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My "theory" of baldness


#1

For any of you who may be newbies wondering about baldness-------------you inherit a variant of the androgen receptor gene that can express itself more or less strongly depending on genetic chance. If it expresses itself strongly with CAG-repeates, the hair outside your wreaths androgen receptor’s are much more adept at uptaking male hormone, especially dihydrotestosterone. Having alot of DHT in the scalp tissue (bald men have been shown to have more DHT in their scalps, but not in the blood, indicating that the alpha five reductase enzymes in the root sheaths of each and ever hair follicle on your head are probably more active than a guy with all his hair) has been shown to be able to invigorate androgen receptors even MORE. One too much androgen is uptaken…eventually something happens to the hair follicle and a different set of genetic instructions are obeyed within it. The dermal papilla starts cranking out way too much DKK_1, which leads to the cell death of the keratincoyetes in the root sheath…these dead cells in turn hanging around the infidulum is probably why the immune system begins attacking the hair follicle and TGF beta and excessive collagenous deposition is downstream from it. That is probably “baldness”, as the immune system is going to try to eliminate dead cells and anything around the area is going to be effected by all the infllammatory subtstances the immune system will use. Baldness looks like organ rejection microscopically. Its been shown that wreath area hairs can succumb to testosterone and DHT if experiments give enough of them to the hairs…so I dont believe their is some magic difference in the hair’s basic characteristics but a difference in the amount of DHT the hair can make via its alpha five reductase enzyme in their root sheaths and a big difference in how well the hairs androgen receptors work and how chemcially stable they are. In a way male baldness is probably because you have too-well-working-androgen-receptors and too-well-working-alpha-five-reductase-enzymes in your hair. You are “too manly” in a place you dont want to be.

Obviously, “my theory” places the blame at DKK-1’s doorstep, but its all because of too-well working androgen receptors and too well working alpha five reductase enzymes. I honestly think if you could get Brad Pitts hair to uptake the amount of androgen our follicles uptake…he’d be going bald too, by the same mechanisms we are for the most part dependent on the intesitity of his immune systems response. Its known that the variant of the androgen receptor gene is located on the x-chromosome and comes from your mother, but the other genes in baldness are autologous (or are thought to be) and aren’t parent specific. Too many androgens duing fetal development may play a role. We will know if someone ever does a study on digit ratios and baldness in a large population. Im guessing at least a small correlation will be found myself.


#2

» For any of you who may be newbies wondering about baldness-------------you
» inherit a variant of the androgen receptor gene that can express itself
» more or less strongly depending on genetic chance. If it expresses itself
» strongly with CAG-repeates, the hair outside your wreaths androgen
» receptor’s are much more adept at uptaking male hormone, especially
» dihydrotestosterone. Having alot of DHT in the scalp tissue (bald men have
» been shown to have more DHT in their scalps, but not in the blood,
» indicating that the alpha five reductase enzymes in the root sheaths of
» each and ever hair follicle on your head are probably more active than a
» guy with all his hair) has been shown to be able to invigorate androgen
» receptors even MORE. One too much androgen is
» uptaken…eventually something happens to the hair follicle and
» a different set of genetic instructions are obeyed within it. The dermal
» papilla starts cranking out way too much DKK_1, which leads to the cell
» death of the keratincoyetes in the root
» sheath…these dead cells in turn hanging around the
» infidulum is probably why the immune system begins attacking the hair
» follicle and TGF beta and excessive collagenous deposition is downstream
» from it. That is probably “baldness”, as the immune system is going to try
» to eliminate dead cells and anything around the area is going to be
» effected by all the infllammatory subtstances the immune system will use.
» Baldness looks like organ rejection microscopically. Its been shown that
» wreath area hairs can succumb to testosterone and DHT if experiments give
» enough of them to the hairs…so I dont believe their
» is some magic difference in the hair’s basic characteristics but a
» difference in the amount of DHT the hair can make via its alpha five
» reductase enzyme in their root sheaths and a big difference in how well
» the hairs androgen receptors work and how chemcially stable they are. In a
» way male baldness is probably because you have
» too-well-working-androgen-receptors and
» too-well-working-alpha-five-reductase-enzymes in your hair. You are “too
» manly” in a place you dont want to be.
»
»
»
» Obviously, “my theory” places the blame at DKK-1’s doorstep, but its all
» because of too-well working androgen receptors and too well working alpha
» five reductase enzymes. I honestly think if you could get Brad Pitts hair
» to uptake the amount of androgen our follicles uptake…he’d
» be going bald too, by the same mechanisms we are for the most part
» dependent on the intesitity of his immune systems response. Its known that
» the variant of the androgen receptor gene is located on the x-chromosome
» and comes from your mother, but the other genes in baldness are autologous
» (or are thought to be) and aren’t parent specific. Too many androgens duing
» fetal development may play a role. We will know if someone ever does a
» study on digit ratios and baldness in a large population. Im guessing at
» least a small correlation will be found myself.

You lost me with some of this – I don’t know what DKK is for instance – but it overall makes a lot of sense. The itchiness I get in my scalp is IMO and I have thought independently exactly what you said, essentially an autoimmune response to cell death, akin to organ rejection I guess you could say. My itchy scalp that correlates with my hair loss feels a lot like the itch from a wound that is healing – as the immune system clears out dead tissue after the scab has formed. Too bad there’s not a really cheap topical that inhibits DHT only locally and doesn’t smell and doesn’t cause itching, etc.


