Guide Novel Hairloss Guide - The underlying causes of hair loss (7 Viewers)

[depersonalized]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

 

[NorthAfricanRopemaxxer]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

Seems like a good thread brah im bookmarking it and read it later

 

[mirincristian]

good debut post

 

[depersonalized]

good debut post

I have 2 more microthreads to post; superior to minox/latisse and a superior to eplerenone thread. Probably will drop later today after my guy finishes formatting.

 

[hippocamp]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

Nice debut thread

 

[bluesell]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

@FoidSlayer

 

[bluesell]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

Mirin

 

[XvideosDemon]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

great debut post g

 

[Alyx]

Introduction:

Module 1 : Scalp tension

Module 2 : Arginine metabolism

Module 3 : EDA2R

Module 4 : KX-826.

Introduction:
Hair loss has been a popular topic across this forum with the mentions of things like 5AR inhibitors and novel topical anti-androgens. However, surprisingly while looking across the forum I haven’t seen people talk about topics like scalp tension, arginine metabolism, and EDA2R. My thread will cover these topics and also discuss why the new novel topical anti-androgens, specifically KX-826, is superior to RU58841. This will be split into 4 modules.


Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

Now you may be surprised on the Botox part, but it makes sense logically. Botox can possibly manage AGA by 2 distinct mechanisms: decreased TGF-β1 activity in DPCs (through intradermal injections), and relaxation of the scalp perimeter muscles (through intramuscular injections). “Research implicates the secretion of androgen-induced TGF-β1 in the progression of AGA – particularly in regard to DPC-related hair growth inhibition, anagen phase shortening, and hair follicle miniaturization”. Interestingly, researchers found that botulinum toxin type A downregulated TGF-β1 expression in cultured human DPCs which suggests that decreased TGF-β1 activity may partly explain the 5.1% increase in hair counts from intradermal botulinum toxin injections in their 24-week study. Intramuscular injections of botulinum toxin have demonstrated 18–20.9% increases in hair counts likely due to the relaxation aspect which decreases tension.

As for ATP, why is it important to maximise, and how will it help the negatives brought by scalp tension? Cells need energy (ATP) to grow hair. But scalp tension inhibits the oxygen needed to make ATP which triggers ROS downstream. In short, increased local ATP can result in a decrease in the ROS cascade.

The compounds we will be using to mimic or maximise ATP are, topical adenosine, topical Coq10, and topical PQQ.

We can use topical adenosine to bypass the state of low ATP driven by scalp tension and derive benefits such as upregulation of FGF and WNT pathways. Adenosine is formed after the breakdown of ATP and when hypoxia causes a state of low ATP we are bypassing it by supplying adenosine locally (topically).
Coq10 works to maximise ATP by first maximising the mitochondrial electron transport chain. With the scalp tension induced hypoxia causing a disruption in the transport chain, Coq10 can act as an electron carrier, rescuing ATP synthesis.
PQQ works by activating the PGC-1α pathway. PQQ makes cells multiply their own energy networks through mitochondrial biogenesis. This upregulates total ATP and reduces ROS, and should do this locally if applied as well.

We can use 0.75% topical adenosine, 1% topical Coq10, and 0.1% PQQ. Ideally this would be done so by using raws and formulating them yourself as it is giga-cheap that way, but some online formulations exist.
Module 2 : Arginine metabolism
In individuals with AGA it seems that across the board these individuals lack arginine the most among all amino acids. “Leveraging unbiased serum metabolomics, a strikingly differentiated metabolic signature in AGA patients compared to healthy controls is identified, with arginine deficiency exhibiting the most pronounced reduction among all amino acids. “

This is because Hair follicles in balding areas are “starving” for arginine. “ This is due to ARG2 Overactivation and SLC7A1 downregulation. SLC7A1 is a protein that transports blood serum arginine into hair cells. ARG2 is just the enzyme that breaks arginine down. Essentially balding hair follicles have a metabolic dysfunction leading to downregulated utilization of arginine. This is why topical l-arginine is efficient as it is a local delivery to hair follicles compared to oral administration, a bypass. The dysregulation of arginine metabolism is common in AGA individuals and arginine restoration via supplementation or ARG2 silencing reverses HF regression in DHT-induced AGA murine models and primary human HF cultures.

