Retinoids are a class of “anti-aging” compounds derived from vitamin A. Vitamin A is the first vitamin approved by the Food and Drug Administration as an anti-wrinkle agent that changes appearance of the skin surface and has anti-aging effects. Topical retinoids are frequently used to address signs of photodamage, including fine lines and hyperpigmentation.

Riahi RR, Bush AE, Cohen PR. Topical retinoids: therapeutic mechanisms in the treatment of photodamaged skin. Am J Clin Dermatol. 2016;17:265–276.

 

Prescription-grade tretinoin, approved for use in the US by the Food and Drug Administration for the treatment of acne vulgaris, is a common retinoid product used for photoaging, given its effects of inducing procollagen I synthesis and suppressing the expression of enzymes responsible for degradation of collagen.

In other words, topical retinoids increase the amount of collagen, which is one of the key ingredients for skin cell growth. Collagen keeps your skin healthy and youthful-looking by encouraging the superficial, or top layer of skin to regenerate. It also restores dead skin cells and helps repair any damage caused by photodamage. Collagen production naturally decreases as you age, causing your skin to change.

Sitohang IBS, Makes WI, Sandora N, et al. Topical tretinoin for treating photoaging: A systematic review of randomized controlled trials. Int J Womens Dermatol. 2022;8:e003.

 

 

Reduced skin irritation

Despite the demonstrated efficacy of tretinoin, the product is associated with local skin irritation, including erythema (redness), dryness, scaling, and pruritus (itch), among other concerns. As such, some individuals who utilize tretinoin, either for acne or cosmetic aims, find this treatment challenging for the long term, and often have to reduce use, go on “tretinoin breaks” or use a lower strength to avoid unwanted side effects.

Latter G, Grice JE, Mohammed Y, et al. Targeted topical delivery of retinoids in the management of acne vulgaris: current formulations and novel delivery systems. Pharmaceutics. 2019;11:490.

Yin S, Luo J, Qian A, et al. Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity. J Clin Invest. 2013;123:3941–3951.

 

Over-the-counter (OTC) topical retinoids, including tretinoin precursors like retinol, are thought to be associated with less irritation than prescription-grade retinoids.

Motamedi M, Chehade A, Sanghera R, et al. A clinician's guide to topical retinoids. J Cutan Med Surg. 2022;26:71–78.

 

However, recent evidence suggests that retinoid precursors, as found in a non-prescription cosmeceutical product, could provide comparable efficacy as tretinoin in photoaging endpoints.

 

Triple tretinoin precursors vs tretinoin

Compared with tretinoin, OTC cosmeceutical retinoids require several conversion sequences before they ultimately give rise to retinoic acid, the biologically active form of vitamin A that results in skin improvements. To date, little evidence has confirmed whether these extra steps in the conversion process reduce the efficacy of an OTC retinol product compared with tretinoin.

Research published in JAMA Dermatology showed that an OTC cosmeceutical retinol-based product containing 1.1% triple tretinoin precursors (TTPs) comprising retinol, retinyl acetate, and retinyl palmitate offered photoaging outcome benefits that were comparable to those from prescription tretinoin 0.02% during a 24-week treatment period.

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. 2022;e221891.

 

CRABP2 (cellular retinoic acid binding protein 2) is a gene that encodes a member of the retinoic acid binding protein family and is involved in the retinoid signaling pathway, meaning that CRABP2 is an important marker in retinoid-like activity in the skin. This research found a significant CRABP2 messenger RNA (mRNA) induction, meaning that there was confirmed retinoic acid receptor signaling with triple tretinoin precursors (TTPs).

The small study, which included Caucasian women (mean age, 62 years) randomly assigned to either OTC TTP (n = 9) or tretinoin (n = 11), found that TTP was associated with significantly less frequent incidences of erythema (redness), a common tolerability issue seen with prescription tretinoin.

The investigators also reported that TTP-treated skin samples demonstrated a significant reduction in matrix metalloproteinase 2 (MMP-2) mRNA. Matrix metalloproteinase 2 (MMP-2) is known to break down type IV collagen, which is a major component of the dermal–epidermal junction (deeper layers of the skin).

MMP-2 increases in sun-exposed skin with advancing age and is known to be a key factor in the development of basal cell carcinoma (BCC), the most common type of skin cancer.

Kim DJ, Iwasaki A, Chien AL, Kang S. UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner. JCI Insight. 2022;7:e156344.

The MMP-2 suppression observed in the study was associated with clinical improvements in fine lines.

 

 

Findings in context

In an MDLinx interview, Anna L. Chien, MD, the study’s lead author and researcher, explained that retinoids represent one of the most commonly used treatments for skin aging.

It's widely known and assumed that these effects are due to retinoids' ability to increase collagen production in the skin and decrease MMPs that break down the dermal matrix.

Chien, who serves as associate professor of dermatology at Johns Hopkins School of Medicine, noted that despite this knowledge, no previous studies have “directly evaluated the association between improvement in wrinkling due to retinoids and the molecular changes in the skin.”

The study by Chien and colleagues is unique in that it highlighted “the potential role of MMP2 in mediating the effects of retinoids in photoaging,” she commented. “Similar to prior studies, we also found no significant difference in the improvement of photoaging between retinol and tretinoin groups.”

 

Implications, research needs

Chien noted that retinol is widely available in OTC products, and many of them are more cost-effective compared with prescription tretinoin, particularly when using the latter medication for cosmetic purposes.

“The study findings can help put clinicians at ease when recommending OTC retinols knowing generally they can achieve similar improvements in photoaging as tretinoin backed by molecular changes,” she said.

It is also more tolerable than tretinoin.

However, Chien added that the wide availability of retinols on the market also pose some challenges, particularly relating to confidence in the products’ efficacy. “There are many formulations, and more studies to confirm these findings across other retinol preparations would be helpful,” she said.