#3

DKK-1 is a substance in the body that was not known until fairly recently to be involved in the dermal papilla of hair follicles. The antigens (negative growth factors) released by the dermal papilla as currently known are Thrombospondin, TGF-beta 1 and 2, PKC, TNF-alpha, and FGF-5.

DKK1 is a newly discovered one. It directly leads to not only a supression of keratinocyte cell division, but keratinocyte apoptosis (cell death). This would put dead cells in the body (around the infidulum where mysteriously the first inflammation is seen in androgenic alopecia).

DKK-1 has also been shown to, in FOLLICA experiments, to keep new hair follicles from forming AT ALL if it keeps getting applied to mice after wounding.

Here is the DKK-1 info via PubMed:

Click to change filter selection through MyNCBI.

1: J Invest Dermatol. 2008 Feb;128(2):262-9. Epub 2007 Jul 26. Links
Dihydrotestosterone-inducible dickkopf 1 from balding dermal papilla cells causes apoptosis in follicular keratinocytes.Kwack MH, Sung YK, Chung EJ, Im SU, Ahn JS, Kim MK, Kim JC.
Department of Immunology, School of Medicine, Kyungpook National University, Daegu, Korea.

Recent studies suggest that androgen-driven alteration to the autocrine and paracrine factors produced by scalp dermal papilla (DP) cells may be a key to androgen-potentiated balding. Here, we screened dihydrotestosterone (DHT)-regulated genes in balding DP cells and found that dickkopf 1 (DKK-1) is one of the most upregulated genes. DKK-1 messenger RNA is upregulated in 3-6 hours after 50-100 nM DHT treatment and ELISA showed that DKK-1 is secreted from DP cells in response to DHT. A co-culture system using outer root sheath (ORS) keratinocytes and DP cells showed that DHT inhibits the growth of ORS cells, and neutralizing antibody against DKK-1 significantly reversed the growth inhibition of ORS cells. Analysis of co-cultured ORS cells showed a significant increment of sub-G1 apoptotic cells in response to DHT. Also, recombinant human DKK-1 inhibited the growth of ORS cells and triggered apoptotic cell death. In addition, DHT-induced epithelial cell death in cultured hair follicles was reversed by neutralizing DKK-1 antibody. Moreover, immunoblotting showed that the DKK-1 level is up in the bald scalp compared with the haired scalp of patients with androgenetic alopecia. Altogether, our data strongly suggest that DHT-inducible DKK-1 is involved in DHT-driven balding.

PMID: 17657240 [PubMed - indexed for MEDLINE]


#4

» …so I dont believe their
» is some magic difference in the hair’s basic characteristics but a
» difference in the amount of DHT the hair can make via its alpha five
» reductase enzyme in their root sheaths and a big difference in how well
» the hairs androgen receptors work and how chemcially stable they are.
» In a way male baldness is probably because you have
» too-well-working-androgen-receptors and
» too-well-working-alpha-five-reductase-enzymes in your hair. You are
» “too manly” in a place you dont want to be.

But there remains the little problem of explaining why it is that androgens stimulate the growth of (most) body hair, but suppress the growth of scalp hair. That does sound to me like a magic difference in the hair follicles’ basic characteristics! :wink:

.


#5

» For any of you who may be newbies wondering about baldness-------------you
» inherit a variant of the androgen receptor gene that can express itself
» more or less strongly depending on genetic chance. If it expresses itself
» strongly with CAG-repeates, the hair outside your wreaths androgen
» receptor’s are much more adept at uptaking male hormone, especially
» dihydrotestosterone. Having alot of DHT in the scalp tissue (bald men have
» been shown to have more DHT in their scalps, but not in the blood,

However in the case of propecia, they have been shown to have LESS DHT in their blood since prop reduces serum DHT levels, this is why i think prop has the side effects. whereas Saw Palmetto has been shown to not lower blood levels of DHT, thus very rare side effects


#6

Its known that the variant of the androgen receptor gene is located on the
x-chromosome and comes from your mother, but the other genes in baldness

An ectodysplasin gene (which is located on the X chromosome, near the AR gene) has now been linked to MPB. The ectodysplasin signalling system has already been shown to be important in hair biology…do a search on Pubmed for more details. You’ll be hearing about this study in the lay media pretty soon, I’m sure:

J Invest Dermatol. 2008 Apr 3 [Epub ahead of print]

EDA2R Is Associated with Androgenetic Alopecia.

Prodi DA, Pirastu N, Maninchedda G, Sassu A, Picciau A, Palmas MA, Mossa A, Persico I, Adamo M, Angius A, Pirastu M.

1Shardna Life Sciences, Pula, Italy.

Androgenetic alopecia (AGA) is a common heritable polygenic disorder whose genetics is not fully understood, even though it seems to be X-linked. We carried out an epidemiological survey for AGA on 9,000 people from 8 isolated villages of a secluded region of Sardinia (Ogliastra), and identified a large cohort of affected individuals. We genotyped 200 cases and 200 controls (mean kinship 0.001) with the 500k chip array and conducted case-control association analysis on the X chromosome. We identified Xq11-q12 as strongly associated with AGA. In particular, we found that rs1352015 located 8 kb from the EDA2R gene showed the best result (P=7.77e(-7)). This region also contains the AR gene, hence we tested both genes in 492 cases and 492 controls. We found that the non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e(-19)) whereas rs6152 on the AR gene is less significant (P=4.17e(-12)). Further statistical analysis carried out by conditioning each gene to the presence of the other showed that the association with EDA2R is independent while the association with AR seems to be the result of linkage disequilibrium. These results give insight into the pathways involved in AGA etiology.

