PRO HORMONES – STACKING AND BENIFITS…..

Stacking Prohormones

Do Prohormones Work?

For the serious bodybuilder, stacking prohormones is an essential part of the training regimen, as they offer unparalleled muscle building and fat reducing capabilities. However, prohormones do come with side effects that one should be aware of before beginning supplementation.

Put simply, prohormones are hormone precursors, synthetically produced compounds that are converted to anabolic hormones via liver enzymes once they are introduced to the body. Stacking prohormones is a common practice for athletes looking to increase size, strength and endurance, as well as build lean muscle mass and cutting bodyfat.

Do Prohormones Work? This is a topic of much debate. Some bodybuilders swear by prohormones while others claim even the best prohormone stacks offer little to no benefit. There certainly is no conclusive scientific evidence pointing to their efficacy.

Stacking prohormones gives you the best chance of reaping the benefits, as you can enhance gains as well as reduce side effects. Prohormone cycles are between 2 and 8 weeks, with most athletes opting for 4 week cycles.

Stacking Prohormones – What are the side effects?

Unfortunately, the negative effects of taking Androstenedione, DHEA, HGH and others can be the same as those of steroids, and we are all familiar with those: acne, hair loss, prostate enlargement, breast tissue growth, etc.

Prohormone stacking can sometimes reduce some of these side effects, but bodybuilders should be aware of the potential.

It is also important not to overload your system, as your body stops producing its own natural hormones when you are supplementing. You have to make sure you do not permanently impede your body’s natural hormone producing capabilities, which can happen if you are not careful with your cycling.

Make sure you consult your physician before beginning stacking prohormones…perhaps he or she might be able to answer the question do prohormones work, as well as make some recommendations.

What are the best prohormones and prohormone stacks?

Each athlete responds to different prohormones in different ways, so there is no one best prohormone stack. Your best bet is to experiment and firgure out what works best for you.

Most bodybuilders agree that the best prohormones are either the trandermal ones or the sublingual (under the tongue) versions. The oral prohormones are broken down in the liver and stomach, so they would be severely weakened by the time they enter the bloodstream.

Do Prohormones Work? Final Thoughts

There is no clear answer to this question. Even the best prohormones don’t work for some athletes, while other have had much success with stacking prohormones.

After checking with your doctor to make sure you don’t have any preexisting conditions that may make stacking prohormones unwise, you should try different combinations and see what works for you.

- FITNESS-EVENT

IGF – LR3 AND WHAT YOU DIDN’T KNOW……

My take on IGF-1  – writing by: Grunt76 , anabolicminds.com On July 20 I got into some pretty intense discussion on another board about IGF-1. I got so rattled with the misinformation that I decided to loose my 13 years of reading on IGF-1 onto that board. Here’s the result. Quote: If you want to use IGF for localization growth get some rhIGF-1. It binds to the wound only and does not go into the bloodstream. This helps repair the injection wound and makes new cells in that area only. While Long R3 IGF binds somewhat to the would then makes its way to the blood stream causing growth throughout the body.. This is false. The difference between rhIGF-1 and Long R3 is that the Long R3 does not get bound by binding protein and thus is 100% active whereas you do lose a great % of whatever amount of rhIGF-1 you inject to IGFBP3. While technically it is true that if you inject a large amount of the rhIGF-1 it will have almost only localized effect, it is so because the “excess” that does not bind to cells in the muscle in which it is injected is rapidly bound up by IGFBP3 and thus rendered unusable by cells elsewhere. It would be much much better in such a case to inject a smaller amount and not have ANY excess that gets bound up by IGFBP’s. And while technically it is true that if you inject a large amount of Long R3 IGF-1 in a muscle, it will first bind to the nearest available receptor, and spread, binding to more and more receptors and not be bound up and neutralized by IGFBP’s, meaning that it will travel all through your body and grow all kinds of tissue. This is called the systemic effect of IGF-1. Therein lies the only distinction in terms of BOTH half-life and localized/systemic effect between the Long and the human varieties. What does all this mean? It means that technically, for the part of the muscle in which you inject, THERE IS NO DIFFERENCE BETWEEN rhIGF-1 and Long R3 IGF-1. They both have the EXACT SAME LOCAL EFFECT. But rhIGF-1 gets neutralized quick, whereas Long R3 gets to float around until it finds a receptor. What does all this tell us? It tells us many things. Let’s start with what we want, then see where that leads us. What do we want? Bigger muscles. More muscle cells that we will later grow with exercise and gear. A pump? Fatloss? Yeah, right. You can get a pump with a good “pump” product for a quarter of the price of IGF-1. Fatloss? Clen/Alb and T3/T4 will give it to you again at a fraction of the price of IGF-1. More muscle cells, you can ONLY get with IGF-1 (and MGF too). Nothing else will give it to you and if you are using IGF-1 for anything else, you are misusing it. More muscle cells is CLEARLY the best use for IGF-1. What does all this tell us? It tells us that we should use IGF-1 to make more muscle cells. It’s the only thing that can give it to us and more cells is more growth, which is our goal. What does this tell us? The localized effects are the best. Long R3 IGF-1 can float around your body and attach to anything that has IGF-1 receptors. The intestines is the place that has the MOST IGF-1 receptors and it also happens to have lots of blood flow. Injecting large amounts of Long R3 ENSURES that you are growing your intestines. Remember, more cells doesn’t equal more size right away. Wait a bit, and see them grow. What does this mean? It means that if you are injecting upwards of 50mcg of IGF-1 you are growing your intestines. Yes you are also growing muscle and you may be getting leaner in the process. Your waistline looks trimmer. Nice. A few months down the line, your new intestinal cells will be of their full adult size and you will have acquired the perma-bloat look. Guaranteed. Maybe not Coleman-size perma-gut, but SOME perma-gut and it will keep growing. Guaranteed. Just as your new muscle cells can keep growing and growing IF you pin IGF-1 in a way to maximize new muscle cell creation. HOW? Heavy resistance exercise strongly upregulates the IGF-1 receptors on the stressed muscle. That means that after your workout, the muscles you trained are at their BEST STATE for receiving IGF-1 and growing many new cells. That’s when you pin. This upregulation of IGF-1 receptor during exercise is short-lived. The science is not readily available so I am unable to quote a paper, but within 60 minutes of the last set, the receptors are back at baseline. This means, PIN IMMEDIATELY POSTWORKOUT and you will get your new muscle cells. PIN A LESSER AMOUNT and you will get only new MUSCLE cells out of your IGF-1. Pin more and you will grow other things, including stuff you wish you didn’t grow. What else? All the talk about IGF-1’s half-life is UTTER BULL****. It is technicality without any real-world applicability. Yes rhIGF-1 has a “short half-life”. But what does it mean? It means that it is either taken up by a cell receptor or bound up by a binding protein in short order. Does it mean that 20 minutes after the IGF-1 is pinned you should pin more because “blood levels are low”? Not by any means. Once it’s activated a cell receptor, that’s where it initiates a cellular response that will take about 72 hours to be complete and which will consume lots of energy. So the half-life of 20 minutes means NOTHING BECAUSE THE EFFECTS STILL LAST 72 HOURS ALL THE SAME. What about Long R3 IGF-1? Yes technically it has a longer half-life. Why? Because it either gets rapidly taken up by a cell receptor or… Just floats around. Until it can find a receptor or is destroyed by the immune system or some other metabolizing mechanism. BUT THIS MEANS ***NOTHING***!!! Why does it mean nothing? BECAUSE once it attaches to a cell receptor, it initiates a cellular response that will take about 72 hours to be complete. THIS CELLULAR RESPONSE IS ALL THAT INTERESTS US. Not “blood levels”, that’s utter bull****. As a matter of fact, the one thing YOU DO NOT WANT IS FOR BLOOD LEVELS OF IGF-1 TO BE ELEVATED. Because that means you are growing everywhere and this means first and foremost your guts. Sure it feels like it’s working while you’re on. Just you wait 9 months and see that you look like Craig Kovacs. Bravo, you now have the biggest intestines in the world. Half-life means nothing. Localized vs systemic = bad argument. You want localized effects. Period. You get them by pinning immediately postworkout. Period. End of argument. OMFG I am so tired of all the misinformation floating around on IGF-1. Look at the length of this post. Did you read all of it? You should, you know.

