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New treatment could reverse hair loss caused by an autoimmune skin disease

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A colorized microscopic view shows the cone-shaped microneedles laid on out a grid, in yellow, on a purple surface.

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Researchers at MIT, Brigham and Women’s Hospital, and Harvard Medical School have developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss and affects people of all ages, including children.

For most patients with this type of hair loss, there is no effective treatment. The team developed a microneedle patch that can be painlessly applied to the scalp and releases drugs that help to rebalance the immune response at the site, halting the autoimmune attack.

In a study of mice, the researchers found that this treatment allowed hair to regrow and dramatically reduced inflammation at the treatment site, while avoiding systemic immune effects elsewhere in the body. This strategy could also be adapted to treat other autoimmune skin diseases such as vitiligo, atopic dermatitis, and psoriasis, the researchers say.

“This innovative approach marks a paradigm shift. Rather than suppressing the immune system, we’re now focusing on regulating it precisely at the site of antigen encounter to generate immune tolerance,” says Natalie Artzi, a principal research scientist in MIT’s Institute for Medical Engineering and Science, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, and an associate faculty member at the Wyss Institute of Harvard University.

Artzi and Jamil R. Azzi, an associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital, are the senior authors of the new study , which appears in the journal Advanced Materials . Nour Younis, a Brigham and Women’s postdoc, and Nuria Puigmal, a Brigham and Women’s postdoc and former MIT research affiliate, are the lead authors of the paper.

The researchers are now working on launching a company to further develop the technology, led by Puigmal, who was recently awarded a Harvard Business School Blavatnik Fellowship.

Direct delivery

Alopecia areata, which affects more than 6 million Americans, occurs when the body’s own T cells attack hair follicles, leading the hair to fall out. The only treatment available to most patients — injections of immunosuppressant steroids into the scalp — is painful and patients often can’t tolerate it.

Some patients with alopecia areata and other autoimmune skin diseases can also be treated with immunosuppressant drugs that are given orally, but these drugs lead to widespread suppression of the immune system, which can have adverse side effects.

“This approach silences the entire immune system, offering relief from inflammation symptoms but leading to frequent recurrences. Moreover, it increases susceptibility to infections, cardiovascular diseases, and cancer,” Artzi says.

A few years ago, at a working group meeting in Washington, Artzi happened to be seated next to Azzi (the seating was alphabetical), an immunologist and transplant physican who was seeking new ways to deliver drugs directly to the skin to treat skin-related diseases.

Their conversation led to a new collaboration, and the two labs joined forces to work on a microneedle patch to deliver drugs to the skin. In 2021, they reported that such a patch can be used to prevent rejection following skin transplant. In the new study, they began applying this approach to autoimmune skin disorders.

“The skin is the only organ in our body that we can see and touch, and yet when it comes to drug delivery to the skin, we revert to systemic administration. We saw great potential in utilizing the microneedle patch to reprogram the immune system locally,” Azzi says.

The microneedle patches used in this study are made from hyaluronic acid crosslinked with polyethylene glycol (PEG), both of which are biocompatible and commonly used in medical applications. With this delivery method, drugs can pass through the tough outer layer of the epidermis, which can’t be penetrated by creams applied to the skin.

“This polymer formulation allows us to create highly durable needles capable of effectively penetrating the skin. Additionally, it gives us the flexibility to incorporate any desired drug,” Artzi says. For this study, the researchers loaded the patches with a combination of the cytokines IL-2 and CCL-22. Together, these immune molecules help to recruit regulatory T cells, which proliferate and help to tamp down inflammation. These cells also help the immune system learn to recognize that hair follicles are not foreign antigens, so that it will stop attacking them.

Hair regrowth

The researchers found that mice treated with this patch every other day for three weeks had many more regulatory T cells present at the site, along with a reduction in inflammation. Hair was able to regrow at those sites, and this growth was maintained for several weeks after the treatment ended. In these mice, there were no changes in the levels of regulatory T cells in the spleen or lymph nodes, suggesting that the treatment affected only the site where the patch was applied.

In another set of experiments, the researchers grafted human skin onto mice with a humanized immune system. In these mice, the microneedle treatment also induced proliferation of regulatory T cells and a reduction in inflammation.

The researchers designed the microneedle patches so that after releasing their drug payload, they can also collect samples that could be used to monitor the progress of the treatment. Hyaluronic acid causes the needles to swell about tenfold after entering the skin, which allows them to absorb interstitial fluid containing biomolecules and immune cells from the skin.

Following patch removal, researchers can analyze samples to measure levels of regulatory T cells and inflammation markers. This could prove valuable for monitoring future patients who may undergo this treatment.

The researchers now plan to further develop this approach for treating alopecia, and to expand into other autoimmune skin diseases.

The research was funded by the Ignite Fund and Shark Tank Fund awards from the Department of Medicine at Brigham and Women’s Hospital.

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MIT researchers have developed microneedle patches that are capable of restoring hair growth in alopecia areata patients, reports Ernie Mundell for HealthDay . The team’s approach includes a, “patch containing myriad microneedles that is applied to the scalp,” writes Mundell. “It releases drugs to reset the immune system so it stops attacking follicles.” 

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Can we finally reverse balding with these new experimental treatments?

Male pattern baldness could soon be a thing of the past, with new hair loss treatments beginning to show tantalising results

By Joshua Howgego

26 September 2023

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I’LL level with you: a part of me didn’t want to write this story. When I first realised that I was losing my hair, I found it important to mention it often in conversation. I was so embarrassed about it that I was trying some sort of reverse psychology. But I soon realised that if there was one thing less attractive than my balding head, it was how much I was talking about it. I am joking, of course: there is nothing wrong with being bald. Still, for me, the prospect is terrifying. My hair is a big part of my identity, so to lose it is crushing.

I’m not alone. By the age of 50, between 30 and 50 per cent of men have begun to experience male pattern baldness . Despite there being plenty of handsome hairless men out there – I’m looking at you, Thierry Henry – studies suggest that people tend to perceive bald men as less attractive and less friendly . And we don’t need science to tell us that this can be deeply upsetting.

So although I have dialled down the discussion of my growing bald patch, I have been quietly digging into the science of hair loss – and what I found is worth shouting about. It is common knowledge that some treatments can slow hair loss. What is less known is that as we are coming to understand the reasons why male pattern baldness causes people to lose their hair, we are finding new strategies to restore it. There may soon be a way to not just slow balding, but reverse it.

In a field…

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Cure for hair loss? Breakthrough study may pave the way for new treatment

A single molecule may hold the key to battling male- and female-pattern hair loss, recent research suggests.

In mouse experiments, scientists showed that the molecule, dubbed SCUBE3, could spark hair growth in dormant mouse follicles, and even in human ones that had been grafted onto mice. The research was described in a study published in Developmental Cell.

Hair follicles in people who are bald still have the machinery to sprout new strands, study co-author Maksim Plikus, Ph.D., professor of developmental and cell biology at the University of California, Irvine, told TODAY.

All follicles have stem cells at their base that work together to produce strands of hair, Plikus said. In people who are bald or have thinning hair , some of those stem cells don’t seem to be working, he added.

“When it comes to growing hairs, follicle stem cells need to become activated,” Plikus said. “Once activated, they divide into daughter cells that mature and come together to form a strand.”

“Most people when they lose their hair wonder if the follicles are gone,” Plikus said. “They are there, but they are dormant. The reason they are inactive is that they are not hearing signaling molecules.”

That's where SCUBE3 comes in: The molecule carries the message that tells the follicles to activate. Plikus and his colleagues showed in their experiments that when mice were given microinjections of SCUBE3, their hair grew in thick . Even human follicles that were transplanted into the mouse skin turned on when exposed to SCUBE3. The findings suggest that, in people with thinning hair, there isn’t enough SCUBE3 present.

Plikus compares a head covered with dormant follicles to a huge factory filled with 3D printers that are idling and ready to print, but are waiting for someone to push their start buttons.

It’s likely, Plikus said, that it would take very small amounts of SCUBE3 to activate dormant human hair follicles. Moreover, he suspects that treatments would need to be given only two or three times a year.

While the research on SCUBE3 is promising, getting from mouse experiments to a human treatment for baldness isn’t guaranteed, and even if SCUBE3 turns out to grow hair in people, it takes a long time to take a treatment through all of the clinical trials needed to get Food and Drug Administration approval, Plikus said.

“Right now, we are very excited about it,” Dr. Brian Abittan, director of skin and hair rejuvenation at the Mount Sinai Health System, told TODAY. “With this SCUBE3 molecule, we’re hoping to have a more precise understanding of the signaling that controls hair growth. It would be great to have another pathway to treatments.”

But, Abittan said, this is still in the preclinical stage of development.

There is still a long way to go before this could become a baldness treatment, Rui Yi, Ph.D., professor of pathology and dermatology at Northwestern University's Feinberg School of Medicine, told TODAY. “There is a big difference between a human and a mouse. Mice have short hair that grows just long enough to cover their bodies.”

Before doing a clinical trial, the researchers probably will need to do more safety testing, Yi said.

latest research on hair growth

Linda Carroll is a Peabody Award-winning journalist who is a contributing health and medicine writer for NBC News and TODAY. She is co-author of three books: “The Concussion Crisis: Anatomy of a Silent Epidemic”, “Out of the Clouds: The Unlikely Horseman and the Unwanted Colt Who Conquered the Sport of Kings” and “Duel for the Crown: Affirmed, Alydar, and Racing’s Greatest Rivalry”.  

UC Irvine-led researchers reveal new molecular mechanism for stimulating hair growth

Findings may offer road map for next generation of therapies for androgenetic alopecia

Maksim Plikus

Irvine, Calif., June 21, 2023 — The process by which aged, or senescent, pigment-making cells in the skin cause significant growth of hair inside skin moles, called nevi, has been identified by a research team led by the University of California, Irvine. The discovery may offer a road map for an entirely new generation of molecular therapies for androgenetic alopecia, a common form of hair loss in both women and men.

The study, published today in the journal Nature , describes the essential role that the osteopontin and CD44 molecules play in activating hair growth inside hairy skin nevi. These skin nevi accumulate particularly large numbers of senescent pigment cells and yet display very robust hair growth.

“We found that senescent pigment cells produce large quantities of a specific signaling molecule called osteopontin, which causes normally dormant and diminutive hair follicles to activate their stem cells for robust growth of long and thick hairs,” said lead corresponding author Maksim Plikus, UCI professor of developmental and cell biology. “Senescent cells are typically viewed as detrimental to regeneration and are thought to drive the aging process as they accumulate in tissues throughout the body, but our research clearly shows that cellular senescence has a positive side to it.”

The growth of hair follicles is well regulated by stem cell activation; these cells divide, enabling follicles to produce new hair in a cyclical manner. After each bout of hair growth, there’s a period of dormancy, during which the follicle’s stem cells remain inactive until the next cycle begins.

The study involved mouse models with pigmented skin spots that had hyperactivated hair stem cells and displayed accelerated hair growth, strongly resembling the clinical observations documented in human hairy skin nevi. Further detailed analysis of senescent pigment cells and the nearby hair stem cells revealed that the former produced high levels of a signaling molecule called osteopontin, for which hair stem cells had a matching receptor molecule called CD44. Upon molecular interaction between osteopontin and CD44, hair stem cells became activated, resulting in robust hair growth.

To confirm the leading role of osteopontin and CD44 in the process, mouse models lacking either one of these genes were studied; they exhibited significantly slower hair growth. The effect of osteopontin on hair growth has also been confirmed via hairy skin nevi samples collected from humans.

“Our findings provide qualitatively new insights into the relationship between senescent cells and tissue’s own stem cells and reveal positive effects of senescent cells on hair follicle stem cells,” said first and co-corresponding author Xiaojie Wang, UCI associate specialist in developmental and cell biology. “As we learn more, that information can potentially be harnessed to develop new therapies that target properties of senescent cells and treat a wide range of regenerative disorders, including common hair loss.”

The team included healthcare professionals and academics from the U.S., China, France, Germany, Korea, Japan and Taiwan.

“In addition to osteopontin and CD44, we’re looking deeper into other molecules present in hairy skin nevi and their ability to induce hair growth. It’s likely that our continued research will identify additional potent activators,” Plikus said.

This work was supported in part by LEO Foundation grants LF-AW-RAM-19-400008 and LF-OC-20-000611; Chan Zuckerberg Initiative grant AN-0000000062; W.M. Keck Foundation grant WMKF-5634988; National Science Foundation grants DMS1951144 and DMS1763272; and National Institutes of Health grants U01-AR073159, R01-AR079470, R01-AR079150, R21-AR078939 and P30-AR075047. Additional backing came from Simons Foundation grant 594598 and California Institute for Regenerative Medicine Shared Research Laboratory Grant CL1-00520-1.2.

About UCI’s Brilliant Future campaign:  Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Biological Sciences plays a vital role in the success of the campaign. Learn more by visiting  https://brilliantfuture.uci.edu/school-of-biological-sciences .

About the University of California, Irvine:  Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by  U.S. News & World Report . The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit  www.uci.edu .

Media access: Radio programs/stations may, for a fee, use an on-campus ISDN line to interview UCI faculty and experts, subject to availability and university approval. For more UCI news, visit news.uci.edu . Additional resources for journalists may be found at communications.uci.edu/for-journalists .

Advances in hair growth

Affiliations.

  • 1 National and International Skin Registry Solutions (NISR), Charles Institute of Dermatology, University College Dublin, Dublin, Ireland.
  • 2 Hair Restoration Blackrock; Dublin, Ireland.
  • 3 Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland.
  • 4 St Helens & Knowsley NHS Trust, Prescot, UK.
  • 5 Manchester University, Faculty of Biology, Medicine and Health, Oxford Road, Manchester, UK.
  • 6 St. James's Hospital, Dublin, Ireland.
  • 7 Netcare Greenacres Hospital, Port Elizabeth, South Africa.
  • 8 Sinclair Dermatology, Melbourne, Australia.
  • PMID: 35156098
  • PMCID: PMC8808739
  • DOI: 10.12703/r/11-1

Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relating to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence that has advanced our understanding of hair growth in both of these areas to provide a context for outlining current and emerging therapies. These include finasteride, minoxidil, topical prostaglandins, natural supplements, microneedling, low-level laser light, platelet-rich plasma, fractional lasers, cellular therapy, Wnt activators and SFRP1 antagonism.

Keywords: Alopecia; androgenetic alopecia; antiandrogens; exosomes; female pattern hair loss; fractional lasers; hair cycling; hair growth; low-level laser light; male pattern hair loss; micro-needling; minoxidil; platelet rich plasma; prostaglandins.

Copyright: © 2021 Wall D et al.

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  • Review Article
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  • Published: 17 February 2021

Functional hair follicle regeneration: an updated review

  • Shuaifei Ji 1 ,
  • Ziying Zhu 1 ,
  • Xiaoyan Sun 1 &
  • Xiaobing Fu 1  

Signal Transduction and Targeted Therapy volume  6 , Article number:  66 ( 2021 ) Cite this article

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  • Regeneration
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The hair follicle (HF) is a highly conserved sensory organ associated with the immune response against pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing. Although recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration, the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical applications. Given that hair formation and cycling rely on tightly coordinated epithelial–mesenchymal interactions, we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.

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latest research on hair growth

Expansion and characterization of epithelial stem cells with potential for cyclical hair regeneration

latest research on hair growth

Local and systemic mechanisms that control the hair follicle stem cell niche

latest research on hair growth

Deciphering the molecular mechanisms of stem cell dynamics in hair follicle regeneration

Hair follicles (HFs) are a major skin appendage originating from the ectoderm. As a stem cell repository and a hair shaft factory, the HF contributes to remodelling its cutaneous microenvironment, including skin innervation and vasculature. 1 The HF participates in multiple functions, mainly physical protection, thermal insulation, camouflage, sebaceous dispersion, sensory perception and social interactions. In addition, hair in human society greatly affects the quality of life, attractiveness and self-esteem. However, destructive inflammation with various aetiologies and the subsequent replacement of fibres can involve the permanent loss of HFs, which impairs inherent skin function and, especially, psychological well-being. Thus, HF regeneration is in ever-increasing demand and has promising market prospects. HF morphogenesis and regeneration were shown to be dependent on the intensive cooperation of epithelial (epidermal stem cell [Epi-SCs]) and hair-inducive mesenchymal (dermal papilla [DP]) components, also called epithelial–mesenchymal interaction (EMI). EMI is a prerequisite for functional HF formation, regeneration and cycling, mainly through paracrine mechanisms, 2 and has become the theoretical basis of tissue engineering for HF regeneration. Current strategies to regenerate HF in vivo are aimed at simulating EMI, mostly adopting the principle of combining epithelial (Epi-SC and keratinocyte) and mesenchymal (DP cell [DPC] and skin-derived precursors [SKPs]) components. HFs are also a dynamic mini-organ, and their most notable feature is hair cycling (Fig. 1a ), from periods of organ regeneration and rapid growth (anagen) to apoptosis-driven regression (catagen); then, the HF moves back into anagen via an interspersed period of relative quiescence (telogen). 1 The interaction between HF stem cells (HFSCs) and DPCs plays a significant role in the regulation of hair cycling. 3 , 4 The activation, stability and sustainability of hair cycling are considered to be a key factor in achieving the longevity of HF function, but HF loss is often accompanied by the termination and elimination of hair cycling. Thus, the achievement of hair cycling regeneration is important for functional HF regeneration. Although hair transplantation has been widely applied, transplanted hair is not maintained in the long term. Moreover, clinical drugs still fail to meet the patents’ needs and even have drastic side effects. 5 Therefore, there is a need to explore alternative therapeutic solutions capable of generating functional HFs. Current techniques could make it possible to obtain potential cells in vitro (Fig. 1b ), such as DPCs (Fig. 1c ), SKPs, keratinocytes and other stem cells (Fig. 2 ), providing us with a series of cell sources. In addition, the optimization of the culture system also contributes to preserving the HF-inducive ability of potential cells. Based on these findings, we are able to regenerate functional HFs by the transplantation of potential cell mixtures, HF organoid construction in vitro, reprogramming induction and the establishment of a drug delivery system (Fig. 3 ). Here, we will review the potential cell sources and tissue engineering techniques that contribute to HF regeneration. In addition, the limitations and future of functional HF regeneration are summarized.

figure 1

The process of hair cycling and DPCs in HF regeneration. a Mature and actively growing HFs anchored in the subcutis periodically regenerate by spontaneously undergoing anagen (repetitive cycles of growth), catagen (apoptosis-driven regression) and telogen (relative quiescence), which is termed hair cycling and is a typical characteristic of functional HFs. b Skeleton diagram of potential cells that contribute to regenerating HFs. c iPSCs share similar characteristics with embryonic stem cells in terms of morphology, self-renewal and differentiation capacity, and they can be induced into other potential cells in regenerative medicine. The transformation of fibroblasts into DPCs via lineage reprogramming. Optimization of the in vitro system to preserve the HF-inducive potential and the transplantation of cell-based biomaterials or HF organoids in vivo to regenerate HFs

figure 2

Keratinocytes and SKPs in HF regeneration. a iPSCs were reprogrammed into keratinocytes, and biomaterials containing a mixture of fibroblasts and keratinocytes were embedded for de novo HF. b Fibroblasts were chemically induced into SKPs. A mixture of SKPs and epidermal stem cells or bioactive peptides was embedded in the hydrogel to regenerate HFs three-dimensionally

figure 3

Strategies to achieve functional HF regeneration

Potential cell sources and mechanism for HF regeneration

DPCs, a kind of differentiated dermal cell at the base of HFs, 6 originate from blimp1+ fibroblasts (dermal stem cells [DSCs]) during embryonic development. 7 , 8 DPCs have the ability to stimulate epithelial HFSCs and are considered to be a master regulator of HF cycling. Past studies reported that DPCs isolated from rat and guinea pig vibrissae, as well as humans, could also induce HF formation when implanted into recipient non-hairy skin, 9 , 10 which indicates that DPCs could reprogramme non-hairy epidermis to a follicular fate. Subsequently, DPCs, either fresh or after tissue culture expansion, could also reproduce new HFs if placed in proximity to the epithelium. 11 , 12 Based on their strong HF-inducive ability, many attempts to coculture DPCs with other cell types to regenerate HFs have been studied, such as the two-dimensional juxtaposition of other epithelia, 13 cultured epithelial cells, 14 , 15 keratinocytes, 16 , 17 corneal epithelium 18 and amnion epithelium. 19 DPCs can secrete various factors to initiate HF formation by activating skin epithelial stem cells (Epi-SCs), so the mixture of DPCs and Epi-SCs also promotes functional HF regeneration in vivo. 20

DPCs with specific marker molecules possess HF-inducive capacity, including CD133 + DPCs and Versican + DPCs. CD133 + DPCs have been shown to be a specific subpopulation of cells in DPCs, and they can produce Wnt ligands and mediate signalling crosstalk between the mesenchyme and the epithelial compartment, further promoting adult HF growth and regeneration. 21 In addition, Versican + DPCs exhibit the typical characteristics of aggregation growth, 22 on which HF formation is highly dependent. 23 In addition, many functional molecules are involved in the positive regulation of DPC HF-inducive capacity (Fig. 4 ), such as endothelin-1 and stem cell growth factor , 24 insulin-like growth factor-1 (IGF-1) 25 and histidine decarboxylase , 26 but matricellular protein connective tissue growth factor (CCN2) negatively regulates HF regeneration, physiologically curbing HF formation by the destabilization of β-catenin . 27 In wound healing, hedgehog gene activation could shift the dermal fibroblast fate towards DPCs and result in extensive HF neogenesis. 28 Hoxc genes are able to reprogramme DPCs, and a single Hoxc gene is sufficient to activate dormant DP niches and promote regional HF regeneration through canonical Wnt signalling. 29 Monoterpenoid loliolide regulates the HF inductivity of human DPCs by activating the AKT/β-catenin signalling pathway. 30 Although DPCs possess the potential to regenerate HFs, freshly isolated human DPCs are not efficient in regenerating new HFs when they are directly transplanted. 31 To restore their intrinsic properties, three-dimensional (3D) spheres offer a more physiologically relevant system where cell–cell communication as well as microenvironments have been studied. It has been reported that sphere formation increases the ability of cultured human DPCs to induce HF from mouse epidermal cells, 32 in which glucose metabolism 33 and epigenetics 34 may be important regulators. The natural vitamin E form tocotrienol acts upstream of DP formation to induce HF anagen, dependent on the loss of E-cadherin and activation of β-catenin. 35 Pretreatment with 1α,25-dihydroxyvitamin D3 (VitD3) could significantly improve DPC functionality and hair folliculogenesis, which is mediated by the activation of Wnt10b, alkaline phosphatase (ALP) and transforming growth factor β2 (TGF-β2). 36 Consistent with VitD3, platelet-rich plasma has been shown to function in HF regeneration by enhancing DPC proliferation, 37 which may result from the downregulation of MYC, CCAAT/enhancer-binding protein beta and E2F transcription factor-1 gene. 38 Icariin promotes mouse HF growth by increasing IGF-1 secreted by DPCs. 39 Utilization keratinocyte-conditioned medium, 40 coculture with keratinocytes 40 , 41 or the addition of BMP6 42 and basic fibroblast growth factor (FGF) 43 to DPC expansion cultures could preserve their HF-inducive capacity. JAK inhibitor regulates the activation of key HF populations, such as the hair germ, and improves the inductive potential of DPCs by controlling a molecular signature enriched in intact, fully inducive DPs. 44

figure 4

The regulatory factors of DPC HF-inducive capacity. Glucose metabolism and LncRNA-XIST/miR-424 axis in the regulation of HF-inducive potential of DP spheres

Skin-derived precursors

DSCs are stem cells located in the dermis of the skin. Based on distinct phenotypic properties and different cultural environments, DSCs can be divided into dermal fibroblasts and SKPs. 7 , 45 For instance, DPCs are differentiated dermal cells originating from blimp1 + dermal fibroblasts, 7 while SKPs are derived from Sox2 + follicle-associated dermal precursors. 46 SKPs are defined as DSCs that reside in the adult HF mesenchyme and can be isolated and expanded in vitro as self-renewing colonies. SKPs have the capacity to differentiate in vitro and in vivo into multiple lineages of different progeny. 47 Of note is that SKPs could regenerate the dermal sheath and repopulate DPCs in each growth cycle 48 to serially reconstitute HF when subcutaneously engrafted. 46 There are also various molecules affecting the inductive potential of SKPs. Trichostatin A, a potent and specific inhibitor of a histone deacetylase, could restore the HF-inducive capacity of SKPs by markedly alleviating culture expansion-induced SKP senescence, increasing the expression and activity of ALP and elevating the acetylation level of histone H3. 49 Platelet-derived growth factor (PDGF) could enhance SKP proliferation, increase SKP progeny and improve their HF-inducive capacity, but PDGF deficiency results in a progressive depletion of the stem cell pool and their progeny. 50 Many tentative methods to isolate and cultivate SKPs have also been explored, 51 , 52 particularly in computer-controlled stirred suspension bioreactors, which lead to a greater expansion of viable SKPs. 53 This technique allows a large number of SKPs that share a similar expression profile to that in static culture (fivefold greater than in static culture), and both static and bioreactor condition-derived SKPs are able to induce de novo HFs and repopulate their cellular niches. 53

Epidermis-derived cells

HFSCs are heterogeneous Epi-SCs compartmentalized along the longitudinal axis of HFs. They are divided into quiescent and primed HFSCs. For instance, relatively quiescent HFSCs in the follicular bulge region can serve as a reservoir for transient amplifying cells that are able to produce various cell types during HF regeneration. 54 Primed HFSCs have faster activation dynamics in the secondary hair germ of telogen HF. 55 The activation of primed HFSCs could trigger the subsequent activation of quiescent HFSCs, and the coordination of these two populations could fuel HF regeneration from telogen to anagen. 56 , 57 HFSCs express a panel of transcription factors, including Sox9, Tcf3, Lhx2 and Nfatc1. 57 , 58 , 59 HFSCs derived from a single rat vibrissa via organ culture could reconstitute HFs in vivo, 60 and even aged HFSCs still have the potential to regenerate HFs. 61 HFSCs could also differentiate into epidermal and sebaceous gland lineages, participating in the process of skin wound healing, and thus were considered ideal candidates for cutaneous repair and regeneration. Recent studies have reported that basal keratinocytes also have the capacity to facilitate HF regeneration under induction. Transgenic expression of the hairless gene ( HR ) in progenitor keratinocytes could rescue HF regeneration in Hr(−/−) mice, in which the new HFs resemble wild-type follicles and express markers of early anagen. 62 This process may be linked to the regulation of the precise timing of WNT signalling to HR. 62 , 63 Tuberous sclerosis complex 2 (TSC2)-null fibroblast-like cells grown from human TSC skin hamartomas could also induce neonatal foreskin keratinocytes to form HFs, complete with sebaceous glands, hair shafts, inner and outer root sheath (ORS) cells and the anagen-specific expression of versican, in which the TSC1/TSC2/mTORC1 pathway may play a significant role. 64

Reprogrammed cells

The differentiation of stem cells into adult cells in response to defined factors is an important application of cell reprogramming. Induced pluripotent stem cells (iPSCs) have similar characteristics to embryonic stem cells in terms of morphology, self-renewal and differentiation capacity. They are not only free from ethical issues but also able to be propagated as autologous cells, which can avoid the complication of immune rejection. Thus, reprogramming of iPSCs into potential cells could be an approach to providing cell sources for HF regeneration. Under retinoic acid (RA), an iPSC-derived LNGFR + Thy1 + subpopulation with high proliferation could be induced into DPCs in the DP medium. 65 The mixture of iPSC ectodermal precursor cells in keratinocyte culture medium with RA and bone morphogenetic protein (BMP) could also transform into new DPCs. 66 Intriguingly, iPSCs could also be generated from human DPCs upon lentiviral transfection with Oct4, Sox2, Klf4 and c-Myc. 67 In addition, iPSCs, post-culture on Matrigel, could differentiate into keratinocytes when treated with keratinocyte serum-free media supplemented with all- trans RA and BMP4. 68 Human hair follicular keratinocytes could also be reprogrammed into iPSCs, and keratinocyte-derived iPSCs are further capable of differentiating into keratinocytes, 69 which suggests a novel way to provide a source of keratinocytes. Lineage reprogramming is direct cellular reprogramming, which means that targeted cells could bypass the stem cell stage and convert directly to potential cells. Unlike traditional concepts regarding the epigenetic stability of differentiated cells, direct lineage reprogramming can transform one specialized cell type into another using defined factors, which is a more efficient and promising approach for producing functional cells. Treatment with the combination of FGF2, PDGF and 6-bromoindirubin-3′-oxime (BIO) could chemically transform human dermal fibroblasts into DPCs. 70 SKPs can be produced from healthy adult fibroblasts via lineage reprogramming, and their cryopreservation can largely preserve their properties and produce more significant yields. 71 Another way to rapidly expand SKPs via lineage reprogramming is to expose pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKPs. 72 Acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency.

