Inflammation, fibrosis, and the androgenic link.

[docj077]

So, I've been trying to find studies that demonstrate what the outcome of androgenic alopecia truly is at the pathologic level. It's been tough to find a whole lot. But, here's what I've found the likely end result is of sustained inflammation and fibrosis secondary to androgenic inhibition of the hair follicle at the molecular level.

There is a research article here and a discussion of keratin.com that discusses the article.

So, what I need to know and what I need to research apparently is, do men who have androgenic alopecia actually have reversal or maintenance of their hair while on immune system modulating drugs or just simple anti-inflammatories? I've read that drugs that target TNF-alpha have increased hair growth as a side effect. However, no current TGF-beta drugs currently exist, which is most likely the primary mediator of the fibrosis that occurs in hair loss.

Basically, our hair loss treatment goals should be to inhibit DHT formation, inhibit androgen receptor binding, inhibit TGF-beta and TNF-alpha downstream effects and fibroblast production of fibrin and collagen around the follicle, and finally, the inflammation process.

Case study: fibrosing alopecia in a pattern distribution localized on alopecia androgenetica areas and unaffected scalp.Amato L, Chiarini C, Berti S, Bruscino P, Fabbri P.
Second Dermatology Clinic, Department of Dermatological Sciences, University of Florence, Italy.

A 54-year-old man with a 24-year history of androgenetic alopecia was referred to the Department of Dermatological Sciences with follicular inflammatory lesions leading to scleroatrophy in the vertex region (Figure 1) of 1-year duration.These lesions appeared a year ago. There was no previous history of this condition. On examination, the patient showed confluent infiltrative follicular lesions on the frontoparietal and occipital scalp (Figure 2). Some lesions evolved into erosions that developed in ivory white scleroatrophy within weeks. These lesions were localized both in and outside of are as affected by alopecia androgenetica and were associated with mild pruritus. Histopathologic examination, performed on an early lesion of the vertex, documented a mild thinning of follicular epithelium associated with an intense lymphohistiocytic perifollicular infiltrate. The damage of the basal cell layer was limited to the follicle, while epidermis was intact.In particular, follicular keratinocytes under the isthmus showed a very intense degeneration exactly where the infiltrate was the most prominent. The damage of the hair sheath was under the isthmus and involved the lower portions of the follicles (including the hair bulbs). The inflammatory infiltrate was exclusively represented by perifollicular lymphohistiocytes. Finally, a connective fibrotic shell with numerous fibroblasts formed a sheath around the atrophic follicle (Figure 3).Results of laboratory investigations (including complete blood cell counts, basal thyroid-stimulating hormone, C-reactive protein, serum ferritin levels, B and C hepatitis markers, antinuclear antibodies, and cultural examinations) were negative.We diagnosed the patient with fibrosing alopecia in a pattern distribution.


http://www.keratin.com/at/at007.shtml

Be aware, these cases are severe, but the end result is the same in all individuals.

"Fibrosing alopecia in a pattern distribution clinical features

Biopsy specimens of early lesions demonstrated hair follicle miniaturization and a lichenoid inflammatory infiltrate targeting the upper follicle region of the miniaturizing hair folicles. Advanced lesions under the microscope showed perifollicular lamellar fibrosis (growth of excessive amounts of fibrous tissue) and completely fibrosed follicular tracts, identical to end-stage lichen planopilaris, pseudopelade, or follicular degeneration syndrome.
Differential Diagnosis

The inflammation in Fibrosing alopecia in a pattern distribution (FAPD) seems to target the small-miniaturizing follicles, a finding that has not as yet been noted in lichen planopilaris. But then again, this may be because no one else has as yet looked for this particular finding.

Fibrosing alopecia in a pattern distribution shares similar clinical features with Central centrifugal cicatricial alopecia, especially the manner in which the hair loss is centered on the crown and vertex, and lamellar fibroplasia and chronic perifollicular inflammation. FAPD can be distinguished from CCCA by virtue of its lichenoid histological features, but the histological overlap with different hair loss conditions may make it difficult to assign a specific diagnosis.



