[Lotus]

Clelia,
The part of the re-absorption might come from Aldo-keto reductases (AKRs), what do you think?.
Example:

Type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2, aka-AKR acts solely as a reductase to convert 5alpha-dihydrotestosterone (DHT), a potent ligand for the AR

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It's like deconstructing a model (call it a airplane model) that someone else built, only you're working in reverse to deconstruct right. Same applies here, you see a study that states 5 alpha reductase is reduced in the liver, now maybe this study was for cancer research or something similar. Let's take one of these studies,

Role of human type 3 3alpha-hydroxysteroid dehydrogenase (AKR1C2) in androgen metabolism of prostate cancer cells.

Aldo-keto reductases (AKRs) is another superfamily class of enzymes like the Cytochrome P450 enzyme super family, which are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

AKRs are involved in the development and progression of many cancers, as well as chemotherapeutic drug resistance. AKR1B1 and AKR1B10 are overexpressed in tumors, such as liver, breast, and lung cancer. Several AKRs (AKR1A1, AKR1B10, and AKR1C1-3) are involved in tobacco-carcinogenesis, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. In addition, AKR1C1-3 enzymes play a key role in the regulation of proliferative signaling in hormone dependent cancers.

So what they did in this study was to cut off the androgen synthesis to the receptors using another steroid , Four human aldo-keto reductases (AKRs) that belong to the AKR1C subfamily function in vitro as 3-keto-, 17-keto- and 20-ketosteroid reductases or as 3alpha-, 17beta- and 20alpha- hydroxysteroid oxidases to varying degrees. By acting as ketosteroid reductases or hydroxysteroid oxidases these AKRs can either convert potent sex hormones (androgens, estrogens and progestins) into their inactive metabolites or they can form potent hormones by catalyzing the reverse reaction. In this manner they may regulate occupancy and trans-activation of steroid hormone receptors.

In English, I want to find the link to activate AKR1c in the liver to shut off the androgen receptors therefore DHT never gets activated, simple right?.

Regulates access of 5alpha-DHT to the androgen receptor.

Abstract
Pairs of hydroxysteroid dehydrogenases (HSDs) govern ligand access to steroid receptors in target tissues and act as molecular switches. By acting as reductases or oxidases, HSDs convert potent ligands into their cognate inactive metabolites or vice versa. This pre-receptor regulation of steroid hormone action may have profound effects on hormonal response. We have identified the HSDs responsible for regulating ligand access to the androgen receptor (AR) in human prostate. Type 3 3alpha-hydroxysteroid dehydrogenase (aldo-keto reductase 1C2, aka-AKR acts solely as a reductase to convert 5alpha-dihydrotestosterone (DHT), a potent ligand for the AR (K(d)=10(-11)M for the AR), to the inactive androgen 3alpha-androstanediol (K(d)=10(-6)M for the AR); while RoDH like 3alpha-HSD (a short-chain dehydrogenase/reductase (SDR)) acts solely as an oxidase to convert 3alpha-androstanediol back to 5alpha-DHT. Our studies suggest that aldo-keto reductase (AKRs) and SDRs function as reductases and oxidases, respectively, to control ligand access to nuclear receptors.
http://www.ncbi.nlm.nih.gov/pubmed/17223255

Notice how Aldo-keto reductases (AKRs) position themselves between DHT and 3-diols, this is where the estrogenic action takes place. These actions of AKR1C's takes place in androgen metabolism of the prostate.

Aldo-keto reductases (AKRs) is another superfamily class of enzymes like the Cytochrome P450 enzyme super family.






Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer

Estrogen receptor β (ERβ) is activated in the prostate by 5α-andros- tane-3β,17β-diol (3β-Adiol) where it exerts antiproliferative activity. The proliferative action of the androgen receptor is activated by 5α- dihydrotestosterone (DHT). Thus, prostate growth is governed by the balance between androgen receptor and ERβ activation. 3β- Adiol is a high-affinity ligand and agonist of ERβ and is derived from DHT by 3-keto reductase/3β-hydroxysteroid dehydrogenase en- zymes. Here, we demonstrate that, when it is expressed in living cells containing an estrogen response element-luciferase reporter, 17β-hydroxysteroid dehydrogenase type 6 (17βHSD6) converts the androgen DHT to the estrogen 3β-Adiol, and this leads to activation of the ERβ reporter. This conversion of DHT occurs at concentrations that are in the physiological range of this hormone in the prostate. Immunohistochemical analysis revealed that 17βHSD6 is expressed in ERβ-positive epithelial cells of the human prostate and that, in prostate cancers of Gleason grade higher than 3, both ERβ and 17βHSD6 are undetectable. Both proteins were present in benign prostatic hyperplasia samples. These observations reveal that for- mation of 3β-Adiol via 17βHSD6 from DHT is an important growth regulatory pathway that is lost in prostate cancer.

