A Review of male pattern baldness Research.

[Armando Jose]

Why does DHT (or 5-alpha reductase enzyme activity) increase in balding scalp?

How does DHT cause hair loss while exactly the opposite effect is expected?

Why does balding (or increase in DHT levels) occur only at the top of the head?


...

Good and very interesting questions.
I'll add another, it is really necesary DHT and sebum for a healthy hair, independent from head or body area?

Hair follicle regeneration is controlled by an intricate relationship between epidermal stem cells and their microenvironment. http://www.sciencedirect.com/science/article/pii/S1934590912004237

Spatiotemporal coordination of cell growth underlies tissue development and disease. Mechanical feedback between cells has been proposed as a regulatory mechanism for growth control both in vivo and in cultured cells undergoing contact inhibition of proliferation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992650/

Thanks for the link, I suposse that hardened and oxicited sebum have a role regarding spacio issue.

due to differences in chromatin structure between dermal papilla cells of scalp hair follicles and dermal papilla cells of body hair follicles, activated AR will induce a different combination of gene expression changes in each of the two cell types

Woo,..., is it real that differences in chromatin structures in dermal papilla of scalp or body hairs? Have you a study about it?
TIA

 

[Gone]

How much DHT do mice have?

 

[InBeforeTheCure]

Maybe that is true. Humans display neotenic traits in their evolution. https://en.wikipedia.org/wiki/Neoteny

Body hair is relatively diminished compared to other apes and scalp hair is retained, at least in young adulthood. We are naked apes that became naked in order to be more efficient sweating machines. Humans can walk and run long distances in the hunt for food while other hairy animals must stop, rest and pant because they cannot sweat as efficiently. https://en.wikipedia.org/wiki/Endurance_running_hypothesis

A sweaty scalp would help to cool the large human brain. Maybe genetic tendency + biomechanics = balding

This assumes that baldness is actually the trait under selection, but it's also possible that baldness is simply an accident of pleiotropy. Consider the genetic variants just downstream of Pax1, which is the second-most associated gene region (only behind AR) with A.G.A. The exact SNPs associated with increased risk of A.G.A., which are in a Pax1 enhancer region, are protective against idiopathic scoliosis in girls. This would presumably result in selection for those variants that incidentally increase risk of A.G.A.

Here's the idiopathic scoliosis study.

This same region is also associated with nose width.

Another example is a SNP in a melanocyte-specific enhancer in the IRF4 gene which has recently been associated with A.G.A. The allele that increases risk of hair loss disrupts a binding site for TFAP2A in this enhancer, and as a result IRF4 is expressed at a lower level in melanocytes. This variant is associated with lighter skin, which was positively selected for in Europe, probably for more efficient production of Vitamin D in low-UV climates. So again, an increased incidence of hair loss would be a side effect of this selection.

Study on this IRF4 SNP

 

[InBeforeTheCure]

Woo,..., is it real that differences in chromatin structures in dermal papilla of scalp or body hairs? Have you a study about it?
TIA

What matters ultimately is the combination of "intracellular machinery" of these cells -- chromatin structure, which plays an important part in this, was an example I gave. In regard to this intracellular machinery though, Rinn et al. profiled gene expression in fibroblasts taken from throughout the body.

Our local and global analyses revealed that the spatial patterns of fibroblast differentiation are associated with gene expression signatures related to anterior-posterior, proximal-distal, and dermal-nondermal divisions. These observations raise the possibility that fibroblast differentiation is governed in part by the combinatorial superposition of gene expression programs representing broad anatomic divisions, to confer distinct identities to the cells in each unique anatomic structure. To test this hypothesis, we mapped onto the body the positional boundaries suggested by the three distinct binary divisions of gene expression signatures (Figure 5A and Dataset S5). Each fibroblast sample was assigned to one of five classes (proximal, distal, anterior, posterior, or nondermal); we then performed a multiclass comparison to identify genes whose variation in expression most strongly distinguished one or more of the classes (see Materials and Methods). We further required the genes to have differential expression in at least one of three anatomic divisions described above. Modeling the samples in this way allowed us to capture gene expression differences that distinguished fibroblast origin locally and were applicable throughout the body.

