Founded in 1886 to make “friable pills”, Upjohn (now part of Pfizer) had a well earned reputation for serious pharmaceutical research, and did not want to get caught up in miracle baldness cures. But once minoxidil was on the market for hypertension, it quickly became an open secret that the drug stimulated hair growth, and a letter in the New England Journal of Medicine1 put paid to any lingering hopes that Upjohn could keep the side effect under wraps. If it did not develop minoxidil as a hair restorer, someone else would.
Anthony Chu, professor of dermatology, Buckingham University, and consultant dermatologist and honorary senior lecturer, Imperial College, London, explains that, before minoxidil, balding men were prepared to try anything to make their hair grow back, from standing on their heads to stimulate blood flow to the scalp to taking concoctions of anti-androgens that did little for their hair but caused breast enlargement and a loss of libido.
“It was a wasteland, with predatory clinics offering spurious remedies to vulnerable men at considerable cost. In contrast, 40 per cent of men who use minoxidil get reasonable hair growth and, in another 40 per cent, the drug stops them losing more hair. So it’s only about 20 per cent who do not get any benefit,” says Professor Chu.
An unpromising start
Minoxidil emerged from a lengthy research programme started in 1960 by Upjohn chemists who were investigating the gastric acid effects of a compound they had ordered from a chemical catalogue.2 In dog studies, this compound, called N,N-diallylmelamine (DAM) failed to produce the anticholinergic effects that the researchers were looking for, but it did result in a prolonged reduction in blood pressure.2 Because the same effect did not occur in human studies, the chemists turned to DAM metabolites, the most promising of which was an N-oxidation product of DAM, called DAMN-O, which went into clinical trials in hypertensive patients in 1961. DAMN-O was effective in reducing blood pressure but caused salt and water retention resulting in oedema and, owing to a misunderstanding about discontinuing treatment in such cases, resulted in heart failure in some patients. In addition, dog toxicity studies revealed haemorrhagic lesions of the right atrium, so DAMN-O was withdrawn from study.
Undeterred, the Upjohn researchers synthesised hundreds of DAMN-O analogues, including minoxidil. Dramatic blood pressure reductions were achieved with minoxidil in clinical trials of severe, drug-refractory hypertension, though diuretics and beta blockers were needed to reverse the accompanying salt retention and tachycardia, and atrial lesions were again seen in canine toxicity studies.2 Despite the adverse effects, demand for minoxidil from clinicians was so great that the US Food and Drug Administration approved an emergency use protocol for severely ill patients in 1971, but put a two week limit on treatment duration.2 Owing to the drug’s effectiveness, clinicians started to keep their patients on minoxidil for longer than the recommended two weeks and it was then that the first cases of hypertrichosis began to emerge.3
Overwhelmed with volunteers
As word got out that oral minoxidil caused hypertrichosis in 60–80 per cent of hypertensive patients who took it, Upjohn’s headquarters in Kalamazoo, Michigan, was inundated with volunteers for hair loss trials. But dermatologists were dubious that minoxidil could stimulate hair follicles to produce not just fine “vellus” hairs, but coarser, pigmented “terminal” hairs, from the atrophied follicles on bald scalps.
