RENIN-ANGIOTENSIN-ALDOSTERONE SYSYTEM And HAIR LOSS PROCESS

[md_a]

The beneficial effect of Ang-(1-7) in alopecia can be attributed to their vasodilation action on blood vessels (Santos et al., 2000). The vasodilation of arterioles present in the dermis improves irrigation of the hair follicles, increasing the supply of nutrients and oxygen. Thus, the cells of the hair follicle increase their proliferation, accelerating hair growth

US20150313829A1 - Topical formulations for the prevention and treatment of alopecia and inhibition of hair growth - Google Patents
... Mineralocorticoid Receptor Blocker Increases Angiotensin-Converting Enzyme 2 Activity in Congestive Heart Failure Patients.
Abstract
Aldosterone plays an important role in the pathophysiology of congestive heart failure (CHF), and spironolactone improves cardiovascular function and survival rates in patients with CHF. We hypothesized that the mineralocorticoid receptor blockade (MRB) exerted its beneficial effects by reducing oxidative stress and changing the balance between the counter-acting enzymes angiotensin-converting enzyme (ACE) and ACE2. Monocyte-derived macrophages were obtained from 10 patients with CHF before and after 1 month of treatment with spironolactone (25 mg/d). Spironolactone therapy significantly (P<0.005) reduced oxidative stress, as expressed by reduced lipid peroxide content, superoxide ion release, and low-density lipoprotein oxidation by 28%, 53%, and 70%, respectively. Although spironolactone significantly (P<0.01) reduced macrophage ACE activity by 47% and mRNA expression by 53%, ACE2 activity and mRNA expression increased by 300% and 654%, respectively. In mice treated for 2 weeks with eplerenone (200 mg · kg−1 · d−1), cardiac ACE2 activity significantly (P<0.05) increased by 2-fold and was paralleled by increased ACE2 activity in macrophages. The mechanism of aldosterone antagonist action was studied in mouse peritoneal macrophages (MPMs) in vitro. Although ACE activity and mRNA were significantly increased by 250 nmol/L aldosterone, ACE2 was significantly reduced. Cotreatment with eplerenone (2 μmol/L) attenuated these effects. In MPM obtained from p47 knockout mice, where NADPH oxidase is inactive, as well as in control MPMs treated with NADPH oxidase inhibitor, aldosterone did not increase ACE or decrease ACE2. MRB reduced oxidative stress, decreased ACE activity, and increased ACE2 activity, suggesting a protective role for MRB by possibly increasing generation of angiotensin (1–7) and decreasing formation of angiotensin II. These effects are mediated, at least in part, by NADPH oxidase.
https://www.ahajournals.org/doi/10.1161/01.res.0000187500.24964.7a

 

[Estradiol]

Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo
Abstract

Whilst topical steroids represent one of the most frequently administered treatments for skin and hair diseases, predominantly based on their glucocorticoid receptor-mediated anti-inflammatory effects, the mineralocorticoid effects of topical steroids have received surprisingly little attention. However, the role of mineralocorticoid receptor (MR) signaling is now known to extend beyond the kidney, with human skin, including the hair follicle (HF), expressing the MR. Using microdissected female HFs treated ex vivo with MR agonists and antagonists, we sought to determine the effects of MR-mediated signaling in the cutaneous context. Indeed, not only did the skin and HF epithelium express the MR at both the gene and protein level, but its expression was hair cycle dependent. Moreover, the selective MR antagonist eplerenone promoted hair shaft elongation and hair matrix keratinocyte proliferation whilst delaying catagen (HF regression). These novel observations suggest that the female human HF is sensitive to the inhibition of MR signaling and provide the first evidence that sustained MR signaling may even be required to maintain the growth phase (anagen) of human scalp HFs. Indeed, these data encourage the systematic evaluation of MR agonists and antagonists in human hair growth control so as to identify much-needed, novel anti-hirsutism and/or hair growth-promoting agents, respectively.

