Does Retinoic Acid (Tretinoin) Improve Hair Growth From Minoxidil?

Article Summary

Retinoic acid, a biologically active form of vitamin A, has long been known for its role in skin health, but could it also help with hair loss? In this article, we explore the science behind retinoic acid and its derivative tretinoin, their effects on hair follicle stem cells, and whether clinical studies support their use, especially when combined with minoxidil, for treating androgenetic alopecia and other hair disorders.

Full Article

Retinoic acid (RA) is the biologically active form of Vitamin A, playing an important role in regulating cell growth, differentiation, and tissue maintenance in the body.^[1]Peehl, D.M., Wong, S.T., Stamey, T.A. (1993). Vitamin A regulates proliferation and differentiation of human prostatic epithelial cells. Prostate. 23(1). 69-78. Available at: … Continue reading Its signaling pathway is essential not only for embryonic development but also for the maintenance of healthy skin and hair.^[2]VanBuren, C.A., Everts, H.B. (2022). Vitamin A in Skin and Hair: An Update. Nutrients. 14(14). 2952. Available at: https://doi.org/10.3390/nu14142952 

Interest in using retinoids (RA and its derivatives, such as tretinoin and retinol) as hair loss treatments stems from their potential to regulate the hair growth cycle and potentially prolong the anagen (growth) phase of hair follicles. In this article, we will explore what RA is and its derivatives, as well as how they can impact the hair follicle. We will also evaluate the available efficacy and safety data.

Key Takeaways

• Drug. Retinoic acid (RA), especially in the form of tretinoin, is a vitamin A derivative that regulates hair follicle stem cell activation through Wnt/β-catenin signaling. It is available in various topical formulations and is often used in combination with minoxidil to enhance hair regrowth in androgenetic alopecia (AGA).

• Clinical Data.  RA/tretinoin shows moderate standalone efficacy in promoting hair regrowth, particularly in early-stage AGA, but results improve significantly when used with minoxidil. Clinical trials from 1986 to 2024 have demonstrated enhanced hair density, thickness, and stem cell activity with combination therapy. RA also improves sulfotransferase enzyme activity, boosting minoxidil’s effectiveness, and has shown positive results in alopecia areata when combined with pimecrolimus.

• Safety. Generally well-tolerated at concentrations ≤0.025%, but may cause local irritation (redness, itching, dryness). Adverse effects are dose-dependent and typically self-limiting. Systemic side effects are rare with topical use but retinoids should be avoided during pregnancy and in individuals with photosensitivity or scalp inflammation.

• Evidence Quality.  Retinoic Acid scored 34/100 for evidence quality by our metrics.

• Best Practices. 
  • Use in combination with 5% minoxidil for optimal results, especially in early AGA.
  • Apply tretinoin in low concentrations (≤0.025%) once daily to minimize irritation.
  • Consider tretinoin if you’re a minoxidil non-responder or wish to reduce application frequency.
  • Avoid if pregnant, photosensitive, or prone to dermatitis.
  • Always consult a dermatologist before starting treatment.

What is Retinoic Acid?

RA is a biologically active metabolite of vitamin A (all-trans-retinol) and serves as a potent regulator of cell differentiation and proliferation. It plays essential roles in embryonic development, immune function, male fertility, and the regulation of bone growth and development.^[3]de Mendoca Oliveira, L., Teixera, F.M.E., Sato, M.N. (2018). Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases. Mediators of Inflammation. 9(3067126). Available at: … Continue reading 

RA is produced in the body through a two-step oxidation process: retinol (vitamin A) is first reversibly oxidized to retinaldehyde, and then retinaldehyde is irreversibly oxidized to retinoic acid.^[5]Kedishvili, N.Y. (2017). Retinoic Acid Synthesis and Degradation. Subcellular Biochemistry. 81. 127-161. Available at: https://doi.org/10.1007/978-94-024-0945-1_5 This process is catalyzed by retinol dehydrogenases and retinaldehyde dehydrogenases (RALDH1, RALDH2, RALDH3). RA cannot be converted back to retinol, making its synthesis a tightly regulated process.

