Category Archives: Vascular Endothelial Growth Factor (VEGF)

How Does Minoxidil Work to Grow Hair?

How does Minoxidil work in growing hair on a receding hairline? The below post was originally written in 2014. It has now been updated with newer studies discussing Minoxidil’s mechanism of action in stimulating hair growth.

Minoxidil Foam.
Minoxidil foam to grow hair.

Minoxidil (brand name Rogaine) is known to be one of only two medications officially approved for hair loss treatment. With the other being Finasteride (Propecia). It is available in 2% and 5% dosages and in topical and foam versions. Besides Rogaine, another well known Minoxidil brand is Costco’s Kirkland.

Minoxidil was first approved by the US FDA to treat male pattern baldness in 1988. In 1991, the product was also made available for women with female pattern hair loss and thinning hair.

Make sure to read my post on whether Minoxidil can grow a beard. A large number of people are using this product to gain facial hair, not something I would recommend. Also see some before and after results of Minoxidil and Finasteride to regrow hair.

How does Minoxidil Work?

Scientists do not know the exact mechanism via which Minoxidil® (a mitogenic drug) has a positive effect on hair growth. However, there are a number of proven mechanisms of action that suggests how Minoxidil works to stimulate hair growth.

Minoxidil Chemical Structure.
Minoxidil Chemical Structure.

The original use of Minoxidil was as an oral medication for high blood pressure. See my post on oral Minoxidil. The side effect of hypertrichosis (excessive body hair) led to its becoming a popular treatment option for hair loss.

To date, the main theories about how Minoxidil works to grow hair are:

  • Due to its vasodilation effect.
  • Due to its potassium channel opening effect.
  • Via inhibiting the decrease in calcium levels in cells. This prevents the inhibition of epidermal growth factor stimulated hair root growth.
  • By increased blood flow to the scalp.
  • By increasing key growth factors that are conducive to scalp hair growth.

There are also other theories about how Minoxidil (aka Rogaine) helps scalp hair growth. Further below, I outline all of the main ones.

Besides prolonging the growth phase of the hair cycle, Minoxidil has also been shows to increase the diameter of existing hair follicles. According to a study from 1988, seven subjects who received a 5 percent dose of minoxidil had a mean hair shaft diameter of 0.029 mm before treatment. This hair width then increased to 0.043 mm at 12 weeks.

It should be noted that Minoxidil can grow hair on both the crown (vertex) and frontal regions of the scalp. Many people think that it only works in the crown area, but that is incorrect.

History of Minoxidil

  • In 1979, Minoxidil was first approved by the US FDA. However, its usage was as an oral blood pressure medication (brand name Loniten) rather than as a hair loss treatment.
  • In 1988, the FDA first approved Minoxidil as a hair loss treatment. This was via a topical 2% solution formulation under the brand name Rogaine, owned by Upjohn Company. However, Rogaine was only available via prescription, and it was only meant for use by men.
  • In 1991, the FDA approved Minoxidil as a hair loss treatment for women, but by prescription only.
  • In 1992, Rogaine launched a 2% Minoxidil topical solution for women, only available via a prescription.
  • In 1996, the FDA approved the over-the-counter sale of 2% topical Minoxidil and also allowed the production of generic formulations of Minoxidil. Upjohn subsequently drastically cut the price of Rogaine in order to compete in the now much more competitive market.
  • In 1997, Upjohn released a 5 percent topical solution formulation of Rogaine. It was only available by prescription and for men only.
  • In 1998, the FDA approved a 5 percent formulation of Minoxidil for over-the-counter sale to men.
  • In 2006, Rogaine launched a 5% Minoxidil foam product for the first time. It was immediately available for over-the-counter purchase, but only recommended for men.
  • In 2011, men’s Rogaine foam was made available in unscented format.
  • In 2014, Women’s Rogaine 5% Minoxidil foam was approved by the FDA, but with a once a day treatment recommendation. Men are always supposed to use Minoxidil twice a day.