With progress in HF developmental biology and cellular reprogramming techniques, several cells with the potential for HF regeneration have been identified. These results have greatly expanded the seed cell bank for HF regeneration and solved the problem of the lack of a cell source. However, the problems these cell sources have in common are that their potential to regenerate HF fails to be maintained during long-term culture in vitro. In addition, HFSCs are few in number and extremely difficult to obtain, and SKPs in vitro senesce soon when isolated from their physiological environments. 73 In addition, the efficiency of reprogramming by gene editing is still low. The optimization of the culture system in vitro and the improvement of reprogramming efficiency are challenges for HF regeneration. Therefore, we believe that the construction of 3D culture systems that simulate the in vivo environment may provide an alternative approach, similar to hydrogel scaffold-based cell culture, which contributes to maintaining cell proliferation and growth as well as the potential to regenerate HFs. In addition, chemical reprogramming, a new reprogramming technology, is characterized by high security and efficiency. 74 To improve the reprogramming efficiency, the replacement of chemical reprogramming with gene editing has broad prospects in HF regeneration.

Mechanisms for the restoration of HF-inducive capacity

After birth, mature and actively growing HFs eventually become anchored in the subcutis and then undergo hair cycling, periodically and spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Therefore, the HF is regarded as a dynamic mini-organ. The activation and maintenance of hair cycling is a prerequisite for the functional regeneration of HFs. HFSCs play an indispensable role in maintaining hair cycling. The HFSC population remains largely quiescent during hair growth, but a subpopulation actively proliferates and promotes the production of the new hair shaft under the control of Axin2 expression. 75 At the onset of anagen following stimulation by growth-inducing signals from the DP, primed HFSCs also contribute to new hair shaft production. 76 Under induction by such signalling, primed HFSCs undergo rapid proliferation to fuel the initial stage of hair growth, and then, the quiescent HFSCs undergo a second round of activation that replenishes cells lost at the onset of anagen, finally supporting prolonged growth of the hair shaft. 56 At the beginning of anagen, activated HFSCs migrate from the bulge to the matrix area and become transit-amplifying cells that proliferate and differentiate to form the new hair shaft. 77 Therefore, the coordinated activation of primed HFSCs and quiescent HFSCs is instrumental for the maintenance of hair cycling. The mechanism underlying HFSC homeostasis and hair cycling regulation is a complex molecular controlling process (Table 1 ) that is highly dependent on hormonal action. 78 WNT/β-catenin and BMP signalling are considered to be the core pathways in the regulation of hair cycling. 79

The dynamic characteristics of HFs enable their sustainable and periodic regeneration. We think that the activation and maintenance of hair cycling are indispensable for achieving functional HF regeneration. Past studies have not only led to a better understanding of the molecular mechanisms of hair cycling, which makes it more possible to find the key molecules therein, but also have revealed the complexity of HF dynamic characteristics. Therefore, it is still difficult to discover the key molecular event in hair cycling.

In vivo strategies for functional regeneration of HFs

Cell transplantation and hf regeneration.

Cell-based transplantation without biomaterials is a minimally invasive approach to in vivo HF regeneration. Current cell transplantation mainly involves the transplantation of stem cells or a mixture of epidermal and dermal components. The injection of a mixture containing Epi-SCs and DPCs into nude mice could induce new HFs with the correct histological structures and form a multilayered stratified epidermis containing HF-like structures. 20 Although the new HFs are relatively small, this result proves again that the rearrangement of the EMI and the niches of the potential cells are essential and necessary for HF construction. A mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, and a bilayer structure resembling the epidermis and the dermis formed on the fifth day, followed by de novo HF. 80 In the regeneration process, the SKPs formed DPCs in neogenic HFs and abundant dermal cells in the dermis, and the Epi-SCs formed the epidermis and trunk of the HF. More importantly, this experiment also demonstrates that the PI3K-Akt signalling pathway plays a crucial role in the interactions between Epi-SCs and SKPs and de novo HF regeneration, which may suggest potential therapeutic applications in enhancing hair regeneration. 80 During the hair growth cycle, HFSCs periodically switch between the active and inactive stages to maintain stem cell populations and generate new HFs, while this potential is impaired in aged HFSCs. 81 However, in transplantation assays in vivo, aged HFSCs could still regenerate HFs when supported with the young dermis, while young HFSCs failed to regenerate HFs when combined with the aged dermis, which shows that the ageing skin microenvironment dictates stem cell behaviour and illustrates the dominant role of the niche microenvironment. 61 This research discovered that the HF regeneration potential of aged HFSCs can be rejuvenated by neonatal dermis during in vivo transplantation, providing promising new avenues for regenerative and geriatric medicine. In recent years, for the fully functional regeneration of ectodermal organs, a bioengineered organ germ has been developed by reproducing the embryonic processes of organogenesis, including bioengineered HFs. 82 Bioengineered HF germ could be reconstituted with embryonic skin-derived epithelial and mesenchymal cells and was able to develop histologically correct HFs when ectopically transplanted. The bioengineered HFs not only properly connected to the host skin epithelium by intracutaneous transplantation and reproduced the stem cell niche and hair cycling but also autonomously connected with nerves and the arrector pili muscle at the permanent region and exhibited piloerection ability. 83 Another way to construct bioengineered HF is with pelage and vibrissae reconstituted with embryonic skin-derived cells and adult vibrissa stem cells. After intracutaneous transplantation, this bioengineered HF germ not only develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres but also shows restored hair cycling and piloerection through the rearrangement of follicular stem cells and their niches, with fully functional hair organ regeneration. 84 It is worth mentioning that the in vivo transplantation of bioengineered HFs also achieves the partial restoration of hair cycling, which is a great step forward for functional HF regeneration.

Cellular reprogramming and HF regeneration

Cellular reprogramming is not only a tool for tissue engineering to enrich potential cell sources for the regeneration of HF but also a participant in physiological de novo HF induction. Secreted proteins (apolipoprotein-A1, galectin-1 and lumican) from embryonic skin conferred upon non-hair fibroblasts the competency to regenerate HF via the activation of IGF and WNT signalling, thereby endowing non-HF skin with the ability to reproduce HFs, which suggests the involvement of cellular reprogramming. 85 Because DPCs and dermal fibroblasts originate from common fibroblast progenitors in the developing embryonic mouse skin and have highly correlated gene expression profiles (96%), 86 adult dermal fibroblasts can be reprogrammed into a neonatal state, with the capacity of inducing ectopic HF formation similar to DPCs through the epidermal activation of β-catenin. 87 Furthermore, treatment with the combination of FGF2, PDGF and BIO in adherent culture followed by suspension culture could induce the generation of DP-like cells from foetus- or adult foreskin-derived fibroblasts. The integration of foetal/adult DP-like cells can be recruited to replenish DP of de novo generated HFs, and the regenerated HF structures were reconstructed in 65% nude mice implanted with foetal DP-like cells and in 70% nude mice with adult DP-like cells. 70 Finally, the combination of MITF, SOX10 and PAX3 could directly convert mouse and human fibroblasts into induced melanocytes, which have the ability to generate pigmented epidermis and HF in vivo when properly integrated into the dermal–epidermal junction. 88 Healed wounds with the loss of HF are usually filled with a large number of fibroblasts, so the exploration of fibroblast-based reprogramming holds great promise for HF regeneration in situ.

Cell-laden biomaterials for the establishment of HF equivalents

Biomaterials are implantable, inactive materials that can replace or repair damaged tissue with high biocompatibility. Biomaterials can create a 3D environment for cell-to-cell interactions, simulating the function of cell niches to a certain extent, and they have been widely used in wound repair and tissue regeneration. 89 The combination of potential cells with biomaterials, such as hydrogels, scaffolds and other self-assembled materials, could contribute to HF regeneration (Figs. 1c and 2 ). For in vivo HF regeneration, a 3D hydrogel with a mixture of epidermal keratinocytes, dermal cells and β-catenin-expressing CD133 + DPCs not only performed better than CD133 + DPCs alone (average of 28 ± 6 HF per field vs. 13 ± 6 HF per field) but also exhibited a more advanced hair cycling stage; 90 an average of 71% of the HFs reached anagen stage III, and 19% reached anagen stage IV in reconstituted skin containing β-catenin-expressing CD133 + DPCs, while 67.5% of the HFs in the control remained in anagen I and II, and only 27.5% reached anagen III. 90 The stable expression of β-catenin could promote the clonal growth of CD133 + DPCs in vitro in 3D hydrogel culture. An alternative strategy to reproduce EMI is to use a collagen-chitosan scaffold (CCS)-based 3D system containing dissociated epithelial cells and DPCs followed by treatment of the CCS with Wnt-CM from Wnt1a + bone marrow mesenchymal stem cells. The results suggested that the cell mixture was able to induce hair regeneration in nude mice, and Wnt-CM can maintain the hair induction ability of DPCs in expansion cultures, which may be associated with the activation of the Wnt/β-catenin signalling pathway. 91 Therefore, how to enhance the HF induction efficiency of cultured human DPCs is a priority in bioengineering for clinical HF regeneration. It has been reported that DPCs retain HF inductivity best when cultured and transplanted as multicellular aggregates, and DP spheroids could form a structure similar to the natural intercellular organization in vivo. 92 Therefore, another strategy is to achieve the scalable fabrication of controllable DP spheroids to regenerate HFs. Scalable production of controllable DP spheroids on polyvinyl alcohol surfaces has high viability and preserves DP characteristics, and at DPC numbers of 5 × 10 3 to 30 × 10 3 cells each, both human and rat DP spheroids are able to induce HF neogenesis. Larger DP spheroids exhibit higher HF inductivity. The researchers developed a method that can be automated for mass production of DP spheroids with controllable size and cell number in a wide range, 93 although the average diameter of regenerated hair fibre did not significantly change with increasing size of the transplanted DP spheroids. Likewise, the hanging-drop approach could also lead to a controllable 3D spheroid model for the scalable fabrication of inductive DP microtissues. That technique is based on surface tension and the interaction between surface tension and a gravity field that causes the convergence of liquid drops. With the converged drops, DP spheroids could endow high-passaged DP microtissues with many similarities to primary DP. Subcutaneous implantation of these microtissues mixed with new-born mouse epidermal cells has achieved reproducible HF induction in the hypodermis of nude mice, and a large amount of extracellular matrix (ECM) components is found in the intercellular space within the DP microtissue, similar to an anagen DP. 94 These models provide the potential to elucidate the native biology of human DP and show promise for the controllable and scalable production of inducive DPCs for future follicle regeneration. Exosomes derived from DP spheroids (3D DP-Exos) are also able to promote the proliferation of DPCs and ORS cells and accelerate anagen onset to influence hair cycling. Local injections of 3D DP-Exos (exosomes) could induce anagen from telogen and prolong anagen in mice. Moreover, DPC spheres treated with Exos could augment HF neogenesis when implanted with mouse epidermal cells, 95 which may be associated with high levels of miR-218-5p in Exos. 96 Cell surface engineering technology also advances HF regeneration by accurate micro/nanoscale control in cell-biomaterial ensembles and DP spheroid formation. Owing to the security and tuneable thickness at the nanoscale, the nanogel could encapsulate a single cell by layer-by-layer (LbL) self-assembly and further form DPC spheroids by physical cross-linking on nanogel-coated cells. LbL-DPC aggregation is akin to that of primary DPCs and has the capacity to restore HF induction potential in vitro and regenerate HFs in vivo. 97 Other biomaterials that contribute to the restoration of HF-inducive ability include human placenta ECM hydrogel, 98 synthesized ECM 99 and a chitosan/polyvinyl alcohol nanofibre sponge with an open-cell cellular structure, 100 which expands the biomaterial libraries for the optimization of the culture environment in vitro to restore the ability of DPCs to regenerate HFs. 3D printing technology for HF regeneration by recapitulating the physiological 3D organization of cells in the HF microenvironment is an innovative biomimetic approach. 101 It permits the controllable self-aggregating spheroid formation of DPCs in a physiologically relevant ECM, the initiation of EMI and further HF formation in human skin constructs. Remarkably, the vascularization of HF-bearing human skin constructs increases graft survival and enables efficient human hair growth in mice. 101 This method represents a novel bioengineering strategy for the feasible generation of hair-bearing human skin constructs entirely ex vivo from cultured human cells, and adaptation of this new technology by hair researchers, hair restoration surgeons and the pharmaceutical industries will have overwhelming implications in the maintenance and regeneration of HFs.

Similar to DPCs, long-term culture could also impair the HF-inducive capacity of SKPs. It is likely that SKPs rely on special environments for their self-renewal and stable gene expression. In tissue engineering, scaffolds are created to mimic environments for stem cells to survive, differentiate and form functional tissue structures. In this regard, scaffolds such as hydrogels and matrix could be candidates to support stem cells for organogenesis and regenerate HFs. 102 , 103 Self-assembling peptide nanofibres are made of natural amino acids and form hydrogels that surround cells in a manner similar to the ECM. RADA16 (Ac-(RADA)4-CONH2) is a representative example of such peptides that has been shown to promote nerve regeneration and wound healing. 104 , 105 A PRG (PRGDSGYRGDS) solution functionalized by mixing with RADA16 promoted the proliferation and migration of periodontal ligament fibroblasts. 106 The self-assembling peptide hydrogels formed by RADA16 and PRG (RADA-PRG) could facilitate the attachment, proliferation and survival of SKPs, ultimately supporting HF neogenesis in vivo. The transplantation of a combination of culture-expanded SKPs and neonatal epidermal cells into RADA-PRG hydrogel resulted in a significantly increased number of neogenic hairs compared to Matrigel and other peptide hydrogels. This may be attributed to the similarity of the properties of these designer peptide nanofibres to those of ECM molecules. 102 In addition, a mixture of culture-expanded Epi-SC and SKPs derived from the adult human scalp in a hydrogel was capable of reconstituting functional HFs, and the mechanisms of the expression of ALP in SKPs in vitro and the maintenance of HF-inducive properties in vivo may be associated with BMP4. 103 More importantly, Epi-SC implanted in wounds in combination with SKPs could also form functional sebaceous glands in association with HFs. Normal human neonatal foreskin keratinocytes were induced to differentiate into several cellular components that compose normal HFs, with the expression of anagen-specific versican when grown on a collagen matrix embedded with TSC2-null fibroblast-like cells or with fibroblasts. 64 Regenerated HFs were complete with sebaceous glands, hair shafts and inner and ORSs. 64

Drug delivery systems for HF construction

Drug delivery systems consist of molecules with pharmacological activity modified into advanced materials, which have been widely used in skin wound treatment. Currently, it has been reported that many drug delivery systems could promote wound healing as well as HF regeneration. Newly developed multidomain peptide hydrogels have exhibited regenerative potential in a diabetic wound healing model, resulting in wound closure, accelerated HF regeneration and a greater average number of HFs at both the edge and the centre. 107 Multifunctional Zn-doped hollow mesoporous silica/polycaprolactone electrospun membranes exhibit excellent antibacterial activity for wound healing and are ~20 times as likely to regenerate HFs as the control. 108 Most excitingly, the treatment of deep second-degree scalding injuries with human erythropoietin (EPO) to, whether by the local subcutaneous injection of nanosized rhEPO (recombinant human EPO)/infusion pumping or the topical application of rhEPO gel, achieved excellent skin repair with conical and HF structures, which was related to the combined expression of EPO receptor and β-subunit receptor. 109 , 110 A novel fibrous membrane (P/Qu/Cup, P: PCL, Qu: Quercetin, Cup: cuprorivaite, CaCuSi 4 O 10 ) containing quercetin-copper (Qu-Cu) chelates was fabricated by using quercetin and highly bioactive bioceramic (CaCuSi 4 O 10 ) incorporated in PCL/gelatine electrospun fibres. The fibrous membrane can effectively release Qu and Cu ions to induce the proliferation, migration and differentiation of skin- and HF-related cells, and the Qu, Cu ions and Si ions released from the composite membrane revealed synergistic activity to stimulate HF regeneration and wound healing in burned skin. 111 However, drug delivery systems mainly contribute to wound repair, accompanied by the acceleration of wound-induced HF neogenesis (WIHN). WIHN is a regenerative phenomenon separate from physiological regeneration, as its cellular origin is not from the HFSCs in the bulge at the wound edge. In WIHN, a fully functional follicle can regenerate in the centre of a full-thickness wound with a large enough size, and the cellular origin of this process is similar to an embryonic process. The neogenic follicles have similar functions to embryonic HFs, which also have a growth cycle. 63 Currently, there are few studies about drug delivery systems for HF regeneration alone outside the wound environment. However, because of their controllability, targeted delivery, sustained release and even intellectuality, we think drug delivery systems hold great promise for HF regeneration in the future.

Organoid technology and HF replacement

An organoid is defined as a 3D structure grown from organ-specific stem cell types. It can recapitulate key aspects of in vivo organs and avoid many of the disadvantages associated with cell lines. 112 HF organoids can be established from skin stem cells or a mixture of dermal and epidermal components. DP spheroids encapsulated by silk-gelatine hydrogel and HF keratinocytes as well as stem cells could be used to construct in vitro HF organoids. These organoids show enhanced DPC-specific gene expression and ECM production, and their structural features and cell–cell interactions are similar to those of in vivo HFs. 113 This simple in vitro DP organoid model system has the potential to provide significant insights into the underlying mechanisms of HF morphogenesis and distinct molecular signals relevant to different stages of the hair cycle and hence can be used for the controlled evaluation of the efficacy of new drug molecules to induce HF regeneration. To date, in vitro skin derivation strategies have focused on first generating keratinocytes and fibroblasts from iPSCs in separate cultures and then combining the two types of cells to form a skin-like bilayer. A major challenge is how to realize the synchronous construction of its appendages. Under initial treatment with the TGF-β inhibitor SB431542 (SB) and recombinant BMP4 and subsequent treatment with FGF2 (FGF) and a BMP inhibitor LDN-193189 (LDN), a homogeneous population of mouse pluripotent stem cells and constituting epidermal and dermal layers in a 3D culture formed skin organoids with a cyst conformation, in which HFs were spontaneously produced de novo. However, the new HFs entered catagen and degenerated during long-term culture. 114 These results suggest how skin organoid structures can be generated de novo without the use of embryonic tissue or undefined media, which will be useful for studying the minimal cellular and microenvironment requirements for HF induction. Scalp-derived dermal progenitor cells mixed with foreskin-derived Epi-SCs at a 2:1 ratio could aggregate in suspension to form a large number of HF organoids, and the dermal and epidermal cells self-assembled into distinct epidermal and dermal compartments. The addition of recombinant WNT3a protein to the medium enhanced the formation of these aggregates, and the transplantation of these organoids in vivo achieved HF formation. 115 Finally, a 3D integumentary organ system (IOS) obtained by the self-assembly of mesenchymal and Epi-SCs from iPSCs using the clustering-dependent embryoid body transplantation method also regenerated fully functional HF organoids. 116 After transplantation into nude mice, the HF organoid in that system could form proper connections to the surrounding host tissues, such as the epidermis, arrector pili muscles and nerve fibres, without tumorigenesis, and show appropriate hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. 116 These findings reveal the generation of a bioengineered 3D IOS from iPSCs, including appendage organs such as HFs and sebaceous glands, with appropriate connections to surrounding tissues, which significantly advances the technological development of the bioengineered 3D IOS and its potential applications, including an in vitro assay system, an animal model alternative and bioengineered organ replacement therapy.

The transition from traditional culture to 3D culture constitutes excellent progress in HF regeneration. 3D culture enhances the proliferation and HF regeneration ability of potential cells, and a mixture of epidermal (Epi-SC) and dermal (SKP and DPCs) components in a 3D system simulates the characteristics of EMI, especially organoid technology and 3D printing technology. In 3D culture, regenerated HFs in vivo not only connect appropriately to surrounding host tissues but also undergo hair cycling activation. However, some problems are less thoroughly addressed. How long can the regenerated HFs last? Can the regenerated HFs go through full hair cycling? Will HF regeneration-induced hair be superior to transplanted hair? We think these are key questions and important challenges in functional HF regeneration.

Achievements, limitations and future perspectives

Much progress has been made in the developmental biology and regeneration of HFs. (1) A variety of cells with the potential to regenerate HFs have been identified, including DPCs, SKPs, HFSCs, keratinocytes and reprogrammed cells (iPSCs and fibroblasts), which provide a wide range of cell sources for HF regeneration. (2) We have gained a more comprehensive and in-depth understanding of the hair cycling-related mechanism, which provides the biological basis for finding key molecules to initiate and sustain the hair cycle. (3) Optimization of the in vitro culture system and the construction of a 3D culture environment could overcome the loss of the ability of potential cells to proliferate, self-renew and regenerate HFs caused by 2D culture. (4) The transplantation of a mixture of epidermal and dermal components, such as cell-based transplantation with or without biomaterials and HF organoids, could simulate EMI to a certain extent and successfully induce new HFs with the correct structure in vivo. (5) The HF organoid is a model for the exploration of mechanisms of HF morphogenesis and drug research to reproduce hair. (6) Drug delivery systems are characterized by strong controllability and high security, and they can promote wound healing accompanied by HF regeneration.

Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies.

In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress. For example, the creation of transplantable HFs that closely mimic the structures and functions of native tissue may be accomplished by combining organoid technology with a drug delivery system. Depending on the controllable release of the relevant factors in hair cycling, such as WNT or BMP, hair cycling activation and maintenance of HF organs may be achieved. We also need to continue to optimize the in vitro culture systems of potential cells and look for more efficient reprogramming techniques, such as chemical reprogramming induced by small molecules or genetic reprogramming of genes delivered by biomaterials. Finally, we want to reiterate that, based on existing work, it is worth considering whether the achievement of the activation and maintenance of hair cycling in regenerated HFs could be the heart of the next phase.

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Acknowledgements

This work was supported, in part, by National Key Research and Development Plan (2018YFC1105704, 2017YFC1103304, 2016YFA0101000, 2016YFA0101002), the National Nature Science Foundation of China (81871569, 81830064, 81721092), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-059) and the Military Medical Research and Development Projects (AWS17J005, 2019-126).

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Shuaifei Ji, Ziying Zhu, Xiaoyan Sun & Xiaobing Fu

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S.J. conceived and drafted the manuscript. S.J. and X.S. discussed the concepts of the manuscript. S.J. and Z.Z. drew the figures and summarized the tables. X.S. and X.F. approved the version to be submitted.

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Ji, S., Zhu, Z., Sun, X. et al. Functional hair follicle regeneration: an updated review. Sig Transduct Target Ther 6 , 66 (2021). https://doi.org/10.1038/s41392-020-00441-y

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FDA Approves First Drug to Treat Hair Loss Caused By Alopecia

In a clinical trial with 1200 patients, more than half grew their hair back after a year

Elizabeth Gamillo

Elizabeth Gamillo

Daily Correspondent

An image of four alopecia patients showing their before and after hair growth after taking the drug baricitinib.

The U.S. Food and Drug Administration (FDA) has approved the drug  Olumiant  (baricitinib) for adult patients with severe alopecia areata, an immune disorder that often results in hair loss. The medicine is the first FDA approval of a systemic or full-body drug for the condition, per a  statement .

The drug was originally developed by the pharmaceutical company  Eli Lilly  and has already been on the market for about four years for treating rheumatoid arthritis and other autoimmune diseases. Oluminant was studied in two trials for the treatment of alopecia areata, and the results were published last month in the  New England Journal of Medicine .  

Alopecia areata  is a disease that occurs when the immune system attacks hair follicles, causing hair loss. Hair loss is usually found on the head and face but can occur in small, round, coin-shaped patches anywhere on the body, according to the National Institutes of Health. About 700,000 individuals in the United States are living with alopecia areata. Roughly 40 percent of those individuals have a severe form of the autoimmune disorder, meaning that they are missing at least half of the hair on their scalp,  STAT  reports.

Until now, no approved treatment existed to make hair grow back in patients with alopecia areata. Those with the disorder had to rely on unapproved creams, cosmetic solutions and injections to manage their condition, Jonathan Wosen and Akila Muthukumar report for  STAT . "Access to safe and effective treatment options is crucial for the significant number of Americans affected by severe alopecia," Kendall Marcus, director of the Division of Dermatology and Dentistry in the FDA's Center for Drug Evaluation and Research, says in a statement. "Today's approval will help fulfill a significant unmet need for patients with severe alopecia areata."

