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Stress Related Hair Loss

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Stress-Related Hair Loss: Hair Follicle Stem Cells on Strike

Laura Neville ND | November 23, 2021

Background
Approximately 25% of those who contract COVID-19 experience hair loss several months after the onset of symptoms, a phenomenon known as telogen effluvium. This phenomenon is also known to follow severe illness, childbirth, or intense physical and/or psychological stress. However, during the past 19 months of the pandemic, many clinicians also report an uptick of hair loss in patients who have not contracted COVID-19.
Various studies have reported that stress, specifically chronic psychological stress, plays a role in 75% to 90% of human diseases. Chronic stress has been anecdotally associated with hair loss in humans, but the underlying mechanism that links stress to hair loss remains elusive.
Can stress imposed by the current pandemic account for the increase in patient reported hair loss? To answer this, it must first be confirmed if stress-related hair loss can be explained by a scientific mechanism or if stress is just a catch-all etiology. Recently published research is getting closer to a true understanding.

Hair Growth Cycle
Throughout its lifespan, human hair cycles through three distinct stages. During the anagen (growth) phase, a hair follicle continuously pushes out a growing hair shaft. During the catagen (degeneration) phase, hair growth stops but the hair remains in place. During the telogen (rest) phase, the hair remains dormant for some time, eventually falling out – this is sometimes referred to as the exogen phase.
Mechanistically, the arrector pili muscle acts as an anchor, supporting sympathetic nerve innervation to the hair shaft. The sympathetic nerves form a synapse-like connection with hair follicle stem cells (HFSC), located in the region of the hair follicle called the bulge, and regulate the cells through vesicles secreting chemical messengers.
Overall, HFSCs play a crucial role in hair growth via growth factors, cytokines, hormones, and various neuropeptides. In fact, not only is the hair follicle (HF) the target of stress hormones and autoimmune activity, it can secrete its own stress factors that affect the skin. As such, it has been described as a mini organ.

Stress-Related Hair Loss Mechanism
During telogen, HFSCs are kept in an inactive state and therefore do not divide. Under severe stress, many hair follicles enter telogen prematurely, leading to quick fall-out of the hair strands. For mice under chronic stress, telogen phases become progressively longer and entry into anagen becomes sporadic and inconsistent. This same pattern of hair loss is seen in humans under stress and with age.
It was previously thought that stem cells eventually lose robust function with age and stress due to overuse, but a study published this year showed that when mice started to grow old and lose their hair, their HFSCs began to escape the HF bulge through holes in the follicle. Outside the bulb they recovered their normal shape and darted away. Bottom line – the cells responsible for hair growth didn’t lose function due to overuse, they simply walked off the job.

Norepinephrine (NE)
At a microcosm level, human hair follicles display HPA axis-like regulatory feedback systems. The sympathetic nerves are stimulated by stressors, which in turn release NE, the key regulatory point of the local HF stress system.
In the absence of NE signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism and up-regulating the resting regulatory factors. In tumor therapy, the local application of a NE skin patch to neonatal rats before high-dose radiation or chemotherapy can prevent traumatic alopecia post-therapy. The phenomenon of the sympathetic nerves directly activating HFSCs with NE to proliferate hair in mice has not yet been made clear in human clinical studies.

Cold Therapy
Sympathetic regulation of the HF has been proposed, where the arrector pili muscles (APMs) and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. In this structure, sympathetic neurons directly regulate stem cells with NE through synaptic-like structures, while the APMs maintain sympathetic innervation of stem cells.
This unit can be stimulated by cold, creating sympathetic excitation and contraction of pili muscles, manifesting as goosebumps, but also activating the HFSCs through NE.

Corticosterone
Though the adrenal gland produces several hormones in response to stress, including corticosterone in rodents (thought to be equivalent to cortisol in humans), adrenaline (epinephrine), noradrenaline (norepinephrine) and aldosterone, a recent study proposed that corticosterone is the main regulator of hair follicle stem cell (HFSC) in mice.
The same study investigated further. They quantified levels of adrenal hormones in adrenalectomized (ADX) mice to find that corticosterone showed the most substantial decrease – becoming barely detectable – when compared with control mice. These ADX mice showed shortened telogen phases and repeatedly entered anagen in a synchronized fashion, resulting in substantial hair growth. Of note, past studies have shown that adrenalectomy to remove the source of corticosterone accelerates hair growth in rats, rabbits and minks.
To test if increased corticosterone levels inhibit HFSC activation, telogen mice were given supplementary corticosterone in their drinking water, leading to enhanced levels of circulating corticosterone. Transient increases in corticosterone levels had a minimal effect on the hair cycle, but long-term supplementation prolonged the telogen phase. When corticosterone was removed, mice were able to enter anagen, suggesting that the effect of chronic corticosterone on HFSCs is reversible.