Three hundred thirty-seven genes met these criteria and appear enriched for several functional themes (Figure 5B). The 337 genes identified by position-specific variation in expression included many transcription factors involved in specifying positional identity (HOXA5, HOXA11, HOXA13, HOXD8, TBX2, TBX15, EMX2, FOXF1, FOXP1, and TRPS1), signaling pathways involved in cell fate determination (WNT1, WNT5b, WISP2, DKK2, GPC6, BMP4, GREM2, SMAD3, PTCH, and GULP1), guidance molecules in cell migration (NTN4, SLIT2, SLIT3, CXCL1, CCRL1, and THBS1), extracellular matrix components (COL4A2, COL4A5, COL8A2, COL10A1, COL11A1, FN1, EMILIN2, and HS3ST3B1), and enzymes for remodeling the extracellular matrix (ADAM9, ADAMTS5, MMP3, CSTE, CTSZ, PLAT, and PLAU) (Figure 5B). These biological themes are also supported by a quantitative enrichment analysis based on the public annotation Gene Ontology [16] (Table S1). The different combinations of these transcription factors, signaling proteins, and matrix environments could potentially regulate position-specific differentiation of fibroblasts and also provide signals to influence site-specific fates of neighboring cells, an important characteristic for specifying positional information in the stroma.

In addition, hierarchical clustering of all fibroblast samples based on variation in expression of these 337 genes placed all fibroblasts samples (47 of 47) into clusters composed exclusively of their anatomic neighbors (Figure 5B and 5C). The five anatomic clusters defined by their patter of expression of this set of genes were upper limb, lower limb, head and trunk, foreskin, and nondermal tissues. These anatomical groupings were similar to the groups obtained by unsupervised hierarchical clustering of samples using all 7,580 variably expressed genes (Figure 1C), but substantially more fibroblast samples were correctly grouped with their anatomic neighbors when these selected 337 genes were used. This improved organization by anatomic origin suggest that these 337 genes can capture much of the positional information of fibroblasts relative to three anatomic axes.

Notice how the three scalp fibroblast samples (#30, #31, and #32) cluster together compared to dermal fibroblasts of the body (the other pink circles). Dermal papilla cells are of course derived from these fibroblasts of varying characteristics.

 

[Galeaoman]

...but it's also possible that baldness is simply an accident of pleiotropy.

Interesting that senescence could be a form of antagonistic pleiotropy...

https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis

The antagonistic pleiotropy hypothesis was first proposed by George C. Williams in 1957 as an evolutionary explanation for senescence. Pleiotropy is the phenomenon where one gene controls for more than one phenotypic trait in an organism. Antagonistic pleiotropy is when one gene controls for more than one trait where at least one of these traits is beneficial to the organism's fitness and at least one is detrimental to the organism's fitness. The theme of G.C. William's idea about antagonistic pleiotropy was that if a gene caused both increased reproduction in early life and aging in later life, then senescence would be adaptive in evolution. For example, one study suggests that since follicular depletion in human females causes both more regular cycles in early life and loss of fertility later in life through menopause, it can be selected for by having its early benefits outweigh its late costs.

Male pattern baldness appears to be an irreversible process. Dr. James Hamilton used inmates as his test subjects. He observed their hair growth patterns and saw that castration ceased the balding process and stopped further hair loss. If an inmate had a full head of hair when he was castrated, he would never lose his hair. If he was partially balding, he would retain what hair he had left, but the lost hair would not regrow.

Balding human hair follicles regrow on immunodeficient mice but not on the balding human scalp which is also interesting. It seems to be a clue that the scalp tissue becomes permanently changed even after androgens are taken away.

 

[Galeaoman]

Good and very interesting questions.
I'll add another, it is really necesary DHT and sebum for a healthy hair, independent from head or body area?

