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I. Physio-metaboliс method of treating androgenic alopecia.
This method is based on the study of hyperresponders https://www.reddit.com/r/tressless/ to therapy with antiandrogen and (or) minoxidil in order to find out why some patients get new hair from therapy with minoxidil and (or) antiandrogen, exceeding the results of hair transplantation, while others get nothing but a decrease in libido. At the same time, in fact, there are very few cases of hair restoration. It turned out that most hyperresponders experienced muscle stress (mainly from aerobic exercise on the legs) and were influenced by cold stress for various reasons or other factors causing piloerection. In fact, the result of using antiandrogen and minoxidil is affected by the environment (weather conditions, water parameters, country traditions) and behavior (habits, work, hobbies, food preferences, muscle load, sports preferences) of a particular patient.
The names “physio” and “metaboliс” mean the use of physiotherapy to influence a person’s metabolism in order to improve the result of FDA-approved drugs (finasteride, minoxidil). In this case, aerobic exercise (running, cardio) and anaerobic exercise (weightlifting) and cryotherapy (exposure to cold) are used. Natural substances (primarily food) that affect the reaction of cold receptors to cold are also used.
The point of the method is to remove the causes that contribute to the development of the disease with antiandrogen and minoxidil, and at the same time train the large muscles of the body and the follicle muscle by piloerection. At this point, the effects of training large muscles (primarily legs in aerobic exercise) will affect the growth of the follicle muscle (APM, arrector pili muscle) and the follicle itself. When the follicle muscle grows, it activates the follicle stem cells and they deminiaturize the follicle. The question of complete recovery is a matter of time. When using cold and exercise, tissue and follicle obesity also decreases, which contributes to the therapeutic effect. The method is also aimed at improving the functioning of the connection between cold receptors and the follicle muscle by using receptor agonists such as capsaicin (red pepper), garlic, onion, mustard, wasabi, menthol (there are many agonists). DHT, according to the author, inhibits not only the follicle but also cold receptors on the scalp, preventing piloerection. The method has already been described in detail in articles about the method:
Compressed part of research of theory of androgenic/anabolitic balance. Androgenetic Alopecia h-responders analytic. Theory of physio-metabolitic method of anti Androgenetic Alopecia treatment
https://www.reddit.com/user/MagicBold/comments/1cv2bog/brief_explanation_of_the_physiometabolic/
The best exercises for a positive effect were determined: running/cardio (aerobic active exercise with a heart rate of 125-145 beats per minute) - H-responders list here - H responders list - Google Sheets
However, little attention has been paid to the issue of the influence of cold and other aspects of the reaction to cold (piloerection). The effect of water composition on therapy and other methods of influencing the follicle muscle that promote hair growth have not been studied.
The author considers androgenic alopecia as a complex metabolic disease that disrupts the metabolism of fats and carbohydrates, disrupts the work and growth of a certain type of muscle (for example, cardiac muscle fibers), disrupts thermoregulation and thermogenesis, disrupts the sebaceous glands and neuromuscular connections. Androgenetic Alopecia is an eternal companion of such diseases as obesity, diabetes, hypertension, prostate hyperplasia and cancer. Baldness is only a symptom of a serious disease that reduces life expectancy, quality of life, premature aging and fatal chronic diseases.
