Tretinoin for Hair Growth

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Can a vitamin derivative like tretinoin help treat hair loss? The answer is yes, but not on its own. Instead, you should use it in combination with minoxidil.

In this article you will learn:

  • Why minoxidil on its own is not very particularly effective
  • How tretinoin interacts with minoxidil for superior hair growth
  • If you can use tretinoin on its own
  • The practical steps you can take to use tretinoin for your hair loss

The Problem With Minoxidil

The first drug to be approved for male-pattern hair loss was minoxidil (Rogaine). To this day, it remains the most popular. It is over the counter, low-cost, and without any serious side effects.

Yet despite being a commercial success, when it comes to actual results minoxidil does not fare so well. A recent review found that “despite significant clinical efficacy, cosmetically acceptable results are present in only a subset of patients (1).”

After 16 weeks of treatment with the stronger 5% formulation, about one out of two patients will have no visible regrowth. One out of three will have minimal, barely visible regrowth. Less than one out of every 10 patients will achieve regrowth that is easily visible to the naked eye (2).

Though far better than placebo, these are not particularly exciting results. They can also help explain why the majority of minoxidil users will quit treatment within a few months of starting (3).

Who Responds to Minoxidil Treatment?

Over the past decade, researchers have made substantial progress in explaining who will respond favorably to minoxidil. The key is that minoxidil does not directly promote hair growth.

After topical application, minoxidil converts to minoxidil sulfate. This, in turn, is responsible for Rogaine’s hair growth properties. The reason that companies sell minoxidil instead of minoxidil sulfate is that the latter is very expensive and chemically unstable. Manufacturers simply cannot put it in a cost-effective, commercially viable product.

The human body naturally produces the enzymes that break down minoxidil into minoxidil sulfate. They are called sulfotransferases. After Rogaine application, the sulfotransferase enzymes in the outer root sheath of the follicles metabolize the minoxidil to its active minoxidil sulfate.

There is substantial individual variation in the level of sulfotransferase activity. In other words, some people express these enzymes far more than others.

The more someone expresses these endogenous enzymes, the more they convert minoxidil to minoxidil sulfate. This gives better regrowth. On the other hand, men with low levels of sulfotransferases will fail to metabolize minoxidil. These men will not respond well to treatment.

A fascinating 2014 study looked at a group of patients who were treated with topical minoxidil 5% for a minimum of six months (4). At the end of treatment, the patients were classified as simply responders or non-responders. Responders had some regrowth, non-responders had none.

When researchers measured the individual levels of endogenous sulfotransferase activity, they found something startling. The non-responders almost universally had sulfotransferase levels below a certain threshold value. The opposite was true for the responders.

The strength of this relationship is very strong. So strong that it is possible to predict in advance who will respond to minoxidil, with over 95% accuracy!

All that is needed is to measure a person’s sulfotransferase activity prior to treatment. In a field like hair loss, such a degree of precision is remarkable.

Converting Non-Responders: Enter Tretinoin

It is very useful to know in advance who will respond to minoxidil treatment. Yet even better would be to take someone who would normally be a non-responder and make them into a responder. The most obvious way to do this would be to raise their endogenous sulfotransferase activity levels. Scientists are now discovering just how to do this.

Earlier in-vitro studies had found that tretinoin (also called all-trans-retinoic acid) induces sulfotransferase activity in cancer cells (5).

Recently, a 2019 study looked at the effects of daily topical tretinoin on the scalp of balding men and women. After only five days, the tretinoin induced a substantial increase in follicular sulfotransferase activity. This was particularly apparent in subjects with low sulfotransferase baseline levels (i.e. those who would normally be non-responders to treatment) (6). 43% of these subjects who were originally classed as non-responders (based on their low baseline sulfotransferase levels) were converted to putative responders.

This showed that tretinoin was very effective in increasing sulfotransferase activity.

But What is Tretinoin?

Tretinoin is a vitamin A derivative (or retinoid). Scientists developed it in the 1950s. It is used in the treatment of various skin conditions, primarily acne (7). Researchers do not yet know its precise mechanism of action.

tretinoin structure
Tretinoin chemical structure.

Doctors often prescribe it in conjunction with other topical medications. They believe it enhances their absorption. They also sometimes prescribe it orally for certain forms of cancer.

When a patient applies tretinoin topically as a cream it is relatively safe. The side effects are minor. They typically involve skin reactions like redness or itching. Tretinoin cream comes in three strengths: 0.1%, 0.05% and 0.025% by weight.