Now that we've covered why Topical L-Arginine can be used as a hair loss preventative, let's go into its benefits in inducing hair growth.
When we look into the mechanisms of hair growth, it is one of the most metabolically demanding tasks in the human body. Hair matrix cells must divide at a rapid pace to physically elongate the hair shaft. Arginine has a few ways in inducing hair growth, firstly as said before in balding areas arginine metabolism is disrupted. This disruption leads to ROS accumulation and deactivation of mTOR. Arginine rescues the deactivation of mTOR which allows for the hair roots to start rapid protein synthesis again.
L-Arginine works similarly to minoxidil as well. Arginine is the precursor to Nitric Oxide. Arginine, through NOS synthesizes NO which then acts as a strong vasodilator causing opening of vessels. This results in maximised ATP through the chain mentioned prior. No also upregulates growth factors like VEGF through angiogenesis.
There are a few more mechanisms but we can see overall in the outcomes that “while alanine, aspartic acid, and glutamic acid had minimal effects on HF growth... arginine significantly promoted hair growth." Arginine was also found to promote hair matrix cell proliferation in a dose-dependent manner.
One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.
All in all, we can conclude topical l-arginine to be a strong compound in preventing hair loss and inducing hair growth. We can simply use topical formulations of Arginine at % like 5%.


Module 3 : EDA2R
Disclaimer : this module is the most theoretically
A candidate for baldness, other than the androgen receptor, is EDA2R. EDA2R is part of the tumor necrosis factor receptor superfamily. EDA2R is activated by Ectodysplasin A. An example of when this would be a problem is individuals with NAFLD, as EDA is a byproduct of NAFLD in this context. EDA induces DKK-1, which is the same transcription factor that is responsible for androgenic alopecia. Now it is very unlikely for your hair loss to be caused by EDA. However, your risks to this susceptibility increase when you have impaired liver function as it causes circulating EDA to increase due to decrease in breakdown. This would mainly be a problem for heavy roiders, but as always having a proper protocol in place should mitigate this. A cheap and simple liver protection stack I would use is tudca, nacet, bempedoic acid, and ezetimibe (yes ezetimibe has some liver benefits).


Module 4 : KX-826.
Lately a lot of novel topical anti-androgens have been gaining traction, and my choice to use would be KX-826. To preface, we all know what topical anti-androgens do; they antagonize the androgen receptor in hair follicles blocking androgens like DHT from binding to it. KX-826 in particular has a stronger antagonizing effect than RU58841 which is one way it is superior. Now the main problem with Ru58841 is that like RU56187 they both form a slow acting systemic metabolite - RU 56279 . Although, Ru58841 forms this metabolite in miniscule percentages this can vary per person.
In conclusion, I would use a novel topical anti-androgen like KX-826 rather than Ru-58841 to have no risk in terms of systemic metabolites and have a strong antagonizing effect.


Sources : If you want to read them, just click.
Phase III KX-826 Tincture 1.0% For AGA Reached Primary Endpoint-Kintor Pharmaceutical Limited
Preliminary pharmacokinetics and metabolism of novel non-steroidal antiandrogens in the rat: relation of their systemic activity to the formation of a common metabolite - PubMed
Ectodysplasin-A2 induces dickkopf 1 expression in human balding dermal papilla cells overexpressing the ectodysplasin A2 receptor - ScienceDirect
Circulating ectodysplasin A is a potential biomarker for nonalcoholic fatty liver disease - ScienceDirect
Arginine Metabolic Disruption Impairs Hair Regeneration via ROS‐Mediated Inactivation of mTOR Signaling in Androgenetic Alopecia
Involvement of Mechanical Stress in Androgenetic Alopecia - PMC
Perifollicular fibrosis: pathogenetic role in androgenetic alopecia - PubMed
Use of Botulinum Toxin for Androgenic Alopecia: A Systematic Review
(PDF) Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia
PQQ activates nuclear respiratory factor activity and expression of... | Download Scientific Diagram
Big head? Bald head! Skull expansion: alternative model for the primary mechanism of AGA - ScienceDirect
Oral or topical administration of L-arginine changes the expression of TGF and iNOS and results in early wounds healing - PubMed
https://europepmc.org/article/med/33878855

Bad post. misinformation.

 

[depersonalized]

Bad post. misinformation.

explain, Im free to converse with you.

 

[Alyx]

explain, Im free to converse with you.

Scalp tension does not cause hairloss.

 

[depersonalized]

Scalp tension does not cause hairloss.

Well you can try to disprove that with papers, but the ones I provided definitely show the implications it have. I think I know what your trying to right now JFL.

 

[Alyx]

Well you can try to disprove that with papers, but the ones I provided definitely show the implications it have. I think I know what your trying to right now JFL.