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Fibrosing alopecia in a pattern distribution pathology

The biopsy specimens of patients with fibrosing alopecia in a pattern distribution as studied by Trueb and Zinkernagel showed evidence of lichenoid inflammation with destruction of the follicular basilar epithelium. This inflammation was most evident around the upper half of the follicle. Terminal hairs (deep-rooted coarse hairs) as well as vellus hairs (tiny colorless hairs) were affected. Advanced lesions under the microscope showed perifollicular lamellar fibrosis (growth of excessive amounts of fibrous tissue) and completely fibrosed follicular tracts, as seen in end-stage lichen planopilaris, pseudopelade, or follicular degeneration syndrome.



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Fibrosing alopecia in a pattern distribution treatment

During the course of the research study, three patients seemed to have responded to “antiandrogenâ€￾ therapy and appeared to have experienced a halt in the progress of the distinctive form of alopecia. An antiandrogen obstructs the effects of androgens (male hormones) normally by blocking the receptor sites. As this is a relatively newly identified condition, there is very little research on effective treatment."


Thoughts and opinions are welcome.

 

[Felk]

I'm glad to see you're one of the intelligent ones talking about other ways to combat hair loss besides simply blocking DHT. Thanks for posting this

I don't understand enough to follow all of the studies, but you seem to share a similar opinion to Dr Proctor - he believes the immunological side of treating hair loss is the most important.

Basically, our hair loss treatment goals should be to inhibit DHT formation, inhibit androgen receptor binding, inhibit TGF-beta and TNF-alpha downstream effects and fibroblast production of fibrin and collagen around the follicle, and finally, the inflammation process.

I've heard of inhibiting the formation of DHT, blocking androgen receptors, and combating inflammation, but how does one "inhibit TGF-beta and TNF-alpha downstream effects and fibroblast production of fibrin and collagen around the follicle" ?

I've been meaning to ask you about some of your alternative things in your regimen - I assume the things like curcumin, soy, green tea are targeting the things i mentioned above?

 

[docj077]

Curcumin is a known anti-fibrosis herb that is proven in its effectiveness both in vitro and in vivo. It's used to prevent digestive system cancers, melanoma, and even some cancers involving the immune system. One of its greatest achievements is its ability to prevent and even reverse fibrosis within kidneys that are undergoing an inflammatory process. It does this by inhibiting TGF-beta and I believe it can also inhibit TNF-alpha.

Green Tea extract is a TNF-alpha inhibitor, as well as, a very mild DHT synthesis blocker. I use it as a TNF-alpha inhibitor, but I mostly use it for the recent research that clearly demonstrates it lowers mortality secondary to cardiovascular events. Not only that, but it seems to make my face not seem so oily.

My hairloss plan is actually a little out of date. I haven't been using my finasteride for nearly three and half weeks now. I made that decision based upon some studies I read that showed the molecular problems that may occur with using 5alpha reducatase inhibitors. I also quit, because it was affecting my school work a lot.

Even though I've stopped by finasteride, my hair hasn't started shedding in giant piles everywhere. In fact, I don't think I've lost a single hair since I stopped. Stopping finasteride was only one part of hopefully showing that only inhibiting the downstream effectors like TGF-beta and TNF-alpha could possibly prevent hairloss.

It's actually been shown either in vitro or in vivo (sorry, but I can't remember) that finasteride actually decreases TGF-beta due to preventing the formation of DHT in the first place.

 

[Felk]

Thanks for that! I might get my hands on some curcumin and green tea supplements.

