THIS IS IT! Skull look! Everybody else too!

[Warrior21]

If you don't read the whole thing, at least read the last 4 sentences. You will see why I have not been responding to steroids. Megalin has to do with exogenous steroids.

Does Megalin Mediate Steroid Hormone Uptake?
Androgens and estrogens circulate through the bloodstream bound to sex hormone binding globulin (SHBG), in what has been believed to be an inactive form that prevents these small, lipophilic steroids from diffusing across the plasma membrane to activate intracellular targets (see Adams). A research group that previously showed that the low-density lipoprotein receptor-related protein megalin acts as an endocytic receptor for carrier-bound vitamins A and D has now implicated megalin in the uptake of SHBG-bound sex steroids. Hammes et al. showed that 125I-labeled SHBG was taken up and degraded by rat choriocarcinoma (BN16) cells, which express megalin, and that this was blocked by receptor-associated protein (RAP), an antagonist of ligand binding to megalin. Most circulating sex steroids are bound to carrier, and the ability of RAP to inhibit [3H]testosterone uptake depended on the ratio of SHBG and testosterone, such that inhibition was maximal when most of the testosterone was bound, whereas RAP was ineffective when most of the testosterone was free. RAP also inhibited the uptake of SHBG-bound dihydrotestosterone (DHT) and 17ß-estradiol. Uptake of fluorescein isothiocyanate (FITC)-labeled DHT together with SHBG was confirmed with confocal immunofluorescence microscopy; moreover, DHT internalized together with SHBG activated an androgen-sensitive reporter. The phenotypes of megalin knockout mice were consistent with impaired sex-steroid signaling: Megalin—/— females exhibited vaginal blockade whereas megalin—/— males exhibited impaired descent of the testes. Further, megalin-deficient embryonic tissues were resistant to the effects of exogenous androgens. Thus, the authors conclude that megalin plays a role in the cellular uptake of carrier-bound sex steroids that is critical to the proper development of steroid-responsive tissues.

[guest589745]

Ok but does this mean that it only effects DHT based compounds or ALL steroids?

How do we change this?

[Warrior21]

Megalin is involved with uptake of cholesterols. Steroids are based off of cholesterol, so Megalin takes care of them. Basicaly what happens is when you take steroids they are first processed by the kidney. Think of the steroids as your groceries. Megalin is the bag boy. The bag boy comes over to bag your groceries. Your groceries will not have any effect until they are bagged and off on their way.

So basically Megalin attaches steroid to receptors, then they enter the bloodstream. Several studies have proven this. Now the next step is to figure out how to increase Megalin.

Search "Megalin agonist" or "increase Megalin". Thyroid may also increase Megalin.

I'm not leading you on a wild goose chase again =-). If you want to verify that this information is true search "Steroid Hormone Uptake". We got it this time, I swear!

Dude I blow myself away sometimes hehe.

[Warrior21]

Steroid Hormones
Steroid hormone dependent tumours
Rational
Megalin is not only responsible for retrieval of lipid-soluble vitamins and hormones in the kidney but also in other tissues that express the receptor. Work in ReceptIcon now has identified megalin as a novel pathway for cellular uptake of steroids hormones such as androgens and estrogens in steroid-dependent tissues, a finding with far reaching implications for treatment of steroid-dependent tumors.

Steroid hormones need to cross the plasma membrane of target cells to exert their biological functions. Until recently, it was believed that these lipophilic hormones enter cells by non-specific diffusion after dissociation from their carrier proteins. However, specialized cell types that require large amounts of steroids for maintenance of normal function or carcinogenesis are likely to require additional mechanisms for specific and efficient uptake of steroid hormones. R&D efforts in ReceptIcon demonstrated that megalin is this uptake pathway used by steroid-dependent cells to actively acquire androgens and estrogens.

