5a-dehydroprogesterone And 3a- Hydroxysteroid Dehydrogenase

[Drareg]

Sorry i did not understand but what exactly does displacing DHT mean here(displacing from what)?

That what's I was asking in the first question about the enzyme converting DHT into a less potent form,I was guessing the enzyme must displace the DHT before conversion takes place,not all will get converted that quick leaving some free DHT.
I don't really understand the complexity of enzymes so I'm guessing,I'm not sure their are many who do right now particularly when they can possibly "quantum tunnel ".
Targeted light frequencies might be the best way to influence them hence the red light for hair loss,it may need a more specific wavelength,all devices despite claims are not always accurate.

 

[Dante]

That what's I was asking in the first question about the enzyme converting DHT into a less potent form,I was guessing the enzyme must displace the DHT before conversion takes place,not all will get converted that quick leaving some free DHT.
I don't really understand the complexity of enzymes so I'm guessing,I'm not sure their are many who do right now particularly when they can possibly "quantum tunnel ".
Targeted light frequencies might be the best way to influence them hence the red light for hair loss,it may need a more specific wavelength,all devices despite claims are not always accurate.

Interesting point about quantum tunneling . May i ask where you read that (any link to the paper)?

 

[LeeLemonoil]

A new review (Nature) about 3ß-diol in prostate cancer. Also discussed are several roles of the DHT-metabolites and precursors, highly relevant read:
Dihydrotestosterone synthesis pathways from inactive androgen 5α-androstane-3β,17β-diol in prostate cancer cells: Inhibition of intratumoural 3β-hydroxysteroid dehydrogenase activities by abiraterone : Scientific Reports

 

[Drareg]

Interesting point about quantum tunneling . May i ask where you read that (any link to the paper)?

This is a quick overview.
My guess is it's something else.
http://www.the-scientist.com/?artic...s-Evolve-to-Capitalize-on-Quantum-Tunneling-/

 

[haidut]

A new review (Nature) about 3ß-diol in prostate cancer. Also discussed are several roles of the DHT-metabolites and precursors, highly relevant read:
Dihydrotestosterone synthesis pathways from inactive androgen 5α-androstane-3β,17β-diol in prostate cancer cells: Inhibition of intratumoural 3β-hydroxysteroid dehydrogenase activities by abiraterone : Scientific Reports

At the same time, a synthetic version of 3a-androstandeiol is being patented and sold as treatment for prostate cancer. So, while the pharma industry will publish nonsense to scare you of the natural steroid, they will at the same time sell you a synthetic (and probably toxic) version of the same steroid for the same condition they warned you about.
3α-Androstanediol - Wikipedia
"...An orally active synthetic analogue of 3α-androstanediol, 17α-ethynyl-5α-androstane-3α,17β-diol (HE-3235, Apoptone), was formerly under investigation for the treatment of prostate cancer and breast cancer."

That same study references in the Wikipedia quote above also found potent reductions in all estrogens after administering that steroid, which would explain both its effects against both prostate and breast cancer.
17α-alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism. - PubMed - NCBI
"...Investigation of the steroidogenic enzymes indicated there was no HE3235 mediated enzyme inhibition. We note that a preliminary experiment in female rats indicated that HE3235 also dramatically reduced plasma concentrations of estradiol and estrone, without an apparent effect on plasma levels of LH, FSH, and ACTH (unpublished observations)."

So, DHT and androsterone (both are precursors of androstanediol) FTW!

 

[Dante]

A new review (Nature) about 3ß-diol in prostate cancer. Also discussed are several roles of the DHT-metabolites and precursors, highly relevant read:
Dihydrotestosterone synthesis pathways from inactive androgen 5α-androstane-3β,17β-diol in prostate cancer cells: Inhibition of intratumoural 3β-hydroxysteroid dehydrogenase activities by abiraterone : Scientific Reports

Lol, now they are trying to inhibit 3β-HSD . It's interesting where they say 3β-HSD is a bidirectional enzyme
with conversion of 3β-diol to DHT in presence of ample NAD+. That would make it similar to 3a-HSD. It's very interesting when they acknowledge the anti-cancer and pro-differentiating properties of 3β-diol but at the same time they try to inhibit it's production (just because at very high doses to extracted and cultured PCa cell lines, it can convert back to DHT!!)

