Minoxidil Response Bottlenecks?
For a long time, I kept wondering why some people just do not respond to minoxidil no matter how religiously they apply it. And I am not talking about people who skip doses or apply it to a wet scalp and expect miracles or even using low doses like below 2%.
I’m talking about people who apply it properly and still see nothing. That is when I started digging deeper into the bottlenecks of minoxidil’s response.
Bottleneck 1: Sulfation of Minoxidil and the Foundational Understanding of Minoxidil and Hair Growth
We should understand that minoxidil itself is not the active drug. What really grows hair is minoxidil sulfate which medical literature informs us on this being the case. For instance, Back in 1992, Johnson and colleagues published a study in the Journal of Investigative Dermatology titled “Minoxidil Sulfotransferase, a Marker of Human Keratinocyte Differentiation” that gave us a clearer look into the biology behind how minoxidil gets sulfated in human hair follicle cells. What they found was that the enzyme responsible for this conversion, minoxidil sulfotransferase, is not just randomly expressed. It actually ramps up during early keratinocyte differentiation. That alone already set it apart from other sulfotransferases like the ones used in cholesterol processing.
They did not stop there. To make sure they were really measuring minoxidil specific sulfation, they used a selective inhibitor called U77581. This compound specifically blocks minoxidil sulfotransferase activity. When they applied it and saw sulfation activity sharply drop off or disappear altogether, it confirmed that this was a distinct pathway. That detail is key because it showed that this enzyme was not just floating around doing general sulfate transfers. It had a clear and targeted role tied to minoxidil’s metabolism.
Sulfation of Minoxidil
So, in order for that transformation to happen, your outer root sheath (ORS) cells, which are keratinocytes, need to express a particular enzyme called sulfotransferase also known as SULT1A1. Without that enzyme, you can apply all the minoxidil you want and still see no real results. Your body just never activates it.
And this is where tretinoin caught my attention. A lot of people know tretinoin as a retinoid for acne or wrinkles. We also know from various literature that Tretinoin and other retinoids seem to enhance minoxidil’s effects in people, especially those low in SULT1A1, to the point where they become minoxidil responders or even better responders…presumably. We gain our understanding from some literature:
Literature
- A study from Bazzano et al. 1986 titled, “Topical tretinoin for hair growth promotion” shows researchers using a combo lotion of 0.5% minoxidil and 0.1% tretinoin. In this 56‑patient split‑scalp trial, it produced measurable terminal regrowth in ≈ 58 % of androgenetic‑alopecia subjects after a year, and when the same tretinoin was paired with just 0.5 % minoxidil (one‑tenth the usual strength) the response rate jumped to 66 %. The authors argued that retinoic acid’s well‑known effects on epithelial turnover, vascular proliferation, and keratinocyte differentiation could be awakening miniaturized follicles that minoxidil alone can’t reach. An issue with this study though is that it tested tretinoin in a setting that no longer mirrors real‑world practice (very low concentration of minoxidil. typically topical minoxidil is sold between 2% to 5% these days). Because 0.5 % minoxidil is sub‑therapeutic for many patients, any “66 % regrowth” they reported tells us more about how tretinoin behaves in a low‑drug environment than how it would interact with the 5 % solutions people actually buy.
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Then there’s the Sharma et al. 2019 paper titled, “Tretinoin Enhances Minoxidil Response in Androgenetic Alopecia Patients by Up‐Regulating Follicular Sulfotransferase Enzymes”.
Here, twenty men and women first had their follicles tested with the Minoxidil Response Test (MRT). After five consecutive days of 0.1 % tretinoin cream, 43 % of the subjects who had initially tested as ‘non‑responders’ were re‑classified as responders, thanks to a statistically significant lift in their follicular SULT1A1 activity. Sounds great, but they never actually measured minoxidil sulfate levels in the follicle. They didn’t track hair growth or check whether the boost stuck around after stopping tretinoin. So all we really know is the SULT1A1 enzyme ticked up a bit. We don’t know if that actually translates to better hair growth or if it even lasts more than a few days. -
Next is Shin et al. 2007 study titled, “Efficacy of 5% Minoxidil versus Combined 5%
Minoxidil and 0.01% Tretinoin for Male Pattern Hair Loss.”. They tried making life easier for patients by lowering tretinoin to 0.01% and only giving it once at night. The idea was to let people skip the morning minoxidil dose. After 24 weeks, that approach gave the same results as regular 5% minoxidil used twice a day. The methods are weird because it implies that there is an advantage here where tret/min combo gives the same effects as twice-a-day minoxidil 5% application. The truth is, there’s no real difference between once or twice a day minoxidil 5% topical application. -
In 2007, Shin and his team tried to simplify the typical minoxidil routine by mixing 5 percent minoxidil with 0.01 percent tretinoin and applying it just once at night. The goal was to see if this combo could replace the hassle of using plain 5% minoxidil twice a day. They ran a randomized double-blind trial for 18 weeks on men with Norwood III to V hair loss, ages 28 to 45.