Mineralocorticoid Receptor Antagonists Stimulate Human Hair Growth Ex Vivo - PubMed

...
Eplerenone, sold under the brand name Inspra, is a steroidal antimineralocorticoid of the spirolactone group that is used as an adjunct in the management of chronic heart failure and high blood pressure, particularly for patients with resistant hypertension due to elevated aldosterone. Classed as a selective aldosterone receptor antagonist (SARA),[5] it is similar to the diuretic spironolactone, though it is much more selective for the mineralocorticoid receptor in comparison (i.e., does not possess any antiandrogen, progestogen, glucocorticoid, or estrogenic effects), and is specifically marketed for reducing cardiovascular risk in patients following myocardial infarction. Eplerenone is a potassium-sparing diuretic, meaning that it helps the body get rid of water but still keep potassium.

It was patented in 1983 and approved for medical use in the United States in 2002.[6][7] Eplerenone is currently approved for sale in Canada, the US, EU, Netherlands and Japan.[7] Eplerenone costs an estimated $2.93 per day when treating congestive heart failure and $5.86 per day when treating hypertension.[8]

Eplerenone may have a lower incidence than spironolactone of sexual side effects such as feminization, gynecomastia, impotence, low sex drive and reduction of size of male genitalia.[8] This is because other antimineralocorticoids have structural elements of the progesterone molecule, causing progestogenic and antiandrogenic outcomes.[3] When considering taking these medicines, it is important to note the variations in their ability to offset the nongenomic effects of aldosterone.[3]

Eplerenone - Wikipedia

...

Eplerenone: A Selective Aldosterone Receptor Antagonist (SARA)

ABSTRACT
Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensinconverting enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels — a phenomenon termed “aldosterone synthesis escape.” Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone — the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs) — is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

CONCLUSION
Eplerenone will be the first drug in a new class of SARAs. The ability to effectively block the MR while avoiding limiting side effects promises to be an important advancement in the chronic treatment of life-threatening cardiovascular disorders. Ongoing phase III trials in hypertension and heart failure will soon reveal if the promising preclinical and phase II clinical data can be extended to large patient populations and are likely to uncover additional benefits of this unique agent.

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Do not trust spironolactone/eplerenone or any other receptor blocking substance.

Plasma potassium and plasma aldosterone shoot up when you block the receptor.

 

[GorillaHead]

The biggest questions we need to answer are

is aldosterone or cortisol the primary substance responsible for mineral corticoid receptor activation.

what causes the uoregulation of mineral corticoid receptor in endothelial tissue

 

[GorillaHead]

Do not trust spironolactone/eplerenone or any other receptor blocking substance.

Plasma potassium and plasma aldosterone shoot up when you block the receptor.

We need to find ways to do regulate the expression of the receptor rather than block it

 

[Estradiol]

We need to find ways to do regulate the expression of the receptor rather than block it

Or you can inhibit the synthesis. So it won't circulate in your blood or won't activate receptor.

Keep in mind that high plasma aldosterone is an indicator of heart failure.

 

[wavelength123]

High cortisol / cortisol excess binds aggressively to the MR which can cause high plasma aldosterone

it all always traces back to cortisol and I’d rather target 11bHSD1/2 instead of playing with Eplenorone

 

[GorillaHead]

High cortisol / cortisol excess binds aggressively to the MR which can cause high plasma aldosterone

it all always traces back to cortisol and I’d rather target 11bHSD1/2 instead of playing with Eplenorone

okay but why is dht locally elevated in the scalp why don’t we see this in other areas of the body.

There’s only a few possible explanations. Balding has to do with the brain. Scalp vasculature is highly sensitive to damage due to its tightness Of the galea or subaceous glands and fats have something to do with it.

 

[GorillaHead]

Here’s the thing potassium is a big player in all this. Minoxidil forces potassium in cell boom hair growth. Whether that’s due to the potassium begin forced in the endothelial cell or epithelium not sure.

what causes hypopolarization? What are the causes of calcium being forced into a cell

 

[mrchibbs]

okay but why is dht locally elevated in the scalp why don’t we see this in other areas of the body.

There’s only a few possible explanations. Balding has to do with the brain. Scalp vasculature is highly sensitive to damage due to its tightness Of the galea or subaceous glands and fats have something to do with it.

I may be wrong but we do see elevated DHT in many other tissues; lungs, prostate etc.

 

[mrchibbs]

Really nice civilized informed discussion guys. Nice to see.

