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British Journal of Dermatology 2004; 150: 186–194.
Minoxidil: mechanisms of action on hair growth A . G . M E S S E N G E R A N D J . R U N D E G R E N * Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K.
*Pharmacia Consumer Healthcare, Box 941, SE-251 09 Helsinborg, Sweden We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding ofits mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidilshortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has asimilar action in humans. Minoxidil may also cause prolongation of anagen and increases hairfollicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smoothmuscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarco-lemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hairgrowth is also due to the opening of potassium channels by minoxidil sulphate, but this idea hasbeen difficult to prove and to date there has been no clear demonstration that KATP channels areexpressed in the hair follicle. A number of in vitro effects of minoxidil have been described inmonocultures of various skin and hair follicle cell types including stimulation of cell proliferation,inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and pros-taglandin synthesis. Some or all of these effects may be relevant to hair growth, but the applicationof results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. Inthis article we review the current state of knowledge on the mode of action of minoxidil on hairgrowth and indicate lines of future research.
Key words: androgenetic alopecia, hair, minoxidil Minoxidil was introduced in the early 1970s as a stimulates hair growth. Nevertheless, understanding treatment for hypertension. Hypertrichosis was a minoxidil’s mechanism of action is important, both common side-effect in those taking minoxidil tablets1,2 from the point of view of developing more effective and included the regrowth of hair in male balding.3 treatments for hair loss disorders and for the insights This led to the development of a topical formulation of it may give into the biology of hair growth. In this minoxidil for the treatment of androgenetic alopecia in article we review what is known about the pharma- men and subsequently in women. The 2% product was cology of minoxidil, with particular reference to its first marketed for hair regrowth in men in 1986 in the action on hair growth, and suggest directions for United States and the 5% product became available in Despite much research over 20 years we still have Response of the hair follicle to minoxidil only a limited understanding of how minoxidil There are a number of ways in which a drug maystimulate hair growth; it may increase the lineargrowth rate of hair, increase the diameter of the hair Correspondence: A.G.Messenger.
E-mail: a.g.messenger@sheffield.ac.uk fibre, alter the hair cycle, either shortening telogen orprolonging anagen, or act through a combination of Conflicts of interest: Dr Messenger is a dermatologist and has been a these effects. Present evidence suggests that minoxidil consultant for Pharmacia and other pharmaceutical companies with acts mainly on the hair cycle; it may also increase hair an interest in the field of hair growth. Dr Rundegren is an employee ofPharmacia.
Ó 2004 British Association of Dermatologists M I N O X I D I L A N D H A I R G R O W T H Mori and Uno4 studied the effect of topical application of minoxidil on spontaneous hair cycles in the rat frombirth to 80 days of age. Minoxidil had no effect on the duration of anagen, but telogen was shortened. Thetelogen phase of the third cycle lasted approximately re-entered anagen after only 1–2 days in telogen in minoxidil-treated animals. The same shortening oftelogen by minoxidil treatment was also seen in the fourth cycle. The effect of minoxidil on hair growth hasbeen studied extensively in the stump-tailed macaque, a primate that develops postadolescent scalp hair loss closely resembling human androgenetic alopecia. Top- ical minoxidil prevents the development of scalp hairloss in periadolescent macaques and promotes re-growth of hair in balding animals. Histological studies showed that treatment with minoxidil causes an increase in the proportion of follicles in anagen, a reduction in telogen follicles, and an increase in hair Little is known of the effect of minoxidil on normal human hair growth and studies have been limitedmainly to the response of androgenetic alopecia to topical minoxidil. In male pattern balding (male androgenetic alopecia) there is a gradual reduction in the duration of anagen and a prolongation of the latent period of the hair cycle (the time between shedding of Figure 1. Results of two clinical trials of minoxidil topical solution in the telogen hair and the onset of the next anagen).6 the treatment of male androgenetic alopecia using different methods Hair follicles also become miniaturized.7 There is some for measuring the response. Both methods show a rapid increase controversy over whether female androgenetic alopecia in hair growth which has reached a plateau by 12–16 weeks.