 

[LeeLemonoil]

Some thoughts on the high 3ß-HSD expression in MPB sebaceius glands:

First, that does not mean 3ß-diol is anyway a "harmful" steroid - as with DHT, it might really be a genetic thing that makes some specialized tissue react different to some hormones.

Counter-intuitively, high 3ß-HSD expression in balding areas could also mean that the tissue trie to compensate against high DHT-sensitivity by upregulating 3ßHSD, thus trying to prevent strong hairloss by degrading DHT - this mechanism might in part be the reason for different levels of severity and speed of hairloss. Individuals with genetic hairloss (DHT-sensitivity) might differ in the activity of 3ß-HSD in these tissue and thus experience different patterns of hairloss. This theory would mean 3ß-diol/3ß-HSD is a "protective" thing in those tissues.

What is striking about the study already posted above (http://www.biomed.cas.cz/physiolres/pdf/64 Suppl 2/64_S275.pdf) is that 3ß-diol is present in the serum of healthy individuals as it's glucoronide, in much higher quantities than in men with affective disorders.
Curiously, most other steroids are sulfated when they get conjugated. To understand the role of 3ß-diol it would be important to know why it gets glucoronidated instead.
I've read a paper that de novo synthesized steroids in the brain diffuse from the brain into circulation via BBB in higher quantities than vice versa. Steroid-sulfates are likely the primary neuractive steroids, as the linked up study also indicates - quite consequenty, the brain synthesizes them and gives off higher levels into serum in healthy individuals.

 

[LeeLemonoil]

And because this thread also discusses SHGB, here is an intriguing write-up on it's role:
Understanding SHBG

 

[TubZy]

As always, respect. Now The bolded lines become very important from MPB point of view. I would not be surprised if the enzyme 3a-HSD(at the follicle level) is somehow towards its reductive side while 3b-HSD is also impaired (due to lack of thyroid,NAD+,other factors etc) ,hence the buildup of DHT there simply because it is not getting properly broken down into further metabolites.
I have read some odd reports on MB regrowing hair back. There was a user BenjaminButton who literally changed from near Norwood 4 to somewhere near Norwood 3 after adding thyroid and sugar. Does topical niacinamide also help ? However , he also got a massive shed while taking androsterone. So, does taking androsterone could exert a negative feedback loop on the 3a-HSD or deplete NAD+ or something like that? (BTW small amounts of estradiol is also needed for hair growth especially in the anagen phase if i remember but i guess you already know this)

You have the link for the MB hair reports?

 

[mujuro]

And because this thread also discusses SHGB, here is an intriguing write-up on it's role:
Understanding SHBG

That post was ripped from a private forum that I was a part of. It doesn't exist anymore. It was a really great place.

 

[TubZy]

Niacinamide definitely improves my hair for sure both topically and orally. The amount in Solban was too low though. I had to use 250mg or more (better results with 500mg). I tried MB topically (oxidial) only two drops and my hair looked darker the next day. I never combined them but perhaps the NAD activity does have to do with something...

I never combined niacinamide and MB however..

 

[TubZy]

The 3a-HSD is what converts the 5a-DHP into allopregnanolone, as you said, and it is also responsible for the reversible conversion of DHT into androstanediol as well as androsterone into androstanedione. It is a bi-directional enzyme, it has a reductive and oxidative function. It has been shown that in aging the reductive side of 3a-HSD increases while the oxidative one decreases. This is not surprising since the oxidative side needs NAD as cofactor while the reductive one needs NADH, and the NAD/NADH raio declines with age. Supplementing niacinamide or MB can reverse that pattern.
I would not call 3a-HSD a deactivating enzyme. Reality is much richer than what the simplistic modern endocrinology would have you believe. Some of these "inactive" metabolites of DHT like androstanediol are actually what drives much of the protective effects of DHT observed clinically.
3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats. - PubMed - NCBI