One thing i've been meaning to ask you regarding your theory about finasteride having effects on people's cognitive ability. You've probably taken this into account, but what about the pseudohermaphrodytes? (sp)

The people from the Dominican Republic born without 5AR2, found to have no body hair, no hair loss, and underdeveloped penises, but otherwise led healthy lives. Wouldn't they have suffered from these mental problems as well, and if so, why was that never recorded along with everyone else about them?

 

[docj077]

It's tough to say, but there would quite possibly be a difference between not being born with 5AR type II and suddenly taking 5AR type II away from the body with a drug.

People being born without 5AR type II could possibly have developed brains that had no need for any metabolite of that enzyme.

I really don't know, but I do know that I've been thinking a lot clearer and feeling a lot better since I got off the drug.

 

[CCS]

It would be nice if curcumin orally could replace dutasteride. That would save a lot of money. But until I hear of side effects in a significant percent of users that is greater than placebo side effects, I like having the extra insurance.

So the vote on pine oil is still out?

 

[docj077]

I don't know a whole lot about the pine oil. I've tried finding studies regarding beta-sis, but there seems to be very little research out there. In fact, I don't even know what it does. From what I keep seeing on the boards, everyone is leading me to believe that metabolizes testosterone into estrogen.

Is that right?

 

[CCS]

Some have said that, but I highly doubt it. If you think about it chemically, beta sis is a steroid, just like spironolactone, finasteride, dutasteride, cholesterol, estrogen, DHT, testosterone. 5ar and aromatases are giant molecules coded for by DNA. Even if we could synthesize them, they are too big for topicals, and would get digested if we eat them. How could beta sis possibly metabolise testosterone into estrogen? Maybe it could chemically react to give testosterone two extra double bonds. But looking at the two structures, I doubt they would react. At best beta sis might mimic estrogen. Micheal berry is doing a test to see if it blocks the androgen receptor. It is in saw palmetto in low concentrations, after all.

I think the only thing it can do is get jammed inside 5ar or block the androgen receptor, and that's an if.

I'd like to know if estrogen grows hair. But while women have more hair and estrogen than men, they also have less testosterone. And while older men have more estrogen, they also have more DHT. The two seem to naturally change inversly, so I don't think we have enough information to know what estrogen does to hair. We just know it grows fat. Some guys are taking aromatase inhibitors because they think the excess estrogen is worse than testosterone, and others are eating estrogen like compounds because they think they help, since they think alcoholics tend to have more hair.

If beta sis can act like cholesterol, then I don't want it gumming up my capilaries. I'll wait for micheal berry to finish his tests, and just use topical spironolactone and curcumin and apple poly for now.

 

[CCS]

I don't know why micheal berry wants to boil pine cones to get the pine oil when he can buy 4oz for $5, which is less than the electriciy to boil the water. He must live in a forest.

 

[powersam]

in a forum lately full of fluff this thread is a breath of fresh air.

 

[michael barry]

CCS.

I have a bottle of pine oil. Believe me, as enticing as it is to use a steamer and make my own..................................Im probably way to lazy to do that when it came down to pointing and clicking or going outsite to climb a pine tree.


There is only one other compound that would interest me for anti-androgenic effects topically and that is blueberries. They are noted to really not only help against getting prostate cancer, but to fight prostate cancer once one has it. Spend a little time with google on blueberry or berries and prostate cancer and you'll probably pull some of the same articles I have. All the rest of the known compounds that inhibit alpha five are in revivogen. Id just buy that and use it if it came down to that.

 

[CCS]

I have a bag of organic frozen mixed berries, $3 for one pound. I eat a couple table spoons a day. Looks like anti-oxidants are the key to everything, unless you and docj077 sent each other PMs and decided to type up fake studies and post them for all the lazy people to read and not check.

 

[docj077]

I have a bag of organic frozen mixed berries, $3 for one pound. I eat a couple table spoons a day. Looks like anti-oxidants are the key to everything, unless you and docj077 sent each other PMs and decided to type up fake studies and post them for all the lazy people to read and not check.

