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|CONTINUING MEDICAL EDUCATION
|Year : 1990 | Volume
| Issue : 3 | Page : 187-192
Topical minoxidil in androgenetic alopecia, how good is it ?
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Kubba R. Topical minoxidil in androgenetic alopecia, how good is it ?. Indian J Dermatol Venereol Leprol 1990;56:187-92
Minoxidil (2-4diamino-6-piperidinepyrimidine-5-oxide), a product of Upjohn research (Upjohn Company, Kalamazoo, Michigan, USA), is a potent anti-hypertensive agent. It also makes hair grow! A pharmacologic effect that came to light as an incidental observation (side effect) has, after a decade of systematic and thorough scientifc scrutiny, become the principal usage of the drug. Enough information is now available to allow rational and optimal use of minoxidil as a hair growth promoting agent. But how good is it in its new role?
It all began about 1968, when a group of investigators observed hypertrichosis in several hypertensive patients receiving oral minoxidil. The trichotrophic effect of minoxidil was soon verified by applying a solution of minoxidil on a limited area of the upper arm skin and observing the appearance of terminal hair. A key observation was made a year later; the baldness of a patient with severe hypertension gradually disappered following treatment with oral minoxidil (which also controlled his blood pressure). In 1979, minoxidil was approved by FDA (Food and Drug Administration, USA) for hypertension and it became available as Loniten (10 mg tablet). This was quickly followed by several case reports further attesting the effect of minoxidil on hair growth,,. The frequency of this side effect was subsequently estimated at 60-80%. Minoxidil is a potent vasodilator capable of reducing the peripheral resistance by 50%. However, this latter effect and fall in blood pressure is not seen in normotensive individuals.
After 1979, the clinical evaluation of minoxidil as hair growth promoting agent in normotensive subjects was taken up in a big way by the dermatologists in the USA. Early clinical studies were informal, open-label, and used extemporaneously prepared minoxidil solution (crushed Loniten tablets in a vehicle of ethanol, propylene glycol and water, and sometimes containing additional medications such as steroids). Fifty ml of minoxidil solution (2%) required 100 Loniten tablets and cost over $100. Tosti treated 670 male subjects with androgenetic alopecia with 1% minoxidil solution for 6 months; 430 males completed the study; 18% showed enough hair growth to be regarded cosmetically significant; the study yielded no correlations such as with age or severity of alopeica; the treatment was well tolerated with 10% of the subjects reporting headaches, and 3 subjects developing contact dermatitis to minoxidil solution. Bergfeld treated 1200 patients with 3% minoxidil solution over a period of 2 years; 20% of her patients showed moderate to dense growth; younger patients (below 30 years) and those with short duration alopecia did better; the treatment was regarded safe. Stern did a postal survey of 900 dermatologists in the USA; 549 dermatologists responded of which 395 dermatologists had prescribed topical minoxidil; 50 dermatologists were high prescribers (having treated over 30 patients each); from this survey Stern concluded that the dermatologists in the USA were treating as many as 100,000 cases of androgenetic alopecia with topical minoxidil per year, and that no major adverse effects had been encountered; he did not comment on the success rate.
The process of evaluating the trichotrophic effect of topical; minoxidil has been facilitated by the availability of a good animal model. Stumptailed macaques (monkeys) have a unique genetic tendency to develop frontal alopecia that resembles human androgenetic alopecia. This alopecia develops both in male and female macaques and appears between the age of 3-4 years (coinciding with descent of testes into scrotum in males and onset of ovulation in females). Uno and his group at the Wisconsin Regional Primate Research Centre, Madison, Wisconsin, USA treated periadolescent and adult macaques (male and females) with topical minoxidil (2% and 5%) over a period of several years. The study included control animals who were treated with the vehicle alone. The assessment of the results was based on gross observations of hairiness and folliculogram analysis of the sequential skin biopsies (a folliculogram is a morphometric method of microscopic three dimensional reconstruction of hair follicles in a given area). Topical minoxidil produced enlargement of the vellus follicles to the size of terminal follicles; the enlarged follicles regressed when the minoxidil was withdrawn; it maintained the terminal follicles in the prebald scalp of periadolescent macaques; the hair growth was more prominent in the early stage of baldness in the younger macaques compared to baldness of longer duration in older macaques; 5% solution was more effective than 2% solution. Furthermore, in the same study, labelled 3Hminoxidil was preferentially taken up by the follicles where its conversion to its active metabolite, minoxidil sulfate, was also seen. In 5 macaques, the topical minoxidil applications were continued for 3 years and 8 months and all these animals retained terminal hair in the frontal area and did not become bald as would have been expected.