@Syna @Dexter

 

[depersonalized]

@Syna @Dexter

hmm you can call your friends for help, I was wishing for you who claimed this to actually make some good points though.

 

[Syna]

@Syna @Dexter

lol niggas doing anything but taking dutasteride.

 

[Alyx]

hmm you can call your friends for help, I was wishing for you who claimed this to actually make some good points though.

View: https://www.youtube.com/watch?v=0g1H2Or1dKY
Debunk. I tagged them because I wanted them to see this cagefuel.

 

[Syna]

View: https://www.youtube.com/watch?v=0g1H2Or1dKY
Debunk. I tagged them because I wanted them to see this cagefuel.

Another fellow follower of the hairloss Witcher

 

[depersonalized]

lol niggas doing anything but taking dutasteride.

thats not really a good point, I covered topics that are conversed in AGA that haven't been discussed before. And there are superior options to dutasteride again for a few reasons I mentioned. if you want to argue this in a peaceful manner though without some baseless claims from "alyx" feel free to add me on discord : depers0nalized.

 

[depersonalized]

Another fellow follower of the hairloss Witcher

hahaha, hair cafe JFL. Don't listen to him

 

[Syna]

superior options to dutasteride

Explain which then.

 

[depersonalized]

Explain which then.

A popular example would be like KX-826. It has signifcantly higher antagonizing effect than RU and no systemic metabolites. Now the only reason why I don't like dutas/finas is the NS depletion. Now that I know you watch hair cafe you will probably be saying bro it barely crosses the BBB so neurosteroids won't be depleted in the brain. This simply isn't true we know both finas/dutas to be lipholilic and low in mole weight, so logically they should cross the BBB easily.

 

[depersonalized]

A popular example would be like KX-826. It has signifcantly higher antagonizing effect than RU and no systemic metabolites. Now the only reason why I don't like dutas/finas is the NS depletion. Now that I know you watch hair cafe you will probably be saying bro it barely crosses the BBB so neurosteroids won't be depleted in the brain. This simply isn't true we know both finas/dutas to be lipholilic and low in mole weight, so logically they should cross the BBB easily.

Sorry for the late response, add me on discord if you want quicker replies I am in a vc right now.

 

[Alyx]

A popular example would be like KX-826. It has signifcantly higher antagonizing effect than RU and no systemic metabolites. Now the only reason why I don't like dutas/finas is the NS depletion. Now that I know you watch hair cafe you will probably be saying bro it barely crosses the BBB so neurosteroids won't be depleted in the brain. This simply isn't true we know both finas/dutas to be lipholilic and low in mole weight, so logically they should cross the BBB easily.

@Dexter This is not true. Dutasteride is practically incapable of crossing the blood brain barrier due to its formulation.

 

[Syna]

Sorry for the late response, add me on discord if you want quicker replies I am in a vc right now.

I'm good.

 

[depersonalized]

@Dexter This is not true. Dutasteride is incapable of crossing the blood brain barrier due to its formulation.

again, why do you make baseless claims, provide some SS in papers at least or the papers themselves. You also keep @ other people, if you were so confident in your claims why do you need to do that?

 

[depersonalized]

I'm good.

hmm ok then.

 

[Dexter]

he “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior.

not the primary reason DHT is harmful. the core pathology is genetic susceptibility of dermal papilla cells to DHT via androgen receptors leading to TGFβ1, DKK1 and miniaturization. tension is a contributing physical factor not the root.

One study concluded that “Based on our results, the combination of arginine and zinc tested in our study could represent a good therapeutic option for the treatment of AGA and TE and it might represent a valid alternative to finasteride”.

what... what the fuck is this
arginine is a semi essential amino acid that serves as a substrate for nitric oxide synthase. nitric oxide causes vasodilation. that is it. arginine does not lower DHT. It does not block the AR. It does not reduce 5AR activity. It does not affect TGFβ1 signaling directly from androgens

 

[Syna]

A popular example would be like KX-826. It has signifcantly higher antagonizing effect than RU and no systemic metabolites. Now the only reason why I don't like dutas/finas is the NS depletion. Now that I know you watch hair cafe you will probably be saying bro it barely crosses the BBB so neurosteroids won't be depleted in the brain. This simply isn't true we know both finas/dutas to be lipholilic and low in mole weight, so logically they should cross the BBB easily.

yeah you're right, so? you can take HCG, the sexual sides are mostly nocebo.

