Long history of hair loss treatment

In the past 50 years or so, research aimed at understanding the onset of male pattern baldness, particularly this form called alopecia areata, has followed two distinct pathways: ‘hormonal’ or ‘immunological’.

The “hormonal” path was justified by the results obtained during one of the darkest hours of American history. When the eugenics movement took hold and the forced sterilization of genetically “unqualified” individuals was legal in Kansas and in 27 other states, it was observed that giving testosterone to castrated males led to the development of typical male pattern baldness.1 The ‘immune’ pathway was justified in the presence of hair follicle autoantibodies in pediatric dermatomyositis.2 JD is a disease that, in addition to general muscular weakness and telangiectasia of the eyelids and nail coverings, may lead to a change in the shape of the hair, from straight to curly.

Historical errors, convincing results

For years, scientists have fed hairless mice with cyclosporine and other inhibitors of the immune response, and only noticed three or four hairs growing on their scalps. For years, scientists injected 5-a-reductase inhibitors into mice and had no single effect on hair physiology. Why 5-a-reductase? Because it is an enzyme that converts testosterone into dihydrotestosterone, the hormone responsible for the development and maintenance of the prostate gland and seminal vesicles.

These scientists may have been pioneers (and I was one of them), but they were using the wrong model. In fact, the hair of rodents is the same on the scalp, on the back, on the legs, in the perineum region – while in human males, the hair shape and biochemistry change with the anatomical region. For example, as we know very well, testosterone increases hair growth on the male face and causes hair loss on the scalp. After years of research, it appears that the two pathways, hormonal and immune, have led to a dead end in the search for a hair loss treatment and hope for a cure for male pattern baldness has faded.

Minoxidil and more breakthrough research

As is sometimes the case, discoveries in one field are the result of experiments in other fields. In this case, the glowing shell came to help. In the late 1960s to early 1970s, the Food and Drug Administration approved clinical trials to evaluate the effectiveness of a new vasodilating agent, minoxidil, a treatment for high blood pressure. In the course of these experiments, patients noted an unexpected induction of hair growth. Ironically, minoxidil has really gotten its chance because it was originally developed to treat ulcers and turned out to be a vasodilator instead. Its mechanisms of action are not clearly understood, however, in 1988, the Food and Drug Administration authorized the topical use of OTC minoxidil to treat male pattern baldness. However, the FDA noted that the product was approved “although the product will not work for everyone.”

In subsequent years, chance played a major role in the field of hair loss pharmacology. Research on BPH led to the development of finasteride, an inhibitor of 5-a-reductase, due to the observation that individuals deficient in both 5-a-reductase and di-hydro-testosterone have small prostates. Finasteride has also been found to stimulate hair growth and in 1997 the US Food and Drug Administration approved it as a prescription drug against hair loss, to be given on a regular basis. The drug was approved despite clinical evidence of sensitive side effects such as a disproportionately large number of men with sexual dysfunction associated with α5 reductase inhibitors and infertility. Although uncommon, use of 5-α-reductase inhibitors has been associated with serious and persistent sexual and reproductive side effects, such as erectile dysfunction, decreased ejaculatory volume, decreased libido and infertility.3

BARICITINIB and the JAK/STAT . signaling pathway

Earlier this year, the “immune” pathway appeared to have led to remarkable success. On June 13, 2022, the US Food and Drug Administration approved the use of baricitinib as a systemic treatment for severe alopecia areata. Baricitinib is an inhibitor of the Janus Associated Kinase/Signaling and Activated Transcriptional Proteins (JAK/STAT) signaling pathway.

What is the signaling pathway? Signaling pathways in the cell are collections of biochemical reactions aimed at delivering signals to the nucleus. The signal, for example, is the presence of a certain molecule in the environment on the outside of the cell. These exogenous molecules bind to a specific receptor on the cell membrane and trigger one or more biochemical reactions. One of the interactions can be, for example, the activation of kinase, an enzyme capable of attaching a phosphate group to another protein. Other modifications can follow other proteins or a chain of them, so that the last modified molecule enters the nucleus, binds to DNA and triggers the expression of a specific set of genes.

In skin care industry, marketing managers are familiar with NFkB pathway, Toll receptor signaling pathway, MAPK signaling pathway, mTOR signaling pathway and so on. The JAK/STAT pathway is involved in immunity, cell division, cell death and tumorigenesis. It has received wide interest in the medical and cosmetic fields. JAK/STAT pathway inhibitors have been studied for the treatment of rheumatoid arthritis and baricinib was approved by the US Food and Drug Administration in 2018 for the treatment of rheumatoid arthritis. Because of its anti-inflammatory effects, and because of its well-known association with hair loss With the inflammatory condition, baricitinib was tested in two randomized, double-blind, placebo-controlled clinical trials in volunteers with alopecia areata. The results were relevant, and the US Food and Drug Administration (FDA) granted approval for systemic use against alopecia areata.

As far as baricitinib’s effectiveness is concerned, there are still some caveats. The treatment helps 20% to 30% of treated patients regrow hair. In comparison, only 5% of patients in the placebo group achieved hair regrowth. Side effects range from headaches and acne to high cholesterol, anemia, shingles, nausea, infections, and weight gain.

1. Ayob SM, Messenger AG (2015) Androgens, Hair Loss and Eugenics: A Story of Discovery and American Social History. exp. Dermatol 24: 412-413
2. Alexander S, Stimmler L (1971) Antibodies to hair follicles and striated muscle in pediatric dermatomyositis. Archives of Childhood Diseases 46: 363-365
3. Saeed MA, Mehta A (2018) Effect of 5-a-reductase inhibitor use of male pattern hair loss on men’s health. Curr Urol Rep 19:65

Paolo Giacomoni, Ph.D.
Insight Analysis Consulting

Paolo Giacomoni works as an independent consultant for the skincare industry. He served as Executive Director of Research at Estée Lauder and was Head of Biology at L’Oréal. He has built a track record of researching DNA damage and metabolic impairment caused by UV rays as well as the positive effects of vitamins and antioxidants. He has authored over 100 peer-reviewed publications and holds over 20 patents.