Topical minoxidil has undergone extensive clinical trials in the last few years. The most convincing, scientifically valid data have come from Upjohn sponsored multicentre, doubleblind, placebo contolled, trials conducted not only in the USA but also in Europe and other countries. The efficacy study was done over a period of 12 months in patients with grade III and IV androgenetic, alopecia who were otherwise in good health and especially free of cardiovascular problems. The patients were divided into three groups. One group received placebo (vehicle only) for the first 4 months and then all patients were changed over to 3% minoxidil solution for the remaining 8 months; in another group, all patients were treated with 2% minoxidil solution; in the third group, all patients were treated with 3% minoxidil solution. The minoxidil solutions were proprietary preparations (Rogaine) made from base powder, and were applied twice daily to the bald areas, in measured quantities of 1 ml per application. The pre-study evaluation included detailed history, complete physical examination, CBC, urinalysis, blood chemistry, ECG, echocardiography, and chest x-ray. All investigative procedures were repeated at 4 months and 12 months. Serum minoxidil levels were assayed at 2 weeks, 4 months, and 12 months. The results were assessed by monthly hair counts in a marked area of 2.5 cm diameter; this process was facilitated by the use of a template that waspositioned at a fixed distance relative to both ears and nose, and a binocular magnifying lens.
The results of the 27-centre North American study were recently made available. Of the 2326 patients who entered the study, 1833 patients completed the full 12 months of the study. The ages of these patients ranged between 18-50 years. Although there were differences in results from patient to patient, and in results from different centres, overall, statistically significant (more) hair growth was noted in patients using 2% minoxidil and 3% minoxidil compared to the placebo group at 4 months, thereafter, as the patients in the placebo group had been switched to 3% minoxidil, all three groups showed progressive increase in mean non-vellus hair counts, and the differences between the groups were no longer statistically significant. In general, compared to baseline, the mean non-vellus hair counts had increased about 3 folds by the end of 12 month study. Most investigators in this study agreed that topical minoxidil retarded or stopped further progression of androgenetic alopecia in their patients. However, cosmetically acceptable new hair growth was only seen in 20-30% of the patients. Certain prognostic factors have been recognised that, although not fully verified, are worth knowing. It seemed that younger individuals (below 40 years) profited more from using topical minoxidil. Small areas of alopecia (less than 10 cm), especially on' the vertex rather than the frontal area, responded better. The degree of alopecia, whether parital or complete, was also important; patients with at least 100 non-vellus hairs of 2 cm or more length per 2.5 cm diameter of balding area at baseline did better.
What are the kinetics of hair regrowth following topical.minoxidil? The new hair growth is evident as early as one month (usually vellus hair) but in the majority requires 3-4 months of patient wait! It seems to reach a maximum level at about 12 months, after which continuing use of topical minoxidil merely maintains the new growth. The cessation of treatment is followed by prompt shedding of the regrown hair and resumption of the alopecic process.
Tachyphylaxis, even in study patients who have continued using topical minoxidil for over 4 years, has so far not developed.
The Upjohn Company has also sponsored a multicentre dose-response study of topical minoxidil,. In a double blind study, the placebo was compared with 0.01%, 0.1%, 1 % and 2% minoxidil solutions in 500 males with grade III-IV alopecia over a 6 month period. Only 1% and 2% minoxidil were found to be effective, and 2% minoxidil gave the best results. No difference in efficacy was found between 2% and 3% minoxidil.
The Upjohn study has also confirmed the safety of topical minoxidil. No major problems have been encountered. Dermatologic side effects were observed in 316 (13.6%) of 2326 patients and included itching, burning sensation, erythema and flushing, scaling and follicultis. Hypertrichosis at distant sites was noted in the Upjohn study as well as in other studies, and has been ascribed to a blotter effect. Allergic contact dermatitis, confirmed by patch testing, has also been documented. Side effects of general medical nature were recorded in 418 (18%) of 2326 patients and included headache, oedema, dizziness, syncope, visual disturbances, altered taste, impotence, and cardiovascular changes. Blood pressure decreases and increases of 15 mm or more from baseline were noted in a few patients (in some requiring discontinuation of minoxidil treatment) but changes of mean blood pressure from baseline indicated that topical minoxidil did not produce clinically significant changes in the systolic or diastolic blood pressure. Eight deaths were recorded amongst patients in the Upjohn study, but a critical appraisal of these cases exonerated topical minoxidil.
