-Hormones and Training-
-Strategies for manipulating hormones-
Table of Contents
The Steroid Manifesto
By John Berardi
Cortisol – The Stress Hormone
Author Unknown
Muscle Breakdown- Cortisol and Catabolism
By Rehan Jalali
The Big T
By John Berardi
Elevating Free Testosterone
By Thomas Incledon
Estrogen
By TC
The War on Estrogen
By Cy Willson
The Anabolic Power of Insulin
By John Berardi
The Fountain of GH
By John Berardi
T2 - The Fat Terminator?
By John Berardi
Hungry, Hungry Hormones
By John Berardi
Steroid Manifesto, Part 1
What Your Doctor, Your Friends, Your Mamma,
and Maybe Even You Don't Know About Steroids
by John M Berardi and Kris Aiken
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.
A Steroid By Any Other Name
What do you get when you put dianabol, stanzolol, Testosterone propionate, Testosterone enanthate, etc. together in a room? Well, besides one big mofo, you get the terms steroids, androgens, androgenic steroids, anabolic steroids, anabolic-androgenic steroids, or one or another in a laundry list of names — depending on which expert you speak to.
Unfortunately, all the aliases serve only to confuse the general public as well as our weight-lifting brethren. So, in an attempt to use a single name for "that group of testosterone-like compounds that make 'ya huge," I reduced the list down to two names: steroids and hormonal bigness. Although I prefer the latter, from here on out, we will, quite simplistically, refer to this class of hormones as steroids simply for brevity and simplicity.
Steroids can be Testosterone itself or one of the naturally produced or artificially produced derivatives of this sex hormone. When we say "derivative," we mean compounds with a relatively similar chemical structure that possess only a few structural modifications. Take the Testosterone ring structure seen below and add a carbon here, take one away there, add an alcohol here, take one away there, and you're forming all sorts of different steroids.
Figure 1: Unaltered Testosterone
If this chemical modification occurs in the body, then we say that the steroid is naturally produced. The natural production of steroids occur through what we call endogenous (made within the body) Testosterone metabolism. In this pathway, cholesterol goes through a series of metabolic steps to form all of the sex hormones. The eventual pathway to Testosterone includes intermediates such as DHEA and androstenedione (seen below).
DHEA Androstenedione Testosterone
Figure 2: Endogenous Steroids Leading Up To Testosterone
On the other hand, the artificial production of steroids, or the production of exogenous (meaning made outside the body) steroids, can occur in a research laboratory, a manufacturing facility, or some black market drug dealer's leaky bathtub.
Oxandrolone Testosterone Cypionate
Figure 3: Two Exogenous Steroids
Below is a list of some of the endogenous steroids as well as some of the exogenous steroids. The endogenous steroids are mostly produced in men by the testis and in women by the adrenal glands. These steroids are responsible for the masculinization (androgenic) and the tissue building (anabolic) effects seen during adolescence and adulthood.
Endogenous Steroids Exogenous Steroids
DHEA
Androstenedione
Androstenediol
Testosterone
DHT
Testosterone Cypionate (ester)
Testosterone Enanthate (ester)
Testosterone Propionate (ester)
Dianabol
Oxandrolone
Oxymetholone
Stanozolol
Nandrolone
While adequate production of the endogenous (made by the body) steroids is critical for normal homeostatic function, exogenous (made outside the body) steroids can be used to increase lean body mass, decrease fat mass, increase nitrogen retention, restore sexual function, alleviate depression, and promote a host of other effects, especially in those who suffer from hypogonadism (low endogenous manufacture of testosterone).
With the aforementioned health, sport, and functional links clear, there are several groups of individuals who use steroids, including athletes interested in performance improvement or body composition changes, non-athletes interested in body composition changes or "cosmetic enhancement," and clinical patients. The latter group is, of course, the only group that can obtain a prescription for legal steroid use. Illegal use of steroids, however, is widespread.
Bodybuilders obviously use them to increase lean body mass while decreasing fat mass.
Similarly, competitive weight lifters use them to increase muscle strength and nervous system activation, thereby increasing the amount of weight they can lift as well as their explosiveness.
Since anaerobic sport athletes benefit from increased muscle mass, decreased fat mass, increased muscle strength, and increased explosiveness; they also use steroids for performance enhancement and recovery.
Even endurance athletes frequently use steroids to combat the decline in endogenous steroid production seen with high volume training, along with wanting to provide some anti-catabolic protection, and to boost blood volume.
However, of course, the biggest population of steroid users is not made up of elite athletes. Instead, recreational athletes and weight lifters tend to make up the largest population of steroid users, their goals being to improve body composition in order to look better clothed or naked. Some people have called this cosmetic enhancement.
Since Joe Weider Invented Bodybuilding, Did He Invent Steroids Too?
I hate to break it to ya but Joe Weider didn't invent bodybuilding nor did he invent steroids. Steroids were "discovered" back in the 1920's. At this time, male urinary extracts were shown to increase the skeletal growth and reproductive development of experimental dogs and roosters.
After some tinkering around with the extracts, the scientists discovered a purified lipid soluble chemical that was derived from cholesterol. This compound was called Testosterone (as it was produced in the male testis).
After more tinkering, it was found that Testosterone wasn't the only substance that would induce growth and development. Other naturally produced compounds could also do the same, including DHEA. These experiments and others also demonstrated that small chemical modifications could enhance the effectiveness of Testosterone when extracted and given to other organisms.
Oral studies demonstrated that the addition of a functional group to the 17th carbon made Testosterone orally active. Without this addition, Testosterone seemed to have no effect. In addition, fatty-acid additions (etherification) increased the biological activity and half-life (i.e. the time that the stuff sticks around in the body) of Testosterone. Again, without these additions, Testosterone would be much less effective, either never making it to the target cells or only sticking around for a few minutes if they did. These new preparations, made way back in the 30's, were the precursors to today's popular Tstosterone esters (again, basic Testosterone with functional groups attached to prolong life) including propionate, cypionate, and enanthate.
The medical community was then made aware of the effects of steroids in the 30's. Of course, shortly thereafter, it was rumored that athletes were getting "the juice" from their doctors. In particular, it's been discussed that German athletes had been given steroid preparations by their team doctors in preparation for the 1936 Berlin Olympic games. Throughout the next decade or two, as doctors and athletes gained more experience with steroid use, the performance and "anti-aging" benefits were becoming evident. As was bound to happen, by the 1950s, a significant number of bodybuilders and Olympic athletes around the world had been reporting dramatic gains with steroid use.
While, back then, steroid use was only associated with a small percentage of the world's athletic population, presently an estimated 3 million male and female athletes in the United States alone have used steroids. Interestingly, despite nearly 70 years of positive feedback on the performance benefits of steroids, it wasn't until recently (within the last five or six years) that steroids were convincingly proven (via well controlled experimental studies) to increase lean mass and strength.
Of course it seems somewhat of a puzzle that so many experts, for so long, insisted that didn't work. The reason could very well be that they were simply trying to dissuade people from using them. After all, why would someone want to use steroids if they didn't work?
In addition, the early research didn't demonstrate the effectiveness of steroids. These studies, many of which demonstrated that anabolic steroids offered no athletic benefit whatsoever, had several design flaws. Many were neither blinded nor randomized, nutritional intake was usually not controlled, and the exercise stimulus wasn't controlled. Moreover, the biggest problem was probably that many of the studies used only small doses (replacement doses or less), unlike the supraphysiological doses (above the normal physiological range) that are necessary to promote positive effects. Regardless of the medical community's lack of support, athletes have known for decades that steroids undoubtedly improve body composition and performance.
The medical community has finally caught up with what the athletes have known all along.
Wanna' know how steroids work and what, exactly, they do? Check back next week for part II. At this point, now that we've introduced some definitions, structures, and a brief history of their discovery and use in sport, we'll give you a week to process this information. Next week we'll talk about how steroids are used, how they work, and we'll discuss the side effects (both positive and negative).
Steroid Manifesto, Part 2
What Your Doctor, Your Friends, Your Mamma,
and Maybe Even You Don't Know About Steroids
By John M Berardi and Kris Aiken
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.
Steroid Manifesto, Part 3
What Your Doctor, Your Friends, Your Mamma, and Maybe Even You Don't Know About Steroids
By John M Berardi and Kris Aiken
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, while part 2 discussed how they're used. This final installment addresses the legal concerns.
Legal, Illegal, Am I Going To Jail?
Since steroids are often sold in locker rooms around the country without a second thought and since the status of steroids has changed over the years, many individuals have no idea as to the true legal status of the drugs or the implications of being caught dispensing or possessing them. If you're gonna play the game, at least know the rules.
Before 1988, steroids were classified as mere prescription drugs by the FDA (Food and Drug Administration). The job of the FDA is to determine which drugs will be classisified as over-the-counter and which will be available only through prescription. In addition, during this time, the Federal Food, Drug, and Cosmetic Act, an act designed to restrict the access of certain drugs to those with "legitimate" medical uses (i.e. with a prescription) by categorizing drugs, determined that steroids could only be distributed with a prescription.
Importantly though, at this time, steroids were not classified as "controlled substances" by the Controlled Substances Act. "Controlled substances" are substances that are more tightly regulated than "uncontrolled" prescription drugs. With tighter control comes a longer paper trail, more intense scrutiny of doctors prescribing these drugs, and more severe penalties associated with illegal dispensation and use.
By the early 80's, due to more frequent reports of steroid use in athletes, especially young athletes, policy makers began to discuss elevating steroids to "controlled" status. Finally, in 1988, the Anti-Drug Abuse Act was passed, putting steroids in a special prescription category, one that carried severe legal penalties for illegal sale or possession with intent to distribute. Remember, before 1988 steroids had always been illegal to sell or possess without a prescription. This new act simply added a very real threat of serious legal penalty (making it a felony, in fact).
Contrary to their attempts to reduce steroid use via legislation, steroid use only accelerated in years following the passage of this act. In response, Congress decided to go ahead and add steroids to the Controlled Substances Act as an amendment (Anabolic Steroid Control Act of 1990), making steroid possession, possession with intent to distribute, and distribution serious offences with penalties similar to those associated with morphine and other scheduled substances.
Interestingly, the transcripts from the Congressional hearings were clear in indicating that health concerns were not the main reason for making steroids controlled substances despite the fact that nearly every other controlled drug was on that list because of associated (and sometimes severe) health risks and dependency. Instead, Congress decided to control these drugs in response to the cries of athletic organizations and in response to a desire to limit adolescent use. Sure, the health risks were considered. But they were not the main motive or force for scheduling these drugs as "controlled." While there are several categories of controlled substances ("schedules"), steroids are placed in Schedule III, along with amphetamines, methamphetamines, opium, and morphine. Buying, possessing, and selling steroids, nowadays, is legally equivalent to buying opium and morphine.
Confused yet? If so, let me break it down. In 1990 steroids were vaulted to an extreme category of highly specialized prescription drugs, drugs that are more difficult to prescribe or obtain, drugs that carry severe penalties for their illegal possession, use, and distribution. This, of course, occurred on a federal level. To add more confusion to the issue, state laws vary with respect to steroid classification and the severity of penalties. All of this legislation, interestingly, occurred without the support of the American Medical Association, the FDA, the DEA, and the National Institute on Drug Abuse! All of these expert agencies actually testified, sometimes vehemently, against the federal and state legislation.
In direct response to the changes in steroid law, many individuals, from big-time black market steroid traffickers to small-time steroid users, have served significant prison sentences for their unlawfulness. Nevertheless, it's clear that these laws have not reduced steroid use in the general public or in athletics, which was their original intent. In addition, with respect to health issues, many believe that the Anabolic Steroid Control Act, rather than protecting the public, created the two biggest health problems associated with steroid use: counterfeit drugs and improper medical supervision.
Understand that regardless of whether on not drug laws are right or wrong, they are still on the books and we are all subject to them. If you choose to use steroids without a prescription, you are choosing to defy the law. In choosing to defy the law, you're accepting the risk of getting caught, serving time in prison, and/or paying some hefty fines and lawyer fees.
I'm An Athlete — What Do I Have To Know?
Whether this is an appropriate view or not, athletics have historically been seen as an endeavor that promotes health and well-being as well as the idea of fair play. Therefore, an embarrassing hypocrisy is present when drug use is rampant at the highest levels of athletics (pro and Olympic level sport).
In an effort to prevent the "tarnishing" of a long-standing athletic ideology, sport-governing bodies, historically, have attempted a two-tiered approach: lobby Congress for more severe drug regulations, and implement mandatory drug testing of athletes. Arguably, neither has produced the desired effect. At the same time though, abandonment of these policies would be an admission of defeat; indirectly condone drug use; and allow athletes who are more pharmaceutically daring to gain a competitive edge over those more conservative athletes. Therefore, governing bodies have remained steadfast in their commitment to their testing programs.
Drug testing in sport began in the late 1950's. However, the first testing for steroids was implemented during the 1976 Montreal Olympic Games after the creation of specific screening procedures (RIA — radioimmunoassay, and GCMS — gas chromatography — mass spectrometry). At this time, the testing consisted of analyzing urine samples (the only permitted testing fluid) using RIA for exogenous steroids. If they were found in urine, GCMS was used to confirm the results. Since this type of testing lacked specificity and since this method could not distinguish between endogenous and exogenous Testosterone, new methods were required.
Later, in 1984, GCMS was used as the main method of analysis. This method could test for more specific steroid metabolites as well as testing the Testosterone to epitestosterone ratio (T/E). This latter method could distinguish whether a person was on Testosterone because endogenous Testosterone is produced in the testis in a 1:1 ratio with epitestosterone. Therefore, if someone were on exogenous Testosterone, this ratio would be out of balance. Due to some natural variations in this ratio it was established that a 6:1 ratio of T/E determined suspicion while a 10:1 ratio established guilt.
This method of testing, however, could be overcome by a variety of methods:
— Simply co-administering a cocktail of Testosterone and epitestosterone to maintain the appropriate ratio. This cocktail would also contain other appropriate endogenous steroids since the administration of only T and e would inappropriately elevate these two hormones relative to the other endogenous steroids, thereby raising caution flags. On the other hand, the co-administration of Testosterone and epitestosterone alone, if done in smaller doses, might not be cause for suspicion.
— The use of Testosterone patches or gels. These drugs have a slower release and deliver steroids in such a way as to lower peak blood concentration, perhaps allowing athletes to still pass using the 6:1 ratio as the standard. However this use, due to 5 alpha reductase activity in the skin, can lead to elevated blood DHT and the DHT may be detected in the urine.
— Having a good lawyer. The T/E ratio is flawed due to the fact that very little is known about individual variation based on diet, gender, training, etc. In addition, there are several scenarios that will raise the T/E ratio without the accused actually taking Tstosterone. As a result, several cases have been thrown out due to inconclusive evidence that drugs were used.
Since there are serious problems with the T/E ratio for detecting steroid use (the current method), a new technique is being proposed for use. This technique uses IRMS (isotope ratio mass spectrometry) to distinguish exogenous Testosterone from endogenous Testosterone. Since Testosterone is made up of carbon atoms and different carbon atoms have different weights, IRMS can figure out how many of the lighter carbons (C12) and how many of the heavy carbons (C13) are around.
Endogenous Testosterone (naturally produced) is made up of 98.9% C12 and 1.1% C13. If any Testosterone shows up in the urine that doesn't contain these percentages, it's suspected that the person is using exogenous Testosterone.
In addition, Testosterone and other steroids can be used without penalty by:
— The use of masking agents (drugs designed to mask the metabolites of certain steroids) and/or specially formulated drugs that are not currently detectable.
— Monitoring by, what some call, "rogue labs." Many athletes will have their blood and urine monitored regularly in order to ensure that the drugs they are using are not detectible.
As you can see, the drug testing procedures are becoming increasingly more complex in an attempt to keep pace with new drugs and new techniques designed to beat the current tests. Unfortunately, with this complexity comes exponential growth in the expenses associated with testing. Off-season testing can cost up to $1000 per sample. In addition, in competition testing can cost upwards of several million dollars for an event like the Olympic games. Finally, it costs millions of dollars to fund research to keep ahead of drug users. As a result, some experts believe that testing methods are destined to fail.
However, regardless of the outcome, athletes are faced with the choice of avoiding steroids and risking victory or using steroids and risking detection. To the average athlete without advanced drug use and masking techniques, there's a good chance of getting caught.
Of course, the intensity of these efforts is directed at Olympic and international level athletes. Professional sport tends to treat drug use much differently and therefore avoids much of the controversy associated with Olympic sport.
Summing It All Up
This three-part introduction to steroids has attempted to provide an overview of the T-Nation's namesake by discussing steroid definitions, chemical structures, a brief history of steroids, an overview of how steroids were introduced to sport (part I). In addition, we've provided a brief introduction to modes of steroid delivery, how steroids work, and side effects (both good and bad) (part II). Finally, we've provided some information about legal issues and testing in sport (part III).
Cortisol: The "Stress Hormone"
This critical hormone is released in response to stress.
The hormone cortisol, which is released in the body during stressed or agitated states, has gained widespread attention as the so-called "stress hormone." But this hormone is more than a simple marker of stress levels- it is necessary for the functioning of almost every part of the body. Excesses or deficiencies of this crucial hormone are also lead to various physical symptoms and disease states.
Background
Cortisol is a steroid hormone made in the adrenal glands, which are small glands adjacent to the kidneys. Among its important functions in the body include roles in the regulation of blood pressure and cardiovascular function as well as regulation of the body's use of proteins, carbohydrates, and fats.
Cortisol secretion increases in response to any stress in the body, whether physical (such as illness, trauma, surgery, or temperature extremes) or psychological. When cortisol is secreted, it causes a breakdown of muscle protein, leading to release of amino acids (the "building blocks" of protein) into the bloodstream. These amino acids are then used by the liver to synthesize glucose for energy, in a process called gluconeogenesis. This process raises the blood sugar level so the brain will have more glucose for energy. At the same time the other tissues of the body decrease their use of glucose as fuel. Cortisol also leads to the release of so-called fatty acids, an energy source from fat cells, for use by the muscles. Taken together, these energy-directing processes prepare the individual to deal with stressors and ensure that the brain receives adequate energy sources.
The body possesses an elaborate feedback system for controlling cortisol secretion and regulating the amount of cortisol in the bloodstream. The pituitary gland, a small gland at the base of the brain, makes and secretes a hormone known as adrenocorticotrophin, or ACTH. Secretion of ACTH signals the adrenal glands to increase cortisol production and secretion. The pituitary, in turn, receives signals from the hypothalamus of the brain in the form of the hormone CRH, or corticotropin-releasing hormone, which signals the pituitary to release ACTH. Almost immediately after a stressful event, the levels of the regulatory hormones ACTH and CRH increase, causing an immediate rise in cortisol levels. When cortisol is present in adequate (or excess) amounts, a negative feedback system operates on the pituitary gland and hypothalamus which alerts these areas to reduce the output of ACTH and CRH, respectively, in order to reduce cortisol secretion when adequate levels are present.
Measurement of Cortisol Levels
The body's level of cortisol in the bloodstream displays what is known as a diurnal variation - that is, normal concentrations of cortisol vary throughout a 24-hour period. Cortisol levels in normal individuals are highest in the early morning at around 6-8 am and are lowest around midnight.
Normal levels of cortisol in the bloodstream range from 6-23 mcg/dl (micrograms per deciliter).
In addition to early morning, cortisol levels may be somewhat higher after meals. While the most common test is measurement of the cortisol level in the blood, some doctors measure cortisol through a saliva sample, as salivary cortisol levels have been shown to be an index of blood cortisol levels. Sometimes by-products of cortisol metabolism are also measured, such as 17-hydroxycorticosteroids, which are inactive products of cortisol breakdown in the liver. In some cases measurement of urinary cortisol levels is of value. For this test, urine is collected over a 24-hour period and analyzed.
Normal 24-hour urinary cortisol levels range from 10-100 micrograms/ 24 hours.
Abnormal Cortisol Levels
Certain drugs can lead to increased cortisol levels. Examples include the diuretic spironolactone and estrogen hormone therapy. Low cortisol levels can be due to drug therapy with androgens or the anti-seizure medication phenytoin. Highly-trained athletes can have higher-than-average cortisol levels, and women in the last trimester of pregnancy also generally have elevated cortisol levels. Recent research has even shown that drinking 2-3 cups of coffee per day can elevate cortisol levels. Likely due to the increased physical and psychological stresses associated with these conditions, persons suffering from depression, anxiety, panic disorder, malnutrition and alcohol abuse also often have elevated cortisol values. Rare tumors of the adrenal glands or pituitary gland can also lead to abnormally high levels of cortisol.
