By John Goss, Founder of Adegen
I hear this constantly. Someone tried minoxidil for six months. They were consistent. They did not miss applications. They waited the full cycle. And they got nothing. Or so close to nothing that the difference was not worth the daily routine.
Most of them drew the same conclusion: minoxidil does not work for me. My hair loss is too advanced. I am a lost cause.
That conclusion is wrong, and it is costing people real results.
The reason minoxidil fails roughly 40 to 50% of users has nothing to do with the severity of their hair loss, how long they have been losing it, or anything about them personally. It comes down to a single biochemical bottleneck at the follicle level that almost nobody in this industry bothers to explain. Understanding it changes everything about how you should evaluate whether minoxidil has actually failed you.
Minoxidil Is Not What You Think It Is
Most people think of minoxidil as the active ingredient in their hair loss treatment. It is not. Not in the form you apply it.
Minoxidil is a prodrug. That is a pharmacological term for a compound that is therapeutically inactive until your body converts it into something else. The minoxidil in your bottle does nothing on its own. It has to be transformed before it can affect a single hair follicle.
So if that conversion does not happen, you are not using a weaker version of the treatment. You are effectively not using the treatment at all.
The active compound is minoxidil sulfate. That is what actually does the work: opening potassium channels in the cells surrounding the follicle, triggering vasodilation, improving nutrient and oxygen delivery to the root, and extending the anagen phase, which is the active growth phase of the hair cycle. Minoxidil sulfate is what reverses follicular miniaturization. Minoxidil itself is just the delivery vehicle.
The conversion from minoxidil to minoxidil sulfate happens in the outer root sheath cells of your hair follicles. It is carried out by a specific enzyme called sulfotransferase, particularly the isoform known as SULT1A1.
If you have enough SULT1A1 activity at your scalp, that conversion happens efficiently, minoxidil sulfate is produced, and the treatment works. If you do not have enough, the conversion is incomplete. The minoxidil sits there unactivated. You apply it every day and your follicles never receive the compound that was supposed to help them.
That is the enzyme gap. And it explains why a drug that works well for one person does nothing for the person sitting next to them.
The Research Is Specific and Consistent
This is not a fringe theory. The data is clear.
Goren et al. (2015), published in Dermatologic Therapy
This study of patients presenting at a hair loss clinic found that 49.3% of subjects had low sulfotransferase activity in their scalp tissue. That number maps almost exactly onto the clinical non-response rate seen in minoxidil trials. This is not a coincidence. The enzyme gap and the non-response problem are the same problem.
Roberts et al. (2014), published in Dermatologic Therapy
Independent researchers demonstrated that sulfotransferase activity measured in plucked hair follicles could predict minoxidil response with 93 to 95% sensitivity and 73 to 83% specificity. That means a simple follicle assay, before you even start treatment, can tell you with reasonable accuracy whether standard minoxidil is going to work for you. The test exists. Most prescribers never mention it.
Pietrauszka and Bergler-Czop (2022), published in Postepy Dermatologii i Alergologii
This review confirmed what the clinical data consistently shows: enzyme activity in the hair follicle is a reliable prognostic marker for minoxidil response, and the variation in that activity between individuals is primarily genetic. This is not a deficiency you caused. It is not something you can fix by applying more product or being more consistent. It is biochemistry.
The implication of all three papers is the same. A significant portion of everyone who has ever been told that minoxidil did not work for them was not actually a non-responder to the treatment. They were a non-responder to an incomplete formulation, one that never addressed the conversion bottleneck that was blocking the active compound from being produced.
What Determines Your Enzyme Activity
Sulfotransferase expression varies significantly between individuals. The primary driver is genetic. Some people are born with lower SULT1A1 activity in their scalp tissue. Others have adequate systemic enzyme levels but reduced local expression at the follicular level specifically, which is where the conversion needs to happen.
There is currently no simple consumer test to check your sulfotransferase status before starting treatment. The clinical assays that exist operate in research and dermatology practice settings. This means most people discover they have low enzyme activity the hard way: after months of consistent use with nothing to show for it.
Enzyme activity exists on a spectrum. There are people with very high activity who respond strongly to standard minoxidil. There are people with essentially no local activity who will not respond regardless of how much they apply. And there is a large group in the middle who respond partially, inconsistently, or more slowly than expected. Addressing the enzyme bottleneck benefits all three groups, including people who were already responding.
The Tretinoin Solution
So the question becomes: can you increase that enzyme activity?
The answer is yes. And the compound that does it has been in the published literature for decades.
Tretinoin, the prescription-grade form of retinoic acid, has been shown to directly upregulate sulfotransferase enzyme expression at the follicular level. In plain terms: it increases your scalp’s capacity to convert minoxidil into the active compound that actually works. It addresses the bottleneck directly.
It does this through two mechanisms.
First, tretinoin increases epidermal turnover and reduces the thickness of the stratum corneum, the outermost layer of skin. This improves the penetration and delivery of minoxidil deeper into the follicle, where the conversion needs to occur.
Second, and more significantly for non-responders, tretinoin upregulates the expression of SULT1A1 itself. It does not just move the minoxidil closer to the enzyme. It produces more of the enzyme. That is a different category of intervention.
Sharma et al. (2019), published in Dermatologic Therapy
In this study of patients with androgenetic alopecia, 43% of subjects who were predicted to be minoxidil non-responders based on enzyme testing were converted to responders following just five days of topical tretinoin application. Five days. The enzyme deficit that had blocked their response to minoxidil was partially corrected in less than a week of tretinoin use.
