Q: What is more important against baldness, decreasing DHT in serum with oral finasteride or decreasing DHT in the scalp with topical finasteride? — A.G. ~ Brooklyn, N.Y.
A: Decreasing serum DHT with oral finasteride is more effective in combating hair loss, as the decreased blood levels also lowers the DHT in follicles and seem to do it better than finasteride applied topically.
Posted byDr. Angela Christiano and her team of researchers at Columbia University studying the autoimmune disease alopecia areata, have shed new light on how to move hair follicles from their resting stage (telogen) into the growth stage (anagen) in which they can produce normal hairs. The study, published in the October issue of Science Advances, introduces the possibility of a new topical medication for hair growth stemming from a class of chemicals that block enzymes in the Janus kinase (JAK) family. ((Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015 Oct; 1(9): e1500973.)) The findings on the topical application of JAK inhibitors have implications in the treatment of common hair loss as well as alopecia areata, which causes a non-scarring form of localized hair loss.
Scientists had, until now, tried unsuccessfully to use drugs to induce follicles en masse into the anagen phase. The two FDA-approved medications currently used to treat hair loss each use a different approach. Finasteride (Propecia) blocks the conversion of testosterone to dihydrotestosterone (DHT) – the hormone that causes genetically susceptible hair follicles to progressively shrink or miniaturize. Minoxidil (Rogaine) extends the anagen phase, thereby delaying the onset of hair follicle miniaturization. JAK inhibitors could develop into a third major medical option for the treatment of hair loss.
Background: Research Investigating Alopecia Areata
Dr. Christiano, herself diagnosed with alopecia areata, has made several significant breakthroughs involving hair loss and its treatment in the past. Bernstein Medical has written extensively about her study of alopecia areata, hair loss genetics, and hair cloning.
Building on initial research in 1998 implicating a type of white blood cell known as “T lymphocytes” in the development of alopecia areata, ((Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest. 1998 Jan 1; 101(1):62-7.)) Dr. Christiano and her team set out to find ways to modulate them. In research published in the September 2014 issue of Nature Medicine, they looked at two different FDA-approved chemicals, ruxolitinib and tofacitinib, and how they act as inhibitors of enzymes in the family Janus kinase (JAK). Inhibiting JAK cut off communication to the T cells. Without an accumulation of T cells, alopecia areata could not progress. ((Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, Singh P, Petukhova L, Mackay-Wiggan J, Christiano AM, Clynes R. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014 Sep; 20(9):1043-9.)) The JAK inhibitors both prevented the onset of the disease, and reversed the condition where it was already established.
The most surprising finding of this study concerned the effect of topically applying the inhibitors.
“We found that topical ruxolitinib and topical tofacitinib were both highly effective in reversing disease in treated lesions (applied to back skin). A full coat of hair emerged in the ruxolitinib- or tofacitinib-treated mice by 7 weeks of treatment, and we observed complete hair regrowth within 12 weeks following topical therapy.”2
Findings: JAK Inhibitors and Hair Growth in Normal Subjects
Having successfully tested JAK inhibitors against alopecia areata, Dr. Christiano and her team sought to investigate JAK inhibition on normal mice and humans.
The researchers applied solutions of tofacitinib and ruxolitinib to one side of the backs of mice with hair in the telogen phase, while the other side was treated with a control solution. Within seven days of treatment, each mouse saw robust hair growth on the treated side, while the control side did not. This indicates a rapid transition of the hair cycle from telogen (resting) to anagen (growth). Furthermore, they found that treatment with JAK inhibitors resulted in “significant proliferation” of hair follicle stem cells, indicating that the inhibitors activated progenitor stem cells within the follicles. The topical application of JAK inhibitors in mice unmistakably resulted in rapid onset of hair growth.