Evidence for a role of megalin in steroid hormone metabolism is substantial. Firstly, the receptor is expressed in many tissues that take up and respond to steroid hormones, including prostate, mammary gland, epididymis, and uterus. Secondly, the expression of the receptor is up-regulated in steroid-dependent tumours of the breast and prostate. Thirdly, the receptor is able to internalize large amounts of androgens and estrogens bound to carrier proteins, and blocking this receptor by antagonists impairs delivery of steroid hormones to cells (Figure 4). Most importantly, a role for megalin in steroid hormone action is confirmed by the steroid hormone insensitivity of receptor-deficient mouse models.


Business concept
Some of the most common types of cancer including prostate and breast cancers are dependent on estrogens or androgens. As a consequence, steroid hormone receptors have been major therapeutic targets to treat these diseases and steroid-antagonists have already proven their worth in the clinics.

Most current drugs against steroid dependent tumours block biosynthesis of steroid hormones (aromatase inhibitors) or target the binding of steroids to their intracellular receptors (anti-androgens or anti-estrogens) Preventing the steroids from getting into the cells in the first place through inhibition of megalin offers an alternative point of attack for such tumours (Figure 5). Megalin antagonists may be effective either alone or work synergistically with current drugs, providing two independent strategies in treatment of tumours. Androgen-deprivation or estrogen-antagonist therapies suffer from systemic side effects significantly reducing quality of life for the patients. Inhibition of steroid hormone uptake through inhibition of megalin in specific cell types only is likely to be more selective towards cells requiring active uptake of steroids, and may therefore have fewer systemic side effects than traditional steroid targeting therapies.

In conclusion, megalin offers a novel target for the development of therapeutics for the treatment of steroid dependent cancers.

Development Strategy
The development of megalin antagonists to prevent the delivery of androgens and estrogens to tumors of the breast and prostate represents a second business area for ReceptIcon with significant potential. Compounds capable of inhibiting steroid hormone uptake into tumour cells will be developed as independent medicinal products in line with other anti-neoplastic drugs currently on the market.
With respect to this business area, the company pursues two research aims. Firstly, it aims to establish novel test systems in vitro, in cell culture, and in animal models to demonstrate that the megalin pathway is responsible for the delivery of steroid hormones into cancer cells, and that blocking the receptor is a useful strategy to block the growth of steroid-dependent tumors. Secondly, the company aims to identify the binding site on megalin for steroid-hormone-binding proteins in order to facilitate the development of pharmaceutically acceptable megalin antagonists capable of preventing steroid hormone uptake into cells (Figures 4 and 5).

[guest589745]

Well it wasnt a wild goose chase last time, we found out exactly how to surely increase the absorption of orals, that was worth it IMO.

[Warrior21]

Originally Posted by Skullsmasher

Well it wasnt a wild goose chase last time, we found out exactly how to surely increase the absorption of orals, that was worth it IMO.

I'm glad you see we didn't waste time. We found out how to increase their absorption for sure. Now once we know how to get passed all that needs to happen at the kidneys (injects included), were golden =-).

Lets do this man, I'm not going to give up.

[guest589745]

Im lookin.......

[Warrior21]

You know how excited I get =-). I fear that since the discovery of megalin is so new that we might be out of luck to induce/agonize it. Were going to have to figure out everything that interacts (raises/lowers) Megalin. We want Megalin high. If were deficient, our kidneys will basically just excrete the hormones before they even enter out bloodstream. This has to be the case with me, seeing as I never even got any side effects from steroids.

[guest589745]

But steroids get directed into the bloodstream without entering the kidneys really I thought ?

[guest589745]

" In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression."


"Chenodeoxycholic acid is a bile acid, a white crystalline substance insoluble in water, with melting point at 165-167 °C. Its salts is called chenodeoxycholates. Chenodeoxycholic acid is one of the 4 main organic acids produced by the liver. It is soluble in alcohol and acetic acid.

Chenodeoxycholic acid is synthetized in the liver from cholesterol.

