The “hormonal” path found its justification in results obtained during one of the darkest hours of American history. When the eugenic movement took over and the enforced sterilization of genetically “unfit” individuals was legal in Kansas and in 27 other states, it was observed that administering testosterone to castrated males provoked the development of typical male baldness.1 The “immunological” path found its justification in the presence of autoantibodies to hair follicles in juvenile dermatomyositis.2 JD is a disease that, in addition to generalized muscular weakness and capillary dilatation at the eyelids and nailbeds, may lead to a change in hair morphology, from straight to frizzy.
HISTORICAL FAILURES, SOBERING RESULTS
For years, scientists fed hairless mice with cyclosporin and other inhibitors of the immune response, and only observed three or four hairs growing on the scalp. For years, scientists injected inhibitors of 5-a-reductase into mice and did not obtain one single effect on hair physiology. Why 5-a-reductase? Because it is an enzyme that converts testosterone into di-hydro-testosterone, the hormone responsible for the development and maintenance of prostate gland and seminal vesicles.
These scientists might well have been pioneers (and I was one of them), but they were using the wrong model. Indeed, the hair of rodents is the same on the scalp, on the back, on the legs, in the perineal region—whereas in human males, the morphology and the biochemistry of hair change with the anatomical region. For instance, as we well know, testosterone increases hair growth on the face of males and provokes hair loss on their scalp. After years of research, the two paths, the hormonal one and the immunological one, seemed to have led to a dead end the quest for treating hair loss and the hope to find a therapy for male baldness was vanishing.
MINOXIDIL AND MORE BREAKTHROUGH RESEARCH
As it is sometimes the case, discoveries in one field are the consequence of experimentations in other fields. In this case, serendipity came glowingly to help. In the late 1960s to the early 1970s, the FDA approved clinical trials to assess the efficacy of a new vasodilating agent, Minoxidil, a hypertension treatment. In the course of these trials, the patients observed an unexpected induction of hair growth. Paradoxically enough, Minoxidil had already received the blessing of serendipity because it had been originally developed to treat ulcers and turned out to be a vasodilator instead. Its mechanisms of action are not clearly understood and yet, in 1988, the FDA authorized the topical use of the OTC drug Minoxidil to treat baldness in men. FDA did, however, point out that the product was approved “although the product will not work for everyone.”
In later years, serendipity again played a major role in the field of hair loss pharmacology. Research on benign prostatic hyperplasia led to the development of Finasteride, an inhibitor of 5-a-reductase, because of the observation that individuals with deficiencies in both 5-a-reductase and di-hydro-testosterone had small prostates. Finasteride was also found to stimulate hair growth and in 1997 the FDA approved its use as a prescription drug against hair loss, to be administered systemically. The drug was approved in spite of clinical evidence of fastidious side-effects such as a disproportionately high number of men with 5-α reductase inhibitor-associated sexual dysfunction and infertility. Although uncommon, the use of 5-α reductase inhibitors is associated with serious and persistent sexual and reproductive side effects, such as erectile dysfunction, decreased ejaculate volume, decreased libido and infertility.3
BARICITINIB AND THE JAK/STAT SIGNALING PATHWAY
Earlier this year, the “immunological” path seemed to have led to a remarkable success. On June 13, 2022 the FDA approved the use of baricitinib as a systemic treatment for severe alopecia areata. Baricitinib is an inhibitor of the Janus Associated Kinase/Signal Transducer and Activator Transcription Proteins (JAK/STAT) signaling pathway.
What is a signaling pathway? Signaling pathways in a cell are groups of biochemical reactions meant to deliver signals to the nucleus. A signal, for instance, is the presence of a specific molecule in the environment on the outside of the cell. These external molecules bind to a specific receptor on the membrane of the cell and trigger one or more biochemical reactions. One reaction can be for instance, the activation of a kinase, an enzyme able to bind a phosphate group to another protein. Other modifications of other proteins or a cascade thereof can follow, so that the last modified molecule enters the nucleus, binds to the DNA and triggers the expression of a certain group of genes.
In the skin care industry, marketing executives are familiar with the NFkB pathway, the Toll-like receptor signaling pathway, the MAPK signaling pathway, the mTOR signaling pathway etc. The JAK/STAT pathway participates in immunity, cell division, cell death and tumor formation and has received wide attention in the medical and cosmetic arenas. Inhibitors of the JAK/STAT pathway have been studied to treat rheumatoid arthritis and baricitinib was approved by the FDA in 2018 to treat rheumatoid arthritis. Because of its anti-inflammatory effects, and because of the well-known association of hair loss with and inflammatory status, baricitinib was tested in two randomized, double-blind, placebo-controlled clinical trials on volunteers affected by alopecia areata. The results were relevant, and the FDA granted approval for its systemic use against alopecia areata.
As far as the efficacy of baricitinib is concerned, some caveats remain. The treatment helps 20% to 30% of the treated patients to regrow hair. In comparison, just 5% of the patients in the placebo group achieed hair regrowth. Side effects vary from headache and acne to high cholesterol, anemia, shingles, nausea, infections and weight increase.
References
1. Ayob SM, Messenger AG (2015) Androgens, hair loss and eugenics: a tale of discovery and American social history. Exp. Dermatol 24 : 412-413
2. Alexander S, Stimmler L (1971) Antibodies to Hair Follicle and Striated Muscle in a Case of Juvenile Dermatomyositis. Archives of Diseases in Childhood 46 : 363-365
3. Said MA, Mehta A (2018) The impact of 5-a-reductase Inhibitor Use for Male Pattern Hair Loss on Men’s Health. Curr Urol Rep 19 : 65
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Paolo Giacomoni, PhD
Insight Analysis Consulting
paologiac@gmail.com
516-769-6904
Paolo Giacomoni acts as an independent consultant to the skin care industry. He served as executive director of research at Estée Lauder and was head of the department of biology with L’Oréal. He has built a record of achievements through research on DNA damage and metabolic impairment induced by UV radiation as well as on the positive effects of vitamins and antioxidants. He has authored more than 100 peer-reviewed publications and has more than 20 patents.
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