Journal of Investigative Dermatology advance online publication, 3 April 2008;

doi:10.1038/jid.2008.60.

PMID: 18385763 [PubMed - as supplied by publisher]


#7

» > Its known that the variant of the androgen receptor gene is located on
» the
» > x-chromosome and comes from your mother, but the other genes in
» baldness
»
» An ectodysplasin gene (which is located on the X chromosome, near the AR
» gene) has now been linked to MPB. The ectodysplasin signalling system has
» already been shown to be important in hair biology…do a search on Pubmed
» for more details. You’ll be hearing about this study in the lay media
» pretty soon, I’m sure:
»
» J Invest Dermatol. 2008 Apr 3 [Epub ahead of print]
»
» EDA2R Is Associated with Androgenetic Alopecia.
»
» Prodi DA, Pirastu N, Maninchedda G, Sassu A, Picciau A, Palmas MA, Mossa
» A, Persico I, Adamo M, Angius A, Pirastu M.
»
» 1Shardna Life Sciences, Pula, Italy.
»
» Androgenetic alopecia (AGA) is a common heritable polygenic disorder whose
» genetics is not fully understood, even though it seems to be X-linked. We
» carried out an epidemiological survey for AGA on 9,000 people from 8
» isolated villages of a secluded region of Sardinia (Ogliastra), and
» identified a large cohort of affected individuals. We genotyped 200 cases
» and 200 controls (mean kinship 0.001) with the 500k chip array and
» conducted case-control association analysis on the X chromosome. We
» identified Xq11-q12 as strongly associated with AGA. In particular, we
» found that rs1352015 located 8 kb from the EDA2R gene showed the best
» result (P=7.77e(-7)). This region also contains the AR gene, hence we
» tested both genes in 492 cases and 492 controls. We found that the
» non-synonymous SNP rs1385699 on EDA2R gave the best result (P=3.9e(-19))
» whereas rs6152 on the AR gene is less significant (P=4.17e(-12)). Further
» statistical analysis carried out by conditioning each gene to the presence
» of the other showed that the association with EDA2R is independent while
» the association with AR seems to be the result of linkage disequilibrium.
» These results give insight into the pathways involved in AGA etiology.
»
» Journal of Investigative Dermatology advance online publication, 3 April
» 2008;
»
» doi:10.1038/jid.2008.60.
»
» PMID: 18385763 [PubMed - as supplied by publisher]

That link you posted, showing a gene that is statsitically signifigant in baldness, and almost assuredly has a direct influence on it, got me to looking around and I came up with this…

Article

Min Zhang 1, Anna Brancaccio 2, Lorin Weiner 1, Caterina Ectodysplasin regulates pattern formation in the mammalian hair coat Missero 2, Janice L. Brissette 1 *
1Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA
2Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy

email: Janice L. Brissette (janice.brissette@cbrc2.mgh.harvard.edu)

*Correspondence to Janice L. Brissette, Cutaneous Biology Research Center, Massachusetts General Hospital-East, Bldg. 149, 13th St., Charlestown, MA 02129

Funded by:
National Institutes of Health
Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd. Agreement
Italian Telethon Foundation
TIGEM with funding from Regione Campania

Keywords
Eda • tabby • ectodermal dysplasia • ED1 • Edar

Abstract
Summary: develoIn mammalian skin, hair follicles develop at regular intervals and with site-specific morphologies. This process generates distinct patterns of hair, but the mechanisms that establish these patterns remain largely unknown. Here we present evidence of follicular patterning by ectodysplasin-A1 (Eda-A1), a signaling protein necessary for the proper development of hair and other appendages. In transgenic mice, Eda-A1 was targeted to the epithelial compartment of the ping skin. At periodic locations, multiple hair follicles were induced side by side, without any interfollicular space. These follicles grew into the dermis as a fusion and subsequently branched to create discrete stalks and hair bulbs. Thus, at sites where interfollicular skin normally forms, hair follicles developed instead. This result shows that Eda-A1 can regulate basic developmental decisions, as cells were switched from interfollicular to follicular fates. Given these effects, it is likely that Eda-A1 is among the key regulators of pattern formation in the skin. genesis 37:30-37, 2003. © 2003 Wiley-Liss, Inc.

Me again…perhaps this ‘Ectodermal-A1’ gene is the one that makes the decisions as your head skin grows up over your head in fetal development and determines where your most androgen-sensitive hair will be (the shape of your hippocratic wreath), or where your best working androgen-receptors will be (Im basing this on a study I saw that showed androgen receptors in sebaceous glands in male pattern baldness subjects were much better at uptaking androgens that receptors from sweat glands from occipital scalp). A working “guess” is forming anyway in my mind about it. Here is another study showing that ectodysplasin ‘gene’ and the development of the sweat glands (Do you remember how Stephen Foote used to go on about how bald areas of scalp are better at sweating than hairy areas of scalp? Maybe this is a reason why----other than the sweat glands in bald scalp receptor-sites probably have more available testosterone around due to the tiny vellus hairs not having as many androgen receptors available to uptake androgen in a competing sense physically:
[Relationship of ectodysplasin gene signaling with development and regeneration of sweat glands][Article in Chinese]

Zhou G, Li H, Fu X.
Key Research Laboratory of the Wound Repair, the 304th Clinical Department, General Hospital of PLA, Beijing, 100037, P.R. China.

