As you might imagine, almost every secret, or even not-so-secret club, gang, pack, or gaggle has a manifesto, a document detailing all the important information that every devotee should possess. The Christian club has the Bible, the US gang has got the Constitution and the Bill of Rights, and even that Bill Phillips, Body For Life pack has a glossy, estrogen- soaked manual that describes how to place your lips directly onto Bill Phillips' butt while sliding your hard earned dollars into the front pockets of his freshly pressed chinos.

This makes me wonder what the world would be like if there were a Book of T, The Word of Testosterone, if you will? Perhaps a book like this might, in some small way, negate the damage caused by years of indelibly stamped images of Richard Simmons's flabby thighs in spandex. Perhaps it might also help erase years of erroneous fitness mythology from the memory centers of fitness trainers and exercisers alike.

If such a book were to be written, I might expect that every full-fledged, card-carrying member of T-Nation would have a copy and this holy book would provide information essential to all T-Nation members. Hence this hypothetical introductory chapter, my vision of what the members of Testosterone Nation should know about their namesake.

Part 1 of this three-part series discussed steroid fundamentals. This week's installment talks about how steroids are used, how they work, and what their side effects – both positive and negative – are.

 
Getting The Steroid In Ya'

Before you need to worry about the side effects of steroid use, first, you gotta' get the steroids in ya'. Most people employ one of the two most common forms of delivery for steroids – oral administration and intramuscular injection. Of course, nowadays there are patches, transdermal creams, and implant pellets but the two biggies remain.

Regardless of which method one chooses, as discussed above, unaltered Testosterone tends to be of no use to anyone when taken either orally or by intramuscular injection. This is due to the fact that it's susceptible to relatively rapid breakdown by the liver.

In order to overcome this obvious problem some modifications are made to Testosterone's chemical structure. Most commonly, Testosterone is alkylated at the 17-alpha position (an alkyl group is added to the 17th carbon in the steroid ring structure) to form an orally available steroid. The addition of this alkyl group allows the steroid to survive its first pass through the liver, a trip that would normally lead to complete degradation. As you'll see later, this alkylation, in addition to preventing degradation, also has been linked to some liver problems.

To form an effective injectable steroid, the steroid is usually esterified at the 17-beta position (as discussed earlier) and then suspended in oil. This prolongs the life of the steroid, giving it more time to produce a biological effect.

Once the steroids are swallowed or injected and progress into general circulation, they are free to promote their anabolic (tissue building) and androgenic (masculinizing) actions. Unfortunately, most steroids promote both the anabolic and androgenic effects. This is unfortunate because in most clinical situations, one or the other is desired. Anabolic benefits are desirable in individuals prone to losses in lean-body mass with disease, aging, or surgery. Androgenic benefits are desirable in situations of inadequate sexual development, infertility, and impotence. Bodybuilders have discovered that a combination of both anabolic and androgenic effects tends to offer the biggest gains in muscle strength and size. Often, though, more anabolic effects alone are desired.

As a result of these clinical needs, much work has been done in an attempt to separate the androgenic and the anabolic effects of steroids. Since the androgenic effects of steroids are more likely to promote undesirable side effects in those needing only enhanced tissue building, creating a purely anabolic steroid has been of particular interest. In addition, creating a completely anabolic steroid is desirable in order to prevent the development of the male characteristics in women, children, and individuals with protein irregularities who could likely receive anabolic androgenic hormone therapy.

Nandrolone decanoate, oxandrolone, and stanzolol are just a few of the steroids that were synthesized as a result, and displayed greater anabolic activity than androgenic activity. To this end, studies have shown that compounds with a lower affinity for the steroid receptor tend to have a greater anabolic effect relative to the androgenic effect. But this means that these compounds would need to be taken in much higher doses since more drug would be needed to accomplish the same level of receptor binding. Regardless, a purely anabolic steroid without any androgenic properties has yet to be discovered (the reasons for this go beyond the scope of this article and frankly, you probably don't give a damn).

So How Do These Anabolic and Androgenic Things Work?

There have been many recent studies that demonstrate the fact that steroids produce muscle hypertrophy by increasing muscle-protein synthesis and reducing muscle-protein breakdown. However, the molecular basis of this anabolic effect is not totally understood. But scientists do have some clues.

It's believed that the steroid initially diffuses into the cellular cytosol (the liquid portion of the cells), where it combines with the cell's androgen receptor like a lock (receptor) and key (steroid). Together, the receptor-steroid complex then migrates into the cell nucleus where it interacts with the DNA and initiates transcription to RNA. This new RNA is then translated into new protein. When this occurs in muscle tissue, the new protein equals muscle growth. If this process is Greek to you, we can summarize it simply. The steroid is shuttled to the genetic material where it tells the cell to get bigger.

