Inflammation, DHT, and the Biochemical Cascade of Hair Loss: A Scientific Overview

Written By: Jordan R. Plews, PhD

 Introduction: Prevalence and Onset of Hair Loss

Hair loss, or alopecia, is a prevalent condition affecting millions worldwide, with significant variations across age, gender, and ethnicity. In the United States, androgenetic alopecia (AGA), commonly known as male or female pattern baldness, impacts approximately 50 million men and 30 million women. The onset of AGA can occur as early as a person's teens, with risk increasing with age; notably, over 50% of men aged 50 and above experience some degree of hair loss.[1] In women, hair loss is more likely after menopause. Globally, the prevalence of AGA varies, but up to 80% of men and 50% of women are affected in the course of their life. [2] 

Regarding the average age of onset, AGA typically begins in the third and fourth decades of life. However, it can start immediately after puberty and progresses over time. Hair greying, another common concern, often starts in the mid-30s for Caucasians, late 30s for Asians, and mid-40s for Africans, though individual variations are considerable.

DHT and Inflammation in Hair Loss: Sex Differences and Causes

Dihydrotestosterone (DHT), a potent androgen derived from testosterone via the enzyme 5α-reductase, plays a central role in AGA. DHT binds to androgen receptors in hair follicles, leading to follicular miniaturization and a shortened anagen (growth) phase, culminating in hair thinning and loss. [3] 

Inflammation is increasingly recognized as a contributing factor in hair loss. Chronic inflammation may exacerbate androgen activity, creating a vicious cycle that accelerates hair follicle damage. Lifestyle choices and genetic predispositions can lead to scalp inflammation. Factors such as poor diet, stress, smoking, and certain hair care practices may contribute to an inflammatory environment. Additionally, genetic variations can influence individual susceptibility to inflammation and androgen sensitivity, impacting hair loss patterns.[4]

Molecular Evidence of Inflammation in Hair Loss

The inflammatory process in AGA involves various cytokines and interleukins. Elevated levels of pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), have been observed in the scalps of individuals with AGA. These cytokines can lead to the destruction of hair follicles, resulting in hair loss. [5]

Furthermore, DHT has been shown to upregulate inhibitory cytokines like transforming growth factor-alpha (TGF-α), epidermal growth factor (EGF), and interleukin-1α (IL-1α), which in turn upregulate matrix metalloproteinase-9 (MMP9). Excessive MMP9 may impede hair growth by interfering with the hair cycle. [6] 

The Biochemical Cycle of Inflammatory Hair Loss

The cycle of hair loss involving inflammation can be outlined as follows:

1. Initiation: Factors such as elevated DHT levels or other triggers induce inflammation in the scalp. [3,4]

2. Cytokine Production: Inflammatory molecules, including IL-1β, IL-6, and TNF-α, are produced, leading to an inflammatory response. [5,6,7] 

3. Cellular Response: Immune cells infiltrate the hair follicle area, attempting to combat the perceived threat.

4. Follicular Damage: The inflammatory response exposes hair follicles to oxidative stress and may reduce blood flow, depriving follicles of essential nutrients. Can lead to fibrosis in some. [5]

5. Hair Cycle Disruption: The damage leads to a shortened anagen phase and prolonged telogen (resting) phase, resulting in hair thinning and loss.

6. Addressing this cycle involves strategies to reduce inflammation, inhibit DHT production, and promote follicle health.

7. Strategies for Prevention and Intervention

To mitigate hair loss associated with DHT and inflammation, consider the following approaches:

• Anti-Androgenic Treatments: Medications like finasteride inhibit 5α-reductase, reducing DHT levels and slowing hair loss progression. Some forms of red light have also been shown to limit DHT in the scalp. [8]

• Anti-Inflammatory Interventions: Topical corticosteroids or other anti-inflammatory agents can reduce scalp inflammation. Nutritional supplements, such as omega-3 fatty acids, curcumin, and antioxidants, have also been found to have anti-inflammatory effects and may be beneficial for hair disorders. Certain forms of red light, such as in the 620nm range, help uncouple NO2 and have an anti-inflammatory effect. [8]  

• Lifestyle Modifications: Adopting a balanced diet rich in anti-inflammatory foods, managing stress, getting good sleep, and avoiding smoking can contribute to overall scalp health.