OBJECTIVE: To investigate the expression of ectodysplasin (EDA) gene signaling and its relationship with the development and regeneration of sweat glands. METHODS: The articles concerned in the latest years were extensively reviewed. RESULTS: EDA gene is an important signaling pathway associated with the developmental procedure of sweat glands in early fetal stage. Abnormality or depletion of function in sweat glands partially owed to the defect of EDA gene. CONCLUSION: EDA signaling has its biological significance in inducing development and morphogenesis of sweat glands and in maintaining physiological function of skin. It could be a new approach to repair or regenerate the sweat glands for clinical therapy by regulating the expression of EDA gene.

PMID: 16752854 [PubMed - in process]

Me again (again–LOL)…TAGOHL, I know the sweat glands would at first seem to be unimportant, but they are tissues in the dermis and here we have that same gene again seemingly being involved on an important part of the skin. Loren Pickart has wrote on his site that the hair follicle seems to be the “command center” for skin-remodelling and signalling. I always noticed that women who pluck out their moustaches repeatedly after menopause seemingly have the upper portions of their mouths age terribly after the hair follicles get destroyed from repeatedly pulling them out-----


#8

»
» But there remains the little problem of explaining why it is that
» androgens stimulate the growth of (most) body hair, but
» suppress the growth of scalp hair. That does sound to me like a
» magic difference in the hair follicles’ basic characteristics! :wink:

Bryan,
The thing is man…is that androgens stimulate body hair in men and women and everyone. In looking at DKK-1, I suppose I am (again) looking for a piece of the puzzle in which we can “stick our finger” in the MPB process and stop it. For example, Peter Proctors product, Prox-n (which I use and has turned me to a fairly brown-headed man from a blonde in the past few years <unreleated, Bryan did you know that menthol stimulates melanocytes and piperene does also? They can make someones dermal tissues darker-----and licorice has something in it that lightens the skin by suppressing the melanocytes by 41% or some such-----you can google it>. » However, the prox-n is designed to deal with the immunological response and not as an anti-androgen. Im wondering why the immunological response happens in the first place. Docj077 used to assert that it was overexpression of TGF-beta and noted that TGF-beta and excessive collageneous deposition is seen in other autoimmune disorders in the body…but we know that the first inflammation in AGA is seen at the infidulum, and Im guessing that something happening right there is what is alerting the immune system that something is going wrong. In acne, hyperkeratinization is happening withing the hair follicle and the inflammation follows, etc. So I reason why should baldness be different? When I found out that androgen receptors are in the keratinocytes near the infidulum and also alpha five reductase type one…perhaps they get overstimulated as the CAG repeates on the AR gene might get expressed here also, making them supersensitive to androgens and leading to hyperkeratinization near the infidulum, HOWEVER the info about DKK-1 directly leading to apoptosis in root sheath keratinocytes led me to look back at the dermal papilla. Perhaps “after it goes bad” at the mitochondrial DNA level in baldness, DKK-1 is the substance that kills keratinocytes and leaves dead KT cells haging around the infidulum----riding the hair follicle out of the body as it grows, but not fast enough not to elicit the attention of the immune system which begins and attack in this area----the first area where inflammation is seen in AGA, and where it is primarily (the upper third of the follicle) restricted to. All the things around the inflammation, like being too close to a hand grenade, get damaged by the immune systems substances.

Bryan, the only way to test this would be for an experiment to be done with a DKK-1 antagonist in MPB and compare the regrowth with that of TGF-beta inhibitors or see if a further cessation of the progression of AGA was observed in human beings (not macaques, because inflammation isn’t seen in them like it is in us).

I’d like to see, in short, if no keratinocytes were dying in the infidulum, whether the immunological attack would not take place. I’ll never forget you posting that study years ago showing that androgens in test tubes only slowed hair growth by 16% alone. That shouldn’t “kill” hair, or attract an immuno response of its own accord, but dead KT cells in the body would (my opinon) anyway.

Bryan, on another note…as far as “2 different types of hair on the head”…I just dont believe that. I reposted that study showing high testosterone added to occipital scalp hairs caused apoptosis and I seen another study (dont know if I put it up anywhere) that showed the androgen receptors in MPB-area sebacous glands were much better at binding male hormone than androgen-receptors from non-MPB areas…leading obviously to the conclusion that more-active androgen receptors or more chemically stable ones in MPB-areas are the reason for the “difference” in the hairs. Ive suggested over and over that if we could transfect someone without MPB hairs in an ex vivo experiment with the whole hair cultured with extra androgen receptors and give them a dose of androgens like a guy with MPB probably sees his follicles uptake, I’d bet they’d respond negatively. I simply think Brad Pitt’s hair isn’t seeing as much androgens as ours is via less DHT in the area, and androgen receptors that dont function “as well” as ours do.

This, if it worked, might be a “stick-our-finger-in-the-chain-of-events”-type of treatment…
» .


#9

http://ghr.nlm.nih.gov/gene=eda

(maybe this gene set being active in a particular way along with a particular variant of the AR-gene are what is necessary for MPB-to be inherited. I wonder if they can “block” what is necessary in pregnant mothers someday----not that this will help us)

Reviewed August 2006
What is the official name of the EDA gene?
The official name of this gene is “ectodysplasin A.”

EDA is the gene’s official symbol. The EDA gene is also known by other names, listed below.