When a hormone has this type of effect we say that this is a direct effect. To this end, direct steroid actions promote a positive nitrogen status in that they can shift a neutral or negative status into the positive range. This means that a larger quantity of nitrogen is retained than is eliminated. And a positive nitrogen status indicates that muscle tissue is being deposited.

While most scientists agree on the direct, receptor-dependent effects of steroids, there is some debate as to whether steroids have indirect, receptor independent effects. Interestingly, in the absence of viable steroid receptors, steroids have been shown to exert androgen specific or anabolic effects in various tissues of the body. This means that some steroid may act as above (via the receptor) while others may act independent of the receptor by binding directly to DNA, by influencing the binding of other hormones/compounds to certain receptors, or by increasing the production of certain hormones.

If there is no receptor, then how might the steroid work? Well, no one knows just yet but some receptor-independent effects may include:

• Displacing glucocorticoids (cortisol, etc) from their receptor and prevent them from interacting with genetic components of the cell and inducing catabolism.

• Increasing liver produced and locally produced IGF-1 [insulin-like growth factor] mRNA and IGF-1 protein as well as decreasing IGFBP (the binding protein that sequesters IGF).

Relating this information back to bodybuilding, many steroid theorists have suggested that the use of a combination of receptor-dependent steroids and receptor independent steroids might offer the best results. And of course, for years, athletes knew that "stacking" steroids (concurrently taking several different steroids) might offer unique benefits. These two types of effects might just explain why stacking works.

Big, Strong, What Else?

Still, to this day, there is a ridiculous stigma attached to steroids and their use. When most people hear "steroid," they think "bad." Fortunately. this is slowly changing. Not everyone, though, has gotten the message.

Logically speaking, despite the negative connotations still associated with steroid use, there must be certain positive attributes or positive "side effects" associated with their use. And these positive side effects must, in some way, supercede the negative side effects for some individuals. Either that or individuals are simply exchanging short-term benefits for long-term problems. In addition, if steroids were universally evil, why would scientists spend countless hours and millions of dollars researching them? Therefore, lets take a look at some of the positive side effects associated with steroid use.

 
The Clinical Stuff

When men age, endogenous Testosterone concentrations diminish. Some have adopted the term "andropause" to describe this natural hormonal decline. While the name seems cute as we now have the male equivalent of menopause, the effects of andropause are not cute at all.

Associated with "andropause" and this decrease in endogenous Testosterone are:

• Increased cardiovascular risk (via increased triglyceride concentrations and decreased HDL cholesterol concentrations).

• Increased fat mass.

• Decreased lean mass (water, bone, and – gasp!- muscle).

• Decreased sex drive and performance.

• Decreased mood scores / increased incidence of depression.

Clinically, these changes are all improved with low dose steroid use (a couple hundred milligrams per week). Both experimental and clinical studies have demonstrated these benefits of low dose Testosterone administration on body composition, showing increased muscle mass, bone mass, and body water. In addition, fat mass is consistently diminished with Testosterone use, especially concerning that health bandit, abdominal adiposity.

In addition to favorable body composition changes, Testosterone replacement in middle-aged men with visceral obesity improves insulin sensitivity and decreases blood glucose and blood pressure, clearly improving health. This, in addition to observed decreases in LDL, total cholesterol, and increased HDL, links overall health with normal blood levels of Testosterone.

Oh yeah, and don't forget about improvements in sex drive and erectile function. So, with more muscle mass, less fat mass, improved overall health, and the ability to shag the misses on a regular basis, shouldn't these guys be improving in their mood scores? Well, they are, regardless of whether it's a direct or an indirect effect (it tends to be direct, but who cares?!?). So on the basis of it's direct and positive clinical effects, why on earth would we want to demonize the stuff?

And not only does Testosterone offer these benefits to aging men using "replacement doses," "medicinal doses" can assist in the achievement of many of these endpoints in patients subjected to muscle wasting due to cancer, AIDS, COPD (chronic obstructive pulmonary disease), injury/disease recovery, bed rest, and low endogenous production of Testosterone. While these individuals don't always have low Testosterone per se, they do receive benefit from steroid use.