Quote: Grunt, I am also interested in the amount your recommend shooting post workout? 40mcg is plenty. We have to realize that this is a huge amount compared to what the body naturally produces. Maybe we can ask TheGame46 who is working on his master’s degree in endocrinology what the actual amount produced by a normal human, say even with exercise, but it’s probably something less than 1mcg. 20mcg each side. 30 each side in the quads. That’s plenty. Now, you won’t see major, immediate LBM increases, but THAT IS NOT WHAT IGF-1 IS FOR. That’s what AAS are for. 40-50mcg total will let you get plenty of hyperplasia, not grow your intestines too much, and save you plenty of $. The newly added muscle cells will take months to grow, but they will, and you will use IGF-1 again because it gets reasonably inexpensive with such a protocol. Another thing: much of the newer research shows that EOD and even E3D igf-1 treatment is better than ED because ED downregulates the receptors too quick. It takes some time for receptors to be able to come back in full after a megadose of even 20mcg of IGF-1. So you may want to think about switching to EOD lifting and IGF-1 immediately postworkout every workout, or 2on/1off and pin the lagging muscle E3D. These dosing patterns won’t give you pounds of immediate muscle, but they will give you hyperplasia, which means continued growth at very decent rates, and the ability to continue treatment for a long while until response diminishes. And no Coleman guts. Quote: I was thinking about trying IGF, very interesting info here. Thanks Grunt for posting this info. A couple of other questions that maybe you can answer, if you don’t mind. How does IGF interact with insulin, i.e. can it be pinned with insulin post workout? Also, what are your thoughts on taking IGF durring a cycle of HGH? Great questions. I’ll start with some background on the peptides from back before IGF-1 was commonly used. GH was the first peptide to be used in Bodybuilding. We pretty much know what GH does and doesn’t do and all that, so I’ll skip this part. Then came along insulin. It quickly became apparent that slin on its own doesn’t do much for muscle. It does make you fat but not much bigger. With AAS and tons of food, it’s better. Later it became extremely clear that Slin & GH was the winner combo, the most synergistic combination around. What few people realize even today – and it’s been what, nearly 20 years of insulin usage in BBing, is that the very reason why slin and GH are synergystic is that when levels of both are high, the liver turns the GH into IGF-1. That’s right, when doing slin & GH, you are in fact using these because your body makes more IGF-1 with them. So it isn’t the slin OR the GH nor actually the compounding of the effects of each, but rather good old IGF-1. Even the name Insulinlike Growth Factor, has been made such because of the origin of the compound in Insulin and Growth Hormone. Now, the IGF-1 from slin & GH is not long R3 IGF-1, it’s hIGF-1. It’s different and possibly the effects are somewhat different than when using Long R3, especially with regards to IGF-1 receptor downregulation, which is likely much lesser with the liver-synthesized IGF-1 than with the Long R3. No studies proving this, it is theory at this point and such a study will possibly never be made, for many good reasons. One reason why receptor downregulation is lesser with hIGF-1 is its half-life, or its very limited ability to run around the body and saturate all receptors everywhere. And here we join up with the EOD and E3D protocols which state that letting the receptors rest is extremely important to continued results. You get the same effect out of slin & gh because of IGFBP3 that mops up the IGF-1 within minutes of synthesis, which makes it impossible to saturate the receptors and lets them rest. Similar effect, completely different way of achieving it. So slin & gh are synergistic. Then the next question: what about slin & IGF or Gh & IGF? IGF is synergistic with both. MOST of the effects of GH are mediated through IGF-1 but not ALL of them. Among the good effects of GH that IGF-1 does not exert is anabolism to ligaments, for example. This is just an example to show that there is a benefit to using GH & IGF-1 at the same time. There is evidence that ED dosing of LR3 reduces GH release in the body, so it makes plenty of sense to use both at the same time. Slin & IGF is a different animal. Most of the benefits of insulin come from its ability to increase IGF-1. Unless you are diabetic, your body makes enough insulin. Eat more, it releases more insulin. More carbs? More slin. The limit to the body’s ability to release slin isn’t easily reached. Even feeding 10,000 cals ED your body can produce the slin to store that. Easily. Am I stating there is no use in pinning slin & IGF together? No. There is evidence that shows that pinning slin with IGF-1 increases the length of the effects of IGF-1. Especially the hypoglycemic effects, obviously, but this has pretty far-ranging and beneficial implications, among which saturating the lean cells with nutrients and having a low blood sugar level are not the least. Obviously they are both hypoglycemic compounds so carbs have to be adjusted up when adding IGF-1 to slin, or slin reduced. I prefer the second option, although I am at a loss as to the amount of slin you would have to remove for compensation with, say, 40mcg IGF-1. Personally I have not done this. Both my grandfathers were diabetics, so I’m not playing with slin. Especially that I have a natural tendency to go hypoglycemic easily. IGF-1 though is simply GREAT for me. What I did do, over 10 years ago, is use an extremely potent GH releaser named GHB and combined that with a few ounces of sugar, the idea being of course a cheap version of GH & Slin. Obviously it worked great over a few months and it did produce hyperplasia, as made very obvious by the muscle size I retained when taking a 2 year layoff from lifting because of a non-training related injury. Quote: Dont take this as me being a **** but do you have some experience with IGF Grunt? If so what were your gains? And have you tried rhIGF? What kind of gains from those? I would guess with as much knowledge you have on this you’d have to have run it before. I have run LR3 at 20, 30, 40 and 50mcg ED as well as variations of only postworkout pinning. I suggested EOD and gapped dosing way before lab research showed that this would be a better dosing protocol. In my experience, IMMEDIATELY-POSTWORKOUT dosing is all-important to hyperplasia. SOME benefit is had by pinning preworkout and at other times, but the vey best resutls from pinning immediately postworkout. I have experimented with 5-minutes postworkout and 20-30 minutes postworkout and have found the 5-minutes postworkout dosing to be VASTLY superior to any other dosing protocol. I know it isn’t the most practical for most of us, but I’m saying what I have seen on myself. Gains out of IGF-1 are difficult to account for. Firstly, it is much more a recomposition compound than a mass or fatloss compound. On AAS, the gains are “this many lbs of LBM”. On clen/Thyroid, gains are “so many lbs of flab”. On IGF-1 the gains are “some fatloss, some muscle gain/retention, and this many new cells that I will grow in the coming months”. But suffice it to say that my first experimentation protocol was 5 minutes postworkout in my biceps, delts and chest because my previous research had indicated that the postworkout window was limited, and because those were my lagging