Same with androsterone - it may very well be the most pro-thyroid of all androgens and it is considered "inactive" by most endocrinologists. There are no inactive metabolites, if something is truly inactive it gets excreted or stored. If it gets metabolized into something else then it is not inactive and has some kind of role in the health of the organism. If thyroid promotes 3a-HSD activity it should be in indication enough that the steroids it produces are probably very important. In contrast, thyroid inhibits aromatase. Aging and and boredom inhibit while environmental stimulation promotes both 5-AR and 3a-HSD.
Environmental enrichment attenuates the age-related decline in the mRNA expression of steroidogenic enzymes and reduces the methylation state of th... - PubMed - NCBI

How does nicotine increase allopreg if it inhibits 3a hsd and by inhibitng that enzyme would possibly upregulate it?

 

[haidut]

How does nicotine increase allopreg if it inhibits 3a hsd and by inhibitng that enzyme would possibly upregulate it?

Where did I say nicotine increases allopreg?

 

[TubZy]

Where did I say nicotine increases allopreg?

Never mentioned you said anything, was just asking

Neurosteroids in nicotine and morphine dependence. - PubMed - NCBI

 

[haidut]

Never mentioned you said anything, was just asking

Neurosteroids in nicotine and morphine dependence. - PubMed - NCBI

That study basically says nicotine is a stressor, the increase in neurosteroids is adaptive, and its effects are blocked by adrenalectomy. I don't think nicotine has any direct effects on increasing steroidogenesis.
"...CONCLUSIONS: Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear."

Also, can you please elaborate on nicotine inhibiting 3a-HSD?

 

[TubZy]

That study basically says nicotine is a stressor, the increase in neurosteroids is adaptive, and its effects are blocked by adrenalectomy. I don't think nicotine has any direct effects on increasing steroidogenesis.
"...CONCLUSIONS: Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear."

Also, can you please elaborate on nicotine inhibiting 3a-HSD?

That study basically says nicotine is a stressor, the increase in neurosteroids is adaptive, and its effects are blocked by adrenalectomy. I don't think nicotine has any direct effects on increasing steroidogenesis.
"...CONCLUSIONS: Changes in neurosteroid concentrations mediated by activation of the HPA axis may both contribute to the early acquisition phase of nicotine or morphine addiction and serve to counteract the anxiety-like behavior associated with nicotine or morphine withdrawal. However, the evidence that nicotine withdrawal did not increase neurosteroids, unless precipitated by mecamylamine, suggests that the role of these neurosteroids in spontaneous nicotine withdrawal may not be clear."

Also, can you please elaborate on nicotine inhibiting 3a-HSD?

I see, do you think nicotine has any effects on 5AR similar to caffeine or neurosteroids in general? I notice a mild androgenic effect after using it.

Here is the one on 3a HSD
Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate. - PubMed - NCBI

 

[haidut]

I see, do you think nicotine has any effects on 5AR similar to caffeine or neurosteroids in general? I notice a mild androgenic effect after using it.

Here is the one on 3a HSD
Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate. - PubMed - NCBI

It is hard to say how much of the androgenic effect of nicotine is from direct influence on 5-AR and how much is due to its elevating levels of pregnenolone, progesterone, DHEA, etc. In low doses it is probably OK but nicotine is a beta agonist and used systemically it increases lipolysis. I think its main benefit is its mildly dopaminergic effect in the brain.

 

[TubZy]

It is hard to say how much of the androgenic effect of nicotine is from direct influence on 5-AR and how much is due to its elevating levels of pregnenolone, progesterone, DHEA, etc. In low doses it is probably OK but nicotine is a beta agonist and used systemically it increases lipolysis. I think its main benefit is its mildly dopaminergic effect in the brain.

Thanks, yeah niacinamide/aspirin would be smart to take with it. Nicotine has been shown to increase DHEA levels as well and also lower estrogen.