In general, the idea of a positive effect on the follicle muscle is based on the following scientific works:
Shwartz Y, Gonzalez-Celeiro M, Chen CL, Pasolli HA, Sheu SH, Fan SM, Shamsi F, Assaad S, Lin ET, Zhang B, Tsai PC, He M, Tseng YH, Lin SJ, Hsu YC. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell. 2020 Aug 6;182(3):578-593.e19. doi: 10.1016/j.cell.2020.06.031. Epub 2020 Jul 16. PMID: 32679029; PMCID: PMC7540726. Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor - PMC
Torkamani N, Rufaut Norwood, Jones L, Sinclair RD. Beyond goosebumps: does the arrector pili muscle have a role in hair loss? Int J Trichology. 2014 Jul;6(3):88-94. doi: 10.4103/0974-7753.139077. PMID: 25210331; PMCID: PMC4158628. Beyond Goosebumps: Does the Arrector Pili Muscle Have a Role in Hair Loss? - PMC
Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton JM, Sato Y, Hartner A, Sekiguchi K, Reichardt LF, Watt FM. The basement membrane of hair follicle stem cells is a muscle cell niche. Cell. 2011 Feb 18;144(4):577-89. doi: 10.1016/j.cell.2011.01.014. PMID: 21335239; PMCID: PMC3056115. The basement membrane of hair follicle stem cells is a muscle cell niche - PMC
Torkamani N, Rufaut Norwood, Jones L, Sinclair R. Destruction of the arrector pili muscle and fat infiltration in androgenic alopecia. Br J Dermatol. 2014 Jun;170(6):1291-8. doi: 10.1111/bjd.12921. PMID: 24579818. Destruction of the arrector pili muscle and fat infiltration in androgenic alopecia - PubMed
Ezure T, Amano S, Matsuzaki K. Quantitative characterization of 3D structure of vellus hair arrector pili muscles by micro CT. Skin Res Technol. 2022 Sep;28(5):689-694. doi: 10.1111/srt.13168. Epub 2022 Jun 21. PMID: 35726958; PMCID: PMC9907649. Quantitative characterization of 3D structure of vellus hair arrector pili muscles by micro CT - PMC
Pascalau R, Kuruvilla R. A Hairy End to a Chilling Event. Cell. 2020 Aug 6;182(3):539-541. doi: 10.1016/j.cell.2020.07.004. PMID: 32763185. https://www.cell.com/cell/fulltext/S0092-8674(20)308692?_returnURL=https://linkinghub.elsevier.com/retrieve/pii/S0092867420308692?showall=true
Method scheme:
II. Cold receptors.
Two receptors are responsible for sensitivity to cold:
A) TRPA1 (The Mustard and Wasabi Receptor) is sensitive to temperatures below +17.5C degrees. Its work is influenced by ion channels Ca2+ K+ Na+ (modulation). High activity suggests an acidic environment (pH<7). Agonists are spicy foods of Asian cuisine garlic/onion//wasabi/mustard (this is one of the controversial issues why Asians are marked as reditors in hyperresponding, which of course requires study), capsaicin (red pepper through cooperating with TRPV1). Studies indicate that receptor activation is also possible cinnamaldehyde from cinnamon, organosulfur compounds from garlic and onion, tear gas, acrolein and crotonaldehyde from cigarette smoke, CBD, but the main ones, of course, are red chili peppers, garlic, wasabi and mustard. Cold below +17.5 degrees Celsius should also activate the receptor. TRPA1 cooperates with TRPV1 (capsaicin receptor and the vanilloid receptor).
B) TRPM8 (cold and menthol receptor 1 (CMR1)) is sensitive to temperatures below +26C and below +16C. The work is influenced by the ion channel Ca2+ K+ (modulation). High activity suggests an alkaline environment (pH> 7) The main agonist is menthol. TRPM8 expression is regulated by androgens. There is a direct relationship between DHT expression and TRPM8 expression. The cold and menthol receptor TRPM8 is highly expressed in prostate and prostate cancer (PC). Identified that TRPM8 is as an ionotropic testosterone receptor. The TRPM8 mRNA is expressed in early prostate tumors with high androgen levels, while anti-androgen therapy greatly reduces its expression. Androgen response element (ARE) mediates androgen regulation of trpm8. It is also obvious that the receptor is activated by cold below +15C.
These receptors are responsible for the activation of the goosebumps and piloerection mechanism, which should affect the activation of follicle stem cells. The correct reaction to cold also activates thermogenesis, namely fat burning. It is the mechanism of the connection “cold receptors-> follicle muscle → follicle stem cells” that is the key to understanding the treatment of non-scaring alopecia.