Most users here take lots of compounds that have some significant effects to the CNS anyways.

AAS themselves are very stimulating to the CNS, does that mean you are against AAS too?

I like KX-826 too, great compound.

Dutasteride still mogs in potency, every pharma has sides, people just choose to live with them and to just mitigate them as much as possible.

 

[Dexter]

A popular example would be like KX-826. It has signifcantly higher antagonizing effect than RU and no systemic metabolites. Now the only reason why I don't like dutas/finas is the NS depletion. Now that I know you watch hair cafe you will probably be saying bro it barely crosses the BBB so neurosteroids won't be depleted in the brain. This simply isn't true we know both finas/dutas to be lipholilic and low in mole weight, so logically they should cross the BBB easily.

this is like comparing a water gun to a fire extinguisher and saying the water gun is better because it has no chemicals. they do completely different things. Dut nukes 5AR enzymes type 1 and 2 so you get about a 90% drop in scalp DHT. KX826 just competes for the AR it doesnt lower DHT levels at all. If you have high DHT floating around, a topical antiandrogen can get overwhelmed pretty quickly

 

[depersonalized]

not the primary reason DHT is harmful. the core pathology is genetic susceptibility of dermal papilla cells to DHT via androgen receptors leading to TGFβ1, DKK1 and miniaturization. tension is a contributing physical factor not the root.

what... what the fuck is this
arginine is a semi essential amino acid that serves as a substrate for nitric oxide synthase. nitric oxide causes vasodilation. that is it. arginine does not lower DHT. It does not block the AR. It does not reduce 5AR activity. It does not affect TGFβ1 signaling directly from androgens

I semi-adressed your first claim in the thread, I agree that signals like TGFbeta1 are induced by DHT which is when I included that finasteride decreased fibrosis in studies. However, you missed the part where I stated how tension synthesizes and ampifies the transcription of things like dkk1 and tgf like you mentioned, via hic-5. I may have wrote it weird where comprehension would be hindered, thats on me. What I meant in part of the first module was that tension amplifies how detrimental dht is from tension induced signalling. AKA can make DHT bad even in physiological levels. Also my claim isn't that arginine will modulate 5ar n vivo/humans read my whole module on it, i only included that one paper to indicate how rsrchers hypthosized the effiaciousness with effects it had in vitro in for TE and AGA. Most vivo studies wouldn't cover the 5ar effect but rather the effects on telogen. If i truely though l-arginine would have measurable effects on 5ar then I would've listed that as a possible mechanism, which I didn't.

 

[depersonalized]

this is like comparing a water gun to a fire extinguisher and saying the water gun is better because it has no chemicals. they do completely different things. Dut nukes 5AR enzymes type 1 and 2 so you get about a 90% drop in scalp DHT. KX826 just competes for the AR it doesnt lower DHT levels at all. If you have high DHT floating around, a topical antiandrogen can get overwhelmed pretty quickly

I semi-agree but you need to understand why I say kx is superior, in individual context. high levels of DHT won't overwhelm KX, not only would the topical application flood the area with a much higher concentration of the AA mole, its binding affinity is giga-high, especially compared to RU for example. The main reason for my claim isn't because KX is neccesiraly "stronger" than dutas but rather, individually it has no possible negative effects like the ones I mentioned from dutas: ns. Now your probably going to say DUTAS is cheaper, which it usually is. However, I think if you are able to supply yourself with raw power while formulating it your self it will be very cheap as well for the KX.

 

[depersonalized]

yeah you're right, so? you can take HCG, the sexual sides are mostly nocebo.

View attachment 51146

Most users here take lots of compounds that have some significant effects to the CNS anyways.

AAS themselves are very stimulating to the CNS, does that mean you are against AAS too?

I like KX-826 too, great compound.

Dutasteride still mogs in potency, every pharma has sides, people just choose to live with them and to just mitigate them as much as possible.

I am not against AAS i've ran Tren before.

 

[Syna]

I am not against AAS i've ran Tren before.
View attachment 51163

So then you must understand how much it rapes your CNS right? You take stuff like tren but you are against stuff like dutasteride because of the neurosteroids? selective fear lol.

 

[depersonalized]

So then you must understand how much it rapes your CNS right? You take stuff like tren but you are against stuff like dutasteride because of the neurosteroids? lol

I responded to your hcg claim, your making a strong jump with your implications of CNS compared to how dutas work. Also I never neccesiraly said I am against dutasteride, I just stated neurosteroids as a negative. Its a bit suspicious 3 people suddenly try to argue against me though, one of them being an imbecile ( alyx ).