Beyond "replacement therapy," the use of "medicinal" Testosterone to induce male contraception has been investigated by the World Health Organization. A multicenter study was done in 7 countries on 271 healthy fertile men. Each subject received 200 mg of testosterone enanthate weekly by intramuscular injection for approximately one year. Subjects experienced azoospermia (low sperm production) and an increase in body weight. The study concluded that Testosterone enanthate could provide highly effective, sustained, and reversible male contraception (i.e. fertility would be restored with the removal of steroid treatment) with minimal side effects. Of course, this points out one of the negative side effects of steroid use – infertility. As indicated, this is reversible with cessation of use.

While the aforementioned benefits of steroids are mostly associated with low ("replacement" or "medicinal") doses in order to normalize health and function, athletes, on the other hand, have not been interested in how steroids could bring their body to "normal" functioning, but have used them in order to promote super functionality. Athletes know that the use of steroids by physically developed people enhances certain physiologic functions, including an increase in lean body mass, strength, and aggressiveness and a reduction in recovery time between workouts. Both strength and power are two aspects of athletics that athletes are constantly seeking to improve.

 
The Athletic Stuff

• Increased Muscle Size, Strength and Power: Bhasin et al and Friedl et al have both conclusively demonstrated Testosterone's effects on strength and power. This research has shown that in healthy men receiving doses of 300-600 mg of testosterone enanthate intramuscularly weekly, muscle strength (50 lb increase in bench press in experienced lifters over 12 weeks), power, and muscle size (13 lb weight gain) have shown dramatic improvements. Other studies have shown that methandienone (Dianabol), oxandrolone (Anavar), and stanzolol (Winstrol) also produce improvements in strength and/or size. Strength gains tend to be due to increased muscle size and neuromuscular improvements. Mass gains tend to be due to increased water weight, increased protein mass, increased bone mineral mass, increased non-bone mineral mass, and glycogen content.

• Hypertrophy and Hyperplasia: In addition, Kadi et al demonstrated that steroids, combined with strength training, induce an increase in muscle size by enlarging the fibers themselves (hypertrophy) and by increasing the number of new fibers (hyperplasia). This means bigger fibers and more fibers.

• Improved Neuromuscular Transmission: Work by Blanco et al at the UCLA School of Medicine has linked steroid use with improvements in neuromuscular transmission; specifically steroids decrease skeletal muscle fatigue by minimizing the contribution of neuromuscular transmission failure to peripheral muscular fatigue. In more comprehensible terms, muscle fatigue may be diminished with steroid use. This is thought to occur in the nerve fibers that innervate fast twitch muscle fibers by, among other things, increasing acetylcholine (the neurotransmitter responsible for nerve transmission) synthesis.

• Improved endurance performance: Steroids may increase maximal oxygen uptake, red blood cell production, hemoglobin synthesis, and muscle glycogen concentrations, in addition to preventing the catabolic effects of glucocorticoids and preventing declining blood Testosterone concentrations. This last effect improves the anabolic to catabolic hormonal balance.

• Improved training tolerance and injury repair: Intense strength and/or endurance training programs may shift the anabolic to catabolic hormonal balance in a negative direction. Steroid use may counter these shifts (as indicated above). In addition, Testosterone may stimulate bone healing, therefore accelerating the recovery from sports related injuries.

Wow, that's a lot of benefits for athletes as well as clinical patients! No wonder a lot of athletes and those interested in the cosmetic benefits of steroids are willing to break the law (more on this later) to use them.

Yeah, Steroids Do Some Cool Things, But Won't They Kill Me?

The use of steroids is commonly believed to cause numerous adverse and even fatal effects. We've seen a lot of posters and presentations over the years and we can't recall a single one saying anything positive about steroids. They did, however, discuss a laundry list of ridiculous negative side effects.

Despite this, the incidence of serious effects thus far reported has been extremely low per reported user, far lower than those associated with most prescription drugs currently on the market and even lower than some over-the-counter drugs, including aspirin. That's right, aspirin may cause more serious side effects in a larger percentage of the population than steroids.

I don't want to get off on a rant here but what's interesting to me is that with respect to the steroid literature, authors tend to snoop through every obscure medical reference for wimpy case studies that document the rare health problems experienced by steroid users. If you think this is an exaggeration, you might change your mind when you consider that in one report someone actually thought it provocative to mention that a steroid user had contracted chickenpox pneumonitis during his use.

Rather than interpret this seek and destroy phenomenon as the medical equivalent of planting a bag of uppers on a suspect you want to get down to the station, I'll simply say this. Since most of the reported side effects of steroid use have been derived from these single-subject case reports rather than well-controlled scientific studies, I think it prudent to exercise caution when interpreting these reports. After all, with case reports we have no idea as to any of the background factors that could have contributed to these effects. But slow down, tiger. I want to make it clear that my comments above are anything but an attempt to offer my blanket approval for the use of steroids.