Topically applied minoxidil is absorbed into systemic circulation in some individuals. In the Upjohn study, the serum levels of minoxidil were measured at 2 weeks, 4 months and 12 months; in the majority of the patients the serum levels were below 2 ng/ml (including some in whom no minoxidil was detectable); in 23 patients the serum levels exceeded 10 ng/ml; no correlation was found between the concentration of minoxidil used and the serum levels; nor did the serum levels correlate with the duration of the usage. In an absorption study using radiolabelled minoxidil (C-14), application of 1% or 2% minoxidil to 50% of scalp surface was considered safe as the average absorbed dose was found to be less than 1.2 mg per application. At the present time, the possibility of a systemic effect from topically applied minoxidil is considered unlikely.
Topical minoxidil is also being evaluated in female androgenic alopecia and as adjunct to hair transplant surgery in male androgenic alopecia,. In an open-label study, Hardinsky and Shrank, treated 25 patients with female androgenic alopecia with 3% minoxidil solution over a period of 48 weeks; the study design was similar to the Upjohn study (vide supra); statistically significant hair growth was obtained and the side effects were minimal; the treatment was regarded as promising. Kassmir used 3% minoxidil in 12 hair transplant patients; the treatment was started 48-72 hours after the hair transplant surgery; 2 patients escaped the usual post-surgery telogen effluvium (anagen defluvium) that manifests as hair shedding in the grafts at 2-4 weeks, and in 2 other patients the post-surgery telogen effluvium was considerably shorter. Bouhanna in Paris observed the same phenomenon but with a different protocol; in 16 patients, 2% minoxidil was used for 4 weeks immediately prior to hair transplant surgery, and then resumed 3 weeks after surgery and continued for 3 months; 4 grafts were monitored in each patient for hair shedding and hair growth; 71% of 64 grafts thus studied showed no shedding or only partial shedding. From these studies it may be extrapolated that patients who elect to use topical minoxidil will make better candidates for hair transplantation subsequently, and in others starting topical minoxidil after surgery will have a beneficial effect.
How does minoxidil induce hair growth? It is likely not simple vasodilation and increased vascular perfusion of the hair follicles. For it has been observed that other potent vasodilators, such as transdermal nitroglycerin, fail to stimulate hair growth. Studies to investigate the biological effects of minoxidil have revealed that it is, besides being a smooth muscle relaxer and vasodilator, a cell mitogen, an immune suppressant, and, phosphodiesterase inhibitor.
Minoxidil inhibits prostaglandin 1-2 formation in cultured human keratinocytes, inhibits lysyl hydroxylase in cultured human fibroblasts, and acts as K-channel agonist in human vascular smooth muscle.
At a cellular level minoxidil is believed to act in the region of the dermal papilla, a specific receptor site for minoxidil is being considered but is yet to be found. Of the various histopathological changes that occur in androgenetic alopecia, viz, follicular miniaturisation and reduction in mean hair shaft diameter, increase in telogen germinal units, lamellar proliferation of perifollicular fibrous tissue, closed lumina of perifollicular blood vessels, and inflammatory infiltrate of variable proportions of T-cells (helper/suppressor, activated/non-activated), monocytes and Langerhans cells, only the follicular features are altered by topical minoxidil. Following topical minoxidil treatment, the hair diameter enlarges, and the anagen phase appears to become prolonged,
In conclusion, it is clear that topical minoxidil is no magic for making hair grow! cHowever, it is an important step in the realm of skin care and in preservation of what we cherish. It is, even with its modest hair growing potential, a great blessing to many individuals. Besides, minoxidil has provided the greatest impetus to the study of hair physiology. It is my view that topical minoxidil should be considered for any man who resents his androgenetic alopecia. But decision to start treatment should be left to a physician familiar with the modality; only then best results will be obtained and disappointments, unnecessary costs, and unnecessary physical suffering (from adverse effects) will be avoided. Furthermore, until more is known about minoxidil, it should be used only under the supervision of a physician. Currently available 2% minoxidil proprietary formulations seem adequate, and twice daily applications are necessary. The patient who embarks on topical minoxidil treatment must make a psychologic commitment to using it forever.
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