is the same entity as male balding. Nevertheless, the (A) Comparison of mean percentage change in interval hair weightper square centimetre for three treatment groups: 5% minoxidil, 2% follicular changes are very similar,8,9 if not identical, minoxidil and placebo. Vertical line at 96 weeks indicates cessation of although prolongation of the latent period has not yet treatment. Adapted from Price et al.65 (B) Mean change from baseline been demonstrated in women. Clinical trials of topical in nonvellus hair counts (per square centimetre) in men treated with minoxidil in male and female hair loss all show a 5% minoxidil solution (TMS), 2% minoxidil and placebo. From Olsenet al.66 remarkably rapid increase in hair growth, measured byhair counts or hair weight. The increase is evidentwithin 6–8 weeks of starting treatment and has limbs. The increased length of hair at these sites generally peaked by 12–16 weeks (Fig. 1). It seems suggests that minoxidil also prolongs the duration of improbable that a response of this rapidity can be accounted for by reversal of follicular miniaturization, The results of histological studies in humans are less and a more likely explanation is that minoxidil triggers conclusive than in the macaque. Abell10 found a trend follicles in the latent part of telogen into anagen. The towards an increase in anagen ⁄ telogen ratios after hypertrichosis that develops in humans taking minoxi- 12 months of minoxidil treatment in balding men, but dil orally, and occasionally following topical use, may the main change was an increase in mean hair affect the forehead as well as other sites such as the diameter. This was most apparent at 4 months and Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 A . G . M E S S E N G E R A N D J . R U N D E G R E N mean diameter had declined at 12 months. He sugges- channels (KATP channels), and its relaxant effect on ted this might be due to later recruitment of small vascular smooth muscle is mediated through this diameter hairs into anagen. Headington and Novak11 mechanism.24,25 KATP channels are heteromultimers reported that minoxidil treatment caused hypertrophy composed of a small subunit that belongs to the inwardly of follicles but, although there was an increase in mean rectifying potassium channel superfamily (KIR6.1 or hair diameter in minoxidil-treated balding men after KIR6.2), and a large sulphonylurea receptor (SUR1, 12 weeks, a similar increase occurred in control SUR2A or SUR2B) that binds sulphonylureas and ATP subjects. Care should be taken in interpreting change and belongs to the ATP-binding cassette (ABC) super- in mean hair diameters. This does not necessarily imply family.26 SUR1 ⁄ KIR6.2 KATP channels are found in that individual hair follicles become larger, as an pancreatic and neuronal tissue, whereas SUR2A ⁄ KIR6.2 increase in mean diameter may also occur through and SUR2B ⁄ KIR6.1 (or KIR6.2) form the cardiac and preferential recruitment of large diameter hairs in a vascular smooth muscle KATP channels, respectively.
Potassium channel openers act through binding to thesulphonylurea receptor moiety.26 ATP channels are widely distributed in a variety of tissue and cell types, including cells of the heart, The antihypertensive activity of minoxidil is due to pancreas, vascular smooth muscle and the central rapid relaxation of vascular smooth muscle by its nervous system, where they couple intracellular meta- sulphated metabolite, minoxidil sulphate.12,13 The bolic changes to the electrical activity of the plasma conversion of minoxidil to minoxidil sulphate is cata- membrane.27 These potassium channels sense the lysed by sulphotransferase enzymes. Minoxidil sulpho- metabolic state of the cell—channel opening is inhib- transferase activity was initially demonstrated in rat ited by ATP when energy levels are high and is liver12 and has since been found in human liver,14 activated when energy stores are depleted.28 The platelets15 and epidermal keratinocytes,16 as well as in consequence of KATP status depends on the cell and mouse vibrissae follicles,17 rat pelage and vibrissae tissue type. For example, in pancreatic b cells, KATP follicles and rat epidermal keratinocytes.18,19 In scalp channels are involved in regulating insulin secretion.
skin of stumptail macaques, sulphotransferase activity In vascular smooth muscle cells the vasodilating action is largely localized in the hair follicle.20 In rat pelage of potassium channel openers is due to membrane and vibrissae follicles, immunoreactivity for minoxidil hyperpolarization and a reduction in Ca2+ influx, sulphotransferase was seen in the outer root sheath.18 which reduces the electrical excitability of the cell. It Five human cytosolic sulphotransferase genes have has also been suggested that potassium channel been discovered to date. They encode three classes of activity is required for early-stage cell proliferation by enzymes responsible for sulphating phenols and cate- G1 progression of the cell cycle.29 Minoxidil was shown cholamines, oestrogens and hydroxysteroids.21 In hu- to increase DNA synthesis, whereas glibenclamide man liver extracts, sulphation of minoxidil is catalysed suppressed DNA synthesis in rat primary hepatocyte by at least four sulphotransferases. Biochemical evi- cultures.30 Hepatocyte potassium currents were aug- dence for minoxidil sulphation by two phenol sulpho- mented by minoxidil and attenuated by glibenclamide.
transferases has been found in human scalp skin22 andDooley21 reported finding mRNA expression for four sulphotransferases in human epidermal keratinocytes.
