Scientific publications

The only known role of FGF5 in healthy adults is to signal the transition of hair follicles out of the growth (anagen) phase and into the resting (telogen) phase. Hair cycle dysfunction and shortening of anagen are key features of pattern hair loss, age related hair loss, and hair loss after stress or trauma (including chemotherapy). Extending anagen by blocking FGF5 is effective in restoring the hair cycle, reducing hair fall, and increasing the proportion of actively growing follicles.

évolis products are based on many years of research by our dedicated scientists in Australia and Japan. Our scientists have screened thousands of botanical molecules for efficacy against FGF5 activity using in-vitro cell-based assays. The scientists at évolis have also performed two randomized, placebo-controlled efficacy studies in humans and one safety study in humans. The results are summarized in a publication section below. A growing body of scientific evidence surrounding FGF5 and its role in hair loss and hair growth is also summarized below.

Our products contain three key botanical actives

  • Sanguisorba officinalis root extract
  • Rosa multiflora fruit extract
  • Swertia chirata plant extract

Publication summary: The science behind évolis

évolis publication 1

Burg D., Yamamoto M., Namekata M., Haklani J., Koike K., and Halasz M. Promotion of anagen, increased hair density and reduction of hair fall in a clinical setting following identification of FGF5-inhibiting compounds via a novel 2-stage process. Clinical, Cosmetic and Investigational Dermatology. 10: 71-85. 27 (2017)

Key Results:

  • évolisscientists have screened hundreds of botanical extracts and molecules for FGF5 inhibitory activity using two in vitro cell based assays
  • Several members of the monoterpene family were identified as powerful inhibitors of FGF5, up to seven times more potent (p< 0.005) than previously identified crude plant extracts (S. officinalis root) extract. A significant improvement in potency and precision.
  • A small, blinded placebo controlled clinical study (32 individuals) with a novel formulation of évolis tonic was performed against males and females with early to mid-stage androgenetic alopecia (Hamilton-Norwood 2-4, and Ludwig i-2 to ii-2 respectively). The study period was 16 weeks (112 days), with readings taken at 8 and 16 weeks.
  • After 112 days (16 weeks) of treatment Participants using évolis had:
    • 44.2% increase in the number of anagen follicles (p=0.002)
    • All but one participant improved in visual grading (p=0.002)
    • 82.1% less hair fall (p=0.007)
  • Comparing évolis to placebo: the évolis group performed better for: A) visual grading p=0.0005 and B) Hair fall p=0.002. C) A non-significant trend for better performance was observed in anagen telogen ratio (p=0.11) with an average improvement of 44% compared to an average improvement in placebo of 11%. High variance in the placebo group influenced this result.
  • No significant trends in any direction were seen for the placebo group except in hair fall, where the placebo group had a trend of increased hair fall at day 112.
  • Six participants undergoing treatment with évolis were selected for global photography and hair density measurement All participants improved over the course of the study compared to baseline and these increases remained significant between day 56 and day 112 (p=0.03)

**All data in this summary has been collapsed into one treatment group. The published study had two treatment groups. Similar statistical significance was reached for all measures in the published study. Please see paper via PubMed or the Journal website for full dataset

évolis publication 2

Maeda, T., Yamamoto, T., Isikawa, Y., Itoh, N. & Arase, S. Sanguisorba Officinalis Root Extract Has FGF-5 Inhibitory Activity and Reduces Hair Loss by Causing Prolongation of the Anagen Period. Nishinihon J. Dermatology 69, 81–86 (2007).

The évolis scientists identified FGF5 inhibitory activity in several botanical extracts including Rosa multiflora and Sanguisorba officinalis.

A topical solution of S. officinalis extract was tested in a double blind, randomized, placebo-controlled trial of 39 individuals (males and females) suffering hair loss. After 4 months of use, participants in the topical S. officinalis treatment group had a significant reduction in shed hair (p< 0.01) with a concurrent reduction in shed vellus hair (p< 0.01). Hair growth rate was assessed by phototrichograms and was shown to be increased by 18% (p< 0.01). The proportion of anagen follicles in treated individuals was increased by 10% (p< 0.01). User surveys highlighted performance satisfaction, with >75% of the treatment group labelling the solution as at least somewhat effective vs. only 25% of the placebo group.

évolis Safety Study

Advangen has performed a safety study via an independent CRO AMA labs NY, USA. AMA labs performed repeated insult patch testing (RIPT) on 50 individuals (male and female). No reactions were reported over the course of the study in any individual.

Key evidence around FGF5 in hair growth and hair loss

Key Publications

Higgins et al., discovered that mutations in FGF5 resulted in families that had high proportions of actively growing hairs and extremely long eyelashes.

Higgins, C. a et al., FGF5 is a crucial regulator of hair length in humans. PNAS USA, 111(29), pp.3–8 (2014).

