Hypothyroidism (Cortisol, Prolactin And Adrenal Hyperactivity) Causes Balding

[Scenes]

Buy PO 12 Skin Protector Cream with Enoxolone (2%) 40 Gr in Cheap Price on m.alibaba.com

All I can find for enoxolone is this 2% cream. Is this worthwhile or too low to do anything @Travis ?

 

[ivy]

Buy PO 12 Skin Protector Cream with Enoxolone (2%) 40 Gr in Cheap Price on m.alibaba.com

All I can find for enoxolone is this 2% cream. Is this worthwhile or too low to do anything @Travis ?

I'd be suspicious of that product.
Check this out:

Actif Pur Enoxolone

 

[Brandon]

That link has no Ray Peat quotes, and mentions the word "hair" not once.

When respondin

 

[Brandon]

[QUOTE="Brandon, post: 289507, what about progrest-e ?

 

[johnwester130]

what would work better as a topical for hair ? DHT gel or testosterone gel ?

 

[Travis]

Enoxolone in any amount would be expected to inhibit the cortisone cortisol ⟶ conversion. It's safe, and doesn't appear to have much affinity for anything other than 11β-HSD₁.

The 2% can also be found on Ebay.

I would think that 2% would be effective. It is used in cosmetics for this very reason, to inhibit cortisol production on the skin.

There are prostaglandin and cytokine signalling events downstream of cortisol which seems to transduce the signal. Cortisol upregualtes prostaglandin D₂ synthase through the glucocorticoid receptor and TGF-β₁ through to nuclear mineralcorticoid receptor. The enzyme prostaglandin D₂ synthase produces the only prostaglandin shown to inhibit hair growth, a prostaglandin found greatly elevated in bald parts of the head—compared to haired regions of the same person. The mRNA for this enzyme was also found upregulated, showing that this is a transcriptional event. Cortisol is both the main glucocorticoid and nuclear mineralcorticoid—it does not activate the mineralcorticoid receptor on the cell membrane, aldosterone is the only endogenous molecule that can do that.

The cytokine TGF-β₁, also upregulated by cortisol, activates phospholipase A₂ which releases arachidonic acid. This later can become either prostaglandin E₂, prostaglandin F₂, or prostaglandin D₂ (and their derivatives). Oddly, prostaglandins E₂ and F₂ slightly stimulate hair growth while prostaglandin D₂ powerfully inhibits it. The effect of prostaglandin D₂ is unambiguous.

As the only ligand of both the glucocorticoid receptor and n-mineralcorticoid receptor, cortisol is the only thing that can powerfully upregulate both prostaglandin D₂ synthase and TGF-β₁. Cortisol also exists in much higher concentrations than aldosterone, especially in places like the skin where 11β-HSD₁ is powerfully unidirectional. This is where enoxolone can help, by inhibiting the cortisol ⟶ conversion; but unfortunately, it can do nothing about the cortisol produced in other places and transported to the skin. It might not be complete in itself, and could take oleuropein to inhibit the downstream prostaglandin signalling events.

And cyclosporine works on a different level. I think that it must bond to an extracellular receptor, like that for TGF-β₁, or inhibit soluble prostaglandin D₂ synthase—a unique enzyme which exists in the plasma, lymph, CSF, and extracellular space and carries vitamin A in addition to being the only thing capable of transforming prostaglandin E₂ to prostaglandin D₂ through it's catalytic thiol domain inside its β-barrel structure. Mice lacking this enzyme appear normal, but exhibit better wound healing and hair growth.

Since COX-2 inhibitors also promote hair growth, at times, you would think that simply limiting the amount of linoleic acid would lessen the amount of drugs needed to inhibit excessive prostaglandin D₂ formation and upstream cortisol production and/or binding.

 

[Koveras]

And cyclosporine works on a different level. I think that it must bond to an extracellular receptor, like that for TGF-β₁, or inhibit soluble prostaglandin D₂ synthase—a unique enzyme which exists in the plasma, lymph, CSF, and extracellular space and carries vitamin A in addition to being the only thing capable of transforming prostaglandin E₂ to prostaglandin D₂ through it's catalytic thiol domain inside its β-barrel structure. Mice lacking this enzyme appear normal, but exhibit better wound healing and hair growth.

Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor: a cell-based model to investigate partial aldost... - PubMed - NCBI

"Renal transplant recipients treated with cyclosporine A (CsA) and FK506 (tacrolimus) develop signs of hypoaldosteronism despite normal plasma aldosterone levels, suggesting a relative resistance of the distal nephron to aldosterone action. To examine the effects of immunosuppressants on human MR (hMR) function, we established the M cell model, renal tubular cells stably transfected with hMR. Upon CsA and FK506 administration, hMR mRNA levels and aldosterone binding in M cells remained unchanged (maximum number of sites, approximately 80 fmol/mg protein; K(d) = approximately 1 nM). Aldosterone-dependent intracellular localization of green fluorescent protein-hMR was not affected by immunosuppressants. A major impact of CsA or FK506 on the multidrug resistance gene product in cellular accumulation of aldosterone was also excluded. In contrast, aldosterone-stimulated hMR transcriptional activity was reduced to 53 +/- 11.2% (P < 0.03) after pretreatment of M cells for 3 d with CsA and to 71 +/- 9.6% (P < 0.05) after pretreatment with FK506. These effects were both time and concentration dependent (IC(50) of CsA, 10(-6) M; IC(50) of FK506, 10(-5) M) and needed at least 2 d to develop. Such an inhibitory effect does not depend on the N-terminal part of hMR, as CsA also reduced transcriptional activity of a 1-453 deletion mutant of hMR. Our results demonstrate that immunosuppressants inhibit hMR transcriptional activity without affecting hMR expression, aldosterone binding properties, and hMR nucleocytoplasmic trafficking. They suggest that ion transport alterations in renal graft recipients are in part induced by impaired hMR function."

 

[Travis]

Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor: a cell-based model to investigate partial aldost... - PubMed - NCBI

"Renal transplant recipients treated with cyclosporine A (CsA) and FK506 (tacrolimus) develop signs of hypoaldosteronism despite normal plasma aldosterone levels, suggesting a relative resistance of the distal nephron to aldosterone action. To examine the effects of immunosuppressants on human MR (hMR) function, we established the M cell model, renal tubular cells stably transfected with hMR. Upon CsA and FK506 administration, hMR mRNA levels and aldosterone binding in M cells remained unchanged (maximum number of sites, approximately 80 fmol/mg protein; K(d) = approximately 1 nM). Aldosterone-dependent intracellular localization of green fluorescent protein-hMR was not affected by immunosuppressants. A major impact of CsA or FK506 on the multidrug resistance gene product in cellular accumulation of aldosterone was also excluded. In contrast, aldosterone-stimulated hMR transcriptional activity was reduced to 53 +/- 11.2% (P < 0.03) after pretreatment of M cells for 3 d with CsA and to 71 +/- 9.6% (P < 0.05) after pretreatment with FK506. These effects were both time and concentration dependent (IC(50) of CsA, 10(-6) M; IC(50) of FK506, 10(-5) M) and needed at least 2 d to develop. Such an inhibitory effect does not depend on the N-terminal part of hMR, as CsA also reduced transcriptional activity of a 1-453 deletion mutant of hMR. Our results demonstrate that immunosuppressants inhibit hMR transcriptional activity without affecting hMR expression, aldosterone binding properties, and hMR nucleocytoplasmic trafficking. They suggest that ion transport alterations in renal graft recipients are in part induced by impaired hMR function."

I read that study a few months ago, but started doubting the conclusions after reading about TGF-β₁. Cyclosporine is a very large molecule, and I started wondering how it would get into the cell.

I need to look at that article again. The last sentence says:

"Our results demonstrate that immunosuppressants inhibit hMR transcriptional activity without affecting hMR expression, aldosterone binding properties, and hMR nucleocytoplasmic trafficking." ―Deppe
​

So he proposed this strange mechanism in which cyclosporine bound to both the n-mineralcorticoid receptor and a transcription factor—essentially binding them both together. But I came across these other proposed mechanisms a few days ago that involve cytokine signalling, but didn't read to far into it since cyclosporine is hard to find.

