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Finasteride-cels: In all, our three-dimensional co-culturing revealed mitochondrial dysfunction in balding DPC, suggesting a metabolic component in the aetiology of AGA. “George, all these sound too complicated”. Well, there’s no “one magic thing” that causes hair loss. Let’s say for example, that only DHT is to blame. Then explain why these are frequently mentioned in the bibliography: -Insulin-Like Growth Factor-1 (IGF-1) -Vascular Endothelial Growth Factor (VEGF) -Fibroblast Growth Factor-7 (FGF-7 (keratinocyte growth factor)) -Wnt/β-Catenin Pathway -Transforming Growth Factor-Beta 1 (TGF-β1) -Hepatocyte Growth Factor (HGF) -Platelet-Derived Growth Factor (PDGF) Of course, it doesn’t take more than 12 hours to figure out why these are important when it comes to hair loss and that these are not just a “downstream effect”. Here are a few basic explanations. First, IGF-1 is a critical anagen-promoting growth factor that stimulates matrix cell proliferation in the hair bulb, extends anagen duration and also prevents follicle miniaturization. Plus, it supports hair shaft formation and HFSC activation in the bulge. Here’s how: it binds to IGF-1 receptors (IGF-1R) on matrix cells and HFSCs, activating the PI3K/Akt pathway to enhance cell survival, mitosis and keratin synthesis. It upregulates VEGF expression, promoting perifollicular angiogenesis for nutrient and oxygen delivery. It counteracts catagen-inducing signals like TGF-β1 and prostaglandin D2 (PGD2) by stabilizing anti-apoptotic proteins (such as Bcl-2) and synergizes with Wnt/β-catenin to maintain anagen and HFSC pluripotency. It also up-regulates PDGF-A and PDGF-B. Its sources are: -DPCs: Primary source within the hair follicle, secreting IGF-1 to regulate matrix cell activity. -Hepatocytes: Systemic production via the liver, contributing to circulating IGF-1 levels. -Keratinocytes and Adipocytes: Local sources in the scalp microenvironment. Cool note: In mice, IGF-1 supplementation is shown to extend anagen by even up to 30% and topical analogs by even up to 25%. Common interventions for AGA for example either partly upregulate IGF-1 or enhance its delivery. Then, VEGF promotes angiogenesis around follicles, ensuring oxygen and nutrient delivery to support the high metabolic demands of matrix cells during anagen. It maintains perifollicular vascular networks critical for hair growth. Here’s how: it binds to VEGF receptors (VEGFR-1, VEGFR-2) on endothelial cells, stimulating capillary formation and vasodilation. Enhanced blood flow to the dermal papilla, supports IGF-1 and FGF-7 activity. Its sources are DPCs, keratinocytes, endothelial cells and platelets. Cool note: VEGF overexpression in mice increases follicle size and hair growth by 30%. Scalp tension, calcification, reduced blood flow, the use of vasoconstrictants such as nicotine, vitamin D deficiency, magnesium deficiency and high homocysteine partly affect hair loss so much because they suppress the release and delivery of VEGF. Also common interventions such as minoxidil, LLLT, scalp masssages and PRP increase VEGF expression and delivery. To put in perspective how much, a daily 4–10 minute scalp massage is shown to increase hair thickness by 10%. FGF-7 is also quite important since it stimulates epithelial cell proliferation in the hair matrix, promoting anagen and supporting hair shaft formation. It enhances follicle size and strength by binding to FGFR2 on matrix keratinocytes and activating MAPK/ERK pathways to drive cell division. It also works synergistically with IGF-1 and Wnt/β-catenin to maintain anagen and inhibit apoptosis in the hair bulb, prolonging growth. Elevated PGD2 also downregulates FGF-7 through TGF-β1 which is why it is well known that FGF-7 is downregulated in AGA. Histamine can also inhibit it by upregulating IL-1 and cortisol as well by upregulating TGF-β1. FGF-7 supplementation in mice extends anagen by 15–20%. Then the Wnt/β-catenin pathway is also a key regulator of anagen initiation, activating HFSCs to regenerate the follicle and drive hair shaft production. Wnt ligands such as Wnt3a and Wnt10b bind Frizzled receptors, stabilizing β-catenin, which translocates to the nucleus and activates genes such as LEF1 and Axin2 for anagen entry. PGD2 for example directly inhibits Wnt/β-catenin in AGA, shortening anagen while cortisol and prolactin for example do this more indirectly by upregulating TGF-β1 and thus suppressing Wnt in AGA and TE. Also, one of the reasons why melatonin promotes hair regeneration is that it modulates the Wnt/β‐catenin signalling pathway and one of the reasons why circadian disruption increases telogen follicles is that disrupted CLOCK/BMAL1 reduces Wnt expression Now, TGF-β1 a catagen-inducing growth factor that terminates anagen by promoting matrix cell apoptosis and inhibiting proliferation. It binds to TGF-β receptors, activating Smad signaling to upregulate pro-apoptotic genes such as Bax and downregulate anagen genes such as Bcl-2. It also antagonizes IGF-1, FGF-7 and Wnt/β-catenin, accelerating catagen. Here’s something cool: topical curcumin downregulates TGF-β1/Smad signaling to reduce fibrosis and support hair growth, extending anagen by ~20% in animal models. TGF-β1 inhibitors are also promising for scarring alopecia. HGF promotes anagen by stimulating matrix cell proliferation and HFSC activation (overexpression in mice increases hair growth by even up to 25% for example). It enhances follicle vascularization and growth by binding to c-Met receptors on keratinocytes and HFSCs activating PI3K/Akt and MAPK pathways. It also upregulates VEGF, supporting