In addition, before you get your panties in a twist about conspiracies and violations of personal freedom, hold on one second. There are a number of studies linking steroid use to some serious side effects, especially when the doses used are those that actually promote athletic benefits; doses in excess of what is used in hypogonadal individuals. And while the rigor with which some authors will scour the case study literature may be inappropriate, it's important to discuss their findings. If enough of these case studies contain similar effects, the implications should be considered. Therefore, a decision to take steroids represents a balance between your need to take them (for clinical or athletic reasons) and your willingness to suffer the documented negative side effects listed below. This is where it's important to realize that the difference between high dose steroid use and low dose steroid use is paramount to the side effects, positive or negative.

Since steroid receptors are ubiquitous (simultaneously present in most cells of the body), it stands to reason that steroids can affect all these tissues in both positive and negative ways. Of biggest concern, however, are the effects of steroids on height in adolescents, liver damage, serum lipid changes, reproductive dysfunction, psychological abnormalities, and prostate damage.

Clinically, high-dose steroid treatment has been used during puberty to reduce the predicted height of excessively tall boys due to the fact that steroids lead to premature physeal closure in teenagers. This use may seem a bit ridiculous and, in fact, highlights one side effect of steroid use – a decrease in attainable height in adolescents.

One of the areas of greatest concern when taking anabolic steroids is the effect on the liver. Unfortunately, much of the data linking steroid use to compromised liver function used nonspecific liver function tests, tests that are affected by intense training alone in the absence of steroid use. Interestingly, many "steroid-friendly" doctors that I've spoken to do suggest that these markers can tend to be further elevated with combined steroid use and weight training. What this means is unclear since they are, in fact, nonspecific. Regardless, these elevated measures do return to normal after the cessation of use. Therefore, although there isn't a clear link between liver function measures and steroid use, this effect is worth mentioning (whether or not it's something to be concerned about).

However, aside from the unclear data regarding non-specific markers of liver function, there is cause for concern when taking the orally active (17 alpha alkylated) steroids over long periods of time. Liver problems such as peliosis hepatis (blood filled liver cysts), hepatomas (liver cancer), and hepatic cholestasis (a cessation of bile flow) have been well documented with the chronic use of oral steroids.* Of these three, only the last one is reversible but that's only the case if the cholestasis hasn't progressed to cholestatic jaundice and end organ liver failure (resulting in death if untreated). Last time I checked, death was irreversible.

Again, as indicated, the other problems may cause permanent hepatic damage or death. And, just to be clear, these effects are only associated with the long-term use of oral steroids and not short-term use of oral steroids or the use of injectable steroids. However, even when using injectables, some specific markers of liver function should probably be monitored.

*Why anyone would play around with long-term oral steroid use is beyond me. Exploding blood filled cysts in my liver tend to prevent me from using them. How 'bout you?

Other research has suggested that excessive (high dose and/or long term) steroid use can severely lower HDL and increase LDL concentrations in the blood, leading to unaltered total cholesterol concentrations. Again, these effects tend to be associated with oral steroid use rather than injectable use but injectable steroids may still induce this effect to some extent.

Interestingly, while the effects on LDL and total cholesterol have been challenged, the effects on the reduction in HDL have been unanimous (especially with respect to orals*), presenting an increased risk for cardiovascular disease. Again, though, these effects are completely reversible after cessation of use.

*Yet another reason to keep orals off your Christmas wish list. In addition, if you've got a family history of peripheral vascular disease or congenital heart defects, you should probably never consider taking any steroids. If you still wish to tempt the fates, get a regular cardiovascular profile done including blood pressure, blood lipids, and an EKG.

Other effects on the cardiovascular system, including increased risk for thrombosis (blood clots leading to blood vessel blockage), myocardial infarction, elevated blood pressure, and left ventricular hypertrophy have been reported in case studies but not in well controlled clinical trials. These case studies have been reported without any information as to type of steroid used, pattern of use or abuse, or predisposing factors. For all we know, these individuals could have had family histories of heart disease and have been overweight and over fat. As indicated above, while these reports can help us identify potential problems, no well-controlled scientific studies have proven the validity of these concerns.

In all, with respect to cardiovascular risk, there have been no studies done in the Western literature to show a true increase in peripheral vascular disease rates in athletes who have used steroids. But remember, the literature is limited so that doesn't mean increased vascular disease rates aren't possible.