Mechanism of Action (References and Studies):

  • In 1997, researchers found that Minoxidil increased prostaglandin synthesis (more specifically, prostaglandin synthase-1, abbreviated as PGHS-1) in cultured dermal papilla cells. In more recent years, the issue of prostaglandins and hair loss has garnered a great deal of attention and you can search for “PGE2” on this blog to learn more.
  • A French study from 1998 is among many that has found that Minoxidil upregulates growth factors, in particular vascular endothelial growth factor (VEGF).
  •  A 2001 study found that the positive effect of Minoxidil on hair is mediated by adenosine.
  • An excellent article from 2008 on hair loss medical treatments by Dr. Nicole Rogers and Dr. Marc Avram that discusses Minoxidil in detail. They mention that one of the main effects of Minoxidil is angiogenesis and increased blood flow in the area of application. They also discuss the enhanced cell proliferation and DNA synthesis effects on Minoxidil that might be benefiting hair growth.
  • In 2011, South Korean researchers found that Minoxidil activated the β-catenin pathway in human dermal papilla cells and therefore extended the anagen (growth) phase of the hair cycle.
  • In April 2014, Taiwanese researchers came up with yet another reason as to why Minoxidil works, concluding that it may suppress androgen receptor-related functions. i.e., the drug has anti-androgenic properties. Their conclusion is especially interesting:

The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.

Minoxidil enhances hair keratinocyte proliferation and activates hDP cells to induce growth factors. IGF-1 is among these growth factors, and has been shown to exhibit a potent hair elongation effect.

  • In June 2017, US researchers published a new study that provided significant insights into how Minoxidil foam worked via upregulating and downregulating various genes. Interestingly, vertex and frontal scalp of patients showed a generally similar response to Minoxidil. Many online reports suggest that minoxidil might work better in the crown than in the front, but perhaps that is not true based on these findings.
  • In February 2018, South Korean scientists discovered that Minoxidil promotes hair growth through the stimulation of growth factor release from adipose-derived stem cells. This growth factor secretion may enhance hair growth by promoting dermal papilla cell proliferation.

Minoxidil Side Effects

In general, topical Minoxidil is well tolerated in most people at the typical 5% dosage. Most people even tolerate higher concentration levels of the drug. However, some people will get side effects.

The most common entail adverse skin reactions such as burning, itching, redness and stinging in the areas of application. Another common complaint is an increase in body hair growth after taking Minoxidil, especially in the forehead, eyebrow and beard regions.

In rare instances, people complain about dizziness or breathing difficulties after taking Minoxidil. Allergic reactions, including rashes, are also possible in some cases. Please see a doctor immediately if you get such serious side effects. Also make sure to stop using this medication right away.

Rogaine Shedding

Some people will shed a lot of hair after changing their Rogaine (Minoxidil) dosage. For those who quit Rogaine entirely, a major shed of scalp hair is almost always guaranteed. Sometimes this can take weeks or even months after drug use cessation. In many instances, sheds are temporary and just a regular part of the hair growth cycle. i.e., anagen, catagen, kenogen and tologen.

Toxicity in Cats and Dogs

If you own pets, note that Minoxidil is very poisonous to some animals, especially cats. If your cat is exposed to Minoxidil via a spill or accident, some side effects to look out for include:

  • Fatigue and lethargy.
  • Changes in heart rate due to cardiac damage.
  • Dehydration.
  • A drop blood pressure (hypotension).
  • Coughing.
  • Changes in appetite.

Prompt action and treatment by a veterinarian will prevent your cat from dying. If the medication was applied topically, make sure to wash the cat’s paws and fur promptly and thoroughly.

Key Growth Factors in Platelet-Rich Plasma

I have mentioned platelet-rich plasma (PRP) in a dozen or so posts on this blog over the past three years. The positive effect of PRP on hair growth is somewhat controversial. However, there is no controversy when it comes to the fact that PRP contains numerous concentrated growth factors (GFs). And many of these growth factors are known to at least modestly benefit hair thickness as well as hair quantity.

PRP Growth Factors
Platelet-Rich Plasma (PRP) Growth Factors.

In the past I have briefly discussed some of the key growth factors that are highly concentrated in PRP. I think it is worth having a separate post here that discusses all of them in a bit more detail. There is a good chance that I am still missing things, so any corrections and suggestions are welcome via the comments.

It should be noted that even many non-PRP related hair loss products target one or more of the below listed growth factors in order to stimulate hair growth. There is a good chance that both PRP as well as hair loss products that contain some of the below growth factors make existing hair stronger. It is probably unlikely that such products ever bring back hair that has been lost for a long time.

Growth Factors in Platelet-Rich Plasma

The key growth factors in PRP that are supposedly beneficial to hair growth are:

  • Insulin-Like Growth Factor 1 (IGF-1).
  • Fibroblast Growth Factor (FGF).
  • Platelet-Derived Growth Factor (PDGF).
  • Vascular Endothelial Growth Factor (VEGF).
  • Epidermal Growth Factor (EGF).
  • Transforming Growth Factor Beta (TGF-β).
  • Nerve Growth Factor (NGF).