Bazzano, Terezakis, and Galen (1986), published in Journal of the American Academy of Dermatology
This earlier study found that combining topical tretinoin with 0.5% minoxidil produced terminal hair regrowth in 66% of subjects after one year. Terminal hair is fully pigmented, full-diameter hair, not the fine vellus hair that represents incomplete response. Two thirds of subjects regrowing terminal hair is a meaningful clinical outcome.
Ferry et al. (1990), published in Clinical Pharmacology and Therapeutics
Independent pharmacokinetic research confirmed that tretinoin significantly improves the percutaneous absorption of minoxidil from topical solutions. More minoxidil reaching the follicle means more substrate available for the enzyme to convert.
Kwon et al. (2007), published in Journal of Korean Medical Science
In vitro research on human hair follicles demonstrated that minoxidil combined with tretinoin additively enhanced hair growth compared to either compound alone. The combination was protecting the follicle while also promoting active growth.
The pattern across four decades of independent research is consistent. Tretinoin and minoxidil work better together than either does alone. For people with adequate enzyme activity, the combination produces stronger results. For people with low enzyme activity, the combination may be the difference between a response and no response at all.
What This Means for You
If you used a standard over-the-counter minoxidil product and saw no results, you have not necessarily tested what minoxidil can do for your follicles. You have tested what minoxidil can do without addressing the enzyme bottleneck. Those are not the same experiment.
One tests whether minoxidil can work. The other tests whether it was ever given the chance to.
Standard OTC minoxidil contains no tretinoin. It makes no attempt to address the enzyme gap. For people with strong baseline enzyme activity, it works reasonably well. For the 40 to 50% with low activity, it is an incomplete solution being sold as a complete one.
This is not a secret. The research on sulfotransferase activity and minoxidil response has been in the published literature since the 1990s. The Goren enzymatic assay work has been replicated multiple times. The Sharma tretinoin study is sitting in PubMed. The information exists. It just has not been translated into standard formulation practice, largely because the companies selling generic minoxidil have no financial incentive to complicate a product that already dominates the market.
A Note on Micronized Minoxidil
There is a second formulation variable worth understanding alongside the enzyme question.
Standard minoxidil is formulated with alcohol-based solvents that cause significant scalp irritation in many users, contribute to dryness and flaking, and limit how consistently people actually apply the product. Inconsistent application is one of the most common reasons clinical results do not replicate in real-world use.
Micronized minoxidil reduces the particle size of the compound to less than 10 microns. At that scale, the particles penetrate the skin’s outer barrier more effectively and reach the follicle with less solvent-driven irritation. The delivery is cleaner. The formulation is more tolerable. And better tolerability directly translates to better real-world consistency.
Why Tretinoin Stability Matters
Tretinoin is one of the most effective ingredients you can add to a topical hair loss formula. It is also one of the most delicate.
Tretinoin can degrade when exposed to heat, light, and oxygen. Because of that sensitivity, how a formula is compounded directly impacts its stability.
The ingredient on the label tells you what was intended. The compounding process determines what actually reaches your scalp.
At Adegen, we compound without heat and handle tretinoin under controlled conditions, including protection from light exposure throughout formulation. This is the foundation of our CryoSafe process, which is specifically designed to preserve the stability and potency of delicate actives like tretinoin from the moment they are compounded to the moment they reach your scalp. With a compound this sensitive, those details directly impact the effectiveness of the formula.
With tretinoin, the question is not just whether it is in the formula. It is whether it is still active when it reaches your scalp.
How We Built Around This at Adegen
When I built our formulas, the decision to include tretinoin in every topical was not a feature decision. It was a prerequisite. A minoxidil formula without tretinoin accepts a 40 to 50% failure rate as a design outcome. That was not acceptable to me.
Every Adegen topical includes tretinoin. Not retinol. Tretinoin. The prescription-grade compound that the Sharma study demonstrated could convert predicted non-responders into actual responders in five days. We also use micronized minoxidil for the tolerability and absorption reasons above.
That is why our formulas require a prescription. Tretinoin is a prescription ingredient, and the concentration matters.
If you tried minoxidil before and got nothing, that is not a verdict on your hair. It is a verdict on the formulation.
If you tried minoxidil and did not see results, the next step is not to give up. It is to fix the formulation. Start with our 60-second HairIQ Assessment. Answer a few questions and it will identify what is missing from your current approach and build a protocol tailored to your specific situation.
Sources: Goren A et al. (2015), clinical utility of minoxidil response testing, Dermatologic Therapy; Roberts J et al. (2014), sulfotransferase activity in plucked follicles predicts response, Dermatologic Therapy; Pietrauszka K and Bergler-Czop B (2022), SULT1A1 as prognostic marker for minoxidil response, Postepy Dermatologii i Alergologii; Sharma A et al. (2019), tretinoin upregulates follicular sulfotransferase enzymes, Dermatologic Therapy; Bazzano GS, Terezakis N, Galen W (1986), topical tretinoin for hair growth promotion, Journal of the American Academy of Dermatology; Ferry JJ et al. (1990), tretinoin influence on percutaneous absorption of minoxidil, Clinical Pharmacology and Therapeutics; Kwon OS et al. (2007), minoxidil combined with tretinoin on human hair growth in vitro, Journal of Korean Medical Science; Buhl AE et al. (1994), minoxidil sulfotransferase activity and efficacy, Journal of Investigative Dermatology; Hebbring SJ et al. (2007), human SULT1A1 gene copy number and functional implications, Human Molecular Genetics.