Next, the team looked at the effects of JAK inhibitors on cultured dermal papilla (DP) spheres. In 2013, Dr. Christiano achieved a breakthrough in using an ingenious technique, called a “hanging drop culture.” Using this process, her team caused dermal papilla cells to clump together in a spherical (tear drop) shaped configuration. They found that DP cells in this three-dimensional mass more easily communicate with one another and are then capable of forming new hair follicles. When cultured in a solution containing the JAK inhibitor, tofacitnib, the DP spheres showed an enhanced ability to induce hair follicle development in larger sizes and in significantly greater numbers.
Conclusion/Summary
Topical application of JAK inhibitors leads to the activation and proliferation of hair follicle stem cells and a rapid transition to the anagen phase of the hair growth cycle. This research could be the catalyst for the development of a new topical treatment for hair loss that could potentially benefit individuals who are not indicated for, or who have not seen a positive response from, traditional hair loss medications or are not candidates for hair transplantation. Additionally, JAK inhibitors may be developed into a topical treatment for alopecia areata and potentially other autoimmune conditions that cause localized hair loss or other skin problems. JAK inhibitors might even aid in the development of hair cloning techniques, which could effectively cure hair loss.
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Research published in the International Journal of Trichology in 2012 found that the antiandrogen ((Alonso R, Prieto L, Hernandez C, Mas M. “Antiandrogenic effects of the pineal gland and melatonin in castrated and intact prepubertal male rats.” J Endocrinol. 1978 Oct; 79(1):77-83.)) and antioxidant ((Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ. “Melatonin: A potent, endogenous hydroxyl radical scavenger.” Endocr J. 1993;1:57–60.)) properties of the hormone melatonin could be made into a topical solution for the treatment of early stage androgenetic alopecia, or common male and female pattern baldness. Four different study designs observed that daily application of the melatonin solution to the scalp reduced hair loss and, in some cases, caused new hair growth. ((Fischer, Tobias W et al. “Topical Melatonin for Treatment of Androgenetic Alopecia.” International Journal of Trichology 4.4 (2012): 236–245. PMC. Web. 25 Mar. 2015.))
Background
Melatonin is primarily known as a neurohormone that is produced in the brain’s pineal gland and is involved in regulating the body’s physiological response to natural cycles of light and darkness, called circadian rhythms. ((Lerner AB, Case JD, Takahashi Y. “Isolation of melatonin, a pineal factor that lightens melanocytes.” J Am Chem Soc.1958;80:2587.)) More recent research showed that not only is melatonin produced by other organs, including the skin, ((Slominski A, Pisarchik A, Semak I, Sweatman T, et al. “Serotoninergic and melatoninergic systems are fully expressed in human skin.” FASEB J. 2002 Jun;16 (8):896-8. Epub 2002 Apr 23.)) but melatonin is produced by, and melatonin receptors are found in, hair follicles. ((Fischer TW, Slominski A, Tobin DJ, Paus R. Melatonin and the hair follicle. J Pineal Res. 2008 Jan; 44(1):1-15.)), ((Fischer TW. “The influence of melatonin on hair physiology.” Hautarzt. 2009 Dec; 60(12):962-72.)), ((Kobayashi H, Kromminga A, Dunlop TW, et al. “A role of melatonin in neuroectodermal-mesodermal interactions: the hair follicle synthesizes melatonin and expresses functional melatonin receptors.” FASEB J. 2005 Oct; 19(12):1710-2.)) In year 2000, a low dose of melatonin was found to stimulate hair follicle growth in a laboratory setting. ((Fischer TW, Fischer A, Knöll B, Hipler UC, Elsner P. “Melatonin in low doses enhances in vitro human hair follicle proliferation and inhibits hair growth in high doses.” Arch Derm Res. 2000;292:147.))
In the 2012 study commissioned by ASATONA AG; out of Zug, Switzerland; a solution consisting of a 0.0033% concentration of melatonin, along with the antioxidant ginkgo biloba and important micronutrient biotin, was tested for its efficacy in slowing hair loss and its safety and tolerability. This was the first attempt to confirm the in vitro year 2000 findings in a clinical setting.
