So to summarise my opinion on the all literature sources i have read in relation to the pathology of AGA:
1)IMO, not all studies are accurate. Some older studies were even refuted by later studies.
2)Not all proposed/suggested pharmalogical solutions in those studies were effective. Some were even refuted as being harmful to the hair follicles in later experiments.
3)The best indicative and in IMO referral source on the pathology of AGA in my course of reading countless studies on literature relevant to AGA comes from the Scoliosis study. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365504/ The fact that Idiopathic Scoliosis http://en.wikipedia.org/wiki/S...tionary_considerations , and not AGA- was the (A)original intended topic of the study, along with the fact that the gene locus indicated by the study and supported by (B)others as being a genetic susceptibility locus in multiple ethnic groups for AGA further lends its findings enhanced credibilit(on AGA):
(A)"Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition."*
(B) Abstract
Background
Androgenetic alopecia (AGA) is a well-characterized type of progressive hair loss commonly seen in men, with different prevalences in different ethnic populations. It is generally considered to be a polygenic heritable trait. Several susceptibility genes/loci, such as AR/EDA2R, HDAC9 and 20p11, have been identified as being involved in its development in European populations. In this study, we aim to validate whether these loci are also associated with AGA in the Chinese Han population.
Methods
We genotyped 16 previously reported single nucleotide polymorphisms (SNPs) with 445 AGA cases and 546 healthy controls using the Sequenom iPlex platform. The trend test was used to evaluate the association between these loci and AGA in the Chinese Han population. Conservatively accounting for multiple testing by the Bonferroni correction, the threshold for statistical significance was P ?3.13×10?3.
Results
We identified that 5 SNPs at 20p11 were significantly associated with AGA in the Chinese Han population (1.84×10?11?P?2.10×10?6).
Conclusions
This study validated, for the first time, that 20p11 also confers risk for AGA in the Chinese Han population and implicated the potential common genetic factors for AGA shared by both Chinese and European populations.
We carried out a genome-wide association study in 296
individuals with male-pattern baldness (androgenetic alopecia)
and 347 controls. We then investigated the 30 best SNPs in an
independent replication sample and found highly significant
association for five SNPs on chromosome 20p11 (rs2180439
combined P ¼ 2.7 1015). No interaction was detected
with the X-chromosomal androgen receptor locus, suggesting
that the 20p11 locus has a role in a yet-to-be-identified
androgen-independent pathway.(possibly why castrates dont regrow hair)
Male-pattern baldness susceptibility locus at 20p11
J Brent Richards,1,2 Xin Yuan,3 Frank Geller,4 Dawn Waterworth,3 Veronique Bataille,1 Daniel Glass,1 Kijoung Song,3 Gerard Waeber,5 Peter Vollenweider,5 Katja K H Aben,6,7 Lambertus A Kiemeney,8,9 Bragi Walters,4 Nicole Soranzo,1,10 Unnur Thorsteinsdottir,4 Augustine Kong,4 Thorunn Rafnar,4 Panos Deloukas,10 Patrick Sulem,4 Hreinn Stefansson,4 Kari Stefansson,4 Tim D Spector,1,11 and Vincent Mooser3,11
Author information ? Copyright and License information ?
The publisher's final edited version of this article is available at Nat Genet
See other articles in PMC that cite the published article.
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Abstract
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 × 10?14 for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 × 10?15).