 

[GorillaHead]

I may be wrong but we do see elevated DHT in many other tissues; lungs, prostate etc.

Def in prostate you are right. Perhaps we see that also in lungs for asthma?

interestingly enough pressure seems to be the cause of the prostate Upregulating dht

 

[GorillaHead]

Minoxidil causes hyperpolarization. Which is the normal state.

Spiro probably helps revert the cell back to the normal state.


whatever is causing the depolarization is what we need to look into

 

[wavelength123]

Hyperglycemia causes depolarization. When glucose rises, ATP/ADP increases, metabolism is stimulated, this normally closes the kATP channels, depolarizing cells, opening up Calcium channels, causing calcification and disease. Calcification of tiny vessels hits first: this could be up in the scalp, or down in the penis. Why do T1D males seem to exhibit great hair? Well they know they can’t let their blood sugar go crazy.

Back to cortisol: look at Shawn baker. Dude massively over trains, has standard fasted low insulin, low test, mega high A1c and fasted glucose. This is what cortisol does. Just one example among many. Keto zealots will say it’s because their cells have a longer lifespan or whatever but that’s their head in the sand strategy.

I think blood sugar should be absolutely rock stable in the mid upper part of normal. This implies avoiding high insulin foods / high glycemic load. To avoid HYPOglycemia and relying on cortisol-adrenaline-GH, I’d make sure that liver glycogen is in check as well. This implies eating fructose/galactose throughout the day and pre bed. Anecdotal: been sleeping like a log chugging whole milk at night.

 

[wavelength123]

Note that Cialis also opens up potassium channels. Would make sense that something that works down there might have beneficial effects up there, and vice versa

 

[mrchibbs]

Note that Cialis also opens up potassium channels. Would make sense that something that works down there might have beneficial effects up there, and vice versa

Aspirin also mimics the effects of cialis extremely well.

 

[mrchibbs]

Anecdotal: been sleeping like a log chugging whole milk at night.

Good for you! I’ve always suspected whole milk to be so much better, if one is not concerned with their weight, because the fat content allows the protein to be digested slowly throughout the night. And with the calcium, that pretty much prevents excess levels of cortisol, parathyroid etc. during sleep.

 

[GorillaHead]

Hyperglycemia causes depolarization. When glucose rises, ATP/ADP increases, metabolism is stimulated, this normally closes the kATP channels, depolarizing cells, opening up Calcium channels, causing calcification and disease. Calcification of tiny vessels hits first: this could be up in the scalp, or down in the penis. Why do T1D males seem to exhibit great hair? Well they know they can’t let their blood sugar go crazy.

Back to cortisol: look at Shawn baker. Dude massively over trains, has standard fasted low insulin, low test, mega high A1c and fasted glucose. This is what cortisol does. Just one example among many. Keto zealots will say it’s because their cells have a longer lifespan or whatever but that’s their head in the sand strategy.

I think blood sugar should be absolutely rock stable in the mid upper part of normal. This implies avoiding high insulin foods / high glycemic load. To avoid HYPOglycemia and relying on cortisol-adrenaline-GH, I’d make sure that liver glycogen is in check as well. This implies eating fructose/galactose throughout the day and pre bed. Anecdotal: been sleeping like a log chugging whole milk at night.

so chromium?



also guys i was going through my blood work and something interesting i noticed was potassium levels.

when on a cycle of androgens they were lower. When healthy and no substance use they were higher and when i started losing hair they were lower than even when i was on androgens and when my hairloss seems to slowed down alot or stabilized a bit they are back to the normal number. Of 3.9.

 

[wavelength123]

Androgens promote calcium influx inside the cell so it’s possible that potassium follows to balance it all out.

 

[Ableton]

Have potassium channel opener protocols been tried? Meaning a multitude of interventions just targeting this aspect

 

[md_a]

I did a forum search about licorice and found several comments made by Travis regarding it and hair regeneration, I selected only a small part. Licorice is an interesting plant due to its ability to treat hirsutism and hair regeneration on the scalp, at least on paper.


Travis:

I went down this rabbit hole a bit more last week, and I found-out some interesting stuff.