The one benefit that I prefer it over caffeine is I don't really seem to get blood sugar crashes as often. They both seem to be a solid pre-workout as well, nicotine is more androgenic in my experience.

So nicotine doesn't actually raise progesterone? That study showed that progesterone levels raises due to stress response from withdrawal? That has been the big debate, some people says nicotine raises progesterone while others say it lowers it.

 

[tomisonbottom]

I tried MB topically (oxidial) only two drops and my hair looked darker the next day...

Could that just be from the blue dye darkening it? Did you continue doing it?

 

[Drareg]

This enzyme is interesting relative to this thread- Retinol dehydrogenase 4 (RODH4)
Like @haidut mentioned its all NAD+ dependent, vitamin A is very much NAD+ dependent, it may explain many of the negative reactions to vitamin A if it’s metabolites can’t be produced if we don’t have enough NAD+.

We really need to discuss the "oxidative direction" more on this forum keeping in mind it’s tissue specific.

The below study is trying to pin it prostate cancer, tidbits can be gleaned from it, they claim a retinol dehydrogenase like 3a-HSD is responsible for converting 3a-diol back to DHT.

Identification of the molecular switch that regulates access of 5α-DHT to the androgen receptor.

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. ...

www.ncbi.nlm.nih.gov

‘Regulation of ligand access to the AR by HSDs in human prostate has been our focus. 5α-DHT is the most potent natural male hormone and is produced by the reduction of testosterone catalyzed by 5α-reductase type 2 (Russell and Wilson, 1994). 5α-DHT has a Kd of 10−11 M for the AR and will trans-activate the AR leading to gene transcription and normal and abnormal prostate growth. Our data show that this androgen signal is eliminated by human type 3α-HSD (aldo-keto reductase (AKR) 1C2) which reduces 5α-DHT to 3α-androstanediol (3α-diol). 3α-Diol is a weak androgen Kd of 10−6 M for the AR that is incapable of trans-activation. Studies in rats (Orlowski, et al., 1983), dogs (DeKlerk, et al, 1979; Jacobi, ,et al 1978), marsupials (Shaw, et al., 2000) and humans (Horst, et al., 1975) have demonstrated that 3α-diol can be converted back to 5α-DHT to stimulate growth of the prostate, but the identity of the oxidative 3α-HSD responsible for this back reaction has remained elusive. Our data shows that “RoDH like 3α-HSD” (a short-chain dehydrogenase /reductase (SDR)) (Biswas and Russell, 1997) is responsible for this reaction in human prostate. Thus the HSD pair that regulates ligand access to the AR has been identified".

"Transient transfection into COS-1 cells followed by measurement of the conversion of 0.1 μM 3α-diol to 5α-DHT showed that three enzymes (RoDH4, RoDH5, and RL-HSD) converted 100% of the steroid substrate within 30 min, whereas NT-3α-HSD and ERAB converted less than 5–10% of this substrate over the same time Figure 3. Transfection studies showed that these enzymes were unable to reduce 5α-DHT to 3α-diol. Steady state kinetic parameters for the NAD+ dependent oxidation of 3α-diol catalyzed by RoDH4, RoDH5 and RL-HSD in the COS-1 cell lysates showed that only RoDH4 and RL-HSD were high affinity low capacity enzymes for the oxidation reaction"

"To determine whether the oxidative 3α-HSDs were able to convert sufficient 3α-diol to 5α-DHT to trans-activate the AR, reporter gene assays were performed. COS-1 cells were co-transfected with AR, a p(androgen response element)2-tk-CAT reporter gene construct in the absence or presence of the oxidative 3α-HSD of interest and exposed to 10−12 to 10−6 M 3α-diol. Oxidative 3α-HSDs that regulate ligand occupancy of the AR should convert 3α-diol to 5α-DHT and increase reporter gene activity, and shift the 3α-diol dose response curve to the left (i.e. an apparent increase in affinity). Only RoDH4, RoDH5 and RL-HSD were able to increase the affinity of the AR for 3α-diol by a 100-fold in this assay"

Below is an interesting study on vitamin A‘s metabolic process, NAD+ is vital.