What is the normal function of the EDA gene?
The EDA gene provides instructions for making a protein called ectodysplasin A. This protein is part of a signaling pathway that plays an important role in development before birth. Specifically, it is critical for interactions between two embryonic cell layers called the ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the body’s organs and tissues. Ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands.

The EDA gene provides instructions for producing many slightly different versions of ectodysplasin A. One version, ectodysplasin A1, interacts with a protein called the ectodysplasin A receptor (produced from the EDAR gene). On the cell surface, ectodysplasin A1 attaches to this receptor like a key in a lock. When these two proteins are connected, they trigger a series of chemical signals that affect cell activities such as division, growth, and maturation. Before birth, this signaling pathway controls the formation of ectodermal structures such as hair follicles, sweat glands, and teeth.

How are changes in the EDA gene related to health conditions?
hypohidrotic ectodermal dysplasia - caused by mutations in the EDA gene
More than 80 different mutations in the EDA gene have been identified in people with hypohidrotic ectodermal dysplasia. These mutations cause the X-linked form of the disorder, which accounts for 95 percent of all cases of hypohidrotic ectodermal dysplasia. (X-linked disorders are caused by mutations in genes on the X chromosome, one of the two sex chromosomes.)

Some mutations in the EDA gene change single DNA building blocks (base pairs), whereas other mutations insert or delete genetic material in the gene. These changes lead to the production of a nonfunctional version of the ectodysplasin A protein. This abnormal protein cannot trigger chemical signals needed for normal interactions between the ectoderm and the mesoderm. Without these signals, hair follicles, teeth, sweat glands, and other ectodermal structures do not form properly, leading to the characteristic features of hypohidrotic ectodermal dysplasia.

Where is the EDA gene located?
Cytogenetic Location: Xq12-q13.1

Molecular Location on the X chromosome: base pairs 68,752,635 to 69,176,046


#10

» Bryan,
» The thing is man…is that androgens stimulate body
» hair in men and women and everyone. In looking at DKK-1, I suppose I am
» (again) looking for a piece of the puzzle in which we can “stick our
» finger” in the MPB process and stop it.

But there’s no real lack of different ways we can potentially stick our finger in the MPB processs and stop it. For a long time on hairloss sites there’s been this utter fascination with the veritable “alphabet soup” of substances of all kinds that show a difference in production levels between balding and non-balding hair follicles. Just look at all the times that TGF-beta-1 and TGF-beta-2 and IGF-1 and VEGF have been mentioned and discussed on these sites, and thought to be the final key to the mystery of balding! DKK-1 is just the latest addition to this list, and the “alphabet soup” is getting really robust and full-flavored! :smiley:

Again, I feel this fascination with all the various factors that are different between balding and non-balding hair follicles is ok, but we’re really just treading water here. It’s all mainly just a smoke screen until we find out the fundamental REASON for the difference in production levels of that “alphabet soup” of substances which are different between balding and non-balding hair follicles. And who knows?? We may even stumble upon reasonably effective treatments for balding here and there by searching for TGF-beta inhibitors, DKK-1 inhibitors, etc. But in my humble opinion, it’s still basically just a waiting game until we can find out the fundamental REASON for those differences.

» Bryan, on another note…as far as “2 different types
» of hair on the head”…I just dont believe that. I reposted
» that study showing high testosterone added to occipital scalp hairs caused
» apoptosis and I seen another study (dont know if I put it up anywhere) that
» showed the androgen receptors in MPB-area sebacous glands were much better
» at binding male hormone than androgen-receptors from non-MPB
» areas…leading obviously to the conclusion that more-active
» androgen receptors or more chemically stable ones in MPB-areas are the
» reason for the “difference” in the hairs. Ive suggested over and over that
» if we could transfect someone without MPB hairs in an ex vivo experiment
» with the whole hair cultured with extra androgen receptors and give them a
» dose of androgens like a guy with MPB probably sees his follicles uptake,
» I’d bet they’d respond negatively. I simply think Brad Pitt’s hair isn’t
» seeing as much androgens as ours is via less DHT in the area, and androgen
» receptors that dont function “as well” as ours do.

I don’t have any doubt about that, either. But I personally have relatively little concern for all the various factors which get discussed ad nauseum on hairloss sites which have to do with different levels of androgenic stimulation, and the resulting different severities of balding from one person to another. To me, that’s a relatively trivial and obvious matter. What interests me far more is what accounts for the FUNDAMENTAL DIFFERENCE between body hair follicles and scalp hair follicles which makes them respond to androgens in an OPPOSITE fashion. Until we can figure that out, we’re mainly just spinning our wheels.

.


#11

Bryan, since you’ve been on these forums/newsgroups for over a decade now, I have a question. Have you come across anyone using garlic on their heads and regrowing hair? or maybe after wounding their scalp followed by garlic and regrowing any hair?

Thanks!


#12

Sorry, but after 13 years on these boards, I don’t recall anybody ever putting garlic on his scalp!

.


#13

Bryan,

Men WITHOUT MPB have body hair that responds well to androgens.

Studying the difference between body hair and head hair is an empty procedure in my opinon. Body hair does not grow in big follicular units of groups of 3-6 hairs like head hair does in donor-areas of the scalp. Body hair grows in 1 and 2 hair units (mostly ones), is usually thinner, and does not grow as long as head hair, even when transplanted to the scalp (usually about doubles its length at best).We are never going to be able to “change” head hair so fundamentally that it will actuall “like” androgens. Beard hair has the longest growth cycle on the body, but beard hairs are huge in thickness and only grow one hair at a time. I see no way to convert beard hairs into head hairs or vice versa. Im interested in the difference between MPB-hairs and donor-area hairs…and what we can do to get these two similar hair types to behave the same, i.e. be relatively unaffected by androgens most of one’s life.