The scalp becomes like the forehead in that the pattern balded area is only covered with tiny almost microscopic vellus hairs. The bald scalp must have larger sweat glands too because it sweats very easily compared to a hairy scalp. No dandruff on the bald scalp either

 

[H]

So basically we are screwed?... if transplanted hairs that are resistant to dht won't work, massage only works to an extent as well as all the topicals drugs and becoming a eunich. I'm skeptical of the thought of finding an efficiant plumbing system for the liquid that makes my scalp less pliable will sprout me back to my previous pubescent days so games over. I guess this is just the body asserting it's dominance.

 

[Galeaoman]

What causes hair follicles to become sensitive to androgens? Maybe it could be a type of feedback cycle? Hypothetically speaking, the causal factors for male pattern baldness appear to be several - including androgens, that will all work in tandem. When one is triggered then the rest will automatically follow suit and become a chain reaction that becomes compunded, leading to the progressive and apparently irreversible stages of male pattern baldness.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639964/

Context:

Androgenetic alopecia (Androgenetic Alopecia) is a frequent disorder characterized by progressive hair miniaturization in a very similar pattern among all affected men. The pathogenesis is related to androgen-inducible overexpression of transforming growth factor β-1 from balding dermal papilla cells, which is involved in epithelial inhibition and perifollicular fibrosis. Recent research shows that hair follicle androgen sensitivity is regulated by Hic-5, an androgen receptor co-activator which may be activated by the mechanical stimulation. Moreover, the dermis of scalp susceptible to be affected by Androgenetic Alopecia is firmly bounded to the galea aponeurotica, so the physical force exerted by the occipitofrontalis muscle is transmitted to the scalp skin.

Aims:

To know whether mechanical stress supported by hair follicles is involved in Androgenetic Alopecia phenomenon.

Materials and Methods:

It is performed with a finite element analysis of a galea model and a schematic representation of Androgenetic Alopecia progression according to Hamilton–Norwood scale in order to establish the correlation between elastic deformation in scalp and clinical progression of male pattern baldness.

Results:

The result was a highly significant correlation (r: −0.885, P < 0.001) that clearly identifies a mechanical factor in Androgenetic Alopecia development.

Conclusions:

All these data suggest that mechanical stress determines Androgenetic Alopecia patterning and a stretch-induced and androgen-mediated mechanotransduction in dermal papilla cells could be the primary mechanism in Androgenetic Alopecia pathogenesis.

 

[coolio]

New replacement follicles being susceptible to DHT could be an issue but I doubt it would be a huge deal-breaking problem.

Our original lost hair was absolutely blasted with androgens during puberty for the greater part of a decade. Remember how horny you were back then? Androgen levels are still pretty high until well into our 20s.

New replacement hair will never be subjected to anything like that. Not even close.

 

[InBeforeTheCure]

Right, and the scalp to arm hair transplant is also very important and similar to the experiment I proposed. I wish I knew how to find it though

Synchronous balding of scalp and hair-bearing grafts of scalp transplanted to the skin of the arm in male pattern baldness - R E Nordstrom

The author transplanted composite skin grafts from balding, non-balding, and bald areas of the scalp, to the skin of the arm. The galea aponeurotica was trimmed away from the grafts. The patient was a 29-yr-old male with progresive male pattern baldness (male pattern baldness). The transplants from the balding area became bald at the same rate as the balding donor site in the receding frontal, hairline, whereas the transplants taken from the non-balding area in the occiput continued to grow the same amount and quality of terminal hairs. Bald grafts taken in front of the receding hairline remained bald. This shows that the cause of male pattern baldness lies in the follicle itself or in its very close surrounding and does not depend on the galea aponeurotica, the increased tension of the scalp or of its muscles, the diminished vascular supply to the scalp or any other regional factor localized to the head area. It also shows that the 'balding clock' keeps time even when the follicle is transplanted to another region of the body.

Balding human hair follicles regrow on immunodeficient mice but not on the balding human scalp which is also interesting. It seems to be a clue that the scalp tissue becomes permanently changed even after androgens are taken away.

In the Krajcik study, not only did the vellus hairs from the bald men regrow, but the terminal hairs shrank. In the end, both formerly vellus hairs and formerly terminal hairs were the same size.