There is an enzyme in the skin which turns cortisone into cortisol, but it has a counterintuitive name. It's called 11β-hydroxysteroid dehydrogenase type I; and if you look it up, you will probably find that it converts cortisol into cortisone like the name implies—the reverse reaction. This is true, but the enzyme is reversible; it goes both ways, and this depends on the NADH/NAD⁺ ratio. In the skin, this enzyme runs in the nonintuitive direction at a rate about 10:1 that of the reverse. It goes both ways everywhere, but which direction and how much depends on the tissue. This is why this enzyme is so confusing at first.

Cortisol inhibits growth everywhere; this appears to be one of it's main function. No hormone can slow the growth of hair follicles more than cortisol.

There is a strong natural inhibitor of this enzyme called glycyrrhizic acid, and it's found in licorice root. This has been demonstrated to increase the hair's rate of growth in mice. As far as I know there has only been one study on this, but the mechanism is clear: glycyrrhizic acid inhibits the enzyme 11β-hydroxysteroid dehydrogenase preventing the conversion of cortisone into cortisol in the skin. Other drugs which inhibit this enzyme show increased cell growth, proving that cortisol is normally-produced on the skin by this enzyme.

But this is not to be taken internally, as it inhibits a related enzyme called 11β-hydroxysteroid dehydrogenase type II. This exists in the kidney in high amounts and drives the reverse reaction: it turns cortisone into cortisol. Both type II and type I have the same name, but they are different enzymes. Type II is not reversible and goes one way, while type I is found to work in either direction. In some articles, biochemists refer to the 11β-hydroxysteroid dehydrogenase type I as 11β-hydroxysteroid oxidoreductase, or simply 11β-hydroxysteroid reductase. This name is less confusing because now it does what we are actually calling it, reducing cortisol to cortisone. It could also be called 11β-hydroxysteroid hydrogenase.

So instead of writing 11β-hydroxysteroid dehydrogenase type I (oxidoreductase function) every time, I propose writing it as such: 11β-hydroxysteroid de-dehydrogenase. The double negative. I want to start using the term 11β-hydroxysteroid reductase, but it's only been used in seven articles. If someone searchers for it, they probably wont be able to find it. It's unfortunate that it has such a confusing name.

So with the enzyme, the hair follicle cortisol levels could be higher than that plasma levels. And since it converts cortisone into cortisol, this adds another steroidal risk factor for hair loss. The baldness-inducing mineralcorticoid receptor of this skin can be activated by aldosterone and cortisol, with cortisone becoming cortisol through 11β-hydroxysteroid dehydrogenase. Cortisone is proto-cortisol in this framework. This enzyme can easily be blocked by topical glycyrrhizic acid.

And spironilactone is a good inhibitor of the mineralcorticoid receptor itself, if you can source it. Cyclosporine A is another good one, but its a very large molecule and it has a hard time getting into the cell. But when it does, it works like nothing else.

I don't think that any these things should be taken internally.

Glycyrrhizic acid is the glucose ester found in the plant. When this is ingested, this bond is hydrolyzed and you get active glycyrrhetin. This is the active drug. Of course you don't want to take this internally; I just had to point-out that some molecules are naturally attached to glucose and this can confer a different name to the entire molecule.

Glycyrrhetin has a synonym: enoxolone.

Enoxolone | ≥99%(HPLC) | Selleck | Dehydrogenase inhibitor

It is actually a flavoring agent so it is easy to find.

Glycyrrhetin (enoxolone) looks like it would have excellent coconut oil solubility. This, along with spironolactone, would sound most effective according to the Cortisol/Aldosterone Theory of Hair Loss.

The Cause Of Baldness

...

Interesting. I'll have to look into how bacteria raise mineralcoticoids.

Your info goes to support the idea that hairloss is adrenal upregulation, thyroid downregulation similar to W.D Dencklas experiments.

Yeah, but it could also be partly the prevalence and 11β-hydroxysteroid dehydrogenase and which direction the reaction is going. With the NADH cofactor, it can only make cortisol from cortisone—it needs NAD⁺ to run the reverse reaction. Since this enzyme is freely reversible, the redox balance is actually what's causing this. This ties-in with those obscure gas theories, as sulfur containing blood gasses can theoretically affect redox balance.