There are interindividual variations in scalp sulpho-transferase activity and this correlates with the level in Several lines of evidence, from clinical observations, platelets.22 In a clinical setting, scalp sulphotransferase animal studies and in vitro experiments, suggest that activity was higher in men who responded to minoxidil the promotion of hair growth by minoxidil is related in compared with those who did not respond.23 some way to its action as a potassium channel opener(Table 1).
Minoxidil sulphate is a potassium channel opener Minoxidil sulphate is one of several chemically unrelateddrugs which cause opening of plasma membrane In addition to minoxidil, the potassium channel open- ers diazoxide31,32 and pinacidil33 cause hypertrichosis Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 M I N O X I D I L A N D H A I R G R O W T H Table 1. Does minoxidil act on hair growth via potassium channels? hair growth in this model by opening potassium channels, but attempts to verify this idea have been 1. Chemically unrelated potassium channel openers stimulate unsuccessful. The broad-spectrum ion channel blocker tetraethylammonium chloride and the KATP channel a. in humans (minoxidil, diazoxide, pinacidil) blockers, glyburide and tolbutamide, failed to inhibit b. in macaques (minoxidil, cromakalin, P-1075) 2. Chemically unrelated potassium channel openers stimulate minoxidil stimulation of cultured vibrissae follicles at thymidine and ⁄ or cysteine uptake by mouse vibrissae follicle doses that were not themselves toxic.34 To test whether in vitro (minoxidil, pinacidil, cromakalin, nicorandil, minoxidil opened ion channels, vibrissae follicles were labelled with 86Rb+, an ion with specificity for potas- 3. Stimulation of 3T3 fibroblast proliferation by minoxidil in vitro inhibited by potassium channel antagonists sium channels similar to K+. In this model, the potassium channel opener pinacidil increased efflux of 1. Stimulation of thymidine ⁄ cysteine uptake by minoxidil Human hair follicle organ culture has been used in cultured mouse vibrissa follicles not blocked by potassiumchannel antagonists.
extensively in hair biology but there is only a single 2. 86Rb efflux in vibrissae follicle cultures not increased published report describing increased uptake of thymi- dine by cultured human hair follicles in response to 3. KATP channels not demonstrated in cultured hair follicle cells minoxidil.38 Minoxidil causes premature entry of folli- cles into anagen, and probably prolongs anagen andincreases hair follicle size. Of these effects only the in humans. Buhl et al.34 tested the effect of topical prolongation of anagen is possibly modelled by hair application of minoxidil and three other potassium follicle organ culture and even here the alteration in channel openers on scalp hair growth in balding follicle survival in vitro is measured in days rather than macaques. Minoxidil, cromakalin and P-1075 (a the weeks or months achieved in vivo. The rather mixed pinacidil analogue) all stimulated hair growth over a responses of cultured follicles to minoxidil may there- 20-week treatment period. A fourth potassium channel fore be due to insensitivity or inapplicability of the opener, RP-49,356, was not effective.
model. However, minoxidil does prolong survival ofcultured follicles that would otherwise undergo rapiddegeneration in vitro, albeit at concentrations which are unlikely to be achieved in vivo. This effect appears to Buhl et al.35 carried out a series of experiments on be mediated by the sulphated metabolite and there is minoxidil action using cultured mouse vibrissae fol- circumstantial but, as yet, unconfirmed evidence that it licles. In 3-day cultures, 1 mmol L)1 minoxidil pre- involves opening of potassium channels.
served follicular morphology, whereas follicles culturedin the absence of minoxidil degenerated rapidly. Folli- cles cultured in 0Æ5–5 mmol L)1 minoxidil grew longerthan controls and showed higher levels of uptake of Sanders et al. showed that the stimulatory effect of radiolabelled cysteine, amino acids and thymidine. This minoxidil on the growth of 3T3 fibroblasts is inhibited effect appears to be mediated by minoxidil sulphate.