Eli Lilly's drug prevents the immune system from attacking hair follicles. Pharmaceutical companies like Pfizer and Concert Pharmaceuticals are working on similar drugs to Oluminant.

The phase III trials for Eli Lilly's drug involved 1,200 patients with severe alopecia areata. Study participants either took a daily pill containing two milligrams or four-milligrams of the drug, or a placebo containing no medication. Almost 40 percent of individuals who took the higher drug dose had complete or near-complete hair regrowth after 36 weeks, and after a year, nearly half of patients had their hair back, reports the  New York Times . Patients who received the drug also reported regrowth of hair along their eyelashes and eyebrows.

Mild side effects were reported and included an increased risk for acne, urinary tract infections, headaches, high cholesterol and other infections. The drug’s list price is $2,500 for a one-month supply of the two milligram dose. But, Patrik Jonsson, Eli Lilly's president of immunology, told  STAT that the company is dedicated to making sure out-of-pocket costs for the drug are as little as $5 a month for insured individuals and $25 for those who are uninsured.

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Elizabeth Gamillo

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Elizabeth Gamillo is a daily correspondent for  Smithsonian and a science journalist based in Milwaukee, Wisconsin. She has written for Science magazine as their 2018 AAAS Diverse Voices in Science Journalism Intern.

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SCUBE3: New Molecule Discovered That Strongly Stimulates Hair Growth

By University of California - Irvine August 13, 2022

A team at the University of California, Irvine, has identified a signaling molecule called SCUBE3 that potently stimulates hair growth.

SCUBE3 has been found to be a potential therapeutic option for treating androgenetic alopecia.

A signaling molecule known as SCUBE3, which was discovered by researchers at the University of California, Irvine , has the potential to cure androgenetic alopecia, a prevalent type of hair loss in both women and men.

The research, which was recently published in the journal Developmental Cell, uncovered the precise mechanism by which the dermal papilla cells, specialized signal-producing fibroblasts found at the bottom of each hair follicle, encourage new development. Although the critical role dermal papilla cells play in regulating hair growth is widely established, the genetic basis of the activating chemicals involved is little understood.

Maksim Plikus

“There is a strong need for new, effective hair loss medicines, and naturally occurring compounds that are normally used by the dermal papilla cells present ideal next-generation candidates for treatment,” says Maksim Plikus, Ph.D., UCI professor of developmental and cell biology and the study’s corresponding author. Credit: Julie Kennedy / UCI

“At different times during the hair follicle life cycle, the very same dermal papilla cells can send signals that either keep follicles dormant or trigger new hair growth,” said Maksim Plikus, Ph.D., UCI professor of developmental & cell biology and the study’s corresponding author. “We revealed that the SCUBE3 signaling molecule, which dermal papilla cells produce naturally, is the messenger used to ‘tell’ the neighboring hair stem cells to start dividing, which heralds the onset of new hair growth.”

For mice and humans to effectively develop hair, the dermal papilla cells must produce activating chemicals. Dermal papilla cells malfunction in people with androgenetic alopecia, drastically lowering the typically plentiful activating chemicals. For this study, a mouse model with excessive hair and hyperactivated dermal papilla cells was created. This model will help researchers learn more about the regulation of hair growth.

“Studying this mouse model permitted us to identify SCUBE3 as the previously unknown signaling molecule that can drive excessive hair growth,” said co-first author Yingzi Liu, a UCI postdoctoral researcher in developmental & cell biology.

Further tests validated that SCUBE3 activates hair growth in human follicles. Researchers microinjected SCUBE3 into mouse skin in which human scalp follicles had been transplanted, inducing new growth in both the dormant human and surrounding mouse follicles.

SCUBE3

Several large human hair follicles and numerous small mouse hair follicles are shown growing in response to treatment with SCUBE3 protein. Credit: Nitish Shettigar, Plikus lab

“These experiments provide proof-of-principle data that SCUBE3 or derived molecules can be a promising therapeutic for hair loss,” said co-first author Christian Guerrero-Juarez, a UCI postdoctoral researcher in mathematics.

Currently, there are two medications on the market – finasteride and minoxidil – that are approved by the Food and Drug Administration for androgenetic alopecia. Finasteride is only approved for use in men. Both drugs are not universally effective and need to be taken daily to maintain their clinical effect.

“There is a strong need for new, effective hair loss medicines, and naturally occurring compounds that are normally used by the dermal papilla cells present ideal next-generation candidates for treatment,” Plikus said. “Our test in the human hair transplant model validates the preclinical potential of SCUBE3.”

Reference: “Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state” by Yingzi Liu, Christian F. Guerrero-Juarez, Fei Xiao, Nitish Udupi Shettigar, Raul Ramos, Chen-Hsiang Kuan, Yuh-Charn Lin, Luis de Jesus Martinez Lomeli, Jung Min Park, Ji Won Oh, Ruiqi Liu, Sung-Jan Lin, Marco Tartaglia, Ruey-Bing Yang, Zhengquan Yu, Qing Nie, Ji Li and Maksim V. Plikus, 30 June 2022, Developmental Cell. DOI: 10.1016/j.devcel.2022.06.005

UCI has filed a provisional patent application for the use of SCUBE3 and its related molecular compounds for hair growth stimulation. Further research will be conducted in the Plikus lab and at Amplifica Holdings Group Inc., a biotechnology company co-founded by Plikus.

The study team included health professionals and academics from UCI, San Diego, China, Japan, Korea, and Taiwan.

The study was funded by the LEO Foundation, the Chan Zuckerberg Initiative, the W.M. Keck Foundation, the National Science Foundation, the NIH/ National Institutes of Health , the Simons Foundation, the National Natural Science Foundation of China, the Training Program of the Major Research Plan of the National Natural Science Foundation of China, and the Ministry of Science and Technology of Taiwan.

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49 comments on "scube3: new molecule discovered that strongly stimulates hair growth".

latest research on hair growth

New molecule that helps people: first things first – patent it so that a small number of people can profit greatly from it at the expense of the majority! Patents need two urgent changes:

1. in the modern world, they need to be greatly shortened. 3-5 years is more than enough

2. nobody should be allowed to patent a compound that people make in their own bodies

latest research on hair growth

If funding was provided by the the National Science Foundation (of the US), then by law the findings/formulas/devices cannot be proivately patented.

Prove me wrong.

latest research on hair growth

https://en.wikipedia.org/wiki/Bayh-Dole_Act

you are right if funding for any scientific endevour is provided in any way by the us goverment then they own it and will be the ones to profit and given the number of such projects it is a small miracle that the us defecit continues to rise as the ammount of money they should be getting should more than offset the debt but thier is no such thing as a poor politician.

The guy in the video at the top of the article clearly has a fully healthy head of hair. Seems pretty bogus to me.

Absolutely. He has a perfectly formed buzz cut and the time-lapse merely shows it growing back out. Brazenly bogus claim.

latest research on hair growth

Here here. First name I see and recognize is Zuckerberg. Must they own everything?

The Zuckerberg Chan Initiative is a philanthropic organization funded by Mark Zuckerberg and his wife Patricia Chan.

First name I see and recognize is Zuckerberg. Must they own everything?

latest research on hair growth

I would love to know the effects of PRP on hair activation. I don’t believe it’s as available as treatment because of price, but it’s not daily and produces wonderful results. There’s other options/serums also to be injected or microneedled in the scalp. This can be done in tandem with current topicals. So when I say I would like to know, I mean conversely… the curiosity to regulate hair stopping. Sincerely, your fuzzy friend

And once it’s available to the public, we can purchase it for an overly high price, monthly subscriptions etc… and pretty much not be able To afford it. Isn’t that wonderful.

latest research on hair growth

How about figuring out how to locally shut off production of SCUBE3 as well for women with PCOS and other conditions as well as trans women and non-binary people to get rid of facial hair?

latest research on hair growth

Grace X, funding by a charitable foundation in the pursuit of knowledge is quite different than one person behind that foundation owning that idea. This is now paying it forward than scooping up profits.

latest research on hair growth

Every couple of years you see these articles, then you hear nothing. There will never be a cure!

The Zuckerberg Chan Initiative is a philanthropic organization funded by Mark Zuckerberg and his wife Patricia Chan

latest research on hair growth

I’m getting major “latisse” vibes from this. That had major and permanent disfiguring side effects that no one paid attention to until it had already been patented and released to market. Will this be similarly hiding a horrific side effect? Also, patenting biologically occuring chemical compounds shouldn’t be legal. They don’t want to help people, they just want money.

Keep my wife’s condition off yo f&cking ARTICLE

latest research on hair growth

I am not a scientist or doctor or anything else like that but the human body has its own ability to stop peoples hair from falling out and to regrow and even has the ability to regrow hair thicker longer in in places that you don’t even want it to grow up and the reason that I know this is because of one occasion about 25 years ago my left hand was cut wide open from the middle of my ring finger and my pinky straight across the top of my hand almost to my thumb knuckle and it was actually filleted open only the skin in the healing process after getting stitched back up a couple of weeks later my hand started growing hair like a wolf man growing so much being thicker and longer and spreading across my hand in more volume and in places that he didn’t ever grow before I actually had to cut the hair with a pair of scissors because it was getting so long I asked the doctor why this was happening and he said that the traumatic experience to my hand I sent my body into a survival mode and sent all of its soldiers to that hand into that wound to help heal it and protect it from bacteria and infection that is why the hair was growing so sick in so long and spreading around my wound on my hand we had never been before because it was protecting its own self and healing its own self and fighting off bacteria it’s own self find out what properties and what proteins are that the human body produces naturally to cause this and that’s exactly how baldness in women and men can be stopped whether it be naturally or or due to another illness or even an outside cause like chemotherapy the body can heal itself and hair loss is a wound to the body that it has its own Natural serum to accomplish This. Another words there’s no need for man-made chemicals or that you would apply to your place of hair loss and end up having to indefinitely take this same medication that was man-made for the rest of your life because if you did stop taking it all of the hair that you just regroup including all of the hair that is being subjected to this chemical will all fall out.

Punctuation is your friend, John.

latest research on hair growth

Great! My ears and back and inner nose and pubic Himalayas thank the scientists. So do the boys at Harry’s Razors!

latest research on hair growth

Soon available in a cookie form. Called Scube snacks.

latest research on hair growth

I have been suffering from alopecia totalis for 8 years. My hair was 3 feet long thick wavy and white, then it all fell out in 3 months time. I went through a year of cortisone injections to my scalp. It help a tiny bit. The hair I have now is very thin and it has only grown about 8 inches. The front is so thin I only wear headscarves in public. This would be a godsend for my self esteem not to mention getting to shed the damn headscarves!

Ask a rheumatologist for a sample bottle of Xeljanz or Rinvoq. Alopecia Totalis is likely autoimmune, and those medications inhibit enzymes that attack your body. Pfizer and AbbVie reps hand out sample bottles to rheumatologists and medical (not cosmetic) dermatologists like Halloween candy. They’re off-label and not covered by insurance for AT, but maybe your doc will “find” (wink, wink) that you have RA or PsA as well, which insurance will pay for.

latest research on hair growth

I hope that really work and the side efect not be other than help you grow hair and then give you erectal disfuntion I mint you get hair and then loose you manhood

latest research on hair growth

Finesteride is a very dangerous drug with serious side effects that can ruin sex drive (and even seems able in some cases to shrink penile tissue) for years or sometimes it seems for life. The company knows it but won’t stop selling it. Do your research before trying this as a solution to hair loss.

latest research on hair growth

I would like a gallon, please.

latest research on hair growth

How do I get these for my sons…young but balding

latest research on hair growth

How can I grow my I always cover my head because of bad hairlosss

latest research on hair growth

Investigate Ebola or covid you learned asinine person. No one cares about baldness when you are in the coffin.

Go eat cow dung, you asinine fool.

Investigate Ebola or covid you learned asinine scientist fool. No one cares about baldness when you are in the coffin.

latest research on hair growth

Hmm. I thought you can’t patent naturally occurring substances. But may be the patent is for use. But then again a new intended use does not make it patentable. They may or may not be able to get a patent for it.

latest research on hair growth

Weird that participants in the study are scientists from China…AND Taiwan. F*** the Chinese lose their s**t at the mear mention of Taiwan.

latest research on hair growth

>2. nobody should be allowed to patent a compound that people make in their own bodies

Then there should be an alternative document that gives a time-limited sole right to profit from the results of research and investment, in which case the law would decide this will not be deemed as ownership of nature (the thought of which sets some people off)

latest research on hair growth

Grammar Both drugs are not universally effective is poor usage. It is ambiguous at best and erroneous at worst. You are stating that one drug is effective while the other is not. Correct phrasing is that neither drug is universally effective. Basic proper English has become a victim of technology.

latest research on hair growth

And did they mention that this same molecule also stimulates lung cancer cells?

latest research on hair growth

“Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression.” (Wu, et al. 2011)

https://pubmed.ncbi.nlm.nih.gov/21441952/

References: Wu, YY., Peck, K., Chang, YL. et al. SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer. Oncogene 30, 3682–3693 (2011). https://doi.org/10.1038/onc.2011.85

latest research on hair growth

Some people in the comments seem to think this is ready for human trials. No human trials have been done yet. Once more animal trials are done then they will seek approval for human trials if it is safe to proceed. I agree that this should only get a limited time to solely profit from their research, consisting of 3 to 5 years after approval for human use. It will be years before this is ready for human use though. As a balding male, I want it sooner if safe, but I understand the need for rigorous safety trials.

latest research on hair growth

Who cares. Im sexy with no hair. This popped up on google, of course i clicked. Its interesting. I understand the emotional amd psychological stress hair loss causes. Mine fell out at 20. But i didnt care, shaved it and kept livimg my life. If someone didnt like me bald, their loss. Didnt stop me from getting a smoking hot wife, six figure job, multiple degrees, and accomplishing a multitude of goals. I focused on my physique because it was my passion. If you are worried about gow you look, first step get on the scale. Overweight (probably) stop eating crap. Scrawny physique, well if you dont like it eat better and lift. So much we can easily control yet people aim for hair? Its dumb. Teeth i understand, hair i do not. People spens millions on hair replacement. Wouldnt you rather have a boat or sweet car or i dont know more retirement? Hair…gimme a break. Embrace the dome. Be confident in other areas or create that confidence other ways. Moreover, this is science? Why arent they dedicating these resources and efforts to cancer? Seems less selfish and vain to me. But what do i know, im just a baldy, jacked 40yo.

latest research on hair growth

Simple solution to haor loss- Locate and tweak the gene that causes wild hair growth in/on my ears, eyebrows, and in my nose. As I get older the top goes and the random grows.

latest research on hair growth

“2. nobody should be allowed to patent a compound that people make in their own bodies”

Insulin would like to have a word with you.

latest research on hair growth

She asks me why… I’m just a hairy guy…

Some people here seem to think that scientists should spend years educating themselves and work for nothing to “help” humans by discovering medicines to improve disease outcomes.

Likewise for the pharmaceutical companies who they believe are evil for wanting to make a lot of money.

I say go on make some money and bring us effective treatments for baldness for cancer for whatever. The market will pay what it’s prepared to pay.

Pharmaceutical companies have to cover the losses for all the hard work trying to find treatments that end up a failure.

So I have no problem paying someone for their work. The higher salary scientists make the more talent will be drawn into the field. I say bring it on charge what you can. If it’s really important to human health governments will step in to subsidise medicines. Here in Australia we have seen this happen with many medicines including the marvelous cancer immunotherapy drugs that have heralded the future of cancer care.

As for the guy who said forget about hair loss and shave your head. Well not everyone looks so good shaved plus there’s nothing wrong with wanting to wear a full set of hair which also protects your scalp skin from developing skin cancer.

I’ve had two fue transplants and it doesn’t cost that much. An average new car costs more and you’ll get way more satisfaction out of a full head of hair.

I look good with my head shaved or with a full head of hair and I have the option.

I am eagerly waiting for the positive results as I am one of the hair loss patients. Pls help. Loosing hair makes me loose my confidence.

latest research on hair growth

How can I be a patient in this study in SCUBE3: New Molecule That Strongly Stimulates Hair Growth? I am willing to test it on me thank You

latest research on hair growth

Where can I get this from…how much diss it cost???

When will this become avaible…

when will this be ready for use?

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Going bald? Lab-grown hair cells could be on the way

These biotech companies are reprogramming cells to treat baldness, but it’s still early days.

  • Antonio Regalado archive page

mouse engineered to grow human hair

Biologists at several startups are applying the latest advances in genetic engineering to the age-old problem of baldness, creating new hair-forming cells that could restore a person’s ability to grow hair.

Some researchers tell MIT Technology Review they are using the techniques to grow human hair cells in their labs and even on animals. A startup called dNovo sent us a photograph of a mouse sprouting a dense clump of human hair—the result of a transplant of what the company says are human hair stem cells.

The company’s founder is Ernesto Lujan, a Stanford University–trained biologist. He says his company can produce the components of hair follicles by genetically “reprogramming” ordinary cells, like blood or fat cells. More work needs to be done, but Lujan is hopeful that the technology could eventually treat “the underlying cause of hair loss.”

We’re born with all the hair follicles we’ll ever have—but aging, cancer, testosterone, bad genetic luck, even covid-19 can kill the stem cells inside them that make hair. Once these stem cells are gone, so is your hair. Lujan says his company can convert any cell directly into a hair stem cell by changing the patterns of genes active in it.

In biology, we “now understand cells as a ‘state’” rather than a fixed identity, says Lujan. “And we can push cells from one state to another.” 

Reprogramming cells

The chance of replacing hair is one corner in a wider exploration of whether reprogramming technology can defeat the symptoms of aging. In August, MIT Technology Review reported on a stealthy company, Altos Labs , that plans to explore whether people can be rejuvenated using reprogramming. Another startup, Conception , is trying to extend fertility by converting blood cells into human eggs.

A key breakthrough came in the early 2000s, when Japanese researchers hit on a simple formula to turn any type of tissue into powerful stem cells, similar to ones in an embryo. Imaginations ran wild. Scientists realized they could potentially manufacture limitless supplies of nearly any type of cell—say, nerves or heart muscle.

In practice, though, the formula for producing specific cell types can prove elusive, and then there’s the problem of getting lab-grown cells back into the body. So far, there have been only a few demonstrations of reprogramming as a way to treat patients. Researchers in Japan tried transplanting retina cells into blind people. Then, last November, a US company, Vertex Pharmaceuticals, said it might have cured a man’s type 1 diabetes after an infusion of programmed beta cells, the kind that respond to insulin.

The concept startups are pursuing is to collect ordinary cells such as skin cells from patients and then convert these into hair-forming cells. In addition to dNovo, a company called Stemson (its name is a portmanteau of “stem cell” and “Samson”) has raised $22.5 million from funders including from the drug company AbbVie. Cofounder and CEO Geoff Hamilton says his company is transplanting reprogrammed cells onto the skin of mice and pigs to test the technology.

Both Hamilton and Lujan think there is a substantial market. About half of men undergo male-pattern baldness, some starting in their 20s. When women lose hair, it’s often a more general thinning, but it’s no less a blow to self-image.

These companies are bringing high-tech biology to an industry known for illusions. There are plenty of bogus claims about both hair-loss remedies and the potential of stem cells. “You’ve got to be aware of scam offerings,” Paul Knoepfler, a stem-cell biologist at UC Davis, wrote in November .

latest research on hair growth

Tricky business

So is stem-cell technology going to cure baldness or become the next false hope? Hamilton, who was invited to give the keynote at this year’s Global Hair Loss Summit , says he tried to emphasize that the company still has plenty of research ahead of it. “We have seen so many [people] come in and say they have a solution. That has happened a lot in hair, and so I have to address that,” he says. “We’re trying to project to the world that we are real scientists and that it's risky to the point I can’t guarantee it’s going to work.”

Right now, there are some approved drugs for hair loss, like Propecia and Rogaine, but they’re of limited use. Another procedure involves cutting strips of skin from someplace where a person still has hair and surgically transplanting those follicles onto a bald spot. Lujan says in the future, hair-forming cells grown in the lab could be added to a person’s head with a similar surgery.

“I think people will go pretty far to get their hair back. But at first it will be a bespoke process and very costly,” says Karl Koehler, a professor at Harvard University.

Hair follicles are surprisingly complicated organs that arise through the molecular crosstalk between several cell types. And Koehler says pictures of mice growing human hair aren't new. “Anytime you see these images,” says Koehler, “there is always a trick, and some drawback to translating it to humans.”

Koehler’s lab makes hair shafts in an entirely different way—by growing organoids. Organoids are small blobs of cells that self-organize in a petri dish. Koehler says he originally was studying deafness cures and wanted to grow the hair-like cells of the inner ear. But his organoids ended up becoming skin instead, complete with hair follicles.

Koehler embraced the accident and now creates spherical skin organoids that grow for about 150 days, until they are around two millimeters across. The tube-like hair follicles are clearly visible; he says they are the equivalent of the downy hair that covers a fetus.

One surprise is that the organoids grow backwards, with the hairs pointing in. “You can see a beautiful architecture, although why they grow inside out is a big question,” says Koehler.

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Fda approves second yale-researched treatment for alopecia areata.

A side by side comparison of the same patient before and after treatment.

A side by side comparison of the same patient before and after treatment.

Just a year after the U.S. Food and Drug Administration (FDA) approved the first treatment for severe alopecia areata, the federal agency has approved a second treatment for the disfiguring skin disease — both the result of pioneering research by the same Yale dermatologist.

On June 23, the FDA announced its approval for the use of ritlecitinib — a Janus kinase (JAK) inhibitor — to treat alopecia areata in both adolescents and adults. The medicine, taken orally, goes by the product name Litfulo.

Alopecia areata is an autoimmune disease characterized by sudden, often disfiguring, loss of hair. It is the second most common cause of hair loss, affecting up to 7 million people in the United States.

Dr. Brett King , an associate professor of dermatology at Yale School of Medicine, worked with pharmaceutical company Pfizer to conduct a series of clinical trials with ritlecitinib. He worked with Eli Lilly and Company on clinical trials for the earlier medicine — baricitinib (which goes by the product name Olumiant), approved as a treatment for patients with severe alopecia areata in June 2022 .

King’s groundbreaking work with JAK inhibitors, which were originally designed to treat rheumatoid arthritis and myelofibrosis (a rare blood cancer), has shown significant potential to treat an array of intractable skin diseases, including eczema, erosive lichen planus, vitiligo, granuloma annulare, and sarcoidosis.

King spoke with Yale News about this latest FDA approval.

How does FDA approval for ritlecitinib change the treatment landscape for people with alopecia areata?

Brett King: Ritlecitinib [Litfulo] changes the treatment landscape for people with alopecia areata enormously. Last year, history was made when baricitinib [Olumiant] was FDA approved for the treatment of adults with severe alopecia areata. But alopecia areata affects people of all ages and, indeed, it commonly affects children of all ages. Ritlecitinib is approved in patients ages 12 years and older.

Childhood and adolescence are such vulnerable times, and children and adolescents have so much to do and learn and become during these years. It is challenging enough to be a kid, but when alopecia areata happens and suddenly one has big bald spots or is completely bald and missing eyebrows, the normal trajectory of that kid’s life, and the family’s life, too, can be derailed. Kids withdraw from sports and other social activities, and even from school. Extreme sadness and anxiety are common. It is awful. There is a way out of the darkness, however, and that is to regrow the hair that was lost, to restore the person as they had been prior to alopecia areata.

Normalcy is so important for everybody, but especially when we are developing. So it is easy to understand what a monumental breakthrough it is to have a medicine, ritlecitinib, approved for adolescents. Ritlecitinib restores normalcy and will make life better — literally will change life — for so many people.

When can patients in the U.S. expect ritlecitinib to be available for use?

King: Hopefully in the days or weeks ahead.

You have been at the center of two FDA approvals for major treatments of alopecia areata in two years. Has that sunk in yet — and how does that make you feel?

King: These new medicines for alopecia areata are historic, and I feel super fortunate to be a part of their development. Being a doctor is amazing because I get to share in the lives of others, hopefully making those lives better. It happens one person at a time, though. To have played a central role in the development of treatments for alopecia areata and other diseases — treatments that doctors around the world will give to thousands and thousands (or even millions) of people to make their lives better — is really incredible. We are all a part of something bigger than ourselves, and for me this experience highlights that as well as the possibility that we can change the world.

What are you working on next?

King: The next horizon is approval of these and other treatments for younger patients. Remember, alopecia areata is not uncommon in pre-adolescents. Also, JAK inhibitors do not work for everybody with alopecia areata, and so work needs to be done both to understand why that is and to develop treatments other than JAK inhibitors. The goal is for everybody to be able to have effective treatment. We have come so, so far but we still have a ways to go. It’s exciting.

  • New Alopecia Areata treatment aims to help adults and adolescents
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The Key to Locks: Columbia Team’s Breakthrough Led to Hair Loss Treatment

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For over a decade, Columbia geneticist Angela Christiano , PhD, has attended the annual meeting of the National Alopecia Areata Foundation, where hundreds of individuals affected by the hair loss disorder gather to support one another and learn about the latest scientific research. The meeting is a safe space where patients with alopecia, many of whom have lost all their hair, joyfully remove their wigs and head coverings for the three-day celebration, without fear of shame or judgment.

But this year’s meeting was a bit different. Christiano had trouble recognizing conference attendees she’s known and worked with for years, because many of them now have full heads of hair.

For people with alopecia areata, an autoimmune disease that can cause hair loss so complete that people even lose their eyebrows, the change in appearance was dramatic.

drug_restores_hair_growth_in_patients_with_alopecia_areata

It was also a direct result of Christiano’s groundbreaking research on the condition, which led the FDA in June to approve the first systemic treatment specifically developed for severe alopecia areata.

“It’s a strange feeling. It’s what every geneticist dreams of, to find the genes for a condition and develop a treatment that can directly benefit patients. But it’s extremely rare that it actually works out that way,” says Christiano, who has studied alopecia areata for more than 20 years, motivated by her own bout with the disease.

Mysterious origins

Unlike hormone-driven male pattern baldness, alopecia areata is an autoimmune disease in which the body’s own immune system mistakenly attacks the hair follicle and shuts down hair production.

When Christiano began working on it, though, nobody knew exactly what caused the problem.

Starting with a series of basic research studies on the genetics and cell biology of hair growth, Christiano and a multidisciplinary team of collaborators produced a steady stream of advances, first in the lab and then in the clinic.

The first major clue came in 2010, from a study led by Christiano’s team that looked through the genomes of a thousand patients. The study, published in Nature, uncovered a gene that, when abnormally expressed, produces a known "danger signal" that causes the body to recognize the hair follicle as foreign. 

