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Old 10-16-18, 10:18 AM
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Generally, when people discuss the effects of anabolic steroids— benefits or harm— they are referring to events that occur over a short period of time. Only recently have researchers and clinicians taken a longer view of the metabolic effects of testosterone replacement therapy (TRT). Dr. Farid Saad of Bayer Pharma, manufacturer of Nebido (testosterone undecanoate), has published a number of articles looking at the latency to maximal benefits from TRT in men who have been treated for several years— how quickly or slowly benefits fully arise (six months to six years or longer).1,2 Of course, this has received little press; especially in comparison to the highly disputed speculation that an association between TRT and cardiovascular disease may exist if you tilt your head, squint and nudge around the data a bit (of course, that does not include otherwise healthy, non-elderly men).3-5

Aside from some frightful revelations, such as those exposed by the East German doping scandal during the Cold War era (late 1945 through the 1980s), there is little published data on the long-term effects of anabolic steroids used for extended periods of years or decades. The East German program was harmful to many athletes, but realize that they were initiating the use of anabolic-androgenic steroids (AAS) as early as age 10 in both boys and girls.6 This pattern of coerced pediatric AAS abuse is not relevant to the discussion at hand.

In a healthy adult male, moderate AAS use/misuse is generally well tolerated in those not predisposed to clotting disorders or psychological effects (e.g., changes in mood, emergence of subclinical depression, provoked anger responses, altered libido). Certainly, there is a risk of long-term suppression of endogenous (natural) testosterone production and fertility, as well as legal consequences if obtained illicitly. However, in the tissue of interest— skeletal muscle— what is the long-term net effect? Are there changes that occur over time that make the muscle “better” or “worse?”

Cycles of Six-Time Mr. Olympia

Before getting into the meat of the article, it is interesting to note that the cycles described in a recent issue of Muscular Development by six-time Mr. Olympia Dorian Yates are similar to those detailed in the studies. Mr. Yates described eight-week, off-season cycles (three times a year interspersed with four-week “off” cycles) consisting of testosterone ester (750 mg/week), stacked with either nandrolone decanoate (500 mg/week) or equipoise (boldenone undecanoate— dose not specified), along with daily oral Dianabol (50 mg/day). His pre-contest cycle differed, but his off-season AAS use was consistent with the subjects in soon-to-be-discussed studies. Mr. Yates does acknowledge later periods wherein his AAS cycles were as much as 60 percent greater (weekly dose), but with little additional (self-reported) benefit. The popularity of testosterone and nandrolone were recorded during the period referenced by Mr. Yates, as documented in a report of drug testing performed in Flanders, Belgium.7 Testosterone and nandrolone remain “foundation” agents in current anabolic regimens.8

Numerous studies of interest followed subjects who had several years of resistance training, along with AAS use, often compared against drug-free powerlifters or weight-trained subjects.9-14 As well, comparison groups of drug-tested powerlifters were reported to demonstrate the possible effects of AAS on muscle structure and performance over a range of five to 15 years use in two recent studies.11,14 Collectively, these studies span a period of greater than 30 years.

In 1984, it was noted that weightlifters following their own AAS cycles outperformed “clean” weightlifters significantly in terms of increasing size, strength and muscle fiber area (a measure of the size of each muscle fiber under a microscope).9 The findings supported the authors’ theory that “strength training in combination with administration of androgenic-anabolic steroids causes improvements in selected neuromuscular parameters.” This was actually fairly groundbreaking at the time, as most research was designed to prove that AAS provided NO benefits in regard to athletic enhancement— a statement included in the package insert of pharmaceutical AAS at that time. The concluding line of the abstract in that study understated what had long been obvious: “These changes may be greater than those of caused by the strength training alone.”

As science finally accepted that supraphysiologic AAS misuse increased muscle size and strength, attention turned to the changes occurring within the muscle to account for the observed increase in size and strength. Muscle as a tissue is similar to a rope, consisting of numerous strands that combine to provide tensile strength (ability to withstand stretching forces). These “strands” are “muscle fibers” and each fiber is an individual cell. Nearly unique among the tissues of the body, skeletal muscle fibers are multi-nucleated. This means that instead of each cell having one nucleus— like an egg has one yolk— containing the DNA that controls the cell’s function and structure, skeletal muscle cells contain several nuclei that control “zones” within the muscle cell. Each nucleus can only manage so much “space” (cytoplasm— the cell's “insides”). This means that there is an absolute ceiling as to how large a muscle fiber (and collectively, the whole muscle) can get, UNLESS it can increase the number of nuclei the cell contains.