Chenodeoxycholic acid and cholic acid are the most important human bile acids. Some other mammals synthetize predominantly deoxycholic acid.


http://www.pnas.org/cgi/content/full/98/24/13895


"Steroids destined for intracellular metabolic conversion or binding to nuclear receptors are believed to cross cell membranes by passive diffusion. According to this free hormone hypothesis, steroids bound to plasma carrier proteins are inactive because they cannot reach their intracellular targets (1). However, recent data show that carrier proteins may greatly facilitate steroid uptake by endocytosis of steroid-carrier complexes followed by intracellular release of the steroid (2, 3). Megalin, a member of the low density lipoprotein receptor family abundant in kidney proximal tubules, mediates endocytic uptake of complexes between the steroid 25(OH) vitamin D3 [25(OH)D3] and vitamin D-binding protein (DBP) filtered in the glomeruli. The receptor-mediated uptake is required to prevent loss of 25(OH)D3 in the urine and to deliver the precursor for generation of 1,25(OH)2 vitamin D3 [1,25(OH)2D3], a potent regulator of calcium homeostasis and bone turnover. Accordingly, megalin knockout mice lose DBP and 25(OH)D3 in the urine and develop severe vitamin D deficiency and bone disease (2

The Australian biotechnology company Giaconda has developed a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.
"

[Warrior21]

Nice finding. Keep in mind in vitro though. In vivo more accurate for us. But hell I'll look it up more man.

check here for some good info, I sent them an email already;

http://www.recepticon.com/introduction.htm

[Warrior21]

Originally Posted by Skullsmasher

" In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression."


"Chenodeoxycholic acid is a bile acid, a white crystalline substance insoluble in water, with melting point at 165-167 °C. Its salts is called chenodeoxycholates. Chenodeoxycholic acid is one of the 4 main organic acids produced by the liver. It is soluble in alcohol and acetic acid.

Chenodeoxycholic acid is synthetized in the liver from cholesterol.

Chenodeoxycholic acid and cholic acid are the most important human bile acids. Some other mammals synthetize predominantly deoxycholic acid.

The Australian biotechnology company Giaconda has developed a treatment for Hepatitis C infection that combines chenodeoxycholic acid with bezafibrate.
"

Dude you're a badass. I bet in a week we have this huge puzzle solved. I'm going to start Clomid tommorow, research more, gear up, and then hit it again....and gain! Were going to tear shit up man! Damn I'm getting too riled up it's 12:30 lol.

[guest589745]

Im finding shit but getting relatively nowhere in terms of discovering how to increase the absorption and or effects of intramuscularly administered steroids.

[Warrior21]

Megalin-deficient mice could not absorb exogenous steroids. Wouldn't it be pretty accurate to assume that increasing Megalin would help absorb exogenous steroids?

[guest589745]

Suppose so. Where did you find that statement? I must have missed it.

[Warrior21]

Conventional dogma holds that steroid hormones traverse cell membranes passively, owing to their lipophilic nature. The recently characterized protein megalin, however, functions as a transport protein on cell surfaces to carry steroids across the plasma membrane. Upon hydrolysis of steroid-associated binding globulins in lysosomes, free hormone is liberated and may exert its effects in the cell. Megalin-independent mechanisms of steroid uptake are likely important too, as the phenotypes of megalin-deficient mice do not completely mimic the phenotypes of androgen receptor- or estrogen receptor-null mice.

[stupidhippo]

on my way to schol so dont have the time to read the whole thread but if that would be your problem u would have other signs of hypogonadism.. i doubt that u are on to sumin here..

[Warrior21]

Originally Posted by Skullsmasher

Suppose so. Where did you find that statement? I must have missed it.

Further, megalin-deficient embryonic tissues were resistant to the effects of exogenous androgens. Thus, the authors conclude that megalin plays a role in the cellular uptake of carrier-bound sex steroids that is critical to the proper development of steroid-responsive tissues.