Cushing's Syndrome
Persons exposed to abnormally high levels of cortisol over time develop a syndrome known as Cushing's Syndrome.
This condition generally affects adults, and approximately 10-15 per million persons will develop this condition each year. Signs and symptoms of Cushing's Syndrome include elevated blood pressure, development of diabetes, pink-to-purple stretch marks on the abdominal skin, fatigue, depression, moodiness, and accentuated fatty tissue on the face and upper back. Women with Cushing's Syndrome often have irregular menstrual periods and develop new facial hair growth. Men may show a decrease in sex drive. Treatment options are varied and depend on the cause of the excess cortisol.
Addison's Disease
Primary problems with the adrenal glands or with the pituitary gland can lead to a condition known as Addison's Disease, in which the adrenal glands fail to produce adequate amounts of cortisol. This condition occurs in persons of all ages and affects approximately one in 100,000 people per year. Symptoms are fatigue, low blood pressure, weight loss, weakness, loss of appetite, moodiness, nausea, vomiting, and diarrhea. The production of other hormones by the adrenal is also often affected, with reduced levels of the hormone aldosterone, which is important for body salt and water balance, often accompanying the reduction in cortisol. This condition can be treated by the administration of synthetic steroid hormone preparations.
Cortisol, Stress, and Weight Gain
Role of the "Stress Hormone" in Weight Control
Eating when under stress isn't just about filling an emotional need. Your body has a system of hormonal checks and balances that actually promote weight gain when you're stressed out.
The so-called "stress hormone" cortisol is released in the body during times of stress along with the hormones epinephrine and norepinephrine that constitute the "fight or flight" response to a perceived threat. Following the stressful or threatening event, epinephrine and norepinephrine levels return to normal while cortisol levels can remain elevated over a longer time period. In fact, cortisol levels can remain persistently elevated in the body when a person is subjected to chronic stress.
How does cortisol influence weight gain? Cortisol has many actions in the body, and one ultimate goal of cortisol secretion is the provision of energy for the body.
Cortisol stimulates fat and carbohydrate metabolism for fast energy, and stimulates insulin release and maintenance of blood sugar levels. The end result of these actions is an increase in appetite. Thus chronic stress, or poorly-managed stress, may lead to cortisol levels that stimulate your appetite, with the end result being weight gain or difficulty losing unwanted pounds.
Cortisol not only promotes weight gain, but it can also affect where you put on the weight. Doctors have shown that stress and elevated cortisol tend to cause fat deposition in the abdominal area rather than in the hips. This fat deposition has been referred to as "toxic fat" since abdominal fat deposition is strongly correlated with the development of cadiovascular disease including heart attacks and strokes.
Whether or not your stress levels will result in high cortisol levels and weight gain is not readily predictable. The amount of cortisol secreted in response to stress can vary among individuals, with some persons being innately more "reactive" to stressful events. Studies of women who tended to react to stress with high levels of cortisol secretion showed that these women also tended to eat more when under stress than women who secreted less cortisol. Another study confirmed that women who stored their excess fat in the abdominal area had higher cortisol levels and reported more lifestyle stress than women who stored fat primarily in the hips.
What does this mean for weight control?
Experts agree that stress management is a critical part of weight loss regimens, particularly in those who have elevated cortisol levels. Exercise is the best and fastest method for weight loss in this case, since exercise leads to the release of endorphins, which have natural stress-fighting properties and can lower cortisol levels. Activities such as yoga and meditation can also help lower your stress hormone levels. To effectively reduce elevated cortisol due to stress, lifestyle changes are essential.
Muscle Breakdown: Is Cortisol Leading You Down the Catabolic Pathway?
By Rehan Jalali
Walk into any so-called "hardcore" gym these days, and you’ll likely see ‘em by the dozens. They’re easy to spot… they’re the guys who spend hours on end pushing up plates, searching for supreme physical perfection, yet rarely finding it. They are the hopelessly overtrained, and they’re afflicted with that old Protestant work ethic: a little training is good, so a whole lot must be better.
The very idea of producing a peak physique leads to a perverse temptation among these fellows to do all but pitch tent in the weight room and camp out there 24/7. "There’s no such thing as overtraining," they declare. Indeed, they know a lot of clichés and can spout them off with machine-gun repetition—No Pain, No Gain… If the Bar Ain’t a Bendin’, You’re Just Pretendin’… Go Heavy or Go Home. But ask them anything specific about exercise physiology or the dynamics of muscle-fiber hypertrophy and repair, and they’re as quiet as Tori Spelling playing Trivial Pursuit.
The bottom line is, if you’re among the band of hard-and-heavy lifters, cortisol may be literally eating away at your muscle-building potential. Weight training enthusiasts must declare all-out war on this catabolic hormone if they have any aspirations of building muscle. But before we attack all of your cortisol problems, some background on this intriguing subject is in order. After all, understanding leads to solutions (or was it madness?). Anyways, here goes….
Cortisol is the primary glucocorticoid. It is a natural hormone of the adrenal glands. Although cortisol's precise actions are not completely understood, we know that it is essential for life. Cortisol is necessary to maintain important processes in times of prolonged stress. Most of its effects are not directly responsible for the initiation of metabolic or circulatory processes, but it is necessary for their full response.
Cortisol Synthesis: Cholesterol--> Pregnenolone--> Progesterone -->
17-Hydroxyprogesterone-->11-Deoxycortisol --> Cortisol.
Cortisol can exert its effects on peripheral tissue. Once in circulation, cortisol is typically bound to a specific glucocorticoid-binding alpha2-globulin called transcortin. About 75% of cortisol is bound to transcortin, 15% to 20% bound less tightly to albumin, and 5% of circulating cortisol is unbound (1). This is an important factor to take into consideration when measuring cortisol levels. The 24-hour urinary excretion of unmetabolized cortisol is one of the best ways to accurately gauge cortisol levels. This helps take into account bound and free cortisol. Exogenous cortisol has a half-life of about 70 to 90 minutes. Cortisol can be converted to its 11-keto analogue cortisone (you know, the stuff you take when you have some bad swelling or inflammation).
The major catabolic effects of cortisol involve its facilitating the conversion of protein in muscles and connective tissue into glucose and glycogen (cortisol may increase liver glycogen). Gluconeogenesis involves both the increased degradation of protein already formed and the decreased synthesis of new protein. Cortisol can also decrease the utilization of glucose by cells by directly inhibiting glucose transport into the cells (1). A cortisol excess can also lead to a decrease in insulin sensitivity. Cortisol also reduces the utilization of amino acids for protein formation in muscle cells. A cortisol excess can lead to a progressive loss of protein, muscle weakness and atrophy, and loss of bone mass through increased calcium excretion and less calcium absorption. That is one of the reasons long-distance runners tend to have skinny physiques. With the amount of stress that runners place on their bodies, they have high levels of free radicals as well as cortisol. Excess cortisol can also adversely affect tendon health. Cortisol causes a redistribution of bodyfat to occur through an unknown mechanism. Basically, the extremities lose fat and muscle while the trunk and face become fatter. Some of the signs of overtraining include higher cortisol levels, which may cause depression-type effects.
Cortisol excess can also lead to hypertension because it causes sodium retention (which can make you appear bloated) and potassium excretion. In other words, excessively high cortisol levels may turn you into a girly man! So the real challenge becomes how can cortisol levels be controlled but not inhibited completely because of cortisol's necessary anti-inflammatory effects?
One way is to take anti-cortisol supplements in the morning upon rising and then before bedtime, as these are two times that cortisol levels seem to be raised. Timed release would not be an option here because this may suppress cortisol levels over too long of an extended period. The key is to suppress elevated levels of cortisol, not decrease normal physiological levels of this hormone because as I mentioned earlier, a small amount is needed for it's anti-inflammatory and other effects.
Another one of cortisol's undesirable effects for athletes is it causes insulin resistance by decreasing the rate at which insulin activates the glucose uptake system, likely because of a post-insulin receptor block (2). Any type of stress that occurs to the body signals the nervous system to relay this to the hypothalamus. The hypothalamus then responds by initiating the stress-hormone cascade starting with CRF (corticotrophin releasing hormone) followed by ACTH (adrenocorticotropic hormone) release, and finally glucocorticoid production (pretty intense, huh?). Stress to the human body can include trauma, anxiety, infections, surgery, and even resistance training and aerobics. Recent research has shown that increased cortisol levels also increased protein breakdown by 5% to 20%. (3) Even mild elevations in serum cortisol can increase plasma glucose concentration and protein catabolism within a few hours in healthy individuals. (4) Cortisol increases with increasing time of intense exercise. In overtrained individuals, cortisol levels increase while testosterone levels decrease. That is why one measure of overtraining is the testosterone: cortisol ratio. By the way, overtraining is defined as an increase in training volume and/or intensity of exercise leading to a decrease in performance. Cortisol can increase bodyfat levels especially when it’s increased dramatically in the body. Increased cortisol levels have an adverse effect on testosterone levels. In fact, one of the primary anti-catabolic effects of testosterone and anabolic steroids is it's decreasing muscle cortisol metabolism. (5) That is one reason why many athletes can completely overtrain when taking anabolic steroids and still increase lean body mass and strength.
Some research indicates that cortisol response to resistance training normalizes after about five weeks and that the testosterone: cortisol ratio is not adversely affected after long periods of resistance training. (6) This suggests that the body has an adaptive response.
Cortisol can inhibit growth-hormone levels by stimulating the release of somatostatin (a growth-hormone antagonist). It may also reduce IGF-1 expression (IGF-1 is one of the most anabolic agents in the body and is the substance that is responsible for most of growth hormone’s positive effects because GH converts into IGF-1 in the liver).
Cortisol has other hormone-modifying effects. Cortisol can directly inhibit pituitary gonadotropin and TSH (thyroid stimulating hormone). (7) By doing so, it can make the target tissues of sex steroids and growth factors resistant to these substances. It may also suppress an enyme known as 5' deiodinase, which converts the relatively inactive thyroid hormone T4 to the active one known as T3 or triiodothyronine. This can decrease metabolic rate and make it harder to lose bodyfat (it's already hard enough for people and anything making it harder definitely needs to be kicked to the curb).
There are different stages in sleep and during one stage, cortisol levels are elevated because protein is being re-cycled. This is one reason that cortisol-suppressing supplements should be taken before bedtime to help minimize excess cortisol production during sleep.
Cortisol also seems to play a role in various disease states. It is found in higher-than-normal levels in diseases ranging from AIDS and multiple sclerosis to Alzheimer's. Prolonged high levels of cortisol can throw the immune system into chaos and ravage the human body. A growing number of researchers believe that many of the worst, and least-understood, diseases will soon be identified as caused by high cortisol, and subsequently treated with cortisol- reducing drugs or supplements.
There was an anti-cortisol conference (the second one ever conducted) held in Las Vegas in 1997 and headed up by Steroidogenesis Inhibitors Inc. and Dr. Alfred T. Sapse. This conference had many researchers involved in anti-cortisol research. Abstracts were presented on various supplemental and drug therapies for decreasing cortisol levels, especially in excessive cortisol-production disorders. In particular, there was an abstract presented by Dr. Sapse that mentioned some nutritional supplements to lower cortisol levels in the body. These included gingko biloba, Vitamin A, Zinc, and acetyl l-carnitine (8). Other abstracts presented there discussed the role of DHEA and its metabolites in helping to decrease cortisol levels. (9) Some abstracts presented looked at the progression of cortisol-induced diseases. Overall, the conference was very informative and helped researchers answer many questions on cortisol and anti-cortisol therapies as well as opened the door for further anti-cortisol research.
Cortisol suppression may be an essential part in the recovery process for athletes involved in a rigorous training program. In fact, one of the signs of overtraining syndrome is high cortisol levels. Moderating (not completely diminishing) cortisol levels is an essential factor in allowing weight-training individuals to completely recover from their exercise session and maximize results (something we would all like to do).
It may be a very good idea to get cortisol levels tested by a qualified physician (when I say qualified, I mean one who has done this sort of thing before and has been to medical school) on a regular basis. One of the best times to test cortisol levels is first thing in the morning on an empty stomach. This reference value or proper range for cortisol first thing in the morning should be between 4 mcg/dl and 19 mcg/dl with the sample being taken from blood. The normal range for free cortisol levels measured from urine is between 10 pg/ml and 110 pg/ml. There is also another way to measure cortisol through a salivary cortisol screening.
The normal range for cortisol with this test first thing in the morning is between 100nmol/L and 300nmol/L. These tests may not have the final say in determining high cortisol levels but, it will certainly give you an idea about where your cortisol levels stand.
Controlling Cortisol Levels
Here are some solid tips to help control cortisol levels:
1) Diet: Make sure you are supplying your body with all the essential nutrients you need to prevent deficiencies and for optimal function. This includes plenty of high-quality protein, complex carbohydrates, essential fatty acids, and vitamins and minerals. Try not to restrict calories continuously as some research suggests that restricting normal caloric intake by 50% can lead to a subsequent increase in cortisol levels by 38%. (10)
2) Do not overtrain: Try not to work out three or more days in a row without taking a day off. Keep workouts to under an hour at the most and train efficiently and intensely. I know this phrase has been beaten to death but LISTEN TO YOUR BODY!
Take enough rest days between workouts - If you are really sore, then wait an extra day to train until your body fully recovers from your previous workout. Remember, less may be more in this case.
4) Relax and try not to get stressed out easily: Take an evening walk with a loved one or take a nap when you get a chance.
5) Try to get at least eight hours of sleep per night: Sleep is crucial to the recovery and recuperation process.
6) Spike Insulin levels after a workout: Insulin actually interferes with cortisol and may enhance cortisol clearance from the body. Spiking insulin levels after a workout (by consuming a high-glycemic index carbohydrate) may help minimize excessive cortisol levels since cortisol levels are elevated significantly post resistance training.
Supplements that may help control increased cortisol levels secondary to intense exercise
Phosphatidylserine (PS):This phospholipid, which has been known mainly for its cognitive effects, seems to have cortisol-suppressive properties. Recent research shows that 800 mg Phosphatidylserine given in two divided oral doses helps suppress cortisol secondary to intense weight training. (11) In fact, in this same study, the individuals using PS experienced less muscle soreness as well. Earlier research by Monteleone confirms these results. By decreasing cortisol levels, the testosterone: cortisol ratio can increase possibly relating to anabolic effects. PS seems to only decrease cortisol levels when they are elevated and does not seem to decrease cortisol levels below normal. Decreasing cortisol levels or suppression of cortisol production is not desired in many instances as it may cause adverse effects such as a decrease in reaction time to wounds and healing mechanisms in the body. There are two forms of PS available: a brain cortex derivative and a soy lecithin derivative. The brain cortex PS has been used in most of the studies and shown to be effective.
Acetyl-L-carnitine: This is basically the acetylated ester of L-carnitine. This supplement may help prevent the decline in testosterone that occurs during and after an intense resistance training session. It seems to lessen the response to stress.
L-Glutamine: This is the most abundant free amino acid in muscle tissue. (12) It seems to play a very important role in protein synthesis and is very important to weight-training athletes. Some research suggests that glutamine levels may be a good indicator of overtraining or overreaching. (12) In other words, athletes who were overtrained generally had low levels of glutamine along with high levels of cortisol. One study actually showed that glutamine directly prevents the cortisol-induced degradation of muscle contractile proteins.(13) Some of its positive effects include enhancing protein synthesis; increasing GH levels, which can counteract some of the catabolic effects of cortisol; potent cell-volumizing effects, which can create an anabolic environment in muscle cells; and partially determining the rate of protein turnover in the muscle. An oral glutamine supplement can help athletes prevent some of the symptoms of overtraining. It may also enhance glycogen synthesis through an unknown mechanism. It also helps provide a source of fuel for the small intestine and may enhance anti-inflammatory function. It has been shown to boost immune function. I hope you get the point -Glutamine is a vital nutrient for weight-training athletes.
Vitamin C: This vitamin, mainly known for it's anti-oxidant properties, may also have some anti-cortisol effects. A study done by Stone entitled "Effects of Vitamin C on Cortisol and the Testosterone: Cortisol Ratio" showed a decrease in cortisol levels in 17 junior elite weight lifters. This study also showed that the individuals taking Vitamin C (an extra gram a day) improved their testosterone:cortisol ratio by over 20%. This type of decrease in cortisol can lead to increased muscle and connective-tissue hypertrophy and enhanced recovery from training. Since Vitamin C also decreases your chances of suffering from a cold or flu infection by 30% (14) and may aid in collagen synthesis, it would be wise to take some extra vitamin C when involved in an intense weight-training program.
Zinc: A mineral that is an essential cofactor in over 300 enzymatic reactions in the body including testosterone synthesis and steroid hormone production. Getting enough zinc may make the difference between making great gains and only making average gains in a weight training program.
Vitamin A: This vitamin, which is often times used for healthy skin function, may also minimize cortisol levels according to Dr. Sapse. He suggested this in an abstract he presented at the 1997 conference on cortisol and anti-cortisols. (8)
Gingko Biloba: This herb is mainly used for its excellent cognitive effects by increasing blood flow and oxygen to the brain, which can lead to greater mental focus and concentration. It may also have additional benefits of decreasing cortisol levels according to an abstract presented at the 1997 conference on cortisol and anti-cortisols. (15) The anti-stress and neuroprotective effects of ginkgo biloba in this study were due to its effect on glucocorticoid biosynthesis. The EGb 761 standardized gingko biloba extract was used in this study and many of the studies showing that it enhances cognition.
DHEA: This natural hormone of the adrenal glands that declines after the age of 30 seems to have some powerful anti-cortisol effects. Many abstracts presented at the 1997 conference on cortisol and anti-cortisols discussed DHEA's role in decreasing cortisol levels. DHEA is fat soluble so it can cross the blood-brain barrier and have some effects on cognition as well.
Androstenedione: This prohormone is a direct precursor to testosterone, which may explain its anti-cortisol effects since increases in testosterone can blunt elevated cortisol levels secondary to intense weight training. Different metabolites of androstenedione and testosterone, such as 4-androstenediol, 5-androstendiol, and nornadrostenediol, may also exert some anti-cortisol effects. However, more research needs to be done in this area to make this clear!
Androstenetriol: This steroid metabolite, which is chemically known as Delta 5-androstene-3b,7b,17b,triol, was shown in an abstract presented at the 1997 conference on cortisol and anti-cortisols to counteract the immunological effects of glucocorticoids. (16) This is an interesting compound that definitely needs to be looked at further.
Conclusion
This is a subject that will be studied thoroughly in the future. Studies investigating supplemental strategies against cortisol may help weight trainers get the most out of their workouts and help enhance the recovery and recuperation process. Now before you think suppressing cortisol levels can make you Hercules, remember, cortisol levels are one piece to a large and complex puzzle. It takes a combination of proper training, nutrition, and supplementation to achieve your true muscle-building potential. However, getting cortisol levels checked by your doctor and implementing strategies against cortisol may be a good idea, especially during a calorie-restrictive dieting phase. So, the next time you feel tired, sluggish, or sore for an abnormally long time in your weight-training program, and you don't know why, look into cortisol levels, and you might find the answer.
The Big T
How your lifestyle influences
your Testosterone levels ? Part 1
by John M. Berardi
Like it or not (and I'm sure T-mag readers really like it), Testosterone is the hormone of the decade. The granddaddy of the male hormones has gotten more media attention over the last few years than any other hormone around. Heck, I even heard a rumor that some crazy bodybuilding media guys were thinking of naming a magazine after it. Can you imagine that?
While Testosterone (the hormone, of course) has been the target of much bad press, I think that if you asked this big dog of hormones what he thought of all of this, he would bark out something to the effect of "What of it? I must be doing something right if they keep talking about me! Now can't you see I'm trying to work this shaved little poodle over here?"
Although the popular media has made Testosterone out to be a destructive bad guy, researchers have been slowly but surely embracing its use. Clinical trials have been conducted in diverse groups of individuals from HIV wasting patients and burn victims to people with compromised immunity, along with older men whose "Testosterone" hasn't been up in years. There have even been a number of recent trials investigating the use of Testosterone in healthy weight trained men. So where do I sign up?
The results of these investigations have shown that Testosterone is not the demon the medical community once thought it to be and that it actually can be of great benefit to certain individuals and, in certain patients, possesses very few risks.
I'm pretty positive though, that the use of Testosterone will never be condoned for use in healthy weight trained males. To this end, us law abiding citizens have to do the best we can with what we've got to work with. So let's talk about how our own body provides us with the big T and what we can do, both naturally and with dietary supplements, to maximize our T levels.
When most people think of steroids, they tend only to think of Testosterone. This, my friends, is yet another fact which tends to make me believe that T is the hormone of the decade. Testosterone, however, is only one member of the steroid family. Some of the other steroids in this family include cholesterol, progesterone, the estrogens, cortisol, and aldosterone.