 

[XvideosDemon]

I responded to your hcg claim, your making a strong jump with your implications of CNS compared to how dutas work. Also I never neccesiraly said I am against dutasteride, I just stated neurosteroids as a negative. It’s a bit suspicious 3 people suddenly try to argue against me though, one of them being an imbecile ( alyx ).

Nigga called him a ( imbecile )

 

[depersonalized]

thats what he is, all he could do is make baseless claims on his end and @ 2 staff members. Its a bit suspicious though, if they truely understood what im implying, and my main points then I doubt they would try to constantly argue this with weak evidence. I don't think its a coincidence.

Nigga called him a ( imbecile )

 

[Syna]

I responded to your hcg claim, your making a strong jump with your implications of CNS compared to how dutas work. Also I never neccesiraly said I am against dutasteride, I just stated neurosteroids as a negative. Its a bit suspicious 3 people suddenly try to argue against me though, one of them being an imbecile ( alyx ).

Fair, your theory regarding hairloss is still nonsene tbh, men experience hair loss well after craneofacial development has concluded.

https://www.sciencedirect.com/scien...?fr=RR-2&ref=pdf_download&rr=a00f10776adf05f9

This whole study is literally just a hypothesis and is outdated asf.

 

[Alyx]

Fair, your theory regarding hairloss is still nonsene tbh, men experience hair loss well after craneofacial development has concluded.

View attachment 51167

https://www.sciencedirect.com/scien...?fr=RR-2&ref=pdf_download&rr=a00f10776adf05f9

This whole study is literally just a hypothesis and is outdated asf.

The Neuro-steroids claim is BS too.

 

[depersonalized]

Fair, your theory regarding hairloss is still nonsene tbh, men experience hair loss well after craneofacial development has concluded.

View attachment 51167

https://www.sciencedirect.com/scien...?fr=RR-2&ref=pdf_download&rr=a00f10776adf05f9

This whole study is literally just a hypothesis and is outdated asf.

finally, some form of consensus but again both you and dexters claims against me are side tracked a bit. If you read one of my first rhetorical to one of you guys, you will see my main point which isn’t neccesiraly intertwined to what u just stated.

 

[depersonalized]

The Neuro-steroids claim is BS too.

why are you still here?low iq imbecile. You got 2 other people to try to argue against me with your baseless claims lol, you can see that ive provided some evidence in almost every rhetoric or connected back to my thread.

 

[Dexter]

I semi-adressed your first claim in the thread, I agree that signals like TGFbeta1 are induced by DHT which is when I included that finasteride decreased fibrosis in studies. However, you missed the part where I stated how tension synthesizes and ampifies the transcription of things like dkk1 and tgf like you mentioned, via hic-5. I may have wrote it weird where comprehension would be hindered, thats on me. What I meant in part of the first module was that tension amplifies how detrimental dht is from tension induced signalling. AKA can make DHT bad even in physiological levels. Also my claim isn't that arginine will modulate 5ar n vivo/humans read my whole module on it, i only included that one paper to indicate how rsrchers hypthosized the effiaciousness with effects it had in vitro in for TE and AGA. Most vivo studies wouldn't cover the 5ar effect but rather the effects on telogen. If i truely though l-arginine would have measurable effects on 5ar then I would've listed that as a possible mechanism, which I didn't.

your own mechanism (HIC-5/mechanical stretch) modulates fibrosis via integrin signaling and FAK phosphorylation. thats a mechanotransduction pathway and not a primary androgenic pathway
in a genetically resistant follicle you could apply infinite mechanical tension and you will not get AGA. youll get scarring alopecia or traction alopecia which is a completely different histopathology (no miniaturization and no stepwise DHT driven regression)
why did you bring it up in a debate about androgenic alopecia pharmacology?

arginine -> NO -> vasodilation. that is literally it.
Vasodilation does nothing to AR binding affinity, 5AR enzyme activity, DHT concentration in scalp tissue, DKK1 or TGFβ1 transcription from DHTAR signaling

Your "in vitro TE/AGA paper" likely used keratinocyte or dermal papilla cell culture with supraphysiological arginine and measured some meaningless endpoint like % viability which is bs.

you are arguing that a competitive antagonist (KX) is "superior" to an enzyme suicide inhibitor (Dut) because "binding affinity is giga high" but in pharmacology 101 If you have any residual 5AR activity (and you will bcz KX doesn’t touch 5AR) then DHT is still being produced locally in the follicle and if DHT is present at concentrations achievable in scalp tissue (which can be high in AGA) then it will kinetically compete with KX for the AR

