Prohormones and prcursors. My first real research.

[bigrobbie]

I know most Meso members take a pretty firm "anti" prohormone stance, myself inclulded. I must admit however, I have not researched PH's to the degree that this "self proclaimed know-it-all" should have. I am starting to try and look past the obvious and investigate the chemistry and biology behind prohormones and test-boosters...in other words...I'm going to start to learn more about "legal steroids!" Read along, comment, ignore....basically, think what you will but I'm not going to discount steroid hormone precursors until I have learned as much as possible. Here is a little info to maybe get someone else interested. I will say this...if a mind like Patrick "the clear chemist" Arnold is intrigued by diones and diols....well, maybe there is more here than I assumed!

Prohormones (PHs) in the essense is a chemical structure with a hormonal action that covert into any number of other things, including a sex hormone. If you think about it, all hormones are PHs by the simple rules of chemistry. What I mean is this...well...this link may explain it better than I can=

Steroid - Wikipedia, the free encyclopedia

The below paragraph I found on Andro Cycles - Androstenedione Information and Effects (1) explains the prohormone/prosteroid relationship so a layman such as myself can begin to grasp the chemistry.

Prohormones in modern times (post 1994) have meant androgenic steroid precursors that convert into active androgens like testosterone and other steroids. Prosteroids are active androgens that work on their own without conversion, so for example testosterone and 1-testosterone are active androgens where androstenedione and 1-andro would be their prohormones. Prosteroids are simply active steroids. but unfortunately steroids are typically illegal due to chemical modifications. These steroids like M-Drol, Superdrol and other similar agents are active androgens that require no conversion. Also there can be synthetic steroids like H-Drol that require enzyme activation yet are chemically modified.

Enzymes?

There are really two main enzymes that convert a prohormone to an active steroid are 3b-hydroxysteroid-dehydrogenase and 17b-hydroxysteroid-dehydrogenase. These enzymes act on the 3 carbon position or the 17 carbon position to make an active steroid. Basically, add or subtract carbon atoms at the correct position on the molecular structure of a hormone and that structure can change. For example: Androgens and Estrogens are chemically seperated by a single carbon atom. Check this neat chart I found on Wikipedia:

Derivatives

Changing the position of the double bond also changes the activity of the prohormone as well as what enzymes can act on it. Testosterone is a “4-ene” steroid, meaning it has a double bond at the 4 position as shown here.(1)

Embedded Image Unvailable

I know, this is almost stupid to discuss, but it really is intriuging if you read up on it. Based on the "route of conversion" a prohormone takes they can be similar to anabolic steroids, even convert into the "bigdaddy of sex hormones" testosterone, but they are limited due to enzymes needed to complete this "transformation!" Everyone has different body chemistry, so I believe this is why I have seen person A. take the same PH as person B. and end up with totally different results!!

I would love to have some feedback guys....aside from the toxicity I have to admit that most hybrids from the original "Superdrol" (I believe by Anabolic Xtreme), yeild results very near Anadrol but that's just my observations. I am posting this hoping to open a dialog about PHs. I am also researching SARMs, so anyone who wants to chat about the poor underated selective androgenic receptor modulator....lets chew the fat on that topic also!

This will also be posted on my blog so feel free to comment there as well!

Thanks to my main reference:
(1) Andro Cycle Online Andro Cycles - Androstenedione Information and Effects

(2) Wikipedia: File:Steroidogenesis.svg - Wikipedia, the free encyclopedia
[ame=http://en.wikipedia.org/wiki/Androgen]Androgen - Wikipedia, the free encyclopedia[/ame]
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SIDE NOTE:

Bill Roberts or Dr. Scally would most surely take me to school on this topic, but I am self learned and trying to convey to other interested persons complex chemical reactions using my limited vocabulary and intellect, so please forgive any inconsistancies or poor wording.

Last thing...I read this in an article by the guy that publish "AndroCycle.com" and I thought it was extremely important for anyone using PHs or AAS!