http://www.ncbi.nlm.nih.gov/pmc/articles...117772.pdf

[Lotus]

The estrogenic DHT response, I wonder if we're seeing a possibility of any links to mammary DHT?. I mean, if we can explain it in normal function of the male reproductive tract and aquaporins what's the next logical step?, aromatase??, mammary DHT's???.

From an earlier post,

DHT has an estrogenic action,

The existence of this estrogenic DHT metabolite has raised the possibility that estradiol may not be the major estrogen in males [29]. For instance, in the prostate there is a growing body of evidence that 3β-diol, acting through ERβ, may regulate important physiological events.


Recent data have shown that DHT may be converted into 5α-androstane- 3β-17β-diol (3β-diol) in a virtually irreversible reaction. Once considered inactive, 3β-diol is present in high concentrations in the male and indeed has biological activity. However, 3β-diol does not bind to the androgen receptor (AR), but rather to ERα and ERβ, with higher affinity for ERβ. Based upon these findings, we hypothesized that the modulation of AQP9 by DHT could be indirectly mediated by 3β-diol.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1615873/


Effects of 3-beta-diol, an androgen metabolite with intrinsic estrogen-like effects,

Abstract

Background: Fluid homeostasis is critical for normal function of the male reproductive tract and aquaporins (AQP) play an important role in maintenance of this water and ion balance. Several AQPs have been identified in the male, but their regulation is not fully comprehended. Hormonal regulation of AQPs appears to be dependent on the steroid in the reproductive tract region. AQP9 displays unique hormonal regulation in the efferent ductules and epididymis, as it is regulated by both estrogen and dihydrotestosterone (DHT) in the efferent ductules, but only by DHT in the initial segment epididymis. Recent data have shown that a metabolite of DHT, 5-alpha- androstane-3-beta-17-beta-diol (3-beta-diol), once considered inactive, is also present in high concentrations in the male and indeed has biological activity. 3-beta-diol does not bind to the androgen receptor, but rather to estrogen receptors ER-alpha and ER-beta, with higher affinity for ER-beta. The existence of this estrogenic DHT metabolite has raised the possibility that estradiol may not be the only estrogen to play a major role in the male reproductive system. Considering that both ER-alpha and ER-beta are highly expressed in efferent ductules, we hypothesized that the DHT regulation of AQP9 could be due to the 3-beta-diol metabolite.

Methods: To test this hypothesis, adult male rats were submitted to surgical castration followed by estradiol, DHT or 3-beta-diol replacement. Changes in AQP9 expression in the efferent ductules were investigated by using immunohistochemistry and Western blotting assay.

Results: Data show that, after castration, AQP9 expression was significantly reduced in the efferent ductules. 3- beta-diol injections restored AQP9 expression, similar to DHT and estradiol. The results were confirmed by Western blotting assay.

Conclusion: This is the first evidence that 3-beta-diol has biological activity in the male reproductive tract and that this androgen metabolite has estrogen-like activity in the efferent ductules, whose major function is the reabsorption of luminal fluids.





a) It has been shown that 3β-diol may have hormonal activity, not acting through the AR, but rather as a ligand for both ERα and ERβ.

b) 3β-diol has higher affinity for ERβ [31], which is abundant in the efferent ductule epithelium [40].

c) In human testis, the 3β-diol concentration is higher than DHT and estradiol [44,45]. It is reasonable to postulate that high concentrations of this metabolite may enter the lumen of efferent ductules.

d) The existence of this estrogenic DHT metabolite has raised the possibility that estradiol may not be the major estrogen in males [29]. For instance, in the prostate there is a growing body of evidence that 3β-diol, acting through ERβ, may regulate important physiological events [26,28,32,46].

