How Does Minoxidil Work? 3 Hypotheses + Debates

Article Summary

Despite decades of study and FDA approval, researchers still aren’t sure exactly how minoxidil regrows hair. Over the last few years, investigators have explored a number of hypothetical mechanisms ranging from vasodilation to prostaglandin modulation to anti-androgenic effects. In this article, we’ll formulate the strongest arguments for and against each mechanism – and reveal why no one mechanism has yet to be confirmed or dismissed by the scientific community.

Full Article

In this article, we’ll explore the history of minoxidil, how it became a hair loss drug, and the debate over its mechanisms of action for hair growth.

Despite decades of study, researchers still do not know how minoxidil promotes hair growth. But they do have some ideas, and these ideas have remained the subject of significant debate – even 70 years after the discovery of the drug.

What Is Minoxidil?

Minoxidil is a drug that was originally developed in the 1950’s by Upjohn Company, which later became a part of Pfizer. In early experiments, minoxidil consistently improved vasodilation in animals, which led to human trials as a potential treatment for hypertension (i.e., high blood pressure).

In 1979, the FDA approved the use of oral minoxidil as a treatment for hypertension. But during its clinical trials and post-marketing studies, “nearly all” oral minoxidil users reported excessive hair growth as a side effect – and even the development of new hair along the face, chest, back, and scalp.^[1]https://pubmed.ncbi.nlm.nih.gov/7030707/

This led to the reformulation of minoxidil as a topical, followed by clinical studies to evaluate topical minoxidil’s effectiveness in men and women facing androgenic alopecia (AGA) – one of the world’s most common hair loss disorders.

Throughout the 1980’s, a series of clinical studies consistently demonstrated that topical minoxidil was able to improve hair counts, increase hair thickness, and reduce hair shedding in male and female hair loss sufferers. And in 1988 and 1992, topical minoxidil at 5% and 2% formulations were approved by the FDA for male and female pattern hair loss, respectively.^[2]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691938/

How Does Minoxidil Work?

Despite decades of study, it’s still unclear exactly how minoxidil improves hair growth.

In animal studies, topical minoxidil has been shown to shorten the telogen (rest) phase of the hair cycle and stimulate the initiation of the anagen (active) stage of the hair cycle.^[3]https://pubmed.ncbi.nlm.nih.gov/14996087/ These effects also consistently translate to humans using minoxidil (oral and topical) to treat AGA. But despite knowing what minoxidil does to most hair follicles, researchers still aren’t exactly sure of the mechanisms governing the hair growth improvements.

With that said, investigation groups do have some ideas what might be going on. In particular, there are (at least) three suspected ways minoxidil might regrow hair: its activity as a vasodilator, as well as its anti-inflammatory and anti-androgenic effects.

We’ll explore arguments for and against each hypothesis – all to elucidate why there’s still debate.

Hypothesis #1: Vasodilation (i.e, Increased Blood Flow)

The hypothesis: minoxidil improves blood, oxygen, and nutrient transport to balding hair follicles – which stimulates more robust hair growth.

Argument For

Minoxidil opens potassium ion channels, which improves circulation in microvascular networks. These potassium channels are located in a variety of places – including the muscles of peripheral arteries and within and nearby the hair follicles themselves.^[4]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691938/^[5]https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.07-099424

The human scalp has a broad network of blood vessels, and is considered one of the most densely vascularized regions of the body. However, as AGA progresses, balding scalp regions undergo a loss of blood supply. For instance, clinical studies have shown 40% declines in transcutaneous oxygen levels in frontal balding regions versus non-balding controls.^[6]https://pubmed.ncbi.nlm.nih.gov/8628793/ Similarly, another study found that subcutaneous blood flow is 2.6x lower in balding versus non-balding scalps.^[7]https://www.jidonline.org/article/0022-202X(89)90189-9/pdf

Whether reduced blood supply is a cause or effect of the balding process is still debated – with research groups arguing both sides. However, current consensus is that if blood flow is causally linked to pattern hair loss, it is probably a secondary contributor to the balding process – rather than its root cause.