Zhang X. Molecular sensors and modulators of thermoreception. Channels (Austin). 2015;9(2):73-81. doi: 10.1080/19336950.2015.1025186. PMID: 25868381; PMCID: PMC4594430. Molecular sensors and modulators of thermoreception - PMC
Xiong S, Lin S, Hu Y, Xia W, Wang Q, Wang L, Cao T, Liao Y, Scholze A, Tepel M, Zhu Z, Liu D. Dietary Cinnamaldehyde Activation of TRPA1 Antagonizes High-Salt-Induced Hypertension Through Restoring Renal Tubular Mitochondrial Dysfunction. Am J Hypertens. 2024 Aug 14;37(9):708-716. doi: 10.1093/ajh/hpae068. PMID: 38820173. https://academic.oup.com/ajh/article-abstract/37/9/708/7686069?redirectedFrom=fulltext&login=false
Logashina YA, Korolkova YV, Kozlov SA, Andreev YA. TRPA1 Channel as a Regulator of Neurogenic Inflammation and Pain: Structure, Function, Role in Pathophysiology, and Therapeutic Potential of Ligands. Biochemistry (Mosc). 2019 Feb;84(2):101-118. doi: 10.1134/S0006297919020020. PMID: 31216970. TRPA1 Channel as a Regulator of Neurogenic Inflammation and Pain: Structure, Function, Role in Pathophysiology, and Therapeutic Potential of Ligands | Biochemistry (Moscow) TRPA1 Channel as a Regulator of Neurogenic Inflammation and Pain: Structure, Function, Role in Pathophysiology, and Therapeutic Potential of Ligands | Biochemistry (Moscow)
Zurborg S, Yurgionas B, Jira JA, Caspani O, Heppenstall PA. Direct activation of the ion channel TRPA1 by Ca2+. Nat Neurosci. 2007 Mar;10(3):277-9. doi: 10.1038/nn1843. Epub 2007 Jan 28. PMID: 17259981. Direct activation of the ion channel TRPA1 by Ca2+ - PubMed
Asuthkar S, Velpula KK, Elustondo PA, Demirkhanyan L, Zakharian E. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells. Oncotarget. 2015 Jul 10;6(19):17221-36. doi: 10.18632/oncotarget.3948. PMID: 25980497; PMCID: PMC4627303. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells - PMC
Szolcsányi J. Effect of capsaicin on thermoregulation: an update with new aspects. Temperature (Austin). 2015 Jun 2;2(2):277-96. doi: 10.1080/23328940.2015.1048928. PMID: 27227029; PMCID: PMC4843897. Effect of capsaicin on thermoregulation: an update with new aspects - PMC
Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R. Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br J Pharmacol. 2004 Feb;141(4):737-45. doi: 10.1038/sj.bjp.0705652. Epub 2004 Feb 2. PMID: 14757700; PMCID: PMC1574235. https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0705652
III. DHT, cold receptors, minoxidil and antiandrogens.
It is known that the TRPM8 receptor is androgen-dependent, the more androgens, the greater the expression. As a result of hypersensitivity to androgens, it can be assumed that four situations can arise:
A) There may be too many TRPM8 receptors, and they become the main cold receptors in different parts of the human body.
B) Due to excessive exposure to androgens, TRPM8 receptors may not work properly, and zones of insensitivity to cold may appear, for example, in the region of +17-22 degrees Celsius.
C) The neuromuscular connection between the follicle muscles and the cold receptor is disrupted by unknown mechanisms associated with sympathetic nerves and SHH.
D) The connection between the follicular muscle and the central nervous system is disrupted, as a result of which piloerection from emotions and other factors does not occur in some areas of the body.
F) Because dihydrotestosterone affects calcium ion channels - DHT disrupts the work of all temperature receptors based on calcium (Ca2+) channels (Transient receptor potential cation channel) by influencing the expression and activity of only some calcium channels (L-type calcium channel) introducing an imbalance in calcium channels of which there are many (L, N, P, R.T Types of Ca2+ ion channels)
The effect of androgens on the heat sensitivity of a man can be explained by the phenomenon when a woman and a man stand under the same shower with the same water temperature. The woman freezes, but the man does not. The woman feels the cold more and gets more pain from the cold. According to the author’s observations, the scalp of a patient with baldness constantly sweats and overheats, the sensitivity of the bald scalp to cold is significantly reduced. Thermography studies of people with hair loss also show that thermal patterns in general followed the anatomical location of the main superficial arteries and veins of the head as described in anatomy books although there were some variations, especially with regard to the forehead and top of the head (superior aspect), ranging from an asymmetrical distribution pattern to a lack of a clear thermal pattern. Thus, hair loss creates thermal anomalies (impaired thermoregulation and thermogenesis).
In other words, the author believes that decreased sensitivity to cold depends on androgens, which increase the number of TRPM8 receptors (i.e. TRPM8 becomes larger than TRPA1 in androgen-sensitive areas such as the scalp) or change their sensitivity parameters (making them less sensitive to cold).
Probably, DHT causes dips in cold sensitivity in the range between +15°C to +20°C for androgen-sensitive areas (scalp).