Experimental small molecule pharmalogical solutions for AGA by topical/oral route administration in order of descending preference(would be updated from time to time):
1):
All affected genes indicated in the Scoliosis study:
TATA <= Topical Calcitirol/Calcipotriol
HNF4 <= Topical Carbamazepine(direct activator of SHBG for disactivating circulating sex hormones with highest affinity for DHT=>increased bone resorption in the balding skull. Has sides), Topical Valproic acid(Androgen Receptor Blocker, Wnt/B-catenin agonist, CD34 upregulator and several other pro-hair growth properties. Has sides if taken orally), Topical RU58841(Androgen Receptor Blocker- less systemic side effects), topical CB(Androgen Receptor Blocker), topical/oral Dutasteride(5A Redutase Inhibitor to decrease circulating DHT. Used carefully- will dramatically slow down, but not stop- AGA and increase 'free' Testosterone levels for the muscles), topical/oral Finasteride(5A Redutase Inhibitor to decrease circulating DHT- almost the same profile as Dutasteride but with less potency), oral Spironolactone(Androgen Receptor Blocker, Aldosterone Inhibitor=> Less sodium reabsorption in kidneys=>less vasoconstriction=>increased blood supply to hair follicles. Has feminizing sides.)
RAR <= Ultra low dose topicalTretinoin (0.0005%. Ultra low doses of it induces hair differentation at a stabilised rate with stem cells as the fuel while increasing dosages depletes stem cells rapidly and leads to apoptosis instead. Is also toxic when used in dosages above a certain threshold)
RXRA <= Topical Calcitriol/Calcipotirol(Calcitriol-binded VDR is needed for full transcription of PPAR Alpha, Beta and Gamma. VDR-null cells on the scalp diverts pluripotent stem cells to the sebocyte(sebum) and sudoriferous(sweat) lineage)
STAT <= Topical Calcitriol/Calcipotriol(Calcitriol acts as a modulator of this central inflammation pathway- the JAK-STAT pathway.)
BATF <= Topical Calcitirol/Calcipotriol(Calcitriol acts as a modulator of this TH17 cytokines regulatory gene)
COMP <= Topical Calcitirol/Calcipotriol, topical Valproic acid(Both Calcitriol and Valproic acid increase expression of this gene- and it is upregulated only in haired-scalp.)
VDR <= Topical Calcitirol/Calcipotriol(Calcitriol's own receptor. It is a receptor that regulates, modulates and thus- controls hundreds of genes involved with Immunity, Calcium homeostasis, Bone formation/resorption(in synergy with BMPs) and many, many more in the human body.)
HDAC2 <= Topical Valproic acid(inhibitor of HDAC2- which inhibits AGA-afflicted hair follicles stem cell renewal's function)
Top 5 upregulated genes in haired-scalp and Top 5 downregulated genes in haired-scalp as indicated by Dr Cotsarelis's patent in order of descending preference:
PTGDS<= Topical/oral TM30089(Long half-life- allowing once/day applications High potency. Analog of Ramatroban.) topical/oral Setipiprant(Newest CRTH2 inhibitor in trials, topical/oral Ramatroban(Short half-life, Demanding twice/day applications to keep itch and pain away continuosly. 1% topical is sufficient.), topical/oral OC(Shortest half-life and lowest out of the four listed here potency. Twice/day applications.)
CORIN<= Oral Spironolactone(indirectly by antagonising Aldosterone=> CORIN downregulation=> FURIN-Cleaved proBNP=> 1-32 BNP(the pro-hair growth form of BNP) => hair pigmentation + keratinization)
4):
Three 'endpoint' genes indicated by Dr Cotsarelis's patent that are significantly-upregulated in haired-scalp:
CD34<== Topical Valproic acid(via existing cell self-renewal), Topical 16,16-Dimethly-PGE2(via homing from bone marrow), Topical PGE2(PGE2=>EP2 Receptor=>Survivin=>CD34. Also- PGE2=>EP4 Receptor=>BMP-2=>SMAD1/5/8=>SMAD4=>DLX3=>RUNX2=>Hair shaft differentiation), Topical Butaprost(This is a selective EP2 receptor and EP4 receptor agonist. An PGE2 analog), topical/oral Sulfasalazine(Upregulates PGE2 while inhibiting COX-2)
Intergrin A6<= Ultra low dose topical Tretinoin(0.0005%. Tretinoin is the only small molecule that could be found to upregulate IntergrinA6 with the other being the Parathyroid hormone-related protein(not a small molecule))
END
09-03-2015 01:58 AM
eldarlmario
I recommend any1 who sincerely wants to help himself with his hairloss to spend a couple of hours reading:
These 2 studies are like the Old and New testament. it links up the puzzle of the pathological cause of AGA. If we were to look at the genes being altered in the Scoliosis study, it's very easy to understand why the genes mentioned in Dr Cotsarelis patent are being upregulated/downregulated.