Several families in remote Pakistan with familiar trichomegaly (unusually long and thick hair, including very long eyelashes) were studied using a combination of whole exome sequencing and homozygosity mapping. The authors identified a distinct series of mutations within the fibroblast growth factor 5 (FGF5) gene underlying the disorder. Hair fibers from forearms of those affected were identified as significantly longer than hairs from control individuals, with an increased proportion in the growth phase, anagen.

Using hair follicle organ cultures, the authors demonstrated that FGF5 induces regression of the human hair follicle, and immunostaining identified FGF5 accumulation in the outer root sheath and in perifollicular macrophages in late anagen.

The study was the first to identify FGF5 as a crucial regulator of hair growth in humans.

In a Nature communications report Heilmann-Heimbach et al., described a study of thousands of men and found that FGF5 was associated with male patter baldness

Heilmann-Heimbach, S. et al. 2017 Meta-analysis identifies novel risk loci and yields systematic insights into the biology of male-pattern baldness. Nat. Commun. 8, 14694 (2017)

Stefanie Heilmann-Heimbach and colleagues described a genomic investigation where almost 11-000 men with early onset androgenetic alopecia (AGA) were compared to over 11 500 men without AGA, with genome data sourced from several European and Australian studies. The authors performed a genome wide association study (GWAS) to identify phenotype associated variations in genes between the AGA population and the non-alopecia population.

The authors highlighted a small variation in FGF5, among a number of other genetic variations, as a strong candidate genetic factors in the men with AGA. The authors highlighted: "the newly identified candidate genes and pathways, perhaps most notably FGF5 and melatonin signalling are promising targets for the development of novel therapeutic options for male pattern baldness"

British authors examined the genes of 52000 men and found FGF5 was a top 20 gene associated with male pattern baldness

Hagenaars et al., Genetic prediction of male pattern baldness. PLOS Genetics (2017)

Using data from over 52 000 men in the UK biobank the authors used powerful data mining techniques to look for genes associated with hair loss.

The scientists identified FGF5 as a top 20 gene contributing to male pattern baldness: "the top 20 hits from autosomes were located in or near to genes that have been associated with, for example, hair growth/length in mice (FGF5)". The authors went on to describe the importance of FGF5 in pattern baldness "it is possible that genetic variants leading to higher levels of expression of this gene result in greater inhibition of hair growth, leading to male pattern baldness"

A third GWAS study of more than 70 000 men independently confirms FGF5 as a key genetic component of male pattern Baldness

Pirastu et al., (GWAS for Male-Pattern Baldness Identifies 71 Susceptibility Loci Explaining 30% of the Risk. Nature Communications (2017)

Publications highlighting FGF5’s role in the hair cycle and in hair length determination

Wang, X. et al. Disruption of FGF5 in Cashmere Goats Using CRISPR/Cas9 Results in More Secondary Hair Follicles and Longer Fibers. PLoS One 11, e0164640 (2016).

Knock out of FGF5 using CRISPR technology resulted in cashmere goats with longer hair fibers and more secondary hair fibers, increasing yield. Goats were otherwise healthy and were fertile.

He, X., Chao, Y., Zhou, G. & Chen, Y. Fibroblast growth factor 5-short (FGF5s) inhibits the activity of FGF5 in primary and secondary hair follicle dermal papilla cells of cashmere goats. Gene 575, 393–398 (2016).

The receptor for FGF5, FGFR1 was identified in the dermal papilla of both types of hair follicles in Cashmere goats (Primary and secondary hairs). Adenovirus mediated overexpression of FGF5 upregulated IGF1, versican and noggin and downregulated BMP4 in dermal papilla cells. The regulation of these genes was only partially reversed by FGF5s overexpression.

Chen, Z., Wang, Z., Xu, S., Zhou, K. & Yang, G. Characterization of hairless (Hr) and FGF5 genes provides insights into the molecular basis of hair loss in cetaceans. BMC Evol. Biol. 13, 34 (2013).

Cetaceans have evolved from terrestrial mammals but have adapted to the aquatic environment; including through the loss of hair/fur. The authors identified indications of positive selection for the FGF5 gene and hypothesized that this may have been a factor in disruption of the hair cycle and early catagen entry during the evolutionary loss of hair in cetaceans.

Galant, R. et al. Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes. Nature 415, 4213–4222 (2009).

GWAS studies of over 1000 dogs from 80 breeds identified three genes accounted for most coat phenotypes in purebred dogs. Mutation in FGF5 was predominantly associated with long haired breeds.

Kehler, J. S. et al. Four independent mutations in the feline Fibroblast Growth Factor 5 gene determine the long-haired phenotype in domestic cats. J. Hered. 98, 555–566 (2007).