 

[depersonalized]

your own mechanism (HIC-5/mechanical stretch) modulates fibrosis via integrin signaling and FAK phosphorylation. thats a mechanotransduction pathway and not a primary androgenic pathway
in a genetically resistant follicle you could apply infinite mechanical tension and you will not get AGA. youll get scarring alopecia or traction alopecia which is a completely different histopathology (no miniaturization and no stepwise DHT driven regression)
why did you bring it up in a debate about androgenic alopecia pharmacology?

arginine -> NO -> vasodilation. that is literally it.
Vasodilation does nothing to AR binding affinity, 5AR enzyme activity, DHT concentration in scalp tissue, DKK1 or TGFβ1 transcription from DHTAR signaling

Your "in vitro TE/AGA paper" likely used keratinocyte or dermal papilla cell culture with supraphysiological arginine and measured some meaningless endpoint like % viability which is bs.

you are arguing that a competitive antagonist (KX) is "superior" to an enzyme suicide inhibitor (Dut) because "binding affinity is giga high" but in pharmacology 101 If you have any residual 5AR activity (and you will bcz KX doesn’t touch 5AR) then DHT is still being produced locally in the follicle and if DHT is present at concentrations achievable in scalp tissue (which can be high in AGA) then it will kinetically compete with KX for the AR

i already discussed everythign with your friend @Syna . You also keep misintrepeting my points which is partly due to my wording, downplaying DHT in the thread. Can you read the my rhetorics properly? I literallt adrsssed basically every thing you replied to me with ( as you were gone for a while ) to either one of your comments or likely synas.

 

[Alyx]

i already discussed everythign with your friend @Syna . You also keep misintrepeting my points which is partly due to my wording, downplaying DHT in the thread. Can you read the my rhetorics properly? I literallt adrsssed basically every thing you replied to me with ( as you were gone for a while ) to either one of your comments or likely synas. you missed the part where I stated how tension synthesizes and ampifies the transcription of things like dkk1 and tgf like you mentioned, via hic-5.

You got debunked. Neuro-steroid depletion on Dut and the bloodflow mechanism of hair loss have been debunked countless times.

 

[depersonalized]

You got debunked. Neuro-steroid depletion on Dut and the bloodflow mechanism of hair loss have been debunked countless times.

nope, stop talking to me retard.

 

[Alyx]

nope, stop talking to me retard.

 

[Dexter]

i already discussed everythign with your friend @Syna . You also keep misintrepeting my points which is partly due to my wording, downplaying DHT in the thread. Can you read the my rhetorics properly? I literallt adrsssed basically every thing you replied to me with ( as you were gone for a while ) to either one of your comments or likely synas.

Module 1 : Scalp tension
It's a common hypothesis among Org users to think DHT is very negative for hair and that they should nuke it with 5AR inhibitors. While you guys aren’t necessarily wrong, we need to look into the underlying roots of why DHT is mainly negative for hair; it's due to craniofacial growth in peri/post puberty, and both the hyperplasia/contraction ( chronically ) of muscles connected to the galea aponeurotica which leads to scalp tension.


Firstly, DHT naturally ( natural levels ) should be positive for hair growth, right? Since steroid hormones such as DHT promote facial and body hair growth. Logically, this might mean that DHT should stimulate hair growth within the MPB region and not hair loss. But this isn’t the case because DHT also has an anabolic effect on bone formation, and this stimulation of bone growth will overwhelm the hair growth promoting effects of DHT.

Secondly, in individuals who develop AGA, their bones tend to continue developing into adulthood. Furthermore, the skull expansion of the frontal and parietal bones will progressively stretch and pull tight the scalp tissue that overlies it. Consequently a constriction of blood vessels within the capillary network that serves the MPB region will subsequently develop. This results in a decrease of blood flow, reducing the supply of nutrients required by follicles to grow hair. The occipitalis, frontalis, auricularis, and temporalis are often reported by investigators to be chronically and involuntarily contracted in AGA-affected males.


