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Retinoids — The Gold Standard Face Cream That Nothing Has Yet Replaced

Decades of use, an unmatched evidence base, and a breadth of biological effect that no newer topical ingredient has come close to replicating. Here is an honest clinical account of what retinoids actually do, how the different forms compare, and why the gentlest option is not always the wisest choice.

A five-decade head start

The story of retinoids in dermatology begins not with but with acne. Tretinoin (all-trans retinoic acid) was first approved for acne treatment in the 1960s. Its anti-ageing were identified almost by accident, as and clinicians observed that skin treated with tretinoin looked not just clearer but structurally improved, smoother, firmer, more evenly pigmented, with a quality of renewal that went well beyond what acne treatment alone could explain.

The subsequent decades of research into that observation have produced one of the most robust evidence bases in all of dermatology. No topical skincare ingredient has been studied as thoroughly, over as long a period, or with as consistently positive results as retinoic acid and its derivatives.

That head start matters clinically. When a patient asks a new topical ingredient might be as effective as their retinoid, the honest answer almost always begins with an acknowledgement that nothing has had the time, the research investment, or the clinical validation to make that comparison . The newer ingredients may be . The retinoid evidence is established.

What is a retinoid?

The term "retinoid" refers to the entire family of vitamin A derivatives, both natural and synthetic, that share the ability to bind to retinoic acid receptors in the skin and influence gene . The family includes distinct compounds that are encountered in clinical and cosmeceutical practice, and understanding their relationship to one another is essential for everything that follows.

At the top of the hierarchy sits tretinoin, all-trans retinoic acid, the fully active form that binds directly to nuclear without any conversion.

One step removed is retinaldehyde (also called retinal), which requires a single enzymatic to become retinoic acid.

Two steps removed is retinol — the form most commonly found in over-the-counter skincare — which must be converted first to retinaldehyde and then to retinoic acid before it can exert any biological effect.

Further still are the retinyl esters, retinyl palmitate & retinyl acetate, which require an additional hydrolysis step before entering the conversion pathway.

Beyond these naturally occurring forms sit the synthetic retinoids: adapalene, tazarotene, and the newer hydroxypinacolone (HPR), each designed to interact with specific receptor subtypes or bypass the conversion pathway in different ways.

What retinoids actually do

The breadth of retinoid effect at the cellular and molecular level is, genuinely, remarkable. Topical tretinoin's mechanisms include keratolytic activity, regulation of proliferation and differentiation of epidermal cells, activation of fibroblasts, induction of collagen synthesis and collagen recycling, prevention of collagen loss, in matrix metalloproteinases MMP-1 and MMP-8, and a decrease in epidermal melanin through inhibition of tyrosine kinase.

Retinoids accelerate the turnover of the epidermal surface, producing a progressive improvement in skin texture and tone.

They stimulate dermal fibroblasts to produce new collagen while simultaneously inhibiting the responsible for collagen degradation — a dual action that is particularly valuable in ageing skin where both processes are .

They normalise the disordered pigmentation that accumulates with sun exposure.

They improve the organisation of the stratum corneum.

And they do all of this a single, elegantly coherent mechanism: to nuclear retinoic acid receptors (RARs) in keratinocytes, triggering a cascade of gene expression changes that affect virtually every aspect of skin biology simultaneously.

Retinoids are central regulators of skin biology, influencing keratinocyte proliferation, differentiation, immune modulation, and barrier maintenance.

Their therapeutic has long been attributed to retinoic acid receptor-mediated transcriptional activity; however, recent studies have revealed additional layers of regulation, including epigenetic modifications, kinase signalling networks, and interactions with the skin microbiome. The more closely the mechanism is examined, the more sophisticated it appears.

The sebum question

A word about sebum ( skin oils) — because it is frequently cited as one of retinoids' beneficial effects and the evidence deserves honest examination.

Oral retinoids, such as Roaccutane used systemically for severe acne, produce a powerful and well-documented in sebaceous gland activity and sebum production. The same effect in topical application is considerably less certain.

The clinical impression that skin treated with topical becomes less oily may reflect improved and normalised keratinocyte turnover rather than a direct reduction in sebum output. The distinction is worth making; not to diminish the value of topical retinoids, whose benefits are substantial and well-documented in other respects, but because accuracy matters more than a convenient simplification.

The conversion pathway — and why it matters

Every retinoid must be converted, in the skin, to retinoic acid before it can bind to the nuclear that drive its biological effects. The skin can only use one form of vitamin A: all-trans retinoic acid. Everything else is a precursor.