bodypart. My biceps went from 17″ to 17½” in the first 2 weeks along with some fatloss and another ½” in the 2 months afterward, my DB curls going from 55 x 10 to 65 x 10. That was after 12 years of natural training, with genetic potential pretty maxed out. Chest and delt results I did not even attempt to quantify but the difference was clearly visible. On another board there was a log where the guy was shooting only his biceps because he read that local effects were little and his bis were lagging. A couple months after his log was done I asked about his biceps and he said they had now taken the lead in his muscular development. Quote: WOW this thread is awesome. I am 100% with you on the conservitave part, why put your health and life and for alot of of us here LOOKS in jepordy? On the other hand I must be the devils advocate, even though I feel a bit overwhelmed by some of these knowledgable bros… Could this change with large doses of AAS? I could be wrong. Completely so, but with verry large amounts of certain anabolics your IGF raises drasticaly. Why would this not result in some for of perma gut? I beleive GH can cause some organ growth correct? Maybe that has a different mechanism but it seams this only happens at verry high doses over verry long periods of time. Why do we not see such organ growth with the use of extreme amounts of AAS over periods of years? And a more importantly, if you were to take large doses of AAS especialy those of the stronger breed do you think that the doses could increase, perhaps from increasing the rate of the receptors processing the IGF-1r3. Also wouldn’t it be verry usefull to use this chemical post cardio because of the blood pumping so drasticaly to the muscle sites, even pre or mid cardio work out? I’m sorry if I’m being dense, I gotta ask the questions!! Those are actually some very good questions. The answers are equally good. There are two completely different ways in which IGF-1 is produced in the body. Even the IGF-1 molecule itself is slightly different in each case. The first, well known case, is where GH & Slin are used by the liver to make IGF-1 which is then released into the bloodstream. AAS has little to no bearing on this systemic, or “paracrine” IGF-1. It just circulates in the bloodstream and eventually finds an IGF-1 receptor on the outside surface of a cell and attaches to it, activating it. The other pathway, the one that is rarely discussed, is the autocrine pathway. This is where a cell will produce its own IGF-1, a slightly different peptide than the systemic, for its own internal use. It is produced inside the cell, and acts on receptors within the cell. This is the pathway that AAS will greatly upregulate. This IGF-1 never leaves the cell. So on one hand you have the systemic with its effects on the surface receptor and you have the autocrine with its effects on the internal receptor. So obviously when you know this it becomes obvious that the IGF-1 from AAS – the autocrine – will never give you the GH gut because the IGF-1 that it makes your cells produce never leaves the cell itself, it doesn’t circulate around to go attach to an intestinal wall receptor. The pathway through which GH causes organ growth *IS* systemic IGF-1. Most of the effects of GH are actually effects of IGF-1. GH is simply not very active on many cells but it is much converted by the liver into IGF-1 and this is what mediates the effects of GH. As I posted above, there ARE some effects of GH that are not mediated through IGF-1 but most of them are. As far as upregulating the surface receptors through AAS usage, I have seen no evidence that points that way, but that is not entirely impossible. Improbable, but not impossible. As far as pinning post-cardio, I don’t see it. In my opinion, for bodybuilders IGF-1 has two main purposes: firstly hyperplasia, its main use, and secondly general tissue repair, meaning healing and preventing injury. Ligaments aren’t repaired by IGF-1 but they’re a rare exception. It is too expensive and too good at better things IMO to be wasted on a simple pump. Quote: How would one transport this to the gym for post wo injection? What’s the best way to maintain integrity, avoid heat and not losse any? Suggestions? Diluted in AA, it is stable for a year at 98 degrees F. Of course, the insides of your car in the midst of a sunny summer day will be much hotter than that. Not the inside of your locker though. What I always do is to load up a syringe with just the needed amount of IGF & AA, then use a small amount of aluminum foil to make a spacer between the end of the plunger and the cylinder to avoid discharging the syringe in transit, and put this and a couple alcohol pads and my BW inside a sunglass case in my gym bag. I grab my bag after my workout, go change in the shower or toilet and pin at the same time. Then I get my shake. IGF-1 is totally legal, so even if you get caught with some in a syringe, even if it comes to that, the police can only apologize politely for the trouble of questioning you and all that. I still don’t see how someone is going to find out what I do in my toilet stall though… Never was a problem for me. I know a guy who tried in his car and was seen a few times, and got in some crazy situations with that. No police or anything, just zany adventures of a stressed guy. Quote: Great info Grunt….I always like reading your stuff. I am in the middle of a 16week AAS cycle, and I started it using IGF, by the end of this 16 weeker I should have not only larger cells from the AAS but new cells from the IGF that are now larger cause of the AAS correct. Indeed my friend. It should be noted that the new cells are myoblasts, pre-muscle cells, that will fuse with your existing muscle cells and donate their nucleii which are in fact myonucleii. A muscle’s protein-repair engine is the myonucleii. The more of them in a cell, the bigger the cell and the greater the ability to regenerate protein. This explains the permanent gains from IGF-1 in that the number of myonucleii does not easily decrease, which gives a cell a new minimum size. Unless of course a person undergoes starvation, but that’s not the case around these parts. When we take AAS, it’s the myonucleii that get stimulated into overdrive. Quote: i know nuttin about igf so dont take this wrong im just curious, was this info from research or someones theroy. the only reason i ask is cuzz you put a limit on the mcgs before it went to intestins. everyone is different where did the # come from? thanks for your time. It’s all Grunt76’s work. 13 years of research and human trials. You are right, the number is a guesstimate. From talking with other users, 40mcg is a dose at which, when injected immediately postworkout, good long-term gains are experienced with slowly diminishing effect. The ideal dose would be the one that you can use forever. Remember, if you inject just the right amount immediately postworkout, there will be no spillover of the IGF-1 into other receptors and so these (local) receptors will have plenty of time to re-upregulate before next injection time, and so for every bodypart. Sadly I must report that I have not yet found that “perfect dose” so 40mcg is a good place to go, where you get your results, no major gut effect and only slow desentitization. No matter how you split it, the “perfect dose” would be variable depending on muscle worked, intensity of workout and about a zillion other factors, making it just a theoretical thing. ***GREAT INFORMATION FROM SOMEONE WITH A LOT OF KNOWLEDGE ON THIS PRODUCT***

