Alopecia: Hair Follicles, Wake Up!

24. October 2017
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Hair loss is more than just a cosmetic problem. People suffer mentally from having lack of hair. At present only a few medications exist for treating it. Biologists are now trying to manipulate the metabolism involved and to develop implants from stem cells.

An estimated 80 per cent of all men and 42 per cent of all women have to battle various versions of androgenetic alopecia. Whereas in the beginning men usually watch their hairline recede, women lose their hair predominantly in the middle crest region.

Currently hardly any space in which to work

Dermatologists have cast a critical eye over the already yellowing pages of the S3 guideline which deals with treatments for androgenetic alopecia. In their evaluation of literature sources, the authors found 396 articles, 85 papers of which fulfilled the methodological inclusion criteria. Ultimately only minoxidil and finasteride received good reviews.

Minoxidil is equally suitable for women and men. The prodrug minoxidil ends up, through the action of the enzyme sulfotransferase, becoming minoxidil sulfate in the follicles during anaphase. Blood circulation improves and cells increasingly excrete growth producing factors such as vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). Moreover, protective prostaglandins are increasingly produced. In men the 5% formulation is more effective, the same formulation in women yields no significant added value when compared to 2% minoxidil. If patients discontinue using this preparation, their hair will increasingly fall out once again in the medium term.

For men suffering from hair loss, there is still another option. In the male metabolism dihydrotestosterone(DHT) is a centrally important molecule. DHT-sensitive follicles react by shortening their anagen phase, and the hair falls out faster. In addition there are indications of upregulation of the insulin-like growth factor 1 (IGF-1). Finasteride comes into the picture here. In being a 5α-reductase inhibitor it brings down the DHT level in the blood. Dutasteride has a similar effect, but has not been approved for use against androgenetic alopecia.

Association with erectile dysfunction

New studies have put finasteride and dutasteride in a bad light when used in men. Tina Kiguradze and William H. Temps from Northwestern University, Chicago, have found correlations with persistent erectile dysfunction (PED) for both pharmaceuticals. The US Food and Drug Administration had issued appropriate warnings earlier, albeit with a much poorer body of data. A large part of all studies had methodological distortions.

Kiguradze and Temps evaluated data from 11,909 men who for various reasons had been prescribed 5α-reductase inhibitor by a doctor. Their subjects were between 16 to 89 years of age. PED occurred with 167 people (1.4 percent). After discontinuation of the preparation, it took an average of 1,348 days for normal erections to return. This pharmacotherapy is therefore an individual and independent risk factor, according to the authors. They compare the effect to that of the negative consequences of type 2 diabetes, obesity, alcohol abuse or severe nicotine consumption. As far as physicians and pharmacists are concerned, it is a possible further limitation for pharmacotherapies.

New targets, new opportunity

This is why scientists are eagerly looking for new target structures. A working group led by Aimee Flores from the Department of Molecular Cell and Developmental Biology at UCLA succeeded in activating hair follicle stem cells. The focus of her experiments was the question of which factors move quiescent follicles from the telogen phase into the anagen phase with renewed growth. The results were surprising. If cells convert glucose into pyruvate and metabolise it in their mitochondria, the cells remain in their arrested sleep phase. If lactate however is formed from the sugar, hair follicle stem cells are stimulated into hair production.

Flores immediately identified two suitable candidate molecules in order to intervene in regulation. RCGD423 acts as an inhibitor in the intracellular JAK-STAT signalling pathway, which leads to more lactate in the stem cells. Alternatively, UK5099 prevents pyruvate uptake in mitochondria of the hair follicle stem cells. In an animal experiment both molecules initiated hair growth.

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Untreated mice and those treated with UK5099 in comparison (vl.). New hair grew through use of the pharmaceutical agent. © UCLA Broad Stem Cell Center

Transplanting one’s own building blocks

Stem cells are also interesting in other respects. In the laboratory Japanese researchers produced so-called “embryoid bodies”, that is three-dimensional tissue lumps, from induced pluripotent stem cells (iPS cells) derived from wild-type mice. Administering signal proteins such as Wnt10b resulted in skin layers with hair follicles. They then transplanted small tissue portions onto hairless naked mice. These animals, due to genetic anomalies, have no thymus and no body hair. After 14 days, hair grew in this area. What’s more no anatomical anomalies appeared:

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Cross-section through normal skin and through an implant of iPS cells following transplantation © RIKEN Center for Developmental Biology

According to co-author Takashi Tsuji the method is generally also suitable for humans. He works at the RIKEN Center for Developmental Biology in the Japanese city Kobe. Whether Tsuji is proven correct remains to be seen in new studies. Opportunities for finding new treatment methods look good.

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Non-medical professions

Hello. What frequency of application minoxidil 5% per day was for men?

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