Ostarine - SARM in Phase III Trials

Pharma / TRT
21

It is not the same mechanism, though, to inhibit 5AR as it is to supply endogenous DHT?

Anyway I really raised that only as a side point, that the fact that the "SARM"s weren’t found in a trial to increase prostate size is hardly any striking fact necessitating a new mechanism or necessarily providing any advantage over existing non-aromatizing anabolic steroids, or even aromatizables with concomitant control of estrogen.

I don’t actually think DHT is an androgen of choice for HRT. It was just an illustration of a point.

22

Bill,

Thanks for the time you’ve spent on this thread. Molecular biology is a ridiculously complicated subject when you get to the level of trying to understand all the interactions of macro proteins and their functions.

If you have any articles or know the best book to read about this, I’d appreciate it. I have purged my med chem and pharmacology textbooks, but as you know the textbooks are the last literature to add new findings.

So a couple of questions. (I think I know the answers to some of these, but I want to ask soley for clarification)

Can the same SERM elict different responses from estrogen receptors in different tissues?

Have any co-factors been identified as responsible for the different responses of SERMs?

Will 2 different SERMs give 2 different responses in the same tissue? If so, do you know of any examples off hand?

I am mainly interested in the 3rd question. I understand if you don’t have any answers, but you seem more educated in this area than I, so I wanted to ask.

Thanks

23

[quote]Bill Roberts wrote:
It is not the same mechanism, though, to inhibit 5AR as it is to supply endogenous DHT?
[/quote]

I am not sure of this specific case, but when it comes to dopamine regulation in the brain there is a HUGE difference in which route is taken (to the same endpoint) that will yield the least side effects.

Side tracked to illustrate my point

Parkinson’s is a disease caused by the loss of dopamine producing neurons. So, to help delay the effects of Parkinson’s you have to find a way to still activate the dopamine receptors in the brain. There are many ways to do this.

  1. Increase dopamine w/ injected dopamine (actually L-dopa)
  2. Decrease metabolism of natural dopamine
  3. Use non-dopamine molecules to stimulate dopamine receptors

All three of these will delay the effects of Parkinson’s and they are all 3 used, BUT the first way has the greatest side effects.

So, even though they have the same end result the path taken can have different side effects.

24

I will try to dig up whatever electronic copy there is of the review I did on it before, as that would provide the best answers. A lot of the details, I have forgotten by now. There is quite a bit to it. However I’m not sure how easily it will turn up nor am absolutely sure that it will. I tend to think that all I copied from the last computer to this one was stuff related to my thesis and some porn, while that paper is not related to my thesis.

On the first question, yes. For example all the SERMs, I think, are estrogenic in bone but anti-estrogenic in breast tissue.

On the third question, yes. The most clinically-important example, I suppose, is that tamoxifen and clomiphene are estrogenic in uterine tissue, while raloxifene is anti-estrogenic there.

25

[quote]phiphika1453 wrote:
Bill Roberts wrote:
It is not the same mechanism, though, to inhibit 5AR as it is to supply endogenous DHT?

I am not sure of this specific case, but when it comes to dopamine regulation in the brain there is a HUGE difference in which route is taken that will yield the least side effects.

Side tracked to illustrate my point

Parkinson’s is a disease caused by the loss of dopamine producing neurons. So, to help delay the effects of Parkinson’s you have to find a way to still activate the dopamine receptors in the brain. There are many ways to do this.

  1. Increase dopamine w/ injected dopamine (actually L-dopa)
  2. Decrease metabolism of natural dopamine
  3. Use non-dopamine molecules to stimulate dopamine receptors

All three of these will delay the effects of Parkinson’s and they are all 3 used, BUT the first way has the greatest side effects.

So, even though they have the same end result the path taken can have different side effects.

[/quote]

Agreed.

Also in this specific case, 5AR inhibition results in decreased conversion of testosterone / production of DHT at the target tissue, as well as some other tissues, while not much affecting LH production or testosterone production, and not much affecting estrogen levels.

In contrast administration of DHT quite likely reduces testosterone production, perhaps quite significantly, and quite likely by that mechanism as well as by aromatase inhibition via high plasma DHT levels, reduces estrogen levels.

It’s even conceivable that high plasma DHT from administration of DHT might yield lower DHT levels in the prostate. While counterintuitive, it’s possible that local conversion of testosterone to DHT may produce higher DHT levels in the prostate than the serum levels from the exogenous administration, and perhaps by such a large difference that if T levels are suppressed with the DHT administration, DHT could possibly be lower in the prostate with DHT administration than it is without. Hypothetically anyway. That might be more of a reach, but it would take facts to rule it out, if it is not the case.

