View Full Version : Androgenetic Pathway Update and Possible Cure

11-05-2014, 02:00 AM
Here is an update to the androgenetic alopecia pathway and information on important topics for hair growth. I will include information about products and a possible cure.

1)))Androgen receptors are the main key. The factors that act on them, such as DHT and other androgens kick starts the alopecia pathway.

GSK3-beta is involved in androgen receptor nuclear binding. It is also involved with stem cell differentiation (causes it), inhibits stem cell proliferation and the canonical wnt/beta catenin pathway. It has been shown in prostate cells that LITHIUM CHLORIDE a gsk3-b inhibitor, inhibits the nuclear binding of the androgen receptor even if it is bound to DHT. So, this means no transcription or translation of the androgen receptor= cessation of androgenetic alopecia.

Creating a topical gsk3-b is key. Lithium chloride, lithium succinate (used in seborrheic dermatitis), and lithium orotate are options. However, be careful as not all gsk3-b inhibitors have to same action on the androgen receptor.

2))) Androgen receptors create a cascade of growth inhibitors like TGF-beta to cause cell death and IL-6 expression in the hair follicle.

IL-6, Stem Cell factor (in follicle), and CD34+ progenitor cells(follicle) cause the differentiation of CD34 cells into mast cells. This is my theory as to what is happening to the CD34+ cells and why there is a depletion of them. Mast Cells are being produced and the types being produced are large, filled with ILs, chymase (involed with atherosclerosis/fibrosis), and histamine. This is important to understand the itching, tingling, burning, and inflammation on the scalp. The yeast on the scalp is reacting to the change of fatty acids produced by sebaceous gland hyperplasia (I will explain this later). This causes the allergen reaction, IgE activation of these mast cells, and the eventual cascade of microinflammation involving lymphocytes(th2), basophiles, and eosinophils. This will a create a vicious PGD2 cycle, miniaturization, and fibrosis.

3))) Mast cells and lymphocyte created PGD2. This is due to the DHT/androgen receptor IL-6 production. These cells also produce various ILs. IL-6 is one of them that cause the microinflammation around the follicle which leads to eventual miniaturization and possible death. Hematopoietic PGD2 is produced by these cells. H-PGD2 causes a gene called NRF2 to activate. NRF2 causes sebaceous gland hyperplasia and hair follicle regression via hyperkeratosis (why I believe the hair follicle miniaturizes and can, eventually, die). TGF-beta via androgen receptor/DHT causes NRF2 activation.

NRF2 is extremely important. It is an anti-inflammatory activator and its product is LIPOCALIN PGD2 SYNTHASE (L-PGD2s). Whenever nrf2 is exposed to any type of pgd2, it will keep producing L-PGD2S, hence the vicious PGD2 cycle. What happens when Prostaglandin H2 from COX2 is converted to L-PGD2? It eventually produces 15D-PGJ2.

15D-PGJ2 is a PPAR GAMMA receptor agonist. What does PPAR GAMMA do? It is for ANTI TUMOR protection. Interestingly it can cause anti inflammation or inflammation. PPAR GAMMA still needs to be studied more, however from research I found out that 15D-PGJ2 inhibits the proliferation of CD200.

CD200 is one the the two type of progenitor cells that are lacking in balding hairs. It is involved with self protection, causing production of IL10 and IL12 to down regulate inflammation against the host (hair). follicle) and involved with melanocytes (low cd200 positively correlated with graying hair). My theory is that PPAR gamma has anti tumor effects and that the hair follicle is being viewed as a tumor, hence the depletion of CD200 in order to removed the tumor(hair). PPAR gamma is needed in order to prevent scarring alopecia as it maintains functional stem cell compartment. Like I said, PPAR gamma in studies have been shown to causes inflammation or the opposite probably due to which ligand /receptor is activated and needs to be studied more.

Stem cell factor is decreased in androgenetic alopecia, so a decrease in all progenitor cells and loss of CD34 (mast cells) and CD200 (15D PGJ/ppar gamma)

Inflammation is not all bad. Certain types of inflammatory processes are needed for hair growth, but they need to be done in a certain time and manner which is not being allowed in androgenentic alopecia. This topical should be discussed further.

