Since these initial studies, much research has been done to identify exactly how the topical application of minoxidil can lead to increased hair growth. One important hypothesis is based on its vasodilatory properties. Diazoxide is another antihypertensive potassium channel opener which increases blood flow and is reputed to increase hair growth. Laser Doppler velocimetry studies showed an increase in cutaneous blood flow after applying 1%, 3%, and 5% minoxidil solutions to the scalps of 16 balding men.16 All three groups showed increases compared to a control group, and the 5% group showed the greatest increase. A significant increase in blood flow occurred as soon as 15 minutes after application, and lasted for up to an hour. The role of minoxidil in angiogenesis is further supported by evidence that it upregulates the expression of vascular endothelial growth factor mRNA in human hair dermal papilla cells.
Minoxidil sulfate is the active metabolite that
stimulates hair follicles. The conversion of minoxidil
to minoxidil sulfate is catalyzed by sulphotransferase
enzymes, which exist in the scalp. In scalp skin
of the stump-tailed macaque, this enzyme has been
localized mainly to the hair follicle, which contains
50% to 85% of the enzyme (versus 10-20% in the
epidermis and dermis). Immunolocalization studies
of minoxidil sulphotransferase demonstrated that
the lower outer root sheath is the most likely site of
conversion of minoxidil to its sulfated form. Just as
is the case with dihydrotestosterone (DHT), there are
interindividual variations in scalp sulphotransferase
levels. Patients with a better response to topical
minoxidil were found to have a greater level of
enzyme activity.
Cultures of human epidermal cells treated with
minoxidil have been shown to survive longer than
control cultures. Minoxidil slows the senescence of
keratinocytes and reduces the rate at which cells are
lost from the germinative pool. This is similar to what
has been found with epidermal growth factor.
Minoxidil has been shown to increase the proliferation
of dermal papilla cells of the human hair
follicle. Specifically, minoxidil increased levels of
Erk and Akt phosphorylation, with an increased ratio
of Bcl-2/Bax, prolonging anagen and preventing cell
death with antiapoptotic effects. This same study
found that minoxidil elongated individual hair follicles
in organ culture.
Minoxidil may also enhance cell proliferation. The
uptake of tritiated minoxidil and its conversion to
minoxidil sulfate has been found to be relatively
higher in the hair follicles than in the epidermis and
dermis. This group also found that minoxidil
caused the enhancement of DNA synthesis in the
follicular and perifollicular cells but not in the epidermal
keratinocytes. Another study showed a
marked dose-dependent second peak of DNA synthesis
8 to 10 days later in epidermal cells cultured
with minoxidil. There were two morphologically
distinct cell types, suggesting that minoxidil can
affect epidermal cells in culture by altering their
growth pattern and phenotypic appearance.
Whether the minoxidil indeed prolongs anagen or
simply shortens telogen is still a matter of debate. It
has been shown to shorten the length of telogen
phase in the follicular cycle of rats but did not
prolong the anagen phase. Rather, there was found
to be a premature entry of resting hair follicles back
into the anagen stage, with an increased rate of DNA synthesis during the anagen stage. However, another
study in balding stump-tailed macaques found that
treatment with minoxidil increased the proportion of
hair follicles in anagen, reduced the number of
telogen follicles, and increased the follicle size
overall. This suggests at least a relative shift chronologically
from telogen to anagen. Abell supported
the finding of increased anagen/telogen
ratios after 12 months of minoxidil treatment in
balding men. However, the main finding was an
increase in mean hair diameter, which was evident at
4 months. Other histologic studies also demonstrated
an increase in the shaft diameter from 0.029 mm at
baseline to 0.043 mm at 12 weeks and 0.042 mm at 24
weeks.
Lastly, it is possible that minoxidil plays an
immunoregulatory role in the hair follicle. In vitro
studies demonstrate that minoxidil had a suppressive
effect on normal human T-lymphocytes in vitro. This may explain minoxidil’s reported efficacy in
treating some patients with AA. This is supported
by histologic findings of a reduced perifollicular
infiltrate. There is also evidence that minoxidil can
selectively inhibit prostacyclin production by cells in
culture. Somewhat like aspirin, minoxidil has been
found to prevent the aggregation of platelets by
causing a reduction in the synthesis of prostaglandin
E2 and thromboxane B2.36 This inhibitory effect on
the cyclooxygenase enzyme awaits further study.
Regardless of its exact mechanism of action, there
is sound histologic and clinical evidence that minoxidil
works. A complete list of proposed mechanisms
is provided in Table below.
Minoxidil: proposed mechanisms of action
_______________________________
Vasodilatory properties
______________________________
Angiogenic properties
______________________________
Enhanced cell proliferation and DNA synthesis
______________________________
Potassium channel opener
______________________________
Antiandrogen effects
______________________________
Suppression of collagen synthesis
______________________________
Immunosuppressive effects