angiogenesis and inhibits TGF-β1. PRP for example delivers HGF, scalp massages and LLLT improve HGF delivery. PDGF stimulates DPC proliferation and angiogenesis, supporting anagen maintenance and follicle development. It binds to PDGFR on DPCs and endothelial cells, activating PI3K/Akt and MAPK pathways, enhancing VEGF expression, supporting HFSC activation and matrix cell growth. PDGF is also reduced in AGA scalps (PDGF-enriched exosomes show ~15% regrowth in preclinical AGA models). Calcification restricts PDGF diffusion in scarring alopecia, scalp tension impairs PDGF delivery and reduced blood flow limits PDGF availability in AGA and TE. PRP, scalp massages and LLLT support PDGF delivery. Now on the flipside, someone might think “i thought things such as scamp tension, hypothyroidism and gut issues could also cause hair loss”. Yes, here’s a basic summary of the key interactions: -Scalp tension induces IL-6 and TGF-β1, suppressing IGF-1, VEGF, FGF-7, HGF, PDGF and Wnt/β-catenin, particularly in traction alopecia and AGA. -Reduced blood flow limits delivery of IGF-1, VEGF, HGF, and PDGF, causing hypoxia in AGA, TE and scarring alopecia. -Calcifications restrict growth factor diffusion, enhancing TGF-β1-driven fibrosis in scarring alopecia and AGA. -Heavy metals damage DPCs and reduce IGF-1, VEGF, FGF-7, HGF and PDGF in AGA, TE, and anagen effluvium. -Hypothyroidism impairs IGF-1, FGF-7, HGF and PDGF in TE and AA. -Histamine upregulates IL-1 and TNF-α, inhibiting IGF-1, FGF-7, HGF, PDGF, and Wnt/β-catenin in AA and traction alopecia. -LPS increases IL-6 and TGF-β1, suppressing IGF-1, VEGF, FGF-7, HGF, PDGF, and Wnt/β-catenin in TE and AA. -PGD2 inhibits FGF-7, Wnt/β-catenin, and IGF-1 in AGA, promoting catagen. -Cortisol and prolactin upregulate TGF-β1, suppressing anagen-promoting factors in AGA and TE. -Disrupted CLOCK/BMAL1 reduces Wnt/β-catenin and FGF-7, increasing telogen in TE. -Nutritional deficiencies reduce IGF-1, VEGF, HGF and PDGF in AGA and TE. -Homocysteine-induced ROS upregulate TGF-β1, suppressing other growth factors. So there’s no one thing that causes hair loss. Or someone else might think “what about certain topicals? don’t they just inhibit DHT?” No, not at all. A lot of them do but not all. Rice bran mineral extract is recently for example and here’s how it might (there’s no serious research behind it yet) help with hair loss: It significantly upregulates type I collagen, type IV collagen, fibronectin, alkaline phosphatase and versican (increased via immunohistochemistry). It activates the Wnt/β-catenin pathway It downregulatedsTGF-β2 and IL-1α Or someone else might be in favor of procedures such as PRP. Well, here’s how PRP helps, platelets in PRP release multiple growth factors such as: -Platelet derived growth factor (PDGF) that stimulates dermal papilla cell (DPC) proliferation and angiogenesis. -Vascular endothelial growth factor (VEGF) that promotes perifollicular angiogenesis, increasing blood flow to deliver oxygen, glucose and other nutrients such as amino acids for matrix cell proliferation and keratin synthesis during the anagen phase. -IGF-1 that extends anagen by stimulating matrix cell division and inhibiting apoptosis, -HGF that enhances matrix cell proliferation and follicle vascularization by activating PI3K/Akt and MAPK pathways. -FGF-7 that promotes epithelial cell proliferation in the hair matrix, supporting anagen and hair shaft formation. PRP also contains anti-inflammatory cytokines such as IL-10 and thus modulates pro-inflammatory cytokines such as IL-6 or TNF-α, reducing perifollicular inflammation. Where is DHT in that list? Am i saying that DHT or genetics are irrelevant? Absolutely not. The prevalence of androgenic alopecia for example is highest in Caucasians (80% by age 70), lower in East Asians (40%) and Africans (30%). One hypothesis of why this is the case, is that variants such as rs12203592 in IRF4 are more prevalent in Europeans. Or in the case of rs10521339 (T/T), here’s what’s going on. DHT binds to AR in the dermal papilla (DP). This is totally normal and happens to everyone since: A) DHT is a paracrine hormone, meaning it acts locally where it is produced rather than circulating widely in the blood. B) Hair follicles have a higher concentrations of 5-alpha-reductase, especially the type II isoenzyme. But in case the person has this specific variant, an excess can upregulate genes like TGF-β and DKK1 (Dickkopf 1), which inhibit Wnt/β-catenin signaling and thus suppress HFSC activation and matrix cell proliferation, shortening anagen and reducing follicle diameter. So these things do matter and we can’t simply dismiss genetic factors. Heck, i have this and even though i do not struggle with hair loss whatsoever, if for whatever reason in the future i decide to run a steroid cycle (we are talking about doses that go beyond TRT) and do other dumb stuff such as to start consuming 30mg of nicotine per day, not eating the way i do and so on, i will 100% have to take measures to prevent hair loss. I know that it will 100% happen because i understand the topic in general, how it applies to me and what will load the gun based on my genetics. But despite the impact genetic factors, we also can’t dismiss the mouse models of dihydrotestosterone-induced androgenetic alopecia, which were reversed by allogenic adipose-derived stem cells supplemented with ATP. Or for example, in one person who i helped with a minor case of hair loss, lowering his uric acid and working on his liver helped him A LOT. But of course, if you ask most doctors and “hair loss experts” if these two play a role, they will say that they don’t despite the existing research.