Understanding Androgenetic Alopecia

[Swooping]

Ok guys thought it would be a good idea to give an update about androgenetic alopecia. Basically I just want to give an insight about what the latest research is showing, but also define some basic characteristics of androgenetic alopecia (perhaps you might know allot of this) We’ll start from the beginning;

In the 50’s experiments were done by Dr. James Hamilton. He was also the first one who created the term “androgenetic alopecia”. He saw that men who had been castrated before puberty never went bald. Interestingly when he injected testosterone into these castrated men, some suddenly started balding but some did not. Most notably the ones with a family history of baldness started balding.
Why were his experiments so important? Well he showed that baldness is androgen dependent, because castrated men before puberty showed no signs of balding. He also showed that there is a genetic side to the story because when he injected some with testosterone, not everyone started balding. This is also why we call it “androgenetic” alopecia. Because for baldness to occur as we know it you need both androgens + genetics.

To verify this even more Imperato- McGinley studied pseudo-hermaphrodites in the Dominican republic. These pseudo-hermaphrodites were born looking like a girl with female genitals. At puberty however they virilized, developing musculature, a deeper voice and would even develop a penis some of the time. They found out that these pseudo-hermaphrodites had a deficiency of type-2 5-reductase. Then you have people who suffer from androgen insensitivity syndrome. This condition results in a partial or complete inability of cells to respond to androgens. Guess what? Well both of these type people who suffer from this condition never display androgenetic alopecia. This is again a very important observation to make that androgenetic alopecia is androgen dependent. A fun fact is that Merck developed a drug based on the study of Imperato- McGinley; finasteride a type-2 5-reductase inhibitor (5ar2) as we all know it.



Next I want to explain hair follicle cycling in short. A hair follicle cycles as you may know. Everyone experiences this, even your norwood 1 friend. This primarily exists of the following stages; anagen, catagen and lastly telogen, this cycle repeats itself. Anagen is the active growth phase of the hair, catagen is the regression phase and telogen is the resting phase. Now look at the following picture;



What important to know about these cycles is that the hair follicle itself, specifically the micro environment of the hair follicle is able to communicate with the macro environment (surrounding tissue) . For instance in telogen a hair will lack vascularization and blood vessels, not only that it will also lack adipose tissue. In anagen however there is a tremendous increase in vascularization and also adipose tissue. This leads to a thicker dermis in anagen, and a thinner dermis in telogen. Scalp hair follicles reside generally 80-90% in anagen, 1-2% in catagen and 10-15% in telogen. Ok this is enough for general cycling.

Back to androgenetic alopecia again. You should already know that androgenetic alopecia is androgen dependent and has a genetic basis. However for androgenetic alopecia to occur these androgens need to bind to the androgen receptor in the hair follicle. Because as you know people with androgen insensitivity syndrome have hormones but they have impaired androgen receptors and they don’t bald. So where are the androgen receptors located in the hair follicle? They are solely located in the dermal papilla at the base of the hair follicle;



So in order for androgenetic alopecia to occur, androgens which are expressed in the blood need to bind to the androgen receptors located in the dermal papilla. A treatment for example like RU-58841 or CB-03 binds to the androgen receptors there and will stop androgens to attach to these androgen receptors, preventing or slowing androgenetic alopecia. There is evidence that people suffering from androgenetic alopecia have increased androgen receptor expression and increased 5ar2 expression.

In androgenetic alopecia as you guys may very well know too is that with each cycle the hair becomes more miniaturized. The hair becomes thinner, shallower and keeps reducing each cycle until you are basically left with almost nothing. Important to know is that the dermal papilla cells specify hair size, shape and the reduction of them causes a follicular decline (1), (2).

Now to the (latest) advancements about the pathology of androgenetic alopecia;

In the study named “Premature Senescence of Balding Dermal Papilla Cells In Vitro Is Associated with p16INK4a Expression”(3). They confirmed as other studies already did(4) that balding dermal papilla cells grow way slower in vitro when compared to non-balding dermal papilla cells. Not only that they found out that balding dermal papilla cells undergo premature senescence. This was associated with the following in the balding dermal papilla cells;

- Increased Expression of p16ink4a
- Increased Expression of pRb
- Expression of senescence-associated β-galactosidase
- Loss of expression of bmi-1
- Increased expression of oxidative stress and dna damage markers like HSP-27, ATM and ATR

Now a study published in November 2014 called “ Androgen Receptor Accelerates Premature Senescence of Human Dermal Papilla Cells in Association with DNA Damage” (5) found ;

- Also a increase of p16ink4a in balding dermal papilla cells and not in non-balding in vitro
- DNA damage accompanied with senescence in the balding dermal papilla cells
- Most importantly when you remove the androgen receptor from the balding dermal papilla cells DNA damage does NOT occur and senescence does NOT occur.
- The dermal papilla cells changed in morphology, they enlarged.

A other study in 2009 called “Proliferation, DNA repair and apoptosis in androgenetic alopecia (6)” found out that in comparison with occipital scalp and frontal balding scalp;
- P53 was overexpressed frontal balding scalp
- P53 showed a inverse correlation with APE-1 (dna damage repair marker)

Now you know the evidence of senescence occurring in androgenetic alopecia in the dermal papilla cells (with the accompanied factors), but also know that P53 is overexpressed in balding scalp. Soon you will know why this is such a ridiculous hard disease to treat and why reversal of androgenetic alopecia is so rare and damn difficult, but prevention is way easier.

Read the following picture this is taken from “Cellular senescence: when bad things happen to good cells(7)”. It is NON-AGA related but related to general cellular senescence;



I underlined the parts in red that compare with the evidence from the androgenetic alopecia studies. P16(ink4a), pRB, P53 etc. In blue I underlined something that is very typical and extremely important for cellular senescence and that is that these cells release pro-inflammatory factors and even compromise the function of non-senescent healthy cells. Not only that note how they say that it may even lead to a decrease or even a loss in progenitor stem cells. Well as you guys know we are coping with inflammation too in androgenetic alopecia, there are a shit ton of inflammatory factors expressed. Not only that we have a lack of CD34+ and CD-200 progenitors. Even the whole morphology of the hair follicle changes. Kinda correlates huh?

So you might be asking yourself, what about DKK-1 isn’t that the cure? What about PGD2? Playing with those factors won’t cure androgenetic alopecia in my opinion. In the grand scheme of things they are relatively not important if cellular senescence occurs, which I believe is the culprit of AGA, due to fault of the dermal papilla cells. I’ll write a post later going more in-depth about this (more explanation of cell senescence ,why estrogen can work so good in reversing AGA sometimes , possible ways to tackle this problem etc.)

For now I can only say f*ck you dermal papilla cells . Thanks for reading.





1. http://www.ncbi.nlm.nih.gov/pubmed/23487317
2. http://www.nature.com/jid/journal/v1.../5600534a.html
3. http://www.nature.com/jid/journal/v1.../5701147a.html
4. http://www.ncbi.nlm.nih.gov/pubmed/8...ct&holding=npg
5. http://www.plosone.org/article/info%...l.pone.0079434
6. http://www.ncbi.nlm.nih.gov/pubmed/18702626
7. http://www.nature.com/nrm/journal/v8...l/nrm2233.html


P.S if you have anything to add which is related to this story feel free. If you want to delve further into cellular senescence this is a very nice one to start but might be challenging;

http://jcb.rupress.org/content/192/4/547.full.