The genome study was also crucial since the findings also explained why previous efforts to treat the condition hadn’t worked.

“Drugs for other autoimmune skin diseases had been tested in alopecia, but they had largely failed,” Christiano says.

“At that point, we realized that was because alopecia doesn’t share genetic pathways with other autoimmune skin diseases.”

Taming killer T cells

The genome study led the team to focus on investigating a particular kind of "killer" T cell recruited by the danger signal, which became central to understanding the mechanism of hair follicle destruction.

Columbia alopecia team . Dermatologist Julian Mackay-Wiggan (left), immunologist Raphael Clynes (center), and geneticist Angela Christiano (right) made key discoveries that have led to a new drug for alopecia areata, an autoimmune disease that can cause severe hair loss. Photo: Columbia University Irving Medical Center.

Christiano is not an immunologist, so she needed to enlist an expert to help make inroads into understanding the behavior of these cells. She approached Raphael Clynes, MD, PhD, at that time a faculty member in the Department of Medicine, who was an expert in studying the same kinds of killer T cells in type 1 diabetes and in cancer. 

Clynes looked at the list of genes from the genome study and images of the "swarm" of killer T cells surrounding the hair follicle and suggested that inhibiting enzymes known as JAK kinases might be one way to treat the disease.

The team showed that small molecule drugs called JAK inhibitors could shut down signaling inside the killer T cells. Amazingly, by inhibiting the JAK pathway, the team found they could reverse alopecia areata in a mouse model of the disease.

Dramatic regrowth of hair

Armed with photos of mice with alopecia that had regrown all their hair, Christiano next approached her colleague Julian Mackay-Wiggan, MD, a Columbia dermatologist who specialized in hair disorders and had an interest in early-stage clinical research.  

Excited by the early results in the mice, Mackay-Wiggan began treating a few patients with alopecia areata using JAK inhibitors that were already FDA-approved for other disorders. The first few patients experienced dramatic regrowth of their hair, just as the researchers had observed in the mice. Christiano’s team reported these groundbreaking studies in 2014.

Building on these early results, Mackay-Wiggan conducted additional Columbia clinical studies that showed that 75% of patients experienced significant hair regrowth after treatment with two different JAK inhibitors.

Pharma attention

Soon after the Columbia team reported its findings, additional case reports began appearing in the published literature that replicated the results in alopecia patients from around the world.

Because there were no FDA-approved drugs for alopecia when their work began, it didn’t take long for pharmaceutical companies to turn their attention to developing JAK inhibitors specifically for alopecia treatment. These efforts led to newly approved Olumiant from Eli Lilly, Incyte (previously approved for rheumatoid arthritis and hospitalized patients with COVID-19), and two additional JAK inhibitors being developed by Pfizer and Concert Pharmaceuticals and now in late-stage clinical trials.

Christiano welcomes the pharmaceutical companies’ new attention to alopecia areata after the condition had long been neglected and was frequently dismissed as a cosmetic problem.

For patients with complete hair loss, the barrage of stares and intrusive questions can be demoralizing and psychologically devastating. “It’s the stigma of unwanted attention; how do you quantify that?” says Christiano. “The impact of this treatment on patients has been truly transformative.”

Male pattern baldness next?

While Olumiant and other new JAK inhibitors are often life-changing for patients who respond well to them, the treatments are still far from perfect.

“These are potent immunosuppressive drugs, so there are safety considerations to be taken into account when assessing the risk/benefit ratio for individual patients,” says Christiano. After the treatment ends, some patients’ alopecia relapses for reasons the researchers don’t fully understand. In addition, about a third of patients don’t respond to the drugs.

Fortunately, Christiano has no intention of resting on her laurels. Her lab is hoping to understand what causes the condition to relapse after JAK inhibitor treatment.

And by continuing to investigate alopecia areata with new tools and techniques, her team is developing both new biological insights and more potential ways to attack the disease process. “We’re now looking upstream of the JAK signaling pathway to see if other mechanisms can lead to the common endpoint of alopecia areata,” she says.

Christiano’s team also hopes to extend these insights and apply the same approaches to treat other types of hair loss.

Hair follicles grown in a dish in the Christiano lab. Made possible with 3D printing technology, engineered human hair follicles created in this way could generate an unlimited source of new hair follicles for patients undergoing robotic hair restoration surgery. Read more .

In one recent study, for example, Christiano’s team found that JAK inhibitors also reawaken dormant hair follicles , a problem common to male and female pattern baldness.

They also discovered a previously unknown type of immune cell that puts hair follicles into a dormant state by secreting a substance called oncostatin M and that the hair cycle can be reactivated by blocking this pathway.

While translating these results into effective treatments for hair loss will likely take years, it’s a process Christiano now knows well.

More information

Angela M. Christiano, PhD, is the Richard and Mildred Rhodebeck Professor of Dermatology, vice chair of research in the Department of Dermatology, and professor of genetics & development at Columbia University Vagelos College of Physicians and Surgeons. She also serves as an Advisory Dean for Basic Science Faculty. In 2020, Christiano was elected to the National Academy of Sciences.

Raphael Clynes, MD, PhD is currently vice president of translational biology at Xencor Inc.

Julian Mackay-Wiggan, MD, MPH, is currently in practice in the Siperstein Dermatology Group. 

Angela Christiano and Raphael Clynes are co-inventors on several patents filed by Columbia University on the use of JAK inhibitors in treating hair loss disorders, which have been licensed to Aclaris Therapeutics, Inc. Angela Christiano is a shareholder of Aclaris Therapeutics, Inc. and has served as a consultant/scientific advisor for Arcutis Biotherapeutics, Inc., Almirall, S.A., Aclaris Therapeutics, Inc., Bioniz Therapeutics, Inc., Dermira, Inc., Intrinsic Medicine, Inc., Janssen Pharmaceuticals, Inc., and Pfizer, Inc. She is a shareholder of Intrinsic Medicine, Inc., has received research grant support from Bristol-Myers Squibb, Inc., Pfizer, Inc., and Sanofi Genzyme S.A. and serves on/chairs the scientific advisory boards for the Dystrophic EB Research Association of America and the National Alopecia Areata Foundation. She previously served as president of the Society for Investigative Dermatology and currently serves as president of the American Hair Research Society. She is a scientific co-founder of Rapunzel Bioscience.

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Integrative and Mechanistic Approach to the Hair Growth Cycle and Hair Loss

Nicole natarelli.

1 Morsani College of Medicine, University of South Florida, Tampa, FL 33602, USA

Nimrit Gahoonia

2 College of Osteopathic Medicine, Touro University, 1310 Club Dr, Vallejo, CA 94592, USA

Raja K. Sivamani

3 College of Medicine, California Northstate University, 9700 W Taron Dr, Elk Grove, CA 95757, USA

4 Integrative Skin Science and Research, 1495 River Park Drive, Sacramento, CA 95819, USA

5 Pacific Skin Institute, 1495 River Park Dr Suite 200, Sacramento, CA 95815, USA

6 Department of Dermatology, University of California-Davis, 3301 C St #1400, Sacramento, CA 95816, USA

The hair cycle is composed of four primary phases: anagen, catagen, telogen, and exogen. Anagen is a highly mitotic phase characterized by the production of a hair shaft from the hair follicle, whereas catagen and telogen describe regression and the resting phase of the follicle, respectively, ultimately resulting in hair shedding. While 9% of hair follicles reside in telogen at any time, a variety of factors promote anagen to telogen transition, including inflammation, hormones, stress, nutritional deficiency, poor sleep quality, and cellular division inhibiting medication. Conversely, increased blood flow, direct stimulation of the hair follicle, and growth factors promote telogen to anagen transition and subsequent hair growth. This review seeks to comprehensively describe the hair cycle, anagen and telogen balance, factors that promote anagen to telogen transition and vice versa, and the clinical utility of a variety of lab testing and evaluations. Ultimately, a variety of factors impact the hair cycle, necessitating a holistic approach to hair loss.

1. Overview of Hair Cycle

Hair follicles differ in size and shape depending on location, although they are characterized by the same structural components [ 1 ]. The hair shaft is produced by proliferating matrix cells found in the hair bulb, with melanocytes interspersed and responsible for pigmentation. Differentiation and upward movement contribute to the growing hair shaft, whose cortex is composed of intermediate filaments and proteins [ 1 ]. Located at the follicle base, the dermal papilla controls the number of matrix cells and subsequently the size of hair.

Hair growth occurs in a continuous process characterized by four phases: anagen, growth; catagen, regression; telogen, rest; and exogen, shedding. Individual hair follicles cycle independently, with each hair follicle undergoing ten to thirty cycles in a lifetime [ 2 ]. While most individuals have about 100,000 scalp hairs at any time, normal shedding occurs at a rate of 100 to 150 telogen hairs per day [ 2 ]. As some hairs reside in the anagen phase while others are resting or shedding, the density and total hair strand number remains relatively stable in healthy conditions.

As the longest phase of the hair cycle, anagen lasts about two to eight years among scalp hair, although various factors can promote anagen to telogen transition, reducing growth while fostering rest and eventual shedding [ 2 ]. Anagen is characterized by the production of an entire hair shaft from hair follicles; as such, hair length in the absence of cutting directly corresponds to anagen length. For example, whereas scalp hair follicles reside in anagen for two to eight years, eyebrow hair follicles reside in anagen for only two to three months [ 1 ]. However, anagen phase length decreases with age, resulting in weaker and thinner hair over time [ 3 ]. Similarly, the proportion of follicles in the anagen phase declines with age [ 4 ]. Importantly, anagen hair shedding resulting from premature termination of anagen growth or anagen arrest secondary to insult is never normal.

The catagen phase represents the transition from anagen to telogen, lasting about two weeks. Throughout the catagen phase, hair follicles regress and detach from the dermal papilla, the population of mesenchymal cells in hair follicles, resulting in epithelial cell apoptosis in the bulb of the follicle [ 3 , 5 ]. Following catagen, the dermal papilla moves upward towards the hair-follicle bulge. If the dermal papilla is unable to reach the bulge during catagen, follicle cycling terminates resulting in loss of hair [ 1 ]. The telogen resting phase follows, lasting about two to three months. At any time, about 9% of total scalp hair resides in the telogen phase [ 4 ], in comparison to 40–50% of total hair on the trunk [ 1 ]. While old hair is resting, new hair begins to develop at the base of the hair follicle, eventually pushing old hair out. However, if anagen enters the resting phase prematurely, excessive shedding and thinning can occur, known as telogen effluvium (TE). Conversely, reducing the percent of hair follicles residing in the telogen phase manages hair loss [ 1 ]. Lastly, exogen describes the termination of telogen and the initiation of anagen. During this period, newly developing hair continues to grow upward, pushing the old hair out, resulting in its ultimate shedding.

Figure 1 shows a hair growth cycle depiction of the balance between anagen and telogen along with the factors that may influence the hair growth cycle.

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Schematic of the hair growth cycle and the factors that may influence a transition from anagen to telogen vs. telogen to anagen phase.

1.1. Anagen and Telogen Balance

The anagen to telogen ratio among healthy subjects is approximately 14:1 to 12:1 among healthy subjects [ 6 , 7 ]. However, various subtypes of alopecia are characteristic of decreased anagen to telogen ratios and subsequent hair shedding above the normal rate of 100–150 strands daily.

The causes of alopecia can be categorized as scarring, such as cicatricial alopecia, and non-scarring, including alopecia areata (AA), androgenetic alopecia (AnA), and TE. Alopecia areata is characterized by circular bald patches that may or may not overlap, whereas AnA refers to male- and female-pattern hair loss, characterized by the progressive shortening of anagen cycles [ 1 ]. A descriptive study of alopecia patterns among 1232 patients presenting to a clinic over the course of 25 months found diffuse alopecia to be the most prevalent form of hair loss (71.35%). A total of 14.3% of patients presented with AnA, in comparison to 11.8% with AA [ 8 ].

AA is characterized by an anagen to telogen ratio of approximately 6:4 or 5:5, and in some cases the proportion of hair follicles in telogen can exceed that of anagen [ 9 ]. The anagen to telogen ratio decreases to approximately 5:1 in AnA [ 6 ] and 8:1 in TE [ 7 ]. Thus, alopecia is fundamentally characterized by an imbalance of anagen and telogen. Importantly, a variety of factors can increase anagen to telogen transition, fostering hair loss. Conversely, factors and treatments can increase telogen to anagen transition, prompting hair growth.

2. Factors Increasing Anagen to Telogen Transition and Hair Loss

As a variety of factors increase the transition from anagen to telogen, it is essential to consider all possible contributing factors when presented with a general complaint of non-scarring alopecia. Obtaining a thorough history is crucial to consider the root causes of alopecia and optimize therapeutic approaches for individual cases.

2.1. Inflammation

Inflammation fosters anagen to telogen transition and has been associated with the progression of alopecia [ 10 ]. Inflammation has been suggested to mediate a variety of hair loss subtypes, including stress-induced hair loss, alopecia areata (AA), and male- and female-pattern hair loss, also known as androgenic alopecia (AnA). Each of these alopecia subtypes are associated with a decreased anagen to telogen ratio, as described in Section 1.1 . In addition, chronic, systemic inflammatory disorders can cause TE, characterized by premature progression from anagen to telogen [ 7 ].

A 1975 study observed lymphocytes and histiocytes, markers of chronic inflammation, in approximately half of 347 tissue specimens collected from patients with male-pattern androgenetic alopecia (MPAnA) [ 11 ]. Furthermore, significant perivascular infiltration of mast cells was observed in 40% of specimens. Similarly, a study found moderate to severe inflammation with lymphocytic and histiocytic infiltrates in 36% of 106 biopsy specimens from patients with MPAnA, compared to 9.1% of control specimens [ 12 ]. In a separate study, the same author observed 36.8% of specimens from 412 MPAnA and female-pattern androgenetic alopecia (FPAnA) patients depicting moderate or severe perifollicular inflammation, compared to 9.1% of control specimens [ 13 ]. Similarly, in 2011 authors conducted scalp biopsies with 52 FPAnA patients and observed lymphocytic folliculitis targeting bulge epithelium in many cases [ 14 ]. These studies describe the association between chronic inflammatory cell infiltrate and AnA, suggesting inflammation may partially mediate pathophysiology and contribute to increased anagen to telogen transition. Furthermore, lotion application consisting of antimicrobial and antifungal agents were found to decrease the number of activated T cells over the course of treatment among patients with MPAnA, highlighting inflammation as a therapeutic target [ 15 ].

In addition, a mouse study found that inflammatory events in the hair follicle environment may mediate stress-induced hair loss. Authors observed perifollicular macrophage cluster and excessive mast cell activation in the hair follicle environment of stressed mice, suggesting inflammatory and immunological events of the stressed mouse may contribute to stress-induced hair loss [ 16 ]. In addition, the authors found that stress-related hair growth inhibition can be replicated by substance P, which exhibits proinflammatory effects in immune and epithelial cells [ 17 ] in non-stressed mice [ 16 ]. Similarly, another murine study found an increased number of substance P-immunoreactive nerve fibers in the skin during the early stages of AA, and substance P cutaneous application led to a significant increase in mast cell degranulation and accelerated catagen [ 18 ]. These studies suggest that inflammation may mediate both stress-induced hair loss and AA, with proinflammatory substance P as an important regulator.

In addition to murine studies, human studies have described inflammation associated with AA, which is associated with a decreased anagen to telogen ratio of 6:4 or 5:5 [ 9 ], compared to the normal ratio of 12:1. A 2012 study described greater serum immunoglobulin (Ig)E levels among patients with diffuse or patchy AA [ 19 ]. Compared to patchy AA biopsies, diffuse biopsies depicted more intense mononuclear, eosinophil, CD3+, and CD8+ T cell infiltration around hair bulbs, and IgE levels positively correlated with infiltration intensity [ 19 ]. A 2013 study observed dermal inflammatory infiltration and epithelial cell damage of the hair follicle infundibulum in early AA lesions [ 20 ]. A total of 40% of patients showed eosinophilic infiltration, which was positively correlated with elevated serum IgE levels, severe perivascular lymphocytic inflammation in the upper dermis, and peri-follicular infiltration [ 20 ].

These studies effectively associate inflammatory infiltrate and fibrosis with alopecia conditions characterized with a decreased anagen to telogen ratio. Inflammation is an important factor mediating anagen to telogen transition.

2.2. Hormones

A variety of hormones have been shown to impact the hair cycle and mediate hair growth, including thyroid hormones, dihydrotestosterone (DHT), estrogen and testosterone.

2.2.1. Thyroid Hormone

Hypo- and hyperthyroidism can cause reversible, diffuse hair loss [ 2 ] and can promote premature transition from anagen to telogen, potentially resulting in telogen effluvium. In fact, diffuse hair loss may be the only presenting sign of thyroid dysfunction [ 8 ]. A study published in 2013 assessed alopecia patterns related to thyroid dysfunction among all patients presenting to a clinic from December 2007 to December 2009 [ 8 ]. Thyroid dysfunction, based on a thyroid-stimulating hormone reference range, was observed most frequently in AA and diffuse alopecia patients among those aged 0–20 and 21–40 years, and in AA and AnA patients among those 40 years and older. A greater association between thyroid dysfunction and alopecia was observed with increasing age [ 8 ].

The mechanisms of aberrant thyroid hormone levels and hair loss have been described. The deletion of murine thyroid hormone nuclear receptors has been shown to impair epidermal proliferation and hair growth [ 21 ]. In addition, a 2015 study found that mice with deficient thyroid hormone receptors had increased label-retaining cells in the bulges, the hair follicle stem cell niche, resulting in reduced activation of stem cells and accumulation in bulges [ 21 ]. Authors concluded that thyroid hormone signaling is necessary for proper mobilization of stem cells from the hair bulge, and improper stem cell signaling may mediate hair loss associated with thyroid hormone deficiencies. In addition, prolonged thyroid hormone stimulation has been shown to promote progenitor cell differentiation and subsequent stem cell depletion [ 21 ]. As such, both deficient and excessive levels of thyroid hormones can contribute to anagen to telogen transition and hair loss. Thyroid-stimulating hormones (TSH) and thyroxine levels should be obtained as part of a standard work-up for non-scarring alopecia.

2.2.2. Dihydrotestosterone

Dihydrotestosterone (DHT) is an androgenic steroid hormone produced via the action of 5-alpha-reductase type 2, which converts testosterone to DHT at target tissues. While androgens increase hair follicle size in androgen-dependent locations, they can result in miniaturization of scalp follicles later in life and contribute to AnA [ 1 ]. DHT is a pure androgen, as it cannot be converted to estrogen [ 22 ]. In addition to the sexual development of males, DHT promotes male-pattern hair loss and is implicated in MPAnA pathophysiology. Upon binding to androgen receptors in the hair follicle, DHT promotes the shortening of the anagen phase and elongation of the telogen phase [ 23 ], resulting in enhanced apoptosis of hair cells and thus hair loss [ 24 ]. A mouse-model study found that DHT promoted premature hair regression, hair miniaturization, loss of hair density, and altered hair morphology in male mice, with partial reversal with an androgen receptor antagonist, bicalutamide [ 25 ].

Unsurprisingly, men with MPAnA may be genetically predisposed to greater levels of 5-alpha-reductase and hair follicle androgen receptor activity [ 25 ]. In addition, those with 5-alpha-reductase enzyme deficiencies are less likely to develop MPAnA. The role of DHT in the promotion of transition to telogen and MPAnA pathophysiology justifies the use of oral 5-alpha-reductase inhibitors, such as finasteride, in the management of hair loss. Two one-year trials encompassing 1553 men with male-pattern hair loss found 99% of subjects to show decreased progression or the reversal of hair loss with oral finasteride. In addition, authors observed clinically significant increases in hair count with oral finasteride treatment compared to placebo ( p < 0.001) [ 26 ]. However, as DHT is an androgen, treatment with 5-alpha-reductase inhibitors and a reduction in DHT levels has the rare side effects of sexual dysfunction and diminished libido [ 22 ].

Interestingly, however, the usefulness of collecting serum DHT levels in a routine hair loss work-up has been debated. A 2014 study analyzed serum DHT concentrations among 19 women and 9 men with AnA, in addition to 17 healthy women and 4 healthy men without hair loss [ 27 ]. Although increased serum DHT concentrations were observed in patients with AnA, as expected, increased serum DHT concentrations were also observed in the control group with no statistically significant difference between groups [ 27 ]. In addition, the authors found no correlation between DHT concentrations and the progression of alopecia, although the study is limited by a small sample size. The authors concluded that rather than serum DHT concentration, the genetically determined sensitivity of hair follicles to DHT may mediate DHT-associated hair loss [ 26 ]. However, these results are conflicting with another study including 178 patients with MPAnA and 61 healthy controls, which found a significantly greater level of DHT in MPAnA patients than normal controls. Yet, similarly to the prior study, authors found no significant difference in serum androgen levels based on hair loss severity [ 28 ].

In conclusion, there is questionable utility for routine serum DHT testing for patients with hair loss. However, it is necessary to understand the role of DHT in the pathophysiology of hair loss, as the enzyme converting testosterone to DHT, 5-alpha-reductase, is an effective therapeutic target for MPAnA.

2.2.3. Estrogen to Testosterone Ratio

Numerous studies have assessed the effects of testosterone and estrogen in isolation on hair parameters, including anagen phase length. While testosterone conversion to DHT can promote hair loss, estrogen has been postulated to have protective effects against hair loss based on differential observations of hair parameters throughout pregnancy, postpartum, and menopause, each characterized by estrogen concentration differences. In pregnancy, characterized by high levels of estrogen, hair growth, and hair diameter increases while the hair shedding decreases [ 29 ]. These observations have been attributed to estrogen, although other pregnancy-related changes, such as increases in human chorionic gonadotropin, progesterone, prolactin, growth factors, and cytokines, may additionally contribute [ 29 ]. In contrast, a decrease in estrogen and progesterone following delivery is associated with postpartum TE. Furthermore, estrogen depletion characteristic of menopause is associated with FPAnA, with decreased hair density and diameter, and decreased anagen phase length [ 29 ]. The protective role of estrogen in hair loss is further supported by the observation that the frontal hairline of women, often spared in FPAnA, depicts a relatively increased level of aromatase, the enzyme responsible for the conversion of androgens to estrogen [ 30 ].

However, rather than serum values in isolation, research has suggested that a decreased estrogen to testosterone ratio, rather than absolute values of either hormone, may instead contribute to FPAnA [ 31 ]. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, free and total testosterone, sex hormone binding globulin (SHBG) and dehydroepiandrosterone sulfate (DHEAS) were studied among 20 premenopausal women with FPAnA and 9 healthy controls [ 31 ]. Absolute values of androgens were normal in both groups, although the patients with FPAnA depicted reduced estradiol to free testosterone and estradiol to DHEAS ratios. The authors therefore concluded that the estradiol to free testosterone ratio may contribute to FPAnA.

Thus, rather than increasing the absolute values of estrogen, deliberately increasing the estrogen to testosterone ratio may be an effective therapeutic strategy. Estrogen replacement therapy has been assessed for the management of alopecia, both in female and male patients. A case report depicted extensive hair regrowth in a male-to-female transition candidate with AnA treated with estradiol supplementation and estrone solution, although simultaneous treatment with minoxidil inhibits the ability to make direct conclusions of the efficacy of estrogen replacement. However, the patient was also treated with anti-androgenic Aldactone (spironolactone), so it is possible extensive hair regrowth occurred due to increased estrogen to testosterone activity [ 32 ].

In addition, a study compared the efficacy of two oral contraceptives, one containing antiandrogenic chlormadinone acetate with synthetic estrogen and another containing synthetic progestin with synthetic estrogen, on acne parameters; the authors also reported resolution rates of alopecia [ 33 ]. Alopecia resolution rates were 86% and 91% among those receiving chlormadinone/synthetic estrogen and synthetic progestin/synthetic estrogen, respectively. This suggests anti-androgenic activity coupled with estrogen replacement, and thus an increased estrogen to testosterone activity ratio may be as effective as an estrogen and progestin replacement for the resolution of alopecia.

Ultimately, larger, controlled studies are necessary to assess the efficacy of therapy specifically targeting the estrogen to testosterone ratio. However, prior reports suggest the estrogen to testosterone ratio may be of more value than the absolute values of either hormone, which may further explain why sex hormone concentrations often fail to correlate with reported alopecia symptoms [ 34 ].

2.3. Stress

The association of stress and hair loss has been widely documented. As previously described, Arck et al. suggested that substance P-dependent inflammatory pathways may mediate stress-induced hair loss [ 16 ]. In 1998, a case-control study used the Social Readjustment Rating Scale to compare stress among twenty-five women who experienced recent hair loss compared with twenty-five healthy controls [ 35 ]. Compared to ten control subjects, twenty-two of those experiencing unexplained hair loss reported high stress, resulting in an odds ratio of eleven; based on this study, authors concluded that women experiencing high stress are eleven times more likely to experience hair loss [ 35 ]. However, this study is limited by its small sample size and potential recall bias. Still, this study depicts an early documentation of the association of stress and hair loss.

Stress can foster anagen to telogen transition and is closely related to telogen effluvium, with resulting telogen elongation [ 36 ]. Furthermore, cortisol, the primary stress hormone, has been shown to affect cyclic regulation of the hair cycle and proteoglycan synthesis [ 23 ]. The effects of cortisol on the hair cycle and proteoglycans are important to understand, as elevated cortisol levels have been observed in both men and women with androgenetic alopecia in comparison to healthy controls [ 37 , 38 ].

Research has highlighted the importance of proteoglycans, such as versican and decorin, and glycosaminoglycans in normal hair follicle and hair cycle functioning. For example, while versican functions to protect cells from oxidative stress-induced apoptosis, decorin acts as an anagen inducer, promoting hair growth [ 23 ]. However, high cortisol levels have been shown to exhibit damaging effects on proteoglycans in the hair follicle, with reduced synthesis and increased breakdown [ 39 ]. Thus, cortisol inhibition may promote anagen and hair growth via increased proteoglycan concentrations.

A study compared shampoo containing 2% ketoconazole, an antifungal cortisol inhibitor, with unmedicated shampoo among 39 patients with MPAnA. Medicated shampoo increased hair density and the size and proportion of hair follicles residing in the anagen phase, both in isolation and in combination with minoxidil [ 40 ]. Similarly, a 2007 study including six patients with MPAnA found hair regrowth with 2% ketoconazole topical lotion [ 41 ]. Interestingly, one patient stopped using the lotion and depicted hair loss recurrence three months later, suggesting continual ketoconazole application is required for maintenance of hair regrowth. In addition, the authors found that ketoconazole may promote hair regrowth via both androgen-dependent and androgen-independent mechanisms [ 41 ].