Some readers with a basic understanding of biology may initially think that the nuclei already in the muscle cells would increase in number through a process called mitosis— the “duplication” of all the DNA in the nucleus to generate a second nucleus in most cells. However, this is not the case. Mitosis only happens when a cell is getting ready to divide into two brand-new and separate cells— each taking a nucleus with it. In the skeletal muscle cell, there is not a second muscle fiber being generated from within. New muscle fibers can be created, as will be discussed later. The process that happens in skeletal muscle, when the need for a larger muscle (hypertrophy) is present, involves some pretty neat mechanisms (from a nerd point of view).

There is a pool of precursor cells within the “neighborhood” of the muscle fibers called satellite cells. Typically, they are just around, dormant and not doing anything to contribute to muscle size or function. However, when the conditions support muscle hypertrophy, these satellite cells start dividing (there is an example of mitosis) and some begin differentiating— this means they start looking and acting like “grown-up” cells. When the right signals are present, such as those generated by exercise or the use of certain growth-promoting factors (e.g., AAS, mGF, IGF-1), these grown-up satellite cells merge with the existing muscle fibers and are assimilated like a Borg from “Star Trek: The Next Generation.” The nucleus of the satellite cell is now included in the muscle fiber, increasing the number of myonuclei in that cell. To put it clearly, the increase in nuclei in the muscle fibers comes from “outside”— the satellite cells.

So, as the nuclear number goes up, the amount of “space” (muscle volume) each nuclei is managing (nuclear-to-cytoplasmic ratio or N-to-C ratio) goes down. In a setting where the muscle was near its maximal allowed (by N-to-C ratio limits) size, the addition of new nuclei from satellite cells allows that muscle fiber to get bigger— achieving the goal of bodybuilding.

Strength, Size and Cellular Changes

The measures of interest in the most recent studies were the overall performance (strength), size (fiber area) and cellular changes (myonuclei count) in resistance-trained AAS users versus non-users. Following the 1984 study that reported greater force production (strength) and muscle fiber area, a later study in 1999 looked at the muscle fibers more closely. Both groups had the same proportion of fiber types— sometimes referred to as slow-twitch and fast-twitch, though the classification is more complex than that. So, assuming that the groups had similar proportions prior to AAS use, no change in fiber type was evident. However, the AAS-using lifters had significantly larger muscle fibers (as expected), but it was also reported that the myonuclei count was higher and more nuclei in the muscle fibers were centrally located in the cell, meaning they were more active in regulating cell functions. Even more exciting, there was evidence of “developmental” muscle fibers, meaning not only were the existing muscle fibers getting larger, but the signals created by exercise and the drug regimens were stimulating the generation of NEW muscle fibers. This is called “hyperplasia” and is a second, and potentially more significant pathway to growth.

It is interesting that a 2010 study noted that the satellite cell population of AAS-using powerlifters differed from those of drug-free powerlifters.12 This may be indicative of AAS having a direct effect on the “destiny” of satellite cells.

Jump to 2005, when a study between AAS-using lifters and drug-free powerlifters reported that (again), the AAS-using men (with an average nine years of use, 938 mg/week of testosterone and other AAS) had larger muscle fibers of all types, more myonuclei, with more myonuclei being central (more active).11 However, it was interesting that this study was designed to compare two different muscle groups, the trapezius (traps) and the vastus lateralis (quads); as well, the short-term use of AAS compared to long-term use was compared. The reported results of two prior studies were used for the comparison groups of AAS users.10,15 The effect of AAS was notably different between the two muscle groups, with the traps showing a greater effect on muscle fiber hyperplasia (new muscle fibers), whereas the quads had a larger nuclear-to-cytoplasmic ratio. This means the quads were nearing their maximal size, as the N-to-C ratio is the “ceiling” to growth. Consistent with prior studies, AAS users had significantly larger muscle fibers (61% for type I fibers and 44% for type II) and more myonuclei per fiber, as well as more fiber area (size) per myonuclei. The AAS users had muscles that were larger, capable of getting larger and were capable of getting closer to the N-to-C ratio ceiling. For reference sake, the fiber area in the traps of the AAS users was 58% (type 1) and 33% (type 2).