Gene Involvement
Rodent studies reveal the genes FOXC1 and NFATC1 seem to be less active in older hair follicle cells. These genes act to keep HFSCs within the confines of the bulge. Mice who lack these genes experience a greater escape of HFSCs, lose most of their hair by middle age, and what strands remain are sparse and gray.
Additionally, corticosterone acts on the dermal papillae to suppress the expression of GAS6, a gene that encodes the secreted factor Growth Arrest Specific 6. Adrenalectomized mice exhibited upregulation in GAS6, along with hair growth. Even in chronically stressed mice, injection of GAS6 overrides stress-induced inhibition of HFSC activity and restores hair growth.
The good news continues: Researchers have demonstrated that the tissue-regeneration capacity of HFSCs remains robust even in older mice.
It might therefore be possible to harness the ability of HFSCs to promote hair-follicle regeneration by modulating the corticosterone–GAS6 axis. HFSCs would need to stay in place at the follicle bulge (via FOXC1 and NFATC1), have the correct supply of NE via sympathetic nerve innervation (cold therapy to induce goosebumps could be utilized to stimulate NE and therefore, HFSCs activity), and avoid chronic corticosterone inhibition by restoring GAS6.

Next Steps for Human Hair Growth
Although corticosterone is considered the rodent equivalent of human cortisol, it is not yet known whether cortisol signals similarly to human HFSCs. Moreover, if GAS6 expression in human dermal papillae is also similar, it will also be crucial to see whether forced GAS6 expression could cause growth of dormant, yet potentially mutated HFSCs, as many of these cells contain damaged DNA over time. Because hair growth is directly connected to skin, dermal pathologies may be inadvertently amplified.

Summary
Modern life for humans is inevitably stressful. But perhaps, one day, with a sprinkle of GAS6, patients may enjoy a full head of hair throughout the ups and downs of daily living. Until then, support of the HPA axis can be utilized.
Diurnal cortisol testing pre and post-treatment can help to track progress after implementing treatments know to combat the effects of chronic stress: Mindfulness, optimal sleep, nutrition (specifically foods and supplements containing vitamin B5, B6, vitamin C), daily movement, engagement in community, and adaptogenic botanicals such as ashwagandha and holy basil.
A handful of other therapies shown to improve stress-related hair loss include: Minoxidil, Eclipta alba (also known as bhringaraj or “false daisy”) orally and/or topically; topical Ganoderma (reishi mushroom); collagen; vitamins C, B and E; Polygonum multiflorum; Equisetum arvense extract (horsetail); Allium cepa L. (onion); scalp stimulation, and topical essential oils such as rosemary, lavender or peppermint.

References
Choi, S., Zhang, B., Ma, S. et al. Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence. Nature 592, 428–432 (2021). https://doi.org/10.1038/s41586-021-03417-2
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Glynis Ablon, ”A 3-Month, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Ability of an Extra-Strength Marine Protein Supplement to Promote Hair Growth and Decrease Shedding in Women with Self-Perceived Thinning Hair”, Dermatology Research and Practice, vol. 2015, Article ID 841570, 8 pages, 2015. https://doi.org/10.1155/2015/841570
Hajare, Rahul & A.G.Tated,. (2012). Onion Juice: An Effective Home Remedy for Combating Alopecia. International Journal of Pharmaceutical Research and Development. 4. 93-97
Liu, Yun-Zi et al. Inflammation: The Common Pathway of Stress-Related Diseases. Frontiers in human neuroscience vol. 11 316. 20 Jun. 2017, doi:10.3389/fnhum.2017.00316
Oh JY, Park MA, Kim YC. Peppermint Oil Promotes Hair Growth without Toxic Signs. Toxicol Res. 2014 Dec;30(4):297-304. doi: 10.5487/TR.2014.30.4.297. PMID: 25584150; PMCID: PMC4289931
Panahi Y, Taghizadeh M, Marzony ET, Sahebkar A. Rosemary oil vs minoxidil 2% for the treatment of androgenetic alopecia: a randomized comparative trial. Skinmed. 2015 Jan-Feb;13(1):15-21. PMID: 25842469
Pérez, P. et al. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J. 15, 2030–2032 (2001)
Shwartz Y., Gonzalez-Celeiro M., Chen C., Pasolli H., Sheu S., Fan S., et al. (2020). Cell types promoting goosebumps form a niche to regulate hair follicle stem cells. Cell 182 578–593.e19
Yi R. Relax to grow more hair. Nature. 2021 Apr;592(7854):356-357. doi: 10.1038/d41586-021-00656-1. PMID: 33790434
Zhang J, Chen R, Wen L, Fan Z, Guo Y, Hu Z, Miao Y. Recent Progress in the Understanding of the Effect of Sympathetic Nerves on Hair Follicle Growth. Front Cell Dev Biol. 2021 Aug 26;9:736738. doi: 10.3389/fcell.2021.736738. PMID: 34513851; PMCID: PMC8427189