Although these molecules are part of the same family and have strikingly similar structures, their functions differ like night and day. This is important to recognize because although the steroids tend to act very differently, they are subject to similar rules with respect to biochemistry and metabolism.
For a simplified view of steroid metabolism in the body, you can assume that all steroid hormones begin with cholesterol. From cholesterol, steroid metabolites are formed in various tissues of the body. For example, enzymes in the adrenal glands are responsible for converting cholesterol into cortisol, while enzymes in the gonads are responsible for converting cholesterol to Testosterone.
With this simplified view, it's easy to make the mistake of thinking that by simply providing the body with more cholesterol (make that two large fries, please), we can make more Testosterone. This is a mistake because the body has regulatory mechanisms that control hormone production. These regulatory mechanisms, not your bedtime prayers to the iron gods, are what determine which steroid metabolites will ultimately be formed.
So the next important questions are, what magic does it take to make Testosterone out of cholesterol (now don't get too excited, you can't do this in your bath tub), what regulates this conversion, and ultimately, what regulates Testosterone production? In order to get the gonads to produce T, the body has a chain of command that must be dealt with just like any smooth running business.
In business, the action plan comes down from the CEO to upper management, the plan is solidified and delegated to the production team, and the production team gets the job done. Well, in the body, a portion of the brain called the hypothalamus is the CEO, the pituitary gland is the upper management, and the testes are the production team members.
As in business, the buck stops with the CEO/hypothalamus, which is known as a "pulse generator," because during the day it sends out pulses of hormones that are designed to stimulate other organs. With respect to T, the hypothalamus sends out numerous daily pulses of GNRH (gonadotropin releasing hormone) through the blood stream. These pulses are designed to stimulate the pituitary gland to get to work.
The pituitary gland then senses the pulses of GNRH and sends out a work order of its own, consisting of LH (leutinizing hormone) pulses. The LH message travels down to the leydig cells of the testis to stimulate the enzymatic conversion of cholesterol to Testosterone.
Cholesterol conversion to T is no easy process and I'm not going to go into all of the details (partly because no one really knows them all). One fact that you should understand, though, is that there's a high level of complexity to this pathway and that there are many enzymes and intermediates that cholesterol has to encounter before forming T.
Some of these intermediates include pregnenolone, DHEA, androstenedione, and other well-known androgens. So, although the hypothalamus might be functioning well, the pituitary might be doing the right thing, and the testis are getting the "ball" in motion, ultimately the enzymes in the leydig cells determine whether you're pumping out loads of muscle building T or simply forming other intermediates at the expense of the top dog.
As a result of the process I mentioned above, T levels fluctuate wildly. If you were to measure your Testosterone levels throughout the day, you'd likely be amazed. One minute you have the hormonal profile of a hyper-muscular bull ready to "fertilize" an entire herd of cattle?the next minute your blood profile is that of a fully menstruating Martha Stewart intent on color coordinating your powder room.
These odd fluctuations occur as a result of the pulsatile nature of hormone secretion. Again, this begins with the hypothalamic pulse generator's release of GNRH. Incidentally, researchers now believe that it is this physiologic pulsatility of Testosterone that makes it anabolic. So if you can mimic this pattern of hormone release, you can stimulate muscle growth.
With this hormonal cascade in mind, it's important to realize that each step in the pathway has a regulation point designed to either stimulate or inhibit pulse release. In this respect, the body is a bit of a control freak as it tends to like many control points rather than just one.
In this particular case there are three main control points; the hypothalamus, the pituitary, and the testis. With this type of control, the body can maintain the Testosterone homeostasis (a sort of hormonal status quo) and prevent us from any abnormal changes in muscle development and strength. For example, if our Testosterone levels go way up, the body senses this and the hypothalamus and the pituitary produce less GNRH and LH in order to slow down T production. This, of course, is the famous negative feedback. Damn that homeostasis!
Now that I'm certain you're all experts in Testosterone production (and there will be a test at the end ? I'm serious!), I'd like to address one more important issue that will come up later in the article with regard to Testosterone in the body. When Testosterone is converted from cholesterol in the leydig cells of the testis, it's released into the blood stream where it embarks on an anabolic adventure.
However, when in the blood, 60% of the big T released from the boys down below is bound up by a protein known as SHBG, or sex-hormone binding globulin. SHBG is produced and released by the liver. The important point is that the Testosterone bound to SHBG is biologically inactive and this is why there's an important distinction between total T and bioavailable T.
Total T represents all the Testosterone in the blood, while bioavailable T represents the non SHBG bound Testosterone. There are other proteins in the blood that bind Testosterone, too, but their binding is rather weak, so this T is bioavailable and these proteins can still enter the cells to produce and effect all the things we're interested in.
As I said, bioavailable T represents the Testosterone that is not SHBG bound, while free T represents the Testosterone that's not bound to any blood proteins at all. It's tricky, I know, but I hope that it's now evident that although only about 2% of the T in blood is technically considered free T, there is a larger percentage of T (about 40% or so) that is bioavailable because it's only weakly bound to non SHBG blood proteins.
I'm taking you through this complex path for good reason. When trying to increase T levels in the body, one must attempt to not only increase total T. More importantly, one must attempt to increase bioavailable T. If you increase total T, but you increase SHBG to a larger extent, they you will actually have less bioavailable T for muscle building purposes!
A great example of this is the use of both thyroid drugs and tamoxifen (nolvadex). Both may increase total T levels in the body, but both also increase SHBG to a large extent. Although you may get a bit of a T surge with each (hurray!), the increase in SHBG may bind up any extra, and actually decrease your bioavailable T (boo!).
Well, now that the class is up to speed with our physiology and endocrinology (will someone please wake up Mr. Luoma! ? he's always falling asleep during my physiology lectures), we can dive, full force, into how lifestyle factors including things like diet, training, recreational drugs, over the counter medications, altitude, and how psychological mood states influence T levels. There's an abundance of Testosterone literature out there and some of it is applicable for us while some is not, but to a science geek like me who both likes facts and likes being big and lean, it's all interesting nevertheless.
Oh wait, I almost forgot! Before we go on, I promised a test didn't I? Settle down! Although there are no actual grades on this test, I hope that you take away a few fundamental things from this article. If you can answer these questions, you're ready to take on next week's article in which I'll review a number of environmental and lifestyle factors that can influence your levels of free T, total T, and bioavailable T.
Rest easy, next week's article ties in all that you learned this week and makes some recommendations about how to up the T levels. And next week there won't be a test!
Question #1 ? True or False
John Berardi is the most intelligent man on the face of the earth.
(I thought I'd start off with an easy one ? And the answer of course is "True")
Question #2 ? Short Answer
What are the three main organs/glands that regulate T production and what are the big three hormones they release?
Question #3 ? True or False
Testosterone is synthesized directly from cholesterol.
Question #4 ? Short answer
What are the cells that actually produce T and where are they located?
Question #5 ? Short answer
All the Testosterone in the body, bound and unbound is referred to as what?
Question #6 ? Short answer
All the Testosterone that is not bound to SHBG is referred to as what?
Question #7 ? Short answer
All the Testosterone not bound to any blood protein is known as what?
Question #8 ? True or False
If you are interested in the anabolic effects of Testosterone, the optimal situation is to increase total T levels and decrease SHBG?
This concludes Part 1 of "The Big T". Next week, John will conclude the article with a review of both interesting and applicable Testosterone research.
Elevating Free Testosterone
By Thomas Incledon
Tom Incledon is an author, lecturer, clinician, and nutritional consultant. He's also a first-rate powerlifter, bodybuilder, and strength coach. And, unlike most authors in this field, Tom's actually gone to school! Got himself a mess o' degrees, too. We think he's even one of those doctors?not a real doctor, mind you, but one of those book-learnin' doctors.
As such, he's uniquely qualified to talk about areas that most writers fear treading (or, at least, ought to fear treading). We're proud to present his first contribution to Testosterone magazine.
Recently, I was asked by the guys at T-mag to help co-develop a product that could elevate levels of free testosterone (T). While I think that it's theoretically possible, I know that we'll have some work to do. Throwing a bunch of ingredients in a pill or capsule?like most companies have done?isn't the answer. Each ingredient has to be tested for its effects on the body's endocrine responses to verify that it'll do what it's supposed to do. Then they have to be tested collectively to determine what interactions may or may not take place. As you can see, it's a tough nut to crack.
The first article of this series describes how the body controls T synthesis and release and explains why formulating a product to elevate free T is so difficult. Future articles will review various supplements, extracts, diets, and dietary food components to see if they influence this process.
An overview
Our bodies produce T as part of the hypothalamic-pituitary-testicular (HPT) axis. In the brain, the hypothalamus produces gonadotropin-releasing hormone (GnRH) which is also referred to as luteinizing hormone-releasing hormone (LHRH). GnRH stimulates the anterior pituitary to produce and release luteinizing hormone (LH). LH then stimulates the testes to produce T. Once produced and secreted into the blood, T can exert its biological actions on skeletal muscle. This very basic overview can be seen in the chart below:
Starting from the top
GnRH is an important hormone because it starts the whole cascade of events that eventually leads to T production. In order to understand how to maximize T production, it becomes crucial to learn more about GnRH.
Looking at the chart, it seems that, by increasing GnRH release, LH would increase and then T would increase. However, constant infusion of GnRH into someone doesn't elevate T levels; it actually suppresses them.1 It seems somewhat confusing that the same hormone can both stimulate and inhibit T. The confusion is cleared up when the pattern of GnRH release is studied. The cells that produce this hormone don't do it in a steady, continuous fashion; rather, they produce and release the hormone in spurts or pulses.2 This pulsatile release of GnRH from these cells inspired researchers to coin the phrase "GnRH pulse generator" or "LHRH pulse generator," and that's exactly what happens in the body?it produces GnRH in a series of pulses throughout the day.
The pulse generator is influenced by signals from the eyes and nose, the pineal gland, and even from stress.3 These signals are converted into neural signals which then serve to stimulate or inhibit the release of GnRH. The links that communicate the information from the nerve cells to the GnRH-secreting cells are small molecules collectively referred to as neurotransmitters. Factors that fall into this category include bioamines, neuropeptides, excitatory amino acids, and gaseous neurotransmitters. Examples of some excitatory factors are norepinephrine (acting through beta-1 receptors), neuropeptide Y, galanin, nitric oxide (NO), substance P, transforming growth factor alpha (TGF-alpha), and prostaglandin E2 (PGE2). Under the right conditions, any of these factors can stimulate GnRH. However, blocking the release of one or more of these factors can decrease or prevent the release of GnRH. In addition, research on the endocrine effects of fasting indicates that a lack of calories and/or nutrients decreases GnRH release dramatically.4 After refeeding, the hormonal pattern should return to normal.
I've tried to simplify the process so that it's easy to follow. Note that, in doing so, some of the technical accuracy is lost. For example, some factors may inhibit and stimulate GnRH, depending on the other factors present.5 Rather than bore you with the details, it's better to understand the whole picture. Future articles will discuss this area in depth because I think that the "upstream" stimulation of T may hold some promise.
Many factors influence the amount and pattern of GnRH release. By setting up a scenario in which the pattern of GnRH release is unchanged, yet the amount of GnRH released with each pulse is maximized, you could theoretically maximize T levels. However, at this point, the quest is just getting started.
Journeying downward
After the hypothalamus has done its job of releasing GnRH (or LHRH), the baton is passed to the anterior pituitary. While this organ has the responsibility of synthesizing many different hormones (FSH, GH, TSH, ACTH, etc.), our focus is on the synthesis and release of LH. The pulsatile secretion of the pulse generator causes a similar secretion pattern in LH.6 The secretory pulses in adult men vary in frequency (from 8-14 pulses per 24 hours) and in magnitude.7 LH levels range in men from 1.3-13 IU/L (international units per liter) and, as you might guess, a lot of things can influence just how much is released.
Some of the factors that can influence LH secretion (assuming that GnRH is being produced in a normal, pulsatile fashion) include androgens that have not been aromatized to estrogens, estrogens, and opiate blockers.3 Current thinking, however, is that estrogens inhibit LH release not by acting on the pituitary, but by acting on components of neurons that lie outside the hypothalamus.
A whole slew of supplement companies have tried to come out with estrogen inhibitors reasoning that, by inhibiting estrogen production in men, there would be less of an inhibitory effect on T production. Later, we'll see while this may work in the very short run but how, over time, the body will figure out how to tone down the biological actions of T.
Arriving at the source
After LH receives the baton from T, it travels to the testes, attaches to receptors on Leydig cells, and stimulates the synthesis of T via activation of a rate-limiting enzyme.3 T levels don't just increase indefinitely, though. As T levels increase, more of it is available to inhibit its own production. As T levels increase, T travels in the blood, crosses the blood-brain barrier, and makes its way into the brain where it can directly8,9 or indirectly10-12 inhibit GnRH and LH levels. This process whereby T keeps itself in check is called negative feedback inhibition. It's really kind of elegant. There's even sufficient evidence at this time showing that T (or one of its metabolites) can inhibit its production directly on the testes and indirectly on the hypothalamus or pituitary.
So let's say that we get T up to a level that it deems abnormal. How long will it last before the body says that it's time to go back down? Most likely, the negative feedback effects of T will occur in only a few days.
Obstacles from afar
As T is produced and released, it can travel in the blood attached to a protein or travel in a "free" state. About 54% of T is bound to albumin and other proteins; 44% is bound irreversibly to SHBG (sex hormone-binding globulin, also called TeBG testosterone-binding globulin); and the remaining 2% is free or unattached to any proteins.13 T can be removed from the other proteins, but not from SHBG.14,15 This is another way the body regulates androgen action. By increasing and/or decreasing SHBG levels (a protein produced by the liver), the fraction of T that can be taken up by tissues may be controlled.
The testes also release small amounts of dihydrotestosterone (DHT)16 and estradiol (E2).17 T can be reduced to DHT by the enzyme 5-alpha reductase or aromatized to E2 by the enzyme aromatase. In humans, there are two versions or isozymes of the reductase enzyme18 while only one version of the aromatase enzyme has been identified.19 Since there are two isozymes for reductase, an agent that binds an isozyme of reductase in one tissue may not bind the other version of the enzyme in another tissue.
Another thing to think about is that many supplement companies have made the claim of having a product that could inhibit the conversion of T to E2. The premise of these products is that, to increase T levels, the only thing you need to do is to suppress brain aromatase levels. As pointed out earlier, while this may decrease the inhibitory effects on the hypothalamus, it won't do much for the inhibitory effects of androgens on the anterior pituitary, nor will it address the issue of increased liver production of SHBG.
The problem continues
Let's take another look at that basic model, but this time we'll add in the additional information. Let's say that you want to take a supplement to increase your testosterone levels. We'll assume that you are also a normal, healthy male and that all of the organs in your HPT axis are intact and functioning. The type of supplement is immaterial, at this point. From above, we see that if the supplement increases T levels, the body can respond by increasing the conversion of T to DHT and/or E2. In turn, T, DHT, and E2 can all inhibit future production of T. So elevating T by itself doesn't work well in the long run because the body can compensate for this elevation. That's why any legitimate company would insist, at least, that you cycle their product.
Suppose that you decide to take a dual anti-reductase agent and anti-aromatase agent in the hopes of reducing the conversion of T to DHT and E2. Several things have to happen. In order to decrease the release of DHT and E2 from the testes, the agent must somehow get from your gut, survive digestion intact (assuming that this is an oral agent), and enter the blood. From there, it must travel in the blood to your testes and then somehow bind to the reductase and aromatase enzymes with a high affinity. This might allow more T to be released from the testes and less DHT and/or E2. Now, the question you should have at this point is, "What happens when more T is released from the testes?"
Earlier, it was mentioned that the liver produces SHBG, and this is one way that the body can regulate T bioactivity in the body. So if total T levels increase, more SHBG will be produced. Then while total T may be elevated, the percentage of free T will be decreased because more T will be bound by SHBG. But the body doesn't stop there?most of the controls for T production are in the hypothalamus and pituitary. So if an agent can influence T production from the testes directly, the body can still modulate production higher up. For an agent to have an effect in the brain, it must be able to cross the blood-brain barrier, and this isn't an easy task.
Now you have an idea of why this whole thing is so tough?the body always strives to maintain a "normal" environment. When you look at all of those products on the shelf of your local food supplement store, keep some of these things in mind. It's very difficult to elevate T levels enough to put on muscle without the body somehow decreasing T production or its biological activity. The challenge that we have before us is to develop a product that can increase the free fraction of T without the body rebounding and increasing SHBG levels or decreasing T production. While this is no easy task, I've always enjoyed a good challenge, and this one won't fail to disappoint me. Stay tuned to T-mag and be the first to find out about some T-support supplements that take all of the factors into consideration.
Estrogen’s Dirty Little Secret
by TC
As it stands now, sooner or later, your prostate will start to swell up like the dinner rolls momma’s baking in the oven. At best, this unwanted hypertrophy will just obstruct urine flow. At worst, it’ll develop into cancer.
In North America at least, benign prostatic hypertrophy (BPH) is pretty much inevitable, just like death, taxes, or the birth of some new nauseating boy band. Hell, if a pathologist autopsies just about anybody over the age of 50 — who died of something unrelated to prostate cancer — he’ll most likely find BPH or prostate cancer.
Maybe they’ll be able to treat yours, and maybe they won’t. Either way, the options aren’t pretty. Maybe you’ll be able to just take drugs that make urination easier. Of course, if there’s cancer, you may have surgery and that surgery may leave you impotent. Or, maybe your choice of treatment will just be chemical castration.
Given the prevalence of steroid use and androgen manipulation in general, however, BPH is becoming an issue even with some 25 to 30-year olds.
The medical community is understandably upset, and that’s why they’ve declared war on Testosterone and his pesky little brother, DHT. The latter has been directly implicated in BPH, and that’s one of the reasons the medical community doesn’t like steroids, prohormones, Tribex 500, and even Testosterone itself.
Their reasoning is that you’re better off being a eunuch than a stud who has to get up to pee every half-hour.
The trouble is, I think they’re wrong. I think they’re pointing the finger at the wrong culprit. I think it’s Testosterone’s wicked sister, estrogen, that’s setting up Testosterone to take the fall.
First, a Few Words about One of Our Favorite Glands
The prostate is about the size of a chestnut — not all that big for such a potentially troublesome gland. One end is located just below the neck of the bladder and it kind of wraps around the beginning of the urethra (that’s why any enlargement impedes urine flow). The other end rests on the rectum, which is why the doctor sticks his finger up your ass during your annual physical.
A healthy prostate has an androgen-sensitive epithelium that wraps around a core of fibrous tissue, or stroma. Sex hormones typically traverse this epithelium and bind to receptor sites. Regulator genes are then activated and transcription factors turn on, causing the formation of new proteins (growth).
However, some of these genes might be proto-oncogenes (genes that code for cancer) and they can be transformed into cancer-initiating oncogenes.
The normal human male usually experiences two distinct peaks of prostate growth. The first occurs at puberty — right around the same time that the Testosterone starts flowing. The second occurs at about the age of 50 when there’s an increase in the ratio of estrogen to androgen.
Some Compelling Evidence
While it’s true that Testosterone and DHT definitely play a part in prostate growth, there’s more to the picture than meets the eye.
One of the largest studies ever done on men and BPH shows a strong association between BPH and serum estradiol levels.(5) Furthermore, the study reveals that the risk is confined to men who have low levels of Testosterone!
In fact, every study to date is in agreement that the concentration of Testosterone (the precursor of DHT) in the prostate of males suffering from BPH is low or normal.(1,10,11)
And, as shown in a study reported here in Testosterone a few months back, subjecting hypogonadal BPH patients to Testosterone replacement therapy resulted in prostate shrinkage!
What’s going on here?
Some Explanations
Estrogen
Don’t get me wrong, estrogen is vital to the male, but once levels skyrocket through over-exposure to the real stuff, or constant exposure to phytoestrogens (plant chemicals that resemble human estrogen) or xenoestrogens (environmental chemicals that resemble estrogen), things go awry. The result can be gynecomastia (excess male breast tissue), additional fat storage, decrease in libido, uncontrollable weeping whenever Beaches is on, or, as this article purports, prostate enlargement.
About 75-90% of estrogen in young men occurs in fatty tissue.(4) Testosterone is "aromatized" to estrogen and androstenedione is aromatized to estrone. Only between 10 and 25% is made directly in the testes.
Ah, if only it stayed that way! Trouble is, as we get older, the E/A ratio increases, presumably due to greater estrogen production, unchanged or decreased androgen production, or an increase in the amount of enzyme that changes Testosterone to Estrogen.