Also noteworthy is the fact that 3β-diol stimulates ERβ induced transcriptional activity equal to the cognate ligand estradiol, and the transcriptional selectivity of 3β-diol for ERβ is much greater than its binding selectivity [30,46]

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Concentrations of aromatase and estradiol in the prostate are low, indicating that estradiol may not be the only estrogenic molecule to play a role in the prostate. It is known that DHT can be metabolized to 5alpha-androstane-3beta,17beta-diol (3beta-diol), a hormone that binds to ERbeta but not to AR. The concentration of 3beta-diol in prostate is much higher than that of estradiol. Based on the high concentration of 3beta-diol and since this metabolite is a physiological ERbeta ligand, we hypothesized that 3beta-diol would be involved in the regulation of ERbeta expression.





An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth.
http://www.ncbi.nlm.nih.gov/pubmed/12370428

[Lotus]

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As you can see the pathway for Testosterone, Approximately 7% of testosterone is reduced to 5α-dihydrotestosterone (DHT) by the cytochrome P450 enzyme 5α-reductase, an enzyme highly expressed in male sex organs and hair follicles. Approximately 0.3% of testosterone is converted into estradiol by aromatase (CYP19A1) an enzyme expressed in the brain, liver, and adipose tissues. Note-the percentages are slightly off, (multiple sources).

By inhibiting the enzyme 5-alpha reductase and promoting the enzyme aromatase along with your choice phytoestrogens or pharma E is key for breast growth in bio-males.

Herbs that convert aromatase-White Peony, Liorice root, Genistein (PM), BO.

Herbs that help block 5 ar, Licorice root, WP, Reishi, SP, pygeum, nettle root (NR is tricky though), BO (not an herb), chinese skullcap, linolenic acid, green tea, progesterone cream is a strong 5 ar, pumpkin seed oil, linolenic acid.

(Pharma-Dutasteride and Finasteride). Both finasteride and dutasteride undergo extensive hepatic metabolism primarily via the cytochrome P450 3A4 (CYP 3A4) isoenzyme system.

Bruno deLignieres, an impeccable French researcher and Thiery Hertoghe, MD, fourth generation in the most distinguished family of endocrinologists in Belgium, have put forth the notion that rising estrogen levels are more likely to be the initiator of the process and that testosterone and DHT may then be a secondary player (promoter). In fact, phytotherapy (large doses of phytoestrogens - soy) is commonly used in European medical practices to treat BPH.

(Jonathan Wright and Eugene Shippen have written excellent, and popular books, discussing these more far-sighted notions all too commonly overlooked and even rejected in current conventional American Medical thinking.)

Testosterone is reduced by the enzyme 5-a-reductase to DHT which is then thought to be the real culprit. The argument between the use of Saw Palmetto, Pygeum and Pumpkin seeds vs Proscar are both directed at blocking this enzyme. Strangely, DHT is most important for sexual vigor, so blocking this step may have some unintended consequences!

On the other hand, Testosterone is also converted into estradiol by aromatase (producing the aromatic ring). This occurs increasingly with age in the liver but most importantly ... in the fat stores.

http://www.antiaging.com/andropause/andropause2.html

Its been stated here before that the Androgen to Estrogen pathway is easier than the Testosterone to Estrogen pathway, and once again aromatase continues to demonstrate the factual evidence.

A couple of French researchers recently reported this:

Testosterone is reduced by the enzyme 5-a-reductase to DHT which is then thought to be the real culprit. The argument between the use of Saw Palmetto, Pygeum and Pumpkin seeds vs Proscar are both directed at blocking this enzyme. Strangely, DHT is most important for sexual vigor, so blocking this step may have some unintended consequences!

On the other hand, Testosterone is also converted into estradiol by aromatase (producing the aromatic ring). This occurs increasingly with age in the liver but most importantly ... in the fat stores.
Now you see the connection. As we age, and frequently gain increasing fat stores, we are feeding the aromatase connection, increasing our estradiol levels and if this theory holds, increasing the promotion of prostate disease.

Also that rising estrogen levels are more likely to be the initiator of the process and that testosterone and DHT may then be a secondary player (promoter). In fact, phytotherapy (large doses of phytoestrogens - soy) is commonly used in European medical practices to treat BPH.

Another example of the androgen/estrogen pathway:



http://www.antiaging.com/andropause/andropause2.html

[/quote]

[Lotus]

Here's a great example of the DHT process, my question has always been the preferential binding process, e.g.what influences steroids choice of pathway to aromatase or DHT. According to the above chart it states 7% to DHT and .03% to aromatase without any influence from meds. Id like to see more information (numbers) on the conversion process, and what percentage are certain meds influence, e.g. when meds are introduced how "much" (in concentrations) are shifted?. Imo, that's the $64,000 dollar question, solve that and it opens the door to breast growth, and other conditions too. In men, prostate cancer is ER mediated.




