Fascinating New Paper On Hair Loss

[brocktoon]

Rob at perfecthairhealth dot com has published an interesting peer-reviewed paper with his theory on the causes of androgenic alopecia -- thought some here might enjoy it.
A hypothetical pathogenesis model for androgenic alopecia: clarifying the dihydrotestosterone paradox
http://www.medical-hypotheses.com/article/S0306-9877(17)31041-1/fulltext

 

[Hairfedup]

Interesting but can you break down the conclusion for a layman?

 

[brocktoon]

Interesting but can you break down the conclusion for a layman?

Honestly, no, I can't put it into layman's terms, as it's a long research paper with certain technical language that I don't fully grasp. Basically, the author is saying there are various inter-related factors at play in men's hair loss and that MPB cannot be primarily caused by DHT (the testosterone derivative that is often blamed as the main cause of MPB).

 

[Dhair]

Honestly, no, I can't put it into layman's terms, as it's a long research paper with certain technical language that I don't fully grasp. Basically, the author is saying there are various inter-related factors at play in men's hair loss and that MPB cannot be primarily caused by DHT (the testosterone derivative that is often blamed as the main cause of MPB).

There is simply no real evidence that DHT causes hair loss. The entire hypothesis is null and void.

 

[brocktoon]

There is simply no real evidence that DHT causes hair loss. The entire hypothesis is null and void.

Many authorities on the matter do doubt and/or minimize the role that DHT plays in contributing to hair loss, but comparatively few completely exclude DHT as even a partial cause of hair loss.

 

[Dhair]

Many authorities on the matter do doubt and/or minimize the role that DHT plays in contributing to hair loss, but comparatively few completely exclude DHT as even a partial cause of hair loss.

I cannot see how it has a causative role. Certainly the mainstream explanation makes no logical sense.

 

[brocktoon]

I cannot see how it has a causative role. Certainly the mainstream explanation makes no logical sense.

Right -- the "mainstream" explanation and that of the makers of Propecia is certainly bogus or at least highly incomplete in terms of the cause of MPB. Are you saying you don't think DHT plays ANY role at all?

 

[Dhair]

Right -- the "mainstream" explanation and that of the makers of Propecia is certainly bogus or at least highly incomplete in terms of the cause of MPB. Are you saying you don't think DHT plays ANY role at all?

Nope. Not at all. The DHT in the balding scalp is probably an adaptive change to stress. T and DHT make hair grow thicker and stronger. The original research on the pseudohermaphrodites was conducted by incompetent scientists. High progesterone and youth steroids (including DHT) = no hair loss. No trials involving DHT have had patients drop out due to sudden hair loss. Hair Like a Fox should be required reading for every moron in the medical community. Elevated prolactin is probably the number one cause of hair loss. Doctors rarely check prolactin for any reason. My primary asked, "Are you lactating?" and laughed at me when I asked for the test. These people are not to be taken seriously.

 

[nbznj]

everything dhair is saying is a fantastic +1. As a pharmacist myself I understand I am very ignorant about this and have been fed lies at school. What a disgrace. The other topic we have here on hair loss has everything you need

Read here: Evidence That Cortisol Really Does Cause Hair Loss

I know that this site is more into supplementing other androgens but to me the T/C ratio is critical to health. You can actually deal with a pretty high cortisol when you're on TRT (T doesn't lower Cortisol anyways, but it keeps the androgen expression high so that your health and hair aren't crushed by estrogens, prolactin...)

 

[Dhair]

everything dhair is saying is a fantastic +1. As a pharmacist myself I understand I am very ignorant about this and have been fed lies at school. What a disgrace. The other topic we have here on hair loss has everything you need

Read here: Evidence That Cortisol Really Does Cause Hair Loss

I know that this site is more into supplementing other androgens but to me the T/C ratio is critical to health. You can actually deal with a pretty high cortisol when you're on TRT (T doesn't lower Cortisol anyways, but it keeps the androgen expression high so that your health and hair aren't crushed by estrogens, prolactin...)

Yes, high T is important. I think that people exaggerate the risks of TRT on this forum, and I think the reason for side effects is due to endocrinologists being so irresponsible in how they treat patients.