By the end of the study, both groups saw improvement. The once-daily combo group had an increase in total hair count from 124.2 to 142.4 hairs per cm². The twice-daily group went from 124.0 to 139.9 hairs per cm². That’s a gain of 18.2 hairs for the combo and 15.9 for the plain minoxidil group. For non-vellus hairs, the combo group went from 42.7 to 48.8 hairs per cm², and the plain minoxidil group went from 33.4 to 47.4. So the combo group had a 23 percent increase and the twice-daily group saw a 55% increase.
Now here’s what really matters. Even though the numbers look a bit different, none of these differences were statistically significant. Every p-value was above 0.05. So you can’t say that either group did better than the other in any meaningful way. The study didn’t show that tretinoin helped at all. In fact, they didn’t even include a once-a-day minoxidil-only group, which means we don’t know if it was the tretinoin doing anything or if once-a-day minoxidil is just fine on its own.
https://linkinghub.elsevier.com/retrieve/pii/S0190962287700899
This lines up with what Olsen et al. 1987 titled, “Long-term follow-up of men with male pattern baldness treated with topical minoxidil” In that long-term study, the group that dropped to once-daily minoxidil lost an average of 56 non-vellus hairs in a one-inch target area between year one and year three. Meanwhile, the group that stayed on twice-a-day use gained another 12 hairs. So the total difference between groups was about 68 hairs in a one-inch circle. That difference had a p-value of exactly 0.05. In stats, that’s the bare minimum needed to call something significant, and in real life, 68 hairs isn’t a game changer.
There’s probably no real benefit to adding 0.01 percent tretinoin. What this study actually highlights is that once-a-day 5 percent minoxidil seems to get you most of the way there. It might not preserve quite as many hairs as twice-a-day use, but the gap is small and often not statistically or visibly important. If someone wants a low-maintenance routine, skipping the morning dose is a trade-off they can make without losing everything. And adding tretinoin at that low dose probably just gives people a false sense of doing more when it’s not moving the needle.
But to be honest, I won’t say that the takeaway is that “tretinoin doesn’t work”. I would tend to agree with what the Sharma et al. 2019 paper hints at: It’s that there seems to be a threshold to Tretinoin and its enhancing effects on Minoxidil response; if you go too low ( ≤ 0.01%) you probably wont activate enough sulfotransferase to make a real difference.
I’ll even expand this too where it isn’t just about going to tretinoin at 0.1%. If you switch to stronger retinoids, it may also increase minoxidil sulfation. Consider that Tazarotene agonizes RAR beta with an EC50 around 2 to 3 nanomolar, which is about ten times more potent than tretinoin. Or that Adapalene also targets RAR beta at around 2.2 nanomolar, but barely touches RXR, (which may matter because RXR is believed to play a key role in upregulating SULT1A1).
https://www.medchemexpress.com/Tazarotene.html
Okay, that all sounds well, but how DOES Tretinoin and perhaps other retinoids ACTUALLY increase sulfation of minoxidil? Is it directly doing so by increasing cellular gene expression of SULT1A1 or is it indirectly by some other mechanism?
In my opinion, the middle path holds the truth.
Tretinoin may be working is by increasing keratinocyte differentiation, which could, in turn, indirectly boost the activity of both SULT1A1 and other proteins that may be relevant in minoxidil response since these proteins are more active in mature keratinocytes. By promoting differentiation, you might also be getting a higher number of keratinocytes within ORS, each with the enzymatic capacity to carry out sulfation.
It might be the case, as I will posit here, that when keratinocytes differentiate, they not only express higher levels of metabolic enzymes like SULT1A1
*While there’s no direct study showing that tretinoin upregulates SULT1A1, it seems to do so for many other enzymes include some which relate to transport proteins.
Retinoid-Responsive Transcriptional Changes in Epidermal Keratinocytes - PMC
For example, a 2009 paper by Lee et al., titled “Retinoid-responsive transcriptional changes in epidermal keratinocytes” (Journal of Cellular Physiology), showed that all-trans-retinoic acid rapidly modifies the expression of over 3,000 genes including those linked to membrane transport and detoxification.
Bottleneck 2: Transporter Proteins ABCC3 and SLCO3A1
This part’s kind of niche, but it’s super important if you actually want to understand why minoxidil doesn’t always work for everyone. We learn the following form a 2024 study by Juan Jimenez-Cauhe and his team looked into this exact issue. The study was titled “Hair follicle sulfotransferase activity and effectiveness of oral minoxidil in androgenetic alopecia” and it zeroed in on how the drug gets into the dermal papilla where it actually works.
Even when minoxidil gets converted into minoxidil sulfate (the active form) the process isn’t done. The sulfate still has to move to where it can actually make a difference, and that’s the dermal papilla, the part of the follicle that controls hair growth. But to get there, it has to be transported in two separate steps.