Simply considering the adrenals themselves does nothing to explain why hypercorticolism doesn't cause hair loss on the entire head. Cortisol and aldosterone are a huge part of the puzzle, but I think the selectivity towards the scalp can only be explained through a combination with one of the following:

Decreased blood flow: The crown of the head gets less blood; this seems to be the place where the arteries terminate and become veins. Hats can decrease blood flow even further. The fact that minoxidil works lends support to this idea, but the fact that it doesn't work that well implies other factors.

Gasses: Blood-born sulfur gases could effect the NADH/NAD⁺ ratio by stealing electrons. Blood-born gasses concentrate in the finer terminal capillaries, a fact which has been used to explain the role of alkyl nitrites in Kaposi's Sarcoma.

Lack of Sunlight: The skin has a vitamin D receptor. Besides mineralcorticoid receptor-upregulated mice being totally bald, mice genetically-engineered to lack the vitamin D receptor are likewise (though not as extreme). These are the two receptors which influence hair growth in the mice the most.

It would be nice if we could find that one thing to pin it on, but I think it has to be a combination of at least two of these things—with high cortisol, cortisol, and aldosterone being the main factor. But perhaps just aldosterone or cortisol coupled with the inherently-reduced blood flow of the scalp is enough to explain all of it?


Perhaps I will look at a few more DHT studies. This could be a symptom of the same NADH/NAD⁺ ratio—as DHT is simply testosterone with two extra hydrogens. You would think that the enzyme 5α-reductase is NADH-dependent as well. If the DHT/T ratio correlates with the F/E ratio, then redox balance could be a factor.


CLASH said: ↑

so we have:

minoxidil: blood flow

stemoxydine: blood flow

glychyrrizic acid: anti-glucocorticoid of sorts at scalp

ketoconazole: anti-glucocorticoid

spironolactone: anti-glucocorticoid/ anti-androgenic effects

finasteride: anti- 5ar androgen

dutasteride: anti- 5ar androgen

cyclosporine: immunosuppressant


Travis:

Don't forget that the vitamin D and mineralcorticoid receptors are the only ones shown to cause total balding in mice. Upregulation of the glucocorticoid receptor does not cause major hair issues.


Spironolactone was originally designed to antagonize the mineralcorticoid receptor.


Cortisol is usually referred to as a glucocorticoid, but it has equal affinity for the mineralcorticoid receptor.


Cyclosporines effects on hair is considered independent of it's immunosuppression effects. I don't necessarily agree that this is correct, as molecular mechanisms can be subjective at times and I haven't even examined the immunosuppressive mechanism. But it would certainly be expected to act on T-cells differently that keratinocytes. There are a few detailed studies on the mechanism of cyclosporine A, and it's cousin FK-506, directly on epidermal cells. Western and Southern blots have been made to see exactly which genes are shifted. From this data, most researchers agree that it works on the mineralcorticoid receptor in epidermal cells (keratinocytes).


...


Travis said: ↑

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.

Haidut:

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]"

The opinions expressed here are strictly my own, and provided for informational purposes only. They are not a substitute for a doctor’s medical care/advice. Health decisions about anybody should always be vetted by a doctor. Click HERE for FTC mandated disclosure of material connection.


Travis:

What is implied is that it should be quite safe topically. The kidneys of course have the 11β-HSD₂ working in the opposite direction, so taking enoxolone—or its all natural glycone found in licorice—certain can cause extreme mineralocorticoid effects due to excessive cortisol. I am even fairly certain that this has killed people, as has other natural mineralocorticoid-active molecules like digoxin, oubain, and solanine.


But topically, I think you could expect local inhibition of cortisol synthesis. There are better drugs out there, that work in a more direct way, but this has been tested topically on rats and they all had survived and the all had increased hair growth—proving that cortisol was being inhibited and had not increased, as would occur if the skin were to contained 11β-HSD₂ and not 11β-HSD₁. Although spironolactone would be a more direct approach, topically, it is more expensive and difficult to acquire.

Haidut:

Concur. What about RU486 or even progesterone, both of which block GR? Maybe even combine exonolone and one of these two? What about topical emodin, which is a selective 11b-HSD1 inhibitor?