Exemestane – Estrogen Supression

Aromasin (Exemestane) is a steroidal suicide aromatase inhibitor, which means that it lowers estrogen production in the body by blocking the aromatase enzyme, the enzyme responsible for estrogen synthesization. (1)(2)(3)

This stuff was developed to fight breast cancer in post-menopausal women, who need a particularly aggressive therapy, and for whom first line defenses such as SERMS (Tamoxifen) have not worked. This should be our first clue in inferring that this stuff is pretty strong, or at least stronger than some of the other compounds which are used to fight breast cancer.

Aromasin and Side Effects

Aromasin averages an 85% rate of estrogen suppression (4), so it´s clearly a very effective agent for bodybuilders and other athletes wanting to avoid estrogen related side effects such as gyno, acne, or water-retention brought on by aromatizing steroids. Specifically, Exemestane dose this by selectively inhibiting aromatase activity in a time-dependent and irreversible manner (hence the “suicidal” portion of it´s name, I guess).(7)

As with most of the compounds in this class, it also causes a reasonable rise in testosterone levels (6), and as you may have guessed, this rise in testosterone means that Exemestane can also cause androgenic sides(8)(9)(10). As you can see from the chart below, exemestane is very effective at both lowering estrogen (estradiol) and raising testosterone:

FIG. 1. Estrogen and androgen plasma levels after 10 d of daily exemestane (25 or 50 mg) in healthy young males (mean ± SD; n = 9-11). To convert to Systeme International units: estradiol, picomoles per liter (x3.671); estrone, picomoles per liter (x3.699); androstenedione, nanomoles per liter (*0.003492); and testosterone, nanomoles per liter (x0.03467). (13)

So we can see that 25mgs is a very effective dose from that chart, right? As an added benefit, exemestane not only increases testosterone and lowers estrogen, but it also increases IGF levels (11).Additionally Worth noting is that Aromasin may possibly be less harsh on blood lipids (14)than some of the other (similar) compounds we use in the world of bodybuilding or athletics (other AI´s). It also has, at best no effect on IGF, and at worst could lower (13) it. AI´s are very tricky with regards to inconsistencies in IGF levels.

Unfortunately, you need to take Exemestane for a week to reach steady blood plasma levels of it, and exemestane has a ½ life of 27 hours (12.).

The ability of exemestane to lower estrogen levels by the aforementioned 85% makes it a very nice choice for use in any cycle where aromatizing steroids are used. In addition, since it´s not too harsh at all on blood lipid profiles, it´s a very good choice for longer cycles. It´s ability to raise both testosterone levels also seem to suggest that it would be a very nice addition to a Post-Cycle-Therapy (PCT).