Lastly, a 2019 study compared the efficacy of 2% topical ketoconazole in comparison to 2% minoxidil among patients with FPAnA [ 42 ]. Whereas a significant difference between baseline and months 4 and 6 was observed among those receiving topical minoxidil, significant improvement with ketoconazole was observed only at month 6, suggesting delayed treatment efficacy with ketoconazole. However, whereas treatment-related side effects were reported among 55% of those receiving minoxidil, side effects were reported in only 10% receiving ketoconazole, and there was no difference in patient satisfaction between the groups [ 42 ]. These studies highlight the potential therapeutic role of cortisol inhibition on hair regrowth in patients with both male and female-pattern androgenetic alopecia, although additional large, randomized controlled trials are needed to better assess efficacy.

Work has highlighted the role of stress and cortisol in hair cycle dysregulation and hair loss. Unfortunately, stress can often act as an initiating event and a resulting outcome of hair loss, further perpetuating hair loss. However, cortisol-inhibition may be an effective therapeutic target for the treatment of androgenetic alopecia.

2.4. Nutritional Deficiencies

Proper nutrition is essential for anagen and telogen balance, and caloric or nutritional deficiency can negatively impact hair structure, growth, and pigmentation [ 43 ]. Furthermore, TE can occur following rapid weight loss or reduced protein intake, and diffuse alopecia may be a presenting sign of nutritional deficiency [ 44 ]. Studies have found associations between nutritional deficiency and a variety of types of hair loss, including chronic TE, AnA, and AA [ 44 ]. A variety of nutritional components have been evaluated for their effect on hair structure and growth, including a variety of vitamins and minerals, in addition to fatty acids and protein. There remains continued uncertainty regarding the value of nutritional supplementation for hair loss, especially among non-deficient individuals, and the over-supplementation of some nutrients may increase toxicity and even contribute to hair loss.

2.4.1. Amino Acids and Protein

Protein is an important dietary source of many important vitamins, including B and E vitamins. Protein-energy malnutrition, observed in children with kwashiorkor, marasmus, and marasmic-kwashiorkor conditions, is associated with skin and hair alterations [ 43 ]. A 2017 cross-sectional study sought to determine the prevalence of a variety of nutritional deficiencies, including essential and non-essential amino acids, among one-hundred patients with TE, MPAnA, or FPAnA [ 45 ]. Deficiency of essential amino acids histidine, leucine, and valine were common among alopecia subtypes. Specifically, more than 90% of participants with AnA and 77.8% with TE exhibited histidine deficiency, and 98.2% of patients with TE exhibited leucine deficiency, in addition to all patients with FPAnA. Among non-essential amino acids, alanine and cysteine deficiencies were the most common. A total of 91.67% of patients with FPAnA, 91.18% of patients with MPAnA, and 90.74% of patients with TE had alanine deficiencies; 55.58% and 50% of patients with MPAnA and TE, respectively, exhibited cysteine deficiency [ 45 ]. The results of this study exemplify the association between select amino acid deficiency and various alopecia subtypes.

Many studies assessing amino acid supplementation for hair loss are limited based on non-disclosure of complete supplement composition and the inclusion of other nutritional components, limiting the ability to assess the direct effect of amino acid supplementation [ 44 ]. However, a 2007 study observed statistically significant improvement and normalization of mean anagen hair rate following a six-month treatment with an oral supplement composed of L-cystine, medicinal yeast, and pantothenic acid (vitamin B5) [ 46 ].

Studies have additionally assessed the role of marine proteins on hair loss [ 47 , 48 ]. A 2015 study randomized female participants with self-reported hair thinning to receive either an oral supplement containing marine proteins and glycosaminoglycans (N = 30) or a placebo supplementation (N = 30) [ 47 ]. Twice daily treatment supplementation for 90 days resulted in a significant increase in terminal hair number compared to baseline and placebo ( p < 0.0001). In addition, significantly less hair shedding, greater Self-Assessment, and Quality of Life Questionnaire scores were observed with oral protein supplementation. Similarly, a 2015 study observed significantly decreased hair shedding and significantly increased hair diameter following supplementation with a marine protein-based dietary supplement compared to placebo [ 48 ].

Collectively, these studies demonstrate relative amino acid deficiencies among patients with various alopecia subtypes. Furthermore, oral protein-based supplementation depicts promising results highlighting the importance of a nutritional approach to the management of hair loss among some patients. It remains unclear whether protein or amino-acid supplementation is necessary for all alopecia patients, with or without marked deficiencies. Another unclear question is whether supplementation with select amino acids may provide benefit over a general protein supplement.

2.4.2. Fatty Acids

In addition, studies have suggested that omega-3 and omega-6 fatty acid deficiencies may contribute to an increased proportion of hair follicles residing in the telogen phase and resulting alopecia. Arachidonic acid, an omega-6 fatty acid, has been shown to promote growth factor expression implicated in hair growth, such as fibroblast growth factor (FGF)-7 and FGF-10, in murine models [ 49 ]. In addition, arachidonic acid supplementation prolonged the anagen phase and promoted hair shaft elongation. Furthermore, unsaturated fatty acids may function to inhibit 5-alpha-reductase and modify androgen activity similarly to finasteride [ 44 ].

Fatty acid supplementation reduced alopecia in self-grooming rhesus macaques [ 50 ]. In addition, topical linoleic acid application was shown to reverse scalp dermatitis, alopecia, and depigmentation of hair in one case report [ 51 ]. Lastly, a randomized controlled trial including one hundred-twenty healthy females observed a significantly reduced telogen hair percentage following 6-months of supplementation with omega 3 and 6 fatty acids, in addition to antioxidants [ 52 ]. Compared to the control group, those receiving the supplement exhibited greater promotion of anagen hair, suggesting that fatty acid supplementation may function to increase the anagen to telogen ratio.

2.4.3. Vitamins

Micronutrients, including vitamins, impact the normal hair follicle cycle and foster cellular turnover of matrix cells in hair follicle bulbs [ 43 ]. Furthermore, murine models have demonstrated an increased proportion of hair follicles in anagen with dietary vitamin A supplementation [ 53 ]. However, excess vitamin supplementation has also been shown to have negative effects on hair parameters [ 43 ].

A 2015 murine study found that vitamin A increases nuclear localized beta-catenin and WNT7A levels within the hair follicle bulge in a dose-dependent manner [ 53 ]. This suggests that the effects of dietary vitamin A on anagen induction and stem cell activation occur via increased WNT signaling. Other studies suggest retinoic acid, a metabolite of vitamin A, may regulate hair follicle stem cells in a U-shaped dose-dependent manner [ 54 ].

Interestingly, vitamin A deficiencies have not been directly associated with hair loss, although over-supplementation has [ 43 ]. A 1979 case report detailed a woman experiencing sudden hair loss, and a clinical work-up revealed excess serum vitamin A levels secondary to consumption of a daily vitamin A supplement [ 55 ]. Similarly, authors reported decreased hair count, density, and percent of anagen hairs among thirty acne vulgaris patients receiving isotretinoin, an oral derivative of vitamin A [ 56 ]. Current research suggests that although vitamin A can stimulate stem cells and induce anagen, over-supplementation and excess serum levels can have deleterious effects on hair parameters.

B vitamins, including niacin (vitamin B3), biotin (vitamin B7), and folic acid (vitamin B9) have been implicated in hair loss. For example, in addition to the well-documented pellagra characteristic of niacin deficiency, alopecia is an additional common clinical finding associated with deficient niacin [ 43 ]. However, no studies have directly assessed niacin levels among patients presenting solely with hair loss, and studies have found no significant difference in folate levels between alopecia patients and control subjects [ 57 , 58 ].

Biotin, a cofactor for carboxylation enzymes with dietary sources including protein, has been more extensively assessed for effects on hair parameters, and it is included in a variety of supplements or serums intended for hair health [ 44 ]. Genetic biotin deficiency is associated with severe dermatitis and alopecia (infantile) and sparse or absent scalp, eyebrows, and eyelash hair (infantile). Similarly, acquired biotin deficiency is characterized by alopecia and brittle nails [ 43 ]. A 2016 study assessed serum biotin levels in women with self-reported hair loss and found 38% of patients reported a biotin deficiency [ 59 ]. However, this study did not include matched controls.

Despite many misconceptions, biotin functions to increase hair strength, rather than hair growth. Furthermore, biotin can interfere with troponin and thyroid testing. For example, excess serum biotin can result in a falsely low TSH level [ 60 ], and unnecessary supplementation can lead to missed cardiac events [ 61 ]. Yet, biotin supplement use has depicted increasing trends from 1999 to 2016; a cross-sectional survey study found self-reported use of biotin at 1 mg/d or greater to increase from 0.1% (95% CI 0.0–0.05%) in 1999 to 2.8% (95% CI 1.9–3.9%) in 2015–2016 [ 61 ].

Despite biotin’s popular inclusion in marketed hair supplements, there is no indication that biotin supplementation should be used among healthy individuals [ 43 ]. While biotin supplementation has shown benefit specifically among cases in which acquired or inherited causes of biotin deficiency are identified, there is insufficient evidence supporting supplementation among healthy individuals who are not deficient [ 62 ]. Thus, vitamin B testing may only be clinically useful in cases of suspected biotin deficiency, where biotin supplementation may improve the clinical condition.

Vitamin D is an essential nutrient in the body serving many different functions. The fat-soluble vitamin can be taken orally, present in foods and dietary supplements, or can be synthesized endogenously by the body through a photochemical reaction upon sun exposure through the skin [ 62 ]. Once activated, vitamin D is able to promote the absorption of calcium in the gut, balances bone mineralization via regulation of calcium and phosphate levels, and provides other immunomodulatory functions [ 63 ]. Although the role of vitamin D in hair loss is not completely understood, one predominant theory suggests that the expression of the vitamin D receptor (VDR) is required for a normal hair cycle [ 64 ], including anagen initiation [ 65 ]. VDR was found to be expressed in epidermal keratinocytes and mesodermal dermal papilla cells, both of which make up a hair follicle [ 64 ]. Studies performed in VDR-null mice found that the dermal papilla separates from the hair follicle during the catagen phase and this causes a failure to reinitiate the anagen phase [ 64 ]. This finding has inspired many clinical trials to investigate the role of vitamin D in those experiencing hair loss.

A case-control study performed in 2021 investigated the role of vitamin D serum levels in 30 males with androgenetic alopecia [ 66 ]. Results showed significantly lower vitamin D levels in males with androgenetic alopecia compared to healthy controls ( p < 0.01). A prospective case-controlled study conducted in 2013 also assessed vitamin D serum levels, but specifically in women with FE or FPHL [ 67 ]. Vitamin D levels were also significantly reduced in women with FE or FPHL compared to controls ( p < 0.001) and were found to be increasingly abnormal as disease severity increased.

A review performed in 2017 summarized trials which assessed vitamin D levels in FPHL and TE [ 64 ]. Two studies that were conducted solely in patients with FPHL both revealed significantly lower vitamin D levels compared to controls. Three studies assessed vitamin D levels in patients with TE. Two of the three studies described significantly lower vitamin D levels in patients with TE, however one study conducted by Karadag et al. revealed the opposite [ 68 ]. Serum vitamin D levels were significantly higher in those with TE compared to controls ( p < 0.01). The authors explained that this increase was likely compensatory instead of causatory to the hair loss.

Overall, low vitamin D levels in patients experiencing hair loss has been consistently reported by many studies in both men and women. Data is scarce regarding the efficacy of vitamin D supplementation or topical solution for patients with vitamin D deficiency and concomitant alopecia. However, animal model studies have found benefit with vitamin D supplementation [ 69 ], and oral vitamin D supplementation with minoxidil was found to be significantly more effective than minoxidil alone in the treatment of FPAnA [ 70 ]. Yet, oral vitamin D monotherapy did not result in significant improvement. Overall, additional studies are required to determine vitamin D supplementation efficacy, both among hair loss patients depicting deficiency and those who do not. Assessing the serum vitamin D level in patients presenting with hair loss may be beneficial but the evidence for vitamin D supplementation is supportive of use with minoxidil.

Vitamin E is postulated to increase hair count due to its antioxidant activity and lipid peroxidation inhibition, although data is similarly lacking regarding the benefits of supplementation [ 71 ]. However, a 2010 study describes a significantly increased number of hairs among 21 subjects receiving tocotrienol supplementation compared to 17 subjects receiving a placebo supplementation; a 34.5% increase in hair number compared to baseline was observed after 8 months of tocotrienol supplementation [ 72 ].

Yet, excess vitamin E increases the risk of bleeding and decreases thyroid hormone production, which may ironically promote hair loss. For example, supplementation was associated with adverse effects on hair parameters among volunteers ingesting about 30x the recommended daily intake [ 44 ]. Interestingly, the volunteers exhibited reduced thyroid hormone levels. Additional research is necessary to determine the utility of vitamin E supplementation and effective doses that function to improve hair parameters while avoiding excess.

2.4.4. Minerals

Iron, zinc, and selenium are minerals that have been implicated in hair cycle regulation. Iron deficiency is the most prevalent nutritional deficiency globally, and iron deficiency contributes to TE development [ 43 ]. Iron’s potential impact on the hair cycle is derived from its function as a cofactor for the rate-limiting enzyme of DNA synthesis [ 44 ]. Interestingly, some studies have observed low serum ferritin, the storage form of iron, among patients with chronic TE, AnA, and AA; however, other studies have found no association [ 44 ]. Section 4.1 discusses serum ferritin levels among patients with alopecia in greater detail, further describing testing utility.

Zinc, an important component of various metalloenzymes that regulate protein synthesis and cell division, has been associated with TE and brittle hair among deficient patients [ 44 ]. A study assessing serum zinc levels among 312 alopecia patients (AA, MPAnA, FPAnA, or TE) and 30 healthy controls found a significantly lower serum zinc value among patients exhibiting all types of studied hair loss compared to healthy controls ( p = 0.002) [ 73 ].

Importantly, zinc-associated alopecia is reversible, increasing the utility of assessing serum zinc levels among patients with unexplained alopecia [ 44 ]; prior work has established the benefit of oral zinc supplementation among zinc-deficient patients with TE [ 74 ] and AA [ 75 ]. However, there is no current evidence of the efficacy of zinc supplementation for individuals experiencing hair loss who are not deficient.

Selenium, a mineral that functions in oxidative damage protection and hair follicle morphogenesis, has been associated with sparse hair growth and hair loss among deficient rats [ 76 ] and mice [ 77 ]. In humans, selenium supplementation among deficient patients led to hair re-pigmentation [ 78 ] and improvement of alopecia [ 79 ]. However, similar to other minerals, there is no evidence of the utility of selenium supplementation among non-deficient patients. Furthermore, selenium toxicity can perpetuate generalized hair loss, in addition to other symptoms such as blistering skin lesions, gastrointestinal symptoms, and memory problems [ 44 ].

2.5. Poor Sleep

Poor sleep has been associated with increased risk and severity of alopecia subtypes, including AA and AnA. Conversely, those with alopecia have been found to exhibit reduced sleep quality compared to controls. A 2022 study analyzed the prevalence of sleep abnormalities between 223 patients with MPAnA and 223 control subjects [ 80 ]. The authors found a significant association between severe MPAnA and three sleep profiles: total sleep time less than or equal to six hours (odds ratio (OR) = 2.16, 95% confidence interval (CI) = 1.02–4.57, p = 0.044); a Pittsburgh Sleep Quality Index (PSQI) score greater than 5 (OR = 3.72, 95% CI= 1.42–9.72, p = 0.008); and STOP-Bang score greater than or equal to 5 (OR = 3.01, 95% CI = 1.11–8.13, p = 0.030). The STOP-Bang score specifically assesses signs of obstructive sleep apnea, and higher STOP-Bang and PSQI scores are negative findings, suggesting an association between sleep disturbances and MPAnA [ 80 ]. Similarly, poor sleep habits is associated with increased severity of AnA [ 81 ].

A similar study assessed the prevalence of sleep disturbances among 51 AA patients and 51 age- and sex-matched controls [ 82 ]. As observed among individuals with MPAnA, the PSQI score was significantly greater among patients with AA compared to matched controls (7 ± 4.13 vs. 3.53 ± 1.96, p < 0.001). A greater number of AA patients depicted excess daytime sleepiness, measured with the Epworth Sleepiness Scale, than controls. Furthermore, sleep quality was worse among AA patients also suffering from anxiety or depression, thereby highlighting the importance of addressing both sleep quality and concomitant psychiatric distress in the management of AA [ 82 ].

Furthermore, a 2018 study including 25,800 with diagnosed sleep disorders and 129,000 control subjects found those with sleep disorders to have a significantly greater risk for AA than controls [ 83 ]. The authors found an adjusted hazard ratio of 1.651 among those with sleep disorders (95% CI 1.382–1.974), portraying sleep disorder as an independent risk factor of AA [ 83 ].

Circadian Rhythm and Clock Genes

The circadian rhythm is an internal clock of approximately 24 h that regulates alert and sleep cycles and responds to environmental changes of light [ 84 ]. The circadian rhythm is further regulated by clock genes encoding for clock proteins, which contribute to various positive and negative feedback loops. The core of the circadian clock genes lie with bHLH-PAS transcriptional activators CLOCK and BMAL1 [ 84 ]. Following heterodimer formation, CLOCK and BMAL1 activate period genes (PERs) and cryptochrome circadian regulator genes (CRYs), which translocate into the nucleus and inhibit BMAL1 and CLOCK transcriptional activity in a negative feedback loop. By inhibiting BMAL1 and CLOCK transcriptional activity, PERs and CRYs effectively inhibit their own expression, resulting in the re-activation of BMAL1/Clock. This feedback loop allows for rhythmic expression characteristic of the circadian rhythm.

Interestingly, clock genes have been found to play an important regulatory role in the hair growth cycle [ 85 ]. Furthermore, circadian clock expression changes correlate with hair growth cycle events, with the highest expression characteristic of the telogen-anagen transition. Specifically, CLOCK/BMAL1 target genes such as PEers, Dbp, and Rev-Erbα have been found to increase in telogen and early anagen [ 85 ]. In situ hybridization studies found that rhythmic circadian gene expression occurred more prominently in the secondary hair germ, which contains cycling stem and progenitor cells, in comparison to the bulge region and dermal papilla regions in which it is situated between.

Interestingly, while circadian amplitude reduced within the hair follicle proper during anagen progression, circadian amplitude remained robust in the dermis and interfollicular epidermis. Suspension of the circadian rhythm in the highly proliferative hair follicle proper corresponds to similarly observed circadian rhythm suspension in the testis and thymus, both of which are highly proliferative and differentiating tissues [ 85 ].

In 2010, Geyfman and Andersen analyzed CLOCK and BMAL1 mutant murine models and observed a significant delay in anagen progression, which was more pronounced in BMAL1 mutant mice [ 85 ]. Mutant mice entered anagen at the same time, although they experienced a week-long delay in the first anagen phase prior to resumption of the hair cycle; absence of mitotic cells in the early anagen phase was observed in mutant mice hair follicles, likely mediated by absent phosphorylated retinoblastoma protein, which fosters cell cycle progression through the G1-S checkpoint. Further analysis revealed that increased inhibitory p21 may contribute to G1-S cell cycle arrest. However, no abnormalities were observed in anagen follicle structure in mutant mice, leading authors to conclude that circadian clock genes are involved in the timing of the telogen-anagen transition, rather than hair follicle morphogenesis [ 85 ].

2.6. Cell Division Inhibiting Medication

Similarly, medications directly inhibiting cell division, such as various chemotherapies, can have similar effects on the cell cycle. Chemotherapy drugs, such as paclitaxel, docetaxel, vinblastine, and vincristine function to inhibit mitosis and thereby reduce the dividing capacity of rapidly growing cancer cells. However, due to lack of selectivity for cancer cells, such drugs can impact rapidly dividing cells throughout the body, including dermal papilla cells and epithelial cells of the hair follicle, in addition to matrix keratinocytes. Unsurprisingly, the highly proliferative anagen phase is most sensitive to toxins and drugs, in contrast to the mitotically inactive phases catagen and telogen. Furthermore, in addition to directly affecting cellular proliferation during the anagen phase, chemotherapy can accelerate the transition to telogen [ 86 ].

Upon termination of the drug, hair regrowth can occur, although with an occasionally different color or texture [ 87 ]. Despite reversibility, alopecia secondary to cell division inhibiting medication is an important, emotionally-distressing side effect for cancer patients; almost half of female patients consider hair loss the most traumatic aspect of chemotherapy, with fear of hair loss prompting declination of chemotherapy by 8% [ 88 ].

Unfortunately, there are no approved pharmacologic remedies for chemotherapy-induced alopecia. While topical minoxidil has been shown to reduce the severity and shorten the duration of drug-induced hair loss, it could not prevent alopecia [ 88 ]. However, scalp cooling has been shown to decrease drug delivery to the scalp, thereby mitigating chemotherapy-induced hair loss [ 89 ].

2.7. History-Taking Tips

As a variety of factors can promote anagen to telogen transition and contribute to hair loss, it is essential to take a thorough history for patients presenting with hair loss. Harrison and Bergfeld (2009) recommend obtaining the following information:

  • Duration of hair shedding;
  • Episodic or continuous patterns;
  • Estimated percent hair loss;
  • Potential triggers and temporal relationships;
  • Recent surgery, fever, illness, childbirth, psychological stress;
  • History of chronic disease, malignancy, infection, autoimmune disease, liver or renal disease;
  • Menstrual history;
  • Hair care products and procedures;
  • Dietary history including vitamins and supplements;
  • Family history of AnA, AA, autoimmune disease, or thyroid disorder;
  • Medication history including botanicals;
  • History of radiation therapy or heavy metal exposure.

In addition, we recommend inquiring about sleep patterns. Evaluation and lab testing utility will be discussed in Section 4 .

3. Factors Increasing Telogen to Anagen Transition and Hair Growth

There are a variety of factors that conversely mediate telogen to anagen transition and thereby support hair growth, including increased blood flow, direct stimulation of the hair follicle, and growth factors ( Table 1 ).

Summary of interventions indicated for hair growth.

3.1. Increased Blood Flow

Developing hair follicles are surrounded by deep dermal vascular plexuses. Associated blood vessels function to supply nutrients to the developing follicle and foster waste elimination. As such, proper blood supply is necessary for effective hair follicle growth, further exemplified by the angiogenic properties of the anagen phase [ 90 ].

3.1.1. Scalp Massage

Theoretical benefits of increased blood flow to the hair follicles justifies the assessment of scalp massage on hair parameters. A 2016 study assessed the effect of a 4-min standardized daily scalp massage for 24 weeks among nine healthy men [ 91 ]. Authors found scalp massage to increase hair thickness, upregulate 2655 genes, and downregulate 2823 genes; hair cycle-related genes including NOGGIN, BMP4, SMAD4, and IL6ST were among those upregulated, and hair-loss related IL6 was among those downregulated. The authors thereby concluded that a standardized scalp massage and subsequent dermal papilla cellular stretching can increase hair thickness, mediated by changes in gene expression in dermal papilla cells [ 91 ].

In addition, of 327 survey respondents attempting standardized scalp massages following demonstration video, 68.9% reported hair loss stabilization or regrowth [ 92 ]. Positive associations existed between self-reported hair changes and estimated daily minutes, months, and total standardized scalp massage effort. This study is limited based on recall bias and reliance on patient adherence and technique, although it suggests promising therapeutic potential for standardized scalp massage, which functions to increase blood flow.

3.1.2. Minoxidil

Similarly, minoxidil, a pharmacologic agent that relaxes blood vessels and increases blood flow, has been widely utilized for the management of AnA. While topical minoxidil has been FDA approved for MPAnA and FMPAnA, oral minoxidil, especially in a low dose, is used off-label for AA and TE [ 93 , 94 , 95 ].

In addition to the relaxation of blood vessels, minoxidil also acts as an anti-inflammatory agent, an inducer of the Wnt/β-catenin signaling pathway, and as an antiandrogen [ 96 ]. Effects on anagen and telogen phases have been proposed, although a study in rats found that topical minoxidil increased DNA synthesis rate in the anagen bulb, rather than prolonging the length of the anagen phase [ 97 ]. However, animal studies have described shortened telogen and increased telogen to anagen transition [ 98 ].

A comprehensive review of oral and topical minoxidil found that 2% topical minoxidil prompts hair regrowth in both frontotemporal and vertex areas among males with MPAnA, with peak hair regrowth after one year of use [ 96 ]. No significant differences were found between 2% and 5% topical solutions in terms of efficacy. A meta-analysis assessing topical minoxidil found an average score difference of 16.7 for the promotion of total hair growth between individuals receiving topical minoxidil vs. control (95% CI 9.34–24.03). An average difference of 20.9 (95% CI 9.07–32.74) was observed for non-vellus hair growth [ 99 ]. Similarly, individuals using minoxidil had a 2.28× greater likelihood of exhibiting hair growth than those using a placebo (95% CI 1.343–1.80).

In addition, despite off-label use, oral minoxidil 5 mg/day exhibited significantly greater efficacy than both 2% and 5% topical minoxidil in males with MPAnA [ 96 ]. Low dose oral minoxidil and sublingual may additionally be safe and effective in patients with FPAnA [ 96 ]. Interestingly, a review of 17 studies with 634 patients found oral minoxidil to be an effective strategy among patients refractory to topical formulations [ 100 ].

Despite minoxidil efficacy, authors have sought therapeutic strategies to maintain biological efficacy while reducing side effects, such as hypertrichosis. For example, a 2022 retroactive study of patients with minoxidil-induced hypertrichosis found clear improvement among 35 FPAnA patients following initiation or up-titration of oral bicalutamide, an antiandrogenic medication [ 101 ]. Simultaneous bicalutamide treatment at a mean dose of 14.4 mg allowed an increase in the mean daily minoxidil dose without the development of hypertrichosis.

In addition, authors have sought novel minoxidil delivery methods to maximize effects while minimizing side effects. A 2022 study used biocompatible and safe hyaluronic acid (HA)-constructed microneedles to deliver minoxidil to hair dermal papilla cells [ 102 ]. A chemotherapy-induced alopecia murine model was used to examine the effects of HA-microneedle delivery of minoxidil compared to conventionally applied minoxidil. HA solution alone demonstrated reduced hair loss in mice with alopecia. Yet, authors observed maximal anti-alopecia effects with minoxidil loaded HA-microneedles, measured via hair follicle length, hair density, and dermal thickness, although efficacy was comparable with topical minoxidil treatment [ 102 ]. Despite similar efficacy, microneedle delivery of minoxidil may maximize anti-alopecia effects while minimizing side effects during treatment.