Structurally, RA is a polyunsaturated carboxylic acid with a long conjugated hydrocarbon chain and a terminal carboxyl group.^[6]Sani, B.P., Hill, D.L. (1990). [3] Structural characteristics of synthetic retinoids, Methods in Enzymology, Academic Press, 189. 43-50. Available at: https://doi.org/10.1016/0076-6879(90)89274-L The most prevalent naturally occurring form is all-trans-retinoic acid (ATRA), but other isomers such as 13-cis-retinoic acid (isotretinoin) and 9-cis-retinoic acid (alitretinoin) also exist in lower concentrations.^[7]Bayeva, N., Coll, E., Piskareva, O. (2021). Differentiating Neuroblastoma: A Systematic Review of the Retinoic Acid, Its Derivatives, and Synergistic Interactions. Journal of Personalized Medicine. … Continue reading 

RA is part of a broader class of compounds called retinoids, which includes both natural and synthetic derivatives of vitamin A.^[8]Bushue, N., Wan, Y-J, Y. (2010). Retinoid pathway and cancer therapeutics. Advanced Drug Delivery Reviews. 62(13). 1285-1298. Available at: https://doi.org/10.1016/’j.addr.2010.07.003 

Retinoids are categorized into generations based on their structure:^[9]Baldwin, H., Webster, G., Gold, L.S., Callender, V., Cook-Bolden, F.E., Guenin, E. (2021). 50 Years of Topical Retinoids for Acne: Evolution of Treatment. American Journal of Clinical Dermatology. … Continue reading 

• First Generation: Naturally occurring compounds and their isomers, including retinol, retinal, tretinoin (ATRA), isotretinoin, and alitretinoin.

• Second Generation: Synthetic analogs such as etretinate and acitretin, primarily used for severe psoriasis.

• Third Generation: Polyaromatic retinoids, such as adapalene, bexarotene, and tazarotene, are designed to achieve greater receptor sensitivity and reduced side effects.

• Fourth Generation: Newer compounds with enhanced selectivity, such as trifarotene.

Other commonly used derivatives include retinyl esters (e.g., retinyl palmitate), retinol, retinaldehyde, and synthetic esters like hydroxypinacolone retinate.

How Does Retinoic Acid Work?

RA acts primarily by binding to nuclear receptors in cells, specifically retinoic acid receptors (RARs) and retinoid X receptors (RXRs).^[10]Jin, Q., Huo, C., Yang, W., Jin, K., Cai, S., Zheng, Y., Huang, B., Wei, L., Zhang, M., Han, Y., Zhang, X., Liu, Y., Wang, X. (2022). Regulation of Tyrosinase Gene Expression by Retinoic Acid Pathway … Continue reading Once activated, these receptors function as transcription factors, directly regulating the expression of genes involved in cell proliferation, differentiation, and programmed cell death, also known as apoptosis. This ability to modulate gene expression is what gives RA its wide range of biological effects, from skin remodeling to influence over hair follicle dynamics.

H2: What is the Impact of Retinoic Acid on Hair Follicle Biology?

Retinoic acid (RA) plays a powerful but finely tuned role in hair follicle biology. It affects how hair grows by turning certain genes on or off, acting through specialized receptors found in hair follicle cells, oil glands, and nearby skin tissue.

Too little or too much RA can disrupt the hair cycle. That’s why the body tightly regulates how much RA is made and broken down inside the follicle.

How Is Retinoic Acid Synthesized in the Hair Follicle?

RA is produced in two steps:

1. The enzyme SDR16C5 converts vitamin A (retinol) into an intermediate form called retinaldehyde.^[11]Wu, L., Belyaeva, O.V., Adams, M.K., Klyuyeva, A.V., Lee, S-A., Goggans, K.R., Kesterson, R.A., Popov, K.M., Kedishbili, N.Y. (2019). Mice lacking the epidermal retinol dehydrogenases SDR16C5 and … Continue reading This mostly occurs in the hair follicle bulge, a crucial area where stem cells reside, and in the dermal papilla, which plays a key role in controlling hair growth. SDR16C5 activity peaks during the growth phase (anagen) and helps stimulate both stem cell activity and hair matrix cell development.

