Minoxidil was originally introduced in the early 1970s as a treatment for hypertension. Minoxidil is in the class of treatments called “Potassium Channel Openers” that are used primarily for treating persons with high blood pressure. Although several potassium-channel openers have been used in research for many years, Minoxidil is the only approved one in this category of drugs for use in humans.
Hypertrichosis or undesirable hair growth was seen as a side effect of the medication. This led to the development of a topical formulation of Minoxidil for the treatment of androgenetic alopecia in men and subsequently in women. Now Minoxidil is available in two forms to treat different conditions. Oral Minoxidil is used to treat high blood pressure and the topical solution form is used to treat hair loss and baldness. 2% topical Minoxidil was first marketed for hair re-growth in men in 1986 in the United States and the 5% product became available in 1993.
Response of the hair follicle to minoxidil
Although it is clear that Minoxidil stimulates hair growth, our understanding of its mechanism of action on the hair follicle is very limited. Drugs may stimulate hair growth in various ways. They may increase the linear growth rate of hair, increase the diameter of the hair fiber, alter the hair cycle, either by shortening telogen (resting phase) or prolonging anagen (growth phase), or hair follicles may respond to act through a combination of these effects.
In animal studies, topical Minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen. The effect of Minoxidil on hair growth has been studied extensively in the stump-tailed macaque. Histological studies in these primates 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 follicle size. In humans, the evidence available so far suggests that Minoxidil primarily acts on the hair cycle; though it is possible it may also increase hair diameter.
The importance of a proper understanding Minoxidil’s mechanism of action is two-fold – it can help develop more effective treatments for hair loss disorders as well as give a clearer insight into the biology of hair growth.
How does minoxidil work?
Minoxidil does not appear to have any anti-androgen effect. In animal studies, the drug does not stimulate testosterone secretion or adrenal androgen secretion. In humans, serum testosterone levels remain unchanged after topical application of Minoxidil.
Clinical trials of topical Minoxidil in male and female hair loss all show a remarkably rapid increase in hair growth, measured by hair counts or hair weight. This increase is apparent within 6–8 weeks of starting treatment generally peaks by 12–16 weeks. Reversal of follicular miniaturization can hardly be a plausible explanation for this rapid hair growth. It seems more likely that Minoxidil triggers follicles in the latent part of telogen into anagen. The results of histological studies in humans are less conclusive than in the macaque, with the result that the mechanism of action of Minoxidil is still a grey area.
Since it was originally a blood-pressure drug it was thought that Minoxidil worked by increasing the amount of blood to the hair follicles. However, other vasodilators do not stimulate the same response, so it is evident that local vasodilatation (dilation of blood vessels) does not appear to play a primary role in hair growth associated with Minoxidil. Minoxidil sulfate appears to be the active metabolite responsible for hair growth stimulation. Orally administered Minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, Minoxidil sulphate, as an opener of sarcolemmal KATP channels. The series of experiments by researchers on cultured vibrissae (whiskers) follicles and on the stumptail macaque show some evidence that the stimulatory effect of Minoxidil on hair growth is also due to the opening of potassium channels by Minoxidil sulphate. However this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle.
Minoxidil has a well-recognized effect on the prolongation of keratinocyte (the keratinocyte is the building block of the epidermis) growth and on increasing the proportion of hairs in anagen in monkeys and humans with androgenetic alopecia. Experiments also show that Minoxidil also appears to prolong the survival time of keratinocytes in vitro.
The cellular response to minoxidil
Whatever the mechanism whereby Minoxidil modulates hair growth, there is a primary effect on cell function. The hair follicle is a complex structure comprising epithelial, dermal, pigment and immune cells, and a perifollicular vasculature and neural network. Interactions between these cells are involved in regulating epithelial growth and differentiation and the hair cycle. Several of these cell types have been used in isolation to study Minoxidil action, but attempts to localize Minoxidil or a Minoxidil metabolite binding to a specific cell population within the hair follicle have been unsuccessful.
A number of in vitro effects of Minoxidil have been described in monocultures 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 prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the relation of results obtained in cell culture studies to the enigmatic biology of the hair follicle has not been ascertained.
Of these, Minoxidil has been shown to increase vascular endothelial growth factor (VEGF) in cultured dermal papilla cell extracts. VEGF has been found to be associated with new blood vessel formation and is strongly expressed in anagen dermal papilla when a highly developed vascular network is present and decreased in telogen when these blood vessels largely disappear. Some authors have thus put forward a theory that Minoxidil may play a key role in regulating dermal papilla cell vascularization.
Conclusion
Minoxidil does not appear to have either a hormonal or immunosuppressant effect. However, it has been shown to have a direct mitogenic effect (i.e. it induces cell division) on epidermal cells both in vitro and in vivo. Despite untiring efforts by researchers, we still have only a limited understanding of how hair follicles respond to Minoxidil stimulation.