by pharmacological blockade of potassium channels.39 The same results were obtained using approximately As yet, however, there is no clear evidence that KATP 100-fold lower concentrations of minoxidil sulphate channels are expressed in cells of hair follicle deriv- and the response of cultured follicles to minoxidil, but ation. Nakaya et al. looked for potassium channels in not minoxidil sulphate, was blocked by diethylcarbam- cultured hair follicle outer root sheath and dermal azine and chlorate, agents which interfere with sul- papilla cells using the patch-clamp technique.40 They phation.17 The potassium channels openers pinacidil, identified large and small conductance calcium-activ- cromakalin, nicorandil and P-1075 also stimulated ated potassium channels in cell membranes. These uptake of radiolabelled cysteine in cultured vibrissae channels were not blocked by ATP or glibenclamide (a follicles, although diazoxide did not.36 Harmon et al.37 specific KATP channel blocker) and neither minoxidil also reported that minoxidil, pinacidil, cromakalin and sulphate nor pinacidil increased efflux of 86Rb, sug- diazoxide increased uptake of thymidine in a dose- gesting the absence of KATP channels. However, the dependent fashion in 4-day cultures of mouse vibrissae same group has recently reported that human dermal follicles. These studies imply that minoxidil stimulates papilla cells express mRNA for the sulphonylurea Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 A . G . M E S S E N G E R A N D J . R U N D E G R E N receptor SUR2B,41 the same sulphonylurea receptor Boyera et al.44 studied the effect of minoxidil on human expressed in vascular smooth muscle cells.
keratinocytes of epidermal and hair follicle origin using arange of different culture conditions and proliferativemarkers. They found that micromolar concentrations of minoxidil stimulated proliferation in both cell types and Whatever the mechanism whereby minoxidil modu- in all culture conditions, whereas millimolar concentra- lates hair growth, there must be a primary effect on cell tions inhibited cell growth. In cells cultured from the function (Table 2). The hair follicle is a complex stumptail macaque, minoxidil stimulated thymidine structure comprising epithelial, dermal, pigment and uptake by follicular keratinocytes but not by epidermal immune cells, and a perifollicular vasculature and keratinocytes.45 O’Keefe and Payne46 also failed to show neural network. Interactions between these cells are a stimulatory response to minoxidil in cultured human involved in regulating epithelial growth and differenti- epidermal keratinocytes, although Baden and Kubilus47 ation and the hair cycle. Several of these cell types have reported that minoxidil prolonged the time after conflu- been used in isolation to study minoxidil action, but ence that keratinocytes could be subcultured.
attempts to localize minoxidil or a minoxidil metabolite Studies using fibroblasts have yielded similarly vari- binding to a specific cell population within the hair able results. Murad and Pinnell48 reported that high follicle have been unsuccessful.42 Uptake studies in concentrations of minoxidil inhibited growth of human mouse vibrissae follicles showed that minoxidil and skin fibroblasts. On the other hand, thymidine uptake minoxidil sulphate concentrated in melanocytes and was increased in macaque follicular fibroblasts cultured pigmented epithelial cells in the suprapapillary region of in micromolar concentrations of minoxidil, but not in the follicle. However, this was probably due to nonspe- nonfollicular fibroblasts.45 Sanders et al.39 proposed cific binding to melanin as there was no evidence of that the variable results of cell culture experiments may minoxidil binding in nonpigmented follicles yet pig- be explained by the potassium channel-blocking activity mented and nonpigmented follicles showed a similar of aminoglycoside antibiotics, routinely incorporated into cell culture media. Minoxidil stimulated growth ofNIH 3T3 fibroblasts cultured in the absence of amino-glycosides but not in their presence, and the prolifera- tive response of 3T3 cells to minoxidil was prevented by Several studies have examined the effect of minoxidil the potassium channel blockers tolbutamide and tetra- on cell proliferation in vitro. A variety of cell types have ethylammonium. In cultured human keratinocytes, been used including epidermal keratinocytes, hair aminoglycoside antibiotics partly suppressed the prolif- follicle keratinocytes and skin fibroblasts from humans, erative response to minoxidil but did not abolish it.44 mice and macaques. In some studies, established The variations in the cell types and experimental keratinocyte and fibroblast cell lines have been used.