Kreddig N, Hasenbring MI, Keogh E. Comparing the Effects of Thought Suppression and Focused Distraction on Pain-Related Attentional Biases in Men and Women. J Pain. 2022 Nov;23(11):1958-1972. doi: 10.1016/j.jpain.2022.07.004. Epub 2022 Jul 29. PMID: 35914643. https://www.jpain.org/article/S1526-5900(22)00363-7/fulltext
Yang Z, Wang X, Zhu G, Zhou Z, Wang Y, Chen D, Meng Z. Effect of surgical castration on expression of TRPM8 in urogenital tract of male rats. Mol Biol Rep. 2012 Apr;39(4):4797-802. doi: 10.1007/s11033-011-1271-7. Epub 2011 Sep 23. PMID: 21947852. Effect of surgical castration on expression of TRPM8 in urogenital tract of male rats - PubMed
Xu X, Zhang H, Wu G, Lian Z, Xu H. Sex differences in body temperature and thermal perception under stable and transient thermal environments: A comparative study. Sci Total Environ. 2024 Nov 15;951:175323. doi: 10.1016/j.scitotenv.2024.175323. Epub 2024 Aug 10. PMID: 39128529. Sex differences in body temperature and thermal perception under stable and transient thermal environments: A comparative study - ScienceDirect
https://www.pfizer.com/news/articles/cold_wars_why_women_feel_the_chill_more
Kingma, B., van Marken Lichtenbelt, W. Energy consumption in buildings and female thermal demand. Nature Clim Change 5, 1054–1056 (2015). Energy consumption in buildings and female thermal demand | Nature Climate Change
Linn Eva Hauvik, James B. Mercer,Thermographic mapping of the skin surface of the head in bald-headed male subjects, Journal of Thermal Biology, Redirecting. Thermographic mapping of the skin surface of the head in bald-headed male subjects - ScienceDirect
Feng X, Cai W, Li Q, Zhao L, Meng Y, Xu H. Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress. J Cell Biol. 2025 Jan 6;224(1):e202403104. doi: 10.1083/jcb.202403104. Epub 2024 Nov 5. PMID: 39500490; PMCID: PMC11540856. Activation of lysosomal Ca2+ channels mitigates mitochondrial damage and oxidative stress - PubMed
Ionic mechanism of minoxidil sulfate-induced shortening of action potential durations in guinea pig ventricular myocytes. | Journal of Pharmacology and Experimental Therapeutics
Sun YH, Gao X, Tang YJ, Xu CL, Wang LH. Androgens induce increases in intracellular calcium via a G protein-coupled receptor in LNCaP prostate cancer cells. J Androl. 2006 Sep-Oct;27(5):671-8. doi: 10.2164/jandrol.106.000554. Epub 2006 May 25. PMID: 16728719. https://onlinelibrary.wiley.com/doi/10.2164/jandrol.106.000554
Antiandrogens are known to reduce DHT levels and, as indicated above, reduce TRPM8 expression. Therefore, antiandrogens act not only on the follicle itself, but also on the receptors that have cooled on the skin, which should activate piloerection, and follicle muscle growth stimulation (APM) should activate follicle stem cells for deminiaturization. Minoxidil, in turn, also has antiandrogenic properties. Minoxidil may act by altering hormonal and enzymatic pathways (by CYP17A1, CYP19A1) and demonstrates that minoxidil inhibits AR.
Moreover, minoxidil affects the mitochondrial ion channels - Ca2+, K+, Na+, N, and ATP. As is known, these ion channels modulate the work of TRPA1 and TRPM8, which ultimately trigger the effect of piloerection and goosebumps. Therefore, the effectiveness of minoxidil in the treatment of androgenic alopecia is very high. Minoxidil, like nitrates, for example, is a vasodilator. Goren A, Naccarato T, Situm M, Kovacevic M, Lotti T, McCoy J. Mechanism of action of minoxidil in the treatment of androgenetic alopecia is likely mediated by mitochondrial adenosine triphosphate synthase-induced stem cell differentiation. J Biol Regul Homeost Agents. 2017 Oct-Dec;31(4):1049-1053. PMID: 29254313. Mechanism of action of minoxidil in the treatment of androgenetic alopecia is likely mediated by mitochondrial adenosine triphosphate synthase-induced stem cell differentiation - PubMed
In fact, DHT affects not only the follicle, as is commonly said, but also cold receptors and ion channel activity; this issue in baldness has not been considered by the scientific community. The effect on cold receptors during antiandrogen and/or minoxidil therapy, together with muscle stress from exercise, produces the effect of maximum hair restoration in hyperresponders.
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