Biomarkers of Tretinoin Precursors and Tretinoin Efficacy in Patients With Moderate to Severe Facial Photodamage

Abstract

IMPORTANCE Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear.OBJECTIVES To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy. DESIGN, SETTING, AND PARTICIPANTSThis randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021.INTERVENTIONS Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks.MAIN OUTCOMES AND MEASURES Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas.RESULTS A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP − RA difference: −1; 95% CI, −2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP − RA difference: −0.53; 95% CI, −0.88 to −0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 − baseline mRNA difference: −5; 96% CI, −33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = −0.74; 95% CI, −0.89 to −0.43; P < .001). This trend was mirrored in MMP2 mRNA, with initial expression strongly predicting subsequent changes (r = −0.78; 95% CI, −0.89 to −0.43; P < .001). CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%. However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging.

Vitamin A: It's role in cosmeceuticals for antiaging

“…Accordingly, a comparative study was conducted where patients were randomized to receive tretinoin 0.02% cream or a combination of topical tretinoin precursors 1.1% (TTP) once daily for 24 weeks. 59 TTP 1.1% contained retinol, retinyl acetate, and retinyl palmitate. The patients applied the product once daily to moderate to severe facial photodamage.…”

“…Retinyl esters are often found in cosmeceuticals alongside retinol. Accordingly, a comparative study was conducted where patients were randomized to receive tretinoin 0.02% cream or a combination of topical tretinoin precursors 1.1% (TTP) once daily for 24 weeks 59 . TTP 1.1% contained retinol, retinyl acetate, and retinyl palmitate.…”

“…TTP treatment significantly reduced MMP2 mRNA that encodes for type IV collagenase, and this was strongly correlated with improvement in fine wrinkles. The authors suggest that MMP2 may be a mediator of retinoid efficacy in photoaging 59 …”

Use of Retinoids in Topical Antiaging Treatments: A Focused Review of Clinical Evidence for Conventional and Nanoformulations

“…No statistically significant differences in efficacy between the formulations was observed [ 87 ] Retinol Randomized, parallel, double-blind, whole-face, controlled clinical study 3 months 120 Retinol 0.2%/tetrahydrojasmonic acid 2% cream vs tretinoin 0.025% cream Clinical efficacy evaluations of wrinkles (frontal and glabellar area, eyes area, nasolabial fold), pores, mottled pigmentation and global photodamage Three-dimensional measurements of the periorbital skin relief (wrinkles, fine lines, and skin texture) was performed Both products improved considerably wrinkles, mottled pigmentation, pores, and global photodamage. No statistically significant differences between both products were observed [ 90 ] Retinol Double-blinded, single-center, parallel-arm, whole-face, comparison study 24 weeks 24 Formulation with retinol (1%), retinyl acetate (0.05%), and retinyl palmitate (0.05%) vs tretinoin 0.02% Wrinkles, pigmentation, yellowing, and overall clinical severity of the photodamage as scored on the Griffiths scale for assessment of the global photodamage No significant differences in efficacy between the retinoid formulation and tretinoin 0.02% in Griffiths photoaging scores [ 91 ] Retinaldehyde Randomized, double-blind, vehicle-controlled, whole-face clinical trial 44 weeks 125 Retinaldehyde 0.05% vs tretinoin 0.05% vs vehicle Optical profilometry of skin silicone replica, assessing for deepness and roughness of the wrinkles Significant reduction of the wrinkle and roughness features No statistically significant differences between the treatment groups at any assessment time point was observed [ 107 ] Retinaldehyde Randomized, double-blind, split-face comparison study 12 weeks 30 Retinaldehyde proretinal hydrogel containing 0.025% retinoid vs 0.025% tretinoin hydrogel Evaluation of skin aging (fine lines and wrinkles) and seven skin parameters, namely surface, volume, energy, entropy, homogeneity, contrast, and variance values Retinaldehyde nanoformula...…”

“…Recently, Chien et al [ 91 ] published a study in which a topical formulation containing a combination of three retinoids (1.1%: retinol (1%), retinyl acetate (0.05%), and retinyl palmitate (0.05%)) was compared in terms of antiaging efficacy and tolerability with a topical tretinoin formulation (0.02%), involving patients with moderate to severe facial photodamage. The study suggests that cosmeceuticals containing a combination of retinol and retinyl esters may have a comparable antiaging effect to tretinoin (Table 2 ).…”