So, if minoxidil increases blood vessel diameters by opening potassium ion channels, more blood, oxygen, and nutrients might reach hair follicles and thereby lead to more robust hair growth.^[8]https://pubmed.ncbi.nlm.nih.gov/22409453/

Studies using Doppler devices (a measurement tool for blood flow) showed that minoxidil appears to do this. Specifically, minoxidil improve microvascular vasodilation in skin tissues supporting hair follicles, and that these improvements coincide with hair growth.^[9]https://pubmed.ncbi.nlm.nih.gov/10233226/

Other studies have found that minoxidil application grows new blood vessel openings surrounding the hair follicles themselves – a term known as fenestration.^[10]https://pubmed.ncbi.nlm.nih.gov/10233226/ Fenestration is a process supporting angiogenesis, or the growth and formation of new blood vessel networks.

Therefore, mechanistic, animal, and clinical data all suggest that minoxidil might work by improving blood flow to balding regions – and that this might be the main mechanism by which minoxidil regrows hair.

Argument Against

There are three main counterarguments to the idea that minoxidil might regrow hair by improving blood flow to balding regions:

1. Reduced blood flow is likely a consequence of androgenic alopecia, rather than a cause.

While minoxidil might increase blood flow, reductions to blood flow are not considered to be the fundamental driver of AGA. Instead, the evidence most strongly supports that the overwhelming majority of reductions to blood flow that occurs during the progression of AGA is a consequence of hair cycle-mediated hair follicle miniaturization, rather than a cause of hair loss.Because of the conflation of cause-and-effect, improving circulation to thinning regions cannot be the main way in which minoxidil regrows hair – much like an increase in ice cream sales is not the cause of more shark attacks, despite both being correlated. Instead, there must be some other unidentified variable at play (in the case of ice cream sales and shark attacks, it’s “nice weather”).Therefore, minoxidil must be working to regrow hair through some other mechanism outside of increased blood flow.

2. If minoxidil works primarily by increasing blood supply, why don’t other vasodilating medications also regrow hair?

If increasing blood circulation were truly a plausible treatment target for androgenic alopecia, why don’t other antihypertensive medications regrow hair? Why is it only minoxidil?This is further evidence that minoxidil probably doesn’t work primarily through increasing blood supply to miniaturized hairs. There must be some other mechanism at play.

3. Minoxidil has other suspected mechanisms beyond circulation enhancements.

These mechanisms include, but are not limited to, prostaglandin modulation and anti-androgenic effects – the latter of which is far closer to the suspected root cause of androgenic alopecia: dihydrotestosterone (DHT), a hormone that is causally associated with the balding process.

Altogether, these three arguments form the basis by which some people reject the idea that minoxidil works primarily through increasing blood supply. But – as is the case with many topics in hair loss research – the science isn’t completely settled, because there also counterpoints to each of the above counterarguments.

Rebuttals

While the case against minoxidil working through vasodilation might appear strong, there are also compelling rebuttals to each of the counterpoints raised.

1. “Reduced blood flow is likely a consequence of androgenic alopecia, rather than a cause.”

This can be true, and simultaneously, it can also be true that targeting secondary contributors to AGA – like reductions to blood supply – can still promote hair growth.This has even been demonstrated in the context of human hair loss, whereby targeting to reduce factors such as inflammation in the infundibulum (which is believed to be partly caused by microorganisms) and/or inflammation near the dermal papillae (which is believed to be driven by the hormone DHT) in AGA patients can still improve hair growth outcomes – even without necessarily resolving the root cause(s) of that inflammation.Moreover, despite minoxidil being an FDA-approved to treat AGA, its effects on hair growth are relatively mild – particularly in the long-run – whereby hair density improvements from minoxidil start trending downward after the first year of use. The steepness of minoxidil’s downward slope is not matched by other treatments like finasteride, which directly lower scalp DHT levels and, in doing so, lead to longer-term hair gains – probably because of the drug’s ability to address factors closer to the “root cause” of AGA.

Therefore, minoxidil’s mild and long-run diminishing effects on hair growth actually support the idea that the drug targets an accelerator or secondary contributor to the balding process – rather than something closer to its root cause. There is enough alignment in mechanistic, animal, and clinical data on minoxidil to suggest that this might be increased blood supply via fenestration of vascular networks nearby hair follicles.

2. “If minoxidil works primarily by increasing blood supply, why don’t other vasodilating medications also regrow hair?”