09-03-2015 02:05 AM
eldarlmario
UV light will cause more hairloss. This was proven by Cotsarelis on how a 'surprising'(surprising because UV light exposure is supposed to decrease immunity) increase in leukocyte infiltration was observed in balding hair follicles after exposure to UV light and also by my own experience from suntanning) on the balding scalp- but cause hair growth else where. i noticed that the hairgrowth on my cheeks(induced by oral minox sulfate) was accelerated after the hrs spent suntanning raw. IMO, the balding scalp has a 'preference' due to the altered genes caused by the balding locus- to synthesise PTGDS- enzyme for making PGD2- over making PTGES-enzyme for making PGE2. This is not my own opinion because again- Dr Cotsarelis has already proven that PTGDS- enzyme for making PGD2 is indeed upregulated several times fold in hair from balding scalp.
09-03-2015 02:18 AM
eldarlmario
bump
09-03-2015 02:21 AM
eldarlmario
Accoriding to Dr Cotsarelis's patent, CD200's expression is significantly downregulated in bald-scalp. Here's an article on CD200 phenotypes:
CD200:CD200R-Mediated Regulation of Immunity
1.1.2. Physical Interaction between CD200:CD200R
Information concerning the physical interactions between CD200 and CD200R has come essentially from two methodologies. One has focused on studying the structural constraints and biophysical properties of the interacting molecules. Using site-directed mutagenesis of CD200R1 Hatherley and Barclay showed that, like CD200, this molecule interacts predominantly with CD200 through the GFCC? face of its N-terminal domain, suggesting in turn that the cell-cell interaction between a CD200+ and CD200R+ cell would thus span four Ig superfamily domains, a distance similar to many of the interactions found between T cells and antigen presenting cells [22]. The actual affinity of interaction between CD200 and CD200R(Cd200's receptor that is present on many cell types) is reportedly quite low (KD~2.5??M) [23], similar to that of many other interactions in the immune system which may imply that these serve to modulate cell activity in the context of other cell:cell interactions.
Similar conclusions concerning the importance of interaction between the N-terminal domains of CD200/CD200R were reached from functional studies which focused on the ability of CD200 and CD200R-derived peptides to act as agonists or antagonists of the immune responses set in train by CD200:CD200R interactions [24, 25]. As an example, since CD200 was shown to attenuate inflammatory cytokine production following stimulation of lymphocytes by LPS(CD200 dampens inflammation) in vitro, or TNF? production in vivo after LPS injection, CD200 peptides which antagonized this activity, or alternatively acted independently as agonists, were characterized [24]. Regions in the N-terminal FR2CDR2 and CDR2FR3 domains of CD200 were most relevant for the functional effects seen [24].
Using murine peritoneal macrophages it was shown that the IFN? and IL-17-stimulated cytokine secretion was inhibited by CD200R1 engagement(once cd200 is activated, it inhibits interferon gamma and il-17 production), although surprisingly LPS-stimulated responses were apparently unaffected, unlike results reported elsewhere [40]. Tetanus toxoid-induced secretion of IL-5 and IL-13 from human PBMCs was also inhibited by CD200R1 agonists(Il-5 and Il-13, profibrotic Th2 cytokines, are also inhibited upon activation of cd200's receptor (1)- and many agonistic molecules can bind to it in CD200's place), but the effect was dependent upon cross-linking the CD200R1 on monocytes, but not on CD4 T cells, although CD200R1 is expressed on subsets of T cells [41]. As discussed in more details in the following, one of the earliest reported immunomodulatory effects of over-expression of CD200 in vivo was reported to be an alteration in the cytokine production profile following alloactivation, with preferential production of IL-4 and IL-10(an anti-autoimmune cytokine aka 'good' cytokine) at the expense of IFN? and IL-2 [42].