References:

1. A predictive model for exemestane pharmacokinetics/pharmacodynamics incorporating the effect of food and formulation.Br J Clin Pharmacol. 2005 Mar;59(3):355-64.
2. Exemestane for breast cancer prevention: a feasible strategy?Clin Cancer Res. 2005 Jan 15;11(2 Pt 2):918s-24s.
3. Endocrinology and hormone therapy in breast cancer: Aromatase inhibitors versus antioestrogens, Anthony Howell1 and Mitch Dowsett2. 1CRUK Department of Medical Oncology, University of Manchester, Christie Hospital, Manchester, UK. 2Academic Department of Biochemistry, Royal Marsden Hospital, London, UK. Breast Cancer Res 2004, 6:269-274 doi:10.1186/bcr945. Published 6 October 2004
4. Eur. J. Cancer. 2000, May;36(8):976-82
5. Breast Cancer Res Treat. 1995;36(3):287-97.
6. J Clin Endocrinol Metab. 2003 Dec;88(12):5951-6.
7. Nippon Yakurigaku Zasshi. 2003 Oct;122(4):345-54.
8. Clin Cancer Res. 2003 Jan;9(1 Pt 2):468S-72S.
9. J Clin Endocrinol Metab 2000 Jul;85(7):2370-7
10. J Steroid Biochem Mol Biol 1997 Nov-Dec;63(4-6):261-7
11. Anticancer Res. 2003 Jul-Aug;23(4):3485-91
12. Clin Cancer Res. 2003 Jan;9(1 Pt 2):468S-72S
13. The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 12 5951-5956Copyright © 2003 by The Endocrine Society
14. J Clin Endocrinol Metab. 2003 Dec;88(12):5951-6.

-www.steriod.com

Exemestane – AROMATASE Inhibitors

Exemestane (trade name Aromasin) is an oral steroidal aromatase inhibitor used in the adjuvant treatment of hormonally-responsive (also called hormone-receptor-positive, estrogen-responsive) breast cancer in postmenopausal women. An aim in the treatment of hormone-receptor-positive patients in preventing recurrence is to lower estrogen levels that this breast cancer thrives on.

The main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body’s estrogen is produced in the adrenal gland from the conversion of androgens into estrogen by the aromatase enzyme. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation, an effect also known as “suicide inhibition.” In other words, Exemestane, by being structurally similar to the target of the enzymes, permanently binds to those enzymes, thereby preventing them from ever completing their task of converting androgens into estrogens.

The estrogen suppression rate for exemestane varies from 85% for estradiol (E2) to 95% for estrone (E1).

Clinical uses

Exemestane is indicated for the adjuvant treatment of postmenopausal women with estrogen-receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to it for completion of a total of five consecutive years of adjuvant hormonal therapy.

Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

Exemestane

Systematic (IUPAC) name
10,13-dimethyl-6-methylidene- 7,8,9,10,11,12,13,14,15,16- decahydrocyclopenta[a] phenanthrene- 3,17-dione
Identifiers
CAS number	107868-30-4
ATC code	L02BG06
PubChem	60198
DrugBank	APRD00144
Chemical data
Formula	C20H24O2
Mol. mass	296.403 g/mol
Pharmacokinetic data
Bioavailability	~60%
Protein binding	90%
Metabolism	?
Half life	27 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	D
Legal status	Rx only
Routes	Oral

Anastrozole – AROMATASE Inhibitors

Anastrozole (INN, trade name Arimidex, AstraZeneca) is a drug used to treat breast cancer after surgery and for metastases in post-menopausal women.

Anastrozole is an aromatase inhibitor, which means that it interrupts a critical step in the body’s synthesis of estrogen. Some breast cancer cells require estrogen to grow, and eliminating estrogen suppresses their growth.

Clinical trials

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial represents a long-term follow-up study of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both.^[2] After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.

Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimidex.^[3]

[edit] Mechanism of Action

Anastrozole inhibits the enzyme aromatase, which is responsible for converting androgens to estrogens. Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition.

Elevated levels of estrogens may increase the severity of breast cancer, as sex hormones can cause hyperplasia and differentiation at estrogen receptor sites.

Side effects

Bone weakness : Women who switched to Arimidex (after two years on tamoxifen) reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).^[3]

Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, osteonecrosis of the jaws. Since statins have a bone strengthening effect ^[4], combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks ^[5] without jaw osteonecrosis.^[6] In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or approximately the equivalent of 10 mg Fosamax daily.^[7]

Usage for men

While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men. Excess estradiol in men can cause benign prostatic hyperplasia, gynecomastia, and symptoms of hypogonadism. Some athletes and body builders will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; in particular, gynecomastia and water retention.

Study data currently suggests that dosages of 0.5 mg to 1 mg a day reduce serum estradiol by about 50% in men, which differs from the typical reduction in postmenopausal women. However the reduction may be different for men with grossly elevated estradiol (clinical data is currently lacking).

Dutasteride-DHT Inhibitor – Baldness Treatment

More than half of men are affected by male pattern baldness by age 50, and baldness treatments are estimated to be a US $1 billion per year industry.^[1] Since the 1980s, drug therapy has increasingly become a realistic management option for baldness for men and women. Increased understanding of the role of dihydrotestosterone (DHT) in male and female pattern baldness has led to targeted intervention to prevent this hormone from acting on receptors in the scalp.

Dutasteride-DHT Inhibitor

Dutasteride (marketed as Avodart, Avidart, Avolve, Duagen, Dutas, Dutagen, Duprost) is a 5-alpha-reductase inhibitor, a drug that inhibits the conversion of testosterone into dihydrotestosterone (DHT). It is used to treat conditions caused by DHT, such as benign prostatic hyperplasia (BPH). Avodart is manufactured and marketed by GlaxoSmithKline.