Not necessarily anti-oxidants, but compounds that inhibit downsteam mediators of DHT. For some strange reason, they do happen to be anti-oxidants, as well. That is pretty weird.

 

[powersam]

ages ago i read a french study which found that balding men all had prematurely aged scalp skin. aged as in far thinner than usual skin. the end conclusion of the study was that powerful antioxidant treatment could probably help hair loss.

 

[Red Rose]

http://www.hairloss-research.org/february1.html

Chronic systemic inflammation has been found to at the root of many serious disorders, such as cardiovascular disease, asthma, arthritis, cancer, diabetes, depression and androgenetic alopecia. These “age relatedâ€￾ disorders are accompanied by a pathological increase of inflammatory cytokines. Lowering pro-inflammatory cytokines, such as tumor necrosis factor –alpha, interleukin – 6, interleukin 1(B) and/or interleukin B4, could help prevent and treat many age related diseases. After several published studies, which showed that inflammation is present in androgenetic alopecia, male pattern baldness Research reported these important findings to readers, particularly stressing the need to address inflammation in any hair loss treatment approach, including our recommended protocol. Excessive levels of cytokines can be systemically and topically countered by an appropriate regimen of drugs, nutrients, dietary changes, and/or hormones. For example, fish oil has been shown to effectively lower these levels, as does DHEA, Nettle extract, GLA, and some antioxidants (vitamin E and N-acetyl cysteine). Meanwhile certain herbal extracts patented by Asian companies, Emu oil, copper peptides and ketoconazole can be used to topically partially inhibit cytokine formation. Following is an extensive analysis (in layman’s terms) that makes the connection between inflammation, and the “programmed cell deathâ€￾ of the hair follicle, a process known as “apoptosisâ€￾. It is partially based upon input from Waseda, a Japanese researcher who has been researching inflammation and androgenetic hair loss for many years. He has been able to initiate extensive hair regrowth after being a “slick baldâ€￾ Norwood 5 for many years using an aggressive combination of therapies specifically designed to counter inflammation and an apoptosis factors.



TOWARDS A COMPREHENSIVE TREATMENT OF male pattern baldness

First we must recognize that hair loss is the consequence of hair cell apoptosis, or programmed cell death. Apoptosis is the final result of what is termed the caspase activation cascade. Essentially DHT, superoxide, and other free radicals damage the cell’s mitochondria, and the damaged mitochondria in turn vomits cytochrome C, which activates the caspase 9 cascade. TGF-beta and alpha activate caspase 9 around hair follicles. The activated caspase 9 propagates downstream into caspase 3. Activation of caspase 3 is thought to be a direct cause of cell apoptosis (programmed cell death) in general. What then causes a caspase activation cascade and how can one intervene in the context of hair loss?
Protein Kinase C (PKC) as an executor of apoptosis PKC isozymes are involved in the final execution of hair cell apoptosis in relation to caspase 3. What are good inhibitors of PKC? Cycloporin (dangerous), Grape Seed Extract, Resveratrol (as in red wine), Vitamin E, and N-Acetyl Cysteine. Topically, Grape Seed Extract (a patented treatment for hair loss), and Perilla Leaf Extract.
Tumor Necrosis Factor Alpha (TNF-a) as a promotor of PKC and hair cell apoptosis. TNF-a induces the PKC isozymes and causes cell death through this induction. This pathway is known to be a major cause of hair loss. TNF-a is a quick acting proinflammatory cytokine, and TNF-a is over secreted in cases of rapid hair loss. How can TNF-a be safely inhibited? Ginkgo Biloba Extract, Stinging Nettle Extract, Green Tea Extract, and essential fatty acids found in fish, Emu, Borage, and Perilla oils. Topically, Perilla leaf extract may be useful.
TGF-Family as the bridge between DHT and the activation of the caspase cascade. In recent studies researchers have found DHT promotes TGF, and TGF causes activation of the caspase cascade and thus, hair cell death, which clinically manifests as male and female pattern baldness. What inhibits TGH safely, as opposed to the dangerous anti-cancer compounds? Proteolytic Enzymes such as a bromelain, and the anti-oxidant Curcumin are TGF inhibitors. Shiseido, a Japanese cosmetic company found that Amacha, a sugar alternative found in the orient has TGF inhibition properties. Dr. Sawaya’s latest study about finasteride suggests that the best hair loss prevention would involve the blocking of caspase activation, especially caspase 3. Caspase 3 is the direct cause of programmed hair cell death (apoptosis) that originates “upstreamâ€￾. The first triggers may be DHT damage or oxidative (free radical) stress on the mitochondria, TGF induction from DHT, TNF-A induction from allergic inflammation, or PKC upregulation by caspase activation. Here we can summarize the rationale behind the treatments of various pro-inflammatory mechanisms.