To be continued:

MENOPAUSE TODAY: FINAL METAMORPHOSIS OR PSEUDO-DISEASE By: Dr. Robert Kline According to aging societies, Menopause is defined as  "the cessation of a woman's menstrual periods where she can no longer get pregnant".  They go deeper to illustrate its many disruptive and physical discomforts.  But despite its similar effects, menopause is not a disease or disorder but a biological transitional phase in a woman's life.  It is a notable marker in a woman's timeline where their bodies are more prone to a range of disorders and diseases. Randomly, some women experience various symptoms, including hair loss, hot flashes, night sweats and trouble sleeping.  Others get joint and muscle discomfort, pain during sex, forgetfulness, difficultly concentrating, or a combination of these.  We review these physiological changes and explore touch points for addressing them, perhaps better predict them  and someday even find new solutions to redirect such symptoms to reduce the length of their disruptive effects. Whether you're searching for a primary care physician or a cosmetic specialist, shopping for any doctor can be quite a challenge. Ingredients for finding a professional that you can trust with your life rely heaviest on their reputation, expertise and qualifications found under smart research methods. (See complete feature)

• Growth Stimulants: Agents like minoxidil can promote hair growth by prolonging the anagen phase and improving blood flow to the follicles.  Newer options include topical use of peptides, such as GHK-Cu, growth factor serums, such as those derived from stem cells, skin or hair follicle progenitor cells, or keratinocytes, and in office or at home treatments, such as scalp microneedling or red light caps.

• Exosomes & Secretome Topicals: Advancements in stem cell research have uncovered that mesenchymal stem cell derived exosomes carry a variety of immunomodulating factors as well as messenger RNA (mRNA) and microRNAs (miRNAs) that attenuate autoimmune and inflammatory conditions, including AGA and potentially other forms of alopecia. [9]  More recent advancements support that a more targeted approach to support skin and scalp with progenitor cell secretomes inclusive of exosomes and rare biomolecules present in young skin, which heals much better than older skin, may be superior to broader, less targeted approaches. [10]

• Advanced Extracellular Matrix (ECM): While hair transplants remain a widely used option for recovery of hair density, the process triggers the wound healing cascade, causing an inflammatory response when removing follicles from one region and transplanting them to another.  If this inflammation response is not well resolved, the canonical 4 phase wound healing cascade will stall, and subsequently the follicles will not survive grafting. This is likely responsible for a significant portion of the up to 15% graft failure rate reported in the literature. [11] Recent advances in ECM technology, have shown promise in supporting the cells at the wound bed to move through the inflammation phase (often associated with pain, swelling, and redness) most rapidly, and through the proliferation phase where structural healing occurs. [12] Reyagel by Fettech has adapted their MTP ECM into an easy to use sterile gel that can be applied directly to wounds as an FDA cleared medical device, and FUE follicular units can be dipped in the gel to support engraftment, attenuating inflammation, and providing growth factors and exosomes as well. [13]

Conclusion

Hair loss is a multifactorial condition influenced by genetic, hormonal, and inflammatory factors. Understanding the roles of DHT and inflammation provides insight into the pathogenesis of AGA and informs effective prevention and treatment strategies. Early intervention is crucial, as inflammation and follicular damage can progress unnoticed until significant hair loss has occurred, while genetic factors (such as expression of MMP genes) in some can lead to fibrosis and result in more difficult to treat hair loss. By focusing on inflammation as an early warning sign, treatment target, and significant factor to consider when diagnosing, tracking, and treating hair loss, existing methodologies can be greatly improved. Ongoing research continues to elucidate the complex mechanisms underlying hair loss, paving the way for more targeted and effective therapies.