Lastly, a 2022 study assessed the efficacy of liquid crystal nanocarriers to direct minoxidil to the pilosebaceous follicle, which is difficult to reach given its origination in deeper skin layers [ 103 ]. Authors loaded minoxidil into the liquid crystal nanocarrier and assessed biological effectiveness compared to conventionally applied minoxidil among rats. The crystal nanocarrier selectively targeted the pilosebaceous follicle, increasing efficacy and duration of biological effects while reducing side effects. Whereas untreated rats depicted a mean 3.6 mm regrowth and rats treated with hydro-alcoholic 5% w / v minoxidil showed a mean 4.3 mm regrowth after one month, rats treated with minoxidil-loaded nanocarriers demonstrated a significantly ( p < 0.001) greater mean re-growth (5.6 mm). The percentage of hair length increase was 19% and 59% for rats treated with hydro-alcoholic minoxidil and minoxidil-loaded nanocarriers, respectively. In addition, 12 healthy human volunteers demonstrated tolerability and safety of the nanocarrier via a safety evaluation characterized by treatment application on five ventral surfaces of each forearm [ 103 ]. This study suggests the liquid crystal nanocarrier is a safe and effective vehicle to delivery minoxidil selectively to the pilosebaceous follicle, allowing reduced concentrations of active compound to achieve greater biologic efficacy.

3.1.3. HIF-1α

Hypoxia inducible factor (HIF) is a transcription factor that responds to hypoxic stress via angiogenesis regulation. As dermal papilla cells are reactive to hypoxia, HIF stimulation modulates neovascularization and regeneration, which is necessary to combat the lack of blood vessel and nutrient supply characteristic of AnA [ 104 ]. Thus, a 2023 study assessed the effect of HIF strengthening factor (HSF) hair restoration on various hair parameters [ 104 ]. Twenty subjects, four female and sixteen male, underwent a once-daily application of HSF hair restoration technology for nine months. Authors observed a 7.2% increase in hair thickness, 14.3% increase in hair density, and a 20.3% increase in shine and elasticity. Treatment-responsive subjects (85% of the cohort) depicted a 66.8% reduction in hair loss after six months of treatment, with an increase in hair growth up to 32.5% (mean 1.8%). Lastly, the test area depicted an average anagen hair percent increase of 8.0% and an average telogen hair percent decrease of −14.0%, depicting the ability of HSF hair restoration technology to promote telogen to anagen transition [ 104 ].

3.2. Direct Stimulation of the Hair Follicle

Herbs, supplements, prostaglandins, and light-based approaches have been shown to promote hair growth via direct stimulation of the hair follicle.

3.2.1. Herbs and Phytochemicals

A review article conducted in 2019 summarized a variety of clinical trials that assessed the use of herbs for the treatment of hair loss [ 105 ]. The most evidence for promoting hair growth was attributed to many herbs including, “ Curcuma aeruginosa (pink and blue ginger), Serenoa repens (palmetto), Cucurbita pepo (pumpkin), Trifolium pratense (red clover), and Panax ginseng (Chinese red ginseng)” [ 105 ]. The article states that the beneficial effects on hair growth from these herbs is possibly due to their inhibitory effects on 5-alpha-reductase.

An additional review study, also conducted in 2019, summarized different alternative remedies for the treatment of alopecia [ 106 ]. Among the herbal treatments described, it was noted that Curcumin aeruginosa , when used in combination with minoxidil, can provide synergistic hair growth effects. Multiple studies summarized also supported the efficacy of topical melatonin, with results indicating that melatonin can increase hair counts, hair density, and anagen hair. Five studies also consistently supported the use of capsaicin for hair growth. One study described increased hair growth with oral supplementation and the remaining studies utilized topical capsaicin, which also displayed increases in hair growth.

Furthermore, Morbus alba , otherwise known as white mulberry, is an herb that has been shown to influence the hair growth cycle [ 107 ]. A study conducted in 2021 on hair follicle dermal papilla cells (HFDPCs) displayed promising results. Morbus alba was found to cause activation of beta-catenin in HFDPCs which subsequently caused activation of the anagen phase. This finding supports the potential use of Morbus alba as a possible treatment option for hair loss.

Bhrinjaraj, otherwise known as Eclipta alba , has also shown promising effects on hair growth. A study was conducted on male albino rats, and they received either topical Eclipta alba formulated into a 5% petroleum ether extract or the positive control, Minoxidil 2% [ 108 ]. The results showed that the treatment group with Eclipta alba had higher counts of hair follicles in the anagen phase compared to the control.

Additionally, quercetin, which is a component of Hottuyunia cordata extract, has also shown to have beneficial effects for hair growth. A study conducted in 2020 utilized human dermal papilla cells (hDPCs) to test the effects of the extract [ 109 ]. They found significant effects on the function of mitochondria. Specifically, the mitochondrial membrane potentials and NADPH production was found to be increased, suggesting enhanced mitochondrial function. Furthermore, Bcl2 expression increased which is a marker for the anagen phase and increases cell survival. The expressions of the following were also found to be increased: Ki67 (cell proliferation marker), various growth factors such as VEGF, bFGF, KGF, and phosphorylation of Akt, Erk, and CREB. The extract was found to increase hair shaft growth, specifically in cultured human hair follicles. Overall, the researchers attributed the increased hair growth to the activation of the MAPK/CREB pathway which led to the increased expression of growth factors due to quercetin application.

Another study testing quercetin in mouse models further supported the beneficial effects on hair growth [ 110 ]. Mice with alopecia areata were given either quercetin or placebo injections. The results showed that the mice receiving the quercetin injections had improved hair growth in lesioned areas whereas the placebo group did not. The researchers also utilized non-alopecic mice and heat-treated them to induce alopecia; placebo or quercetin injections were then provided. They found that none of the mice receiving quercetin injections developed alopecia, whereas 24% of the placebo group did develop alopecia. Thus, quercetin may be a viable treatment option for treating alopecia although additional studies in humans are warranted.

Rosemary oil is another herbal remedy that has been suggested to increase hair growth. A study conducted in 2015 recruited 60 patients and assigned them to either use topical minoxidil 2% or rosemary oil for 6 months. By the end of the study both groups displayed significant increases in hair counts ( p < 0.05) compared to baseline, although there was no significant difference between the two groups. Nevertheless, rosemary oil in this study showed comparable results to minoxidil. Interestingly, minoxidil also was observed to be more commonly associated with scalp itching ( p < 0.05) [ 111 ]. Lavender oil (LO) has also been tested as a hair growth remedy. A study conducted in 2016 with mouse models assessed 3% LO vs. 5% LO vs. 3% minoxidil applied topically on the backs of mice once a day, 5 days per week for 1 month. They found that hair follicles significantly increased in all 3 groups by the end of the study, however, they did not comment on the difference among the groups [ 112 ].

Proanthocyanins have also shown promising results for hair growth in the literature. A study conducted on mouse hair follicle cells found that proanthocyanins extracted from grape seeds caused a 230% increase in proliferation compared to the control vehicle. The authors attribute the hair growth effects to the proanthocyanins ability to increase transition from the telogen phase to the anagen phase [ 113 ]. Another study studied the effects of procyanidin B2 derived from apple extract. Thirty male subjects with male-pattern hair loss were recruited and instructed to apply either 1% procyanidin B-2 or placebo to the scalp twice daily for 6 months. Hair density at the end of the study was significantly higher in the treatment group ( p < 0.0001) [ 114 ].

Overall, there are many herbs that have been tested in the literature for their effectiveness in treating alopecia. Many of these trials have found promising results, and thus they provide another treatment modality for patients experiencing hair loss to utilize.

3.2.2. Supplements

Supplements for hair growth have also been heavily researched for hair growth. In a randomized controlled trial conducted in 2018, 40 women with self-perceived hair thinning were recruited to either take the herbal supplement (brand: Nutrafol) or placebo for 6 months [ 115 ]. The supplement was noted to include a variety of ingredients including curcumin, ashwagandha, and saw palmetto. By days 90 and 180, the treatment group experienced a significant increase in the terminal and vellus hair counts compared to the placebo ( p < 0.009). Another supplement composed largely of marine protein (brand: Viviscal) were also tested in a separate randomized placebo-controlled trial [ 47 ]. Participants included 60 women with thinning hair and were asked to take either placebo or the supplement twice daily for 3 months. The results showed a significant increase in the terminal hair counts in the treatment group compared to placebo ( p < 0.0001).

Pumpkin seed oil supplements have also been shown to be beneficial for hair loss. A randomized control trial including 76 males with androgenetic alopecia were instructed to either take 450 mg of pumpkin seed oil supplements or placebo for 24 weeks [ 116 ]. Hair counts improved by 40% in those taking pumpkin seed oil whereas hair counts only improved 10% in the placebo group ( p < 0.001). The exact mechanism in the hair cycle is not known, however it is thought that pumpkin seed oil is enriched for delta-7-phytosterols and may inhibit 5-alpha-reductase activity [ 117 ].

3.2.3. Light-Based Approaches

Low level light therapy refers to therapeutic exposure to low levels of red and near infrared light [ 118 ]. Studies have demonstrated increased hair growth in mice with chemotherapy-induced alopecia and AA, in addition to both men and women human subjects. Proposed mechanisms of efficacy include stimulation of epidermal stem cells residing in the hair follicle bulge and promoting increased telogen to anagen phase transition [ 119 ]. Interestingly, while minoxidil and finasteride are the only FDA-approved drugs for AnA, a 2017 study found comparable efficacy among patients receiving low-level light therapy versus topical minoxidil among patients with FPAnA [ 120 ]. In addition, combination therapy resulted in the greatest patient satisfaction and lowest Ludwig classification scores of AnA.

A meta-analysis including eleven double-blinded randomized controlled trials found a significant increase in hair density among patients with AnA receiving low level light therapy compared to those in the placebo-controlled group; the standardized mean difference (SMD) was 1.316 (95% CI 0.993–1.639) [ 121 ]. Low level light therapy was effective for men and women. Furthermore, a subgroup analysis observed a more significant increase in hair growth in those receiving low-frequency therapy (SMD 1.555, 95% CI 1.132–1.978) than receiving high-frequency therapy (SMD 0.949, 95% 0.644–1.253) [ 121 ]. Despite the limitation of the heterogeneity of included trials, these results suggest low level light therapy to be a promising therapeutic strategy for AnA [ 121 ], although further research is necessary to determine the optimal wavelength and dosimetric parameters for hair growth [ 119 ].

3.2.4. Prostaglandins

Latanoprost is a prostaglandin F2 agonist and has been shown to have a direct effect on hair growth and pigmentation in eyelashes and hair around the eyes [ 122 ]. Clinically used to treat glaucoma, this medication was found to affect the follicles in the telogen phase and cause them to move to the anagen phase; this was supported by the increased number and length of eyelashes seen in patients using latanoprost [ 122 ]. Subsequently, the application of latanoprost for patients experiencing alopecia was assessed in clinical studies. One conducted in 2012 studied the effects of 0.1% latanoprost solution applied to the scalp for 24 weeks [ 123 ]. Participants included 16 males with mild androgenetic alopecia and were instructed to apply placebo on one area of the scalp and the treatment on another area. The results indicated that the area of scalp receiving latanoprost had significantly improved hair density compared to placebo ( p < 0.001).

Another prostaglandin known as bimatoprost, a prostamide-F2 analog, was also found to have a positive effect on hair growth in human and mouse models. A study conducted in 2013 also found that bimatoprost, in both humans and mice, stimulated the anagen phase of hair follicles prompting an increase in hair length, i.e., promoting hair growth [ 124 ]. The study also confirmed the presence of prostanoid receptors in human scalp hair follicles in vivo, opening the strong possibility that scalp follicles can also respond to bimatoprost in a similar fashion.

It is important to note, however, that not all prostaglandins induce hair growth. In a study analyzing individuals with androgenetic alopecia with a bald scalp versus a haired scalp, it was discovered that there was an elevated level of prostaglandin D2 synthase at the mRNA and protein levels in bald individuals [ 125 ]. They were also found to have an elevated level of prostaglandin D2. When analyzing the level of prostaglandin D2 synthase presence through the various phases of hair follicular growth, it was found that the level steadily increased throughout the anagen phase with a peak in late anagen, at the time of transition to the catagen (breakdown) phase. Therefore, the study concluded that PGD2’s hair loss effect represents a counterbalance to PGE2 and PGF2’s hair growth effects. In conclusion, prostaglandins are a promising treatment option for alopecia that require larger clinical studies; however, clinicians should be aware of which one to recommend for hair growth, as not all prostaglandins are alike.

3.3. Growth Factors and Platelet Rich Plasma

Platelet rich plasma (PRP) has conventionally been used to supplement a patient’s endogenous platelet supply to promote increased healing. However, its prominent supply of growth factors has prompted assessment of PRP for alopecia. Growth factors promote hair growth and increase the telogen to anagen transition. For example, a murine study found the fibroblast growth factor (FGF) induced the anagen phase and subsequently promoted hair growth [ 126 ]. Growth factors prominently included in PRP include platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factor (IGF) and FGF [ 127 ].

The growth factors of platelet-rich plasma stimulate the development of new follicles and neovascularization [ 128 ]. Three meta-analyses have assessed the efficacy of PRP injections compared to placebo control on the number of hairs per cm 2 among patients with AnA. One meta-analysis involving 177 patients found a mean improvement of PRP treatment compared to placebo of 17.9 (95% CI 5.8–30.5, p = 0.004) [ 129 ]; a second meta-analysis with 262 AnA patients observed a mean difference of 38.8 (95% CI 22.22–55.28, p < 0.00001) [ 130 ]; and a third meta-analysis including studies with parallel or half-head design found a mean difference of 30.4 (95% CI 1.77–58.93, p < 0.00001) [ 131 ].

Despite the efficacious results described by each meta-analysis for the use in AnA, gender differences have been observed. A 2020 meta-analysis found that while PRP significantly increased hair density and hair diameter from baseline in men, PRP only increased hair diameter in women, in the absence of significantly increased hair density. Furthermore, hair density in men was only significantly increased by a double spin method, in contrast to a single spin method [ 132 ]. The authors conclude that PRP effectiveness may be improved via higher platelet concentrations. Ultimately, PRP injections appear to have clinical efficacy in early studies albeit slightly different effects in men vs. women. Future research is necessary to establish the optimal treatment protocol for both men and women with AnA. Also, the role of diet in the days prior to collection of the PRP has not been assessed in conjunction with hair, although diet influences the quality of the PRP [ 133 ].

4. Diagnostic Lab Testing

4.1. ferritin.

Iron is a mineral that is integral for the body. It allows for humans to produce hemoglobin and myoglobin which are essential for the distribution of oxygen within the body. Additionally, iron plays a role in the production of certain hormones and allows for normal growth and development. Ferritin is a protein that allows for the intracellular storage of iron as, without it, iron intracellularly can produce free radicals which can damage cell machinery. Serum ferritin levels can be a marker for overall iron storage levels in the body [ 134 ]. Low serum ferritin levels have been supportive of an iron deficiency, anemia most commonly, however low levels can also be found in hypothyroidism and ascorbate deficiency [ 134 ].

Clinically, studies have suggested the correlation of low ferritin levels with hair loss. Although the mechanism of how low ferritin may lead to hair loss is not known, one theory highlights the importance of iron as a cofactor for ribonucleotide reductase, which is the rate limiting enzyme in DNA synthesis [ 135 ]. Since hair follicle cells are rapidly dividing, they require the constant use of ribonucleotide reductase and a deficiency of iron may limit the efficiency of this enzyme. In turn, this can lead to decreased cell turnover and regeneration leading to decreased hair growth. Thus, the evaluation in a patient presenting with hair loss has often involved an assessment of iron levels [ 135 ].

4.1.1. Premenopausal vs. Postmenopausal Women

Several studies have investigated the relationship of low ferritin levels and hair loss. One study performed by Rasheed et al. evaluated 80 premenopausal women [ 66 ]. Females aged 18–45 years were included in the study. The serum ferritin levels were assessed in 80 women who had telogen effluvium (TE) or female-pattern hair loss (FPHL), and in 40 women with no hair loss. The average ferritin levels in women with TE was 14.7 μg/L and 23.9 μg/L in those with FPHL; the control group had average ferritin levels of 43.5 μg/L. The average ferritin levels in both types of hair loss were significantly lower when compared to controls ( p < 0.001). Another study conducted in 2022 explored ferritin levels in premenopausal and postmenopausal women with FPHL [ 136 ]. Statistically significant lower ferritin levels <70 μg/L were found only in premenopausal women with FPHL ( p = 0.01).

Furthermore, another study conducted in 2013 also found significantly low levels of ferritin only in premenopausal women with FPHL [ 137 ]. The average serum ferritin level in premenopausal women was 30.67 μg/L and this was compared to age/sex matched healthy controls who had an average ferritin level of 69.32 μg/L ( p < 0.001). Postmenopausal women, on the other hand, had an average ferritin level of 83.22 μg/L and when compared to their age/sex matched healthy controls who had an average ferritin of 85.38 μg/L, there was no statistically significant difference. Thus, overall, many studies seem to consistently highlight a more significantly lowered ferritin level in premenopausal women with FPHL. This may be explained by the fact that iron deficiency tends to be more common in premenopausal women due to monthly blood loss attributed to menstruation [ 138 ]. Although much less common, iron deficiencies can also occur in postmenopausal women due to malabsorption or gastrointestinal bleeding; however, there may be other factors contributing to their hair loss which can explain the lack of statistically significant changes in the ferritin level [ 135 ].

An important fact to highlight, however, is that it is difficult to conclude whether or not a low serum ferritin level is correlated to hair loss in postmenopausal women as most of the studies have been performed only with premenopausal women. Further investigation is required specifically in postmenopausal women with large sample sizes to better understand the role of ferritin in their hair loss.

4.1.2. Men vs. Women

Because the literature has widely highlighted the importance of ferritin levels in regards to hair loss, a few studies have been performed to determine if low ferritin levels are also significant in males experiencing hair loss. In the study described previously by Tahlawy et al., the researchers also assessed 30 males with androgenetic alopecia and compared their serum ferritin levels with 30 healthy males [ 66 ]. The results showed no statistically significant differences in ferritin levels in patients with androgenetic alopecia compared to controls. Furthermore, the study described previously by Park et al. also assessed ferritin levels in 97 males with male-pattern hair loss (MPHL). The average ferritin levels in males with MPHL was 132.3 μg/L which was significantly lower than the average found in controls, 210.2 μg/L ( p < 0.001); however, it is important to note that both of these levels are still considered to be in the normal serum ferritin range. As described previously, the women in this study did show an abnormally low average serum ferritin level in those with FPHL.

In general, based on the current studies it is challenging to make any conclusions regarding the involvement of ferritin in hair loss experienced by males. There are very few studies overall which have assessed ferritin levels in males with alopecia and, in the ones currently described, there seems to be no major significant correlation of ferritin levels to alopecia, especially when compared to the strong correlations found in women. Thus, further investigation is warranted to determine the importance of ferritin in males before clinicians can make any treatment recommendations.

Antinuclear antibody (ANA) is a common lab marker that tests for the presence of an antibody against material within the nucleus of the cell. Its most clinical value has been in the diagnosis of systemic lupus erythematosus; however, the marker has been found to be commonly positive in numerous other autoimmune diseases including polymyositis, dermatomyositis, Sjogren’s syndrome, rheumatoid arthritis, scleroderma, and mixed connective tissue disease. As a result, obtaining an ANA level is more often used as a supplement to making a diagnosis; the clinical signs and symptoms play a more integral role to correctly diagnosing which disease a patient may have since an ANA positive test could occur in a variety of diseases [ 139 ]. Importantly, a positive ANA is estimated to be prevalent in 25% of the population, including healthy individuals. Many studies have shown ANA positivity in individuals with no signs or symptoms of rheumatologic disease. Therefore, its utility has been extremely controversial.

The utility of obtaining ANA markers for patients presenting with hair loss is unclear. A retrospective study was conducted in 2015, with 49 women and 56 men presenting with pattern hair loss [ 140 ]. The researchers found the ANA to be positive in 19.1% of the women and 11.3% of the men, with a total of 30.4% ANA positivity. Thus, the ANA was found to be significantly more positive in women ( p < 0.05). When comparing the severity of hair loss using the BASP classification, there were no statistically significant differences among those with a positive ANA and those with a negative one. Additionally, there was no significant difference in average hair density or hair shaft diameter between ANA positive and negative patients. Thus, although many patients were found to incidentally have a positive ANA, it is unclear whether that has any correlation to their hair loss.

In general, obtaining ANA lab markers should currently be limited only to those patients with a high clinical suspicion of having a rheumatologic or autoimmune disease [ 141 ]. Additional studies must be performed with larger sample sizes of various types of alopecia to obtain a better understanding of its role and importance. Based on the current literature, since ANA positivity seems to be relatively prevalent in the population, a positive test in an otherwise asymptomatic person may have low clinical utility [ 139 , 142 ].

Rapid plasma reagin (RPR) is a test that can be utilized to diagnose syphilis, a sexually transmitted infection caused by Treponema pallidum bacteria [ 143 ]. There are many stages during the infection that each present with specific symptoms. These include primary-, secondary-, and tertiary-stage syphilis. Of importance to hair loss is the secondary stage. Syphilitic alopecia (SA) is defined by the occurrence of diffuse or patchy hair loss and often has been described as having a “moth-eaten” appearance [ 144 ]. Interestingly, SA can mimic various other forms of alopecia including telogen effluvium and alopecia areata [ 145 ]. As a result, it may be easy to miss a diagnosis of syphilis if the patient has not experienced other typical symptoms of syphilis. The literature has described cases where the only clinical manifestation has been hair loss [ 145 ]. As a result, it will be important for clinicians to also consider a sexual history from patients presenting with hair loss and include RPR testing in the work-up if that seems appropriate.

4.4. Thyroid Hormones

One of the known presenting symptoms of hypothyroid and hyperthyroidism is hair loss. There are thyroid hormone receptors present in human skin cells, therefore any alterations in the quantity of thyroxine or triiodothyronine will lead to an alteration in human skin and hair follicles [ 28 ]. In a study analyzing how T3 and T4 directly influence human hair follicles in vitro, it was found that both T3 and T4 have an inhibitory effect on the apoptosis of human hair matrix keratinocyte cells, while T4 was also found to have a significant stimulatory effect on their proliferation [ 146 ]. T3 was not found to have a significant stimulatory effect on the keratinocytes. Furthermore, the study found that increased levels of thyroid hormones had a direct correlation with increased numbers of anagenic hair follicles, and a decrease in catagenic hair follicles. Finally, T3 and T4 were also both found to have a stimulatory effect on hair follicle pigmentation. Overall, the study concluded that both T3 and T4 alter key parameters in human hair follicle growth and support the claim that the deficiency of thyroid hormones in hypothyroid individuals directly plays a role in the symptomatic hair loss.

4.5. Functional Testing

4.5.1. diurnal cortisol slope testing.

Diurnal cortisol slope testing is a functional lab test that assesses the change in cortisol levels throughout one day. Cortisol is the main glucocorticoid hormone released in response to both acute and chronic stress. It has numerous effects on the body including immune function suppression, activation of the sympathetic nervous system, and alter glucose homeostasis [ 147 ]. Although acutely these effects allow the body to adequately function, chronically these changes can be detrimental and lead to inflammation, fatigue, and psychological maladaptation [ 148 ].

Cortisol levels can be assessed through saliva sample collections that a patient collects through the course of one day. A normal diurnal cortisol rhythm follows a distinct pattern throughout the day. As outlined by Adam et al., the first sample taken is to assess the waking cortisol, which is defined as the level established immediately upon awakening in the morning; this level is normally high [ 149 ]. The next sample is taken 30–40 min after waking up and is called the cortisol awakening response; this level will normally display a surge compared to the waking cortisol. The remainder of samples are collected at varying time points in the day, but overall should display a decline with the lowest levels recorded near bedtime. Overall, these cortisol levels can be used to generate a diurnal cortisol slope. Any changes or flattening in the curve of the slope can indicate abnormal cortisol production. Studies have shown that abnormal cortisol rhythms throughout the day can be associated with numerous negative health outcomes and an imbalance of the hypothalamic pituitary adrenal axis (HPA) [ 149 ]. However, this has not been studied specifically in relation to hair loss or hair thinning. Thus, diurnal cortisol slope testing may be beneficial to determine if abnormal cortisol rhythms are contributing to hair loss, as part of future studies.

Correlations to Hair Cortisol

A novel method to assess the function of the HPA axis and cortisol levels is to obtain hair cortisol levels. This method requires obtaining a strand of hair which is then ground or minced to extract cortisol levels [ 150 ]. Interestingly, this method to assess cortisol levels provides a few key differences from the traditional diurnal cortisol slope testing. First, hair cortisol levels do not provide an acute snapshot of cortisol activity much like the traditional diurnal cortisol slope testing provides, but rather it offers a retrospective look into the history of what cortisol levels have been like in the body. On average, since hair grows at a rate of 1 cm/month, the literature has outlined that the most proximal 1 cm of a hair strand to the scalp provides information about the cortisol activity in the last month [ 151 ]. The second centimeter of hair provides information about 2 months prior and the next centimeter provides details about 3 months prior and so on. The hair cortisol levels are considered reliable up to 6 cm from the scalp. Additionally, since this method only requires the extraction of hair strands, it could be more reliable than traditional cortisol testing which is highly dependent on patient compliance to be accurate [ 151 ].

One major drawback of hair cortisol testing and its correlation to hair loss is that there have not been many studies that have included it in their methodology for assessing hair loss, specifically. The current literature is limited to only highlighting, thus far, that hair cortisol testing is a reliable biomarker indicating that the body is undergoing chronic stress [ 152 ]. However, no conclusions can be made from that information regarding its utility in hair loss.

Current studies have focused on testing hair cortisol in rhesus macaques, a species of monkey, experiencing alopecia. A study conducted in 2014 with 99 rhesus macaques monkey’s divided them into two groups [ 153 ]. The alopecia group included monkeys with 30% or more hair loss and the control group included monkeys with less than 5% hair loss. Hair cortisol levels were analyzed in both groups and results showed that the alopecia group had increased concentrations of hair cortisol compared to the control group. Although this study provides a foundation for the incorporation of hair cortisol as a tool for understanding hair loss, further research is still warranted, especially in humans. Overall, it is too early to determine if hair cortisol testing may be beneficial in the work-up for patients presenting with hair loss.

4.5.2. Mitochondrial Function Testing

Thyroid impact on mitochondrial function.