Classification and method of action

Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which block the action of the 5-alpha-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Finasteride also belongs to this group. Dutasteride inhibits both isoforms of 5-alpha reductase, while finasteride inhibits only one. But a clinical study done by GlaxoSmithKline, the EPICS trial, did not find dutasteride to be more effective than finasteride in treating BPH.

Uses

While dutasteride is only officially approved to treat enlargement of the prostate gland (at a dose of 0.5 mg/day),^[1] phase I and II clinical trials for dutasteride as a hair loss drug were also undertaken, but called off in late 2002. The reason the trials were called off is not publicly known. Industry sources speculate that Avodart would have been seen as too similar to Propecia to have proved profitable as a hair loss treatment. However, phase II results indicated that dutasteride 2.5 mg/day generated a superior hair count to finasteride 5 mg at 12 and 24 weeks.^[2]

In December 2006, GlaxoSmithKline started a new Phase III, six month study in Korea to test the safety, tolerability and effectiveness of a once-daily dose of dutasteride (0.5 mg) for the treatment of male pattern baldness in the vertex region of the scalp (types IIIv, IV and V on the Hamilton-Norwood scale). The study has been completed as of January 2009. ^[3] The future impact that this study will have on the approval or disapproval by the U.S. Food and Drug Administration (FDA) of Avodart for the treatment of male pattern baldness in the United States is yet to be determined.

Dutasteride is also in development for Prostate cancer risk reduction.^[4]

The results of the REDUCE trial were presented at the American Urologic Association meeting in 2009 which demonstrated that higher risk patients for prostate cancer with a PSA value of 2.5 to 10 and a prior negative prostate biopsy demonstrated a 23% reduction in the incidence of prostate cancer over a four year period in this population with daily 0.5 mg dutasteride dosage.

Dutasteride is sometimes prescribed off-label to male-to-female transsexual or transgender persons to inhibit the growth of body hair, though more commonly the older drug finasteride is used for this purpose.^{[citation needed]}

Side effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The most common adverse reactions reported in subjects receiving AVODART were impotence, decreased libido, breast disorders (including gynecomastia), and ejaculation disorders. Study withdrawal due to adverse reactions occurred in 4% of subjects receiving AVODART and 3% of subjects receiving placebo. The most common adverse reaction leading to study withdrawal was impotence (1%).^{[citation needed]}

FINASTERIDE- DHT Inhibitor

Finasteride (marketed as Proscar, Propecia, Fincar, Finpecia, Finax, Finast, Finara, Finalo, Prosteride, Gefina, Appecia, Finasterid IVAX, Finasterid Alternova) is a synthetic antiandrogen that acts by inhibiting type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). It is used as a treatment in benign prostatic hyperplasia (BPH) in low doses, and prostate cancer in higher doses. A May, 2008 study indicates that finasteride reduces the rate of prostate cancer by 30%. It is also indicated for use in combination with doxazosin therapy to reduce the risk for symptomatic progression of BPH. In addition, it is registered in many countries for androgenetic alopecia (male-pattern baldness).

In the United States, Finasteride was approved initially in 1992 as Proscar, a treatment for enlarged prostate, but the sponsor had studied 1 mg of finasteride and demonstrated hair growth in male pattern hair loss. In 1997, the U.S. Food and Drug Administration (FDA) approved finasteride to treat male pattern hair loss. Merck sells it under the brand name Propecia.

Contents [hide] 1 Uses 1.1 Prostate cancer 1.2 Benign prostatic hyperplasia 1.3 Hair loss 2 Side effects 2.1 Possible health concerns 3 Propecia’s effects in detail 4 Brand names 5 Generic versions 6 See also 7 Notes and references 8 External links

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Uses

Finasteride is used in the treatment of prostate cancer, benign prostatic hyperplasia, and androgenetic alopecia (male-pattern baldness).

Prostate cancer

The 2005 Prostate Cancer Prevention Trial (PCPT) showed at a dosage of 5 mg per day, as is commonly prescribed for BPH, participants taking finasteride were 25% less likely to have developed prostate cancer at the end of the trial compared to those taking a placebo.^[1] It appeared (incorrectly) that finasteride increased the specificity and selectivity of prostate cancer detection, thus creating an apparently increased rate of high Gleason grade tumor. A 2008 update of this study found that finasteride reduces the incidence of prostate cancer by 30%. In the original study, it turns out that the smaller prostate caused by finasteride means that a doctor is more likely to hit upon cancer nests and more likely to find aggressive-looking cells. Most of the men in the study who had cancer — aggressive or not — chose to be treated, and many had their prostates removed. A pathologist then carefully examined each of those 500 prostates and compared the kinds of cancers found at surgery to those initially diagnosed at biopsy. This study concluded that Finasteride did not increase the risk of high-grade prostate cancer.^[2][3]

Benign prostatic hyperplasia

Finasteride is used for the treatment of benign prostatic hyperplasia (BPH) (also known as enlarged prostate) at a dose of 5 mg once a day. It may take six months or more to see the full effects of finasteride. If the drug is discontinued, any therapeutic benefits will be reversed. Finasteride may improve the symptoms associated with BPH such as difficulty urinating, getting up during the night to urinate, hesitation at the start of urination, and decreased urinary flow.^[4]

Hair loss

In a 5-year study of men with mild to moderate hair loss, 48% of those treated with Propecia (finasteride 1 mg) experienced some regrowth of hair, and a further 42% had no further loss. Average hair count in the treatment group remained above baseline, and showed an increasing difference from hair count in the placebo group, for all five years of the study.^[5] Propecia is effective only for as long as it is taken; the hair gained or maintained is lost within 6–12 months of ceasing therapy.^[6] In clinical studies, Propecia, like minoxidil, was shown to work on both the crown area and the hairline,^[7] but is most successful in the crown area.