The thing that also got me was that cyclosporine seems more powerful than simple mineralcorticoid inhibitors like spironolactone, which you'd expect to be much more effective based on size. I think there could be something missing about the Deppe explanation.

 

[Koveras]

I read that study a few months ago, but started doubting the conclusions after reading about TGF-β₁. Cyclosporine is a very large molecule, and I started wondering how it would get into the cell.

I need to look at that article again. The last sentence says:

"Our results demonstrate that immunosuppressants inhibit hMR transcriptional activity without affecting hMR expression, aldosterone binding properties, and hMR nucleocytoplasmic trafficking." ―Deppe
​

So he proposed this strange mechanism in which cyclosporine bound to both the n-mineralcorticoid receptor and a transcription factor—essentially binding them both together. But I came across these other proposed mechanisms a few days ago that involve cytokine signalling, but didn't read to far into it since cyclosporine is hard to find.

The thing that also got me was that cyclosporine seems more powerful than simple mineralcorticoid inhibitors like spironolactone, which you'd expect to be much more effective based on size. I think there could be something missing about the Deppe explanation.

How do these ones

Nephron segment-specific inhibition of Na+/K(+)-ATPase activity by cyclosporin A. - PubMed - NCBI
Effects of cyclosporine A on Na,K-ATPase expression in the renal epithelial cell line NBL-1. - PubMed - NCBI

Fit with this- Na⁺/K⁺-ATPase Is The Membrane Aldosterone Receptor

 

[Travis]

Good idea. If the Na⁺/K⁺-ATPase is always found upregulated by the mineralcorticoid receptor, this would give further proof towards the idea that it's actually the Membrane Aldosterone Receptor.

I just read that Deppe article on cyclosporine and had realized that it wasn't the one I had read previously. The Deppe article is straightforward, and doesn't propose a molecular mechanism. The one I had read previously months ago was from an Asian scientist, who imagined that cyclosporine "bonded" the entire MR·hsp90·cyP complex together. While not a totally ridiculous proposal, I think he's wrong.

Cyclosporine takes days before it begins to effect mRNA levels, but the n-mineralcorticoid receptor responds in minutes:

• "Figure 4B demonstrates that the nuclear translocation rates for each steroid/MR complex are not the same. Clearly, 11-OP (b) moves at a slower rate than aldosterone (2) or DOC (9), such that the average translocation half-time for 11-OP/MR complexes is twice as long (8.4 ± 0.6 min) as that measured with each natural agonist (4.0 ± 1.0 min)." —Gallo

An image taken from Deppe demonstrates the speed in which the n-mineralcorticoid receptor transports to the cell membrane.

But it doesn't make this trip alone: The n-mineralcorticoid receptor is always found attached to other proteins, the most notable are heat shock protein 90 (hsp90) and cyclophilin (cyP). Threre's also other associated proteins called FKBP52 and FKBP51. The double-labeled image below (Gallo, 2007) shows that FKBP52 is mainly cytosolic, but can be found associated with the n-mineralcorticoid receptor in the cell membrane after aldosterone administration—along with heat shock protein 90 of course (not stained).

The image on the left has the n-mineralcorticoid receptor stained red, and the FKBP51 stained green. The image on the right is the same⟶a few minutes after the addition of aldosterone. The superposition of the two colors appears yellow, visually denoting co-localization.

(One might initially think that FKBP52 and FKBP51 are basically the same protein, but differing in a post-translational modification which makes it one kilodalton heavier. This is not the case. Although similar in structure, function, and mass.. . ..the two are only about 50% homologous.)

The cytoplasmic/nuclear-mineralcorticoid receptor binds aldosterone with very high affinity. This has been shown with purified and isolated mineralcorticoid receptor multiple times, and perhaps even with recombinant mineralcorticoid receptor. This part is unambiguous, and the fact that it then transfers to the nucleus in mere minutes—with others such as hsp90, FKBP52, FKBP51, and cyclophilin (cyP)—would be hard to dispute.