 

[Travis]

He's right. Valerie Randall proved that DHT when applied directly actually stimulated hair growth.

I read it, and the article first starts out with a summary of nearly all observations regarding hair loss. He ends up concentrating on scalp tension, fibrosis, and calcification—with calcification being induced by androgens more‐or‐less directly:

'In mice, dose-dependent DHT and testosterone injections increase arterial calcification lesions by 300–400% [47].' ―Robert English​

The mechanisms linking androgens to fibrosis are not very straightforward, and his final conculsion seems most centered around scalp tension. He does note that physical tension can induce cyclooxygenase‐2, and explains the prostaglandin D₂ in this manner, but I will point out that Garza had also found increased ptgds to match—this is the enzyme which creates prostaglandin D₂ from prostaglandin H₂; this enzyme is induced by cortisol, a steroid Robert English mentions not once.

Since the evidence linking prostaglandin D₂ to hair loss is so strong, I like to focus on that. I think the patterning is just as well explained by the microcirculation: The steroid transfer rate from blood binding proteins—such as cortisol transferred from albumin—has been proven to increase in microcirculatory regions. I think the ptgds gradient observed by Garza, and others, would be superimposable over the cortisol gradient since cortisol is the only thing shown to induce ptgds.

But since he focuses on fibrosis, calcification, and tension, the fundamental final pathway is more‐or‐less reduced blood flow. Prostaglandin D₂ has been shown in dozens of experiments to constrict the lungs, and also to constrict the blood vessels in a few others. One good thing about having reduced blood flow as the final mechanism, besides it being logical, is that it includes nearly all observations. As long reduced blood flow can be logically explained somehow, then most alternative explanations could have merit—disagreement coming only from the relative contributions of each particular one.

I think the two best explanations not touched on in the article for how androgens cause hair loss is through interferon-γ from the thymus and cortisol from the adrenals. In humans, androgens increase both of these and both can cause hair loss (as seen in mice overexpressing either interferon-γ or the mineralocorticoid receptor on the skin—both are nearly completely hairless).

But even if calcium plays only a minor role, people should get enough vitamin K and vitamin D to keep their arteries from calcifying. Warfarin, a vitamin K antagonist, causes rapid calcification of the arteries. Vitamin K is used as a cofactor for the enzyme which creates the γ-carboxyglutamate domain on proteins; this domain strongly binds Ca²⁺ ions and keeps them from precipitating in the blood (with phosphate).

 

[Dhair]

He's right. Valerie Randall proved that DHT when applied directly actually stimulated hair growth.

I read it, and the article first starts out with a summary of nearly all observations regarding hair loss. He ends up concentrating on scalp tension, fibrosis, and calcification—with calcification being induced by androgens more‐or‐less directly:

'In mice, dose-dependent DHT and testosterone injections increase arterial calcification lesions by 300–400% [47].' ―Robert English​

The mechanisms linking androgens to fibrosis are not very straightforward, and his final conculsion seems most centered around scalp tension. He does note that physical tension can induce cyclooxygenase‐2, and explains the prostaglandin D₂ in this manner, but I will point out that Garza had also found increased ptgds to match—this is the enzyme which creates prostaglandin D₂ from prostaglandin H₂; this enzyme is induced by cortisol, a steroid Robert English mentions not once. Also, the induction of cyclooxygenase‐2 will also produce the hair‐stimulating prostaglandin E₂. The induction of cyclooxygenase‐2 would not be expected to change the prostaglandin D₂/E₂ ratio.

Since the evidence linking prostaglandin D₂ to hair loss is so strong, I like to focus on that. I think the patterning is just as well explained by the microcirculation: The steroid transfer rate from blood binding proteins—such as cortisol transferred from albumin—has been proven to increase in microcirculatory regions. I think the ptgds gradient observed by Garza, and others, would be superimposable over the cortisol gradient since cortisol is the only thing shown to induce ptgds.

But since he focuses on fibrosis, calcification, and tension, the fundamental final pathway is more‐or‐less reduced blood flow. Prostaglandin D₂ has been shown in dozens of experiments to constrict the lungs, and also to constrict the blood vessels in a few. One good thing about having reduced blood flow as the final mechanism, besides it being logical, is that it includes nearly all observations. As long reduced blood flow can be logically explained somehow, then most alternative explanations could have merit—disagreement coming only from the relative contributions of each particular one.