"Contrary to what you think you need all of your steroid hormones, including cortisol, estrogen, progesterone and dehydro-testosterone to live. When steroid hormones get out of balance though, you may not feel optimal. For example environmental toxins like BPA and Parabens reduce the ability of the body to make testosterone and also act like estrogen in the body, which can cause men to feel the effects of low testosterone. Additionally, other environmental estrogens like pesticides can throw off the Estrogen to Androgen ratio which would make you appear “healthy” on a blood test, but change the ratio of estrogenic to androgenic agents in the body. This bombardment of estrogenic agents in the diet and in environmental waste products makes it important for men above 21 to supplement with androgen prohormones to look and feel their best. With proper androgen prohormones it is possible to reclaim our masculinity and reverse the damaging effects of estrogen, which are increased fat deposits, loss of sex drive, lost feelings of well being and depressed moods."

Goes to show that 1) Always get your blood work ; 2) Always run a PCT (an educated fact based PCT) ; and 3) Always seek help if you think you've messed your body chemistry up to the point where physical and/or mental health problems can start interfering with a normal healthy life!!!

THANKS!!!

 

[Millard]

The original prohormones introduced by Patrick Arnold i.e. androstenedione, androstenediol, norandrostenediol were originally legal under DSHEA and prior to the Anabolic Steroid Control Act of 2004. As far as a legal steroid product was concerned, they weren't bad. But not as effective as the scheduled III anabolic steroids.

After the prohormone ban, several supplement companies introduced DSHEA-friendly prohormones but many others simply introduced synthetic steroids (unapproved new drugs) that, while not controlled substances, were still illegal.

A lot of these synthetic steroidal products were comparable to some scheduled steroids as far as efficacy.

I've usually preferred androgens with decades of research behind them over most of the steroidal supplements on the market.

If the Anabolic Steroid Control Act of 1990 didn't criminalize real steroids, then the prohormone craze would likely have never happened nor would the widespread introduction of various synthetic steroids into the supplement market.

But it did. And I think the collective health of the bodybuilding community suffered some as a result.

 

[Bill Roberts]

The true prohormones (dependent on enzymatic conversion to become natural androgenic hormones) were unfortunately banned.

4-AD, brought to the market by Patrick Arnold and for the sake of full disclosure, I had an ester version of it as well that was brought to market for the company I work for, was a nice compound that definitely was of some value even orally. I had a report from someone whose opinion I value that it was excellent on injection, but that is only one report.

Research that we did on it revealed that natural 4-AD levels in man are comparable to testosterone levels. This is a little known fact. But 4-AD is a cool thing in my opinion. I'm genuinely sorry it was banned, over and above the fact that I was making money with it. I really liked it. I also really liked our Androsol product, which was topical 4-AD. I've said many times that Androsol is actually my favorite product of anything I ever did. Not because it was the most effective of all, but as an overall thing. Please keep in mind potential personal bias here, however.

Back to the current situation: The modern "prohormones" aren't prohormones at all, but rather synthetic anabolic steroids that never were made into pharmaceutical anabolic steroids, due to the companies not choosing to do so.

Of the current legal crop, the ones I have best opinions of are DMZ and epistane. Both are in no way legitimately legal (they aren't naturally occurring and so are not DSHEA compliant), but haven't been specifically banned.

 

[Millard]

Back to the current situation: The modern "prohormones" aren't prohormones at all, but rather synthetic anabolic steroids that never were made into pharmaceutical anabolic steroids, due to the companies not choosing to do so.

Of the current legal crop, the ones I have best opinions of are DMZ and epistane. Both are in no way legitimately legal (they aren't naturally occurring and so are not DSHEA compliant), but haven't been specifically banned.

4-AD was nice especially for a clearly legal product (at the time). Nowadays, people are spoiled with the non-DSHEA compliant synthetic steroids.

 

[Bill Roberts]

Agreed, they're much more effective than 4-AD ever was.