References

1. Rhodes T, Girman CJ, Savin RC, Kaufman KD, Guo S, Lilly FR, Siervogel RM, Chumlea WC. Prevalence of male pattern hair loss in 18-49 year old men. Dermatol Surg. 1998 Dec;24(12):1330-2. doi: 10.1111/j.1524-4725.1998.tb00009.x. PMID: 9865198.

2. Piraccini BM, Alessandrini A. Androgenetic alopecia. G Ital Dermatol Venereol. 2014 Feb;149(1):15-24. PMID: 24566563.

3. Dihydrotestosterone

4. English, R. S. (2018). A hypothetical pathogenesis model for androgenic alopecia: Clarifying the dihydrotestosterone paradox and rate-limiting recovery factors. Medical Hypotheses, 111, 73–81. https://doi.org/10.1016/j.mehy.2017.12.027

5. The Role of Inflammation in Scalp Health and Hair Loss

6. Xiong HD, Tang LL, Chen HJ, Wu Y, Li WY, Wen SJ, Lin YK. Identification of immune microenvironment changes, immune-related pathways and genes in male androgenetic alopecia. Medicine (Baltimore). 2023 Sep 22;102(38):e35242. doi: 10.1097/MD.0000000000035242. PMID: 37746940; PMCID: PMC10519577. 

7. Evaluation of serum levels of IL-6, IL-10, and TNF-alpha in alopecia areata patients: A meta-analysis

8. Kocher, J., Jandick, N., Spragion, D., DeSena, P. J., Jr., Womble, T. M., Crizer, K., & Stasko, N. (2024). Dual wavelength LEDs induce reactive oxygen species and nitric oxide that inhibit the production of dihydrotestosterone by 5-α reductase. Journal of Biophotonics. https://doi.org/10.1002/jbio.202400388

9. Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells. 2019 Dec 11;8(12):1605. doi: 10.3390/cells8121605. PMID: 31835680; PMCID: PMC6952783.

10. Skin Progenitor Cell Secretome. https://myprovoque.com/science/

11. Jimenez, F., Alam, M., Vogel, J. E., & Avram, M. (2021). Hair transplantation: Basic overview. Journal of the American Academy of Dermatology, 85(4), 803–814. https://doi.org/10.1016/j.jaad.2021.03.124

12. Diller, R. B., & Tabor, A. J. (2023). The Extracellular Matrix (ECM) and Wound Healing: A Review. In Research Advances in Microbiology and Biotechnology (Vol. 8, pp. 95–117). https://doi.org/10.9734/bpi/ramb/v8/8007A

13. Reyagel – Multi Tissue Platform Extracellular Matrix (MTP ECM) gel. https://www.reyagel.com/before-afters

ABOUT THE AUTHOR

Dr. Jordan R. Plews is an expert at the intersection of biochemical engineering, stem cell research, and regenerative medicine with a particular focus on the cellular and molecular mechanisms of aging and human longevity. He graduated with 1st class honors in Biochemical Engineering from the University of London and completed doctorate research in Molecular Biology and Stem Cell Research at University College London, specializing in Somatic Cell Reprogramming. After working as part of Pfizer's bioprocess development group in bioprocess design and scale up, he conducted postdoctoral research at Stanford, looking at ways to apply stem cells in inventive and practical ways to treat disease. He held key roles at med/biotech companies like Velos, Becton Dickinson, and Xytogen Biotech, where he developed innovative products for researchers, clinicians, and consumers. At Natera, he lead the launch of Signatera, a personalized genomics based cancer diagnostic. In 2020, he co-founded ELEVAI, creating advanced skincare solutions using human stem cell exosomes. His research, published in leading journals, explores the relationship between stem cells, aging, and disease to enhance and extend healthy lifespan.