment and time span until maximum effects are achieved. Eur J Endocrinol 2011;165:675-85. 2. Bhasin S, Cunningham GR, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536-59. 3. Isidori AM, Greco EA, et al. Androgen deficiency and hormone-replacement therapy. BJU Int 2005;96:212-6. 4. Zitzmann M, Faber S, et al. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006;91:4335-43. 5. Nyby JG. Reflexive testosterone release: a model system for studying the nongenomic effects of testosterone upon male behavior. Front Neuroendocrinol 2008;29:199-210. 6. Bhasin S, Woodhouse L, et al. Testosterone dose-response relationships in healthy young men. Am J Phys-iol Endocrinol Metab 2001;281:EI172-81.