The Silverstein article analyzed which of these particles could bind with what, and in what order. It is also worth reading because he introduces a useful interpunct (·) notation:

• "Cross-linking studies of steroid receptor·hsp90 heterocomplexes have revealed a common heterotetrameric structure containing 1 molecule of receptor, 2 molecules of hsp90, and 1 molecule of immunophilin." —Silverstein

• "The immunophilins have been shown to exist in independent receptor·hsp90·FKBP52 and receptor·hsp90·CyP-40 heterocomplexes, and inasmuch as the TPR proteins compete for the binding of each other, these complexes must be very dynamic in the sense that a single receptor·hsp90 heterocomplex could be associated sequentially with several different TPR proteins over a short time." —Silverstein

Silverstein also showed that FKBP52 precipitates with dynein, a microtubule-associated protein. You're almost forced to think from this—and from the images—that FKBP52 exists in its native state bound to the microtubule cytoskeleton through dynein. You could also infer from his other data that the transcriptional-mineralcorticoid receptor is attached to FKBP52, possibly through the an intermediary heat shock protein 90.

Although nice, his interpunct notation gives a false sense of linearity. The tetramer is indicated by Silverstein as "MR·hsp90·hsp90·CyP," which could perhaps be telescoped into "MR·hsp9o²·CyP." I get the impression that this is not a linear chain of proteins, since FKBP52 binds far better to a dimer of heat shock proteins (hsp9o·hsp9o) than it does to just one. You might expect then—and by noting that it has 3 TPR binding domains—that the trimer hsp9o·hsp9o·FKBP52 exists normally in a more triangle arrangement (△). The t-mineralcorticoid receptor of course adds to this further—perhaps forming a tetrahedron (◮).

So somehow, the binding of aldosterone alone can do powerful things. I think exactly how this complex is formed, and later released, can be known if one were to take the time to analyze the structure.

How to explain cyclosporine's function? We know from Deppe that cyclosporine doesn't change the process of nuclear translocation, it only changes what mRNA comes-out of the nucleus. You would then almost be forced to assume that the immunophilins—such as FKBP-12 and cyclosporine—are only necessary for transcription.. . ..almost like they hijack-onto these cytoskeleon-associated complexes for transport into the nucleus. These proteins themselves are necessary for the transcription of certain DNA segments, and so could properly be considered transcription factors.

But doesn't cyclosporine need to penetrate the cell membrane?

• "Cyclophilins (Cyps) are ubiquitous intracellular proteins commonly known as the target of the immunosuppressive drug cyclosporine A. In addition to their intracellular role, increasing evidence has suggested a role for Cyps in intercellular communication." —Stemmy

(Although Stemmy uses "Cyp" to denote the cyclophilin protein, Silverstein's notation is probably better. The letters "Cyp"are usually reserved for the class of cytochrome P450 enzymes, so Silverstein's "cyP" or Gallo's "CyP" are probably better.)​

Immumophilins exist extracellular as well, and can be found in higher amounts in asthma patients. Based on the high affinity of cyclosporine to cyclophillin, and of FK-506 to FKBP-12 (though not to be confused with the much larger FKBP-52), you might expect them to also bind with these immunophilins extracellularly—perhaps then later becoming digested by macrophages. This would have the effect of lowering circulating immunophilins—also nuclear transcription factors which dimerize with the mineralcorticoid receptor in ways analogous to the more familiar dimers (i.e. VDR·RXR).

I see immunophilins as occupying the link between the mineralcorticoid receptor and immunity, the crossroads between the Cortisol and the Prostaglandin D₂ Theories of Hair Loss. I think if you were to investigate this further, you might find that cyclophilin is responsible for the transcription of NF-κB, TGF-β, COX-2, or some other executioner of the hair follicle (perhaps even prostaglandin D₂ synthase itself?)