Other anti-hypertensive medications do improve hair growth in humans. So at the outset, this counterargument makes no sense.Studies have shown that medications like diazoxide and pinacidil also increase blood flow by opening the same potassium ion channels as minoxidil, and also promote hair growth in humans.^[11]https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.07-099424^[12]https://www.karger.com/Article/Pdf/248368^[13]https://journals.lww.com/cardiovascularpharm/abstract/1988/12002/clinical_pharmacology_of_pinacidil,_a_prototype.8.aspx^[14]https://www.sciencedirect.com/science/article/pii/S0022202X9290089M

This is important, because it suggests that the mechanism of vasodilation – i.e., opening potassium ion channels – likely matters for hair growth. Because in mechanistic and animal studies, vasodilation stimulated by opening potassium ion channels seems to also enhance the vasculature surrounding the hair follicles and the fenestration of microvascular networks, whereas other vasodilating medications working through other mechanisms might not achieve the same effect.

This is because other anti-hypertensive medications do not all target potassium ion channels. Therefore, other anti-hypertensive medications will not always have the same magnitude of effect on vasodilation as minoxidil, nor will they always influence vasodilation in areas relevant to hair growth – like the microvascular regions of the scalp skin.

For an example, just see our article on peppermint oil for hair growth – in which we reviewed research showing that menthol (which is widely labeled as a “vasodilator”) happens to cause vasodilation in the vascular endothelium but vasoconstriction in vascular smooth muscle tissues.

This degree of specificity matters, but the nuance tends to get left behind by people blindly assuming that all vasodilation medications must improve hair growth in order for vasodilation to be a worthy mechanism of action by which minoxidil might work.

That’s not a reasonable assumption. Depending on the medication, dosing schedule, delivery method, and regions of application – anti-hypertensive compounds can have a range of blood flow-related effects across organ sites, arteries, veins, and microvascular networks – some of which are paradoxical.

3. “Minoxidil has other suspected mechanisms beyond circulation enhancements.”

This is true. It is also true that these mechanisms might also contribute to minoxidil’s hair growth-promoting effects. However, these mechanisms of action remain speculative, and they are supported by low-quality studies (and conflicting research) regarding their plausibility.Therefore, the existence of this speculation does not disprove the possibility that minoxidil might still work through vascular fenestration of AGA-affected hair follicles. All mechanisms can simultaneously contribute to hair growth; there need not be a “one versus the other” mentality.

Hypothesis #2: Prostaglandin Modulation

The hypothesis: minoxidil modifies prostaglandin activity, and in doing so, reduces inflammation in balding regions.

Argument For

Prostaglandins are fatty acid derivatives that come from our ingestion of omega 6 fatty acids. These lipid derivatives can have hormone-like effects on the body, and are often involved in inflammatory processes. Specifically, prostaglandins tend to increase in response to tissue damage or infection – with different prostaglandins playing roles in both inflammation generation and inflammation resolution.

In 2012, a renowned research team from the University of Pennsylvania demonstrated that prostaglandin D2 (PGD2) and prostaglandin J2 (PGJ2) were elevated in balding regions, and that in mouse models, prostaglandin D2 inhibited hair lengthening.^[15]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319975/^[16]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982925/

Moreover, research from more than a decade prior had demonstrated that minoxidil appears to enhance the activity of prostaglandins associated with the growth phase of the hair cycle, and perhaps dampen prostaglandins associated with hair loss.^[17]https://pubmed.ncbi.nlm.nih.gov/9008235/

For these reasons, some researchers now believe that prostaglandin modifications are perhaps one of the ways in which minoxidil might regrow hair. In modifying prostaglandin activity, minoxidil might lower inflammation within certain hair follicle sites and, in doing so, improve hair growth outcomes.

Argument Against

When Garza et al.’s 2012 study on prostaglandin D2 was published, hair loss forums were enthralled with the possibility of developing and/or repurposing a new class of treatments for AGA: prostaglandin analogues. Excitingly, a drug developed to inhibit prostaglandin D2-mediated inflammation – setipiprant – was already undergoing clinical trials to treat asthma. As such, the drug developers repurposed the drug and began a clinical trial to see if it would also help fighting hair loss from AGA.