This ratio also increases sometimes when we start to manipulate our Testosterone levels, either through T replacement or the use of certain aromatizeable steroids. And, we can’t forget the estrogen mimickers in the environment, either.
The prostate itself obtains estrogens, through aromatase activity within its own tissues, and through outside sources. When levels get too high, though, BPH happens. Nodules start to occur in the periurethral transition zone (which signals the onset of BPH), which is the most estrogen-responsive part of the prostate. And, this proliferation of nodules and increased tissue growth is strongly associated with higher plasma estrogen (E2) and higher urinary estrogen secretion, but it’s not associated with T levels.(9)
SHBG
Sex hormone binding globulin is regarded as one of man’s big bugaboos.
Here’s why: In normal men, only about 2% of our Testosterone is "free," or unbound to carrier proteins. That means that presumably, only 2% is free to be ferried into cells to make muscle grow (among other things). About 54% is bound to albumin and other proteins, and 44% is bound to Sex Hormone Binding Globulin, or SHBG, which is synthesized by the liver.
For years, strength athletes have been trying to figure out how to reduce the amount of SHBG so that more free Testosterone was available for all the good stuff, like muscle growth.
However, as studies that have been largely ignored by the strength community have revealed, it seems that we might all be full of hooey.
For one thing, it now seems that red blood cells function as carriers of sex hormones in the blood stream, and in fact may be responsible for as much as 15% of sex hormone delivery to target tissues.(7) What happens is that dissociation of this protein-bound hormone can occur within a capillary bed, meaning that it’s not just the "free stuff" that’s working.
The amount of hormone that can be carried depends on capillary transit time, half time of dissociation, amount of hormone bound to various carrier proteins, and permeability of cell membrane.
That means that these binding proteins in circulation act as kind of a steroid bank. In fact, it’s a lot like how hemoglobin regulates the amount of oxygen in each tissue.
(This may be why the free T levels of strength athletes always seem to come up quite low on blood tests. Obviously, they’re functioning just fine, but judging by their levels of free T, you’d think they were Girl Scouts.)
How does this tie with estrogen and prostate cancer? I’m glad you asked, Bunky. SHBG synthesis (as well as albumin) is regulated by estrogen/androgen balance, and SHBG has been shown to exist in a number of human tissues, including the testis and epididymis. One of SHBG’s traits is that it can increase the ease with which steroids penetrate the cell. It also facilitates steroid binding to the cell. In short, SHBG acts as an additional androgen receptor.(3)
Here’s the hypothesis formulated by Wells Farnsworth, one of the world’s leading prostate researchers:
"With advancing age, there is a decline in androgen secretion and a rise in circulating estrogen. This results in an increase in SHBG to bind to receptors in the prostatic stroma. Then, steroid (Estrogen, androgen) is bound to the SHBG receptor complex. If the steroid so bound is estradiol or an aromatizable precursor thereof, both stromal proliferation, exhibited as BPH, and the synthesis of IGF-1 will occur.
In sum, it may be that estrogen, mediated by SHBG, sets the pace for prostatic growth and function."
Prolactin
Prolactin is a hormone most commonly associated with the production of mother’s milk and possibly breast growth, while its role in males has been considered to be hazy at best. However, recent research reveals that prolactin is a heavy-duty hormone, possibly affecting more physiological processes than all other pituitary hormones combined.(2) And it’s now known to be produced at many sites outside the pituitary, including the prostate.
As far as the prostate is concerned, prolactin greatly increases the sensitivity of prostate tissue to androgen. Furthermore, it enhances the permeability of the prostate to Testosterone.
And guess what stimulates prolactin secretion? Estrogen.
A Few Words about DHT
While DHT is definitely involved in prostate growth, its role may be overstated. A researcher named Krieg found that the DHT level of subjects with normal prostates was much higher in prostatic epithelium than it was in prostatic stroma (the fibrous tissue inside the prostate). In fact, the amount of DHT in the epithelium of these healthy patients was much higher than it was in either the epithelium or stroma of patients between 50 and 95 years of age who suffered from BPH.(8)
In addition, the amount of epithelial DHT in both normal patients and those with BPH decreased significantly with age!
However, estrogen (E1 and E2) levels in both normal and BPH patients went up significantly with age.
What might be happening is that the amount of androgen receptors (DHT or otherwise) in the human prostate is increased by exposure to estrogen and that taking an anti-estrogen might keep the number of receptors in the prostate low, thus preventing androgen binding, transcription, and the resultant growth.
Let’s Wrap it Up
To summarize, estrogen levels, or the estrogen/androgen ratio rises with age, either because of an increase in the amount of estrogen itself; an increase in the production of the enzyme that turns T into E; or decreased production of Testosterone.
This ratio may also change from the use of certain steroids or pro-hormone supplements (thus leading to an increase in estrogen) and exposure to environmental estrogens.
Estrogen itself helps mediate prostate growth, but it’s also responsible for increasing levels of prolactin, which allows estrogen to get into the prostate more easily.
Estrogen also helps regulate the production of SHBG and albumin, which acts as carrier proteins for E on its journey to the prostate. Furthermore, these same binding proteins might also serve as additional estrogen receptor sites — or estrogen parking spaces — in the prostate.
Given this evidence, it seems that every living male might at some point wish to plan his prostate-protection strategy. Since I dabble in manipulating my own Testosterone levels, estrogen’s effects on the prostate are definitely a concern.
I’ve been taking 1 mg of the DHT-blocker finasteride every day for the last 7 years, but I might have been better off taking an anti-estrogen, had one been available to me. (Of course, finasteride still seems to be an effective drug in preventing hair loss, and I’ll continue to take it for that reason, at least until the new drug, dutasteride, is approved.)
Currently, the drugs of choice for blocking estrogen are probably Arimidex or clomiphene, both prescription drugs, but doctors are wary about prescribing them to otherwise-healthy individuals. As such, I have very high hopes for the new estrogen blocker we’re working on and plan on making it part of my daily pro-health cornucopia of pills.
I, for one, am going to take my dinner roll out of the oven before it starts to spill over the pan, if you catch my drift.
What About Saw Palmetto?
For years, most of us in either the life extensionist camp or the physique enhancement camp have touted saw palmetto extract as a weapon against prostate growth. Saw palmetto either blocked DHT from binding to receptor sites, or it somehow limited 5-alpha-reductase (the enzyme responsible for turning T into E) activity.
Trouble is, the largest review of the subject ever undertaken found that neither of the mechanisms "has ever been demonstrated convincingly to be operative in vivo at therapeutic doses."(6)
What they did find, however, was that the substance had some value in treating patients with lower urinary tract symptoms that suggested prostatic obstruction. That means that saw palmetto might just allow men with BPH to pee easier, while not directly affecting the prostate’s size in any way.
Even if saw palmetto is, at some point, vindicated, it doesn’t address what may turn out to be the true problem — estrogen.
The War on Estrogen
A battle plan
by Cy Willson
Know Thy Enemy
Estrogen. It's definitely not a hormone we bodybuilders want circulating in our bodies. If it were up to us, there wouldn't be a damn drop of that stuff around. I mean, after all, it's to blame for everything wrong with a man's world. Lost your big promotion after grabbing the receptionist's ass? It was estrogen. Couldn't convince that drunk girl to come over last night? Estrogen was behind it! Did your favorite football team get spanked Monday night? Yep, someone must've spiked their Gatorade with estrogen!
Okay, okay, so maybe I'm exaggerating just a little. And sure, we need just a smidgen of that crap in order to function properly. Still, with all of estrogen's negative effects ? lowering of GnRH, LH and Testosterone; decreasing lean body mass; increasing fat mass; Richard Simmons, etc. ? it's no wonder why we hate the stuff so much.
The increasing fat mass, in turn increases aromatase activity, which in turn causes further depression of Testosterone levels and a preferential storage of abdominal fat, eventually leading to a state of hypogonadism. Yikes! Even worse, estrogen has recently been implicated in both benign prostate hypertrophy and prostate cancer! It's possible that the correlation between increased Testosterone and prostate cancer occurs because of the simple fact that more T is being aromatized to estrogen, not because of Testosterone itself.
Speaking of aromatase, this should be a very real worry to you. Why? Well, as you age, levels of this particular enzyme can start to increase and cause a general decrease in both free and total Testosterone. Not only this, but you become less responsive to the effects of LH. These particular changes cause the usual decrease in lean body mass and increase in fat mass (stemming from a decrease in oxidation of fat) that you see with older guys, despite their efforts in the gym. These guys may also complain of sagging libido, loss of energy, decreased cognitive function and strength, and can just plain turn into grumpy bastards!
Hence, the idea of Testosterone replacement. It works to reverse these problems, but the solution is only temporary and you must be administered Testosterone for the rest of your life. I could handle that, but some guys find it rather troublesome and expensive. So what to do? Well, I'll give you the answer in a little bit, but first, I have to get the younger guys a reason to be interested, as well as give the older guys even more of a reason to worry about their estrogen and Testosterone levels. Warning: This next part could be frightening!
Xeno: The Warrior Princess
What's the big commotion about? What's the cause of all this stress? They're called xenoestrogens. Think of them as an ex-girlfriend who goes around telling everyone that you have a tiny penis after a bad breakup. These Sci-fi Channel-sounding substances are actually hormone-like chemicals found throughout the environment. They can mimic the effects of estrogen in your body and antagonize the effects of Testosterone and other hormones. They can also disrupt the synthesis and metabolism of hormones. This can lead to an increase in estrogen levels in men and a decrease in T levels. In fact, it has!
This suppression of Testosterone can have detrimental effects such as decreased strength, decreased muscle mass, and increased fat tissue, even in young men. The effects are even worse for older men, as they have to deal with their already decreasing T levels. Xenoestrogens have even been implicated in certain cancers, including prostate and testicular cancer, as well as benign prostate hypertrophy.
In short, xenoestrogens can have the same negative effects as estrogen. The only difference is that they can be easily absorbed into your body. Unlike natural estrogens, these suckers aren't easily broken down, remain intact in the environment for years, and can accumulate in the fat tissue of humans.
The Enemy is Everywhere!
The biggest problem, besides their effects, is that these chemicals are lurking throughout your environment. We get them through the food we eat, household products, lubricants, pesticides, plastics, detergents, and many other sources. Some of these chemicals have been banned, yet are still readily found in the environment, even after 20 years of discontinued usage! A few examples are pesticides, like DDT, endosulfan, methoxychlor, kepone, and toxafene.
Bisphenol A is used worldwide in the manufacturing of polycarbonate plastics found in storage containers and baby bottles. It also happens to be a very potent estrogen agonist. Even pharmaceuticals like cimetidine and birth control pills may play a role in terms of estrogen mimicking. Ordinary household products like detergents, surfactants, and paints have breakdown products called nonylphenol and octylphenol that have estrogenic effects. The spermicide and lubricant called nonoxynol may be metabolized into nonylphenol. However, before you throw out your Trojans, nonylphenol is an extremely rare exception, as it may act as a slight androgen agonist. Still, be careful.
Polychlorinated biphenyls, or PCB's, stem from adhesives, fire retardants, and certain waxes. These are also very potent estrogen agonists. A lot of these chemicals find their way into our bodies by ingestion of food, drinking water, or simple inhalation. In terms of inhalation, chemicals like Benzo[a]pyrene and 3,9-dihydroxy-dmba are both resultants of fossil fuel combustion.
What's even worse is the fact that these chemicals are agonists at the alpha receptor subtype. These xenos may even act synergistically with one another.
Oh yeah, and for you "herb" lovers out there, tetrahydrocannabinol, or THC, the active ingredient in marijuana, is also estrogenic. Damn! There goes my lunch break with the guy in the mailroom who likes to listen to the Grateful Dead!
Oh, and although, this doesn't technically fit under the xenoestrogen category, guard your balls with your life! There's some evidence that testicular trauma may increase estradiol levels. So, wear a nut cup the next time you decide to use your classic pick up line of, "Hey, baby, it's cold in here. Can I use your thighs as earmuffs?"
Breaking Out the Artillery!
Now that we know what the enemy is and what it's capable of doing, it's time to arrange a strike force of our own. We must either prepare to do battle or live the rest of our lives locked in a protective bubble (not a plastic one, of course!). So what can we do to minimize the effects of these chemicals? I know a lot of people would suggest using something like tamoxifen or clomiphene, since they're considered to be estrogen antagonists. Well, in terms of preventing estrogen itself from binding to certain alpha receptor sites in areas like the breast, this is great! However, what people need to understand is that these two ? tamoxifen more so ? are also estrogen agonists in certain tissues as well.
Tamoxifen can even activate the alpha receptor in specific tissues. Now, I don't know anyone who's gained fat just from using tamoxifen, but then again, rarely is anyone using tamoxifen by itself. Don't get me wrong, though, it's a great help in preventing gyno as well as increasing LH (as is clomiphene) in order to get your testes functioning again.
So, clomiphene and tamoxifen won't be of much benefit since they both increase estrogen levels significantly and don't have an effect on aromatase levels. If the goal is to simply increase endogenous LH and Testosterone, then I'm all for them. However, in aging guys, these two compounds won't do as much. In fact, they don't respond to the Testosterone boosting effects of clomiphene to the same degree as younger guys do.
When young men were given clomiphene, their total and free Testosterone increased by 100% and 304% on average. Yet the older men only had an increase of 32% and 8% of total and free T. The antagonism of estrogen still doesn't help in young men exposed to estrogen increasing xenos either.
So what's the solution? Well, it would seem that the solution would be to decrease estrogen itself. The way to accomplish this would be to use some sort of aromatase inhibitor. Cytadren, or aminoglutethimide, used to be the choice drug because of its ability to inhibit the production of estrogen. Unfortunately, it also suppressed the production of corticosteroids as well; thus, it's also referred to as a non-selective aromatase inhibitor. Good for a little while, but when the person stops taking in the drug, cortisol levels would rebound quickly and lead to an accumulation of fat and a general "puffy" look.
Formestane was found to be more potent in terms of decreasing estrogen levels and, unlike aminoglutethimide, it was selective. The only problem is that you have to inject around 250 mg every two weeks just to get a reduction of around 60-70% of estrogen. It has a short duration of action and has now been surpassed by what is the current "big dawg" in aromatase inhibitors. The best drug is Arimidex (anastrozole). This newer, selective aromatase inhibitor has been found to decrease estrogen by as much as 21% more than formestane and only has to be taken one time per day in a little 1-mg tablet. It has a long half life of around 50 hours.
Don't try the "more is better" thing either, as there was no significant difference shown between 1 mg and 10 mg of Arimidex in terms of estrogen suppression. (Also note that food may interfere with its absorption to a slight extent.) It's also been shown to significantly increase Testosterone and LH as a result of the estrogen suppression. Not only that, but it could reduce prostate size. It's also possible that it'll reduce fat mass in areas where estrogen would bind.
So, Arimidex seems to have all of the benefits that we're looking for. We may not be able to stop the xenos themselves, but we can sure as hell negate their effects on our bodies!
To help give you an idea of their potency, note the following comparison of the ability of the various aromatase inhibitors to inhibit the aromatase enzyme in vitro.
Aminoglutethimide (Cytadren)?>
Formestane?P>
Exemestane?P>
Anastrozole (Arimidex)?/P>
Letrozole?/P>
Vorozole?
So, for instance, Arimidex is 200 times more potent than Cytadren in terms of aromatase inhibition. I should note, however, that in vivo, the triazole compounds haven't shown much of a difference in terms of estrogen suppression. So, even though vorozole may appear to be the most potent, it hasn't been shown to surpass the effects of Arimidex. At least, I haven't seen any evidence that points to that, anyway.
Both anastrozole and vorozole have been shown to lower estrogen levels to the point where estrogen can barely be detected, if at all. If vorozole were shown to be more potent than anastrozole, it would be overkill anyhow. Vorozole also has a very short half-life of around 8 hours.
What might work even better would be a combination of clomiphene and anastrozole. This could be a great combo for those with problems in terms of higher estrogen and lower Testosterone levels. This wouldn't be very cheap by any means, however. Over a period of 12 to 16 weeks, the increased T and decreased estrogen levels could produce a rather noticeable increase in muscle size and strength. You could also see other mood boosting and cognitive enhancing effects of increased T, as well as a decrease in fat mass.
Conclusion
Well, hopefully I've convinced you to never wear rubbers, stay in a non-plastic bubble, and hold your breath when you're forced to come out to use the bathroom. Oh, and don't forget, never use any air freshening agents, plastic food containers or detergents. Nah, just joking!
Seriously though, if you can, try to minimize your exposure to these agents and perhaps give Arimidex a try if lab tests indicate that your estrogen levels are the cause of your diminishing progress in the gym. Try that along with the other possible Testosterone enhancing actions, like eating a good amount of monounsaturated fats, getting plenty of protein and fiber, and minimizing your consumption of alcohol. Ditch that lunch break date with Mary Jane, too.
Don't forget, you could also combine clomiphene and/or Tribex-500 with Arimidex. Anything to get that precious T up and beat down that bitch estrogen! Be careful, it's a war out there!
John K
01/30/05
04:22 AM
British Columbia, CAN
I just finished reading the book "Our Stolen Future" and many sections from the similarly themed "Hormone Deception". These are two books that detail the vast number of estrogen imposters that we are exposed to throughout our lives and that have accumulated in our environment, our homes, and within our own bodies.
It really is amazing how many chemicals we have developed in the past century that either mimic hormones or block hormone receptors. As mentioned in this article, everything from certain plastics, to industrial products such as coolants and insulators, to pesticides, fertilizers, and on and on.
This article shares some strategies for protecting yourself, but there are numerous other steps you can take to keep the estrogens and other hormone mimics from reaching you to begin with -- from minimizing household dust (which is composed of a ridiculous array of nasty things), keeping plastic the hell out of the microwave, avoiding the use of pesticides, washing your hands frequently, keeping a window open when running the shower or washing machine or dishwasher (!), to being aware of which foods tend to carry the highest levels of endocrine disruptor residue and reproductive toxins from pesticides, such as strawberries, spinach, and cabbage, and perhaps favoring organic for these particular purchases. These books state that endorcine disruptors tend to be amplified as you move up the food chain, and also tend to be stored in fat, so that animal fats such as butter can wind up carrying a disproportionate dose (again, the recommendation is to go organic for butter.)
The various studies that show how an extra dose of an estrogen during pregnancy can have all sorts of nasty effects on the development of the fetus are quite eye opening as well. The most famous case of this are the infamous DES children, whose mothers were given DES during pregnancy and then the children experienced all sorts of health problems later in life.
Anyway, I just wrote this to bump this article because after reading these two books, it has reinforced the idea environmental estrogens are messing with us in all kinds of nasty ways, and we should probably all be aware of steps we can take to deal with our exposure, minimize our exposure, and ideally to make changes that limit and prevent future generations from being exposed at all.
The Anabolic Power of Insulin
An Interview with John Berardi
by Rob Wilkins
Testosterone readers were orginally introduced to John Berardi last year and since then, he's keystroked several groundbreaking articles. He's also been instrumental in designing Biotest's new postworkout recovery drink, Biotest Surge. Within a week or two, we'll even be introducing John's new nutrition column. (We haven't decided on a title yet, but we've narrowed it down to two choices; either "An Appetite for Construction," or, "Eat Me, I'm a Tuber!")
Given his involvement with Testosterone and Biotest, it seems somehow unnatural to present an interview with him as interviews are usually done to either introduce someone to the audience, or to pick the brain of an outsider who's not associated with the staff. However, since this interview with John was free-lanced and ended up covering topics that were so dang interesting, we thought we'd just break tradition and run it. Hence this exchange between John Berardi and Rob Wilkins, a Technical Sergeant in the US Air Force stationed at Patrick Air Force Base, Florida.
Recently, Biotest and Testosterone magazine held their very first "No Holds Barred" bodybuilding workshop in Orlando, Florida. During the workshop, members of the Testosterone science team provided the audience with the latest and greatest information related to training, supplements, and nutrition to help them take their training to the next level.
One of the speakers was John Berardi, who presented a fascinating presentation on insulin and the insulin index. Insulin is a hormone that regulates the metabolism of carbohydrates, fats, and starches in the body, and it promotes muscle uptake of amino acids for making proteins.
Berardi is a scientist and PhD candidate in the area of Exercise and Nutritional Biochemistry at the University of Western Ontario, Canada. As an athlete, he's been a successful powerlifter, former NABBA Jr. Mr. USA bodybuilding champion, and a member of nationally ranked rugby and track and field teams.
John is highly regarded for his expertise in hormonal regulation of muscle mass and body composition; the interactions between exercise, diet, and nutritional supplementation; methods of strength training and conditioning; and the testing and design of nutritional supplements.