IGF-1

I start with the growth hormone insulin-like growth factor 1 (IGF-1) because I have already covered it a few times before.

  • Promotion of IGF-1 expression is one of the main considerations behind Shiseido’s bestselling adenosine based products.
  • US-based Follicept was targeting IGF-1 delivery in its hair loss product, prior to the company’s demise.
  • Adipose-derived stem cells (ADSCs — an exciting recent development in the hair loss world) are rich in various growth factors, including IGF-1.
  • Last year, an important and widely publicized study found that topical application of oleuropein (derived from the leaves of olive drupes) induces hair growth in mice. According to the study findings, oleuropein-treated mouse skin showed substantial upregulation of IGF-1.

FGF

I list fibroblast growth factor (FGF) next because I have also covered it many times on this blog before. There are 22 types of FGFs numbered FGF-1 through FGF-22. A significant number of these influence hair growth. I may write an entire detailed post on FGFs at some point in the future. I have covered some of the key ones on this blog before, in particular FGF-5, which discourages hair growth and has to be inhibited. Australian company Cellmid’s Evolis line of products claims to inhibit FGF-5.

Note that PRP does not inhibit growth factors. So it is more relevant for the purposes of this post to discuss some of the FGFs that promote hair growth. It seems like the main ones are FGF-1, FGF-2, FGF-7, FGF-9 and FGF-10. Evidence for three of those (FGF-1, FGF-2 and FGF-10) and their positive effects on hair is found in an important 2014 study from China. Fibroblast growth factors stimulate hair growth through β-Catenin and Shh expression.

Note that “hair cell regeneration” or variations of that term are mentioned a number of times in this study, even if in mice.  PRP is said to increase FGF-2 concentration levels. Interestingly, when I interviewed Dr. Malcolm Xing last year, he mentioned that FGF-2 is the preferred growth factor used at this clinic for his work purposes.

FGF-9 has become an especially important growth factor in large part due to the work of the renowned Dr. George Cotsarelis, who holds a patent titled “Fibroblast growth factor-9 promotes hair follicle regeneration after wounding“. Dr. Cotsarelis is also a co-author of a 2013 paper that concludes: “The importance of FGF-9 in hair follicle regeneration suggests that it could be used therapeutically in humans“.

Finally, FGF-7 (also called keratinocyte growth factor, or KGF) is required for hair growth. The well known researcher Dr. Elaine Fuchs co-authored an important study on FGF-7, hair development and wound healing all the way back in 1995. Moreover, Histogen’s Hair Stimulating Complex product is focusing on KGF as one of the key growth factors to be injected in human scalps.

PDGF

Platelet-derived growth factor (PDGF) is a key growth factor involved in blood vessel formation. A 2006 study from Japan found that “PDGF isoforms induce and maintain anagen phase of murine hair follicles“. Adipose-derived stem cells (ADSCs) are rich in various growth factors, including  PDGF, and are increasingly utilized in the hair loss world.

VEGF

Besides hair growth, vascular endothelial growth factor (VEGF) is also involved in blood vessel formation. A 2001 study concluded that “normal hair growth and size are dependent on VEGF-induced perifollicular angiogenesis”. Note that Shiseido’s adenosine based shampoo also promotes the expression of VEGF. The previously discussed adipose-derived stem cells are also rich in various growth factors including  VEGF.

Also, one of the ways in which Minoxidil works to grow hair is via the upregulation of VEGF. Moreover, Histogen’s Hair Stimulating Complex product is focusing on VEGF as one of the key growth factors to be injected in human scalps.

A number of studies have examined natural and synthetic products that increase VEGF and their impact on scalp hair. For example, in 2018, Japanese researchers found that water-soluble chicken egg yolk peptides stimulate hair growth through induction of VEGF production.

EGF

Epidermal growth factor (EGF) promotes cell growth, proliferation and differentiation. A 2003 study from Hong Kong concluded that EGF functions as a biological switch that is “turned on and off in hair follicles at the beginning and end of the anagen phase of the hair cycle“.

TGF-β

Transforming growth factor beta (TGF-β) is a cytokine protein growth factor. From the brief research I did, it seems like TGF-β actually adversely impacts hair growth!  e.g., see here, here and here. So I am not sure if this growth factor in PRP benefits hair.  Will update this if I find out more.

NGF

There seem to be mixed opinions on the impact of nerve growth factor (NGF) on the hair cycle in any significant manner. A 2006 study suggests both anagen-promoting and catagen-promoting effects of NGF on the hair cycle. Another study, also from 2006, seems to also find different effects of NGF on the hair cycle.