And taken from women, the vellus follicles were actually larger after 6 months:

But why do you say the failure for this to happen in humans depends on a change in scalp tissue? It could have been (and probably was) that way all along, with the recovery in mice due to inter-species differences of some sort.

 

[Gone]

^Thank yew

 

[Galeaoman]

But why do you say the failure for this to happen in humans depends on a change in scalp tissue? It could have been (and probably was) that way all along, with the recovery in mice due to inter-species differences of some sort.

That is the big question ...what is the different environment that lets balding follicles grow on the back of a mouse? It could have been something to do with the immune suppression.

http://www.lifeextension.com/magazine/1997/3/cover97/page-01?p=1

Immunosuppression And Free Radical Scavengers
The immune response provoked by male hormones such as DHT probably plays the most significant role in balding. Stimulated by androgens, the immune system targets hair follicles in genetically susceptible areas to cause the premature loss of hair characteristic of male pattern baldness and other forms of accelerated hair loss.

Thus, a side effect of the immunosuppressive drug cyclosporine (which is used to prevent the rejection of transplanted organs) is scalp hair regrowth. It may be that cyclosporine is the most potent single hair regrowth agent known. But the drug causes potentially severe toxic side effects when used systemically, including kidney damage, hypertension (high blood pressure)-and even death-which precludes its use as a hair growth stimulant. However, other ways (with no potential for system toxicity) have been found to inhibit the localized immune response that leads to hair loss.

 

[Seuxin]

i'm on immunosuppressors since my 17' (i'm 30), and, nW3

 

[coolio]

If immune suppression regrew hair (or even slowed loss noticeably) then we would know about it. People would have known about it a thousand years ago.

Whatever role the immune system plays, it's complicated.

 

[Galeaoman]

If immune suppression regrew hair (or even slowed loss noticeably) then we would know about it. People would have known about it a thousand years ago.

Whatever role the immune system plays, it's complicated.

There does appear to be an immune system component to male pattern baldness. After a hair follicle has been miniaturized by androgens, it looks like the immune system worlks to keep it that way, even when androgens are removed. A person castrated before puberty will never go bald unless they are given testosterone. A person who is partially bald that gets castrated will halt further hair-loss but not regrow the lost hair. Miniaturized human hair follicles transplanted onto the backs of immune deficient mice will enlarge and regrow. Dr. Peter Proctor said that cyclosporine(an immune suppressor) could be one of the most powerful regrowth agents. But cyclosporine is a very dangerous and even deadly drug. I remember several years ago(1980's?) watching a documentary about a heart transplant patient who was taking cyclosporine after the operation. Before the operation he was skinny and very bald. A few months later he had become overweight but also had a full head of hair. Many experimental drugs could probably grow some hair but they are too dangerous.

 

[Armando Jose]

There does appear to be an immune system component to male pattern baldness. After a hair follicle has been miniaturized by androgens, it looks like the immune system worlks to keep it that way, even when androgens are removed. A person castrated before puberty will never go bald unless they are given testosterone. A person who is partially bald that gets castrated will halt further hair-loss but not regrow the lost hair. Miniaturized human hair follicles transplanted onto the backs of immune deficient mice will enlarge and regrow. Dr. Peter Proctor said that cyclosporine(an immune suppressor) could be one of the most powerful regrowth agents. But cyclosporine is a very dangerous and even deadly drug. I remember several years ago(1980's?) watching a documentary about a heart transplant patient who was taking cyclosporine after the operation. Before the operation he was skinny and very bald. A few months later he had become overweight but also had a full head of hair. Many experimental drugs could probably grow some hair but they are too dangerous.

Every time I read this mantra on catrates and alopecia...... I think in this:
"Important hormones for hair are not produced in testes but in pilosebaceous unit" . Do you remember Bryan Shelton?

 

[Spanishlad]

I remember Bryan he was a great source of knowledge for many!!! Its a shame for the forum hes not around anymore, even if towards the end his connection to certain treatments was questionable.