[guest589745]

Ugh, I dont get it really.

[Warrior21]

Originally Posted by stupidhippo

on my way to schol so dont have the time to read the whole thread but if that would be your problem u would have other signs of hypogonadism.. i doubt that u are on to sumin here..

They specified resistance only to exogenous steroids. I would have to make sure that Megalin deficiency can pertain to endogenous as well. I've thought about that though.

[Warrior21]

Originally Posted by Skullsmasher

Ugh, I dont get it really.

Read post #18. Keep in mind exogenous means "not from the body" or, "out of the body". I'm basically resistant to exogenous steroids as well. If this is caused by Megalin deficiency, I don't think Im too out of line to think I'm Megalin deficient.

I'm just looking at it from every possible angle.

And take it for what it's worth. In my ethnic background we have "Babalowu's". Basically they are born with a gift and spirits talk to them. The spirits told her that I'm deficient in something. She just couldn't pinpoint it. For her sake, she also told us my father wasn't well. He dosen't complain much. Turns out he had a heart attack one week prior, he had been living in terrible pain. He never said anything. We rushed him to the hospital, where the told us he suffered a heart attack.

[guest589745]

I get it now, hippo made a point but then you made a point on his point too, lol.

[Warrior21]

Originally Posted by Skullsmasher

I get it now, hippo made a point but then you made a point on his point too, lol.

hehe, always thinking. Hippo also said he did not read the whole thing due to time constraints. I know he's a good guy and will come back to chime in eventually. Poor guy has to go to school, now? Damn he's more hardcore than us!

[Warrior21]

Role of endocytosis in cellular uptake of sex steroids.Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE.
Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.

Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.

PMID: 16143106 [PubMed - indexed for MEDLINE]

[Kale]

Skull is that you in you Avi ?

[Warrior21]

Night guys, night SKull. Gotta be awake in 5 hours. When I wake up hopefully that company will have replied to me. I guess when I have free time tommorow I'll be grinding on Megalin. We have to find out where we can get that acid that increases megalin, and find other things to increase it too.

Keep in mind those studies show rats with no Megalin whatsoever. Maybe we have a bit, just are deficient in it.

[Unoid]

So...

WE WANT megalin to increase our muscles.
but we want LESS megalin becuase it will incrase gyno and prostate problems.

....

[Warrior21]

Yes Unoid. We want something to increase Megalin while on cycle. When we get off we can revert back to our normal Megalin levels.

[stupidhippo]

Originally Posted by Warrior21

They specified resistance only to exogenous steroids. I would have to make sure that Megalin deficiency can pertain to endogenous as well. I've thought about that though.

as far as I have read this thread I haev come to the conclusion that its no differnet if its exo or endogenous test in this case... It just says it applies also to exogenous.. second thing: do we know how much muscle cells are dependant on this megalin uptake pathway? I mean there is talk about the kideneys, embryo etc.. but to what I have read the expression of the megalin proteins is very tissue specific.. third: dow e know that if there are any compensatory mechanims if indeed this megalin acticity can be altered? there are so many open questions here and I once again feel like u have too high hopes for this... but Im keeping my fingers crossed..

[stupidhippo]

Originally Posted by Warrior21

They specified resistance only to exogenous steroids. I would have to make sure that Megalin deficiency can pertain to endogenous as well. I've thought about that though.

ˇ
this is not the picture Ive got from reading ur posts.. they jst said in one part that it also applies to exogenous steroids.

[Warrior21]

Originally Posted by stupidhippo

as far as I have read this thread I haev come to the conclusion that its no differnet if its exo or endogenous test in this case... It just says it applies also to exogenous.. second thing: do we know how much muscle cells are dependant on this megalin uptake pathway? I mean there is talk about the kideneys, embryo etc.. but to what I have read the expression of the megalin proteins is very tissue specific.. third: dow e know that if there are any compensatory mechanims if indeed this megalin acticity can be altered? there are so many open questions here and I once again feel like u have too high hopes for this... but Im keeping my fingers crossed..