Sato et al. [43] analyzed the mechanisms(s) whereby CD200R1 expressed on dendritic cells (DCs) led to fine tuning of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT). DCregs generated from bone marrow in vitro (BM-DCregs) expressed an alternate CD200R (CD200R3), resulting in a suppressive function in an antigen-specific CD4 T-cell response. Importantly, CD49+CD200R3+ cells were similar in phenotype and function to classical BM-DCregs, and, like the latter, adoptively transferred protection from cGVHD to mice after alloHSCT. Protection was associated with development of antigen-specific anergic CD4T cells and with CD4+CD25+Foxp3+Tregs, while depletion of CD49+CD200R3+ cells before alloHSCT enhanced cGVHD. Induction of Tregs following CD200:CD200R interactions(As mentioned before- Tregs are immunoregulatory t cells- they help prevent autoimmunity- and this happens when the CD200 receptor is activated by CD200) is, as will become evident in the following, a recurrent theme in CD200R-induced immunoregulation.
09-03-2015 02:22 AM
eldarlmario
On CD200's expression in the bones:
Provocative data has also been reported suggesting a functional role for CD200:CD200R interactions in influencing bone development [53]. Osteoclasts, important mediators of bone loss leading to osteoporosis, are CD200R1+.(osteoclasts have CD200 Receptor 1 on them) Osteoclasts from CD200KO mice differentiate at a reduced rate, with decreased activation of the NF-B and MAP kinase signaling pathways downstream of RANK, a receptor playing a key role in osteoclast differentiation.( http://en.wikipedia.org/wiki/Osteoclast differentiation is negatively affected when CD200R1 is underexpressed. this means bone resorption is reduced- just like what we can see on the balding skull. Bone keeps forming and forming with lesser-than-normal resorption and taking up space at the SubQ adipocyte layer's expense needed to maintain hair growth. Calcium is is needed to form bones. This probably explains why there we often see etopic harden tissue growth on slick-bald scalps. And VDR has got something to do with this because it is the master regulator of calcium homeostasis.) A soluble form of CD200 rescued macrophage fusion to form osteoclasts and macrophage activation downstream of RANK, while a soluble form of CD200R1 prevented this. CD200KO mice contained fewer osteoclasts and accumulated more bone than wt animals. (there you go)The importance of CD200 expression to bone development has also been investigated using a 2-dimensional and 3-dimensional culture systems, and monitoring expression of a number of mRNAs as well as growth of bone nodules and TRAP+ cells in culture, as surrogate markers for preferential osteoclastogenesis versus osteoblastogenesis [54]. These data favored a model in which osteoblast expression of CD200 delivered signals (through CD200R1) to attenuate activity in osteoclasts and promote expression of mRNAs associated with bone formation [55]. In support of this hypothesis, in a follow-up study in which cells were cultured under microgravity conditions in space orbit, preferential expression of CD200 (using cells) overcame the increased osteoclastogenesis seen under microgravity conditions [56].
if we were to look at figure 3A of the patent- we can see 2 familar genes that has been indicated as being altered by the Scoliosis/AGA haplotype in the Scoliosis/AGA study: Comp(1)(Cooperates with myogenic proteins 1 RENAMED to: COMP aka Cartilage Oliogomeric Matrix Protein) and FGF18(via FOXp1- decides how long the telogen phase would lasts)
GPR49 (LGF5, HG38), another leucine rich repeat-containing protein, was upregulated 6.8 fold in the haired samples, and was expressed in human outer root sheath cells, as shown by immuno-histochemistry. (FIG. 6C). GPR49 is known to be upregulated in the mouse bulge (outer root sheath), thus further confirming results of the present invention. Enrichment of this G-protein in anagen/terminal follicles show its utility as a drug target for stimulating hair growth.