With these 2 indications, we can assume that something is causing DHT to be negative in the scalp, inducing hair loss. The “negative” in this context would be scalp tension which is induced by the expanding bone and chronic contraction as mentioned prior. Now what does mechanical stress/tension do? The scalp tension causes a protein called Hic-5 (ARA55) in your dermal papilla cells to detach from the cell wall and shift into the cell nucleus. Hic-5 then binds directly into the androgen receptor and functions as a co-activator. What this results in is the hyper sensitization to androgens in the hair follicle. This can cause even normal levels of DHT to be detrimental, resulting in hair loss.
When chronically contracted, these muscles may pinch vascular networks that indirectly supply blood and oxygen to AGA-prone tissues. The state of hypoxia and local tissue ischemia from the tension induces a cascade of pro-inflammatory signals such as increased ROS, IL-1, COX-2 , and TNF-α. This causes an increase of TGF-β1 with the increased androgen activity. The appearance of TGF-β1 and DHT drives perifollicular fibrosis and the calcification of capillary networks supporting tension-susceptible hair follicles and dermal sheath thickening. Local DHT elevation in this context is a consequence of tension induced hypoxia and compression. In conclusion the information provided above shows the underlying mechanisms of scalp tension and its interactions with DHT. It also explains why DHT inhibitors have historically demonstrated documented reductions in perifollicular fibrosis progression in patients with androgenetic alopecia (AGA). By chemically suppressing androgen-mediated TGF-β1 activity they successfully interrupt the downstream, fibrotic arm of the cascade. However, because they only work at the metabolic level, the upstream mechanical tension driving the entire pathology remains entirely unmitigated.

How can we mitigate the negative cascade of issues that scalp tension brings? We can maximize ATP and utilize Botox.

skull shape differences are not progressive in the sense you imply. frontal and parietal bone expansion does not continue significantly into adulthood in most men but what continues is sutural remodeling at a very slow rate. to claim this “stretches scalp tissue” enough to mechanically induce fibrosis requires a force magnitude that is not observed in vivo. cadaveric measurements show scalp extensibility is limited by the dense connective tissue of the galea and not by bone

hic-5 is a focal adhesion protein under basal conditions. its nuclear translocation is triggered by tgfβ signaling and by androgen stimulation in some contexts but there is zero evidence that mechanical tension alone causes hic-5 nuclear translocation in dermal papilla cells. there is only a cell autonomous difference. you can grow balding dermal papilla cells in a petri dish with no skull, no muscles, no tension and they still overexpress hic-5 and show ar hypersensitization

dht, acting through ar in dermal papilla cells, upregulates tgfβ1 transcription directly. tgfβ1 then induces hypoxia inducible factor 1 alpha (hif1a) via smad3. the hypoxia is a consequence of tgfβ1 and not the initiator. also the calcification of capillary networks the author mentions is not a standard finding in human aga histology. perifollicular fibrosis exists but calcification of capillaries is rare and usually associated with advanced scarring alopecia and not standard aga.

dht is produced locally in the scalp from testosterone via type 2 5AR which is highly expressed in balding dermal papilla cells. hypoxia does not upregulate 5AR activity in any consistent human study. if anything hypoxia decreases steroidogenesis in other tissues

adenosine is a purinergic receptor agonist (a2a, a2b, a3) and has effects on camp, vasodilation and growth factor release independent of atp pool replenishment. coq10 is large, charged at physiological ph, and has minimal transdermal penetration at 1%. pqq at 0.1% is unlikely to reach mitochondria in the dermal papilla through intact stratum corneum without a penetration enhancer. there is no clinical trial combining these three topically for aga.

the entire model ignores occipital resistance. you say scalp tension drives balding but the occipital scalp is under the same galea aponeurotica, same muscles, same bone. if tension were the primary cause the occipital scalp would bald just as fast as the vertex but it doesnt. the only difference between frontal/vertex and occipital dermal papilla cells is genetic ar sensitivity and 5ar activity. you can prove this with a simple experiment you forgot: transplant an occipital hair into a balding area and it stays thick. transplant a balding hair into the occipital area and it miniaturizes. tension can accelerate a pre existing genetic predisposition but cannot create the pattern by itself

 

[Dexter]

great debut post, will read later

dont make me ban you

 

[the wizard]

dont make me ban you

i read 4 sentences and realized it was bullshit, alr deleted the post

 

[Alyx]

alr deleted the post

Thank you.