Some users, in an effort to save money, buy Proscar instead of Propecia, and split the Proscar pills to approximate the Propecia dosage. Doing so is considered unadvisable if women of pregnancy age are in the household; this is because finasteride, even in small concentrations, can cause birth defects in a developing male fetus. The birth defects involve the development of male genitalia (no such effects have been noted in developing female fetuses). On most product inserts, it will be mentioned that the dust or crumbs from broken Proscar tablets should be kept away from pregnant women.

Propecia has been shown to be ineffective for treating hair loss in women.^[8] However, Propecia’s supporters respond that the study was on post-menopausal women whose hair loss was more likely related to the loss of estrogen versus a sensitivity to DHT. Doctors may prescribe it for women, but not without sufficient birth control measures in place or assurance that the woman cannot become pregnant.

Side effects

Recognized side effects of finasteride include impotence (1.1% to 18.5%), abnormal ejaculation (7.2%), decreased ejaculatory volume (0.9% to 2.8%), abnormal sexual function (2.5%), gynecomastia (2.2%), erectile dysfunction (1.3%), ejaculation disorder (1.2%) and testicular pain. Resolution occurred in men who discontinued therapy with finasteride due to these side effects and in most of those who continued therapy.^[9]

In December 2008, the Swedish Medical Products agency concluded a safety investigation of Propecia and advise that use of Propecia may result in irreversible sexual side effects. The Agency’s updated safety information lists difficulty in obtaining an erection that persists indefinitely even after the discontinuation of Propecia as a possible side effect of the drug.^[10]

Finasteride is not indicated for use by women. Finasteride is in the FDA pregnancy category X. This means that it is known to cause birth defects in an unborn baby. Women who are or who may become pregnant must not handle crushed or broken finasteride tablets, because the medication could be absorbed through the skin. Finasteride is known to cause birth defects in a developing male baby. Exposure to whole tablets should be avoided whenever possible, however exposure to whole tablets is not expected to be harmful as long as the tablets are not swallowed. It is not known whether finasteride passes into breast milk, and thus should not be taken by breastfeeding women. Finasteride may pass into the semen of men, but Merck states that a pregnant woman’s contact with the semen of a man taking finasteride is not an issue for concern.^[11] Finasteride is known to affect blood donations, and potential donors are typically restricted for at least a month after their most recent dose.^[12]

Finasteride has been linked with depression.^[13] The drug also caused reductions in allopregnanolone, a potent, endogenous positive modulator of the GABA-A receptor, in very large doses in rodent studies.^[14]

Many sports organizations have banned finasteride because it can be used to mask steroid abuse.^[15] Since 2005, finasteride has been on the World Anti-Doping Agency’s list of banned substances. However, it was removed from the list in 2009.^[16] Notable athletes who used finasteride for hair loss and were banned from international competition include skeleton racer Zach Lund, bobsledder Sebastien Gattuso, footballer Romário and ice hockey goaltender José Théodore.^[17]

SERMs – Selective Estrogen Receptor Modulator

Selective Estrogen Receptor Modulators (SERMs) are a class of compounds that act on the estrogen receptor.^[1] A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Phytoserms are scientifically accepted SERMs from a botanical source.

Contents [hide] 1 Members 2 Uses 3 Mechanism of action 4 Actions 5 References 6 See also 7 External links

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[edit] Members

Members include:

• afimoxifene (4-hydroxytamoxifen)
• arzoxifene
• bazedoxifene
• clomifene
• femarelle (DT56a)^[2]
• lasofoxifene
• ormeloxifene
• raloxifene
• tamoxifen
• toremifene

[edit] Uses

SERMs are used dependent on their pattern of action in various tissues:

• clomifene is used in anovulation
• femarelle is used for managing menopause symptoms and maintaining bone health
• ormeloxifene is used for contraception
• raloxifene is used for osteoporosis and reducing risk of invasive breast cancer
• tamoxifen and toremifene are used for breast cancer

Some SERMs may be good replacements for hormone replacement therapy (HRT), which had been commonly used to treat menopause symptoms until the publication of wide scale studies showing that HRT slightly increases the risk of breast cancer ^[3] and thrombosis.^[4] Some of the above agents still have significant side-effects which contraindicate widespread use.

SERMs are also commonly used during PCT or Post Cycle Therapy after the use of anabolic steroids, or during a steroid cycle in case of the sudden onset of estrogenic symptoms. Bodybuilders who take hormonal supplements can experience gynecomastia and similar symptoms because the body metabolizes some steroids into estrogen. This increase in estrogen can occur during or after a steroid cycle, so responsible body builders will usually cycle a SERM after a steroid cycle to ensure that their body is not flooded with excess estrogen. They also often keep a SERM on hand in case of emergency.

[edit] Mechanism of action

Estrogenic compounds span a spectrum of activity ranging from:

• full agonists (agonistic in all tissues) such as the natural endogenous hormone estrogen
• mixed agonists/antagonistics (agonistic in some tissues while antagonist in others) such as tamoxifen (a SERM)
• pure antagonists (antagonistic in all tissues) such as fulvestrant (ICI-182780).

The mechanism of mixed agonism/antagonism may differ depending on the chemical structure of the SERM, but for at least for some SERMs, it appears to be related to (1) the ratio of co-activator to co-repressor proteins in different cell types and (2) the conformation of the estrogen receptor induced by drug binding which in turn determines how strongly the drug/receptor complex recruits co-activators (resulting in an agonist response) relative to co-repressors (resulting in antagonism). For example, the prototypical SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. The concentration of steroid receptor co-activator 1 (SRC-1; NCOA1) is higher in uterus than in breast, therefore SERMs such as tamoxifen are more agonistic in uterus than in breast. In contrast, raloxifene behaves as an antagonist in both tissues. It appears that raloxifene more strongly recruits co-repressor proteins and consequently is still an antagonist in the uterus despite the higher concentration of co-activators relative to co-repressors.^[5][6]

[edit] Actions

The actions of SERMs on various tissues:

• Bone turnover and postmenopausal osteoporosis respond favorably to most SERMs.
• Breast – all SERMs decrease breast cancer risk, and tamoxifen is mainly used for its ability to inhibit growth in estrogen receptor-positive breast cancer.
• Cholesterol and triglycerides – levels respond favorably to SERMs.
• Deep venous thrombosis – the risk may be elevated in at least some SERMs.
• Hot flashes are increased by some SERMs.
• Pituitary gland – clomifene blocks estrogen action, leading to an increase of follicle-stimulating hormone.
• Uterus – tamoxifen may increase endometrial carcinoma risk, but raloxifene and femarelle do not. Data on toremifene and clomifene is insufficient.