Genomic analysis of a multigenerational cat pedigree identified FGF5 as a strong candidate in the long-haired phenotype. Subsequent sequence analysis of FGF5 in 26 cat breeds and two pedigrees identified 4 mutations in FGF5, and a GWAS analysis of 380 cats demonstrated that FGF5 was the major genetic determinant of long hair in cats.

Ota, Y. et al. Fibroblast growth factor 5 inhibits hair growth by blocking dermal papilla cell activation. Biochem. Biophys. Res. Commun. 290, 169–176 (2002).

The authors examined the action of FGF5 against activated dermal papilla (DP) cells. DP cells were shown to express the receptor FGFR1, and were able to be activated by FGF1. FGF5 was shown to be antagonistic of DP activation by FGF1, demonstrating the catagen inducing effect of FGF5 in vitro.

Suzuki, S., Ota, Y., Ozawa, K. & Imamura, T. Dual-mode regulation of hair growth cycle by two Fgf-5 gene products. J. Invest. Dermatol. 114, 456–463 (2000).

Suzuki and colleagues identified alternative mRNA splicing of FGF5, which results in a long (FGF5) and short (FGF5s) version of the protein being transcribed. The authors identified FGF5s as an antagonist of FGF5, suggesting a role for FGF5s in the regulation of the catagen inducing activity of FGF5.

Rosenquist, T. A. & Martin, G. R. Fibroblast growth factor signaling in the hair growth cycle: expression of the fibroblast growth factor receptor and ligand genes in the murine hair follicle. Dev. Dyn. 205, 379–86 (1996).

Rosenquist and Martin identified the expression patterns of the various FGF receptor tyrosine kinase genes in the hair follicle at different stages of the hair cycle. The authors identified FGFR1 as expressed in the dermal papilla (DP), and confirmed FGF5 is expressed in the outer root sheath during late anagen. The effect of FGF5 on DP cells was also investigated, with the authors indicating that the DP was responsive to FGF5.

Hebert, J. M., Rosenquist, T., Gotz, J. & Martin, G. R. FGF5 as a regulator of the hair growth cycle: Evidence from targeted and spontaneous mutations. Cell 78, 1017–1025 (1994).

The spontaneous angora mouse phenotype, which have abnormally long hair, where identified as having a mutation in FGF5. The phenotype could be replicated by ‘knocking out’ FGF5 in the laboratory. FGF5 was identified as expressed in the outer root sheath of the hair follicle in late anagen, highlighting its role as a regulator of the anagen to catagen transition

Further reading

Yoshizawa, Y. et al. A 1-bp deletion in Fgf5 causes male-dominant long hair in the Syrian hamster. Mamm. Genome 26, 630–637 (2015).

Bao, W. L. et al. Cloning, molecular characterization, and expression pattern of FGF5 in Cashmere goat (Capra hircus). Genet. Mol. Res. 14, 11154–11161 (2015).

Wang, X. et al. Generation of gene-modified goats targeting MSTN and FGF5 via zygote injection of CRISPR/Cas9 system. Sci. Rep. 5, 13878 (2015).

Legrand, R., Tiret, L. & Abitbol, M. Two recessive mutations in FGF5 are associated with the long-hair phenotype in donkeys. Genet. Sel. Evol. 46, 1–7 (2014).

Dierks, C., Momke, S., Philipp, U. & Distl, O. Allelic heterogeneity of FGF5 mutations causes the long-hair phenotype in dogs. Anim. Genet. 44, 425–431 (2013).

Liu, H.-Y., Yang, G.-Q., Zhang, W., Zhu, X.-P. & Jia, Z.-H. Effects of FGF5 gene on fibre traits on Inner Mongolian cashmere goats. Yi chuan = Hered. 31, 175–179 (2009).

Li, C.-X., Jiang, M.-S., Chen, S.-Y. & Lai, S.-J. Correlation analysis between single nucleotide polymorphism of FGF5 gene and wool yield in rabbits. Yi chuan = Hered. 30, 893–899 (2008).

Drögemüller, C., Rüfenacht, S., Wichert, B. & Leeb, T. Mutations within the FGF5 gene are associated with hair length in cats. Anim. Genet. 38, 218–221 (2007).

Housley, D. J. E. & Venta, P. J. The long and the short of it: Evidence that FGF5 is a major determinant of canine ‘hair’-itability. Anim. Genet. 37, 309–315 (2006).

Ito, C. et al. Decapeptide with fibroblast growth factor (FGF)-5 partial sequence inhibits hair growth suppressing activity of FGF-5. J. Cell. Physiol. 197, 272–283 (2003).

Petho-Schramm, A., Muller, H.-J. & Paus, R. FGF5 and the Murine Hair Cycle. Arch. Dermatol. Res. 288, 264–266 (1996).