◮ Silverstein, Adam M., et al. "Different regions of the immunophilin FKBP52 determine its association with the glucocorticoid receptor, hsp90, and cytoplasmic dynein." Journal of Biological Chemistry 274.52 (1999)
☁ Stemmy, Erik J., et al. "Extracellular cyclophilin levels associate with parameters of asthma in phenotypic clusters." Journal of Asthma 48.10 (2011)
➫ Deppe, Christine E., et al. "Cyclosporine a and FK506 inhibit transcriptional activity of the human mineralocorticoid receptor:" Endocrinology 143.5 (2002)
‼ Gallo, Luciana I., et al. "Differential recruitment of tetratricorpeptide repeat domain immunophilins to the mineralocorticoid receptor influences both heat-shock protein 90-dependent retrotransport and hormone-dependent transcriptional activity." Biochemistry 46.49 (2007)

 

[DuggaDugga]

You cannot just give-up so easily considering that so many things have been shown to cause hair growth, and so many things shown to cause hair catagen.

Much work has gone into understanding the cell cycle and I don't think comment #162 is constructive, especially considering the politics in medicine and pharmaceuticals. You can't expect the most effective drugs to be sold, or even widely-known about. You only have to take a look at the history of methylglyoxal, lapachol, and cardiovascular disease (in general) to convince yourself of this. A drug can be too effective to be profitable; the most profitable are often barely effective.

Very effective drugs are commonly sold at low concentrations, causing people to write them off. This could be done intentionally.

Possibly. But I do think that hair loss is indicative of a systemic issue, so while there may be some pharmaceutical intervention that can be effective in slowing or stopping hair loss, it's best to rectify the underlying individual toxicities & deficiencies. I've had success, but it's a comprehensive change in lifestyle. I think it's a much safer bet to increase metabolic function, slow and reverse soft tissue calcification, etc, etc, improvements benefiting health in its entirety, rather than experimenting with pharmaceutical interventions.
Either way, I commend you on your research. Best.

 

[Travis]

Possibly. But I do think that hair loss is indicative of a systemic issue, so while there may be some pharmaceutical intervention that can be effective in slowing or stopping hair loss, it's best to rectify the underlying individual toxicities & deficiencies. I've had success, but it's a comprehensive change in lifestyle. I think it's a much safer bet to increase metabolic function, slow and reverse soft tissue calcification, etc, etc, improvements benefiting health in its entirety, rather than experimenting with pharmaceutical interventions.
Either way, I commend you on your research. Best.

It can be modified on that level, for sure. The immune system appears to be involved, so food allergies could be a cause. This means finding-out which foods could be causing sub-chronic reactions.

Also, the indisputable role that prostaglandins play in all of this almost demands a low-linoleic acid diet. There are at least three studies showing how COX-2 upregulation creates bald mice. In all cases, this was completely reversed by using a COX-2 inhibitor: celecoxib (Bol, 2003), valdecoxib (Müller-Decker, 2002), and even aspirin (Wan 2007).

There is also the 2001 Neufang article which is worth a read as well, and the three of Garza: Who was the first to make the observation that prostaglandin D₂ alone is responsible. This can seem somewhat confusing—in a way—since prostaglanins E₂ and F₂α have actually been shown to promote hair growth, slightly.

What is bizarre is: Like steroid hormones, very small changes in the structure can cause profoundly different hormonal effects. Prostaglandin D₂ and E₂ are nearly isomers of each other; but then again, so are progesterone and DHT—a fact which hardly seems amazing, anymore.

And lipotoxin (LPS) can effect prostaglandin signalling and production. This means, gram-negative bacteria would be expected to be a factor.

Avoid prostaglandins: avoid hair loss: Avoid allergies, linoleic acid, and stress.

But there are things which have been shown to work locally as well . . .

 

[DuggaDugga]

It can be modified on that level, for sure. The immune system appears to be involved, so food allergies could be a cause. This means finding-out which foods could be causing sub-chronic reactions.

Also, the indisputable role that prostaglandins play in all of this almost demands a low-linoleic acid diet. There are at least three studies showing how COX-2 upregulation creates bald mice. In all cases, this was completely reversed by using a COX-2 inhibitor: celecoxib (Bol, 2003), valdecoxib (Müller-Decker, 2002), and even aspirin (Wan 2007).

There is also the 2001 Neufang article which is worth a read as well, and the three of Garza: Who was the first to make the observation that prostaglandin D₂ alone is responsible. This can seem somewhat confusing—in a way—since prostaglanins E₂ and F₂α have actually been shown to promote hair growth, slightly.