He's currently conducting exercise and nutritional supplement research with renowned exercise and nutrition researcher Dr. Peter Lemon, one of the world's leading experts on protein. John's also famous for conducting experiments on himself and his friends to put his theories to use. Sometimes they work, and sometimes they go terribly awry, as former friend, Larry "Two Headed Freak" Dumbrowski can attest.
RW ? Thanks for your time John. First off, can you give us a brief background on yourself and what stimulated your interest in exercise and supplementation?
JB ? Well Rob, I think the introduction you gave was pretty comprehensive. As you said, I'm currently a researcher but have an extensive background in competitive athletics. And that's what holds my passion. I love training and consulting with elite athletes in order to apply my university and real-world training in order to take their games to superior levels. And with each new athlete that becomes part of my clientele, I get supercharged about the new challenges that await us! And that's where the research ties in. Every research project I've conducted and every nutritional supplement I've designed has been done with one goal in mind ? to figure out how to make better, stronger, leaner and meaner athletes.
Lately I've been branded by some of my athletes as "the recovery specialist." This is due to my research that's been focusing on the recovery of ATP, glycogen, and protein balance, and the prevention of overtraining. In addition, I've been working on some nutritional programs and supplements that manage the hormone insulin.
RW ? So let's talk about insulin. What is insulin and why should athletes and those involved in health and fitness care about it?
JB - The current rage in health and fitness is to manage the hormone insulin. But few people really understand this temperamental hormone. You see, insulin is an anabolic giant. It's the most anabolic hormone because it stuffs nutrients like amino acids and carbs into muscle cells to promote growth. But, while it sounds great, getting aggressive with it can lead to serious fat gain. For instance, here are some basics:
Insulin is a hormone released into the blood by an internal organ called the pancreas. Insulin functions in many ways as an anabolic or a storage hormone; in fact it's been called the most anabolic hormone. When insulin is released into the bloodstream, it acts to shuttle glucose [carbohydrates], amino acids, and blood fats into the cells of the body. "Which cells?" you ask. Well, fat and muscle cells are the important ones in terms of quantity. Now, if these nutrients go predominantly into muscles, then the muscles grow and body fat is managed. If these nutrients go predominantly into fat, then muscle mass is unaffected and body fat is increased.
So obviously if there were a way to send nutrients preferentially into muscle rather than fat, trainees would have more muscle mass and less fat mass. That's the goal of my recommended training and eating programs ? to increase the muscle uptake of nutrients preferentially. Isn't that the goal of every trainee whether they know it or not?
RW ? So how can one manage this hormone to promote muscle gains and fat losses?
JB ? Well, this is where things get tricky. Because insulin is a storage hormone, most people think that since insulin stores nutrients, it should be avoided because it has the potential to store fat. This is a mistake for several reasons. First, there's no way to avoid insulin in the blood. Whenever you eat food, insulin is released.
Secondly, if you theoretically could eliminate insulin, you would abolish all of its anabolic effects and its ability to store energy in the muscle. In fact, type 1 diabetics don't produce insulin and as a result, if left untreated, they die.
But don't go the opposite route, either. If blood levels of insulin are always highly elevated, trouble results. Chronic elevation of insulin leads to large amounts of fat gain, risk for cardiovascular disease, and ultimately to type 2 diabetes. This second type of diabetes is characterized by obesity, cardiovascular disease, and the poor ability of the muscle to store nutrients, which leads to muscle wasting and tons of fat storage. This is called insulin resistance.
So my point is that you need insulin, but you must learn how to balance the anabolic effects against the fat storage effects; to trick it into making you muscular while making you lean at the same time. And this is done two major ways; first by increasing insulin sensitivity in the muscle while decreasing insulin sensitivity in the fat cells and, second, by controlling the insulin released during specific times of the day.
RW ? Please explain the difference between insulin resistance and insulin sensitivity?
JB ? Simply put, insulin resistance is bad. If you're insulin resistant, your cells ? especially the muscle cells ? don't respond to the anabolic effects of normal levels of insulin, i.e. they resist insulin's effects. If this is the case, the body then releases massive amounts of insulin to promote nutrient storage in the resistant cells. Remember, though, that chronic high levels of insulin in the blood are very bad and can cause type 2 diabetes.
Insulin sensitivity is therefore very good. In this case, your cells ? especially the muscle cells ? respond very well to small levels of insulin. Therefore, they need very little insulin stimulation to get into an anabolic state. So high insulin sensitivity at the muscle level is very desirable.
One way to remember the difference is as follows. If you're dating someone who responds or reacts to any affection you show them, then he or she is sensitive. So they're a good model for insulin sensitivity. It only takes a little affection to get a big response. On the other hand, if the person you're dating is resistant to your affection, then it takes a lot to get them going. Therefore, they're a good model for insulin resistance. It takes a lot of affection to get even the smallest response.
RW ? Does insulin sensitivity vary or change?
JB ? Insulin sensitivity is unique to each individual but the cool thing is that it can be manipulated by exercise, diet, and supplementation. And that's what I do with my clients to dramatically change their body composition.
Both aerobic and resistance training greatly increase insulin sensitivity through some different and some similar mechanisms. In addition, supplements like omega 3 fatty acids, fish oils, alpha-lipoic acid, and chromium can increase insulin sensitivity. Finally, moderate carbohydrate diets that are rich in fiber can increase insulin sensitivity.
On the flip side, the low-carb, high-fat diets that have become popular can decrease insulin sensitivity. That's why none of my trainees go on no-carb diets, unless they're dieting down for a show and then they'll do occasional no carb diets every few months for a maximum of 3 weeks at a time.
RW ? So what are some practical ways to manipulate insulin sensitivity?
JB ? Well, typically I've seen tremendous increases in insulin sensitivity with 3-4 intense weight training sessions per week, lasting 1 hour per session. These sessions should be coupled with at least 3-4 aerobic sessions lasting 30 minutes per week. To really target insulin sensitivity, you would perform these sessions separately.
After exercise, the next step would be to supplement with 600 mg of alpha-lipoic acid and concentrated fish oils containing a total of 6-10 grams of DHA and EPA, which are the most active omega 3 fats in fish oils.
Finally, your diet can make a big difference. I recommend moderate quantities ? 40-50% of the diet ? of fibrous carbohydrates like oatmeal, fruits, vegetables, and whole grains. I also recommend eating moderate quantities (30-40% of the diet) of high-quality proteins like casein, whey, chicken, beef, fish, dairy and eggs. And finally, I recommend eating low quantities (20% of the diet) of fats from olive oil, flax oil, fish oil, and nut oils.
All of these strategies can be combined to make the muscles more responsive to insulin while simultaneously decreasing the fat's responsiveness to insulin. This means more muscle mass with less fat gain?eternal quest of the bodybuilder!
RW ? How important is the insulin sensitivity to my progress as a "natural" bodybuilder?
JB ? I think that insulin sensitivity dictates your muscle-to-fat ratio, especially when trying to gain or lose weight. If you're more insulin sensitive during a weight-gain program, you'll gain more muscle relative to the fat that you gain. For example, with normal insulin sensitivity, you might gain 1 lb of muscle for every 2 lbs of fat for a 1:2 ratio. With increased insulin sensitivity, you might gain 1 lb of muscle for every 1lb of fat or even better, 2 lbs of muscle for every 1 lb of fat.
And if you're dieting, you will lose more fat relative to your muscle loss if your insulin sensitivity is high.
Are these things important to bodybuilders? You bet they are! And especially to natural ones. Drug-assisted bodybuilders have super insulin sensitivity. In addition, the drugs enhance their muscle-to-fat-gain ratios. If you're clean, you need to use every natural means at your disposal to alter these ratios as well.
RW ? So what about the other step in balancing insulin? Controlling insulin release during specific times during the day, right?
JB ? That's right. Remember, insulin is anabolic so we want bursts of it every day without chronic elevation. An effective way to do this would be to plan insulin bursts after training. In addition, I recommend jacking up insulin at least twice per day, but no more than 3 times. So planning at least 2 high-insulin meals per day is the way to grow and stay lean.
To do this we need to first pay attention to something called theinsulin index of foods. If you think I've made a mistake and that what I really mean is the glycemic index, you're wrong. I mean the insulin index. Never heard of it? You're not alone. Although insulin indices are not new, they've been ignored in health and fitness for far too long.
RW ? What's the difference between the well known glycemic index (GI) and this insulin index (II) you're referring to?
JB ? The popular glycemic index is a measure of the speed at which carbohydrates enter the blood after a meal. A high-glycemic index means that blood sugar rises rapidly in response to a meal while a low-glycemic index means that blood sugar rises very slowly. Traditionally, nutritionists thought that the faster the carbs got into the blood, the bigger the insulin response. So in an attempt to manage insulin, they recommended always eating low-glycemic foods.
However, several studies since have shown that some low glycemic index foods have huge insulin responses! So the correlation between glycemic index and insulin response breaks down with some foods. For example, milk products have a very low glycemic index. But they promote insulin responses parallel to the highest glycemic foods. What's the deal? Well, it appears that there are several other factors that determine insulin release besides carb content and the rate of carb absorption.
This is why the insulin index was generated. This index actually measures insulin response to a food. So rather than assuming insulin response is correlated with carb absorption, these researchers decided to go ahead and measure it. And their results were eye opening!
RW ? If a natural bodybuilder is planning their nutrient intake around the insulin index, what foods would they eat and what foods would they avoid?
JB ? One thing to keep in mind is that there is no such thing as a bad food. Well, almost no such thing. I don't think anyone can make a case for powdered, cream-filled doughnuts, besides the fact that they taste damn good! But I hope you see my point. Since I said earlier that sometimes you want an insulin surge ? especially after workouts ? and sometimes you don't ? especially at night before bedtime ? we have to realize that we use the insulin index not to condemn foods but to decide when to eat them.
The point I want to stress is that the insulin index helps us add information to the glycemic index to make better food choices. So using both indices is the way to go. Since milk products have a low GI but a high II, these foods aren't optimal when you want to keep insulin low. Other example foods or meal combinations for this situation are baked beans in sauce, meals with refined sugars and fats, and meals that are protein and carbohydrate rich. Each of these foods/combos have low GI scores but high II scores, none of which are optimal for low insulin times. But remember, some times you want high insulin so don't relegate these foods/combos to a dark corner of your nutritional closet.
Conversely, unprocessed fibrous grains and cereals as well as fruits and veggies are great on both scales. In addition, most low-fat protein sources are also great on both scales.
RW ? So what times of the day should you increase insulin levels and what times should you concentrate on decreasing them?
JB ? Again, I like to spike insulin 2-3 times per day. Remember, though, that my clients are super insulin sensitive due to the training, diet, and supplementation programs I have them following. So they can handle the insulin surges and can actually grow and get lean at the same time. With this said, natural insulin sensitivity declines at night time so perhaps at night, low insulin choices are best. After training however, the goal should be to send insulin through the roof. A sensible plan is to eat 3 high-insulin meals as your first 3 of the day, and 3 low insulin meals to finish the day. This can be accomplished as follows:
1st 3 meals:
Protein plus carbs with no fat
2nd 3 meals:
Protein plus fat with no carbs
[Editor's note: for more information on John Berardi's eating recommendations, check out "Massive Eating, Part 1", and "Massive Eating, Part 2".]
Post-workout meals:
Hydrolyzed protein, simple carbs, BCAA, free form amino acids
RW ? Are there any supplements that affect the release of insulin and if so, how are they beneficial?
JB ? There certainly are! In fact I'm currently designing a post-workout formula with this goal (as well as a few others) in mind. You see, as I said earlier, I'm sort of a "recovery specialist." I'm hired to consult with many athletes from serious endurance marathoners and triathletes to strength and power athletes like bodybuilders and sprinters. Although I design training and nutritional programs for them, one of my special strengths of focus is how to help those who are "midgets of recovery" (the athletes who are especially prone to over training).
One of the main factors in recovery from training is to increase glycogen in the muscle, increase protein synthesis, and decrease protein breakdown. And the way to do this is to get insulin high right after training. I recently did a series on this in Testosterone [Solving The Post-Workout Puzzle ? Part 1: What Happens After The Workout? and Solving the Post-Workout Puzzle ? Part 2: The Recovery Plan].
The current recovery drink I'm working on is a special blend of glucose and glucose polymers, whey protein hydrolysates, BCAA, glutamine, and some other free form amino acids. This combo of ingredients (in specific ratios) is highly insulin releasing as well as very specific to the recovery of glycogen balance and protein balance.
The best thing about this formula is that every person who works out, no matter the sport, can use it. It has only nutritive ingredients and no mysterious herbs or other compound. And it and targets physiological processes common to all activities.
[Editor's note: Biotest is now accepting pre-order's for John's post-workout recovery formula, Biotest Surge]
RW ? Thanks so much for this informative interview John. Is there anything you would like to leave the readers with?
JB ? Remember, insulin sensitivity is a huge factor in maximizing recovery and making dramatic changes in body composition. Use the insulin index, glycemic index, and smart nutritional advice to take your physique and training to a higher level.
In the end, however, although we really focused in on the insulin index and insulin sensitivity with this interview, I want readers to understand that in athletics and training, there are so many other factors that contribute to gains in performance on improved body comp. As my colleague Tom Incledon says, "The cells of the body are like a space ship being bombarded by meteors (hormones and nutrients)."
The point is that no hormone or cellular system is independent. When we try to focus on any one thing, it's easy to lose sight of other important factors. So remember, after defining your goals, you need to come up with a plan of attack based only on your personal path. Don't follow someone else's plan to the letter or a generic plan that you read in a magazine. Individualize!
RW ? Thanks for your time, John.
The Fountain of GH
By John M Berardi
The year was 1513.
Don Juan Ponce de Leon, better known as "Pump" in transcontinental travel circles, was on a seemingly hopeless mission. Pump de Leon, after numerous world travels, many bodybuilding titles, and huge prize monies, had set out to find the fountain of GH.
It had been rumored for centuries that in the midst of the islands of the Pituitary there was an amazing fountain. This fountain apparently possessed incredible powers of age restoration. In addition it had such a dramatic impact on fat loss and increased muscle mass that no man who walked away from its waters would ever hit a training plateau again. Being as hardcore as they come, Pump de Leon was possessed to find this fountain of GH, even if it cost him all the gold he had won throughout his competitive years.
Meanwhile, back in Spain, Ferdinand Patterson, Pancho de Luoma and Juan Jose Berardi were determined to get Pump de Leon's story first hand (and to get some of that damn GH!). Casting off on the rickety fishing vessel known as "The Male Hormone," Ferdinand, Pancho, and Juan set sail across the Atlantic in search of Pump de Leon and the Pituitary Islands.
After the treacherous journey, they found Pump alone on his own "muscle beach" doing heavy tree trunk squats. After months on the Atlantic with minimal training and poor nutrition, the sailors of "The Male Hormone" were dying for a workout and some good muscle foods. So they began lifting the logs and boulders strewn about in Pump's makeshift gym. Later, over post-workout coconut shakes, Pump shared with his fellow Spaniards the fact that he had not yet found the fountain of GH, but was glad to have three more bodybuilders to help in his quest.
Sadly, Pump, Ferdinand, Pancho, and Juan Jose never made it back to Spain. Nor did they find the fountain of GH.
Now, about 500 years later, the fountain of GH has been found. But not in the area our ancestors sought. It has been found through recombinant technology. And although GH is now available for all, whether it really has the amazing powers that senors de Leon, Patterson, de Luoma, and Berardi sought is another story; one that I plan to tell today.
GH - The Hormone
Growth hormone (GH) is a 191-amino acid protein or peptide that's naturally released from the pituitary gland. GH, much like Testosterone, is released in a pulsatile or episodic manner. The GH pulse occurs every 2-3 hours so each and every day we get about 8-12 big doses of all-natural growth hormone (Hartman et al 1991). The sum of these GH peaks amounts to about 0.5 mg of GH produced per day. The following is an example of what normal 24 hr GH production might look like, with the highest peaks occurring during the first few hours of sleep:
According to the research review published in a new textbook entitled "Growth Hormone in Adults," the release of GH from the pituitary is governed by a balancing act between 2 hormones; GHRH (growth hormone releasing hormone) and somatostatin. GHRH is responsible for stimulating both the synthesis and the release of GH from the pituitary. Essentially, GHRH initiates the strength of the GH pulse.
GHRH's arch rival, somatostatin, counters these effects, however, by inhibiting GH release. Therefore, somatostatin prevents the GH pulse. In the end, GH release occurs when GHRH is at its peak in stimulating the pituitary, while somatostatin is at its low in inhibiting the pituitary. The result of this high GHRH and low somatostatin period is a big spike in blood levels of GH (Juul, 2000).
The following is a chart adapted from Basic and Clinical Endocrinology, 5th Edition depicting other factors influencing the GH secretion spike:
Factors Increasing
GH Secretion Factors Decreasing
GH Secretion
Physiological: Physiological:
Sleep Hyperglycemia
Fasting Elevated Blood Free
Fatty Acids
Exercise Obesity
High Amino Acids
in the Blood Hyper or
Hypothyroidism
Low Blood Sugar
Pharmacologic Pharmacologic
Any hypoglycemic agent GH itself
Estrogens Somatostatin
Alpha-agonists Alpha antagonists
(yohimbine)
Beta antagonists Beta agonists
(ephedrine, clenbuterol)
Serotonin Serotonin antagonists
Dopamine Dopamine antagonists
GABA
Once the GH pulse occurs, blood GH is free to affect target tissues. Some of the well-documented actions of GH are increases in longitudinal bone growth (longer bones), increased bone mineralization (thicker, stronger bones), anabolism (protein building), lipolysis (fat loss), and anti-diuretic actions (Bengtsson, 1999). GH treatment is common in congenital syndromes of GH deficiency and in cases of hypothalamic or pituitary damage.
In addition, it's been recognized that around the age of 30, there's a progressive decline in GH secretion from the pituitary, so much so that by the age of 60, GH production can drop as much as 60%! This means that an aging pituitary that once produced 0.5 mg of GH per day would now produce only 0.2 mg per day, and this is definitely physiologically relevant. In fact, these production levels are often equivalent to those of GH deficient young adults. This age-related GH decline has been termed somatopause by some researchers and treatment requires GH replacement therapy.
GH Deficiencies
GH deficiencies in different populations can occur as a result of impaired GHRH activity or increased somatostatin activity, impaired GH production and release within the pituitary, and/or impaired GH interactions with GH receptors on target tissues (Bengtsson, 1999). Basically GH either isn't produced or the GH is knockin' but it can't come in. Regardless of the mechanism behind GH deficiencies, these conditions can lead to a whole host of physiological abnormalities.
In children, GH deficiency leads to a reduced growth rate. This can occur due to the lack of GH specific effects on bone and connective tissue growth. In addition, skeletal muscle growth can be retarded due to other metabolic abnormalities associated with GH deficiency (decreased protein anabolism).
In adults, there are a number of abnormalities associated with GH deficiency. First, GH deficient adults tend to suffer from a host of psychological symptoms. These symptoms include reduced energy levels, reduced vitality, increased anxiety, reduced emotional reaction, depression, hampered learning capacity, and social isolation (Bjorck, 1989).
Secondly, GH-deficient adults suffer from negative changes in body composition such as increased fat mass, especially in the abdominal area (called android fat distribution), decreased lean body mass and muscle volume, and reduced bone mineral content (Binnerts 1992, Bengtsson 1993, Rosen 993). As a result of these negative changes in body composition, decreased muscular strength, poor exercise capacity, and poor power output are a result (Cuneo 1990, 1991).
Finally, GH deficiency can lead to other symptoms such as dehydration, reduced heart size, reduced cardiac performance (measured by cardiac contractility and output), hypertension, and hypothyroidism (due to low T4 to T3 conversion) (Henneman 1960, Shahi 1992, Jogensen 1989).
The bottom line is that if you can't get GH to do its job in the body, your psychological state, body composition, muscular performance, and cardiac performance will suffer. So you'd better get some GH.
Hey Doc, How's My GH?
So how do you know if you need GH treatment? That's a good question that scientists are still trying to answer. And you can bet that if they're having a hard time with this question, most physicians are quite a bit behind them. Since the symptoms of GH deficiency in adulthood (increased adiposity, decreased muscle mass, reduced strength and exercise capacity, and psychological disturbances) are non-specific, a deficency based on clinical symptoms is difficult to diagnose. Therefore, biochemical markers must be used.
Random sampling of plasma GH isn't a sufficient measure due to the unpredictable pulsatile nature of GH secretion shown in the graph above. If you pull a sample at the peak of a GH burst, it looks like you're fine, but if you pull one at the "trough"; it looks like you need some GH. Normal fasted levels of GH are less than 5 ng/ml, but again, the utility of random sampling is limited. By taking a 24-hour integrated measure, you could get a good approximation of total GH secretion, but who wants to sit in the doctor's office for 24 hours and have 24 blood samples taken; one every hour? Not me!