So evidence that 5AR inhibitors reduce BPH and evidence that administration of DHT itself does not aggravate and may reduce BHP are not necessarily contradictory.

26

Cool.

I was unaware of the ability of 2 different drugs binding the same active site and still causing 2 different responses.

Well I assume they are binding the same active site, correct?

27

Yes.

28

[quote]Bill Roberts wrote:
It is not the same mechanism, though, to inhibit 5AR as it is to supply endogenous DHT?
[/quote]
No. The inhibitors used clinically both reduce circulating DHT and intraprostatic DHT. It does not follow that transdermal DHT would necessarily decrease intraprostatic DHT–although it might. (A testable idea!)

[quote]
Anyway I really raised that only as a side point, that the fact that the "SARM"s weren’t found in a trial to increase prostate size is hardly any striking fact necessitating a new mechanism or necessarily providing any advantage over existing non-aromatizing anabolic steroids, or even aromatizables with concomitant control of estrogen.

I don’t actually think DHT is an androgen of choice for HRT. It was just an illustration of a point.[/quote]

Understood and appreciated.

29

[quote]DrSkeptix wrote:

No. The inhibitors used clinically both reduce circulating DHT and intraprostatic DHT. It does not follow that transdermal DHT would necessarily decrease intraprostatic DHT-.[/quote]

Intraprostatic DHT, a byproduct of Free Testosterone to DHT conversion within the prostate, is activated through 5 alpha enzyme.

The main culprit behind this 5 alpha activity is 4 and 16 hydroxy estrone.

I would hypothesize that the best way to control DHT within the prostate gland would be to minimize estrone conversion to these bad estrone metabolites, 4 and 16 hydroxy.

Also would like to note that 2 hydroxy seems to be the dichotomy in the situation, working as the good guy.

30

Is the drug “selective” in that it causes different expression of the AR on the different tissues of the prostate? Mainly that of the basal cells and the stromal cells?

31

[quote]phiphika1453 wrote:
Hey,

Just wanted to get the word out that this new drug is currently beginning phase III trials, and a VERY reliable source said it could hit the market as soon as late 2010.

Ostarine is a non-steroidal selective androgen receptor modulator. The drug will be marketed at the elderly population, both men and women. Delaying andropause through drug therapy without acceptable side effects has been a challenge, but the clinical trials for this drug seem very promising.

So far it has shown to increase muscle mass in men and women, increase bone density in women, slow the growth of prostates in men and reduce the occurrence of breast cancer in women.

Kinda sounds like a miracle drug, huh? Even better is that the worst reported side effects so far have been nausea and diarrhea.

I know its sounds like I work for the company but I tried to write this in a way as to not tip off my identity. Let’s just say that I was taught by the head medicinal chemist responsible for compounding this molecule.

Just wanted to let everyone know to keep an eye out. The side effects of classic steroids could become a thing of the past if more SARMs are developed.

Here is the link companies website regarding Ostarine.

Forgot the link*

[/quote]

He4y I’ve done a little bit of reading or research about SARMs when I first heard of it. I was wondering if you knew or heard anything about another one I read about called LGD-3303 . . .

32

[quote]DrSkeptix wrote:
Bill Roberts wrote:
It is not the same mechanism, though, to inhibit 5AR as it is to supply endogenous DHT?

No. The inhibitors used clinically both reduce circulating DHT and intraprostatic DHT. It does not follow that transdermal DHT would necessarily decrease intraprostatic DHT–although it might. (A testable idea!)

Anyway I really raised that only as a side point, that the fact that the "SARM"s weren’t found in a trial to increase prostate size is hardly any striking fact necessitating a new mechanism or necessarily providing any advantage over existing non-aromatizing anabolic steroids, or even aromatizables with concomitant control of estrogen.

I don’t actually think DHT is an androgen of choice for HRT. It was just an illustration of a point.

Understood and appreciated.[/quote]

I know it’s been a while, but this thread having just been revived I saw the above again now.

This raises what seems to me an interesting idea for HRT: supplying a mixture of testosterone and DHT with sufficient DHT to maintain normal free DHT levels while also administering a 5a-reductase inhibitor at quite effective dose.

This would result in – obviously – normal overall DHT levels, but lower levels in target areas of concern such as the prostate and scalp, and thus possibly for some individuals being superior to either testosterone-only administration or to testosterone-plus-5AR-inhibitor.