The conversion pathway is sequential and each step inefficiency. Retinoid activity of the first-generation representatives decreases in the following order, from most potent down to weakest:

Retinoic acid (Tretinoin)

Retinaldehyde

Retinol

Retinyl esters

Whilst tolerance and hence side effects are the reverse. With Retinyl esters being the gentlest through to Retinoic Acid being the stongest.

In practical terms: retinyl esters, the gentlest and most commonly found form in mass-market moisturisers, must undergo two enzymatic conversion steps before becoming active. Retinol requires two steps. Retinaldehyde requires one. Tretinoin is already in its active form and requires no conversion at all. The further from retinoic acid a retinoid sits in this pathway, the less efficiently it delivers the active molecule to the tissue but the less irritating it is in the process.

This is the chemical basis for Dr Forrester’s clinical suspicion that gentler retinoids are less effective and the evidence supports it directly. Retinol can take twice as long as to begin showing results.

The newer retinoids — genuine advance or elegant marketing?

Hydroxypinacolone retinoate (HPR), commercially known as granactive retinoid, has attracted considerable attention as a retinoid that supposedly bypasses the conversion pathway by binding directly to retinoic acid receptors without enzymatic conversion.

The theoretical elegance is real. The clinical evidence is thinner. In vitro data suggesting comparable collagen-stimulating activity to tretinoin is not the same as in vivo efficacy data in humans over meaningful timeframes — and the latter remains sparse. Reductions in irritation with newer selective retinoids are biologically plausible, yet they have not been proven against active retinoid comparators in randomised settings.

Retinaldehyde occupies a more interesting position. As the immediate precursor to retinoic acid, it requires only a single conversion step and produces a more controlled delivery of active acid than direct tretinoin application.

Metabolism of retinaldehyde to retinoic acid occurs only by keratinocytes at a pertinent stage of differentiation, leading to a more controlled delivery of retinoic acid and weaker retinoid-associated adverse effects compared to tretinoin. It is, in our view, the most clinically credible of the cosmeceutical retinoids though it from significant formulation instability challenges that have historically limited its availability in reliably effective products.

The adaptation strategy — getting patients to the effective dose

The most practically important clinical insight about retinoids is one that is frequently omitted from prescribing and recommending practice: the adaptation period is manageable, and managing it well is the difference a patient who the full benefit of retinoid and one who abandons it after a few weeks of irritation.

In practical terms: start at the lowest concentration, apply every third night initially, and support the barrier aggressively throughout with ceramide-containing moisturisers and niacinamide.

Increase frequency and concentration only when the skin has demonstrated tolerance at the current level. The goal is to work up to the most potent form the skin can comfortably sustain — not to default to the gentlest option because it requires the least clinical management.

A patient on well-tolerated tretinoin is receiving demonstrably more biological effect than a patient on a cosmeceutical retinol at the same comfort level. the first patient to the second patient's tolerance profile is a clinical skill worth investing in.

The conclusion that the evidence supports

Retinoids remain the best-evidenced topical ingredient in anti-ageing dermatology. The breadth of their biological effect — collagen stimulation, epidermal renewal, pigmentation normalisation, barrier improvement — has not been replicated by any newer ingredient in the same depth or over the same timeframe. The conversion pathway from cosmeceutical to prescription strength is a gradient of both efficacy and tolerability, and the clinical art lies in managing that gradient in the patient's interest rather than defaulting to the most comfortable or the most commercially convenient option.

The newest ingredients in the topical skincare landscape — polynucleotides, growth factors, exosomes, peptides — are interesting, and some of them are genuinely promising. We examine them in the companion piece to this one. None of them has yet earned the right to displace retinoids from their position at the foundation of evidence-based topical skincare. That position has been built over five decades of rigorous clinical research, and it is not easily challenged.

The views expressed in Clinical Perspectives are the Dr Forrester’s own and reflects his personal and professional experience in aesthetic medicine.

References

1.     Cosmetic retinoid use in photoaged skin: A review of the compounds, their use and of action. International Journal of Cosmetic . 2025. 

2.     A Comprehensive Review of the Strategies to Reduce Retinoid-Induced Skin Irritation in Topical Formulation. Dermatology Research and Practice. 2024. 

3.     The Next Generation of Skin Care: Transforming Retinoid Therapeutics. PMC. 2025. 

4.     An Updated Review of Topical Tretinoin in Dermatology. Journal of Medicine. 2025;14(22):7958. 

5.     Use of Retinoids in Topical Antiaging Treatments: A Focused Review. PMC. 2022. 

6.     Retinoids in the treatment of skin aging: an overview of clinical efficacy and Polynucleotide Hair Rejuvenation safety. PMC. 2006. 

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