Therefore, the best clinical test for GH secretory deficiency is an ITT or insulin tolerance test. With this test, a single dose of insulin is administered to promote hypoglycemia. If you check your chart above, you'll notice that hypoglycemia is a good GH secretory stimulant. So, as insulin goes up and blood glucose goes down, GH secretion should go up. Since this test only measures GH secretion and not GH action at the receptor level, other tests are required to determine GH deficiency.
Serum measures of IGF-1 and IGFBP-3 are two markers of GH activity but their utility has been questioned (more on these later). Since daily IGF-1 levels tend to be stable, in the clinical setting, low IGF-1 levels can indicate the need for further assessment of GH secretion and function. Normal IGF-1 levels are 90-318 micrograms/l while IGFBP-3 levels are 2.0-4.9 milligrams/l.
Effects of GH Replacement
Since GH deficiency leads to the aforementioned frightening list of psychological and physiological abnormalities, the treatment of GH deficiency has received much attention within the medical community.
In clinical trials, most of which were referenced above in the "deficiency" section, GH replacement has been shown to remedy most of the physiological abnormalities. The major benefits of GH therapy include positive protein balance (synthesis exceeds breakdown), increased lean body mass, decreased fat mass, increased insulin sensitivity, normalized body water, increased bone remodeling, and increased T4 to T3 conversion.
What about side effects? In GH deficient patients, replacement therapy is usually associated with minimal side effects. The most common side effects typically occur with the onset of therapy but often tend to normalize within a few months' time. These negative side effects include include fluid retention, carpal tunnel syndrome, myalgia (muscle pain), and arthralgia (joint pain). In addition, fasted and post-prandial (post-meal) blood glucose levels tend to be higher in GH replacement as a result of the mild insulin insensitivity that can occur with doses in excess of the exact requirement. Finally, it's been suggested, but not verified, that GH replacement may lead to a risk of malignancy and some cancers.
Although there are a few risks with GH replacement, the risk to benefit ratio of GH therapy in grossly deficient humans remains positive. Since GH can be relatively safe in replacement situations, as well as the fact that GH treatment can greatly impact body composition, researchers and clinicians have begun to explore the use of GH in treating the negative physiological conditions caused by HIV or age-related muscle wasting, obesity, severe physiological stressors (surgery or burn injuries), nutrient restriction, glucocorticoid therapy, and impaired immunity. Unfortunately, the data are mixed in regard to GH therapy in these populations with some studies showing positive results in muscle mass and fat loss and others showing nothing but side effects.
One reason for this may be the fact that in some studies, GH treatment has been given alone while in others, GH treatment was given with several other hormones that may have acted synergistically with the GH to promote the positive changes. One thing is clear though; there is no clarity! At the doses given in research studies, there is no clear consensus on whether GH therapy is warranted in any population other than those with GH deficiency. More research is needed to make this determination.
How GH Works - The GH/IGF-1 AXIS
Due to the rise in recombinant GH availability, the research has been abundant and a clearer picture is emerging of GH action. But make no mistake, the picture isn't all that clear. It may be more like one of those computer-generated 3D pictures that you have to look at in just the right way for just the right amount of time to make any sense of it at all. And no one has yet to look long enough at this particular picture.
With all of this GH floating around, the black market supply of GH has also been on the rise. So after we talk GH action, let's talk bodybuilding. If GH can potentially get bodybuilders big and ripped, then to some, it's a drug worth exploring. So for you die-hard muscle heads, here's a little GH primer with special focus on the pursuit of lean mass.
Circulating GH is thought to act through two distinct but interrelated mechanisms. The first is direct. GH can act directly on many cells in the body via the GH receptor. Once released into the blood from the pituitary, GH either circulates as free GH or circulates bound to GHBP for transport (GH Binding Protein). Free GH is available to interact with cellular receptors to create a response.
Once free GH has interacted with the cellular receptors, it's thought that more GHBPs are formed. With this increased GHBP, some researchers believe that more GH is rendered temporarily unavailable. But at the same time, it stays in the system for a longer amount of time. So although GHBP-bound GH has a much longer half-life, it cannot interact with cellular receptors while bound.
Unfortunately, there's no clear consensus as to whether it's more important to cellular GH action to prolong the half-life of GH (to allow for higher levels to circulate for longer), or to decrease GHBP to allow for higher levels of free GH. And this debate holds true for not only GH, but for other hormones like Testosterone as well. Although the researchers tend to contradict each other and sometimes even themselves on this point, the bottom line is that the effectiveness of GH (and other hormones) is tied up in this balance between bound and unbound GH and the presence of binding proteins.
Binding proteins aside, once free GH does reach the cells, its direct actions include the promotion of lipolytic and hyperglycemic effects. GH can decrease glucose utilization in favor of fat release and oxidation (lipolysis). Unfortunately, because of this shift from carb to fat use, GH also increases insulin resistance. Hyperglycemia is a result of this insulin insensitivity. So although GH itself can make you lean due to lipolysis, this might come at the expense of insulin resistance and might ultimately lead to a diabetic state. As a result, you'll be a lean diabetic rather than a chubby normal guy. I guess it's a trade-off.
The second mechanism by which GH exerts its effects is indirectly through IGF-1. In the liver, circulating GH is converted into IGF-1 and 2 which can travel through the blood to promote their effects. IGF is also bound to one of 6 plasma proteins (IGFBP's 1-6). About 1-5% of IGF-1 is free while 95-99% is bound. Again, this balance is important for hormone action. This systemic IGF is also free to interact with cellular receptors.
In addition to the systemic effects of liver IGF-1, IGF can act locally. Let me explain. GH binding to cells can lead to what is called peripheral conversion of IGF-1. At this specific location (skeletal muscle for example), IGF-1 acts in an autocrine or paracrine fashion to promote its effects. This means that unlike GH, which has endocrine function (it is produced in the pituitary and travels elsewhere to do its work), IGF-1 can both be produced in, and promote changes in, the same tissue or those immediately adjacent to it.
Perhaps the most relevant effect of IGF-1 to this discussion is the ability of IGF-1 to increase protein synthesis by increasing cellular mRNA formation (mRNA makes protein) as well as increasing uptake of amino acids. This effect on protein synthesis can lead to increased lean mass. The research indicates that this effect is dependent on GH presence as well. So IGF-1 alone does not promote such effects. Nor does GH. It appears the combination of the two most consistently lead to increased protein synthesis.
In addition, IGF-1 can also counteract the hyperglycemic effects of GH via insulin-like actions on glucose uptake. Since IGF-1 is typically elevated to a small extent with GH elevations, IGF action is not sufficient to neutralize the hyperglycemic effects of GH, but perhaps it minimizes extreme insulin insensitivity.
The bottom line is that GH and IGF-1 seem to be necessary bedmates. Although each may act most strongly in different tissue types, they are thought to work together to promote anabolism and stimulate lipolysis (Ney 1999, Yarasheski 1994). But all this synergy comes at a price. Both hormones negatively feed back on the pituitary to slow GH production. And this impacts normal GH secretion as well as GH treatment.
When plasma GH levels and IGF-1 levels are elevated with GH treatment, this elevation is non-physiologic. What this means is that after a GH injection, GH levels are elevated for some time and then come crashing down to normal, often being suppressed for hours thereafter. So the pattern seen in the graph above is not the one seen when using exogenous GH. This is probably due to the fact that both GH and IGF-1 are negative regulators of GH release so an increase in either (from a GH injection) reduces the secretion of GH.
So when examining the GH/IGF-1 axis, a few things should be considered. With strong feedback mechanisms in place, it's difficult to maintain consistently high levels of GH without constant exogenous dosing. And that's a hassle. In addition, just like with insulin, there may be something known as GH insensitivity (Grinspoon 1998). It appears that with chronically high levels of GH, liver and peripheral conversions of GH to IGF-1 are decreased. So even with the constant use of exogenous GH, the body may simply try to regulate itself and the actions of GH by preventing the availability of what is thought to be GH's partner, IGF-1.
It seems like a no-win situation. And perhaps this is best. The body has feedback mechanisms for a reason... protection. If GH action isn't kept in check, the medical condition known as acromegaly can result. Acromegaly is characterized by abnormal skeletal growth characterized by enlarged jaw and hands. Individuals suffering from this have abnormally high levels of GH, IGF-1, and IGFBPs. It's apparent, then, that the feedback mechanisms of these individuals aren't working all that well.
Often times, GH users smugly tell me that acromegaly is BS because they've been using GH for X amount of time and they didn't get it. Well guys, guess what? Normal individuals probably won't get it because of the feedback mechanisms described above. You know what else? You're probably not getting muscle building results either.
The Perfect Physique?
GH, Muscle Function, and Body Composition Research
Since most of the benefits of GH were originally thought to impact muscle mass, scores of rodent studies were conducted to examine the effect of GH on muscle mass and contractile ability. The findings did indicate a small increase in muscle mass but no increase in contractile strength. One study looked at rat quads (no they didn't squat) and they did get bigger (quads), but not stronger (Bigland, 1953). In addition, in other rat studies, although there were small increases in body mass, there were absolutely no increases in strength. How could this be? More muscle equals more strength, right? Well, researchers concluded that the increase in quad mass was not contractile protein. The mass could have been fluid or connective tissue.
Since animals did benefit from increased muscle mass, the next step was to take these findings to humans. In cases of GH deficiency, small increases were found in muscle volume (~6-8%) and lean body mass (~11%). Exercise capacity was elevated in such patients (~12%), but strength was either not changed or mildly increased by about 8% (Jorgensen 1989, Salomon 1989). As stated earlier, most of the observed benefits of GH have been seen in GH deficient animals and humans.
Also, as mentioned earlier, there's certainly not much to get excited about in other populations. When GH is administered alone, very few studies have shown any increase in size or strength. In two recent HIV studies, patients given huge doses of up to 27 IU per day (9 milligrams) had no gains in muscle mass. But remember, according to what I said earlier, IGF-1 was the protein anabolic agent. And GH has its biggest effect on lipolysis. And the combination of the two may lead to the greatest results.
So in examining the research, it's been speculated that the levels of IGF-1 adminstered weren't great enough (in conjunction with GH) to make an impact, or that the individuals became GH resistant. Also, since IGF-1 would lower GH secretion, it doesn't make much sense to give it alone. Remember, GH and IGF-1 often work together to change body composition. Newer studies have shown that when adding IGF-1 to the mix, it appears that there's a definite increase in protein synthesis and muscle mass as well as some increase in strength.
So perhaps GH alone is useless at increasing muscle mass while a combination of GH and IGF-1 may be effective if protein anabolism and increased contractile protein is the goal (Kupfer 1993, Snyder 1988). But even the increases seen in these studies were moderate and a cost/benefit analysis is warranted since this combination might also lead to severe side effects.
So what about GH and fat mass? Most studies have shown modest decreases in body fat and skinfold measures with GH treatment (Jorgensen 1989, Salomon F, Tagliaferri 1998). Decreases in fat mass of about 16% and decreases in thigh adipose mass of about 7% have been reported. But remember, a 16% fat decrease doesn't mean they went from 20% to 4% body fat. It more likely means that a 200 lb person with 20% bodyfat or 40 lbs of fat would have their fat mass decreased to about 35.5 lbs. This would put them at about 193.5 lbs and 18% fat.
In another study, obese women on GH lost 2 more lbs than placebo group in a one-month period. So although it does appear that GH can decrease fat mass in clinical populations, when looking at the actual fat loss numbers, it appears that the good old ECA stack or MD6 would be more effective than GH.
GH and The Athlete
I've never been sure why the use of GH has become popular in athletes and bodybuilders. Perhaps it's the name... Growth Hormone. Sounds like it'll make me big. Or perhaps it's the legend of Pump de Leon. Either way, the research on GH use in bodybuilders and men on resistance training programs has shown it to be all but useless. And this is probably due to the feedback mechanisms like the negative feedback on the pituitary and the GH resistance discussed earlier.
In two landmark GH studies conducted at the Washington University School of Medicine, a world-renowned GH researcher named Kevin Yarasheski studied the effects of GH in combination with weight training (Yarasheski 1992, 1993).
In the first study, 18 untrained men were given either GH and exercise or placebo and exercise for 12 weeks. GH subjects were given 40 micrograms/kg of recombinant GH and all subjects were evaluated before and after treatment for fat mass, fat free mass, total body water, whole body protein synthesis, insulin sensitivity, muscle size and muscle strength. Due to the development of carpal tunnel syndrome, 2 subjects were forced to withdraw from the study.
When comparing the GH+exercise group with the placebo+exercise group, the data showed that there was no fat loss, no change in insulin sensitivity, no increase in muscle size, and no increase in strength! Whole body protein synthesis was increased in the GH group relative to the placebo, but muscle protein synthesis wasn't. In addition, lean body mass was increased, but again, this wasn't muscle mass, but probably a combination of water retention, organ mass, and connective tissue instead. The researchers, who seemed quite objective in their conclusions, decided that non-muscle proteins were being formed instead of muscle contractile protein.
In the follow-up study, Dr. Yarasheski pursued the effects of GH on experienced weight-lifters. Since the GH didn't positively impact strength or body comp in the untrained guys, Dr. Yarasheski wondered if well-trained athletes might be different. So another study was conducted to examine protein synthetic rates in GH-treated athletes. After 2 weeks of GH treatment (40micrograms/kg), the data were clear that short term GH had no effect on whole body protein synthesis or breakdown. The reason they chose 2 weeks was that in a number of previous studies on clinical populations, any increases in protein synthesis had only lasted for about a month and then ceased due to some type of down-regulation (Perhaps GH insensitivity?). In this population, however, GH didn't even promote protein synthesis within this time frame.
With all this negative data, it should be mentioned that one study showed something positive happening, but again, it wasn't all that exciting (Crist 1988). This particular study showed a small 4% gain in lean body mass and a modest 12% loss in body fat with GH doses of 8IU per day (2.6 milligrams). Muscle mass wasn't measured, so there was no way to determine the make-up of the increased LMB (lean body mass).
So it's pretty apparent that in weight trained men, GH alone doesn't increase muscle mass. Resulting lean mass gains from GH treatment are probably a combo of water, connective tissue, or organ mass. I say probably because organ mass and connective tissue mass are hard to measure. The indirect evidence is pretty strong, though.
Since non-muscle protein gains and the development of carpal tunnel syndrome (due to growth in the connective tissue sheath in the wrist) were apparent in these studies, connective tissue gain is a reasonable speculation. In addition, acromegaly patients have increased organ mass as a result of the high responsiveness to GH, so it would stand to reason that this could have occurred in these studies, too.
The next logical question is this: Since a lot of guys are still using GH, what are the implications of increased organ mass and connective tissue? Well, to be honest, we don't know.
Acromegaly patients do not have high rates of organ malfunction or pathophysiology, so although growing large organs isn't ideal, the current literature doesn't indicate that the problem is immediately life-threatening. But, acromegaly patients do die prematurely, so if they were to live longer, perhaps these organ changes could have long-term impact.
As far as the issue of increases in connective tissue, the increases themselves may not be too terrible, as long as they don't become pathophysiological. Of course, developing carpel tunnel syndrom is no picnic. On the other hand, if the strength of connective tissue increases with connective tissue growth, athletes could become more injury-resistant. Connective tissue growth will not lead to strength increases in well-trained guys if contractile protein mass doesn't go up, but these connective tissue increases may allow individuals to train with heavier weights with less risk of injury. This, however, merely results from me taking off the "science hat" and speculating a bit.
Let's Get Ready to Rumble
GH vs Testosterone and Beta-Agonists
With all this data flying, I think it's important to put things into perspective. Currently, far and away, the most popular bodybuilding drug for building muscle mass is Testosterone, while the most popular fat-loss drugs are the beta agonists clenbuterol and ephedrine. So if GH is to have any relevance to bodybuilders and athletes, it has to show itself to be superior to these drugs in terms of effectiveness, safety, or price. Since we all know that the price of GH is astronomical (it can run $1000 ++ for a month's supply), the price situation is a losing one on the GH front. What about the other two factors?
As stated in the above sections, fat loss with GH is moderate and GH can probably be outperformed with a simple ECA stack. In addition, it appears that even Testosterone, while not known for its fat-burning abilities, does a nice job of its own. In two studies, Testosterone was shown to decrease fat mass by 5% and 6% (Anawalt 1999, Blackman 1999). In one of the same studies, GH was also administered and decreased fat mass by 12%. So although doubly effective when compared to test, I think that GH would be bested by ECA in a fat-loss contest.
As far as muscle mass, do we even need to waste our time on this discussion? Testosterone is clearly the winner of the muscle building battle, hands down. No data necessary.
And what about safety profiles? Well, it's not all that safe for healthy individuals to mess with endocrine profiles in the first place. But since both Testosterone and GH clearly have their risks, it appears to me that when comparing the doses needed for a positive effect, Testosterone is much less likely to cause any serious harm. So, in the end, when looking at the total cost to benefit profile, it is clear that GH loses the battle with both Testosterone and even with the over-the-counter ECA stack. Sorry GH.
Here's a little chart that's adapted from the June 3, 1999 New England Journal of Medicine comparing the costs of different drug therapies if you were to obtain them legitimately with a prescription. I've also added the cost of MD-6 for a little comparison:
Treatment Dose Annual Cost
Testosterone Analogs (IM) 500mg/week $1,250
Testosterone Transdermal 5mg/day $1,300
Oxandrolone (oral) 20mg/day $10,949
Nandrolone (IM) 250mg/week $1,000
Recombinant GH 6mg/day (18IU/day) $36,000
MD-6 2 servings/day $480
So Long GH
New Options in GH Manipulation
Over the last few years, GH has been a relative disappointment in terms of treating catabolic/wasting disorders. And it has obviously been a disappointment for athletes and bodybuilders. So the pharmacologists got to work and built a better mouse trap. It has been proposed that GH has been disappointing because of the feedback mechanisms described earlier as well as the non-physiologic nature of GH treatment. What this means is that since GH is normally pulsatile, the body may be best adapted to this situation. Perhaps it likes to see frequent short bursts of GH rather than huge single increases followed by hours of suppression.
Since GH treatment results in these non-physiologic GH responses, pharmacologists have speculated that an oral GH secretagogue that could increase the burst frequency and burst amplitude (height) might offer the distinct advantages of less negative feedback, less GH resistance, a better risk profile, and a better mode of delivery (oral).
Lo and behold, such secretagogues, called Growth Hormone Releasing Peptides have been found. Growth hormone releasing peptide 6 (GHRP 6), Hexarelin, and MK-0677 are available and fit the bill. Whereas a GH injection might cause a large spike in GH and the suppress GH for hours thereafter, these drugs, increase GH frequency and amplitude in a more physiological manner as shown below:
As shown, the GH secretagogues offer a pulsatile GH release that is more physiologic than the GH burst that a GH injection gives. Of additional interest is the fact that the inclusion of GHRH injection with GHRP (not shown) can lead to this same profile with huge, rapid peaks in GH release.
With an understanding of natural GH release it is clear that these new types of GH therapy may offer future treatment options for GH deficiency. In the absence of good safety or body compostion data, it is uncertain as to how they will be used or what populations will benefit the most from their use. If these drugs do become more popular treatment options, I would expect that bodybuilders will be testing them out as well and will provide feedback on their efficacy.
If you'll permit me to speculate about potential body comp implications, since GH has shown to be a more effective fat loss agent than anabolic agent, these secretagogues may offer a new and better fat loss approach. Since even just a physiological burst of GH increases lipolysis (Gravholt 1999), especially in the abdominal area, the very large bursts seen with GH injections may not be necessary. They may not lead to increased lipolysis above normal or mildly supraphysiological pulses. And since GH secretagogues mildly increase frequency and amplitude of GH secretion, this increased GH activity may be even more effective at promoting fat loss than GH alone. So if some supplement company comes out with a real-deal, honest-to-goodness, GH secretagogue that really works, it may be a great supplement to promote lipolysis. But for now, the only effective secretagogues I know of are the ones discussed in this article.
GH Plus
Within the last few years, the bodybuilding community has taken drug use to a new high. Being extremists by nature, bodybuilders are always looking for the next drug or combination of drugs to take their muscle mass to the next level. To this end, the new generation of bodybuilders have sworn by a combination of Testosterone, GH, IGF-1, Insulin, and Thyroid drugs. A discussion of these combinations is beyond the scope of this article and beyond the scientific literature at the current time. There is quite a bit of indirect evidence suggesting that, in theory, there may be a synergistic response to a polypharmacy of this type, but there have been very few trials looking directly at such combinations (Mani Maran 2000, Painson 2000, Demling 1999, Grinspoon 1998 and 1999, Juul 1998, Keenan 1996).