In 2014, a paper was published looking at many of the same features, but also looked at capillary density (blood flow in the muscle) as well as force production measures. Not surprisingly, the AAS users again had greater lean mass, more myonuclei and surprisingly, a greater capillary density. However, the AAS users did not show a statistically significant increase in fiber area (the average fiber area for AAS users was 15% greater than drug-tested athletes, compared to a roughly 50% increase noted in prior studies). Perhaps even more surprising was the finding that AAS users developed muscles that were less forceful. This means the muscles were larger and stronger, but not as strong as the drug-free muscles when adjusted for muscle mass.

Well, there are a couple of issues with this study that take away from some of the value. First, the subjects in the AAS-user group were significantly older than the drug-tested group (41 versus 29). While all AAS users had greater than five years exposure to AAS, the cycles were widely varied. Worse, there was no consistency regarding a doping schedule, with many of the AAS users being off-cycle at the time of testing.

Another issue is that the drug-tested athletes were all competitive powerllfters, and the calculations of strength (force) were based upon 1-RM (one-repetition maximum) personal records in the bench, squat and deadlift. Measured force was performed using a simulated squat with 105° of range (below parallel). This is a familiar movement for powerlifters, but is not likely familiar to bodybuilders using 1-RM weight. The AAS users consisted of bodybuilders, strongman competitors and powerlifters. In fact, the subjects using the highest dose of AAS performed worst on several measures relative to muscle mass, leading the authors to propose a ceiling to AAS-augmented force. One might investigate to see if an association existed between the subject, his sport of choice (likely bodybuilding), training style and whether he was “on” or “off” cycle. The force production of the drug-tested powerlifters were all closely clustered, whereas the AAS users varied widely, as did their training styles, drug regimens and hormone levels at the time of testing (some were hypogonadal).

AAS Lifters vs. ‘Clean’ Lifters

The authors attempted to develop an algorithm to differentiate AAS users from “clean” lifters. They also acknowledged that AAS use, combined with resistance training, “could induce enhancements in both muscle mass and strength,” and that the improvements are AAS dose-dependent. If another group of drug-tested bodybuilders was included, the effect of training style on the muscle performance measures could have been clarified.

Over the last several decades, it has been shown that AAS use can promote increases in skeletal muscle size and strength. Though no study has been specifically designed to find the threshold concentration, the results of several suggest that the minimum dose required to affect change in a healthy, adult male exists near 300 milligrams per week of testosterone or nandrolone ester.16,17 As noted by several papers, the anabolic effects in muscle are dose-dependent.

It is interesting to note that observations and reported cycles by experienced AAS users suggest little additional benefit in strength with more than 1,500-2,000 milligrams per week of total androgen exposure, and a concomitant increase in acute adverse effects. However, fiber area seemed to be dose-dependent beyond this range.

An interesting application would be the therapeutic benefits in former, or long-term AAS users in delaying fraility with aging. Animal studies have shown that the increase in myonuclei persists for decades in humans, leading researchers to state, “Anabolic steroids have been shown to increase the number of nuclei; thus, the benefits of using steroids might be permanent … ”18

A later animal study showed that muscle cells treated with supraphysiologic testosterone exposure and resistance (overload) training developed a greater number of myonuclei (66%). After the testosterone was stopped, as well as the exercise, the increase in myonuclei was retained for at least 10 percent of the rat’s life span, and when exercise was reintroduced (without any testosterone given), the muscles of these rats grew 31 percent bigger.19 Rats who were not given testosterone earlier showed no increase in muscle size.

Weakness and sarcopenia (low muscle mass) are features of aging associated with increased poor health, or mortality. If prior exposure to AAS increases myonuclei number for years past use, then past or long-term users may unknowingly be promoting their long-term survival and independence.
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Old 10-16-18, 12:03 PM
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