FGF18 (upregulated almost 6 fold in the haired samples; FIG. 5B) was found to be expressed in the inner root sheath, the companion layer, and to a lesser extent in the suprabasal outer root sheath of the bulge area (FIG. 6F-G).(we know that Foxp1 is 1 of the gene altered by the AGA haplotype variant- and Foxp1 regulates FGF18)
quoted from the FOXp1 study:
We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent(telogen) phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.
This means:
more stem cells recruited => longer hair growth(longer anagen phase)
less stem cells recruited(via 'precocious activation' aka 'premature activation') =>faster anagen entry, BUT shorter hair growth(due to lesser stem cells recruited- And this fits the clinical presentations of AGA. Our hairs enter anagen fast- only to stop growing fast too, only to come back growing fast again- and dying off fast again=> rapid miniaturization.
This is why IMO, minoxidil needs to be cycled once in a while- it uses up the "already-being-depleted-stem cells" in the hair follicle to fund that extra growth. This could be the reason why we have many users mentioning(including myself by my own experience with it) that cosmetically-visible minoxidl-fueled hair growth sheds all of a sudden after awhile.
09-03-2015 02:33 AM
eldarlmario
PTo those who are still pinning their hopeless hope on Bimatoprost:
From Dr Cotsarelis's findings:
GD2 was detected as 17 pg/mg of tissue in haired scalp and 75.5 pg/mg in bald scalp, representing a 4.4 fold increase in bald tissue. PGF2a also was slightly elevated in bald scalp with 6.7 pg/mg in haired scalp and 15.9 pg/mg in bald scalp.
this might be the reason why bimatoprost(Latisse) don't work on the balding scalp
09-03-2015 02:35 AM
eldarlmario
Genes altered by the Pax1/Foxa2 Scoliosis/AGA balding haplotype variant
TATA
HNF4
RAR
RXRA
STAT
BATF
COMP <==== Cooperates with myogenic protein renamed to Cartilage oligomeric matrix protein
VDR
HDAC2
CART1
FOXA
FOXP1
GATA3
H6 family homeobox 2 (inner ear and vestibular function)
IRF
PAX5
P300
Cartilage oligomeric matrix protein (COMP) forms part of the connective tissue of normal human hair follicles.
Ariza de Schellenberger A1, Horland R, Rosowski M, Paus R, Lauster R, Lindner G.
Author information
Abstract
Hair follicle cycling is driven by epithelial-mesenchymal interactions (EMI), which require extracellular matrix (ECM) modifications to control the crosstalk between key epithelial- and mesenchymal-derived growth factors and cytokines. The exact roles of these ECM modifications in hair cycle-associated EMI are still unknown. Here, we used differential microarray analysis of laser capture-microdissected human scalp hair follicles (HF) to identify new ECM components that distinguish fibroblasts from the connective tissue sheath (CTS) from those of the follicular dermal papilla (DP). These analyses provide the first evidence that normal human CTS fibroblasts are characterized by the selective in situ-transcription of cartilage oligomeric matrix protein (COMP). Following this up on the protein level, COMP was found to be hair cycle-dependent, suggesting critical role in this process: COMP is expressed during telogen and early anagen at regions of EMI and is degraded during catagen (only the CTS adjacent to the bulge remains COMP+ during catagen). Notably, COMP gene expression in vitro suggests direct correlation with the expression of TGFB2(Catagen inducing cytokine) in CTS fibroblasts. This raises the question whether COMP expression undergoes regulation by transforming growth factor, beta (TGFB) signalling. The intrafollicular COMP expression suggests to be functionally important and deserves further scrutiny in hair biology as indicated by the fact that altered COMP expression might be associated with scant fine hair(sounds familar) in the case of some chondrodysplasia and scleroderma patients.(and AGA 'patients' as well- because COMP is 1 of the genes being altered by the PAX/1Foxa2 AGA haplotype variant) Together these results reveal for the first time that COMP is part of the ECM and suggests its important role in normal human HF biology.