protocols used mean that it is difficult to compare the The results have been variable and, to some extent, results from these studies. On balance, they suggest that minoxidil can have a stimulatory effect on cellgrowth at clinically relevant concentrations, or delay Table 2. Effects of minoxidil on cell function cell senescence, and there is limited evidence that this is mediated by its action as a potassium channel opener.
of cells in culture. In different studiesminoxidil has been reported to inhibitor stimulate growth of epithelial and fibroblast cell types. Delays senescencein keratinocyte cultures.
Two groups have studied the effect of minoxidil on collagen synthesis. Murad and Pinnell48 showed that minoxidil suppressed activity of the enzyme lysyl hydroxylase in human skin fibroblast cultures at concentrations down to 25 lmol L)1, leading to pro- duction of a collagen deficient in hydroxylysine.49 This appeared to be specific for lysyl hydroxylase as the activity of prolyl hydroxylase, which shares the same VEGF, vascular endothelial growth factor.
substrates and cofactors as lysyl hydroxylase, was Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 M I N O X I D I L A N D H A I R G R O W T H unaffected. Minoxidil (0Æ5 mmol L)1) also suppressed hair follicle diameter induced by subcutaneous capsules collagen synthesis by rat vibrissae dermal papilla cells, filled with testosterone. However, significant inhibition both in monolayer cultures and in cells grown in was seen following topical application of 5% progester- collagen gels.50 The concentrations of minoxidil used in one. The effect of minoxidil on human hair growth is these studies were quite high and the relevance of the not confined to androgen-dependent hair follicles and these findings are consistent with the conclusion thatminoxidil does not act through androgen pathways.
However, Sato et al.58 reported that minoxidil stimu- lates 17b-hydroxysteroid dehydrogenase (17b-HSD) in The prostaglandin PGH2 is formed from arachidonate cultured human dermal papilla cells and also has a by the action of a cyclooxygenase (COX), also known as small stimulatory effect on 5a-reductase activity. 17b- prostaglandin endoperoxide synthase (PGHS). PGH2 is HSD catalyses the interconversion of testosterone and the substrate for subsequent enzymatic modifications androstenedione and may therefore increase or reduce leading to the prostaglandins (PGD2, PGE2, PGF2a), androgen responses. A high concentration of minoxidil prostacyclin (PGI2) and thromboxane A2. There are two (0Æ5 mmol L)1) was used in this study and the rele- isoforms of PGHS, a widely distributed constitutive form vance of the results to hair growth in vivo is unclear.
PGHS-1, and an inducible form PGHS-2. The PGHS-1isoform has been immunolocalized to the dermal papilla of human hair follicles during anagen and catagen.51Immunostaining for PGHS-2 was also seen in the The idea that minoxidil stimulates hair growth by dermal papilla but staining was weaker than that for increasing cutaneous blood flow has been the subject PGHS-1 and was present only in anagen follicles.
of two studies giving contradictory results. Wester Minoxidil (AC50 ¼ 80 lmol L)1) stimulated the activ- et al.59 studied the effect of topical minoxidil (1%, 3%, ity of purified ovine PGHS-1 in vitro and increased 5%) on blood flow in balding scalp using laser Doppler production of PGE2 in cultured human dermal papilla velocimetry (LDV) and photopulse plethymography.