What goes on when scalp skin in the first trimester of a woman's pregnancy "makes" hair at the top of the head so much more sensitive to androgens vs. donor-area hair? That is something perhaps we can effect. I dont think we will ever be able to fiddle with DNA enough to make head hair not only like androgens, but look like head hair is supposed to look (big folliclar units, not kiky and ugly, etc.)


DKK-1 and its causation of keratinocyte cell death in or near the infidulum seems to be the best clue as to why the first inflammation in AGA happens at the infidulum first and its centered around that area for the duration (upper third of the follicle). I'd love to see if this is *the* reason for the immunological response. I keep cyclosporin's prowess in regrowing hair in mind here....................what if we could make the immunse system no longer interested in the follicle with a DKK-1 inhibitor Bryan? Then things like Prox-n might have a chance of regrowing long-miniaturized hairs -perhaps- with a relatively mild anti-androgen like finasteride. Thats my hope anyway. 

Harold, over at HLT, has pointed out before that balding follicles seem to lose CD200 molecules around the follicle itself and that this substance tells the immune system “not to attack”. Ive wondered if that has anything to do with it also.

Other than DKK-1, we are back to DNA within the follicle (which might take years to figure out), and finding better and better skin-remodellers and anti-androgens (AJSC-9 maybe). In other words, kinda stuck.

By the way…here is that article about sebaceous gland androgen receptors uptaking more androgen in experiments that receptors from occipital scalp:

Increased androgen binding capacity in sebaceous glands in scalp of male-pattern baldness.Sawaya ME, Honig LS, Hsia SL.
Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Florida 33101.

Sebaceous glands were isolated by manual dissection under a microscope from surgical specimens of scalp skin with male pattern baldness and skin specimens of hairy and bald scalp obtained at autopsy. The 800 X g pellet (nuclear fraction) and the 164,000 X g supernatant fraction (cytosol) of homogenates of the sebaceous glands were used for measurements of androgen binding characteristics, using dextran-coated charcoal and sucrose gradient methods. Scatchard plots showed high affinity binding for [3H]dihydrotestosterone (DHT) and [3H]methyltrienolone (R1881). Nuclei prepared from bald scalp contained greater total androgen binding capacity than nuclei of hairy scalp, although Kd values of type I binding were similar (0.68 vs 0.56 nM, respectively). On sucrose gradient, the binding protein from cytosol was found in the 7 to 8S density range. Androgen binding by cytosol of sebaceous glands of hairy scalp had Kd of 1.89 +/- .79 and 2.05 +/- .56 nM for DHT and R1881, respectively, and Bmax of 18.7 +/- 4.4 and 20.0 +/- 4.6 fmol/mg protein for DHT and R1881, respectively. Cytosol from sebaceous glands of bald scalp had Kd values approximately half those of hairy scalp, and Bmax values 50%-100% higher. The bound 3H labeled DHT and R1881 could be partially displaced by testosterone (40-50%), moxestrol (28-32%), promegestone (19-26%), and delta 4-androstenedione (6-12%), but not by dehydroepiandrosterone. These data demonstrate the presence of specific androgen binding protein in sebaceous glands, and that sebaceous glands of bald scalp have greater binding affinity and capacity for androgens than those in hairy scalp. This difference may explain the greater androgenic response in androgenic alopecia.

PMID: 2909628 [PubMed - indexed for MEDLINE]


#14

Benji, thanks for the info – very interesting. I need to ponder all this stuff. Here’s a couple more abstracts. The first one is another recent genetic study which shows that a polymorphism in the ectodysplasin-A receptor gene is what gives Asians thick hair. The second study shows that ectodysplasin helps control the switch from anagen to catagen (early termination of anagen – short growth cycles – are a feature of MPB). Gene therapy for baldness would be really, really nice if it happens someday.

Hum Mol Genet. 2008 Mar 15;17(6):835-43.

A scan for genetic determinants of human hair morphology: EDAR is associated with Asian hair thickness.

Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo, Japan.

Hair morphology is one of the most differentiated traits among human populations. However, genetic backgrounds of hair morphological differences among populations have not been clarified yet. In addition, little is known about the evolutionary forces that have acted on hair morphology. To identify hair morphology-determining genes, the levels of local genetic differentiation in 170 genes that are related to hair morphogenesis were evaluated by using data from the International HapMap project. Among highly differentiated genes, ectodysplasin A receptor (EDAR) harboring an Asian-specific non-synonymous single nucleotide polymorphism (1540T/C, 370Val/Ala) was identified as a strong candidate. Association studies between genotypes and hair morphology revealed that the Asian-specific 1540C allele is associated with increase in hair thickness. Reporter gene assays suggested that 1540T/C affects the activity of the downstream transcription factor NF-kappaB. It was inferred from geographic distribution of 1540T/C and the long-range haplotype test that 1540C arose after the divergence of Asians from Europeans and its frequency has rapidly increased in East Asian populations. These findings lead us to conclude that EDAR is a major genetic determinant of Asian hair thickness and the 1540C allele spread through Asian populations due to recent positive selection.

PMID: 18065779 [PubMed - in process]

Involvement of the Edar signaling in the control of hair follicle involution (catagen).

Department of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA 02118, USA.