Here is some information of products used for hair loss:

Lithium: This should be the number one used topical for all hair loss suffers. It inhibits GSK3 beta, so it should totally inhibit the androgen receptor; EVEN IF DHT IS ATTACHED! It increases B-catenin and the wnt canonical pathway by inhibiting gsk3 beta, so it can increase anagen in hairs. It also inhibits TGF-beta which causes hair loss.

Minoxidil: It is a PGH1 synthase activator. This means more prostaglandins production. It will cause an onset of inflammation due PGE2 causing enhanced function of IgE on mast cells and increase IL-6 in those cells. Also, donít forget PGD2 and other products from cox2 that cause inflammation. Hence, the initial shed using minoxidil and it can cause thinning of existing hair (inflammation,pgd2 increase). However, due to its ability to create capillaries in dermal papilla and E2 increase, it causes regrowth of hairs and minoxidil dependent growth of hair by being a canonical wnt pathway weak agonist.

Azelaic Acid: It decreases p53 and p21 causing a decrease in apoptosis. It decreases nf kappab which is overexpressed in hair loss but is needed for anagen. It also is an anti inflammatory by apparently activating ppar gamma which explains why it is used for skin lightening (decrease melanocyes due to a decrease of CD200). PPAR gamma plus p53 causes apoptosis, hence Azelaic acid is anti-apoptotic. Also, combined with high levels of vitamin b6, it decreases DHT production.

Retinoic Acid (tretinoin, all trans retinoic acid): It can possibly cause skin cancer and this is good for hair generation. Remember that hair is being targeted as a tumor/cancer even though it is not, so we need something that can reverse/balance that anti tumor effect and RA is that something. RA inhibits canonical wnt pathway(bad for hair anagen) via tcf2 but upregulated noncanonical wnt pathway. This is good for stem cell generation. RA also inhibits NRF2 (Decrease L-PGD2s and L-PGD2). RA also activates the ERK2 pathway which is different than the ERK1 pathway. ERK2 is involved with cell angiogenesis and ERK1 is involved with apoptosis.
Fenugreek contains Trigonelline and it inhibits NRF2 to downregulated lipocalin pgd2s and l pgd2 and does not effect wnt pathway.

Luetolin inhibits NRF2 but also inhibits the canonical wnt pathway.

Hypoxia causes NRF2 inhibition: Neogenic and ciclopirox

Some information about signaling:

The JAK STAT pathway is key in regulating hair loss. There is a report that a JAK STAT inhibitor was used on a patient with alopecia totalis and all his hair grew back. We know that Androgenetic Alopecia and Alopecia Areata/Totalis are different, but are similar in their pathways.

IL-6 is the problem with Androgentic Alopecia that causes inflammation, hair thinning, fibrosis, and a pathway that leads to NRF2/PGD2. IL-6 is involved with the jak stat pathway, particularly with stat3. If we can inhibit STAT3, we can solve the IL-6 problem. This should shut down the IL-6 mast cell instigation of microinflammation around the hair follicle. There are natural and synthetic JAK STAT inhibitors available. I found one topical that should contain a stat3 inhibitor, but I will not dicuss the product so that we can focus on other important matter written here and I donít want to have to defend myself from being called a shill.

The possible cure:

We first need to realize that if the hair follicle is not there (dead) nothing will grow in its place except for transplanted hair. Second, we need to affirm that fibrosis of the hair follicle is most likely present and is the reason why hair regrowth will be difficult. This is why there needs to be in place a new wounding method. My idea is a non roller, but stamp like process that has needles about the fourth of the width of current dermarollers that go 3-4mm deep. Small width micro wounds that go deep enough to break up the fibrotic plaque, heal, and protect existing hair follicles as much as possible. I do not recommend doing this by yourself. Having a trained physician do this would be ideal.