cells and mouse fibroblasts. Lachgar et al.50 also found Both methods showed an increase in skin blood flow that minoxidil (12 lmol L)1) stimulated PGE2 produc- following application of minoxidil that was statistically tion by cultured dermal papilla cells, in this case derived significant with the 5% solution. On the other hand, from rat vibrissae, as well as production of leukotriene Bunker and Dowd,60 also using LDV, failed to find any B4. They also found that minoxidil inhibited prostacy- change in skin blood flow following application of 3% clin synthesis by dermal papilla cells (measured as minoxidil topical solution to the scalp in 10 balding men, 6-keto-prostaglandin F1a), as had an earlier study using whereas all but one showed an increase in blood flow bovine endothelial cells.52 Prostanoids have many after applying the vasodilator 0Æ1% hexyl nicotinate. The biological functions in different tissues, acting through difference in results may have been due to the higher specific G protein-coupled receptors53 and, in some concentration of minoxidil used in the first study cases, via nuclear receptors.54 We do not know whether although, as Bunker and Dowd point out, 3% minoxidil prostanoids have a physiological role in regulating hair topical solution is clinically effective. Sakita et al.61 growth, although, latanoprost, a topical synthetic studied the effect of minoxidil topical solution on the hair PGF2a analogue used in the treatment of glaucoma, follicle vasculature in the rat using transmission electron causes hypertrichosis of the eyelashes.55 Topical treat- microscopy. In minoxidil-treated animals there was no ment with latanoprost also stimulates hair regrowth on difference in the total area of follicular capillaries the scalp in balding stumptail macaques.56 compared with controls but there was an increase incapillary fenestrations. The authors suggested that theincrease in fenestrations may be due to vascular endot- helial growth factor (VEGF) (see below), but the func- Nuck et al.57 studied the antiandrogenic potential of tional significance of this observation was not discussed.
minoxidil on androgen-dependent cutaneous structuresof the flank organ of female golden Syrian hamsters.
Neither 1% nor 5% minoxidil topical solution applied toone flank for 3 weeks prevented the androgen-depend- VEGF has a central role in promoting angiogenesis as ent growth of the pigmented spot, sebaceous glands or well as influencing diverse cell functions including cell Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 A . G . M E S S E N G E R A N D J . R U N D E G R E N survival, proliferation and the generation of nitric oxide interpreted with care. First, the relationship between and prostacyclin.62 The perifollicular capillary network the complexities of hair growth and the behaviour of a is coupled to the hair cycle, increasing during anagen single cell type cultured in a Petri dish is uncertain.
and then regressing during catagen and telogen. Yano Second, the concentrations of minoxidil used have et al.63 found that capillary proliferation during anagen often exceeded those to which the hair follicle is likely was temporally and spatially associated with expression to be exposed in vivo. Blood levels in subjects taking of VEGF in the outer root sheath of murine hair follicles.
minoxidil orally are in the upper nanomolar ⁄ low Transgenic overexpression of VEGF in the outer root micromolar range (20–2000 ng mL)1) and are lower sheath increased perifollicular vascularization and led to still in those using minoxidil topically ( 2 ng mL)1).
accelerated hair growth following depilation and the Third, the minoxidil target cell population in the hair growth of larger hairs. This effect was prevented by follicle is unknown. Nevertheless, the stimulation of systemic administration of a VEGF antibody. Lachgar VEGF and prostaglandin synthesis by minoxidil in et al.64 found that the expression of VEGF mRNA and dermal papilla cells provides an attractive and logical protein in cultured human dermal papilla cells was starting point for future studies and is backed up by stimulated by minoxidil in a dose-dependent fashion. A evidence from other sources. We need to know more fivefold increase in VEGF protein occurred in extracts of about the signalling mechanisms responsible for these cells incubated with 12 lmol L)1 minoxidil, and there effects—do they involve conventional potassium chan- was a similar increase in mRNA expression. A possible nel physiology or a novel mechanism as suggested by Li mechanism for minoxidil stimulation of VEGF has been et al.?41 Are KATP channels operating in the regulation proposed by Li et al. from experiments on cultured of normal hair growth or the development of andro- dermal papilla cells.41 They found that adenosine also genetic alopecia and, if so, what is their subtype increases VEGF release and the VEGF response to composition and cellular and subcellular distribution? minoxidil was prevented by pharmacological blockade Why is minoxidil important? Although the benefits of A1 and A2 adenosine receptors. mRNAs for the A1, in androgenetic alopecia have been demonstrated in A2A and A2B adenosine receptors, as well as the clinical trials, there is perhaps a tendency to dismiss the sulphonylurea receptor SUR2B, were detected by the significance of minoxidil. Yet, it remains the only reverse transcriptase–polymerase chain reaction. The medical treatment of proven efficacy when used topic- authors suggested that binding of minoxidil to SUR2B ally and is the only treatment approved for hair loss in promotes secretion of ATP, which is rapidly converted to women. Minoxidil affects hair cycling, causing prema- adenosine and activates adenosine signalling pathways.