Travis:

Emodin is nice, cheap, unpatented, prevalent, and it works, but if you look at the binding affinities I think you'd note that enoxolone binds far stronger than anything else. As far as I can tell, enoxolone and its parent compound are the only 11β-HSD₁∶₂ inhibitors that bind so well as to be dangerous.

Hypothyroidism (Cortisol, Prolactin And Adrenal Hyperactivity) Causes Balding

Enoxolone - Wikipedia

...

18β‐Glycyrrhetinic acid: its core biological properties and dermatological applications

The anti‐inflammatory activity of GA makes it useful for hair loss treatment. A histopathological study showed that follicular microinflammation plays an integral role in the androgenetic alopecia that is widely recognized as male pattern baldness. In addition, GA inhibits the formation of DHT, which is clearly involved in baldness 40, 41.

Conclusion

18β‐Glycyrrhetinic acid is characterized by not only a wide range of valuable biological properties but also by interesting dermatological applications.

From the point of view of dermatology and cosmetology, its most significant asset is its anti‐inflammatory efficacy, which is particularly important as inflammation processes form the basis of many skin concerns, such as acne, atopic skin or ageing skin. GA exhibits anti‐inflammatory activity by suppressing the expression of pro‐inflammatory genes, inhibiting the production of inflammatory cytokines and influencing the transformation of arachidonic acid into pro‐inflammatory leukotrienes. Although its structure is similar to that of hormones secreted by the adrenal cortex, it does not promote the growth of viruses or fungi. Additionally, GA has antioxidant properties and this activity is directed to the inactivation of free radicals and inhibition of lipid oxidation. GA displays low toxicity against normal human cell lines, fibroblasts and keratinocytes.

Its substantial antimicrobial activity towards some strains of bacteria indicate that GA could be promising candidate for the treatment of microbial‐inducted diseases and skin disorders. In addition, it is worth noting that GA has an ability to strengthen the activity of some antibiotics towards MRSA: tobramycin, gentamicin, amikacin and polymyxin B. GA could be added to cosmetic formulations to not only support the primary functions of the active substance, but also to perform auxiliary functions as a preservative.

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Using hair growth activity, physical stability, and safety tests to study hair tonics containing ethanol extract of licorice (Glycyrrhiza glabra Linn.)

Objective: The purpose of this study was to determine the safety, physical stability, and hair growth activity of ethanol extract of licorice.Methods: In this study, 2.5%, 5%, and 10% licorice extract was formulated into a hair tonic as a tonic is easier to use and is not sticky like a semisoliddosage. The hair growth activity test was conducted by rubbing the hair tonic preparations on rabbit’s backs; subsequently, the hair length, hairthickness, hair weight, and hair density were measured. Quantitative analysis of glycyrrhizic acid from the licorice ethanol extract with a ultravioletspectrophotometer showed a level of about 156.65 mg/g or 15.665%. The physical stability test was performed on samples of the tonic stored at low(4±2°C), room (25±2°C), and high (40±2°C) temperature, and a cycling test was also performed. The safety test was performed using an eye irritationtest that employed the Hen’s egg test–chorioallantoic membrane (HET-CAM) method and a skin irritation test that employed the patch test method.Results: The hair tonics containing 5% and 10% licorice extract had an equivalent activity of hair growth and even better than the positive controlcontaining 2% minoxidil. The physical stability test showed that the licorice extract hair tonic has good physical stability. The results of the safety testshowed no skin irritation, whereas the HET-CAM test showed that the hair tonic containing licorice extract showed mild eye irritation.Conclusions: Licorice ethanol extract hair tonic solutions in concentrations of 2.5%, 5%, and 10% had hair growth activity similar to that of thepositive control (minoxidil). They have a good physical and chemical stability, also safe for topical use, except the 2.5% licorice ethanol extract hairtonic solution which caused mild eye irritation.

https://www.researchgate.net/public...l_extract_of_licorice_Glycyrrhiza_glabra_Linn

...