 

[bigrobbie]

Patrick Arnold wrote an article in an April 2008 Muscular Development Magazine (I think) on how (in theory) to convert or expedite the conversion process of certain PH's to fully evolved anabolic/androgenic steroids....for example: 2a-17a-dymethel-etiocholan-3-1-17b-ol into oxymetholone. Here is a copy of the article....

Prohormones, Conversion Rates and Broscientists
Written by Patrick Arnold

"OK, it’s time to discuss your favorite subject: prohormones!! It’s my favorite subject too, as I
have spent many years studying and manufacturing the stuff, and have made most of my living
selling them. I do wanna move on to other things— but people keep bugging me about prohormones so I keep discussing them. And I am sure this article won’t be the last one on the subject.

The Folly of Prohormone ‘Conversion Rates’

Ten years ago when I first introduced prohormones to the marketplace, I presented some
research that was meant to illustrate the relative efficiency of a prohormone in converting to an active hormone in the body. I coined the term ‘conversion rate’ which was supposed to represent the amount of active hormone formed in the body after a given period of time. The values for these conversion rates were based on studies done with a series of hormones—androstenedione, DHEA, 5-androstenediol, and 4-androstenediol— which were
incubated in human blood for about an hour. I wish now that I hadn’t used the conversion rate term in the fashion that I did. Since that time,
the concept of conversion rate, based as heretofore described, has become embedded in the
popular terminology used by bodybuilding science dudes— whom I refer to as ‘broscientists.’
This has led to gross misunderstandings of how prohormones work in the body and about how to accurately predict the true endpoint potency that a prohormone possesses. These blood incubation conversion rate numbers represent how much a prohormone converts to an active
hormone, about as well as counting how many cars are on the highway at an exact given time represents how many cars have ever been on the highway! Hormone metabolism in the body is
a multidimensional system and involves way more things going on than just one thing turning into another and stopping. Just like how a car can get on the highway, then get off on another road, then get on again, then get off on another road etc., a prohormone can convert to an
active hormone, then convert back to the prohormone, then convert to the active hormone again, and then convert to something else. And these dynamics are ongoing.
One of the most well-known of the prohormones is 4-androstenediol and it is often stated that it has a conversion rate of 15 percent (the number coming from the aforementioned blood
study). Well then, let me ask you something: what do you think the conversion rate of testosterone is? Or, to put it another way, how much testosterone do you think you will see in
that blood study, relative to the amount you started with? I ask this question to a lot of guys and
then I tell them the answer is probably not much different than 15 percent. They look at me like I am nuts. But using the method of this blood incubation, that’s about the number you would get.
You see how this is so misleading?Examine the chart of hormone metabolism below. This chart is greatly simplified, but it can
effectively illustrate the basics of what happens to steroid hormones after they enter the body.
The arrows between the chemicals represent metabolic transformations, with the single arrows
designating one-way (irreversible) reactions and the double arrows designating equilibrium
(reversible) reactions.
Start by looking at 4-androstenediol (4-AD). Notice that it pretty much has only one direction to
go and that is toward testosterone (research indicates that this is its sole initial metabolic
transformation). Now is that it? Does it just stay as testosterone? Of course not. As you can see
from the chart, this newly-formed testosterone can then go right back to 4-AD— although this
rarely happens. Or this new testosterone can go on to change to androstenedione and then
back again. Alternatively, when it changes to androstenedione, the androstenedione can then
convert irreversibly to estrogens or hydroxylated metabolites. Once it does that, the steroid is out of the picture and can no longer go back to testosterone.
This is how it works. The steroids are constantly changing in your body to other steroids.
Sometimes they go back and forth or on to other things and then perhaps back again, or
whatever. Sometimes these whatevers may be an irreversible pathway and then they become
part of a new metabolic transformation system. The bottom line is that a prohormone’s efficiency cannot be measured by looking at how much target hormone is hanging around an hour after it is added to some blood.
To make a blood incubation test meaningful for our purposes, you would need to keep taking measurements of the blood levels, beginning as soon as the prohormone is added to the sample and up until target hormone levels start to fall to insignificance. Then you simply average the numbers. The more measurements, the more accurate it will be. This will tell us
how much testosterone your body is exposed to over the entire period of time, rather than just at one single time point (e.g., one hour).