The body of anecdotal evidence is greater and I've talked to tons of guys who have used GH, T, Insulin, Thyroid, etc. Many feel that the addition of GH to a drug stack results in some pretty good gains while some say that they don't think the GH helps them at all. But who really knows how much each drug contributes? Since each person is different, uses different doses, and may or may not have real drugs, comparisons are difficult. At a price tag of $1000+ per month for the GH alone, I just don't think that the gains would be worth it either way.
My personal feeling is that when drug use gets to this extreme level where it is "necessary" to take 5 or 6 dramatically powerful, incompletely understood, and potentially dangerous hormones to compete, I think it has gone way too far. Although it's pretty interesting to think that we could control our body compositions by taking the endocrine system off auto pilot and controlling it manually for a while, we may get more than we bargained for.
Auto pilot may never work again and you'll be trying to figure out how you're gonna pay the hormone replacement bills for the rest of your lives. I just don't want to be 65 years old and still giving myself a dozen injections per day because I turned my pituitary into a shriveled, dangling waste of endocrine tissue hanging from my atrophied brain mass.
T2 - The Fat Terminator?
By John M Berardi
Fat Termination
It's no secret that summer is right around the corner. Over the last week or so the weather has decided to show a few glimpses of what's to come, namely warm sun streaming down upon exposed arms, legs, chests, and other miscellaneous body parts that have been cloaked all winter long. You've gotta love this time of year, if for nothing more that the virtual "orgiastic feast for the senses" (as Cosmo Kramer would put it).
But as always, with the good comes the bad. And in most cases, that layer of body fat that has infiltrated the lean physiques most possessed last summer represents the bad. So as summer approaches thousands everywhere are looking for a quick and easy solution to dropping the fat and, as some of my students would say, "get their rip on". They want to quickly and efficiently terminate the fat.
Obviously exercise and nutritional intake are the major determinants of fat loss but few will argue that nutritional supplements can help in the termination of high levels of body fat by either increasing metabolic rate or maintaining metabolic rate while dieting, preserving lean tissue during dieting, and suppressing food intake. When we think of legal, over the counter fat loss supplements, obviously supplements like the ECA stack come to mind. However, many individuals have even tried to shed fat using several prescription medications like the thyroid hormones T3 and T4. For you chem. buffs, T3 is the compound 3,5,3'-triiodo-l-thyronine or just triiodothyronine while T4 is 3,5,3',5' Tetraiodothyronine or just thyroxine.
Thyroid Hormones
Although thyroid hormones are necessary for promoting normal developmental growth, don't confuse this with the muscle growth that occurs with resistance exercise. In addition thyroid hormones are involved in dozens of biological processes including:
- Increased oxygen consumption (metabolic rate)
- Increased thermogenesis (heat production)
- Increased number of beta adrenergic receptors in the heart, skeletal
muscle, adipose tissues, and lymphocytes (these receptors bind fat
mobilizing hormones)
- Increased sensitivity to catecholamines (fat mobilizing, fight or
flight hormones)
- Increased number of red blood cells and increased oxygen delivery
- Increased lypolysis
- Increased liver glycogen breakdown
- Increased liver glucose production
- Increased intestinal glucose absorption
- Increased protein turnover
- Decreased cholesterol levels
From looking over this list, it appears that thyroid hormones do some pretty exciting things in the body, all of which can be beneficial to weight trainers. But before I move on, I want to talk about some of the other effects of thyroid hormones that may not be so ideal for weight trainers.
- Increased heart rate and heart contractility
- Increased free radical production (due to decreased Superoxide
Dismutase concentrations)
- Increased GI motility
- Increased bone turnover (and potentially bone loss or high levels of
calcium in the blood)
- Increased cortisol levels
- Increased sex hormone binding globulin
How's The Thyroid Working?
Now that you've seen what thyroid hormones can do, let's talk about thyroid function. Much like any other hormone system there are tight controls regulating thyroid function. So under most normal circumstances, if thyroid concentrations are low in the blood then the thyroid is stimulated to produce more hormone. And if they are high in the blood, the thyroid will be inhibited and less will be produced. Of course there are a few exceptions to these rules. Disease states, prescription medication use, and interestingly, dieting can throw off this equilibrium. While most people don't have thyroid disorders or use meds that can alter thyroid function, most people do diet at some point in their lives. And during dieting, natural thyroid production is usually suppressed and this can eventually harm fat loss efforts.
Enter thyroid drugs. Some people, in an attempt to harness the fat burning powers of thyroid hormones, are taking T3 or T4 with or without dieting in order to either maintain normal thyroid hormone levels or in order to simply burn more fat than they would have been burning otherwise. However this use comes at a price. You see, too much thyroid hormone in the body can lead to a thyrotoxic state. Side effects of thyrotoxicosis include heart palpitations, nervousness, easy fatiguability, diarrhea, excessive sweating, heat intolerance, and tachycardia. Small to moderate doses of thyroid hormones, however will probably not lead to thyrotoxicosis.
In addition to the risk of thyrotoxicosis, both hormones are very suppressive of thyroid function and it appears that with extended use of these compounds, the thyroid is sluggish in restarting natural production (Vagenakis, et al., New England Journal of Medicine, 293(14): 681-684, 1975). In fact, in this study population, it took between 5-9 weeks for thyroid production to return to normal after suppression therapy. This has pretty dramatic consequences since during this period of thyroid suppression, metabolic rate will be much lower and there is good potential for fat gain.
So with the prescription drugs T3 or T4, the potential benefits of their use must be weighed against the after effects during the thyroid-suppressed period.
Over-The Counter Thyroid Hormone?
Recently, Biotest Laboratories has released a very interesting product that they are calling T2 (otherwise known as 3,5-diiodo-l-thyronine or just diiodothyronine). T2 is definitely a legitimate thyroid hormone, structurally very like T3 or T4. However this product is allowed to be sold as an over the counter dietary supplement due to the fact that is present in meat.
In the past, T2 was thought to be inactive, but many recent papers have shown T2 to have some pretty dramatic effects on metabolic processes. One issue of concern in the interpretation of this data is the fact most of these studies used hypothyroid rats that are producing very little thyroid hormone on their own. Therefore since these studies did not examine the effects of adding T2 into a normal thyroidal environment, they may not be totally applicable to individuals with normal thyroid functioning. In any case, the studies are certainly worth mentioning.
- Significant increases in mitochondrial respiration and cytochrome
oxidase activity were found both in vitro and in vivo (1). These
increases lead to an increase in metabolic rate. Interestingly, these
effects are different from those of T3 and T4 due to the fact that T2
acts directly on the mitochondrial respiration while T3 and T4 must
first increase oxidative enzyme levels. This means that T2 has a much
more rapid stimulation of metabolic rate (1 hour for T2 vs 24 hours
for T3). Some authors have concluded that T2 may be beneficial in
rapid energy requiring situations like cold exposure or overfeeding
(2).
- Significant increases in resting metabolic rate (33%) were found
(1,3). Both T2 and T3 were able to stimulate the recovery of
metabolic rate to normal, euthyroid levels.
- Significant increases in the oxidative capacity of skeletal muscle,
brown adipose tissue, liver, and the heart were found (1,4). Both T2
and T3 promoted full recovery of oxidative capacity but T2 was most
active in the liver and the muscle while T3 was most active in the
liver.
- Significant increases in the liver activities of glucose-6-phosphate
dehydrogenase and malic enzyme were found (5,6). These enzymes are
necessary for fat metabolism.
- Significant increases in GH release were found. Both T2 and T3
increased GH release 5-fold (7).
- In the one human study I found, T2 Significantly increased oxygen
consumption in blood cells in vitro (8).
In most of the studies listed above, the doses of T2 required for physiological and biochemical effects to manifest were larger than the doses of T3 required. This is due to the fact that T2 has a lower receptor affinity for most thyroid hormone receptors than does T3.
So from these data, if the dose is right, T2 supplementation may offer most of the same benefits as T3 but might even be superior in rapidly stimulating metabolic rate. This could come in handy before a big Easter dinner or your weekly dietary cheat day.
The next question then is to ask whether or not T2 can suppress natural thyroid hormone (as measured by TSH concentrations) production like T3 can. This is where things get a little sketchy. In hypothyroid rats, T3 seems to have a much larger suppressive effect than does T2.
- Moreno et al found that it took 5x as much T2 to suppress TSH when
compared to T3 (7).
- Cimmino et al found that it took 25x as much T2 to suppress TSH when
compared to T3 (3).
- Ball et al found that 100x the dose of T2 lead to 5x less suppression
of TSH when compared to T3 (6).
- In vitro data by Everts et al showed that T2 was 100x less
suppressive than T3 (9).
- Finally, Horst et al showed that in euthyroid rats, while it took
over 100x as much T2 to suppress TSH compared with T3, even at these
doses, there were no major changes in body weight with T2
supplementation (10).
So from these data it is pretty clear that it takes a much large dose of T2 to suppress natural thyroid hormone production than T3.
Summary
Hopefully at this point you have a better understanding of how thyroid hormones work and why one would want to supplement with them. In addition, I hope you have a better understanding of T2. The other day a lady-friend of mine came up to me and asked me to give her my opinion as to whether on not she should take T2. And she asked me to tell her in layman's terms. So here's basically what I told her (unfortunately, the following is as "layman" as I get when talking about nutritional supplements); "From the data I've seen, it initially looks like T2 may really help to shed fat. However I have a few concerns. Since T2 is less active and has a lower affinity for the thyroid receptors in the cell than T3, larger doses of T2 are required to get the same fat-burning effects as you would get with T3. And although T2 is less suppressive than T3, the doses required to get full effectiveness may be enough to suppress natural thyroid production anyway. However I don't know the answers to this for sure and I'm fairly confident that no one does. I speculate, however, that the recommended dose of T2 is probably not going to cause much suppression of thyroid function. In addition this dose may have some effects on cellular metabolism but whether this dose dramatically increases fat loss, I can't be
certain."
"So in the end I can see one of four scenarios happening. First, the ideal scenario is that the doses of T2 recommended are effective and will not suppress thyroid function. This means lots of fat will be lost and there will be no rebound with cessation of use. Second, the does of T2 used are not very effective in fat loss and there will be little or no fat loss but at least there will be no suppression of thyroid function. So you wont get much leaner but you won't have any problems either. These are the two most likely scenarios. I sure hope the first one is the case but I can't be sure. There is just not enough data just yet."
"The third scenario is that people may take larger doses of T2 than recommended and lots of fat will be lost but there will also be thyroid suppression. This means that they must be prepared for the dreaded rebound and lower metabolic rate for a few weeks after going off the supplement. And the fourth scenario is that with higher than recommended doses, the thyroid will be suppressed and while some efficacy is evidenced, there will be a metabolic compromise. In response to suppression of the thyroid, T3 levels will go down. Since T3 which is responsible for several functions in the body that T2 isn't known to be active in, while you are on T2 you might not be getting all the benefits that T3 will promote. And again, when you go off, you will have a short rebound period of suppressed thyroid function."
So in the end, the question of whether T2 is a legitimate fat terminator is a tough one to answer. From the available data, there isn't a clear picture that I can present. However, I think that T2 is ultimately pretty safe at the recommended doses. Whether it works as well as some think is another question. Fortunately Biotest has asked me to investigate this very question in the lab so that we can have some real answers in the near future. Stay tuned for updates as to my progress.
Hungry, Hungry Hormones — Part I
by John M Berardi
We here at T-Nation just love them-there hormones. And if you didn't figure that out from the very name of our little publication, you might have figured it out from the dozens of hormone-related articles we've published over the years. Yep, we here at T-mag headquarters love our Testosterone, our Growth Hormone, our Insulin, and our Glucagon. In fact, the last Friday of each month is devoted to the anabolic hormones. "Hormone Friday, as it's called, is a day in which each T-mag staff member dons his or her favorite anabolic hormonal attire. You shoulda' seen JB last month. Hell, with that sterane ring wrapped around what he called his "Testosterone factory," he was a shoe-in for top costume honors.
As a result of his creative costume ideas and his needle-point prowess, JB not only got TC's Real Doll,"Jenny," for the weekend, but he also earned the right to review a relatively new hormone that's lately been the source of much discussion and confusion. JB's already covered the biggies: Testosterone (The Big T, Parts I and II, The Steroid Manifesto, Parts 1, 2, and 3), Growth Hormone (The Fountain of GH), and Insulin (The Anabolic Power of Insulin). Now, it's time for JB to tackle that pesky new guy on the block — the hormone Leptin.
Is It Really That Simple?
I wish someone would hand me a shiny US nickel every time I heard some personal trainer or some gym guru respond to an exercise or nutrition related question with "Well, it's simple really…"
Why am I always doing 3 sets of 10 reps?
Well, it's simple really…
Why should I eat more protein?
Well, it's simple really…
Why do I always seem to plateau after a few weeks of dieting?
Well, it's simple really…
Why won't the fitness model with the lacy thong respond to my loud grunts and pawing hands?
Well, it's simple really…
Whenever I see the "Well, it's simple really…" clowns in action, I wonder how rich I would be if I actually did get those nickels. Next I wonder if anything is really as simple as they make it out to be. Finally I wonder if anyone would miss them if they were buried somewhere in upstate New York.
After all, it seems to me that most exercise and nutrition questions, especially those related to our physiological responses to certain manipulations, are quite complex. Rather than "Well, it's simple really…" I tend to think that the answer to almost every question relating to exercise and nutrition should start off with "Well, it depends on..."
Feeding and Metabolic Regulation
One of the nutrition answers that has recently gained "Well, it's simple really…" status is the idea that eating less tends to decrease your metabolic rate while eating more tends to increase your metabolic rate. While most nutrition faithfuls discuss this idea ad nauseum, I wonder if any of them actually understand this phenomenon.
Just how does the body know we're eating less?
Likewise, how does it know we're eating more?
Furthermore, how can it adapt the overall metabolic rate to accommodate this knowledge of what's happening with energy intake?
These are just a few of the questions that need answering if we're to aspire to better body composition manipulation. After all, if our energy expenditure is intimately linked to our energy intake (see my visual depiction of this below), we need to figure out where the communication is taking place.
By understanding this communication and the integration of intake and expenditure, we can hopefully find ways to dissociate the relationship. For example, if expenditure wasn't so dependent on intake, we could more easily manipulate our body composition by avoiding that nasty metabolic shutdown that accompanies dieting. Conversely, if expenditure didn't send such strong signals that impact our urge to eat, many of you miserable dieters wouldn't feel so hungry when trying to get lean. Of course, with this latter point, we can always just refuse the signals, eating in a way that supports our goals. But that doesn't make us any friendlier while dieting, now does it?
So Where's The Communication?
If you're going around asserting that one's metabolism increases or decreases based on whether they're on a hypercaloric or a hypocaloric diet, you'd better hope that there's some evidence for this hypothesis. You see, if there's any truth to the theory that the body can "sense" energy intake and respond metabolically, scientists would have to find a metabolic pathway that's sensitive to changes in some energy metabolite. If they can't find this, no matter how self-evident they think this idea seems, the "Well, it's simple really" camp is just vehemently defending an unproven hypothesis.
Fortunately for the "Well, it's simple" folks, there seems to be a candidate pathway that can explain the fact that our bodies seem to rapidly respond to changes in energy intake. In other words, a pathway has been discovered that can explain how the body knows whether we're feasting of we're fasting. This pathway is known as the HBP, or Hexosamine Biosynthetic Pathway.
As many of you know, cells of the body are always metabolizing carbohydrates for energy. This metabolism is accomplished by sending glucose through the anaerobic glycolytic pathway (see below). The metabolites of this pathway usually end up fluxing through the Kreb's cycle, providing substrates to resynthesize ATP (the cell's energy currency).
During this normal carbohydrate metabolism, a small amount of the glucose flux (1-3%) is sent through our new friend, the little discussed HBP. This pathway accepts either glucosamine (which is phosphorylated directly) or fructose 6 phosphate (which is phosphorylated by GFAT / glutamine: fructose 6 phosphate amidotransferase) to form glucosamine 6 phosphate. This glucosamine 6 phosphate is then converted to UDP-N-acetylglucosamine and acts as a glycosylation substrate. A glycosylation substrate is one that binds proteins to alter their stability in the cell. This alteration, among other things, influences how the protein interacts with the genetic material. For those "visual learners," a visual depiction of these pathways is provided below.
The important point here is that when you eat more, more glucose is available and there will be more flux through the HBP. Conversely, if you eat less, less glucose is available for flux through the HBP. This means that the HBP can directly "sense" what's happening with the energy in side of the energy balance equation.
At this point, if you're wondering why this matters, I'd like to draw your attention to the effects of increased flux through the HBP (or, a habitual increase in energy intake):
• Decreased glucose uptake
• Reduced insulin sensitivity
• Increased insulin secretion
• Increased fatty acid synthesis in the liver
Now, obviously reduced insulin sensitivity and glucose uptake aren't what weight trainers are striving for. But keep in mind that these reductions occur relative to what's happening on a lower calorie diet. Therefore, these changes would be expected. If you're overfeeding, the cells will be stuffed full of carbohydrate and will obviously have to work harder to get any new carbohydrates in. But keep in mind that if you have excellent insulin sensitivity, overfeeding may reduce this sensitivity (as shown above) a bit. That certainly doesn't mean, though, that you need to immediately get on diabetic meds.
What it does mean is that we now have a candidate mechanism by which acute and chronic food intake can be "sensed" by the body (i.e. through glucose flux). In addition, we also have a mechanism by which the "sensing" can cause a cellular response (glycosylation of proteins by UDP N-acetyl glucosamine).
For you budding physiologists out there, you may be wondering what happens when proteins are glycosylated by UDP N-acetyl glucosamine. Well, scientists aren't completely clear on that one just yet. However, what scientists have done is link HBP flux with the expression of the OB (obesity) gene. And this, my friends, is the hormonal segway you've been looking for. By altering expression of the OB gene, the HPB is directly linked to the expression of the hungry, hungry hormone — Leptin.
As alluded to, Leptin (a term derived from the Greek leptos - meaning slim) is a 16-Kd (this indicates it's size) hormone produced in the translation of the genetic information contained on the Ob (obesity gene). Upon stimulation of the Ob gene, cellular translation initiates the formation of a leptin precursor protein (Leptin mRNA). This Leptin mRNA is then transcribed into the hormone leptin without any significant post-transcriptional regulation (i.e. most all of the Leptin mRNA ends up becoming Leptin).
At this point, I'm gonna give you a week to think about what you've learned with respect to how the body senses energy intake. Now that you have this background, next week we can dive right into Leptin, covering how this hormone helps to regulate feeding, energy balance, and body composition.
Hungry, Hungry Hormones — Part 2
by John M Berard
We here at T-Nation just love them-there hormones. And if you didn't figure that out from the very name of our little publication, you might have figured it out from the dozens of hormone-related articles we've published over the years. Yep, we here at T-mag headquarters love our Testosterone, our Growth Hormone, our Insulin, and our Glucagon. In fact, the last Friday of each month is devoted to the anabolic hormones. "Hormone Friday, as it's called, is a day in which each T-mag staff member dons his or her favorite anabolic hormonal attire. You shoulda' seen JB last month. Hell, with that sterane ring wrapped around what he called his "Testosterone factory," he was a shoe-in for top costume honors.
As a result of his creative costume ideas and his needle-point prowess, JB not only got TC's Real Doll, "Jenny," for the weekend, but he also earned the right to review a relatively new hormone that's lately been the source of much discussion and confusion. JB's already covered the biggies: Testosterone (The Big T, Parts I and II, The Steroid Manifesto, Parts 1, 2, and 3), Growth Hormone (The Fountain of GH), and Insulin (The Anabolic Power of Insulin). Now, it's time for JB to tackle that pesky new guy on the block — the hormone Leptin.
Express Yourself
As discussed last week, Leptin is a hormone produced when the OB (obesity) gene is expressed. While I've already discussed one mechanism to induce OB gene expression and Leptin production, the three main cellular signals involved are:
• Increased energy/carbohydrate flux through the HBP.
• Increased triacylglycerol (triglyceride) metabolites. These include diacylglycerols and/or free fatty acids.
• Increased tension in adipose tissue due to cellular stretching (increases in adipose size).
As you can see, these three phenomena provide response mechanisms whereby both acute and chronic overfeeding or underfeeding will influence OB gene expression and Leptin production. If overfeeding, more carbohydrates will flux through HBP, more triglycerides will be metabolized, and adipose tissue sizes will increase. This leads to more Leptin production. Conversely, if underfeeding, carbohydrate and triglyceride availability will be decreased, as will adipose tissue size. Of course, this means less Leptin.