 

[coolio]

There does appear to be an immune system component to male pattern baldness. After a hair follicle has been miniaturized by androgens, it looks like the immune system worlks to keep it that way, even when androgens are removed. A person castrated before puberty will never go bald unless they are given testosterone. A person who is partially bald that gets castrated will halt further hair-loss but not regrow the lost hair. Miniaturized human hair follicles transplanted onto the backs of immune deficient mice will enlarge and regrow. Dr. Peter Proctor said that cyclosporine(an immune suppressor) could be one of the most powerful regrowth agents. But cyclosporine is a very dangerous and even deadly drug. I remember several years ago(1980's?) watching a documentary about a heart transplant patient who was taking cyclosporine after the operation. Before the operation he was skinny and very bald. A few months later he had become overweight but also had a full head of hair. Many experimental drugs could probably grow some hair but they are too dangerous.

The cases of Cyclo--> hair regrowth are always being brought up on baldness forums but I never see any proof. I'm not calling you a liar, I'm just saying I'd like to see the evidence.

On the other hand there are TONS of transplant patients out there who have been on Cyclo for years without regrowing lost hair. And there are many more people with depressed immune systems to look at. People with weakened immune systems are just not that hard to find, and hair regrowth is.

I realize the immune system does seem to play a role in baldness. But it must be more complicated than just the immune system keeping the balded follicles beaten down.

 

[Galeaoman]

I realize the immune system does seem to play a role in baldness. But it must be more complicated than just the immune system keeping the balded follicles beaten down.

It does appear to be a complex multi-factorial problem and there appears to be no single answer or single treatment that can regrow hair in all cases of male pattern baldness.

It seems that the scalp and hair needs to be rejuvenated to a younger age in order to regrow hair.

End of aging = End of Balding

Aubrey De Grey is an eccentric scientist with long hair and a flowing beard. He does research into the causes of aging. He says there are seven causes of aging.


Seven causes of physical aging...

http://www.sens.org/research/introduction-to-sens-research

The Targets

Decades of research in aging people and experimental animals has established that there are no more than seven major classes of such cellular and molecular damage, shown in the table below. We can be confident that this list is complete, first and foremost because of the fact that scientists have not discovered any new kinds of aging damage in nearly a generation of research, despite the increasing number of centers and scientists dedicated to studying the matter, and the use of increasingly powerful tools to examine the aging body. In its own way, each of these kinds of damage make our bodies frail, and contribute to the rising frailty and ill-health that appears in our sixth decade of life and accelerates thereafter.


Aging Damage_____________Year Discovered________Rejuvenation Biotechnology

Cell loss, tissue atrophy_____________1955____________Stem cells and tissue engineering

Cancerous cells____________________1959, 1982_______Removal of telomere-lengthening machinery

Mitochondrial mutations_____________1972____________Allotopic expression of 13 proteins

Death-resistant cells________________1965____________Targeted ablation

Extracellular matrix stiffening________1958, 1981_______ AGE-breaking molecules; tissue engineering

Extracellular aggregates_____________1907_____________Immunotherapeutic clearance

Intracellular aggregates______________1959_____________Novel lysosomal hydrolases: LysoSENS

Stem cells get old too...

http://sage.buckinstitute.org/stem-cells-get-old-too/

Ray Kurzweil, another promising eccentric scientist(futurist) says that adult skin cells can be transformed to embryonic stem cells in order to rejuvenate tissues and organs...

http://www.cnn.com/2013/12/10/business/ray-kurzweil-future-of-human-life/

Stem cell therapies, including the recently developed method to create "induced pluripotent cells" (IPCs) by adding four genes to your own skin cells to create the equivalent of an embryonic stem cell but without use of an embryo, are being developed to rejuvenate organs and even grow then from scratch.

 

[H]

It seems that the scalp and hair needs to be rejuvenated to a younger age in order to regrow hair.

End of aging = End of Balding

Try again. Some of us start balding as early as teens. There is age related hair loss that starts when the surrounds tissue can't support the follicle based on just integumentary cellular aging. We already know with age the skin gets much thinner thus less able to support follicles but in the case for male pattern baldness...neh keep thinking.