What is bizarre is: Like steroid hormones, very small changes in the structure can cause profoundly different hormonal effects. Prostaglandin D₂ and E₂ are nearly isomers of each other; but then again, so are progesterone and DHT—a fact which hardly seems amazing, anymore.

And lipotoxin (LPS) can effect prostaglandin signalling and production. This means, gram-negative bacteria would be expected to be a factor.

Avoid prostaglandins: avoid hair loss: Avoid allergies, linoleic acid, and stress.

But there are things which have been shown to work locally as well . . .

I'm 100% with you there, Travis.
When you say the immune system appears to be involved, what do you mean specifically? Mast cell degranulation? Or just the low grade inflammation.

 

[Travis]

I'm 100% with you there, Travis.
When you say the immune system appears to be involved, what do you mean specifically? Mast cell degranulation? Or just the low grade inflammation.

Perhaps whatever can produce the immunophilins? And also, what can upregualate COX-2.

• Müller-Decker, Karin, et al. "Expression of cyclooxygenase isozymes during morphogenesis and cycling of pelage hair follicles in mouse skin: precocious onset of the first catagen phase and alopecia upon cyclooxygenase-2 overexpression." Journal of investigative dermatology 121.4 (2003): 661-668.

Imunophilins appear to be transported from cell-to-cell, and the most powerful hair growth agents intercept these. These drugs bind immunophilins to such a degree that were actually named after them: cyclophilin was named after its affinity for cyclosporine; and the FK binding proteins (i.e. FKBP-12) were initially named for their FK-506 affinity, or their ability to be inactivated by Tacrolimus™.

As can bee seen from the above articles (not directly, but further↑), these imunophilin proteins appear necessary for the transciption of certain DNA segments. Aldosterone, for instance, cannot initiate the transcription of many proteins, enzymes, and cytokines without cyclophilin present. Cyclopsporine binds to cyclophilin, preventing cyclophilin-related DNA➝mRNA transcription events.

The classic side-effect of cyclosporine is hair growth. This occurs at rates approaching 100%, but occurs everywhere indiscriminately—even in places where you don't think it should. That so-called "immunosuppresents" are the drugs which initiate hair growth most powerfully may seem paradoxical to some, but this is just a problem in semantics. Cyclosporine binds with, and intercepts, a nuclear transcription factor which helps to create certain proteins integral for hair growth itself (and/or important cytokines necessary for signalling, or inhibiting, such growth.)

Anyone can easily confirm that cyclosporine and FK-506 are the certainly most powerful hair growth agents by visiting GoogleScholar.

Why is this? I think we can examine both downstream events and those upstream: examine which genes precisely are transcribed by cyclophilin; and also, the social and environmental factors that upregulate the immunophilins (and corticosteroids necessary to facilitate transcritption.)

And many things can be said about protstaglandins as well.. .

• Garza, Luis A., et al. "Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia." Science translational medicine 4.126 (2012)

And this article here shows that the ingestion of prostaglandins will cause balding, in mice, in a manner reminiscent to humans.

• Wan, Yihong, et al. "Maternal PPARγ protects nursing neonates by suppressing the production of inflammatory milk." Genes & development 21.15 (2007): 1895-1908.

Of the many articles on COX-2 upregulation, I think the one by Neufang is the best: The article not only the the most well-written of them all, but also the one containing the best images (both the immunohisochemical slides, and mouse pics.)

• Neufang, Gitta. "Abnormal differentiation of epidermis in transgenic mice expressing cyclooxygenase-2 in skin." Proceedings of the National Academy of Sciences (2001)

 

[Murtaza]

Great post @haidut . although i would love it if you could chime and give some advice on what supplements should we use for adrenal hyperactivity

 

[haidut]

Great post @haidut . although i would love it if you could chime and give some advice on what supplements should we use for adrenal hyperactivity

Depends on what's causing the hyperactivity. Usually, this hyperactivity is to compensate for low thyroid function. So, if that's the reason then improving thyroid should remediate the issue. Other than that, taurine, theanine, salt, inosine, etc seem to oppose adrenaline release or its effects. High cortisol can also trigger adrenaline release and progesterone/DHEA seem to be good at lowering/opposing cortisol.