I'm keeping my fingers crossed as well...thank you brother. Some articles state Megalin is very tissue specific, other contradict this. The problem here is that Megalin was discovered in 2005. There is not much research out for it yet.
Skullsmasher did post a way to increase Megalin however. Dosen't hurt to try does it? Also I will look into Cubulin as well. It seems Cubulin works with Megalin.
Well I'm off to call the clinic/endocrinologists.

[stupidhippo]

u mentioned sumin about the steroids not reaching ur bloodstream.. that is also a bit unlogical to me. let me clarify: the gear is freed into the circulation and since it is bound to SHBG (or most of it) it shouldnt be filtrated to the glomerular ultrafiltrate in the kidneys and therfore wouldnt be susceptible to excretion by kidneys (being a relatively large protein it should stay in the blood)

[Warrior21]

Originally Posted by stupidhippo

u mentioned sumin about the steroids not reaching ur bloodstream.. that is also a bit unlogical to me. let me clarify: the gear is freed into the circulation and since it is bound to SHBG (or most of it) it shouldnt be filtrated to the glomerular ultrafiltrate in the kidneys and therfore wouldnt be susceptible to excretion by kidneys (being a relatively large protein it should stay in the blood)

I thought Megalin binded steroid hormones to androgen receptors/SHBG? Your the one whos a doctor right? I'm glad I got you on my team man.

[stupidhippo]

how I understood it is that megalin binds the steroid/SHBG complex and uptakes that complex into the cell.. from what I understood this has nothing to do with free test levels.. but it did indicate that SHBG complex endocytosized would be disintegrated inside the cell thus freeing free test inside the cell... as far as the clinical implication of this thing its pretty much a mystery to me. this thread was the first i heard of this megalin.

[Warrior21]

Originally Posted by stupidhippo

how I understood it is that megalin binds the steroid/SHBG complex and uptakes that complex into the cell.. from what I understood this has nothing to do with free test levels.. but it did indicate that SHBG complex endocytosized would be disintegrated inside the cell thus freeing free test inside the cell... as far as the clinical implication of this thing its pretty much a mystery to me. this thread was the first i heard of this megalin.

Megalin was just discovered late into 2005. I hope theres more doctors out there who know about this. I might be in for a 5-10 year wait if Megalin is my case.

[Iron-man]

Warrior21 or Skullsmasher, are either of you on Cholesterol lowering meds....just a thought. May mean nothing, but.....

[Warrior21]

Nope. My cholesterol has been low as hell for years though. Any thoughts on this? I do eat my oatmeal everyday =-)

[Warrior21]

Whoops. Upon further reflection...it seems that Megalin takes steroids to hormone dependat tissues only (I.E. penis,vagina,prostate, breasts). I'm not sure how much Megalin has to do with uptake of skeletal muscles.

It seems there are other mechanisms for steroid homrone uptake. Can people help me research these other ones? Maybe I have a faulty uptake mechanism.

[FITFANATIK]

Originally Posted by Warrior21

Megalin was just discovered late into 2005. I hope theres more doctors out there who know about this. I might be in for a 5-10 year wait if Megalin is my case.

jeez....serious read! Once is not enough! Thanks for sharin'...might wanna get a patent on your new supp...sounds promising!

...I want some!

[stupidhippo]

Originally Posted by Warrior21

Whoops. Upon further reflection...it seems that Megalin takes steroids to hormone dependat tissues only (I.E. penis,vagina,prostate, breasts). I'm not sure how much Megalin has to do with uptake of skeletal muscles.

It seems there are other mechanisms for steroid homrone uptake. Can people help me research these other ones? Maybe I have a faulty uptake mechanism.

doesnt the normal mechanism just have free test diffusing into the cell were it binds to the AR which then in turn go into the nucleus of the cell..