Findings
From January 2003 to October 2006 the melatonin solution was subjected to five rounds of testing, each with a different study design. The first study tested the safety of the solution in a double-blind, placebo-controlled cross-over study on four fertile and four postmenopausal healthy women. This test found a slightly elevated, but not significantly different, serum melatonin level after 14 days of treatment compared to placebo. There were no safety or health impacts of the treatments.
The second phase of the study found a significant reduction in severity of hair loss in 30 patients with early hair loss after 30 days of treatment, with a further significant drop after 90 days. The importance of the study is limited, however, due to the fact that there was no placebo employed to act as a study control. Also, the results were, in part, obtained through subjective questionnaires completed by the patients.
Phase three was a more reliable and objective open-label, clinically controlled study involving 35 men with androgenetic alopecia. In this study, researchers used TrichoScan, a sensitive software and hardware package that uses epiluminescence to measure hair loss. Hair density was found to increase in over half of the subjects. The average increase in density was 29% after three months and 41% at six months.
In study four, hair stylists at four salons performed a standardized before-and-after comparison on 40 male and 20 female patients with early stage hair loss who applied the treatment for 90 days. Female patients experienced significant reductions after 40 days and further significant reduction after another 40 days. Hair loss in the male patients was stable throughout the treatment.
Study five was a large-scale, open-label, multi-center study involving 1891 female and male patients with early stage androgenetic alopecia. After 90 days of treatment, the proportion of patients with a positive hair pull test (which indicates ongoing hair loss) fell from 61.6% to 7.8%. Negative hair pull tests, which indicate no hair loss, rose from 12.2% to 61.5% in the same period. Using standardized examination forms, investigators found significantly reduced hair loss in two-thirds of patients. New hair growth was measured in 22.5% of patients. Further, the proportion of patients with moderate to severe presentation of the skin condition seborrhea dropped by over 30%.
Summary
Topical application of the solution containing melatonin, ginkgo biloba and biotin was found to reduce hair loss, and in some cases grow new hair. Incidence of seborrhea was also reduced by the treatment. While the exact mechanism for this result is unknown, if effective, it is likely related to the antioxidative effect of melatonin and/or a melatonin receptor-mediated antiandrogenic effects. More research on melatonin needs to be conducted, but this study acts as a proof of concept for the use of melatonin as a treatment for early hair loss in men and women and potentially as a treatment for seborrhea. Currently, only two medications are approved by the Food and Drug Administration (FDA) for the treatment of hair loss, finasteride and minoxidil, and so the addition of a third type of medical treatment might be beneficial for patients who are not indicated for those drugs or would prefer an alternative treatment.
Posted bySince 1993, minoxidil has been the most successful topical treatment for hair loss in both men and women, yet its exact mechanism of action remains unknown.
A 2004 review of minoxidil’s possible mechanisms of action ((Messenger AG, Rundegren J. Minoxidil: mechanisms of action on hair growth. Br J Dermatol. 2004;150(2):186-94.)) suggests that the best evidence supports the idea that minoxidil causes hair follicles in the later phases of their resting phase (telogen) to shift prematurely into an active growth phase (anagen) sooner than they otherwise would; this causes a rapid increase in hair growth. They also found good evidence that minoxidil works to thicken the hair by increasing hair diameter.
While minoxidil’s effects on other critical factors known to affect hair growth — such as cell proliferation, collagen synthesis, vascular endothelial growth factor and prostaglandin synthesis — remain uncertain, more recent research has found evidence that it may also suppress the androgen-androgen receptor responsible for androgenetic alopecia. ((Hsu CL, Liu JS, Lin AC, Yang CH, Chung WH, Wu WG. Minoxidil may suppress androgen receptor-related functions. Oncotarget. 2014;5(8):2187-97.))
Understanding minoxidil’s exact mechanism of action remains today an important line of research both for the development of better hair loss treatments and for a better understanding of the biology of hair growth.
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