In mice, the absence of SDR16C5 and its related enzyme, SDR16C6, results in an 80% decrease in RA levels.^[12]Foitzik, K., Spexard, T., Nakamura, M., Halsner, U., Paus, R. (2005). Towards Dissecting the Pathogenesis of Retinoid-Induced Hair Loss: All-Trans Retinoic Acid Induces Premature Hair Follicle … Continue reading 

This causes hair follicles to exit their resting phase (telogen) prematurely, leading to abnormal cycling and lower levels of key stem cell markers, such as Lgr5 and Sox9.^[13]Goggans, K.R., Belyaeva, O.V., Klyuyeva, A.V., Studdard, J., Slay, A., Newman, R.B., Christine, VanBuren, A., Everts, H.B., Kedishvili, N.Y. (2024). Epidermal retinol dehydrogenases cyclically … Continue reading  

 

1. Another enzyme, ALDH1A2, completes the process by converting retinaldehyde into the active form of retinoic acid. ALDH1A2 is most active in the outer root sheath of the follicle and especially in the bulge during the early growth and regression phases.^[14]Everts, H.B., King Jr, L.E., Sundberg, J.P., Ong, D.E. (2004). Hair cycle-specific immunolocalization of retinoic acid synthesizing enzymes ALDH1A2 and ALDH1A3 indicates complex regulation. Journal … Continue reading One of its key roles is to lower levels of BMP4, a protein that keeps stem cells in a resting state. By reducing BMP4, ALDH1A2 helps “awaken” stem cells and initiate new hair growth.^[15]Suo, L., VanBuren, C., Hovland, E.D., Kedishvili, N.Y., Sundberg, J.P., Everts, H.B. (2021). Dietary Vitamin A Impacts Refractory Telogen. Frontiers in Cell and Developmental Biology. 9. Available … Continue reading When this enzyme is missing, hair follicles take longer to enter the growth phase, and their circadian rhythm becomes disrupted.

How is Retinoic Acid Broken Down?

While synthesizing RA is important, too much can be harmful. That’s where CYP26B1 comes in. CYP26B1 is an enzyme that breaks down RA into inactive forms. During the growth phase, it is found in the dermal papilla and pre-cortex; during rest, it shifts to the bulge to prevent RA levels from building up excessively.^[16]Okano, J., Levy, C., Lichti, U., Sun, H-W., Yuspa, S.H., Sakai, Y., Morasso, M.I. (2012). Cutaneous retinoic acid levels determine hair follicle development and downgrowth. Journal of Biological … Continue reading 

This careful back-and-forth between making and breaking down RA shows how tightly the hair follicle controls its environment. Low, well-regulated levels of RA can support stem cell activity and help promote healthy hair growth. However, high or unbalanced levels can actually prompt follicles to regress or block growth altogether.

To put it plainly: Your hair follicles need just the right amount of retinoic acid. When the balance is right, it may help stimulate hair growth, but when it’s off, it can slow or even reverse it.

Importantly, these regulatory mechanisms are not just theoretical; they appear to be directly involved in common hair disorders, such as androgenic alopecia (AGA).

In vivo/In vivo Evidence

Recent research has demonstrated that retinoic acid signaling is suppressed in miniaturized hair follicles from AGA patients which coincides with impaired hair follicle stem cell (HFSC) activation.^[17]Wen, L., Fan, Z., Huang, W., Miao, Y., Zhang, J., Liu, B., Zhu, D., Dai, D., Zhang, J., Le, D., Zhang, Y., Qu, Q., Hu, Z., Chen, R. (2024). Retinoic acid drives hair follicle stem cell activation via … Continue reading  

Using transcriptomic, in vivo (mouse), ex vivo (human hair follicle organ culture), in vitro (HFSC culture), and clinical approaches, the authors showed that retinoic acid supplementation restored HFSC function by activating Wnt7a/7b and downstream ꞵ-catenin signaling. This promotes HFSC proliferation, differentiation into progenitor cells, and entry into the anagen phase, resulting in improved hair follicle growth (Figure 2), accelerated hair regrowth in mice (Figure 3), and improved hair density and diameter in AGA patients, particularly in early treatment (more on that below). 