Another area of the body in which it is hypothesized that steroids may cause harm is in the prostate. The prostate is a target tissue for steroids and both prostate cancer and BPH (benign prostate hyperplasia) seem to be steroid sensitive. In fact, reduction or complete blocking of endogenous steroids (Testosterone and DHT) generally treats prostate cancer and prostate cancer is usually worsened with exogenous steroid administration. However, just because Testosterone can aggravate prostate cancer, doesn't mean that high levels of Testosterone can cause prostate cancer. In fact, there's no evidence to suggest that Testosterone can cause the onset of cancer in a healthy prostate.

To the contrary, several studies have shown the serum concentrations of prostate-specific antigen (PSA) (a marker for prostate risk) do not change during steroid use. In addition, steroid studies examining the prostate directly have indicated that no abnormalities were detected in the prostate on digital rectal examination.* With respect to prostate cancer's benign cousin (BPH), every study to date is in agreement that the concentration of Testosterone in the prostate of males suffering from prostate hyperplasia is low or normal. In fact, estrogen may be more strongly implicated in prostate risk than Testosterone.

*If your prostate is swollen up like a honeydew, avoid using all steroids. In addition, if you decide to use them, get your PSA concentrations checked out, just in case.

So what about steroids and muscle injury? While there have been a number of case reports (great, more of these damn reports) where bodybuilders and power lifters who have suffered musculotendinous injury while taking anabolic steroids, there can be no assurance of causality. Weightlifters suffer more of these types of injuries due to the high stress placed on the musculoskeletal system, regardless of whether they're using steroids or not.*

*There's probably no increased risk of injury with steroid use while training hard when compared to just training hard without steroids.

And "roid rage"? While reports of abnormal aggression, anger, intensity, and irrational behavior have long been associated with steroid use, it's difficult to associate this directly with a particular drug treatment or dosing. Contrary to these reports of "roid rage," physiologic replacement doses of Testosterone have been shown to improve mood and increase energy levels, along with prompting good feelings and friendliness in hypogonadal men.

Again, this is where the high dose-low dose paradox might come into play. Steroids may normalize mood when blood Testosterone is low and return it to normal but steroids may actually increase aggressiveness and anger when blood doses exceed normal. Unfortunately, there is a real void in the literature with respect to this topic.

In the few well-controlled studies using Testosterone alone, mood and aggression seemed unchanged. However, in self-reported studies examining steroid users, a high percentage of them admit increased irritability and aggression. Some have argued that steroid users may be inherently high-risk individuals and therefore more prone to these effects.* However, many individuals suffering from "roid rage" have no past psychiatric history. On the other hand, the fact that many users often use several drugs and high doses may play into this phenomenon.

*High dose and athletic doses of steroids may lower your threshold for irritants and anger. In addition, the new size and strength you possess while on steroids may be enough to turn you into an aggressive, bloated, ball of machismo. Be cautious and if you must use steroids, be sure to find appropriate channels for outlet (like taking it out on the weights and not on your girlfriend), and be sure not to act like a big, dumb muscle head. You'll give us all a bad name.

In the end, serious negative side effects with low and moderate dose steroid use are extremely rare and only found when doing some medical super sleuthing, dredging up presumably every case of medical treatment in which there was concurrent steroid use, regardless if there was any relationship between the two.

While oral steroids tend to be more closely linked to health problems and increased risk, intermittent use of them has not conclusively been shown to cause long-term concern. With this said, it is important to note that clear, well-controlled investigation into this topic is still in its infancy. More studies may very well be published in the future implicating steroids in a host of other maladies. But, for the time being, we don't have enough information to suggest that this will be the case. It is theoretically reasonable though, to suggest that high dose steroid use or long-term use without cessation (i.e. abuse) might promote more serious side effects. With any drug, seriously exceeding physiological doses may lead to some severe problems.

Therefore, using the available scientific information, it appears that steroids are certainly not the harmful drugs many would have you believe. If used with a prescription for legitimate medical conditions, they are probably safer than most prescription medications. If used responsibly in moderate quantities for performance enhancement or improved body composition, they carry a relatively balanced cost to benefit ratio with respect to physical and mental health (unfortunately responsible, moderate use is hard to define). And if abused, health problems are inevitable.

While, we believe, the health issues are reasonably clear, and the information contained in this article will provide a good basis for rational decision making, there are other concerns with respect to steroid use. These concerns, legality and fair play, will be discussed next week in part III.