Complementary Therapies for Idiopathic Hirsutism: Topical Licorice as Promising Option

Abstract

Hirsutism is one of the most prevalent health problems in women. The aim of the study was to compare the effect of 755 nm alexandrite hair removal laser with that of alexandrite laser plus topical licorice on the improvement of idiopathic hirsutism. A double-blind, randomized placebo-controlled study was performed on 90 female subjects. The patients were divided into two groups: alexandrite laser plus 15% licorice gel (group A) and placebo (group B). Each subject received one of both products over one side of the face, twice daily for 24 weeks on the hirsute locations. Each group underwent five sessions of alexandrite laser at 6-week intervals. To minimize the effects of confounding variables, the test was performed on two separate zones of patients’ skin. The mean ± SD numbers of terminal hairs in group A were 7.05 ± 4.55 for zone 1 and 6.06 ± 3.70 for zone 2. In group B, they were 3.18 ± 1.75 for zone 1 and 2.49 ± 1.63 for zone 2. The difference in the mean number of terminal hairs was statistically significant between the two groups (), and there were no serious adverse reactions. The treatment of idiopathic hirsutism with 755 nm alexandrite laser plus topical licorice is more effective than alexandrite laser only.

Complementary Therapies for Idiopathic Hirsutism: Topical Licorice as Promising Option

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Topically applied glycyrrhizic acid causes hair removal in rats

https://www.tandfonline.com/doi/pdf/10.3109/13880209.2014.884608

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Symptomatic Protective Action of Glycyrrhizin (Licorice) in COVID-19 Infection?

Abstract

The role of the ACE2 enzyme in the COVID-19 infection is 2-fold, with opposing implications for the disease development. 1. The membrane bound angiotensin converting enzyme 2 (ACE2) serves as the entry point of COVID-19 2. Conversely, it supports an anti-inflammatory pathway. This led to the controversy of the impact of medications, which influence its expression. ACE2 is part of the wider renin-angiotensin-aldosterone system (RAAS) and is upregulated via compounds, which inhibits the classical ACE, thereby plasma aldosterone and aldosterone receptor (MR) activation. MR activation may therefore protect organs from binding the COVID-19 by reducing ACE2 expression. Glycyrrhizin (GL) is a frequent component in traditional Chinese medicines, which have been used to control COVID-19 infections. Its systemically active metabolite glycyrrhetinic acid (GA) inhibits 11beta hydroxysteroid dehydrogenase(11betaHSD2) and activates MR in organs, which express this enzyme, including the lungs. Does this affect the protective effect of ACE2? Importantly, GL has anti-inflammatory properties by itself via toll like receptor 4 (TLR4) antagonism and therefore compensates for the reduced protection of the downregulated ACE2. Finally, a direct effect of GL or GA to reduce virus transmission exists, which may involve reduced expression of type 2 transmembrane serine protease (TMPRSS2), which is required for virus uptake. Glycyrrhizin may reduce the severity of an infection with COVID-19 at the two stages of the COVID-19 induced disease process, 1. To block the number of entry points and 2. provide an ACE2 independent anti-inflammatory mechanism.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270278/

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Hair Growth Promotant Activity of Petroleum Ether

Root Extract of Glycyrrhiza Glabra L (Fabaceae) in Female Rats

http://www.bioline.org.br/pdf?pr12089

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Targeted Skin Overexpression of the Mineralocorticoid Receptor in Mice Causes Epidermal Atrophy, Premature Skin Barrier Formation, Eye Abnormalities, and Alopecia

Discussion

Genetic manipulation of several nuclear hormone receptors has revealed important roles in epidermal and hair follicle biology. Constitutive overexpression of the glucocorticoid receptor36,37,38 in the basal layer of the epidermis produces a phenotype that resembles human ectodermal dysplasia.39 K5-GR embryos have epidermal alterations ranging from smooth and thin skin with epidermal hypoplasia and underdeveloped dysplastic hair follicles and vibrissae to complete disruption of the cutaneous barrier and absence of skin at the cranial and umbilical regions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959477/

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Glucocorticoid Effect on Hair Growth Initiation: A Reconsideration