Ectodysplasin (Eda) and its receptor (Edar) are required for normal development of several ectodermal derivatives including hair follicles (HFs). Here, we show that during the murine hair cycle the expression of Eda A1, Edar, Edaradd, and TRAF6 transcripts are minimal in the resting phase and maximal during HF transition from active growth to regression (catagen). Eda A1 mRNA and Edar proteins were expressed in the hair matrix and outer and inner root sheaths of anagen HFs. During catagen, Eda A1 mRNA and Edar protein were expressed in the outer and inner root sheaths and later in the secondary hair germ. Catagen development accompanied by increased apoptosis in the outer root sheath was significantly accelerated in downless mice or after treatment of wild-type mice by a fusion protein that inhibits Edar signaling, compared with the corresponding controls. Microarray, real-time polymerase chain reaction, and immunohistochemical analyses of skin of downless mice revealed a strong decrease of expression of X-linked inhibitor of apoptosis protein (XIAP), compared with the controls, suggesting XIAP as a target for Edar signaling. Thus, our data demonstrate that in addition to its well-established role in HF morphogenesis, Edar signaling is also involved in hair cycle control and regulates apoptosis in HF keratinocytes during catagen.

PMID: 17148670 [PubMed - indexed for MEDLINE]


#15

» Sorry, but after 13 years on these boards, I don’t recall anybody ever
» putting garlic on his scalp!
»
» .

Do you know of any studies on bald vs non-bald scalp? I tried but couldn’t find any. I’m thinking maybe scalp is the reason why we don’t regrow much of our hair because it undergoes changes during baldness. Same reason Intercytex isn’t having much luck with their TRC treatment.


#16

TAGOHL:

Where did you get you LiCl?


#17

» Do you know of any studies on bald vs non-bald scalp?

For garlic? No I don’t. Sorry.

.


#18

» Benji, thanks for the info – very interesting. I need to ponder all this
» stuff. Here’s a couple more abstracts. The first one is another recent
» genetic study which shows that a polymorphism in the ectodysplasin-A
» receptor gene is what gives Asians thick hair. The second study shows that
» ectodysplasin helps control the switch from anagen to catagen (early
» termination of anagen – short growth cycles – are a feature of MPB).
» Gene therapy for baldness would be really, really nice if it happens
» someday.
»
» Hum Mol Genet. 2008 Mar 15;17(6):835-43.
»
» A scan for genetic determinants of human hair morphology: EDAR is
» associated with Asian hair thickness.
»
» Department of Human Genetics, Graduate School of Medicine, The University
» of Tokyo, Hongo, Tokyo, Japan.
»
» Hair morphology is one of the most differentiated traits among human
» populations. However, genetic backgrounds of hair morphological
» differences among populations have not been clarified yet. In addition,
» little is known about the evolutionary forces that have acted on hair
» morphology. To identify hair morphology-determining genes, the levels of
» local genetic differentiation in 170 genes that are related to hair
» morphogenesis were evaluated by using data from the International HapMap
» project. Among highly differentiated genes, ectodysplasin A receptor
» (EDAR) harboring an Asian-specific non-synonymous single nucleotide
» polymorphism (1540T/C, 370Val/Ala) was identified as a strong candidate.
» Association studies between genotypes and hair morphology revealed that
» the Asian-specific 1540C allele is associated with increase in hair
» thickness. Reporter gene assays suggested that 1540T/C affects the
» activity of the downstream transcription factor NF-kappaB. It was inferred
» from geographic distribution of 1540T/C and the long-range haplotype test
» that 1540C arose after the divergence of Asians from Europeans and its
» frequency has rapidly increased in East Asian populations. These findings
» lead us to conclude that EDAR is a major genetic determinant of Asian hair
» thickness and the 1540C allele spread through Asian populations due to
» recent positive selection.
»
» PMID: 18065779 [PubMed - in process]
»
» Involvement of the Edar signaling in the control of hair follicle
» involution (catagen).
»
» Department of Dermatology, Boston University School of Medicine, 609
» Albany St., Boston, MA 02118, USA.
»
» Ectodysplasin (Eda) and its receptor (Edar) are required for normal
» development of several ectodermal derivatives including hair follicles
» (HFs). Here, we show that during the murine hair cycle the expression of
» Eda A1, Edar, Edaradd, and TRAF6 transcripts are minimal in the resting
» phase and maximal during HF transition from active growth to regression
» (catagen). Eda A1 mRNA and Edar proteins were expressed in the hair matrix
» and outer and inner root sheaths of anagen HFs. During catagen, Eda A1 mRNA
» and Edar protein were expressed in the outer and inner root sheaths and
» later in the secondary hair germ. Catagen development accompanied by
» increased apoptosis in the outer root sheath was significantly accelerated
» in downless mice or after treatment of wild-type mice by a fusion protein
» that inhibits Edar signaling, compared with the corresponding controls.
» Microarray, real-time polymerase chain reaction, and immunohistochemical
» analyses of skin of downless mice revealed a strong decrease of expression
» of X-linked inhibitor of apoptosis protein (XIAP), compared with the
» controls, suggesting XIAP as a target for Edar signaling. Thus, our data
» demonstrate that in addition to its well-established role in HF
» morphogenesis, Edar signaling is also involved in hair cycle control and
» regulates apoptosis in HF keratinocytes during catagen.
»
» PMID: 17148670 [PubMed - indexed for MEDLINE]

This is profoundly interesting information. Its the type of literal proof I’d always thought they’d be finding “someday” about how genetics directly controls hair thickness, hairlines, shapes of wreaths, etc. I noticed that the Edar signalling was implicated “involved in hair cycle control and
» regulates apoptosis in HF keratinocytes during catagen”. Its the keratinocyte cell death that is intriguing to me for the reason that I think it just might be dead keratinocyte cells in the infidula downstream of DKK1, that might get the immune system interested in the follicle. If men with baldness lack XIAP, the “X-linked inhibitor of apoptosis protien” or have much less of it genetically, perhaps its why DKK-1 is so detrimental to our follicles over other men.