ture termination of telogen and probably prolonginganagen. Understanding how minoxidil exerts theseeffects may lead not only to better treatments for hair loss but also will increase our understanding of the The emergence of topical minoxidil for the treatment of mechanisms responsible for controlling the hair cycle.
androgenetic alopecia in the early 1980s led to therealization that hair loss is potentially treatable and ushered in a new era in hair research. The series ofexperiments by Buhl and others on cultured vibrissae 1 Limas CJ, Freis ED. Minoxidil in severe hypertension with renal follicles and on the stumptail macaque support the failure. Effect of its addition to conventional antihypertensivedrugs. Am J Cardiol 1973; 31: 355–61.
view that the hair follicle response to minoxidil is 2 Mehta PK, Mamdani B, Shansky RM et al. Severe hypertension.
mediated by its sulphated metabolite acting as a Treatment with minoxidil. JAMA 1975; 233: 249–52.
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4 Mori O, Uno H. The effect of topical minoxidil on hair follicular resolved and this idea must be viewed as unproven. A cycles of rats. J Dermatol 1990; 17: 276–81.
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glandin synthesis. Others, such as the effects on 7 Whiting DA. Diagnostic and predictive value of horizontal sec- collagen synthesis, are more difficult to explain. Viewed tions of scalp biopsy specimens in male pattern androgenetic in isolation, the results of cell culture studies must be alopecia. J Am Acad Dermatol 1993; 28: 755–63.
Ó 2004 British Association of Dermatologists, British Journal of Dermatology, 150, 186–194 M I N O X I D I L A N D H A I R G R O W T H 8 Rushton DH, Ramsay ID, James KC et al. Biochemical and trich- kinase activation in human myeloblastic leukemia ML-1 cells.
ological characterization of diffuse alopecia in women. Br J Der- 30 Malhi H, Irani AN, Rajvanshi P et al. KATP channels regulate 9 Whiting DA. Chronic telogen effluvium: increased scalp hair mitogenically induced proliferation in primary rat hepatocytes shedding in middle-aged women. J Am Acad Dermatol 1996; 35: and human liver cell lines. Implications for liver growth control and potential therapeutic targeting. J Biol Chem 2000; 275: 10 Abell E. Histologic response to topically applied minoxidil in male- pattern alopecia. Clin Dermatol 1988; 6: 191–4.
31 Koblenzer PJ, Baker L. Hypertrichosis lanuginosa associated with 11 Headington JT, Novak E. Clinical and histologic studies of male diazoxide therapy in prepubertal children: a clinicopathologic pattern baldness treated with topical minoxidil. Curr Ther Res Clin study. Ann N Y Acad Sci 1968; 150: 373–82.
32 Burton JL, Schutt WH, Caldwell IW. Hypertrichosis due to diaz- 12 Johnson GA, Barsuhn KJ, McCall JM. Sulfation of minoxidil by oxide. Br J Dermatol 1975; 93: 707–11.
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33 Goldberg MR. Clinical pharmacology of pinacidil, a prototype for 13 Meisheri KD, Johnson GA, Puddington L. Enzymatic and non- drugs that affect potassium channels. J Cardiovasc Pharmacol enzymatic sulfation mechanisms in the biological actions of minoxidil. Biochem Pharmacol 1993; 45: 271–9.
34 Buhl AE, Conrad SJ, Waldon DJ et al. Potassium channel con- 14 Falany CN, Kerl EA. Sulfation of minoxidil by human liver phenol ductance as a control mechanism in hair follicles. J Invest Der- sulfotransferase. Biochem Pharmacol 1990; 40: 1027–32.
15 Johnson GA, Baker CA. Sulfation of minoxidil by human platelet 35 Buhl AE, Waldon DJ, Kawabe TT et al. Minoxidil stimulates sulfotransferase. Clin Chim Acta 1987; 169: 217–27.
mouse vibrissae follicles in organ culture. J Invest Dermatol 1989; 16 Johnson GA, Baker CA, Knight KA. Minoxidil sulfotransferase, a marker of human keratinocyte differentiation. J Invest Dermatol 36 Buhl AE, Waldon DJ, Conrad SJ et al. Potassium channel con- ductance: a mechanism affecting hair growth both in vitro and 17 Buhl AE, Waldon DJ, Baker CA et al. Minoxidil sulfate is the active in vivo. J Invest Dermatol 1992; 98: 315–19.
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