 

[Murtaza]

Depends on what's causing the hyperactivity. Usually, this hyperactivity is to compensate for low thyroid function. So, if that's the reason then improving thyroid should remediate the issue. Other than that, taurine, theanine, salt, inosine, etc seem to oppose adrenaline release or its effects. High cortisol can also trigger adrenaline release and progesterone/DHEA seem to be good at lowering/opposing cortisol.

Thankyou for the suggestions. My cortisol is pretty high since i have hair growth on shoulders, and isnt DHEA the product of adrenal hyperactivity?

 

[haidut]

Thankyou for the suggestions. My cortisol is pretty high since i have hair growth on shoulders, and isnt DHEA the product of adrenal hyperactivity?

It is an adrenal product (mostly) but its function is cortisol antagonism. Google for "dhea cortisol antagonist" or search the forum for the same keywords.

 

[Curiousman]

Enoxolone in any amount would be expected to inhibit the cortisone cortisol ⟶ conversion. It's safe, and doesn't appear to have much affinity for anything other than 11β-HSD₁.

The 2% can also be found on Ebay.

I would think that 2% would be effective. It is used in cosmetics for this very reason, to inhibit cortisol production on the skin.

There are prostaglandin and cytokine signalling events downstream of cortisol which seems to transduce the signal. Cortisol upregualtes prostaglandin D₂ synthase through the glucocorticoid receptor and TGF-β₁ through to nuclear mineralcorticoid receptor. The enzyme prostaglandin D₂ synthase produces the only prostaglandin shown to inhibit hair growth, a prostaglandin found greatly elevated in bald parts of the head—compared to haired regions of the same person. The mRNA for this enzyme was also found upregulated, showing that this is a transcriptional event. Cortisol is both the main glucocorticoid and nuclear mineralcorticoid—it does not activate the mineralcorticoid receptor on the cell membrane, aldosterone is the only endogenous molecule that can do that.

The cytokine TGF-β₁, also upregulated by cortisol, activates phospholipase A₂ which releases arachidonic acid. This later can become either prostaglandin E₂, prostaglandin F₂, or prostaglandin D₂ (and their derivatives). Oddly, prostaglandins E₂ and F₂ slightly stimulate hair growth while prostaglandin D₂ powerfully inhibits it. The effect of prostaglandin D₂ is unambiguous.

As the only ligand of both the glucocorticoid receptor and n-mineralcorticoid receptor, cortisol is the only thing that can powerfully upregulate both prostaglandin D₂ synthase and TGF-β₁. Cortisol also exists in much higher concentrations than aldosterone, especially in places like the skin where 11β-HSD₁ is powerfully unidirectional. This is where enoxolone can help, by inhibiting the cortisol ⟶ conversion; but unfortunately, it can do nothing about the cortisol produced in other places and transported to the skin. It might not be complete in itself, and could take oleuropein to inhibit the downstream prostaglandin signalling events.

And cyclosporine works on a different level. I think that it must bond to an extracellular receptor, like that for TGF-β₁, or inhibit soluble prostaglandin D₂ synthase—a unique enzyme which exists in the plasma, lymph, CSF, and extracellular space and carries vitamin A in addition to being the only thing capable of transforming prostaglandin E₂ to prostaglandin D₂ through it's catalytic thiol domain inside its β-barrel structure. Mice lacking this enzyme appear normal, but exhibit better wound healing and hair growth.

Since COX-2 inhibitors also promote hair growth, at times, you would think that simply limiting the amount of linoleic acid would lessen the amount of drugs needed to inhibit excessive prostaglandin D₂ formation and upstream cortisol production and/or binding.

Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells.

 

[haidut]

Enoxolone in any amount would be expected to inhibit the cortisone cortisol ⟶ conversion. It's safe, and doesn't appear to have much affinity for anything other than 11β-HSD₁.

The 2% can also be found on Ebay.

I would think that 2% would be effective. It is used in cosmetics for this very reason, to inhibit cortisol production on the skin.