Of course, it’s still not that simple. When you ingest a prohormone, it only spends a part of its time in the blood. It spends a substantial portion of its time in the liver and dozens of other
tissues of the body and each of these tissues has its own balance of enzymes, with its own tendency to transform steroids in one way or another. So this means the numbers from the
blood sample paint an incomplete picture, even if you do take a multitude of samples. You really need to give the prohormone to living human beings and then take blood samples from them over the course of the time it takes for the compound to be processed, anyway, I hope you get my point. And I hope when you hear someone throw around that term
“conversion rate” again you tell them to shut up and read this article. And then they can be just as confused as you are right now.

How to Make a Hormone

No, the answer to the question I am talking about is not “Don’t pay her.” I am talking about making active anabolic steroids from readily available prohormones. Actually, this is not something I would normally write about, but I had writer’s block this month and John Romano said this sort of thing would be something he would be interested in reading. So I thought I would delve into it a little. I have to warn you though, unless you have a background in steroid chemistry, this is not gonna make much sense to you.
As you know, prohormones are metabolic precursors to active hormones, which are converted
through the action of enzymes in your body. But these same prohormones can also be converted to the active hormones synthetically— that is, by the use of chemicals in a lab. In
particular, diols and diones can be made into their corresponding active hormones by procedures that are actually remarkably simple.

Diols
The most basic diol is 4-androstenediol. However, it is now illegal. There are still some diols
out there, though. Here is a list containing 4-androstenediol and some other still legal diols.
If you look closely, you will see that all these diols have double bonds in the first ring that are
one carbon atom away from the 3-hydroxyl. The hydroxyl at carbon 17, however, does not have
this feature. We can use this difference to our advantage and perform what is known as an
‘allylic oxidation.’Allylic oxidations can be done using a variety of different chemical reagents; however, activated manganese dioxide is the most convenient one to use. What this chemical
does is oxidize the hydroxyl at carbon 3 to a ketone, while leaving the 17 beta-hydroxyl unaffected. This leaves you with the classic ‘3-one-17b-ol’ structure that most active anabolic steroids possess.

The procedure is simple. You dissolve the steroid (let’s say 5 grams) in an appropriate organic solvent (let’s say 250cc of acetone) and then add about six times its weight in activated manganese dioxide. It is important that you use activated manganese dioxide because regular
manganese dioxide won’t work. The activated manganese dioxide will not dissolve, but rather it will sink to the bottom. You must then mix the slurry for several hours (say 6-8 hours).

After you are done, you filter off the manganese dioxide, or let it settle out and decant the clear layer. This clear layer will contain your active steroid in acetone and you can retrieve it either by slowly evaporating off the acetone, or by adding about five parts water and precipitating the steroid out. The precipitated steroid can then be filtered off and dried.

Examples of this reaction are the conversion of 4-androstenediol to testosterone, the
conversion of 17a-methyl-1,4-Androstadien-3b,17bdiol to dianabol, and the conversion of
4-chloro-17a-methyl-androsta-1,4-dien-3b-17b-diol to oral Turinabol.
Please don’t forget the fact that as soon as you are done with this chemical procedure, you have a controlled substance on your hand and you are therefore committing a felony. It is for this reason that I must remind you now that this is all being presented to you for purely informational and entertainment purposes.
Next month I will continue the chemical information and entertainment by discussing the
chemical conversion of diones.

C’ya!"
There it is....the man, the legend...telling us about a chemical process as simply as I would tell my daughter how to burn a CD on Media Player! WOW!!

 

[Bill Roberts]

If you can, kindly post the next month's article, as that one was excellent!

 

[bigrobbie]

If you can, kindly post the next month's article, as that one was excellent!

Sure bro!!