What is intriguing to me personally is this…what could Follica do if a way to upregulate the “Asian-specific non-synonymous single nucleotide
» polymorphism (1540T/C, 370Val/Ala)” or include it in their topical or internal after the skin-re-epilithialization period in their process someday, and “give” the new hair made great hair genetics no matter where its made.

Ive went on and on (Im sure youve seen it) about my “inkling” that Follica might be able to make very good hair back in the donor area of men post-FUE…but might make hair that is just like MPB hair or might make thinner weaker hairs in MPB scalp due to all the genes that might be at play in the frontal scalp vs. donor scalp. Its a “defeatist”-kinda thought, but all the razzmatazz of promising treatments over the years have left me looking for ways things might fail vs. how they might succeed. ICX, for example (and Aderans), now honestly appear to be at least five years away in the best-case scenario to me now----if indeed within the next 10.

I’ll never forget a doctor going over baldness with me when I was 25, and how he said “let me show you something” and he ran his finger up the side of my head and told me you can “feel” where you wreath is going to start genetically because the hair will start feeling different (weaker) at a certain point. It did. This was before I got on finasteride. Now the “change” in feeling is much more subtle, but it was pretty obvious then. Ive seen Washenik discuss how the skin grows up over the top of the scalp in fetal development and how one’s pattern seems to be determined during this time. It all seems so profoundly genetically hard-wired to me. Its amazing how genes work. I knew a family once that had a Iraqi father and a blonde European mother. Their four kids all looked differnt. One looked very Arab (and was slim), one looked like a farm boy from the midwest with medium brown hair (hefty), one of the girls looked like an middle eastern model (dark skin, dark hair and beautiful), and the other daughter was a very plain (some would say kinda homely) blonde gal with light skin (and blue eyes) that was prone to heaviness. It seemed to me that genetics was like a deck of cards and your chances of inheriting this or that came from those cards getting really mixed up and you drawing this one or that one. Two of those kids looked “very white” and the other to looked very Arabain. It was not a mix of the two as I’d expected. The blonde was very blonde—and the two that had black hair had JET-BLACK hair. Mystifying that such totality was “selected” and the two phenotypes didnt “mix” somewhat to produce brown hair like the hefty brother had.


#19

» » Sorry, but after 13 years on these boards, I don’t recall anybody ever
» » putting garlic on his scalp!
» »
» » .
»
» Do you know of any studies on bald vs non-bald scalp? I tried but couldn’t
» find any. I’m thinking maybe scalp is the reason why we don’t regrow much
» of our hair because it undergoes changes during baldness. Same reason
» Intercytex isn’t having much luck with their TRC treatment.

Info on MPB-area and occipital scalp DIFFERENCES:

Increased androgen binding capacity in sebaceous glands in scalp of male-pattern baldness.Sawaya ME, Honig LS, Hsia SL.
Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Florida 33101.

Sebaceous glands were isolated by manual dissection under a microscope from surgical specimens of scalp skin with male pattern baldness and skin specimens of hairy and bald scalp obtained at autopsy. The 800 X g pellet (nuclear fraction) and the 164,000 X g supernatant fraction (cytosol) of homogenates of the sebaceous glands were used for measurements of androgen binding characteristics, using dextran-coated charcoal and sucrose gradient methods. Scatchard plots showed high affinity binding for [3H]dihydrotestosterone (DHT) and [3H]methyltrienolone (R1881). Nuclei prepared from bald scalp contained greater total androgen binding capacity than nuclei of hairy scalp, although Kd values of type I binding were similar (0.68 vs 0.56 nM, respectively). On sucrose gradient, the binding protein from cytosol was found in the 7 to 8S density range. Androgen binding by cytosol of sebaceous glands of hairy scalp had Kd of 1.89 +/- .79 and 2.05 +/- .56 nM for DHT and R1881, respectively, and Bmax of 18.7 +/- 4.4 and 20.0 +/- 4.6 fmol/mg protein for DHT and R1881, respectively. Cytosol from sebaceous glands of bald scalp had Kd values approximately half those of hairy scalp, and Bmax values 50%-100% higher. The bound 3H labeled DHT and R1881 could be partially displaced by testosterone (40-50%), moxestrol (28-32%), promegestone (19-26%), and delta 4-androstenedione (6-12%), but not by dehydroepiandrosterone. These data demonstrate the presence of specific androgen binding protein in sebaceous glands, and that sebaceous glands of bald scalp have greater binding affinity and capacity for androgens than those in hairy scalp. This difference may explain the greater androgenic response in androgenic alopecia.

PMID: 2909628 [PubMed - indexed for MEDLINE]

Balding scalp has also been shown to have more DHT, less oxygen (probably as a result of the MPB process), larger sebaceous glands, and a higher sweating capacity right off the top of my head. Dont have those studies handy thoug


#20

» Where did you get you LiCl?

I ordered a different form of lithium, as well as a home dermabrasion kit. I’m waiting on that.