Tretinoin Precursors vs Tretinoin for the Treatment of Photodamage

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mixed race Hispanic latino woman sun hat beach
The efficacy of topical tretinoin precursors (TTP) and topical tretinoin for the treatment of moderate to severe photodamage of the face is investigated.

The relative efficacies of topical tretinoin precursors (TTP) and topical tretinoin for the treatment of moderate to severe photodamage of the face was outlined in study data published in JAMA Dermatology. In a randomized clinical trial, TTP did not appear to offer any treatment advantage over tretinoin itself. However, changes in the expression of certain matrix metalloproteinases (MMPs) were observed in the TTP treatment group, highlighting the potential role of MMPs as mediators of retinoid efficacy.

Topical formations of tretinoin precursors are widely available for over-the-counter use. However, the efficacy of these precursors is unclear, as are the precise molecular mechanisms associated with clinical improvement.

To inform this gap, investigators conducted a randomized, double-blind, placebo-controlled trial at the Johns Hopkins Outpatient Center in Baltimore, Maryland. Conducted from 2010 to 2011, the trial enrolled adult patients with moderate to severe facial photodamage per the 9-point Griffiths scale for photoaged skin. Patients were assigned to daily topical application of either 0.02% tretinoin or a 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate. During 24 weeks of treatment, improvement in skin photoaging scores and treatment tolerability were assessed. Target gene expression was captured by real-time polymerase chain reaction (PCR) of biopsied tissue taken from the treated areas.

A total of 20 patients were randomly assigned: 11 to TTP and 9 to tretinoin. Mean age was 62 ± 9.5 years; 100% were women and 100% were White with all patients having a Fitzpatrick skin type of I, II, or III. At week 24, there was no significant difference in median Griffiths photoaging scores between the TTP and tretinoin treatment arms (4 vs 5; P =.27). However, patients treated with TTP were significantly less likely to experience erythema compared with patients in the tretinoin arm (11% vs 64%; P =.01). At the end of the treatment period, 89% of the TTP group participants and 73% of the tretinoin group participants indicated they were interested in continuing to use the product.

In biomarker analyses, no association was observed between TTP treatment exposure and the expression levels of procollagen I, MMP1, MMP3, or MMP9. However, the mRNA expression of MMP2, a type IV collagenase, was significantly suppressed in samples from the TTP group. Suppression of MMP2 was correlated with clinical improvements in fine wrinkles. Specifically, patients with greater improvement in wrinkles had greater suppression of MMP2 at week 24 (P =.01). In the TTP group, greater baseline wrinkle severity was associated with greater response to retinoid therapy (P =.002).

Results from this study suggest that retinol precursors have clinical benefits for photodamaged skin, although the benefits are not greater than standard tretinoin treatment. Expression of MMP2 may be an appropriate biomarker for treatment response, the investigators believe, although the association requires further study.

The investigators wrote that “…there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%.” They continued, “However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging.”

Disclosure: This research was supported by SkinMedica®. Please see the original reference for a full list of disclosures.


Chien AL, Kim DJ, Cheng N, et al. Biomarkers of tretinoin precursors and tretinoin efficacy in patients with moderate to severe facial photodamage: a randomized clinical trial. JAMA Dermatol. Published online June 8, 2022. doi:10.1001/jamadermatol.2022.1891