Table 1. ?Human pathologies related with cartilage oligomeric matrix protein (COMP) disorders and hair follicle phenotypes in humans
Syndrome Mutation Phenotype Reference
Cartilage hair hypoplasia Metaphyseal chondrodysplasia- McKusick type 132 400 Autosomal recessive 9. Cartilage oligomeric matrix protein (COMP) Short-limbed dwarfism, general hypoplasia. Phenotype: Hair hypoplasia Immunodeficiency Short limbed (54,55)
Connective tissue and rheumatic disease Scleroderma COMP is over-expressed probably because of autocrine transforming growth factor stimulation. Induction of pathogenic matrix deposition Early hair greying followed by hair loss Localized scleroderma gives patchy hair loss (29,30,56,5
And when we read about the pathology description of http://en.wikipedia.org/wiki/Sclerod...athophysiology , save for the necrosis-like symptoms aside(and once again, implicating Calcitriol(Vitamin D) and calcium homeostatsis)- it seems to be what we are having, progressively- on the balding scalp:
Pathophysiology[edit]
It is characterised by increased synthesis of collagen (leading to the sclerosis), damage to small blood vessels, activation of T lymphocytes and production of altered connective tissues.[12] Its proposed pathogenesis is the following:[13][14][15][16][17]
It begins with an inciting event at the level of the vasculature, probably the endothelium. The inciting event is yet to be elucidated, but may be a viral agent, oxidative stress or autoimmune. Endothelial cell damage and apoptosis ensue, leading to the vascular leakiness that manifests in early clinical stages as tissue oedema. At this stage it is predominantly a Th1 and Th17-mediated disease.
After this the vasculature is further compromised by impaired angiogenesis and impaired vasculogenesis (fewer endothelial progenitor cells), likely related to the presence of anti-endothelin cell antibodies. Despite this impaired angiogenesis, elevated levels of pro-angiogenic growth factors like PDGF and VEGF is often seen in persons with the condition. The balance of vasodilation and vasoconstriction becomes off-balance and the net result is vasoconstriction. The damaged endothelium then serves as a point of origin for blood clot formation and further contributes to ischaemia-reperfusion injury and the generation of reactive oxygen species. These later stages are characterised by Th2 polarity.
The damaged endothelium upregulates adhesion molecules and chemokines to attract leucocytes, which enables the development of both innate and adaptive immune responses,including loss of tolerance to various oxidised antigens, which includes topoisomerase I. B cells mature into plasma cells, which furthers the autoimmune component of the condition. T cells differentiate into various subsets, including Th2 cells, which play a vital role in tissue fibrosis. Anti - topoisomerase 1 antibodies, in turn, stimulate type I interferon production.
Fibroblasts are recruited and activated by multiple cytokines and growth factors to generate myofibroblasts. Dysregulated transforming growth factor ? (TGF-?) signalling in fibroblasts and myofibroblasts has been observed in multiple studies of scleroderma-affected individuals. Activation of fibroblasts and myofibroblasts leads to excessive deposition of collagen and other related proteins, leading to fibrosis. B cells are also implicated in this stage, IL-6 and TGF-? produced by the B cells decrease collagen degradation and increase extracellular matrix production. Endothelin signalling is also implicated in the pathophysiology of fibrosis.[18]
Vitamin D is also implicated in the pathophysiology of the disease, for one an inverse correlation between plasma levels of vitamin D and scleroderma severity has been noted and vitamin D is known to play a crucial role in regulating (usually suppressing) the actions of the immune system.(there you go)[19]