Mechanistically, blocking either retinoic acid receptors or Wnt signaling reduced these effects, confirming that retinoic acid acts via Wnt/ꞵ-catenin to drive HFSC activation and hair regeneration. 

H2: Is Retinoic Acid Clinically Effective at Treating Hair Loss?

Retinoic acid and its derivative, tretinoin, have been investigated in clinical trials for treating both androgenetic alopecia (AGA) and alopecia areata (AA). Studies have shown potential synergistic effects with minoxidil, including improved enzyme activity and increased hair regrowth rates, although efficacy typically varies by condition and formulation. 

Study One -1986 (AGA)

This study was an open-label trial of 56 participants with AGA treated with tretinoin alone or in combination with 0.5% minoxidil for 1 year.^[20]Bazzano, G.S., Terezakis, N., Galen, W. (1986). Topical tretinoin for hair growth promotion. Journal of the American Academy of Dermatology. 15.880-883. Available at: … Continue reading Twelve participants received 0.025% topical tretinoin, 36 participants received a combination of 0.025% tretinoin and 0.5% minoxidil, 3 participants received 0.5% minoxidil alone, and 5 participants received a topical placebo.

Hair growth was evaluated through photographs and hair counts in a defined 1-inch diameter target area on the scalp. The duration of participation averaged 8-10 months, with some subjects following the protocol up to 18 months. Participants were categorized as:

• Good responders (Group A): ≥46% increase in terminal hairs.
• Moderate responders (Group B): 21–45% increase.
• Non-responders (Group C): <20% increase.

Placebo and Minoxidil Alone:

Placebo goup: No participants showed hair growth

Minoxidil alone: No participants showed terminal hair regrowth; one participant showed vellus hair growth.

Tretinoin Alone:

12 participants: 58% (7 participants) responded positively, 16% (2 participants) shows a “good response”, 42% (5 participants) had a “moderate” response, and 42% had no response.

However, one woman appeared to be highly responsive to treatment with a 1100% increase in hair counts after 18 months of tretinoin-only treatment.

Combination of Tretinoin and Minoxidil:

36 participants: 66% (24 participants) responded positively, 44% (16 participants) had a “good” response, 22% (8 participants) had a “moderate” response, and 33% (12 participants) had no response.

Responses were observed within 4 to 18 months, with photographic documentation showing visible regrowth in both men and women.

Ultimately, this study showed that tretinoin alone moderately improved hair regrowth, but combining the treatment with minoxidil was more effective, with two-thirds of participants showing terminal hair regrowth.

Study Two – 2007 (AGA)

31 male participants aged 28-45 were recruited for this 18-week study, which compared the efficacy and safety of a combined solution of 5% minoxidil and 0.01% tretinoin applied once daily versus conventional 5% minoxidil applied twice daily for male AGA.^[21]Shin, H.S., Won, C.H., Lee, S.H., Kwon, O.S., Kim, K.H., Eun, H.C. (2007). Efficacy of 5% minoxidil versus combined 5% minoxidil and 0.01% tretinoin for male pattern hair loss. American Journal of … Continue reading 

Five parameters were evaluated: total hair count, non-vellus hair count, anagen hair ratio, linear hair growth rate, and mean hair diameter. Subjective global assessments were also conducted by patients and investigators at 9 and 18 weeks. 

Both groups showed significant increases in total hair count and non-vellus hair count after 18 weeks. Mean hair diameter increased significantly in the minoxidil-only group. However, there were no significant changes in anagen hair ratio or linear hair growth rate in either group. Furthermore, there were no statistically significant differences between groups in any hair growth parameter after 18 weeks.