From this article: http://www.nature.com/ncb/journal/v13/n7/full/ncb2267.html

What I understood from it is that stem cell regeneration is possible. The process involves tcf3 and gsk-3 inhibition. We already have a way to do both. Retinoic Acid (tretinoin) creates tcf3 and lithium OR Estradiol is a gsk-3 inhibitor. These two used together in theory should regenerated stem cells and cause the regrowth of hair. I could be completely right or wrong on this, PLEASE DISCUSS!!!!

About the Big 3:

Minoxidil from what I described above causes inflammation, exacerbates andogenetic alopecia (Increase various PGs), but has its own unique pathway to grow hair; which is why hairs become minoxidil dependent. Finasteride/Dutasteride inhibits 5 alpha reductase and reduce DHT, but our bodies are adaptive. Androgen receptors will become more sensitive/increase with time and DHT can be produced by other pathways such as hydroxysteroid dehydrogenase enzymes. Other androgens can cause DHT like effects, for example in prostate cancer; and I donít see why this canít be true for hair as well. As for ketoconazole, it is good to get rid of the inflammation that scalp yeast causes that can cause the onset of androgenetic alopecia. However once that cascade starts, it will not stop it (PGD2 vicious cycle). Also, it is a NRF2 (PGD2) agonist. This is why I believe some people notice hair becoming straw like/thin.

I am not against the Big 3. The reason all three work together well is because the pros outweigh the cons. However, in time it will fail.

Please discuss and add to this. There are too many references for me to put up.

11-05-2014, 10:49 PM
Excellent information sir, you've obviously done your research. I wish I knew more so I could chime in, but from what I read that I DID understand, it sounds like you have a very good theory going. I hope some of the more knowledgeable guys around here will chime in and help you get this figured out. Keep up the great work.

11-07-2014, 04:10 AM
An update to my op

Critical Read: http://ac.els-cdn.com/S0092867411007562/1-s2.0-S0092867411007562-main.pdf?_tid=a6837042-6596-11e4-8af9-00000aab0f01&acdnat=1415266024_afbb1972942da163e9f8076dab7fe2c2

CD34 stem cells:
I found out that they are correlated with lef1 and TCF7. Activating tcf7 will produce the deficient CD34 progenitor cells. We need to find out how to activate TCF7.

CD200 stem cells: This is important. We need to find the pathway for its production, so we can find out how to restore it in the hair follicle.

Androgen Receptor:

Senescence: p53, p21, and p16 initiated by the androgen receptor. P53 and p21 is decreased by azelaic acid, however p16 has its own pathway and so far I do not know how to inhibit it. P16 is key to AGA!

GSK3 alpha and beta are used in androgen receptor activation. Lithium, from lithium chloride only (no information on other types of lithum salts) will inhibit both types of gsk. GSK 3 alpha and beta blockers and androgen receptor inhibitors are used in prostate cancer for increased inhibition of androgen receptor transactivation. So, using CB or RU and lithium topically will completely inhibit androgen receptors.

Some may say lithium does not work, that is because lithium chloride needs to be used. Also, I have read that lithium increases bcl 2 which is already increased in balding hair follicles. BCL 2 is anti apoptotic but hidners growth. This is fine as long as retinoic acid is used as it decreases bcl2 in a time and dose dependent manner. Retinoic acid also increases p53 and p21, but azelaic acid decreases it. It is all about balancing out the cons, so that the pros can work.

Retinoic acid:
Binds to ppar alpha and beta for hair follicle growth, possibly counteracting ppar gamma activated by Platelet derived growth factor and azelaic acid.

Wounding: Think of the fibrotic plaque around the hair follicles as the plaque being formed in arteries. It gets clogged, no/low blood flow, heart attack, and cell death can occur. So it is similar around the hair follicles. Wounding to remove and repair the fibrotic plaque needs to be done in order to allow fat cells to surround hair follicle for optimal growth and thickness of dermal papilla.