A topical formulation was developed and shown to induce regrowth of terminal hairs on the scalps of stump-tailed macaques — a species prone to hair thinning in adolescence and baldness as adults.4 Further research on macaques showed that minoxidil induced enlargement of vellus follicles to the size of middle to terminal follicles in balding animals and maintained terminal follicles in pre-bald, periadolescent animals.5 Enlarged follicles regressed after minoxidil was withdrawn, but follicular growth was restimulated when minoxidil was restarted.5
An in vitro study showed significant enhancement of DNA synthesis in follicular and perifollicular cells of minoxidil-treated macaque skin, but the main mechanism of action was thought to be via vasodilation in the scalp.5
At that time, Upjohn was busy addressing the safety concerns related to the licence application for oral minoxidil in hypertension, and did not start clinical trials of the topical formulation in alopecia androgenetica and alopecia areata until 1978.2
Results of a placebo-controlled, six-month dose-response study of minoxidil 0.01 per cent, 0.1 per cent, 1 per cent and 2 per cent in men with male pattern baldness showed significant increases in non-vellus hair counts in doses of 0.1 per cent and above, although clinically perceptible hair growth was seen only with the 1 per cent and 2 per cent solutions.6
Large scale clinical trials of minoxidil in both alopecia androgenetica and alopecia areata finally got under way at centres across the US. In a multicentre study in alopecia androgenetica, cosmetically worthwhile results were reported in about one-third of subjects after one year of treatment, with around 80 per cent of patients showing some non-vellus hair regrowth.7
Not on the NHS
Upjohn launched minoxidil as Regaine Topical Solution 2% in the UK in 1988, although it was available only on private prescription. Initially the focus was on male baldness, but in 1990 the drug’s licence was extended to women with hair loss. Five years later, Regaine became a pharmacy medicine, and patients could at last buy the brand of topical minoxidil that had passed UK safety and efficacy tests, instead of using unlicensed formulations, often of dubious provenance.
Professor Chu explains that patients should use minoxidil for at least three months to see if it is going to work because of the need to wait for the change from wispy vellus hairs to stronger, terminal hairs as a measure of success. But he believes that previous advice that treatment is only likely to work in the earliest stages of hair loss is out of date.
“Many people benefit even with a bald patch at the back and regression at the front and, unless someone is completely bald, it’s worth a go for three months,” he says.
In a post-marketing surveillance study of over 11,000 men and women who had used topical minoxidil 2 per cent, 92 per cent of patients rated it as excellent, good or fair in slowing or stopping hair loss after one year of use.
Professor Chu knows of patients who have used minoxidil for 15–20 years with continuing good results: “I see patients who started using it many years ago when they noticed slight thinning, and they still have a good head of hair. It’s hard to know how much hair they would have lost without minoxidil, but they feel the effort has been worthwhile.”
A small proportion of patients experience scalp irritation with the original alcohol-based topical formulation, and some feel it makes their hair look dull. A more recently introduced mousse formulation has helped to overcome these problems.
Proud to be bald?
Hair fashions have changed considerably in the 40 years since the hypertrichosis associated with oral minoxidil was first recognised. Today’s men prefer to shave their balding heads than construct elaborate “comb overs”, and are more likely to wax their chests than smear them with minoxidil to make them hairy — as was once the case.
However, Professor Chu believes that men and women will continue to seek solutions to their thinning hair, and that growth factor and hair transplant research hold potential for the future, although at a cost: “At £30 per month, minoxidil is within the grasp of far more people than transplants will ever be. It’s effective and safe and it’s never been bettered as a topical preparation for hair loss.”
- Zappacosta AR. Reversal of baldness in patient receiving minoxidil for hypertension. New England Journal of Medicine 1980;303:1480.
- Zins GR. The history of the development of minoxidil. Clinical Dermatology 1988;6:132–47.
- Gottlieb TB, Katz FH, Chidsey CA. Combined therapy with vasodilator drugs and beta-adrenergic blockade in hypertension. A comparative study of minoxidil and hydralazine. Circulation 1972;45:571–82.
- Uno H. The stumptailed macaque as a model for baldness: effects of minoxidil. International Journal of Cosmetic Science 1986;8:63–71.
- Uno H, Cappas A, Brigham P. Action of topical minoxidil in the bald stump-tailed macaque. Journal of the American Academy of Dermatology 1987;16:657–68.
- Fenton DA, Wilkinson JD. Topical minoxidil in the treatment of alopecia areata. BMJ 1983;287:1015–7.
- Shupack JL, Kassimir JJ, Thirumoorthy T, Reed ML, Jondreau L. Dose-response study of topical minoxidil in male pattern alopecia. Journal of the American Academy of Dermatology 1987;16:673–6.
- Clissold SP, Heel RC. Topical minoxidil. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in alopecia areata and alopecia androgenetica. Drugs 1987;33:107–22.