Thyroid hormones are major regulators of energy expenditure within the body and are responsible for establishing a basal metabolic rate. Mitochondria are the primary organelles in cells that are involved in energy production. Thus, thyroid hormones have been widely supported by the literature as having a role in regulating mitochondrial function [ 154 ]. Many studies have suggested that thyroid hormones alter the levels of mitochondrial oxygen consumption and subsequently ATP production. Specifically, in studies investigating the effects of hyperthyroidism on mitochondria, it was collectively found that mitochondrial oxygen consumption rates were increased along with ATP production rates [ 155 ].

Interestingly, a study conducted in 2014 investigated the impact of thyroid hormones on mitochondria present in hair follicles [ 154 ]. The study utilized organ cultured human scalp hair follicles and subjected them to TSH, T3, and T4 hormones. All of the thyroid hormones were found to increase gene and protein expression of “mitochondrial-encoded subunit 1 of cytochrome c oxidase (MTCO1), a subunit of respiratory chain complex IV, mitochondrial transcription factor A (TFAM), and Porin”. Additionally, complex 1, complex 4, and mitochondrial biogenesis were each upregulated. Furthermore, the study also found that T3 and T4 hormones both decreased reactive oxygen species (ROS) production. This finding is clinically important as high levels of ROS production have been correlated to contributing to a variety of dermatologic conditions. Thus overall, this study highlights the impact of thyroid hormones on mitochondrial energetic dynamics in hair follicles. Clinically, this is important because an imbalance in the hormones could contribute to hair loss. Thus, evaluating thyroid hormones in individuals presenting with hair loss may be useful.

Organic Acid Testing of Krebs Cycle and Electron Transport Chain

Several studies have highlighted the effects of mitochondrial dysfunction on hair [ 156 , 157 ]. The mitochondria is the site of action for major biochemical reactions, including the electron transport chain and the Krebs cycle. In a study performed by Singh et al., mice with depleted mtDNA were found to have profound hair loss suggesting the importance of mitochondrial integrity [ 156 ]. Additionally, a study performed with epidermal specific Crif1 knockout mice found that the hair cycle was significantly reduced [ 158 ]. Crif1 is a mitochondrial protein responsible for the placement of oxidative phosphorylation (OXPHOS) polypeptides in the inner membrane of mitochondria. Furthermore, as discussed previously, the trial conducted by Kim et al. showed that quercetin improved mitochondria function which led to improved hair growth in cultured hair follicles [ 109 ]. Specifically, they noted increased cell proliferation markers, growth factors, increased MAPK/CREB signaling, increased NADPH production and increased mitochondrial membrane potentials, which collectively contributed to the improved hair growth noted in cultured hair follicles after supplementation with quercitrin. Thus, this study further supports the integral role of healthy mitochondrial function in the maintenance of normal hair growth.

As a result, assessing mitochondrial function may be clinically useful for determining its level of contribution to hair loss a patient may be experiencing. One method for testing the function of mitochondria is via organic acid profile testing (OAPT). The OAPT utilizes urine samples from patients to evaluate many different metabolites that can be indicators for how well the Krebs Cycle and electron transport chain (ETC) are functioning, since each of these reactions produce various byproducts [ 159 ]. Although organic acid testing is widely available in the functional medicine space, there are a dearth of studies that correlate it to hair loss or hair thinning. Therefore, given its widespread use within functional medicine, a formal clinical study on the utility of organic acid testing and hair loss should be conducted.

5. Conclusions

Hair growth is mediated by a complex cycle consisting of anagen, catagen, telogen, and exogen. A variety of factors impact the hair cycle, inducing anagen to telogen transition or vice vera. Inflammation has been shown to foster anagen to telogen transition and mediate a variety of hair loss subtypes via proinflammatory substance P regulation. Thyroid hormones and dihydrotestosterone exhibit regulation of the hair cycle, and research has suggested the ratio of estrogen to testosterone may be more clinically relevant than the serum levels of either hormone in isolation. While vitamin and mineral deficiency has been associated with sparse hair and alopecia, there is limited evidence to suggest supplementation in healthy subjects is beneficial. Poor sleep and cell division inhibiting medications, including various chemotherapies, negatively impact the hair cycle and contribute to loss. Conversely, increased blood flow, direct stimulation of the hair follicle, and growth factors promote telogen to anagen transition and hair growth. Specific therapies can include scalp massage, minoxidil, herbs, supplements, low level light therapy, prostaglandins, and platelet-rich plasma. Evidence is promising for the therapeutic success of many such modalities, although limitations commonly include poor study design with small sample sizes and inconsistent therapeutic protocols. A variety of diagnostic tests can be employed to determine contributing factors of hair loss. Useful testing includes serum ferritin and thyroid hormone panels. Diurnal cortisol slope testing may assess the balance of the HPA axis and the influence of stress while OAPT testing may help assess mitochondrial function in a healthy patient. ANA lab markers should only be ordered if there is suspicion for ongoing autoimmunity. There is inadequate evidence to currently suggest utility of obtaining hair cortisol levels. Ultimately, the numerous factors impacting the hair cycle necessitate a holistic and individualized approach.

Abbreviations

Funding statement.

This research received no external funding.

Author Contributions

R.K.S. conceptualized the original idea, provided substantial revisions, and supervised the project. N.N. led manuscript writing with contribution from N.G. All authors provided critical feedback, have approved the submitted manuscript, and agree to be personally accountable for their own contributions and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated, resolved, and documented in the literature. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Conflicts of interest.

The authors declare no conflict of interest.

Disclosures

R.K.S. serves as a scientific advisor for LearnHealth, Codex Labs, and Arbonne and as a consultant to Burt’s Bees, Novozymes, Nutrafol, Novartis, Bristol Myers Squibb, Abbvie, Leo, Biogena, UCB, Incyte, Sanofi, Novartis, Sun, and Regeneron Pharmaceuticals. The remaining authors report no disclosures.

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Growing Your Hair Out: A Survival Guide

By Kerry McDermott

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Louise Brooks has got a lot to answer for. A century after the quintessential flapper made short hair aspirational, Instagram is awash with It-girls tucking their baroque bobs behind their ears as they make their way out of Erewhon or into the reformer Pilates studio.

It’s not just Gen-Z, either. Back in January, Jennifer Lopez managed to steal the show outside the Schiaparelli Haute Couture show when she arrived with her bounteous caramel waves chopped into a wet-look bob. That same month, Penélope Cruz swept onto the red carpet at the Governors Awards having recently been relieved of at least six inches of raven hair.

Far from being immune to this most tenacious of trends, I had short hair for years, convinced that that was the best way of keeping my unruly mane in check (or at least somewhere in that region). But what happens when you get bored of the bob? When you get a sudden pang for the practicality of a ponytail, or start to long for the nonchalance of a top knot? That’s the position I found myself in some months ago: mired in a pit of hair ennui and starting to hate my supposedly low-maintenance bob.

This rut eventually set me on a mission towards changing things up—but not before canvassing some experts on how best to navigate what I knew was coming: the awkward growing-your-hair-out phase. “Regular haircuts are a must,” declares hairstylist Domenico Cassella. Even if you are anxious to be able to tie your hair up as quickly as humanly possible? Apparently so. “I advise all my clients to have a haircut every five to six weeks, and am even more insistent for those seeking to achieve long, luscious lengths,” says Cassella. “By having regular trims you ensure your hair doesn’t thin at the ends. It also prevents pesky split ends and dryness.”

Duly chastened, I asked whether there was anything else I could be doing to speed the whole process up. “Ultimately, long, healthy hair is the positive outcome of a well-cared-for scalp and a good haircare regimen,” said Cassella, who suggests stimulating the hair follicles to promote growth. “Ensuring your scalp’s pH is balanced is the first step—this can be done by using a gentle hydrating shampoo regularly, and combining it with professional scalp treatments.” Cassella, who is based at Neville Hair and Beauty in Belgravia, uses a natural clay-based treatment on his clients that exfoliates away dead skin and provides deep, nourishing hydration. As for changes you can make at home, he said it’s even more important to use heat-protecting products when you’re growing your hair—or better still, cut back on heated appliances altogether.

I write this having finally emerged (relatively) unscathed from this period of personal growth, and I’m ready to embrace the summer with my (past!) shoulder-length hair. So, I sought some haircare advice from women in the industry with famously long—and gorgeous—locks. “I would say don’t over wash it,” London PR guru Daisy Hoppen told me. “Invest in a good conditioner, and I personally never really dye it (unless hiding the greys).” Hoppen also stocks up on claw clips to keep her hair up while sleeping, sulfate-free shampoo, and hair perfume from Diptyque. “Your hair can absorb smells more, it seems, when it’s longer,” she said. Her golden rule? Keratin treatments every six months. “It’s a game-changer for keeping your hair soft and in good condition.”

Model and photographer Laura Bailey, meanwhile, cautions against over-styling. “At home, I only dry my hair naturally—often on my bike! My favorite is just to sleep in a long, twisted plait and undo it in the morning, Rapunzel-style,” she added. Bailey keeps her blonde mane healthy and hydrated with the help of hair masks and Lyma Life supplements, too. And she's a testament to getting regular trims.

Cassella would approve—but Hoppen confesses to avoiding the scissors for months at a time. “Even when your hair is long it’s just as painful to see a few inches go,” she said. “I don’t know why, but you feel like Samson when your hair is cut!”

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Do Hair Growth Supplements Increase Body Hair?

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Key Takeaways

  • Oral hair growth supplements can help with hair growth, retention, and density.
  • The supplements can affect your body hair and the hair on your head.
  • Though you may notice a slight change in body hair after taking the supplements, they shouldn’t cause any significant changes to hair growth anywhere on the body, dermatologists said.

Hair growth supplements have recently received considerable attention on TikTok, with more than 50 million videos on the topic garnering thousands of views. But before you try oral hair growth supplements, you should know that they can affect your body hair, too.

“Since [these] supplements are taken orally, the ingredients are absorbed throughout the entire body and act on all hair follicles,” Michele Green, MD , a board-certified cosmetic dermatologist based in New York, told Verywell.

That said, these products shouldn’t cause a significant increase in body hair. “In my experience, oral hair growth supplements have minimal effect on body hair,” Michael Cameron, MD , a board-certified dermatologist based in New York and assistant clinical professor at the Mount Sinai Health System, told Verywell.

Oral hair growth supplements won’t cause hair growth in new areas. “Facial and body hair growth is caused by fluctuating hormones in the body,” Green explained. “Hair growth supplements do not contain hormones and will not encourage facial or body hair growth that is nonexistent.”

If oral hair growth supplements aren’t a good option for you since they may affect body hair, there are many other alternatives to choose from, Green added.

How Do Hair Growth Supplements Affect Body Hair?

Generally speaking, vitamins and minerals can sometimes promote hair growth, especially if they’re used alongside other treatments. “Overall, vitamins are typically not effective enough to grow and retain hair on its own fully,” Green said. “Still, they can be helpful in conjunction with other medications and procedures to promote hair growth.”

A 2023 review found evidence to suggest that the following name-brand supplements could “potentially benefit” people with hair loss:

Other supplements that contain the following ingredients may also be helpful:

  • Capsaicin and isoflavone
  • Omegas 3 and 6 with antioxidants
  • Apple nutraceutical
  • Total glucosides of paeony and compound glycyrrhizin tablets
  • Tocotrienol
  • Pumpkin seed oil

Though hair growth supplements aren’t always effective, experts don’t consider them dangerous: Adverse events caused by the supplements are rarely reported, and even then, they’re usually mild.

Hair growth supplements may affect your body hair in multiple ways, and it’s important to note that these supplements—along with all other supplements—are not tested for safety and efficacy the way other medications are.

“Hair growth supplements can help promote hair growth, retention, and density by improving overall hair health,” Green said. The same is true for hair growth supplements’ effect on body hair. “However, there are no clinical studies to date proving that hair supplements can work to increase hair growth and density.”

Hair growth supplements’ effects on the diameter of your individual strands of hair are “negligible,” Cameron added.

Whether or not you notice increased body hair when taking hair growth supplements may depend on which kind you are taking, experts said.

“Certainly supplements containing vitamins like biotin can increase the rate of body hair growth and nail growth, [and] some trimming may be needed a little more often,” Cameron explained. But some products will yield different results. “There is some evidence that saw palmetto can actually potentially decrease body hair growth via its antagonist effects on dihydrotestosterone,” he added.

Hair Growth Treatments Outside of Supplements

For some, more body hair is a welcome change, but others may want to avoid this side effect of hair growth supplements. If that’s true for you, there are alternatives to these supplements that can help with hair growth on your head but nowhere else.

“Dermatologists often employ topical medications such as minoxidil to decrease hair follicle miniaturization and increase hair growth,” Green said. “Topical minoxidil is an FDA-approved medication that reduces the conversion of testosterone to dihydrotestosterone, a hormone that increases hair follicle miniaturization.” This treatment can be applied directly to the scalp to encourage hair growth there, and it can be bought over the counter as Rogaine, she added.

Another treatment known as platelet-rich plasma (PRP) injections, which are injected into the scalp, can also help people looking for help with hair loss. “PRP injections are a highly effective, innovative treatment for hair restoration,” Green said. “PRP is drawn from the patient’s blood and contains proteins and growth factors that are necessary for promoting tissue regeneration and healing hair follicles.”

Other options include finasteride and red light therapy, Cameron said. In some cases, hair transplantation performed in a dermatologist’s office may be the best option for people fighting hair loss, he added.

If you want to ensure that your hair growth treatment option does not alter your body hair, speak with a dermatologist before trying anything new. “Prescription oral minoxidil will likely increase hair growth not only on the scalp but also on the body,” Cameron said.

Any dramatic change in hair growth—whether it affects your body hair or not—should prompt you to speak with a healthcare professional, experts said. Several health conditions can affect your hair growth, and a healthcare provider can help you determine what’s causing the change and whether you should follow a treatment plan to correct it.

What This Means For You

Because they’re taken orally, hair growth supplements may affect hair growth, retention, and density in your body hair and the hair on your head. If you’re experiencing hair loss and you’re looking for a treatment that will promote hair on your head but nowhere else, there are alternatives to hair growth supplements that may work better for you, dermatologists said.

Almohanna HM, Ahmed AA, Tsatalis JP, Tosti A. The role of vitamins and minerals in hair loss: a review . Dermatol Ther (Heidelb) . 2019;9(1):51-70. doi:10.1007/s13555-018-0278-6.

Drake L, Reyes-Hadsall S, Martinez J, Heinrich C, Huang K, Mostaghimi A. Evaluation of the safety and effectiveness of nutritional supplements for treating hair loss: a systematic review .  JAMA Dermatol . 2023;159(1):79-86. doi.org/10.1001/jamadermatol.2022.4867

Food and Drug Administration. Facts about dietary supplements .

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Understanding the Hair Growth Cycle Can Help Pinpoint Why Your Hair Is Thinning

Discovering the basics of your hair’s structure is the first step toward finding the simple fix that will bring you thicker, lusher locks! 

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Worrying about your hair because you’ve noticed signs of thinning? Are there more strands in your shower drain, is your hairbrush filling up more quickly and/or is your part widening ? If so, you’re far from alone. But thankfully, understanding the hair growth cycle can be a key factor in figuring out how to combat hair loss. Here, top MDs explain the make up of hair, the hair growth cycle and more so you’re more knowledgeable about thinning hair.

How common is hair loss?

“Hair thinning is much more common than most realize,” shares Samuel M. Lam, MD , hair transplant surgeon and founder of the Lam Institute for Hair Restoration in Plano, Texas. Indeed, it may be surprising to discover just how many of us are dealing with excessive hair shedding. Says Dr. Lam: “30% of women over 30 have signs of hair thinning.” And studies show that this number climbs with the passing years, impacting 40% of us in our 40s and 52% of us in our 50s. “In fact, age-related hair loss impacts everyone to some degree,” notes Mark Nestor, MD , PhD, a board-certified dermatologist and director of the Center for Clinical and Cosmetic Research in Aventura, Florida.

Related: Menopause Hair Care: What Works Best for Women Over 50, According to Hair Pros

hair loss in hair brush

How hair loss impacts women

Yet, despite the vast number of us who are dealing with thinning hair, many suffer in lonely silence. “Hair loss can feel isolating,” says Natalie Kash, MD , a board-certified dermatologist and co-founder of Root Hair Institute in Bellevue, Washington. “In fact, studies have shown it can also impact an individual’s self-esteem, social relationships and career. This matches with many of my patients’ experiences who have shared that their hair loss affects their confidence, emotional health, relationships and even their professional performance.” 

Women are also less likely to talk to their peers about their hair thinning than men, notes Dr. Kash. As a result, instead of asking around about treatments that family and friends are using, they stay mum and just try to cover up the thinning. Thankfully, there’s no need for anyone to continue hiding in shame. That’s because there are proven, easy treatments for most types of excessive hair shedding in women. Finding out the right one for you starts with knowing the basics about hair structure and how hair grows.

Related: 11 Best Hair Growth Products for Women Over 50 to Treat Thinning, According to Hair Loss Experts

What exactly is hair?

close up of grey hair

When most of us talk about our hair, we’re usually referring to the shaft, which is the strand that you can see outside the scalp. While this portion of hair grows in a wide variety of shades and textures, differing from person to person, hair has the same components for all of us. “Hair is essentially made of the protein ­keratin — approximately 90%,” says trichologist David H. Kingsley, PhD , a hair loss specialist in New York City. “The remaining 10% or so of the hair fiber is made up of melanin — which is the pigment that gives hair its color — fats and oils, trace metals and water.”

The diameter of each hair strand is so tiny (a scant .017mm to .181mm thick) that we use the term “a hair’s breadth” to describe something infinitesimally small. Yet a single strand of hair is still wide enough to contain a complex set of parts. 

“The hair shaft itself can be divided into three layers from outside in, which include the cuticle, cortex and medulla,” says Dr. Kash. “The cuticle acts as a layer of protection for the inner portions of the hair shaft. The cortex has the pigment and moisture of the hair. The medulla is the innermost portion in terminal (thick) hair and is typically absent in vellus (fine, short, wispy) hair.”

Illustration of what makes up hair

What is the hair follicle and root of hair?

Beneath the surface of the skin on your scalp is the hair follicle, which is the tube-shaped sac that produces the hair shaft and anchors it into place. The hair follicle is a complex mini organ that is part of the epidermis (top skin layer) but extends through the dermis (middle layer of skin) into the subcutaneous tissue (inner layer of skin), explains Kingsley.

“The part that nourishes the hair is in the bulb region — the ‘root’ that some people can see if their hair falls out,” he adds. It contains the dermal papilla, which delivers the blood supply through capillaries (tiny blood vessels), and the matrix, which consists of cells called keratinocytes that produce keratin needed to form hair strands. As more keratin forms, the hair grows and sprouts out of the scalp, where it’ can be seen’s visible to the eye. And surrounding the follicle are two protective layers consisting of the inner root sheath and outer root sheath.

The root cause of thinning hair

Noting how your hair is thinning can play an important role in figuring out if it’s due to a problem affecting the shaft or the follicle. When hair thins due to breakage or split ends , the cause is typically a problem affecting the shaft, such as how you’re styling it. “The older the hair fiber, the longer the hair, the more chance of weathering through cosmetic procedures, such as coloring, blow-drying, etc.,” says Kingsley. “This weathering may cause the fiber to become damaged, dry and brittle.” Once that happens, the shaft becomes weak, making it easier to snap from everyday use, such as combing.

Alternatively, when you notice a decrease in the thickness of your hair or have fewer strands growing out of certain areas of your scalp, such as the front or top, this is a clue that it’s due to a problem that’s impacting your follicles, which affects hair growth. For instance, if your strands have decreased in diameter, resulting in finer hair, it’s a sign that follicles are shrinking, which is common in some conditions, such as androgenetic alopecia (aka female pattern hair loss).

Related: Dermatologist-Recommended Shampoos for Hair Loss — Discover What’s Right for You

The hair growth cycle explained

The hair on your scalp grows about half an inch per month, totaling about 6 inches per year. While many animals experience seasonal hair shifts, where they shed or grow all of their hair at once, human hair sheds and grows in a random way. This means that at any given time, some strands on your head are brand new, some are several months old, some are several years old and some are ready to fall out. However, your hair does follow a specific growth pattern, which is made up of the following four phases.

hair growth cycle diagram

Hair growth cycle phase 1: Anagen

This is known as the growth phase when the hair strand is actively growing. During this time, cells in the root of the hair are dividing rapidly to form a new strand, keratin is being produced and pigment from melanocytes (melanin-producing cells) is transferred to the hair, giving it its color. “The anagen phase of scalp hair typically lasts 1 to 8 years,” notes Dr. Kash. If your hair stops growing at your shoulders or higher, you have a shorter anagen phase. If your hair grows past your shoulders, it means you have a longer anagen phase. At any point, 85% to 90% of your hair is in this phase.

Hair growth cycle phase 2: Catagen

This is a brief transitional phase. During this time, growth of the hair strand slows and the follicle shrinks. The hair separates from the bottom of the follicle and moves upward, cutting off its blood supply. The result: “The production of protein and pigment decreases,” says Dr. Kash. “The catagen phase usually lasts 2 to 3 weeks.” About 2% of your hair is in this phase at any time.

Hair growth cycle phase 3: Telogen

Also called the resting phase, this is when your hair pauses. It’s no longer growing, but it’s not quite ready to shed either. Beneath the surface of the skin, a new follicle starts to grow on top of the old one and a new hair forms. Sometimes, the old hair will be pushed out in this phase, and if it is, you’ll typically see a small whitish clump at the end, which is the remnant of the hair bulb, called a “club” hair. “The telogen phase usually lasts approximately 3 months,” says Dr. Kash. About 10% to 15% of your hair is in this phase at any given moment. 

Hair growth cycle phase 4: Exogen

This is your hair’s shedding phase that allows you to return to the anagen phase. During this time, a new hair strand is growing and pushing out the remaining old hair that’s ready to be released from your scalp. “There is thought to be a breakdown of protein allowing the hair to shed,” explains Dr. Kash. Once a strand falls out, the bulb on the end appears smaller or absent since it’s been worn away. 

If your hair is thinning, there’s a chance a disrupted growth cycle is behind it. “Decreased length of anagen and increased shift of hairs into the catagen, telogen and exogen phases lead to increased hair shedding,” notes Dr. Kash. “If your hair starts to not be able to grow as long, this can be a sign that your anagen phase may be shortening. Many therapies for hair loss work in part by prolonging the anagen phase of the hair cycle.” 

To learn more about the hair growth cycle, watch the below video from @livetolearnmed2477 on YouTube.

Typical vs. atypical hair shedding

Whenever you see lots of strands falling out of your scalp, it’s natural to worry about thinning. But your scalp is pushing out old hair all the time, assures New York City dermatologist Dina Strachan, MD . “It is normal to lose between 100 and 150 hairs a day,” she says. 

So how much hair loss would be considered excessive? “Hair shedding of greater than 150 per day,” notes Dr. Strachan. And it’s something you likely won’t miss. “People will notice hair thinning if they are shedding abnormally large amounts of hair,” she says. For example, you may notice you can see more of your scalp through your hair or your ponytail feels thinner. 

The right treatment can help

mature woman hair growth

If you’ve noticed that your hair loss is more than what’s considered typical, there’s good news. “Not all hair loss is permanent,” assures Kingsley. Indeed, many causes of hair shedding are reversible with the right treatment. “For example, you might have low blood iron levels, a thyroid condition or be experiencing side effects of certain medications, such as antidepressants,” says William Rassman, MD , medical advisor for the hair treatment service HappyHead.com . Other possible culprits behind hair thinning that can be treated include scalp inflammation, a vitamin deficiency, high stress, low estrogen or genetically inherited conditions. “The quicker you find out the cause, the better the chance of improving the condition,” asserts Kingsley.

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13 Best Hair Growth Serums for Men, Tested by a Grooming Editor and Dermatologist

Bring your hair back to life with these follicle-boosting formulas.

best hair growth serums for men

Our product picks are editor-tested, expert-approved. We may earn a commission through links on our site. Why Trust Us?

Minoxidil 5% Regrowrth Solution

Best Hair Growth Serum Overall

Hims minoxidil 5% regrowrth solution.

Flourish Density Booster Spray

Best Hair Growth Serum For Loss of Volume

Virtue flourish density booster spray.

GRO Hair Serum

Best Hair Growth Serum for Fine Hair

Vegamour gro hair serum.

Men's Hair Growth Supplement and Hair Serum

Best Hair Growth Serum for Hair Thinning

Nutrafol men's hair growth supplement and hair serum.

Multi-Peptide Serum for Hair Density

Best Affordable Hair Thickening Serum

The ordinary multi-peptide serum for hair density.

Destined For Density MegaStrength + Caffeine + Biotin Peptide Density Serum

Best Hair Growth Serum for Black Hair

Briogeo destined for density megastrength + caffeine + biotin peptide density serum.

Scalp Serum

Best Natural Hair Thickening Serum

Divi scalp serum.

Cold Processed Stem Cell Serum

Act + Acre Cold Processed Stem Cell Serum

3D Daily Thickening Treatment

Best Daily Hair Thickening Serum

Amika 3d daily thickening treatment.

The Scalp Treatment

Best Luxury Hair Thickening Serum

Augustinus bader the scalp treatment.

The best hair growth serums tackle hair loss on multiple fronts; they improve the condition of your scalp, which aids in encouraging healthy hair growth, and they also infuse moisture into your existing strands, making them stronger and less prone to breakage. Some hair growth serums also target some of the common signs of aging in hair, which includes a loss of density, fading hair color, and overall dullness. How, you may ask, do hair growth serums work? It depends on the active ingredients that are in the formula, but many feature ingredients like minoxidil, saw palmetto, redensyl, and red clover, which have all been clinically proven to promote hair growth. These serums can revive lackluster locks and reignite your follicles, which in turn encourages hair growth and gives you the thick, healthy hair you once had not so long ago.

Though take note, a lot of haircare brands claim that their hair growth can make hair growth, but doctors say there is only one FDA-approved over-the-counter ingredient to treat androgenetic alopecia (aka male pattern baldness): Minoxidil.

"Minoxidil is thought to act by increasing blood flow and therefore oxygenation of hair follicles and stem cells that exist along the hair follicle," says Dr. Brendan Camp , a double board-certified dermatologist at MDCS Dermatology in New York City. "Improved circulation and oxygenation may encourage growth of stem cells and encourage hairs to remain in anaphase, the growth phase of their life cycle."

Plus, even the best hair growth serums take at least three months for you to see visible results. "Scalp hair typically grows at a rate of about 1 cm per month," says Camp. "If you use a hair growth product for only a month before moving on to the next one, you are not giving the product enough time to prove itself. Use a hair growth product for at least 3-4 months before deciding if it is helpful or not."