Patrick Arnold


Prohormones, Dosage and Mental Masturbation


This month, I’ll review a couple of very interesting prohormone studies. They deal with the first-generation prohormones, androstenedione and 19-norandrostenedione. Of course, these two prohormones are illegal in the United States, but these studies are interesting because they help answer a lot of questions about these products that we asked ourselves for years. So even though all this is probably little more than a session of mental masturbation, here is this month’s column.



19-norandrostenedione Is Ineffective Orally In Rats

An article came out recently that examined the anabolic/androgenic activity of the prohormone 19-norandrostenedione (nordione). This was a popular prohormone back in the late ‘90s, and it was introduced to the marketplace shortly after the original prohormone androstenedione (andro) was first sold. Nordione was touted as a less androgenic alternative to andro, and was fairly popular for a while.

This recent study, entitled “Anabolic and androgenic activity of 19-norandrostenedione after oral and subcutaneous administration—Analysis of side effects and metabolism,” appeared in the journal Toxicology Letters. Researchers utilized the classical Hershberger assay, which takes castrated rats and examines the effect of steroids on their tissues. Androgenic effects and anabolic effects are measured by the change in weight (versus control) of the levator ani muscle.

Researchers first administered nordione to castrated rats by subcutaneous injection. They used 1.0 mg/kilogram bodyweight per day, which is around 60 milligrams per day for a 100-kilogram man (after compensating for body surface area). They also had a control group (placebo injection) and a reference group that was administered an equivalent amount of testosterone propionate. The experiment lasted 12 days, after which the rats were sacrificed (a nice way of saying ‘killed’).

Scientists found that the weight of the seminal vesicles and prostate gland remained pretty much unchanged compared to the control group, while the weight of the levator ani muscle increased substantially— although somewhat less than it did in the testosterone propionate group. This is consistent with the known ‘low androgenic/high anabolic’ effect of 19-nortestosterone derivatives.

The second phase of the experiment used the same protocol, and looked at the effect of oral supplementation of nordione. Researchers used oral doses of 0.1, 1.0, and 10 mg/kg bodyweight (roughly equivalent to 6, 60, and 600 milligrams per day for a 100-kilogram man). After 12 days, the animals were sacrificed and the organs examined.

Surprisingly, in contrast to the subcutaneously-injected rats, the ‘oral’ rats did not show any significant increase in weight of any of the organs, indicating that no anabolic or androgenic activity was occurring. This comes as somewhat of a surprise, as traditional theory assumes that oral administration of prohormones results in substantial conversion to active compounds in the liver— which go on to exert their pharmacological effect on the body. As a matter of fact, the levels of the target hormone (19-nortestosterone) in the highest dosed ‘oral’ group exceeded that of the subcutaneous injection group (two to three times higher). Yet the oral group did not show anabolic effects, while the subcutaneously injected group did. In fact, the high-dose oral group actually lost weight.

How can we explain these results? The authors propose a couple of explanations. The first one considers that liver metabolism of androgens is different for oral supplementation versus injection. Orally-administered androgens undergo ‘first-pass’ liver metabolism, which causes formation of metabolites in different proportions than what are seen with injectables. Some of these metabolites may possess androgen antagonist activity, which would counteract the effect of the nortestosterone formed.

Another explanation involves the differences in pharmacokinetics between the two routes of administration. Oral dosing results in significant but brief peaks in blood hormone levels, while injections provide more even and sustained levels. In this study, the hormone was administered orally in one daily dose, and so perhaps this dosing did not result in long enough exposure of the body’s tissue to 19-nortestosterone.

What is the lesson here? That’s hard to say, as this was just one study. But it does reinforce what I already know— that prohormones administered orally are not as effective as those administered transdermally. Although transdermal administration does not result in the same bioavailability as subcutaneously-injected hormones, it does provide favorable pharmacokinetics due to its prolonged time-release actions.

I have a couple of questions. First, I wonder what the results would have been if the daily oral dosage was split up (i.e., administered three times a day instead of once), which is generally the way people consume oral prohormones. Additionally, I am curious as to whether these results are specific for nordione, or if they are common with other ‘diones’ and perhaps ‘diols’ as well.