I think the two best explanations not touched on in the article for how androgens cause hair loss is through interferon-γ from the thymus and cortisol from the adrenals. In humans, androgens increase both of these and both can cause hair loss (as seen in mice overexpressing either the mineralocorticoid or interferon-γ on the skin—both are nearly completely hairless).

But even if calcium plays only a minor role, people should get enough vitamin K and vitamin D to keep their arteries from calcifying. Warfarin, a vitamin K antagonist, causes rapid calcification of the arteries. Vitamin K is used as a cofactor for the enzyme which creates the γ-carboxyglutamate domain on proteins; this domain strongly binds Ca²⁺ ions and keeps them from precipitating with phosphate in the blood.

Rob focuses on scalp tension, fibrosis and calcification because he has a mechanical approach to the hair loss problem focusing mostly on scalp massage. I have talked to him directly, and he is aware of both Ray Peat and Danny Roddy and he agrees that limiting PUFA is necessary for stopping hair loss. Speaking of vitamins D and K - have you read any literature regarding what an optimal ratio might be for daily supplementation?

 

[Travis]

Rob focuses on scalp tension and calcification because he has a mechanical approach to the hair loss problem focusing mostly on scalp massage. I have talked to him directly, and he is aware of both Ray Peat and Danny Roddy and he agrees that limiting PUFA is necessary for stopping hair loss. Speaking of vitamins D and K - have you read any literature regarding what an optimal ratio might be for daily supplementation?

About 5,000·IU seems enough vitamin D, but vitamin K is so nontoxic that it doesn't much matter how much you take. The IOM sets upper reference values for vitamins, but when they came to vitamin K they literally couldn't even establish one.

Don't think these vitamins oppose eachother at all, and don't think there needs to be a ratio. I do realize that ionic ratios like Na⁺/K⁺ and Ca²⁺/Mg²⁺ are more important than amount of each consumed alone, but vitamin K isn't even a hormone. Both vitamin A and vitamin D are vitamin‐hormones which work on transcription factors within the nucleus; since these two vitamins oppose eachother to a degree, a ratio certainly makes sense. But vitamin E and vitamin K work in other ways: vitamin E basically as just a lipid‐phase antioxidant on the cell membrane and vitamin K as a lipid‐ and water‐soluble enzymatic cofactor.

As soon as all the enzymes are saturated, additional vitamin K has no extra calcemic effect. So unlike vitamin D, there is absolutely no danger in taking more than necessary. Excess vitamin K isn't thought to do anything besides functioning as a general antioxidant, almost like a polyphenol or curcumin, so even taking a bit more could be beneficial.

But vitamin K₂ can also function a bit like CoQ₁₀ in the electron transport chain, so that is andother non‐conventional effect to consider.

 

[Dhair]

About 5,000·IU seems enough vitamin D, but vitamin K is so nontoxic that it doesn't much matter how much you take. The IOM sets upper reference values for vitamins, but when they came to vitamin K they literally couldn't even establish one.

Don't think these vitamins oppose eachother at all, and don't think there needs to be a ratio. I do realize that ionic ratios like Na⁺/K⁺ and Ca²⁺/Mg²⁺ are more important than amount of each consumed alone, but vitamin K isn't even a hormone. Both vitamin A and vitamin D are vitamin‐hormones which work on transcription factors within the nucleus; since these two vitamins oppose eachother to a degree, a ratio certainly makes sense. But vitamin E and vitamin K work in other ways: vitamin E basically as just a lipid‐phase antioxidant on the cell membrane and vitamin K as a lipid‐ and water‐soluble enzymatic cofactor.

Excess vitamin K isn't thought to do anything besides being a general antioxidant, almost like a polyphenol or curcumin, so taking any more than necessary could even be slightly beneficial. But as soon as all the enzymes are saturated additional vitamin K has no extra calcium effects, so unlike vitamin D there is absolutely no danger in taking much more than what is necessary.