Since we now know why Leptin is formed, how about discussing where it's formed? In adult humans, most of the body's leptin is formed in white adipose tissue. This should be self-evident from the signals discussed above. However, Leptin has also been found in the following tissues, making it relatively ubiquitous.
• Brown adipose tissue
• Gastric epithelium
• Placenta
• Skeletal muscle
• Mammary glands
Of Rat and Fat
When Leptin was originally discovered, scientists found that rats that had mutations in the OB gene (and couldn't produce Leptin) became insanely obese. Now when I say obese, I'm not talking a little overweight here. I'm talking so obese that members of NAAFA actually pointed and laughed. In the obese rats, the extreme obesity was caused by mutations in the Ob gene. In these animals, there was simply too little Leptin. Interestingly, when administered Leptin, these tubby rats saw big increases in metabolic rate and lost massive amounts of body fat.
As a result of these findings, researchers speculated that Leptin might be a magical fat loss hormone. Unfortunately for the pharmaceutical companies who immediately jumped all over the rights to sell recombinant Leptin, this hypothesis didn't pan out. You see, another model of rat was discovered, a model that was as obese as the Leptin deficient rats but had adequate Leptin concentrations in the blood. These rats, instead of a Leptin deficiency, had problems with their Leptin receptor. Therefore the Leptin that was present couldn't do its job.
In addition to this new rodent data, thwarting the potential billions to be gained from Leptin sales, new human data also showed that Leptin was unlikely to help the obese drop those few hundred unwanted pounds. Research had clearly demonstrated that:
a) Very few obese humans actually suffer from Ob gene mutations
b) Very few obese humans actually suffer from Leptin receptor mutations
c) Obese humans often have very high concentrations of leptin in the plasma
Since obese humans often have so much Leptin, research has been directed toward how these individuals can have so much Leptin, yet fail to respond with a reduction in body weight, as did our furry rodent friends. One hypothesis that has gained popularity suggests that a Leptin resistance causes human obesity. In other words, the very obese got this way because they were somehow intolerant to rising Leptin. As one researcher put it, "Leptin resistance is not well defined, however this term is usually used to mean that leptin does not perform its central and peripheral functions."
At this point, there is some evidence for the Leptin resistance hypothesis. Since Leptin seems to have central effects, the saturable blood brain barrier transport system for leptin may be linked to obesity. Since obese humans have a CSF (cerebrospinal fluid) to plasma ratio that is much lower than normal-sized humans, it appears that only so much Leptin can get across the BBB into the brain. In addition, in rats, dietary induced obesity (DIO) is accompanied by high plasma leptin concentrations. This leptin doesn't seem to prevent the obesity. However, when administered intracerebroventricular leptin (leptin into the brain), they lose weight, indicating a potential BBB transport limit.
Although these data offer support to the idea that there is a limit to amount of leptin allowed into the brain and therefore a type of Leptin "resistance" exists at the higher levels of Leptin production, some authors believe that leptin resistance is actually a misnomer. These researchers are of the opinion that since leptin may not be designed to function in such high concentrations as seen in obesity, Leptin may be more important in its absence than its presence (i.e. may be more important in calorie restriction and not in calorie excess, as is often seen with obesity). In other words, it's not that the obese are "improperly" responding to their leptin. Instead, these authors are suggesting that the obese aren't "supposed" to have so much leptin and therefore don't respond to it's elevation above a certain point.
What's Leptin Do?
The hormone Leptin seems to affect nearly every system of the body. Since there are Leptin receptors in the brain and throughout the body, we can discuss the effects of Leptin as central or peripheral.
Since Leptin is released (mostly) by adipose tissues, adipose tissue seems to be a peripheral static indicator of the chronic energy balance of the body. Once released into the blood, under normal conditions, Leptin travels across the blood brain barrier and is sensed by the Leptin receptors in the hypothalamus. Since these receptors have some idea of what's a "normal" Leptin signal, changes in Leptin binding initiates the release of a series of anabolic (orexigenic or meal stimulating) and catabolic (anorexigenic or meal preventing) hormones/neurotransmitters. An increase in leptin leads to the expression of several anorexigenic (catabolic) hormones and neurotransmitters including áMSH and CART. These chemicals decrease hunger and meal size.
Conversely, a decrease in leptin leads to the expression of several orexigenic (anabolic) hormones and neurotransmitters including NPY and AgRP. These compounds increase hunger and meal size. This is a rather nice way for the body to deal with energy surplus or energy deficit. If there's a surplus, Leptin increases, signaling the hypothalamus to tell the body to stop eating. Conversely, if there's a deficit, Leptin decreases, signaling the hypothalamus to make us really hungry. For you visual learners, here's a visual depiction of what happens when Leptin concentrations increase in the hypothalamus.
Although I only mentioned a couple key orexigenic and anorexigenic hormones/neurotransmitters, there are many others that can interact with Leptin or the same signaling systems as Leptin. These are listed below:
Orexigenic (stimulate food intake) —
May act in the lateral hypothalamic neurons
Anorexigenic (reduce food intake) —
May act on the ventral & dorsal medial hypothalamus
Neuropeptide Y (NPY)— is the most potent orexiant known; may respond to aberrant leptin signaling; antagonism may reduce hunger and fat mass
Agouti Related Peptide (AgRP) — potent orexiant; may respond to absent leptin; antagonism may reduce hunger and fat mass
Melanin Concentrating Hormone (MCH) — receives signals from NPY to increase food intake
Orexin — increases arousal and food intake
Ghrelin — a potent GH releasing hormone released from the stomach, pituitary, and hypothalamus; increases food intake and body weight; may compete with leptin
Pro-Opiomelanocortin (POMC) — precursor to áMSH
Melanocyte Stimulating Hormone (áMSH) — decreases food intake; may respond to increased leptin; antagonism increases appetite and food
Melanocortin 4 receptor (MC4R) — áMSH receptor; binding of agonist reduces food intake
Cocaine Amphetamine Related Transcript (CART) — decreases food intake; may respond to increased leptin
CCK — gastric released peptide; increases satiety; reduces food intake (single feeding and meal frequency)
Corticotropin releasing factor (CRF) — regulates adrenal hormones and ACTH; decreases food intake, increases energy expenditure
Insulin — increasing concentrations of insulin decrease appetite
While these energy regulating hormones and neurotransmitters may be relatively new to you, the important message here is that they are responsible for sensing a starvation response (with decreased Leptin). In response to these decreases in Leptin concentrations, these chemicals are responsible for promoting the following effects:
a. Increased food intake
b. Decreased skeletal muscle growth
c. Decreased energy expenditure
d. Decreased body temperature
e. Decreased reproductive function
f. Increased adrenal production of stress hormones
g. Increased parasympathetic tone
Conversely, these energy regulating hormones and neurotransmitters are responsible for sensing an energy surplus (with increased Leptin). Therefore, when Leptin concentrations increase, the following effects are promoted:
a. Decreased food intake
b. Increased energy expenditure
c. Increased sympathetic tone
Again, for you visual kids, here's a schematic. Remember, Leptin is regulated in response to acute feeding as well as chronic energy balance (as measured by adipose mass). Therefore, while you'll see weight gain and weight loss as regulators below, you could replace these terms with underfeeding and overfeeding.
Notice that the main discussion today has centered on the central effects of Leptin (in the hypothalamus). However, Leptin, as discussed earlier, also has a number of peripheral effects. The peripheral effects include the following.
In skeletal muscle, leptin increases fat oxidation and insulin sensitivity, explaining part of its effect on weight reduction.
Leptin may act in concert with the immune system since leptin deficient animals have reduced immunity. This may explain part of the effect of dieting on weakened immune function.
Leptin may play a permissive role in female menarche since there is an inverse relationship between Leptin concentrations and age of first menstruation. This means girls with more body fat (and higher Leptin concentrations) may have first menstruation sooner than leaner girls.
Leptin concentrations and Testosterone concentrations are inversely proportional through the normal range of Testosterone. This means that as Leptin goes up, Testosterone down. Conversely, as Leptin goes down, Testosterone goes up. This should be no surprise as very overweight men are often hypogonadal. However, you should wonder why those who are extremely lean are often hypogonadal as well.
The paradox of this relationship is that leptin is partly responsible for increasing GnRH secretion as well as LH, FSH, and Testosterone secretion. Therefore, at very low concentrations there would be an occurrence of hypogonadism. But very high concentrations, Leptin directly inhibits Testosterone release (leptin decreases T secretion from testis, even in spite of increased GnRH activity), again causing hypogonadism. Therefore the best Leptin concentrations would be at the low normal range. Not coincidentally, this usually occurs in those lean individuals who are well fed.
In addition to these peripheral effects, Leptin has shown the following interactions with other hormones:
Leptin increases GnRH at hypothalamus
Leptin decreases Testosterone at testis
Glucocorticoids increase plasma leptin
SNS activity (epinephrine) decreases plasma leptin
Testosterone decreases plasma leptin
Insulin acts with leptin by stimulating the same neuronal populations
Insulin increases Ob gene expression
Ghrelin competes with leptin centrally, with opposite actions as leptin
Leptin and insulin sensitize the hindbrain to the anorexigenic hormone CCK
The following adipocytokines (hormones released from adipose) may also interact with leptin:
Resistin — adipocytokine that may regulate insulin sensitivity
Adiponectin — enhances insulin function - increases with insulin and decreases with obesity — increases UCP2 in muscle — increases fatty acid transporter protein — increases acyl CoA oxidase — decreases triglyceride content in liver and muscle
Adipsin — is found in proportion to adiposity — is required for the synthesis of ASP (acylation stimulating protein — is involved in the uptake and esterification of TAG and FA) — stimulates TAG synthesis more than insulin
What's that sound? Oh, that's the bell! Quickly I'd like to recap this week's lesson. First of all, Leptin is released from many peripheral tissues but the biggest player is white adipose. Once released, Leptin has all kinds of divergent effects on the peripheral systems of the body, many of which are just coming to light. These peripheral effects include interactions with many hormones of the body as well as interactions with the skeletal muscle, the immune system, and the reproductive system. Also, Leptin acts centrally in order to stir up a neurotransmitter soup of meal stimulating and meal reducing chemicals. These central and peripheral effects are important to understand as they are ultimately responsible for metabolic changes with feeding as well as weight gain and loss.
So class is now dismissed for this week. But don't miss out on next week's lecture. I'll be reviewing some of the important feeding studies and discussing some recent data showing how recombinant Leptin injections may actually help prevent the metabolic decline associated with dieting.
Hungry, Hungry Hormones — Part 3
by John M Berardi
We here at T-nation just love them-there hormones. And if you didn’t figure that out from the very name of our little publication, you might have figured it out from the dozens of hormone-related articles we’ve published over the years. Yep, we here at T-mag headquarters love our Testosterone, our Growth Hormone, our Insulin, and our Glucagon. In fact, the last Friday of each month is devoted to the anabolic hormones. "Hormone Friday, as it’s called, is a day in which each T-mag staff member dons his or her favorite anabolic hormonal attire. You shoulda' seen JB last month. Hell, with that sterane ring wrapped around what he called his "Testosterone factory," he was a shoe-in for top costume honors.
As a result of his creative costume ideas and his needle-point prowess, JB not only got TC’s Real Doll,"Jenny," for the weekend, but he also earned the right to review a relatively new hormone that’s lately been the source of much discussion and confusion. JB's already covered the biggies: Testosterone (The Big T, Parts I and II, The Steroid Manifesto, Parts 1, 2, and 3), Growth Hormone (The Fountain of GH), and Insulin (The Anabolic Power of Insulin). Now, it’s time for JB to tackle that pesky new guy on the block — the hormone Leptin.
Fasted and Fed — Why Leptin Matters
As discussed in part 2 earlier, Leptin concentrations are very closely correlated with body fat mass. The fatter you are, the more Leptin you make. This relationship highlights the role of Leptin as a static indicator of chronic energy balance in the body. If you lose fat, Leptin goes down. If you gain fat, Leptin goes up.
To complicate the matter, however, it’s important to note that Leptin concentrations also reflect acute energy status and change very rapidly in response to feeding and fasting, as demonstrated below.
In the scenario graphically illustrated above, when fasting, the decline in Leptin concentrations would be associated with a ravenous hunger, a reduction in metabolic rate, and a decrease in voluntary activity. Since Leptin concentrations play an integral role in these changes at the muscle, fat, and hypothalamic tissues, a critical body composition target would be the maintenance of Leptin concentrations while dieting. At this point, let’s review some feeding research to highlight what exactly happens when dieting (and overfeeding).
Study #1 - (Coleman et al, Diabetologia 42: 636-646, 1999)
During a 52-96 hour fast, subjects experienced a 4% loss in body mass, accompanied by a 54-72% decline in Leptin concentrations.
In some subjects, once Leptin declined, the authors administered a glucose infusion (5% solution totaling 338 kcal/day), causing Leptin to increase by 80%, relative to that large depression. This demonstrates that a small carbohydrate load can almost normalize depressed Leptin concentrations. It's important to note that this small addition of carbohydrate is only associated with an increase in Leptin concentrations during a fast. During a normal diet phase, I doubt a small carb increase will increase Leptin concentrations.
In other subjects, after the 4-day fast, only 12 hours of "refeeding" returned Leptin to baseline, demonstrating that acute feeding is an important regulator of Leptin concentrations.
Study #2 - (Kolaczynski et al Diabetes 45: 1511-1515, 1996)
During the first part of this study, researchers found that after 36h of fasting, Leptin decreased by 77% while after 60h of fasting, Leptin decreased by 82%.
During the second part of the study (the data plotted above), authors found that Leptin decreased by 20% after 12h and 65% after 36h of fasting. However after 12 h of refeeding, Leptin increased to 62% of normal and after 24h refeeding, leptin increased to 100% of normal. These data indicate that 12h fasting is sufficient to reduce serum leptin dramatically — this is concomitant with decreased insulin and increased glucagon, cortisol, catecholamines, and GH. They also indicate that a normal single meal has negligible impact on leptin — it takes prolonged feedings to impact Leptin concentrations.
Finally, in this study the authors demonstrated that after an overnight fast with a small amount of glucose infusion, Leptin doesn’t drop at all.
Study #3 - (Kolaczynski et al J Clin Endocrinol Metab 81 4162-4165, 1996)
In Part 1, subjects were ridiculously overfed as follows: over 12 hours, subjects ate 120kcal/kg (about 12000kcal for a 100kg individual).
During the 5th to 10th hour of overfeeding, there was a 40% increase in Leptin that persisted through the morning and continued beyond. Unfortunately, the researchers only measured out Leptin levels until the morning. We don’t know how long the Leptin remained elevated. These data indicate that with very big, "Victor Richards type" overfeedings, elevations in Leptin concentrations may persist even after an overnight fast.
In Part 2, subjects ate 25kcal/kg (2500kcal for a 100kg individual) above normal intake until they gained an additional 10% body mass. During this study, fasting Leptin tripled in response to weight gain (there was a varied response, though: in subjects that gained the most fat, Leptin increased the most).
Study #4 - (Dallongeville et al Int J Obesity 22, 728-733, 1998)
Leptin increased by 27% over an 8h post meal period while it decreased by 29% during a similar fasted period (these results were obtained during daytime feeding/fasting). These data weren’t simply circadian due to the fact that similar changes were seen during nighttime feeding/fasting where Leptin increased by 37% over 8h when fed, and decreased by 27% over 8h when fasting. These data indicate that meal feeding during a normal circadian cycle increases Leptin concentrations while fasting decreases them.
Studies #5 - #7 - (Evans et al Clin Sci London 100(5) 493-498, 2001; Coppack et al Proc Nutr Soc 57 461-470; Dirlewanger et al Int J Obes Relat Metab Disord 11 1413-1418, 2000)
These studies show that CHO are necessary to induce postprandial Leptin increases, as fat alone doesn’t increase Leptin after meals. They also demonstrate that mixed meals are sufficient to induce Leptin increases. Fat doesn’t have to be avoided.
From Research to Hypotheses
From these data, a number of individuals, including fellow T-mag contributor Joel Marion, have speculated that prolonged (8-12 hour) carbohydrate refeeds can help a struggling dieter’s metabolism. His argument is that while dieting, Leptin declines to a modest extent and, as a result, the metabolism slows, cravings increase, progress slows, and the diet begins to seem futile. He reasons that if carb feeding increases Leptin concentrations (which it will), the metabolic rate will kick up again and fat burning will resume.
While I applaud these speculations of my colleagues, I can’t totally agree with this hypothesis. As the research above has illustrated, Leptin kicks up and down very rapidly as energy intake fluctuates. Therefore, while Leptin may kick up with a 10-hour carbohydrate reefed, it’s likely to drop back down just as rapidly after the reefed is over and another 10 hours of dieting are accomplished. Therefore, a dieter may just end up with a bigger positive energy balance during those 24hours of refeeding and subsequent return to dieting.
Since there is no data, one way or the other, illustrating what happens in dieting weight lifters when refeeding, there's only speculation. Of course, Leptin itself aside, if there were some prolonged increase in Leptin, we should be able to measure the effects of this Leptin increase by observing increases in metabolic rate the day after the refeed. Unfortunately, metabolic increases as a result of acute overfeeding aren’t observed a day after the overfeed (or refeed). But no matter, I don’t want to make a big deal about either of these points.
As I’ve indicated in previous columns, I do see other good reasons (i.e. a psychological break from dieting, increased adherence, better glycogen status, more intense workouts) for refeeding besides the Leptin issue.
Another interesting hypothesis is that fish oil can positively impact Leptin concentrations and Leptin action. While all of the current data is in rats, it appears that dietary fish oil can acutely increase plasma Leptin concentrations, increasing metabolic rate and decreasing hunger. If this were to occur during dieting, it would be beneficial in preventing metabolic decline. However, due to the fact that fish oil feeding prevents fat gain or reduces body fat in rats after a high saturated fat diet, chronic Leptin concentrations should be reduced (as Leptin is correlated with body fat stores). Regardless of what the rat data say, currently I know a grad student who is measuring the effects of fish oil supplementation of plasma Leptin concentrations. Once these data are collected I’ll be sharing them here.
Leptin Injections While Dieting?
Theoretical issues shelved, the last study I want to address today is one demonstrating just what does happen when Leptin is "replaced" (exogenously) during a dieting situation.
Study #8 - (Rosenbaum et al J Clin Endo Metab 87(5) 2391-2394 , 2002)
In this study, subjects were fed a diet until they became weight stable for 2 weeks. Then subjects were fed a diet designed to help them lose 10% of their body mass. After this was achieved, calories were then adjusted up to achieve weight stability for 2 weeks.
At this reduced weight, Leptin was decreased (30%), as was T3 (9%), T4 (13%), total mass (10% or 8.6kg), lean mass (5% or 2.5kg) and fat mass (18% or 6.2kg), and total daily energy expenditure.
At this point, Leptin injections were then given to the subjects for 5 weeks as they consumed the amount of calories required to keep weight stable. The amount of Leptin given was just enough to return Leptin back to their baseline (pre-diet concentrations).
The 5 weeks of Leptin administration led to normalizations in Leptin concentrations, T3, T4, and total daily energy expenditure while leading to further losses in body mass (an extra 1.5kg), fat mass (an extra 1kg), and a small loss of lean mass (an extra 0.6kg)
This study demonstrates that Leptin replacement during a maintenance diet (with a depressed metabolism due to prior dieting) can facilitate a greater rate of fat loss due to the effects of Leptin on normalizing the thermogenic environment of the body.
Body Weight Regulation
As this article has repeatedly stressed, body weight is regulated by short term and long-term signals. The short-term signals include altered meal patterns and individual meal consumption. The long-term signals include the balance of energy expenditure with energy intake.
While, for disciplined dieters, the meal consumption factor is held constant (despite an ever increasing appetite), another problem arises. Dieting efforts can be foiled by metabolic and hormonal adaptations such as decreased metabolic rate, decreased voluntary energy expenditure (exercise), reduced immune function, decreased reproductive function, and decreased anabolic hormonal output (GhRH and GH, GRH and Testosterone, TSH and Thyroid hormones), all the while increasing CRH and adrenal hormones. It appears that Leptin is a big player in these adaptations.
While I don’t have any easy answers as to how we can recruit Leptin to fight the good fight — to help out with our fat loss efforts—Leptin research is coming at us at an alarming rate. As a result, I have no doubt that in the near future, in response to questions about how Leptin operates, some trainer or nutritionist will be starting their answer off with "Well, it’s simple really…"
posted by Musings of a Demented Mind @ 10:09 PM
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