I should mention that no adverse effects were observed in the animals given nordione, which is not a surprise because natural prohormones are not associated with the same toxicities as synthetic steroids (i.e.,17alpha-alkylated compounds). Of course, researchers did not look at cosmetic side effects such as gynecomastia, and we do know that users of nordione were quite susceptible to gyno because of its high estrogen conversion and lack of conversion to naturally anti-estrogenic 5alpha-reduced metabolites.

All in all this was an interesting study, however far too late for practical application (at least in the U.S.)— since nordione and all the other natural prohormones were banned a few years back.



4-androstenedione Is Effective In Hypogonadal Men

4-androstenedione (‘andro’) was the original prohormone (unless you count DHEA). Introduced in 1996, it sold quite well for a while and reached its peak of popularity in 1998 when it was found in Mark McGwire’s locker. Soon afterward, newer and better prohormones such as 4-androstenediol took its place as the preferred supplements for testosterone elevation.

Andro had its problems. At the dosages that were typically used, a substantial elevation in serum estrogens was seen, as well as a weak or non-significant elevation in testosterone. The result of this imbalance made users susceptible to gynecomastia. Furthermore, it just did not seem to do much for people, at least when used at the recommended dosages. This lack of efficacy and increase in estrogens was confirmed by several studies done on young males given andro.

A study in 2005, however, examined andro again— but this time a different population of males was used and a higher dose was administered. The study, “4-Androstene-3,17-Dione Binds Androgen Receptor, Promotes Myogenesis in Vitro, and Increases Serum Testosterone Levels, Fat-Free Mass, and Muscle Strength in Hypogonadal Men,” was published in the Journal of Clinical Endocrinology and Metabolism.

Researchers studied the effects in andro in hypogonadal men. These are the same men who are prescribed testosterone replacement therapy, and they are usually defined as males who have serum testosterone less than 300 ng/dl and experience symptoms of low testosterone.

Before they looked at the in vivo effects of andro, researchers did a series of experiments designed to prove that andro has the ability to activate the androgen receptors and stimulate muscle growth, in vitro. Mind you, they were not looking at the effects of andro after converting to testosterone, but rather the effects of andro itself. The reason they examined this was probably political— so they could define andro as an ‘anabolic steroid’ once and for all, without the confounding issue of whether it was intrinsically active (note that this study was performed before the prohormone ban in 2005).

Researchers found that andro had the ability to bind and activate the androgen receptor, as well as increase the expression of key myogenic markers and stimulation of myotube formation. Of course the potency of straight andro was much, much less than that of testosterone or dihydrotestosterone— but the authors proved their theoretical point.

They chose nine men between the ages of 19 and 65 who had testosterone levels of less than 300 ng/dl. The men had to be relatively healthy otherwise, and men who participated in resistance exercise or moderate to heavy endurance exercise were excluded— as such activity would interfere with the measurement of pure hormonally-initiated anabolic effects. Dosing was set at 500 milligrams, three times a day (1,500 mg total andro per day), and they took the andro for 12 weeks.

After 12 weeks of of andro, levels of testosterone and free testosterone were elevated into the normal range (levels varied substantially between doses). Estrone and estradiol were also elevated, and SHBG was decreased quite substantially. Most importantly, fat-free mass increased by an average of 1.6 kilos in the subjects, and maximal muscle strength increased an average of 4.3 kilograms in the bench press and 18.8 kilograms in the leg press. These increases in strength and lean body mass are rather remarkable, as they are similar in magnitude to those observed in hypogonadal men given standard testosterone replacement therapy. Furthermore, other than a decrease in HDL cholesterol, no other indicators of toxicity were observed.

So what does this study tell us? That the theory of androstenedione behaving as an effective testosterone elevator does have merit. It just took the right dose and the right subjects (hypogonadal males) for its efficacy to be demonstrated. On the other hand, by demonstrating its efficacy, you also reveal andro as an effective anabolic agent, which lends credence to the argument that its classification as a controlled substance was justified.

It’s all interesting stuff— even if it’s all a moot point in today’s world.