No significant differences were observed between the two groups in patient-reported improvement or satisfaction scores at any time point. Furthermore, the investigator’s global assessment also showed no significant differences between groups.

Safety outcomes showed that mild adverse effects (itching, irritation) were observed in 5/15 patients in the combined group and 4/14 in the minoxidil-only group, but these were all self-limiting.

The conclusion? The once-daily application of combined 5% minoxidil and 0.01% tretinoin was as effective and safe as twice-daily 5% minoxidil for treating AGA in men. This means it could potentially be a more convenient alternative to twice-daily minoxidil.

Study Three – 2019 (AGA)

Another study found that combining tretinoin with minoxidil could increase follicular sulfotransferase activity and therefore responsiveness to minoxidil.^[23]Sharma, A., Goren, A., Dhurat, R., Agrawal, S., Sinclair, R., Trueb, R.M., Vano-Galvan S., Chen, G., Tan, Y., Kovacevic, M., Situm, M., McCoy, J. (2019). Tretinoin enhances minoxidil response in … Continue reading  

Sulfotransferase (SULT1A1) is the enzyme responsible for converting minoxidil, a prodrug, into its active metabolite minoxidil sulfate within hair follicles.^[24]Dhurat, R., Daruwalla, S., Paj, S., Kovacevic, M., McCoy, J., Shapiro, J., Sinclair, R., Vano-Galvan, S., Goren, A. (2022). SULT1A1 (Minoxidil Sulfotransferase) enzyme booster significantly improves … Continue reading This sulfation reaction is critical because minoxidil sulfate directly stimulates hair growth.

Twenty participants (10 male and 10 female) with AGA were recruited for this study, which determined the effect of topical tretinoin on follicular sulfotransferase. Non-responders to minoxidil often exhibit follicular SULT1A1 activity <0.4 OD 405 nm. In this trial, pretreatment SULT1A1 levels in participants who were minoxidil non-responders averaged 0.28 OD 405 nm. 

Treatment with topical tretinoin (0.1%) increased SULT1A1 activity by 1.8-fold in 75% of subjects after 5 days, raising levels to around 0.51 OD 405 nm. This shift moved 43% of non-responders above the 0.4 OD cutoff, enabling sufficient minoxidil activation.

Study Four – 2024 (AGA)

The most recent trial was conducted in 2024, with 60 total participants with AGA.^[25]Wen, L., Fan, Z., Huang, W., Miao, Y., Zhang, J., Liu, B., Zhu, D., Dai, D., Zhang, J., Le, D., Zhang, Y., Qu, Q., Hu, Z., Chen, R. (2024). Retinoic acid drives hair follicle stem cell activation via … Continue reading 30 participants received a 0.025% topical tretinoin cream, while 30 received 5% minoxidil solution alone. Each treatment was applied twice daily to the bald scalp. 

Hair growth was measured using photography and dermoscopy assessments at 1, 3, and 6-month follow-ups.

The participants treated with the topical tretinoin cream showed a significant improvement in mean hair count, density, and diameter after the first month compared to the Baseline. A significant increase was also observed in hair count, density, and terminal hair ratio in the tretinoin group compared to the minoxidil-treated group.

Study 5 – 2014 (AA)

A randomized controlled trial was conducted with 80 participants with alopecia areata aged 18-25 years, with one to four lesions on the scalp, and lesion diameter of 1.5 to 6 cm.^[27]Jalai, M.H.A., Mobasher, P., Rabbani, R., Jazi, G.A. (2014). Comparing the Efficiency of Elidel Cream and Elidel Accompanied with Tretinoin Cream in Treatment of Alopecia Areata. Journal of Skin Stem … Continue reading 

Participants were treated with either 1% Elidel (pimecrolimus cream) (40 participants) or Elidel + 0.05% tretinoin (40 participants) twice daily for three days. Treatment response was categorized as complete cure, relative cure, no change, or aggravation of lesions. 