Wounding is COUNTERPRODUCTIVE when done more than once every 30-40 days. When a wound occurs on the scalp, Lhx2 is activated. Lhx2 inhibits Lgr5 which regulates bulge and secondary germ stem cells. Inhibiting Lgr5 will keep hair in anagen by inhibiting stem cell activation. So, creating a new hair in anagen in the follicle will not be possible. Lhx2 stimulates sox9 and tcf4, which is needed for hair follicle progenitor cells. So in short, wounding regenerates stem cells but also inhibits their activation for new growth in a certain time period.

Platelet Dervied Growth Factor:
Is needed for hair regrowth. Hypoxia should increase its production. Also, it is the main factor in PRP therapy. It also activates ppar gamma via akt-something to look into. Maybe this explains why PRP needs to be done often to work due to the inhibitory effect of ppar gamma.

About hypoxia: http://www.rndsystems.com/cb_detail_objectname_SU07_HIF1.aspx

Arrector Pilli:
There is a study stating that since it attaches to the bulge stem cell area of the hair and that it is destroyed in the process of AGA, that miniaturized hair will not/only slightly regrow. It may be an old topic but let us get this cleared up. In a hair transplant, the arrector pilli is not destroyed correct? Is there some way the AP muscle has some neural or other pathway to stimulate the bulge stem cells? From the link I posted about hair follicle stem cells, it stated that neighboring HFSC niches also secrete regulatory factors, allowing one hair to couple with neighboring hairs. This can possibly mean that the Arrector Pilli is the route for allowing the coupling, hence hair losing the connection to the arrector pilli will cause a difficulty for regrowth. Let’s find out if the destruction of the arrector pilli does have to do with the lack of regrowth in AGA.

We need to find out the pathway for CD34 and CD200 progenitor cells and the noncanonical and canonical wnt pathway explained in terms for hair.

Regimen to halt AGA, thicken thinning hair, and regrow vellus/minizurized hair:

Topically: Minoxidil, lithium chloride, azelaic acid, ru58841/cb, retinoic acid, hypoxia inducer, finasterde/dutasteride, jak stat (stat3) inhibitor, and wounding.

Internally: Finasteride/dutaseteride (if not topically and if you have no side effects from them).

11-08-2014, 04:05 PM
You should probably post this into the "cutting edge" section as there are more people with more advanced knowledge about hair loss over there.

I appreciate the information!

11-08-2014, 07:20 PM
Yeah this should be in Cutting Edge, but interesting nevertheless. You obviously have put some significant thought into this. An issue that I see is that altering these pathways could also cause unwanted side effects, especially since there isn't much clinical evidence.

11-08-2014, 09:23 PM
You should probably post this into the "cutting edge" section as there are more people with more advanced knowledge about hair loss over there.

I appreciate the information!

Yeah this should be in Cutting Edge, but interesting nevertheless. You obviously have put some significant thought into this. An issue that I see is that altering these pathways could also cause unwanted side effects, especially since there isn't much clinical evidence.

Can a moderator move this thread or can someone contact a moderator to move it to the Cutting Edge/Future Treatments section?

11-09-2014, 05:41 AM
Nah no need for a moderator to move this, just copy and paste your posts and make a new thread in Cutting Edge (with the explanation that you first posted it in the wrong subforum). I'm sure it will get more attention over there!

11-17-2014, 10:19 PM
Atraric Acid a Potent Topical Antiandrogen:

I have known about Atraric Acid for many years. I learned about it because it is found in Pygeum bark, which many men use for BPH. I read about Atraric Acid a while back and no one seems to be that interested in it. This could be due to the fact that it comes from a natural source. However, Ataric Acid is a potent androgen receptor antagonist and has a high affinity for the androgen receptor. It binds to it and even prevents the translocation, meaning no matter what the androgen receptor will not produce a reaction. Not many antiandrogens can do this. This also applies to even mutated androgen receptors. NBBS is also an antiandrogen from pygeum, but I am more interested in Atraric Acid. If you do a simple search online, there are various articles stating that it is an antiandrogen, prevents nuclear translocation of the androgen receptor, agonist of estrogen receptors, and even a possible cure for prostate cancer.