Enzymology of retinoic acid biosynthesis and degradation: Thematic Review Series: Fat-Soluble Vitamins: Vitamin A

All-trans-retinoic acid is a biologically active derivative of vitamin A that regulates numerous physiological processes. The concentration of retinoic acid in the cells is tightly regulated, but the exact mechanisms responsible for this regulation are ...

www.ncbi.nlm.nih.gov

"It is important to point out that all members of the SDR9C family exhibit dual substrate specificity, recognizing not only retinoids but also 3α-hydroxysteroids (3α-androstane-diol, androsterone, allopregnanolone) as substrates (31). In fact, with the exception of 11cRDH, which shows similar activity toward 11-cis-retinol and 3α-androstanediol (27), all other SDR9C enzymes are several-fold more active toward 3α-hydroxysteroids than toward retinoids (reviewed in Ref. 20). For instance, androsterone added to cells stably transfected with RoDH4 or RL-HSD is fully metabolized within minutes, whereas the oxidation of all-trans-retinol takes several hours (30, 31). The Km values of RoDH4 and RL-HSD for 3α-hydroxysteroids are comparable or even below those of purified recombinant NADPH-dependent cytosolic 3α-hydroxysteroid dehydrogenases of the AKR1 superfamily of proteins, which function in the reductive direction in the cells (32). In fact, recent evidence suggests that in prostate, the NAD+-dependent RL-HSD works as a 3α-hydroxysteroid oxidase in tandem with the NADPH-dependent 3-ketosteroid reductase AKR1C2 to regulate the amount of 5α-dihydrotestosterone available for binding to the androgen receptor (33, 34). This observation brings up important questions. Can SDR9C enzymes contribute to both retinoid and steroid metabolism? Will the extent of their contribution depend on the cell-specific context? Answers to these questions are essential for defining the role of SDR9C enzymes in atRA biosynthesis".

"We were encouraged by our initial finding that the membrane-bound human RoDH4 expressed in microsomes of Sf9 cells produced retinaldehyde from holoCRBP1 (92). At the same time, this activity was not observed with similarly expressed RL-HSD, suggesting specific recognition of holoCRBPI by human RoDH4. However, subsequent analysis using a different HPLC mobile phase, which allowed a better separation of retinoid isomers, revealed that the actual product of RoDH4 activity toward holoCRBPI was 9-cis-retinaldehyde and not all-trans-retinaldehyde, because the chromatographically purified holoCRBP1 contained some amount of 9-cis-retinol, a proportion of which gradually increased with light exposure (69). An even faster accumulation of 9-cis-retinol was observed in the presence of human CRBPIII (E. V. Shabrova et al., unpublished observations), indicating that this phenomenon is not unique to CRBPI. Our finding provided a reasonable explanation for the differential recognition of holoCRBPI by human RoDH4 versus human RL-HSD: RoDH4 oxidized the free 9-cis-retinol accumulated in holoCRBPI because 9-cis-retinol binds to CRBPI with much lower affinity than all-trans-retinol (93–95), whereas RL-HSD was inactive because, unlike RoDH4, it does not recognize 9-cis-retinol as substrate"

13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands? - PubMed

Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This...

pubmed.ncbi.nlm.nih.gov

"Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This oxidative 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity of RoDH-4 is competitively inhibited by retinol and 13-cis-retinol. Here, we further examine the substrate specificity of RoDH-4 and the inhibition of its 3 alpha-HSD activity by retinoids. Recombinant RoDH-4 oxidized 3,4-didehydroretinol-a major form of vitamin A in the skin-to its corresponding aldehyde. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, were potent competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4, i.e., reduced the formation of dihydrotestosterone and androstandione in vitro. Extrapolated to the in vivo situation, this effect might explain the unique sebosuppressive effect of isotretinoin when treating acne".

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