DHT inhibition- Finasteride, Saw Palmetto, Rivoflavin, Green Tea Extract, Copper, Peptides, and Topical Bayberry Extract.

PKC down regulation - Grape Seed Extract, Resveratrol, Vitamin E, Soy Isoflavones.

TNF-a down regulation- Curcumin, Ginkgo Biloba Extract, Stinging Nettle Extract, Green Tea Extract, Fish Oil, Borage Oil, Perilla Oil, and Topical Perilla leaf extract.

TGF down regulation- Curcumin, and topical Amacha.

Taking into account the inhibition of hair apoptosis factors, it is apparent that treatment can be taken to a new level. Again, Waseda himself is experiencing regrowth in all areas of his scalp after being a slick bald “Norwood 5â€￾ for many years.

 

[docj077]

I've seen that site, Red Rose.

It's actually an excellent resource. Most, if not all, of the herbs and drugs mentioned have been shown to have in vivo effects upon fibrosis and collagen deposition in many tissues. Some of them are strictly DHT synthesis inhibitors.

Nice post.

 

[spinner2]

Ok, maybe we should research the strongest antifibrotic drugs and then experiment with injecting these drugs into bald areas of the scalp.

I did a few google searches, and it seems that HGF (hepatocyte growth factor) is the antifibrotic which has been getting the most attention lately. I'd have no problems testing this on myself, but I won't have money until the summer. If any rich people want to buy it for me I'll give it a shot :lol: .

 

[sammy]

Hi,

Is there any more news on this, im thinking of trying it but still using my minoxidil and finasteride?

 

[psych721027]

The question I have then, which 3 suppliments would be best to take. I would assume the following would be best. Would I be correct?

1. Circumin
2. Green Tea Extract
3. Grape Seed Extract

The only thing I have misgivings on is the green tea extract. I had initially thought it was good as a hair loss treatment, but now, after reading that post that it may not be, now I'm not so sure. Well, at least orally. Topically however, I think green tea is still good to go. What are your thoughts Michael Berry, Doctor, collegechemistrystudent? Doctor, I'm also curious, if your regimin is defferent than what's in your posts now, what is your regimin now? Thanks.

 

[Far Too Young]

I hate to invoke Tom Hagerty and his blasted scalp exercises, but while these supplements are certainly a great first step, I think that the importance of an "anti-inflammatory" diet is highly underrated. Tom has a really great article on Hairloss-reversible.com (I'm not selling it, just referring people to his accessible, meaty articles) about the importance of a diet that prevents the body from experiencing too much inflammation. Most essential to this, in his opinion, is the limiting of your glycemic index. Eating foods with a high glycemic index elicits big jolts of insulin, i.e. the highs and the lows, which are highly conductive to the subclinical inflammation so critical in male pattern baldness (and Type II Diabetes and Coronary Disease and any other number of disorders). A diet which limits these glycemic foods and inflammation should be effective towards overall health and hair health, as effective as any heavy supplement use. We need to remember that supplements, while useful, are just that: supplements.