There are prostaglandin and cytokine signalling events downstream of cortisol which seems to transduce the signal. Cortisol upregualtes prostaglandin D₂ synthase through the glucocorticoid receptor and TGF-β₁ through to nuclear mineralcorticoid receptor. The enzyme prostaglandin D₂ synthase produces the only prostaglandin shown to inhibit hair growth, a prostaglandin found greatly elevated in bald parts of the head—compared to haired regions of the same person. The mRNA for this enzyme was also found upregulated, showing that this is a transcriptional event. Cortisol is both the main glucocorticoid and nuclear mineralcorticoid—it does not activate the mineralcorticoid receptor on the cell membrane, aldosterone is the only endogenous molecule that can do that.

The cytokine TGF-β₁, also upregulated by cortisol, activates phospholipase A₂ which releases arachidonic acid. This later can become either prostaglandin E₂, prostaglandin F₂, or prostaglandin D₂ (and their derivatives). Oddly, prostaglandins E₂ and F₂ slightly stimulate hair growth while prostaglandin D₂ powerfully inhibits it. The effect of prostaglandin D₂ is unambiguous.

As the only ligand of both the glucocorticoid receptor and n-mineralcorticoid receptor, cortisol is the only thing that can powerfully upregulate both prostaglandin D₂ synthase and TGF-β₁. Cortisol also exists in much higher concentrations than aldosterone, especially in places like the skin where 11β-HSD₁ is powerfully unidirectional. This is where enoxolone can help, by inhibiting the cortisol ⟶ conversion; but unfortunately, it can do nothing about the cortisol produced in other places and transported to the skin. It might not be complete in itself, and could take oleuropein to inhibit the downstream prostaglandin signalling events.

And cyclosporine works on a different level. I think that it must bond to an extracellular receptor, like that for TGF-β₁, or inhibit soluble prostaglandin D₂ synthase—a unique enzyme which exists in the plasma, lymph, CSF, and extracellular space and carries vitamin A in addition to being the only thing capable of transforming prostaglandin E₂ to prostaglandin D₂ through it's catalytic thiol domain inside its β-barrel structure. Mice lacking this enzyme appear normal, but exhibit better wound healing and hair growth.

Since COX-2 inhibitors also promote hair growth, at times, you would think that simply limiting the amount of linoleic acid would lessen the amount of drugs needed to inhibit excessive prostaglandin D₂ formation and upstream cortisol production and/or binding.

I beg to disagree a bit. Enoxolone is actually an indiscriminate inhibitor of 11b-HSD - i.e. it inhibits both type I and II. This leads to increase in cortisol levels due to decreased degradation, even though new synthesis is also inhibited. This is why enoxolone leads to high blood pressure in humans and it not used more often clinically. I considered it as a supplement years ago but its indiscriminate 11b-HSD activity convinced me not to do it. I have tried it myself and it does lead to excess mineralocorticoid symptoms including water retention and weight gain around the midsection.
Enoxolone - Wikipedia
"...The structure of glycyrrhetinic acid is similar to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action.[citation needed] 3-β-D-(Monoglucuronyl)-18-β-glycyrrhetinic acid, a metabolite of glycyrrhetinic acid, inhibits the conversion of 'active' cortisol to 'inactive' cortisone in the kidneys.[6] This occurs via inhibition of the enzyme by inhibiting the enzyme 11-β-hydroxysteroid dehydrogenase.[citation needed] As a result, cortisol levels are high within the collecting duct of the kidney. Cortisol has intrinsic mineralocorticoid properties (that is, it acts like aldosterone and increases sodium reabsorption) that work on ENaC channels in the collecting duct.[citation needed]Hypertension develops due to this mechanism of sodium retention. People often have high blood pressure with a low renin and low aldosterone blood level.[citation needed] The increased amounts of cortisol binds to the unprotected, unspecific mineralocorticoid receptors and induce sodium and fluid retention, hypokalaemia, high blood pressure and inhibition of the renin-angiotensin-aldosterone system. Therefore, licorice should not be given to patients with a known history of hypertension in doses sufficient to inhibit 11-β-hydroxysteroid dehydrogenase.[7]"