   

[Lotus]

For what's it worth?, imo, part of the answer is correlated with the enzymatic super families.

AKR 1C2 (aldo-keto reductase)
17b HSD (hydroxysteroid dehydrogenase)
3b HSD (hydroxysteroid dehydrogenase)
11b HSD (hydroxysteroid dehydrogenase)
21OH (hydroxylase)

Otherwise known as the "gate keepers".

[Lotus]

well done Lotus, these findings about ER receptor, are very interesting!

Thank you Clelia, I agree.

Differences in physiology can explain different results with the same compound (ex. Genistein), also our receptors exist in "strong or weak version", then more ore less signal response to molecules.

Ok, like partial receptor binding, thanks.

Moreover, there is 35% of population that has not the enzimatic process which converts and activate genisteine and daidzeine (they both need to cut off the glycone, to be active), this occurs in the gut.

Cool, I'd like to understand this more. What's also interesting is how upon excertion steroids are water soluble.

Phytoestrogen also act in opposite way, before and after menopause. I will report links later, because im using a mobile now. We need to make things clear, from the whole information. See you!

Ok great, thanks. till later.

[Lotus]

One way in which a glucose carrier can be driven by a Na+ gradient
http://www.ncbi.nlm.nih.gov/books/NBK268...objectonly

Carrier Proteins and Active Membrane Transport
In these systems, the solute and Na+ bind to different sites on a carrier protein. Because the Na+ tends to move into the cell down its electrochemical gradient, the sugar or amino acid is, in a sense, “dragged” into the cell with it. The greater the electrochemical gradient for Na+, the greater the rate of solute entry; conversely, if the Na+ concentration in the extracellular fluid is reduced, solute transport decreases.
http://www.ncbi.nlm.nih.gov/books/NBK26896/



sugar or amino acid is, in a sense, “dragged” into the cell with it, ok.....so sugar and amino acids up-regulates ion channels and NA+ down regulates?.

[-Clelia-]

hi there

I wanted to edit a post but i cannot anymore...
i found mistakes here:

"my thoughs are: if DHT (and metabolite) is more androgenic, then estrogenic in breast tissue, than it could be helpful low it."-->
i meant: "my thoughs are: if DHT (and metabolite) is more androgenic than estrogenic in breast tissue, then it could be helpful low it"

sorry about that :-/ i'm not mothertongue

[-Clelia-]

lotus, you reported:
"Concentrations of aromatase and estradiol in the prostate are low, indicating that estradiol may not be the only estrogenic molecule to play a role in the prostate. It is known that DHT can be metabolized to 5alpha-androstane-3beta,17beta-diol (3beta-diol), a hormone that binds to ERbeta but not to AR. The concentration of 3beta-diol in prostate is much higher than that of estradiol. Based on the high concentration of 3beta-diol and since this metabolite is a physiological ERbeta ligand, we hypothesized that 3beta-diol would be involved in the regulation of ERbeta expression."

and that's fine, but... you know that this is not the case in male breast tissue, otherwise you should have breast growth like bio-female...
in men there is more androgenic expression than the estrogenic one. Maybe estradiol is not the only estrogen, but the DHT metabolite "3-b-diol" isn't enough to gain breast growth in biomale breast tissue.
I think that DHT is not converted to the "estrogen-like metabolite" in the breast, at least not in the same amount as it is in the prostate.

So that's why i think that is better low DHT for breast growth

[-Clelia-]

Moreover, there is 35% of population that has not the enzimatic process which converts and activate genisteine and daidzeine (they both need to cut off the glycone, to be active), this occurs in the gut.

Cool, I'd like to understand this more. What's also interesting is how upon excertion steroids are water soluble.

sorry, i was wrong, the correct pathway is: 35% of population can convert daidzein and genistein to the active compound "equol".
(glycone is cut off by everyone, i think)
i'm sorry but the source is in italian, i didnt find it yet in english:
http://www.iss.it/binary/cnra/cont/ALIME...270810.pdf
(page 18)


"What's also interesting is how upon excertion steroids are water soluble"-->
mmh... why do you want to know that? for transport?