 

[depersonalized]

skull shape differences are not progressive in the sense you imply. frontal and parietal bone expansion does not continue significantly into adulthood in most men but what continues is sutural remodeling at a very slow rate. to claim this “stretches scalp tissue” enough to mechanically induce fibrosis requires a force magnitude that is not observed in vivo. cadaveric measurements show scalp extensibility is limited by the dense connective tissue of the galea and not by bone

hic-5 is a focal adhesion protein under basal conditions. its nuclear translocation is triggered by tgfβ signaling and by androgen stimulation in some contexts but there is zero evidence that mechanical tension alone causes hic-5 nuclear translocation in dermal papilla cells. there is only a cell autonomous difference. you can grow balding dermal papilla cells in a petri dish with no skull, no muscles, no tension and they still overexpress hic-5 and show ar hypersensitization

dht, acting through ar in dermal papilla cells, upregulates tgfβ1 transcription directly. tgfβ1 then induces hypoxia inducible factor 1 alpha (hif1a) via smad3. the hypoxia is a consequence of tgfβ1 and not the initiator. also the calcification of capillary networks the author mentions is not a standard finding in human aga histology. perifollicular fibrosis exists but calcification of capillaries is rare and usually associated with advanced scarring alopecia and not standard aga.

dht is produced locally in the scalp from testosterone via type 2 5AR which is highly expressed in balding dermal papilla cells. hypoxia does not upregulate 5AR activity in any consistent human study. if anything hypoxia decreases steroidogenesis in other tissues

adenosine is a purinergic receptor agonist (a2a, a2b, a3) and has effects on camp, vasodilation and growth factor release independent of atp pool replenishment. coq10 is large, charged at physiological ph, and has minimal transdermal penetration at 1%. pqq at 0.1% is unlikely to reach mitochondria in the dermal papilla through intact stratum corneum without a penetration enhancer. there is no clinical trial combining these three topically for aga.

the entire model ignores occipital resistance. you say scalp tension drives balding but the occipital scalp is under the same galea aponeurotica, same muscles, same bone. if tension were the primary cause the occipital scalp would bald just as fast as the vertex but it doesnt. the only difference between frontal/vertex and occipital dermal papilla cells is genetic ar sensitivity and 5ar activity. you can prove this with a simple experiment you forgot: transplant an occipital hair into a balding area and it stays thick. transplant a balding hair into the occipital area and it miniaturizes. tension can accelerate a pre existing genetic predisposition but cannot create the pattern by itself

Now Ima bit confused, this is partly due to my weird wording which in turn downplays dht a bit but I adressed or semi-adressed these claims in the thread,
1. I agreed that DHT works through and induces tgf beta and why finas showed to decrease fibrosis. My main points were tension, and this applies to a lot of the things mentioned in the article amplifies the negative effects dht has; essentially making the effects of local dht much more detrimental. Again, like i said me and syna agreed my wording downplays dht in the write-up, im merely saying scalp tension is one of the primary underlying factors people don't know in AGA through a variety of PROVEN mechanisms. Tension also literally induces tgf beta signalling, so I don't see your point but rather its already stated in my original claims.

2. you claimed Bone expansion doesn't continue in adulthood. Galea limits extensibility, so there isn't enough force. But you have to realize that the galea is dense and an inextensible fibrous sheet, it can't stretch to accommodate even minor skeletal remodeling or chronic muscle contraction.

3. You zaid theres 0 evidence that mechcnical tension causes Hic-5 translocation in dermal papilla cells and that cells in a petri dish still show hypersensitivity without tension. Doesn't fucking apply in vivo mate

4. I agree with you that adenosine binds to a2a and a2b to stimulate downstream growth factors, but i explicityly stated adenosine as a signalling bypass, for example fgf7 and vegf like i mentioned . And your semi-right the typical formulation of any topical i mentioned there may fail, but ( this is on me ) it obviouslt depends on the formulation.

5. You do realize mechanical stress isn't distrubteds evenly across the galea right? The galeasanchored tightly over the crown which creates a high-stress perimeter across the frontal and vertex regions due to the opposing vector pulls of the frontalis, occipitalis, and temporalis muscles. The occipital region sits at a mechanical anchor point that experiences significantly lower shear strain. The reason a transplanted occipital hair thrives in the front is because it lacks the genetic sensitivity to respond to the mechanical strain; the reason a frontal hair dies is because it has the genetic programming to be destroyed by the localized mechanical tension .

Theres no point in more arguing, ive already clarified my points with your friend (syna) otherwise you can dm me on here and we can converse a bit more. Just to summarize one more time : My claim is that scalp tension is one of the undelrying primary causes of hair loss and makes the effects of DHT worse, it also has other negative downstream signals which can't be solve dby 5aris. Also Im not saying DUT is shit or that you shouldn't use it as well, you keep side tracking my points without full comprehension of what Im trying to say.