First, after the conversion happens inside a keratinocyte in the ORS, the minoxidil sulfate has to be pumped out of the cell. This is done by a protein called ABCC3. It’s what’s known as an efflux transporter, which just means it pushes stuff out of the cell. Then, once that’s done, the minoxidil sulfate floats in the extra cellular matrix and has to get pulled into the dermal papilla cell. That’s where another transporter comes in: SLCO3A1. This one is an uptake transporter, meaning it helps bring the compound into the cell. Remember, the dermal papilla cells are important to the function of signaling hair growth from hair follicles.
Together, ABCC3 and SLCO3A1 create this loop. One moves the drug out of the keratinocyte, the other pulls it into the dermal papilla. Both of these steps are controlled by your genes. If either transporter isn’t working well (again because of a genetic variation) you hit a bottleneck. The active form of the drug gets stuck or lost before it ever reaches the target, and that can ruin your results.
What Might Tretinoin Actually Be Doing to Improve Minoxidil?
From what I can gather, tretinoin and maybe other retinoids don’t directly turn on the SULT1A1 gene. Instead, they seem to change the overall environment of the skin, especially in the outer root sheath and the top layers of the follicle. What they really do is increase cell turnover and push keratinocytes to differentiate faster. That likely leads to more mature keratinocytes overall, and those cells might have a higher capacity to convert minoxidil to its active form.
The 2024 study by Juan Jimenez-Cauhe and his team makes it clear that the bottleneck isn’t just about SULT1A1. Once minoxidil is sulfated, it still has to be moved out of the keratinocyte by the ABCC3 transporter and then into the dermal papilla cell by SLCO3A1. If either of those steps is weak, the active drug never makes it to the target area.
Even though we don’t have proof that tretinoin increases SULT1A1 or those transporters directly, a 2009 study by Lee et al. in the Journal of Cellular Physiology showed that all-trans-retinoic acid can change the expression of over 3,000 genes in keratinocytes. A lot of those genes are tied to detox enzymes and membrane transporters. So while it’s not spelled out, it’s reasonable to think that tretinoin could help boost the whole pathway just by reshaping the follicle environment and pushing more active, enzyme-rich cells into place.
I’ll try to represent my thoughts in leemas
Leema 1 (Differentiation-Driven Enzymatic and Transport Capacity):
Let K represent keratinocytes in the outer root sheath (ORS). When tretinoin increases the rate of differentiation of K, the population of mature keratinocytes K* ⊂ K increases. Mature keratinocytes express higher levels of metabolic and transporter proteins. If enzyme expression E and transporter expression T both increase with differentiation, then:
dE/dK* > 0
dT/dK* > 0
This means tretinoin may enhance both the sulfation capacity (via enzymes like SULT1A1) and the ability to export minoxidil sulfate (via efflux transporter ABCC3) by promoting keratinocyte maturation.
Leema 2 (Total Follicular Export Capacity):
Assume each mature keratinocyte K* contributes sulfation capacity s and transport capacity a through ABCC3 expression. If there are n mature keratinocytes, the total active minoxidil sulfate available in the extracellular matrix after export is:
S = n * s
A = n * a
Where S is the total sulfated minoxidil and A is the total exported via ABCC3. Tretinoin increases both n and possibly the per-cell efficiency a, meaning it could enhance the flux of active drug toward the dermal papilla.
Leema 3 (Retinoid-Responsive Transport Gene Activation):
According to Lee et al. (2009), retinoids like tretinoin upregulate over 3,000 genes in keratinocytes, many of which include detoxification enzymes and membrane transporters. Let G be the gene set responsive to tretinoin. G_1 and G_2 implies these are different gene subsets or different genes but still subset to an individual Then:
ABCC3 ∈ G_1 *possibly*
SLCO3A1 ∈ G_2 *possibly*
*ABCC3 ∈ G_1: saying that ABCC3 is part of a gene set G_1 that may be upregulated by tretinoin.
*SLCO3A1 ∈ G_2: saying that SLCO3A1 is part of a gene set G_2 that may be upregulated by tretinoin.
If tretinoin upregulates ABCC3 and potentially SLCO3A1 through downstream signaling or paracrine factors, then the whole sulfation-transport process may be improved.
Leema 4 (Two-Step Transport Bottleneck):
Once sulfation occurs in keratinocytes, active minoxidil sulfate Ms must exit the keratinocyte via ABCC3 and enter the dermal papilla cell via SLCO3A1. Let:
Ms_out = ABCC3(Ms)
Ms_in = SLCO3A1(Ms_out)
- Step 1: ABCC3 must function properly to export the active drug.
- Step 2: SLCO3A1 must function properly to import it into the dermal papilla cell.
Then the total delivery D of drug to the dermal papilla is:
D = SLCO3A1(ABCC3(Ms)) = f(Ms)
If either transporter is impaired, D drops, and follicular response is reduced. Genetic variation or poor expression of ABCC3 or SLCO3A1 becomes a functional bottleneck. Tretinoin might help by pushing both enzymes and transporters into higher expression through differentiation.