[edit] References

1. ^ Riggs BL, Hartmann LC (2003). “Selective estrogen-receptor modulators — mechanisms of action and application to clinical practice”. N Engl J Med 348 (7): 618–29. doi:10.1056/NEJMc030651. PMID 12584371.
2. ^ Somjen D, Katzburg S, Knoll E, Hendel D, Stern N, Kaye AM, Yoles I (May 2007). “DT56a (Femarelle): a natural selective estrogen receptor modulator (SERM)”. J. Steroid Biochem. Mol. Biol. 104 (3-5): 252–8. doi:10.1016/j.jsbmb.2007.03.004. PMID 17428655.
3. ^ Reeves GK, Beral V, Green J, Gathani T, Bull D (November 2006). “Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis”. Lancet Oncol. 7 (11): 910–8. doi:10.1016/S1470-2045(06)70911-1. PMID 17081916.
4. ^ Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women’s Health Initiative Investigators (July 2002). “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial“. JAMA 288 (3): 321–33. doi:10.1001/jama.288.3.321. PMID 12117397. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=12117397.
5. ^ Shang Y, Brown M (2002). “Molecular determinants for the tissue specificity of SERMs”. Science 295 (5564): 2465–8. doi:10.1126/science.1068537. PMID 11923541.
6. ^ Smith CL, O’Malley BW (2004). “Coregulator function: a key to understanding tissue specificity of selective receptor modulators”. Endocr Rev 25 (1): 45–71. doi:10.1210/er.2003-0023. PMID 14769827.

[edit] See also

• Selective receptor modulator
• Selective androgen receptor modulator
• Selective progesterone receptor modulator
• Selective glucocorticoid receptor agonist
• Phytoserm
• Femarelle
• Lasofoxifene
• Ormeloxifene
• Raloxifene
• Tamoxifen
• Toremifene

Aromatase Inhibitors

Aromatase inhibitors (AI) are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women.

Some cancers require estrogen to grow. Aromatase is an enzyme that synthesizes estrogen. Aromatase inhibitors block the synthesis of estrogen. This lowers the estrogen level, and slows the growth of cancers.

Contents [hide] 1 Type I and II 2 Mode of action 3 Indication 3.1 Cancer 3.2 Other uses and sources of aromatase inhibitors 4 Members 4.1 Non-selective 4.2 Selective 4.3 Unknown/ungrouped 5 Side Effects of Aromatase Inhibitors 6 References

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[edit] Type I and II

AIs are categorized into two types: ^[1]

• Irreversible steroidal inhibitors such as exemestane form a permanent bond with the aromatase enzyme complex.
• Non-steroidal inhibitors (such as anastrozole, letrozole) inhibit the enzyme by reversible competition.

[edit] Mode of action

Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.

[edit] Indication

[edit] Cancer

In contrast to pre-menopausal women, in whom most of the estrogen is produced in the ovaries, in post-menopausal women most of the body’s estrogen is produced in the adrenal gland from the conversion of androgens. The other main source of estrogen post-menopausally is adipose tissue^{[citation needed]}. Because some breast cancers respond to estrogen, lowering the estrogen level in post-menopausal women using aromatase inhibitors has been proven to be effective in breast cancer treatment.^[2]

Aromatase inhibitors are generally not used to treat breast cancer in premenopausal women. Since most of the circulating estrogen is produced by the ovaries, not by conversion of androgens to estrogen, blocking the enzyme aromatase does not significantly decrease the production of estrogen. When aromatase inhibitors are used in premenopausal women, the decrease in estrogen activates the hypothalamus and pituitary axis to increase gonadotropin secretion, which in turn stimulates the ovary to increase androgen production. This counteracts the effect of the aromatase inhibitor.

An ongoing area of clinical research is optimizing adjuvant hormonal therapy in postmenopausal women with breast cancer. Tamoxifen has been standard treatment, however the ATAC trial has shown that clinical results are superior with an AI in postmenopausal women with localized breast cancer that is estrogen receptor positive. Further studies of various AIs are ongoing.

[edit] Other uses and sources of aromatase inhibitors

Results of an enzyme assay conducted with the white mushroom and the enzyme aromatase.^[3][4]

Investigations are ongoing to look for other applications. Researchers are studying aromatase inhibitors to stimulate ovulation (in a manner similar to, but not exactly the same as, clomiphene citrate) or suppress estrogen production, ie in endometriosis.^[5]

AIs have also been used experimentally in the treatment of adolescents whose predicted adult height is low.^[6]

Bodybuilders who take anabolic steroids may also take AIs to prevent the steroids from being converted to estrogen; an increase in estrogen levels has undesirable consequences for a bodybuilder, such as gynecomastia. This is often the case when a natural aromatase inhibitor 4-OHAD [2] has itself been inhibited. 4-OHAD is a metabolite of testosterone, which can mean 4-OHAD remains inhibited whilst aromatase levels are allowed high.

In one recent study, aromatase inhibitors were found to be no more successful at treating pubertal gynecomastia than a placebo. ^[7]

Aromatase inhibitors have also been shown to reverse age-related declines in testosterone, as well as primary hypogonadism.^[8]

Extracts of certain mushrooms have been shown to inhibit aromatase when evaluated by enzyme assays, the white mushroom has shown the greatest ability to inhibit the enzyme.^[4]