Abstract

It has been demonstrated by various workers in the past that glucocorticosteroids block hair growth. Using the mouse model for studying hair growth induction we reexamined the effect of topically applied steroids on hair growth to establish at what stage the steroid block acts. In accord with studies by others, we found that these steroids block hair growth at the point of anagen initiation, but that once the steroid applications are stopped, hair growth starts. Since steroid withdrawal alone did not induce hair growth, it is clear that these steroids do not block, either spontaneous or manipulated, hair growth induction, but they do block, the apparent next step, i.e., hair formation. Moreover, since hair growth could be induced even while the animals were being treated with the steroid, the induction step appears independent of the steroid block. These studies and those of others lead us to conclude that these steroids block the expression of hair-forming genes, but do not interfere with the signal(s) that initiates those genes. This system appears to be ideal for identifying the signals (perhaps, genes) responsible for initiating hair growth.

https://pubmed.ncbi.nlm.nih.gov/8352950/


Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation

Abstract

Glucocorticoids (GCs) exert their biological and therapeutical actions through the GC receptor (GR), a ligand-dependent transcription factor. Synthetic GC derivatives are widely prescribed for treating numerous cutaneous inflammatory and immune diseases due to their great efficacy. However, chronic treatment with GCs produces adverse side-effects including skin atrophy, delayed wound healing, and in certain cases, GC resistance. The mechanisms underlying the therapeutic actions of the GR in skin have been extensively studied; in contrast, the role of GR as a modulator of epidermal development and homeostasis has received less attention. The ubiquitous functional inactivation of GR results in defective epidermal formation although the underlying mechanisms have not been fully characterized. The use of transcriptomic approaches both in vitro and in vivo allowed the identification of genes that are regulated by GR in developing and adult skin. A main goal to understand the role of GR in skin biology is to identify primary transcriptional targets as well as the signaling pathways mediating GR action. Furthermore, it will be important to decipher the contribution of GR in the different cellular compartments of the skin, including keratinocytes of the interfollicular epidermis and hair follicles, and their respective stem cell progenitors. Additionally, recent findings indicating that the skin acts as a true peripheral endocrine organ implies greater complexity than originally thought. The local production of GCs and other steroid hormones should be considered as a modulator of skin function under homeostatic and diseased conditions. Finally, studying GR function in skin should take into account that the mineralocorticoid receptor may also mediate GC actions and/or regulate transcription either by itself or in combination with GR. Addressing these issues should help to elucidate the mechanisms by which Gr contributes to establishment of a competent epidermal barrier and may also have implications in the context of dermatological treatments based on GC-analogs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219166/

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Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation

Conclusions and Perspectives

Several transcriptomic analyses have reported that in keratinocytes, GR regulates the expression of a variety of genes, including those involved in apoptosis, cellular adhesion, lipid metabolism and formation of the stratum corneum. Based on these data, it is particularly relevant to perform functional studies that help to dissect the exact mechanisms by which GR regulates keratinocyte terminal differentiation and epidermal barrier formation. Alterations in these processes during embryogenesis can result in increased susceptibility of adult individuals to inflammatory skin diseases such as psoriasis and atopic dermatitis. Therefore, studying the mechanisms of GR function during development and identifying GR primary targets will be useful for designing therapies based on GC analogs. A major question that remains unanswered is whether the epithelial contribution of GR is required for normal skin development as well as to mediate the therapeutical actions of GCs in different skin diseases. In order to answer these questions, it is necessary to study a mouse model with constitutive GR inactivation restricted to keratinocytes.


Recently, several additional GR isoforms have been identified, although no information of their expression and activity has been reported in the skin. The tissue-specific expression patterns and post-translational regulatory mechanisms for these isoforms add further complexity to the understanding of GR signaling. GRβ has been postulated as a dominant negative form of GRα-dependent transcription that could be responsible for GC resistance in inflammatory diseases. Considering the wide use of the GCs in clinical practice, the variable outcome of GC treatment among patients, and the phenomenon of GC resistance, it is a main goal to determine the underlying causes for the differential GC responses in order to design and adjust the GC-based treatments to achieve best efficacy with minimal adverse effects.


Additionally, given the interactions among different nuclear hormone receptors and the prescription of combined hormone analogs for treating skin diseases, future work should be aimed at deciphering the complex interactions between different hormone signaling pathways. Supported by recent findings, it seems particularly relevant to analyze a possible cross-talk between GR and MR in keratinocytes, which may have consequences in GC-based therapies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219166/

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The mineralocorticoid receptor as a novel playerin skin biology: beyond the renal horizon?

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.2009.01011.x