Does Tretinoin Really Enhance Minoxidil’s Efficacy?

We do not have as much clinical data on tretinoin as we would like. Nevertheless, the available data is consistent with the sulfotransferase findings. When used alongside minoxidil, tretinoin gives superior regrowth.

A 2007 study out of Korea recruited 31 balding men. Scientists assigned them to receive either topical minoxidil 5% twice daily or a combination of 5% minoxidil and 0.01% tretinoin once daily (8).

The rationale behind this study was that the twice-daily application of minoxidil is a major obstacle to treatment compliance. If tretinoin really does enhance the action of minoxidil it might permit once-daily application. This in turn would increase treatment compliance.

The Korean researchers treated the men for 18 weeks. After this, they compared the efficacy of the two treatments. Compared to baseline, the men in both groups showed statistically significant improvements. They had higher hair counts.

Remarkably, the differences in improvement between the two groups were not statistically significant. In other words, minoxidil twice daily gave essentially the same regrowth as a combination minoxidil/tretinoin topical once daily. If anything, the once-daily combination treatment gave slightly superior regrowth: 17.3% more hairs compared to 12.9% for the twice-daily minoxidil group. This difference was not large enough to be statistically significant.

Also in 2007, the same team of researchers published the results of in-vitro studies. These corroborated the clinical data (9). The researchers removed scalp hair follicles from healthy volunteers and cultured them in vitro in one of three mediums. Each medium contained either a) control solution, b) minoxidil, or c) minoxidil plus tretinoin. After 12 days, the minoxidil-treated cells grew faster than the control-treated cells. Yet the minoxidil plus tretinoin cells grew even faster.

To account for these results, the scientists proposed a molecular mechanism unrelated to sulfotransferases. According to their theory, tretinoin in combination with minoxidil modulates the expression of certain genes and proteins that play a role in cell death. This prolongs hair follicle cell survival.

There is yet another hypothesis regarding the synergistic interaction between minoxidil and tretinoin. It suggests that tretinoin simply enhances the absorption of minoxidil through the skin. In line with this, a study found that applying topical tretinoin on the scalp of balding men increased the absorption of minoxidil by nearly three-fold (10).

Will Tretinoin Work On Its Own?

What about tretinoin monotherapy, without minoxidil?

Already in the 1980s, dermatologists were speculating that tretinoin might affect the hair growth cycle and fight hair loss. They believed this might be due to its effects on cell proliferation and differentiation.

Hair growth phase is important to understand the reasons behind hair loss

A 1986 study recruited a total of 56 balding men to receive either topical tretinoin 0.025%, minoxidil 0.5%, or a combination of the two. There was also a control group that received just the vehicle solution (11). Men in all three groups applied the topical twice daily, for an average of eight to 10 months. Participants were classed as showing good, moderate, or no improvement.

44% of subjects in the combination group had good results, compared to 16% for the tretinoin-only group and 0% for the minoxidil and placebo groups. 22% of subjects in the combination treatment and 42% in the tretinoin group had moderate results. The percentage of non-responders was 100% for the placebo and minoxidil group, 33% for the combination group, and 42% for tretinoin.

There were unequal sample sizes between the various groups, and women were also recruited. This makes the results somewhat difficult to interpret.

Fortunately, the researchers described results for the five men in the tretinoin only group: “two experienced some hair growth after treatment, although the hairs were mostly of the lanugo type.” This means the new hairs resembled the unpigmented hairs of a newborn. They were not fully developed adult terminal hair. This suggests tretinoin on its own will give poor results.

Conclusion

Tretinoin plus minoxidil could be one of the most promising recent breakthroughs in hair loss research. Tretinoin promotes sulfotransferase activity and enhances the efficacy of minoxidil. This effect is especially strong among those who would otherwise not respond well to minoxidil monotherapy.

There is another potential benefit to combining minoxidil with tretinoin. This is the possibility of topical solutions that can be applied once instead of twice daily. The difference in practicality between applying a topical solution once (before going to bed) and twice a day is immense. A once-daily topical could appeal to many men who would otherwise never try minoxidil.

The drawback is that tretinoin is not marketed for hair loss. In its standard cream form, it is impractical for application to the head. This means that balding men who are interested in trying a minoxidil/tretinoin solution should consult with their dermatologist, who will prescribe it off-label. A compounding pharmacy will then prepare the prescription.