Elidel Group:

• Complete cure: 8 patients (20%)
• Relative cure: 14 (35%)
• No change: 10 (25%)
• Aggravation: 8 (20%)

Eliden and Tretinoin Group:

• Complete cure: 18 patients (45%)
• Relative cure: 12 (30%)
• No change: 8 (20%)
• Aggravation: 2 (5%)

The combination therapy group had significantly higher rates of complete cure and lower rates of disease aggravation. However, adverse effects (mainly redness and burning) were more common in the combination group (45%), leading to dose reduction or discontinuation in some cases, but no serious complications were reported.

Unfortunately, the study included no images to show what the initial hair loss severity was and whether the improvements were actually noticeable/

Overall, the clinical evidence suggests that retinoic acid/tretinoin may be most effective as part of a combination therapy, and that patient selection, dosing, and timing play crucial roles in treatment success.

Another point that we can learn from these studies is that tretinoin appears to enhance the effectiveness of minoxidil (and potentially Eliden). This could be due to several mechanisms:

• Enhanced Penetration: Tretinoin may increase skin permeability, allowing better minoxidil absorption.
• Boosts Sulfotransferase Enzymes: Tretinoin upregulates SULT1A1, the enzyme responsible for converting minoxidil into its active form (minoxidil sulfate).
• Stimulates Stem Cell Activity: Both agents independently promote anagen phase entry and follicle regeneration via different pathways (minoxidil via potassium channels, RA via Wnt signaling).

Together, they work on complementary pathways, which helps explain why multiple trials (1986, 2007, 2019, 2024) found better hair growth outcomes with combined use.

How Safe is Retinoic Acid/Tretinoin?

While generally safe, retinoic acid and tretinoin can cause local irritation, especially when used topically on the scalp:

• Common Side Effects: Redness, itching, dryness, and burning sensations.^[28]Yoham AL, Casadesus D. Tretinoin. [Updated 2023 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: … Continue reading
• Dose-Dependent: Higher concentrations (e.g., 0.1%) are more likely to cause irritation.^[29]Griffiths, C.E., Kang, S., Ellis, C.N., Kim, K.J., Finkel, L.J., Ortiz-Ferrer, L.C., White, G.M., Hamilton, T.A., Voorhees, J.J. (1995). Two concentrations of topical tretinoin (retinoic acid) cause … Continue reading
• Mitigation: Reducing application frequency or using lower strengths can improve tolerability. Some studies reported treatment discontinuation due to discomfort.
• Systemic Risks: Rare with topical use, but oral retinoids like isotretinoin carry higher risks and should not be used for hair loss without medical supervision.

In clinical trials, adverse events were mild and reversible, making tretinoin a relatively low-risk addition to hair loss regimens, especially in concentrations ≤0.025%.

Is Retinoic Acid/Tretinoin for Me?

Retinoic acid or tretinoin may be right for you if:

• You’ve had limited success with minoxidil alone, especially if you’re a non-responder.
• You’re seeking enhanced regrowth or wish to reduce the frequency of minoxidil application (e.g., once-daily combo vs. twice-daily minoxidil).
• You’re in the early stages of hair loss, where interventions tend to be more effective.

Caution is warranted if:

• You are hypersensitive to the drug, drug class, or drug formulation. 
• If you are prone to sunburn.
• You have photosensitivity issues.
• You have eczema, seborrheic dermatitis, or other scalp inflammation problems.
• You are pregnant and in the first trimester (retinoids are dangerous for the fetus if they become systemic).

Always consult a dermatologist before starting any retinoid-based hair regimen.

Final Thoughts

Retinoic acid and tretinoin offer a scientifically grounded, mechanistically rich approach to hair loss treatment, particularly for androgenetic alopecia. Although not a magic bullet, they can:

• Enhance minoxidil efficacy
• Support hair follicle stem cell activation
• Offer a new avenue for patients who have plateaued on existing treatments.

That said, results are highly individual, and the treatment must be carefully tailored, balancing dose, frequency, and formulation to optimize results while minimizing irritation. Therefore, we don’t recommend using it by itself.

For now, tretinoin appears best used in combination, especially for those seeking to maximize outcomes from minoxidil therapy.