In 2021, the clinical trial evaluating setipiprant as a hair loss treatment was quietly published, and without a major press release. The results: the drug was well tolerated, but it did not work. Specifically, it produced no statistically significant effects on hair parameters versus the placebo group, whereas the study’s positive treatment-control group (who were taking oral finasteride) saw improvements to hair counts throughout the duration of the study.^[18]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526366/

Over the last two decades, other drugs with prostaglandin-modulating activities have also been tested to treat AGA – such as latanoprost and bimatoprost. While some clinical studies show a mild effect, these studies are poorly designed: they tend to have small sample sizes and poor methods (or no methods) of randomization for participants; they tend to include participants with other hair loss disorders in addition to AGA; and they tend to show relatively low response rates across participants, despite some endpoints achieving statistical significance.^[19]https://my.perfecthairhealth.com/courses/latanoprost/ This makes it difficult to ascertain any true effects on prostaglandin modulation for AGA – if any.

Finally, follow-up studies conducted by Garza et al. (and other research groups) have actually found conflicting results regarding the presence of prostaglandins throughout the progression of AGA – with some studies showing elevated pro-inflammatory and anti-inflammatory prostaglandin levels only during specific stages of the hair cycle or specific stages of AGA’s progression.^[20]https://pubmed.ncbi.nlm.nih.gov/33854354/

Altogether, these findings have significantly dampened excitement surrounding prostaglandin activity as an effective treatment target for AGA.

Rebuttals

Much like it is irresponsible to group together all anti-hypertensive medications as having the same effects on hair growth, we must also not make the same mistake by lumping together all prostaglandin analogues – setipiprant, latanoprost, bimatoprost, minoxidil, and more.

In other words, just because setipiprant failed its phase II clinical trials on AGA, and just because latanoprost appears to be inferior to minoxidil in terms of hair growth, this does not automatically mean that we can dismiss the possibility of prostaglandin modification as a potential treatment target for AGA, nor can we fully dismiss the idea that minoxidil does not work through prostaglandin modification.

Hypothesis #3: Androgen Receptor Antagonization

The hypothesis: minoxidil may reduce androgen activity in the scalp skin, and in doing so, regrow hair.

Argument For

An in vitro study published in 2014 suggested that minoxidil might make androgen receptor pathways less stable – thereby acting as a mild androgen receptor antagonist and/or anti-androgen (at least in cell culture studies).^[21]https://pubmed.ncbi.nlm.nih.gov/24742982/

Overwhelming evidence implicates the hormone DHT as causally associated with the balding process. Drugs like finasteride lower DHT levels in the scalp, and in doing so, consistently improve AGA outcomes across dozens of studies spanning tens of thousands of participants.

If the results of this in vitro study hold true in vivo, this would suggest that minoxidil might help lower hormones in the scalp that are causally associated with the balding process. In doing so, minoxidil might actually target hormonal causes of hair loss – even though the drug isn’t believed to change hormonal profiles in the (serum) blood or elicit significant anti-androgenic effects elsewhere throughout the body.^[22]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691938/

Argument Against

This 2014 in vitro study conflicts with other studies exploring whether minoxidil has anti-androgenic effects.

For instance, a 1987 study and a 2017 study both found that minoxidil doesn’t appear to affect androgens – with the latter study suggesting that minoxidil may even enhance androgenic activity in the scalp.^[23]https://pubmed.ncbi.nlm.nih.gov/3800423/^[24]https://pubmed.ncbi.nlm.nih.gov/30064598/

Therefore, it can just as easily be argued that minoxidil enhances androgenic activity in the scalp skin, rather than inhibits it.

Rebuttals

To our knowledge, there aren’t any strong rebuttals to these counterpoints. With such little evidence existing on this subject – and with the existing studies finding conflicting results – the jury is still out on whether minoxidil has any anti-androgenic effects at all.

Final Thoughts

The way in which minoxidil grows hair is still up for debate.

To date, there are (at least) three leading hypotheses, all of which have their problems:

1. Increased microcirculation to balding regions through vascular fenestration
2. Prostaglandin modulation – specifically related to PGE2
3. Anti-androgenic activity

What’s important to note is that there is not enough evidence to dismiss any of these suspected mechanisms. As such, all of them are still in the running, and all of them might contribute toward minoxidil hair growth-promoting effects.

With more research, we’ll hopefully have a final answer. And if we ever do, we’ll update this article with more information.