Brevilin A the Natural JAK STAT Inhibitor:

Brevilin A is a natural JAK STAT Inhibitor found in a few plants. JAK STAT inhibitors are important. They inhibit the cascade which leads to hair loss caused by an upregulation of IL-6. Brevilin A works via STAT3, STAT1, and Janus Kinase 1 inhibition. Janus Kinase 1 is needed to create STAT6. IL4 inhibits preadipocytes and platelet derived growth factors via STAT6. I have been using Litsea Glutinosa topically it has been a good adjunct to my hair loss treatment. I have noticed some regrowth and thickening of vellus hairs. This may be due to the fact that it contains anti-inflammatory and wound healing abilities. What I find most important is that it contains Brevilin A. Unfortunatley, in a herbal extract we do not know how much Brevilin A is in the solution. I found out that in china there is a patent on it, but here in the US there cannot be a patent on natural compounds. It would be nice to find a reliable source for Brevilin A.

Trigonelline a PGD2 and Proteasome Inhibitor:

Trigonelline is found in nature. It is found in a few food items, one in particular is Fenugreek also known as Methi. I personally used a topical Fenugreek paste mixed with aloe vera for 3 moths a few years ago. At that time I did not know about Trigonelline. I used it because it was a time tested remedy used in south east asia. When I did use it, I did see some noticeable growth and thickening. Unfortunately, I stopped using it due to the fact that it was messy and time consuming to use.

Trigonelline has some important properties that are involved with hair loss. First of all it is a NRF2 inhibitor. NRF2 is the gene factor that creates Lipocalin PGD2 synthase which makes PGD2. Also, it has been shown, in a study regarding the pancreas, that it inhibits the proteasomal genes due to NRF2 inhibition. This means that it is a proteasome inhibitor. It also inhibits PPAR GAMMA(take a look below at Adipose and hair)

The ubiquitin proteasome pathway is responsible for tagging the cytoskeleton and for protease activation and degradation. This causes atrophy. So, if the proteasomal genes are inhibited then there is no tag for degradation via protease. Trigonelline acts as an indirect protease inhibitor, by inhibiting proteasome gene activation.

If Trigonelline is used topically, it should inhibit PGD2 and proteasome. This should mean we can possibly regrow miniaturized hairs. We need to find a supplier for this.

Arrector Pili muscle:

In androgenetic alopecia there is inflammation from the dermal papilla up to the bulge area causing thinning and miniaturization where the hair follicle keeps getting pushed up towards the scalp. In aloepcia areata there is only inflammation around the dermal papilla region, causing a stop in hair growth but the bulge remains untouched. The bulge cells create specific cells for the creation of the arrector pilli muscle seen here: http://www.cdb.riken.jp/tme/

The fact that we lose the arrector pilli muscle means that we lose a possible way for hairs in a follicular unit to "communicate." The loss of the AP muscle is also related to dysfunction of the bulge area which is responsible for the CD200 cells. Remember that CD200 and CD34 are lacking in androgenetic alopecia.

Adipose and hair:

Corticosteroids cause adipogenesis (decrease in preadipocytes) and also is anti-angiogenic (decrease vegf, etc). Corticosteroids are linked to insulin resistance, that is why I mentioned insulin resistance and IL-6, TNF alpha. Insulin resistance in fat cells cause an increase in IL-6 and TNF alpha. An increase in beta catenin, via inhibitor of GSk3, should inhibit PPAR Gamma. PPAR GAMMA causes adipogenesis. We need pre-adipocytes for hair regrowth/anagen.

IL-4 inhibits platelet derived growth factor (PDGH) via STAT6. PDGH is from preadipocytes (also in PRP).

I am not going to post links. If you want to check these facts over or get more information you can use PubMed and Google.

11-21-2014, 08:49 AM
so what's the verdict?

11-24-2014, 05:10 PM
We really need to understand more about androgen receptors and how they change over a few months or years in response to androgen level changes or age. More importantly we need a real FDA treatment that actually does something at the receptor level like RU or CB would in theory. The major issue has always been how do you physically stop androgens or one of those other pathways safely and effectively? Applying the theories is the hardest part by far