What I mean to ask is, is there an optimal dose for vitamin K that would directly offset potential hypercalcemia risks of continuous vitamin D supplementation?

 

[Travis]

What I mean to ask is, is there an optimal dose for vitamin K that would directly offset potential hypercalcemia risks of continuous vitamin D supplementation?

It doesn't work like that because.. .

There is a limit of how many calcium‐binding proteins can be contained within the blood. Vitamin K helps to turn the carboxyl domains (–CO₂⁻) into a dicaboxyl domain (–(CO₂⁻)₂). These two carboxylates each have one negative charge to match calcium's 2+ charge, and the spacing is suitable to accommodate the size of the Ca²⁺ ion. This turns the protein into a high‐affinity calcium binder, but its capacity is finite—limited both by the number of dicaboxyl domains on each protein and the total number of circulating proteins. Once all blood proteins have all their exterior glutamate side‐chains modified, there can be no more calcemic benefit of vitamin K. The test for vitamin K sufficiency is actually dependent upon these proteins, and it determines how many glutamates are modified.

So when it comes to vitamin K, there is essentially one proper dose and this is not really dependent on any other vitamin. A graph of calcium‐binding ability vs vitamin K concentration would rise sharply and then flatline at a certain concentration. I'm not entirely sure what this concentration is, and had never bothered to check since I eat leaves every day.

 

[Such_Saturation]

Wait so minoxidil helps just by vasodilation?

 

[Travis]

Wait so minoxidil helps just by vasodilation?

I think it's possible. I mean, it all has to work somehow.. .

The keratin genes themselves appear to be under control of the PPAR receptors and the vitamin D receptor, and there doesn't seem to be any transcriptional theories for hair loss besides those for enzymes which make prostaglandin D₂—which has been shown to cause artery constriction and Ca²⁺ influx. So on the fundamental level there seems to be no problem with actual hair synthesis, and every observation seems to end with 'reduced blood flow' (i.e. fibrosis, calcification, tension). I think this makes sense because you generally see a progressive thinning and not a one‐time shedding that you'd see with apoptosis or hair follicle ejection. Perhaps the rise‐and‐fall of prostaglandins during the hair cycle simply meter blood flow? The prostaglandins E₂ and D₂ really do seem to have opposing actions on vascular muscle, as shown by experiments on animals.

 

[DrJ]

I didn't read the article yet, but got the email from Rob announcing it and this is his summation if it would be helpful:

Essentially, the paper achieves four things:

1. It challenges the commonly held belief that the hormone dihydrotestosterone (DHT) directly causes hair loss
2. It looks beyond DHT and catalogues several other biomarkers also associated with hair thinning
3. It builds a better pathogenesis model for what causes hair loss — a model that accounts for (1) these additional biomarkers, (2) DHT’s relationship with hair loss and hair growth, and (3) why DHT-reducing drugs stop hair loss, but don't lead to full hair recovery
4. It uncovers three targets to potentially improve treatment outcomes... and maybe lead to full hair regrowth

 

[Hairfedup]

Hey guys I see how knowledgeable you all are on hair loss, if you could please check out my thread and help me/give me some advice I'd really appreciate it. Thank you.

 

[Pablo Cruise]

Interesting but can you break down the conclusion for a layman?

Read the conclusion. This is what stood out for me and the author's hypothesis:
Scalp tension may be a cause of inflammation and fibrosis. DHT, Estrogen hormones etc play a role in the muscle tension. Some physiological findings, ie, lower oxygen in AGA, fibrosis, calcification of the arteries, may be causative or associative.
Also there are changes in skin biology, bacteria and fungi, that may increase sebum production and DHT. Very interesting and novel news for AGA.

Well this article supports what I have thought to some degree and that is my anti dandruff shampoo treatments help hair loss...no loss for 7 months now. I do not work for any shampoo companies. lol but should some people consider it?
(I use Selenium Sulfide 2.5% once a week and Salicyclic Acid-Sulfur 2.5%/2.5% 1-2 tmes a week but leave on for 10-15 minutes. On my "off" days I use a zinc shampoo (anti DHT) 1 or 2%, ie, DHS Zinc). If any of you try this most definitely report back in 8 weeks.