Whether you're dealing with genetic hair loss, hair thinning due to stress or hormonal changes, or simply age-related hair loss, the best hair growth serums can help get your hair to a healthier state, strengthening the hair follicles you do have and boosting the hair follicles that fell off in recent years.Ready to give your hair the boost in nourishment it deserves? Here are the 13 best hair growth serums, tried and tested by Men’s Health editors.

This clinically-proven formula is your express ticket to thicker, fuller hair. Packed with 5% minoxidil, the only topical drug that's approved for the treatment of male pattern hair loss, it reignites dormant follicles, strengthening weak strands and promoting robust hair growth.

"Minoxidil is prescribed as an oral medication to treat high blood pressure, and it was found that hair growth is one of its side effects," says Camp. "Topical minoxidil capitalizes on this side effect to promote scalp hair growth and prevent further hair loss."

Testing Notes: We love the non-greasy formula, which doesn't affect our hair texture or style. One dropper is enough to concentrate the solution only on areas where our hair was thinning, and the applicator made it easy to precisely apply. We like to use our fingertips to gently massage the solution into the scalp, which promotes better absorption and helps distribute the treatment evenly.

If you want to encourage healthy new growth without using any OTC drugs, Virtue’s Flourish Density Booster delivers similar results without minoxidil. In a clinical study, participants had equal amounts of significant hair regrowth, so you can trust that this botanical-based formula actually works to stimulate dormant follicles.

Dr. Camp has co-signed this hairspray as well. "This product includes plant-based nutrients, keratins, and peptides to provide the scalp and hair with the nutrients needed to maintain healthy hair," he says.

Testing Notes: This serum couldn’t be easier to use. We just spritzed it onto damp or dry hair once daily and noticed a difference in hair volume and thickness within three months. We love that you don’t have to be super precise with the application and there’s no need to rinse it out, so you can dry and style your hair as normal. The lightweight formula is nearly invisible on our strands within seconds of application.

This plant-based formulation uses a combination of clinically-tested, vegan active ingredients like red clover and mung bean to help support a healthy and balanced follicular ecosystem (which is important for hair growth) while soothing the scalp and revitalizing hair roots. It won't weigh fine hair down like other thicker serums, and smells delightful, thanks to the blend of powerful phyto-actives.

"Vegan phytoactives are included in this hair growth serum to soothe the scalp and revitalize hair follicles for an improved appearance of hair density and thickness," says Camp.

Testing Notes: We found this hair growth serum most effective as a spot treatment to reduce hair shedding. Using a full dropper across any thinning areas didn't leave behind any visible residue after letting the solution soak into the scalp for a few minutes, and it did not make our hair greasy. This is not a treatment you can skip often and still expect to see some results; you really have to commit to using it every day if you want to continue making progress on your hair growth journey.

This dynamic duo targets the underlying causes of hair thinning from the inside out. The daily supplement features clinically proven ingredients like saw palmetto and biotin, which provide the foundation for promoting healthy hair regrowth from within. The topical serum targets the root of thinning hair, stimulating follicles and strengthening strands.

Testing Notes: Sometimes topical treatments only treat the symptoms, not the underlying cause. This two-pronged approach tackles hair loss and thinning by targeting the nutritional aspect and providing a topical solution, which is what makes it so effective. The supplements were simple to integrate into our routine and while the serum required patience and dedication, we saw the visible results of our efforts faster, perhaps because of this dual-action strategy.

Deputy Commerce Editor Christian Gollayan has been using Nutrafol's supplement and serum combo for the past six months, and he says his hair (and eyebrows) have appeared fuller and thicker. "My side part, temples, and crown area appear darker, fuller, and healthier," Gollayan says. "Downing four pills daily and applying the serum can be a hassle sometimes, but the results are totally worth it."

Affordable yet effective, this science-backed serum packs a punch with a potent blend of trademarked peptides and plant-based extract, encouraging hair follicles to thrive and promoting lush, thick locks.

Testing Notes: While you can certainly use this serum as a spot treatment, we also like using it all over the scalp to encourage overall thickeness, not just in the areas where we noticed thinning. At under $25 for two ounces, we don't mind going through this bottle quickly since it's so easy and cheap to replace. We prefer to use on dry hair, which helps the product to be absorbed more efficiently at the roots instead of traveling down the hair follicle.

Add a little pep to your lackluster strands with this caffeine-powered serum. The unique density-boosting complex stimulates the scalp and strengthens the hair follicle to support elasticity, so your hair can bend without breaking. We especially like using it around the hairline where breakage tends to occur.

"It includes zinc, biotin, copper peptides, and an energy complex composed of caffeine CoQ10 and green coffee oil to supply the scalp and hair follicles with nutrients and antioxidants that help overcome environmental stressors, like free oxygen radicals, that can damage hair," says Camp.

This lightweight serum is infused with a powerful blend of multiple amino acids and peptides to help remove any buildup on the follicles that may be hindering hair growth. Copper Tripeptide-1, peppermint oil, green tea leaf extract, and tea tree oil support thicker hair and encourage overall scalp health, while menthol increases blood circulation to the scalp, boosting follicle activity.

A dropperful of Act + Acre’s Cold Processed Apple Stem Cell Scalp Serum a day keeps hair loss at bay by increasing the length of the anagen (growth) phase in the hair growth cycle, which helps prevents hair loss, thinning, and fallout. Regular use of this serum can even repair the scalp microbiome on a cellular level, improving hair density and providing the scalp with balanced hydration for softer, thicker hair. Dr. Camp also recommends this serum this clients.

Most hair serums take weeks or months to see visible results. This daily treatment gives you an instant lift while also targeting the root of hair thinning. Formulated with innovative ingredients like Redensyl™ and pea sprout extract, it adds volume to thinning hair, giving you a noticeable boost in thickness and texture.

This luxurious treatment is like a vitamin-enriched IV drip for your scalp. Packed with transformative ingredients like Augustinus Bader's patented TFC8® peptide alongside potent hair superfoods that are rich in natural proteins, antioxidants, and omega fatty acids, this serum instantly optimizes hair follicle function, reinvigorating the hair follicles at the root to support natural growth and renewal.

Leonor Greyl Paris Tonique Vivifiant Leave-In Tonic Spray Treatment for Hair Vitality

Tonique Vivifiant Leave-In Tonic Spray Treatment for Hair Vitality

We love using this leave-in tonic as a supplement to a more targeted hair growth serum. Infused with plant proteins for strength, mimosa tenuiflora to help hydrate dry strands, and vitamin-rich seaweed extract, this lightweight spray promotes scalp health by providing everything your hair follicles need for vitality on a daily basis.

The Nue Co SUPA THICK Topical Hair Supplement

SUPA THICK Topical Hair Supplement

A healthy scalp is the key to healthy hair, especially when you're trying to promote new growth. This targeted treatment targets both the hair follicle stem cells and dermal papilla cells, which plays the main role in the regulation of hair growth. At the same time, the prebiotics and probiotics that are infused into the formula help repopulate the scalp’s all-important microbiome, helping hair transition to the anagen phase, which reduces shedding and encourages thicker growth.

PATRICKS RD2 Hair Loss Serum for Men

RD2 Hair Loss Serum for Men

This potent serum is loaded up with 24% active ingredients —all designed to tackle different signs and symptoms of hair loss. The sophisticated formulation is designed to penetrate deep into the scalp, encouraging circulation, blocking the production of DHT and ultimately stimulating hair growth. Capixyl, a blend of peptides and red clover extract, boosts hair follicles by modulating levels of DHT and improving anchorage, keeping your hair on your head. AnaGain aids the rebalancing of the hair life cycle by stimulating hair growth at the root, reactivating hair growth and improving hair density.

Does Hair Regrowth Serum Really Work?

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The hair growth serums that are the most effective contain an effective dose of active ingredients. Some ingredients, such as minoxidil, finasteride, or specific peptides, have faced the scrutiny of multiple studies and been clinically-proven to stimulate hair follicles and promote regrowth. Some plant-based ingredients also have compelling studies behind them to demonstrate their effectiveness, but these may take longer to see visible results. Additionally, hair regrowth serums have been shown to be more effective when used at the first signs of hair loss or thinning, so don't sleep on the decision to add a hair growth serum to your routine—or it might be too late.

What Is Proven to Help Hair Regrowth?

Ingredients like minoxidil, finasteride, and certain patented peptides have all been proven to encourage new growth. Some treatments like low-level laser therapy, platelet-rich plasma (PRP) therapy, and hair transplant surgery are also proven for the treatment of hair loss, however these treatments can be quite invasive and costly.

How Long Does it Take for Hair Growth Serum to Work?

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On average, your hair grows at a rate of approximately half an inch per month if it's healthy, so if you're suffering from hair loss, you can expect that it will take even longer for your hair to grow. While you may notice subtle changes to your hair texture and condition within the first few weeks of using a hair growth serum, it can take 3 to 4 months of consistent use to see real results and visible new growth. After 6 months or more of continuous use, you can expect to see significant and noticeable improvements in hair volume and thickness, but this doesn't mean you can stop using your hair growth serum. You have to keep using the serum even after you have achieved your desired results. If you stop using the product, your original hair growth cycle will start again and your hair will return to its original state.

How We Selected

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For this story, Cristina Montemayor consulted with MH editors like Deputy Commerce Editor Christian Gollayan, as well as board-certified dermatologist Dr. Brendan Camp, on the best hair growth serums for men that really do work. She evaluated our editors' testing notes to see just how effective they were, and considered hair type and price point to find the best picks for as many people as possible.

Shop More of the Best Hair Growth Products for Men

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Hair Growth Products for Men | Rosemary Oil for Hair Growth | Hair Growth Shampoos | Vitamins for Hair Growth

Headshot of Christian Gollayan

Christian Gollayan oversees e-commerce content for Men's Health and Women's Health. Previously, he was the Associate Managing Editor at TheManual.com. Christian's work has also been featured in Food & Wine, InStyle, the New York Post, and Tatler Asia.

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The 9 Best Hair Growth Devices for Achieving Thicker, Fuller, and Healthier-Looking Strands

These cutting-edge gadgets can slow down the process of thinning and stimulate follicle production.

hair growth

Every item on this page was chosen by a Town & Country editor. We may earn commission on some of the items you choose to buy.

"LED Red Light Therapy has been shown to be particularly effective in treating androgenetic alopecia, which is a type of hair loss caused by a combination of genetic and hormonal factors," says Dr. Craig Ziering, D.O., F.A.A.D. , a board-certified dermatologist, hair transplant surgeon, and owner of Ziering Medical . And unlike traditional hair growth treatments, "red light therapy has no known side effects, making it a safer and more natural alternative."

LED isn't the only effective at-home hair growth device, either. According to Dr. Ziering, methods such as micro-needling and low-level laser therapy (also referred to as cold laser therapy) can also deliver promising results for hair follicle health.

To help with your search, here are the best hair growth devices worth adding to your haircare routine.

ONE Hair Growth Laser Cap

Best Hair Growth Device for Hereditary Hair Loss

Capillus one hair growth laser cap.

Ultima 9 (FDA Cleared) Laser Hair Growth Comb

Best Laser Brush for Hair Growth

Hairmax ultima 9 (fda cleared) laser hair growth comb.

Essential Laser Hair Growth System

Best Hair Growth Device for Thinning Hair

Irestore essential laser hair growth system.

LED Hair Regrowth Device

Best LED Device for Hair Growth

Currentbody skin led hair regrowth device.

Red Light Hat

Best New Launch

Higherdose red light hat.

Hair Growth Derma Roller for Hair Growth Therapy

Best Derma Roller for Hair Growth

Bondi boost hair growth derma roller for hair growth therapy.

The Ziering LaserCap

Best Pro-Grade Device

Ziering medical the ziering lasercap.

Intensive LED Hair Growth Brush

Best LED Hair Brush

Solaris laboratories ny intensive led hair growth brush.

Laserband 41 Comfortflex Hair Growth Device

Best Hair Growth Headband

Hairmax laserband 41 comfortflex hair growth device.

The most inconspicuous hair growth device on the market, this cap allows you to grow on the go. It comes equipped with hidden red light therapy technology to prevent shedding, revitalize damaged strands, and rejuvenate the follicles for future growth. It's particularly effective for those dealing with genetic alopecia, but it's also suitable for menopause- and age-related hair loss.

One Amazon shopper says: "It's been 2 months and only a small portion of the hairs fell out and the rest of them are growing like weeds. I can not believe how long they are getting. My receding hairline is way less noticeable and being a woman in my late 50s this is more important than you can ever imagine. If this is what can happen in just 2 months I am excited to see what is in store for me over the next 12 months."

Suggested Use: 6 minutes daily for 6 months

This hair brush features nine medical-grade laser diodes that can be used to spot treat problematic areas or on the full scalp. According to clinical studies conducted by the brand, the device helps regrow hair with "an average hair count of 129 additional new hairs per sq. inch after six months." Plus, its compact size makes it travel friendly.

One Amazon reviewer writes: "My dermatologist recommended this product. He mentioned that I wouldn’t see hair growth right away, but the first signs it began working would be that my hair would stop falling out as much. He was right! I’ve only used it a few times, so far, and my hair falling has slowed substantially! I’m eager to see new hair growth now. One thing I recommend is that you use it every other day until you reach the maximum usage days to follow the three times a week as suggested in the directions."

Suggested Use: 3 times a week for 11 minutes a session.

The iRestore is a hands-free gadget that treats your hair and allows you to multi-task at the same time. The FDA-cleared hair loss treatment uses red light therapy to promote a fuller and denser mane, and it comes with an accompanying remote with a timer display that lets you press pause or restart whenever needed.

One Amazon reviewer raves: "I am a 61-year-old woman, and my hair has been thinning for several years... I've been using the iRestore for almost two months... I'm happy to say that my hair is regrowing beautifully. I'm no longer self conscious about my hair style. I have lots of new baby hair coming in, and it's my natural dark color, not white like a lot of my hair is. I give most of the credit to the iRestore helmet; I've tried Rogaine for women in the past with little result, but this time around my hair is really responding."

Suggested Use: Every other day for 25 minutes. Expect results in 3-6 months

This FDA-cleared helmut-like device harnesses the power of red light therapy to not only hasten regrowth, but to prevent future hair loss, reverse pattern balding, and receding hair lines by restrengthening the follicle. It's also very easy to use, super lightweight, and features built in speakers, so you can sit back, relax, and enjoy your favorite podcast.

One reviewer writes: "Easy to use and size fit in perfectly, it’s so nice that given timer and Bluetooth connected automatically, it’s comfortable to wear and it’s weight not heavy, the light feeling warm and the material feel so durable."

Suggested Use: 10 minutes daily for 16 weeks

MORE: T&C Tried & True: Why the CurrentBody Skin LED Hair Regrowth Device Is a Crucial Part of a Haircare Routine

From the brand behind the T&C-loved infrared sauna blanket and infrared mat , this new red light hat comes built with full coverage LEDs that increase blood flow in the scalp and strengthen the hair follicle to reduce shedding and thinning, and boost growth and density. For best results, use daily for 10 minutes to see its powerful effects by the 2 month mark.

One reviewer says: "Before using I would have handfuls of hair come out in the shower but now I see so much less shedding. I see less white scalp than before and I see new growth."

Suggested Use: Every day for 10 minutes. Expect results in 1-2 months.

If you're considering going down the micro-needling route, Bondi Boost's derma roller has 540 high strength medical grade stainless steel needles designed to be used across the scalp.

One reviewer says: "This is a must have in my products and tool from Bondi! I can already tell a difference in my thinner spots on my head. I just started incorporating this product into my weekly hair care routine! I use it after i shower in my wet hair and so far so good. I'm excited to continue using it to see how it promotes hair growth."

Suggested Use: Once a week on wet hair

When you want to achieve professional results at home, Dr. Ziering's cutting-edge hair growth device is your best bet. "The Ziering LaserCap stimulates inactive hair follicles using low-level laser therapy," Dr. Ziering explains. "It's a safe, all-natural, and painless hair regrowth treatment."

Suggested Use: 3 times a week for 30 minutes for the first 12 months

Not only does this brush use red LED to address hair loss, it also relies on blue LED to help promote maximum growth, as well as gentle sonic vibration that massages the scalp for a soothing brushing experience. Not to mention, it's under $100.

One reviewer says: "I did not think it would work but im kind of desperate and cannot handle monoxodil it left my skin so itchy and I even had some weird hormonal fluctuations with my cycle so my doc advised me to get off. He told me to look into red LED so my search got me to this product, its cheap and has medical grade red 630nm. I used it in combination with a head massage with my fingers and i have seen hair fill out in places that were bald spots!"

Suggest use: Use on dry hair for 5-10 minutes

Created specifically for those dealing with Androgenetic alopecia (the most common form of hair loss in men and women), this head band uses medical lasers to stop thinning in its tracks and help boost hair density and fullness. It's also a great option for people always on the go since the recommended treatment use is only 3 minutes.

One reviewer writes: "I've had mine for about 3 years. My hairdresser is amazed how thick my hair is now. I use it 3-4 times a week."

Suggested use: Start at the front hairline, glid incrementally over the scalp, covering 6 sections. Use 3 days a week for 3 minutes

What is the best technology to regrow hair?

what is the best technology to regrow hair

According to Dr. Ziering, there are many devices one can use to treat hair loss:

  • Red light therapy: "LED therapy provides a comfortable, non-invasive treatment free from side effects and offers a safe and convenient solution to address hair loss."
  • LLLT (low-level light therapy): "Cold lasers are clinically proven to increase hair density in patients with pattern hair loss over a 16-week timeframe using a wearable, helmet-type device."
  • Micro-needling: "The process of creating wounds in the skin is thought to regenerate the health of the hair follicles. It’s thought that this can result in new hair growth, or perhaps, it may thicken thinning hair as seen in androgenic alopecia or male pattern baldness."

When should you start seeing results after using a hair growth device?

when should you start seeing results after using a hair growth device

It all depends on the product you use. People who use Dr. Ziering's medical-grade cap usually notice a difference in their thinning areas within 60 days, while other FDA-cleared devices on the market deliver results starting in 3 months.

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COMMENTS

  1. New treatment could reverse hair loss caused by an autoimmune skin

    Caption: Researchers developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss. The new microneedle patch delivers immune-regulating molecules that can teach T cells not to attack hair follicles, helping hair regrow. Pictured is an up-close view of the microneedles.

  2. Can we finally reverse balding with these new ...

    By the age of 50, between 30 and 50 per cent of men have begun to experience male pattern baldness. Despite there being plenty of handsome hairless men out there - I'm looking at you, Thierry ...

  3. Advances in hair growth

    Microneedling was performed on half the scalp treated with growth factors and the other half treated with normal saline. At 5 weeks, the microneedling with growth factor-treated scalp had an increase in hair count (52.91 ± 10.85) compared with the microneedling with saline-treated scalp (45.91 ± 9.98) ( P = 0.0001).

  4. Hair-raising research: Scientists find surprising link between immune

    Hair-raising research: Scientists find surprising link between immune system, hair growth. ScienceDaily . Retrieved May 18, 2024 from www.sciencedaily.com / releases / 2022 / 06 / 220623110948.htm

  5. The new regenerative and innovative strategies in hair loss

    In vitro, antiapoptotic effects of PRP have been identified as one of the major contributing factors stimulating hair growth (HG) via the Bcl-2 protein's activation (antiapoptotic regulator) and Akt signaling, prolonging the survival of dermal papilla cells during the hair cycle.In particular, the up-regulation of fibroblast growth factor-7 (FGF-7)/β-catenin signaling pathways with PRP ...

  6. New Study Points to Possible Cure for Hair Loss

    Aug. 1, 2022, 10:25 AM PDT / Source: TODAY. By Linda Carroll. A single molecule may hold the key to battling male- and female-pattern hair loss, recent research suggests. In mouse experiments ...

  7. UC Irvine-led researchers reveal new molecular mechanism for

    Irvine, Calif., June 21, 2023 — The process by which aged, or senescent, pigment-making cells in the skin cause significant growth of hair inside skin moles, called nevi, has been identified by a research team led by the University of California, Irvine.The discovery may offer a road map for an entirely new generation of molecular therapies for androgenetic alopecia, a common form of hair ...

  8. Signaling molecule potently stimulates hair growth

    Sep. 22, 2023 — A receding hairline, a total loss of hair from the crown, and ultimately, the classical horseshoe-shaped pattern of baldness: Previous research into male pattern hair loss, also ...

  9. Advances in hair growth

    Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relating to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence that has advanced our understanding of hair …

  10. Functional hair follicle regeneration: an updated review

    The HFSC population remains largely quiescent during hair growth, but a subpopulation actively proliferates and promotes the production of the new hair shaft under the control of Axin2 expression ...

  11. Hair Follicles Can Now be Grown in Labs: What This Means for Hair Loss

    Galina Zhigalova/500px/Getty Images. New research has allowed scientists to generate new hair follicles — those tube-shaped pores that hug the strand and root of a hair — in vitro in a lab. It ...

  12. Reversing Baldness: Surprising New Molecular Mechanism Discovered for

    The study showed that molecules osteopontin and CD44 play a key role in this process, potentially opening new avenues for therapies for common hair loss conditions. The process by which aged, or senescent, pigment-making cells in the skin cause significant growth of hair inside skin moles, called nevi, has been identified by a research team led ...

  13. Studies Uncover New Approaches to Combat Hair Loss in Men and Women

    The engineered follicles also could be used by the pharmaceutical industry to screen for new hair growth drugs. Currently, high throughput screening for new hair drugs has been hampered by the inability to grow human hair follicles in a lab dish. ... The research was supported by the National Skin Center of Singapore, the National Medical ...

  14. FDA Approves First Drug to Treat Hair Loss Caused By Alopecia

    Alopecia areata is a disease that occurs when the immune system attacks hair follicles, causing hair loss. Hair loss is usually found on the head and face but can occur in small, round, coin ...

  15. Hair loss: The latest research on causes and treatments

    Alopecia areata. In June 2022, the FDA approved the first treatment for a type of hair loss in which the immune system attacks hair follicles, known as alopecia areata. The drug, called ...

  16. SCUBE3: New Molecule Discovered That Strongly Stimulates Hair Growth

    The research, which was recently published in the journal Developmental Cell, uncovered the precise mechanism by which the dermal papilla cells, specialized signal-producing fibroblasts found at the bottom of each hair follicle, encourage new development. Although the critical role dermal papilla cells play in regulating hair growth is widely ...

  17. Modulation of Hair Growth Promoting Effect by Natural Products

    Prunus mira Koehne (PK) is a wild peach species that contains various nutrients and fatty acids [ 152 ]. Zhou et al., showed the hair-promoting effect of nut oil from PK [ 42 ]. They demonstrated that nut oil from PK increased hair length in mice and upregulated Wnt10B, β-catenin, and GSK-3β expression in mice [ 42 ].

  18. Going bald? Lab-grown hair cells could be on the way

    Biologists at several startups are applying the latest advances in genetic engineering to the age-old problem of baldness, creating new hair-forming cells that could restore a person's ability ...

  19. FDA approves second Yale-researched treatment for alopecia areata

    On June 23, the FDA announced its approval for the use of ritlecitinib — a Janus kinase (JAK) inhibitor — to treat alopecia areata in both adolescents and adults. The medicine, taken orally, goes by the product name Litfulo. Alopecia areata is an autoimmune disease characterized by sudden, often disfiguring, loss of hair.

  20. Baldness breakthrough? New RNA treatment may stimulate hair growth

    MicroRNA could treat baldness by stimulating growth in aging hair follicles. Researchers have developed a possible cure for baldness using a tiny RNA particle. Jesse Morrow/Stocksy. Researchers ...

  21. New treatment could reverse hair loss caused by an autoimmune skin

    Date: May 9, 2024. Source: Massachusetts Institute of Technology. Summary: Researchers developed a potential new treatment for alopecia areata, an autoimmune disorder that causes hair loss. The ...

  22. The Key to Locks: Columbia Team's Breakthrough Led to Hair Loss

    For over a decade, Columbia geneticist Angela Christiano, PhD, has attended the annual meeting of the National Alopecia Areata Foundation, where hundreds of individuals affected by the hair loss disorder gather to support one another and learn about the latest scientific research.The meeting is a safe space where patients with alopecia, many of whom have lost all their hair, joyfully remove ...

  23. Integrative and Mechanistic Approach to the Hair Growth Cycle and Hair Loss

    Authors observed a 7.2% increase in hair thickness, 14.3% increase in hair density, and a 20.3% increase in shine and elasticity. Treatment-responsive subjects (85% of the cohort) depicted a 66.8% reduction in hair loss after six months of treatment, with an increase in hair growth up to 32.5% (mean 1.8%).

  24. Microneedle Patches Might Reverse a Form of Hair Loss

    Over 6 million Americans suffer from hair loss due to alopecia areata; there are no safe, effective cures. New research in mice suggests that a microneedle patch applied to the scalp might ease the condition. Mice who got the patches displayed new hair growth at the site. MONDAY, May 13, 2024 (HealthDay News) -- Early research in mice suggests ...

  25. How to Grow Out Your Hair: A Guide

    Keratin treatments every six months. "It's a game-changer for keeping your hair soft and in good condition.". Model and photographer Laura Bailey, meanwhile, cautions against over-styling ...

  26. How Oral Hair Growth Supplements Affect Body Hair

    Key Takeaways. Oral hair growth supplements can help with hair growth, retention, and density. The supplements can affect your body hair and the hair on your head. Though you may notice a slight change in body hair after taking the supplements, they shouldn't cause any significant changes to hair growth anywhere on the body, dermatologists said.

  27. Hair Loss News -- ScienceDaily

    Sep. 22, 2023 — A receding hairline, a total loss of hair from the crown, and ultimately, the classical horseshoe-shaped pattern of baldness: Previous research into male pattern hair loss, also ...

  28. Why Is My Hair Thinning? Understanding The Hair Growth Cycle

    "Hair is essentially made of the protein ­keratin — approximately 90%," says trichologist David H. Kingsley, PhD, a hair loss specialist in New York City. "The remaining 10% or so of the hair fiber is made up of melanin — which is the pigment that gives hair its color — fats and oils, trace metals and water."

  29. 13 Best Hair Growth Serums for Men of 2024, Per Hair Experts

    THE ORDINARY Multi-Peptide Serum for Hair Density. The best hair growth serums tackle hair loss on multiple fronts; they improve the condition of your scalp, which aids in encouraging healthy hair ...

  30. 9 Best Hair Growth Devices of 2024, According to Experts

    Best Hair Growth Device for Hereditary Hair Loss. Capillus ONE Hair Growth Laser Cap. $630 at Amazon. Read more. Best Laser Brush for Hair Growth. HairMax Ultima 9 (FDA Cleared) Laser Hair Growth ...