Tretinoin (Retin-A)

Tretinoin is all-trans retinoic acid, the biologically active acid form of vitamin A. Your body makes small amounts of it from retinol; as a cream it goes straight onto the skin. It is the sister molecule of isotretinoin (13-cis retinoic acid), which is taken by mouth, but applied as a cream its effect stays where you put it.

It came out of acne research in the 1960s and has been available as a cream since the 1970s. In the 1980s dermatologists noticed that fine lines and pigment spots were changing under the acne cream as well. Tretinoin became the reference compound against which every new agent for photoaged skin is measured.

The catalogue lists tretinoin as a cream in a 20 g tube at 0.05% and 0.1%. Both strengths sit inside the range the trials used, which runs from 0.025% to 0.1%.

This information is for research and educational purposes only. No medical advice.

Once inside the skin cell, tretinoin binds to retinoic acid receptors (RAR) in the nucleus, mostly the gamma subtype in skin. The receptor then switches genes on and off. In the epidermis that means faster keratinocyte turnover, a thinner and more even stratum corneum and loosening of the keratin plugs that block sebaceous follicles. This is why comedones recede in the trials and fewer new ones form.

In the dermis a second mechanism runs. UV light activates the transcription factor AP-1, which drives matrix metalloproteinases, the enzymes that break down collagen. Tretinoin suppresses AP-1 and with it those enzymes. Fisher and colleagues showed this in irradiated human skin in the New England Journal of Medicine in 1997: pretreatment with tretinoin cut the enzyme induction by 70 to 80 percent. At the same time procollagen synthesis rises; in the two-year trial by Kang and colleagues the procollagen marker was significantly higher at month 12.

Almost none of it reaches the bloodstream. Latriano and colleagues measured about 2 percent percutaneous absorption after a single dose of radiolabelled tretinoin and 1.1 percent after more than a year of daily use, with plasma levels of tretinoin and its metabolites staying within the endogenous range. The action is local, which is why the side effect profile has little in common with oral isotretinoin.

Weiss and colleagues (JAMA 1988) made tretinoin known beyond acne. Thirty participants applied tretinoin to one forearm and the drug-free vehicle to the other for 16 weeks; half also applied tretinoin to the face. Every tretinoin forearm improved measurably, no vehicle forearm did. Fourteen of the 15 tretinoin faces improved, none of the vehicle faces. Under the microscope the changes were significant, but only in tretinoin-exposed skin.

Griffiths and colleagues (Archives of Dermatology 1995) settled the strength question: 99 participants, 0.1% and 0.025% cream against vehicle, double-blind, 48 weeks. Both strengths improved photoaging to the same degree and thickened the epidermis by about 30 percent, but 0.1% irritated the skin significantly more often. That is the single most useful data point for choosing a concentration.

Kang and colleagues (American Journal of Clinical Dermatology 2005) ran the longest placebo-controlled trial: 204 participants with moderate to severe facial photodamage applied 0.05% emollient cream or placebo for two years. Fine and coarse wrinkling, mottled pigmentation and sallowness improved significantly against placebo. Biopsies showed no increase in atypical cells and no damage to the stratum corneum, but a significant rise in the procollagen marker at month 12.

Fisher and colleagues (NEJM 1997) supplied the mechanism in 59 volunteers: a single UV exposure raised three collagen-degrading enzymes and increased collagen breakdown by 58 percent, while tretinoin applied beforehand blocked 70 to 80 percent of the enzyme induction. Latriano and colleagues (JAAD 1997) supplied the pharmacokinetics: roughly 2 percent absorption through the skin after a single dose and after 28 days, only 1.1 percent in participants with more than a year of use. Endogenous plasma levels did not change.

For acne the evidence base is even broader. Topical retinoids are a cornerstone of the American and European acne guidelines. Tretinoin is the oldest member of the group. For hair growth the data are thin: a small 1986 study tested tretinoin alone and together with minoxidil. Little has followed since.

Both are retinoic acids and both descend from vitamin A. Still, they are two different tools. Tretinoin works where it is applied: in the epidermis and the upper dermis. Isotretinoin is swallowed, spreads through the whole body, shrinks the sebaceous glands and brings a strict safety profile with it, above all harm to a fetus.

That gives the division of labour in research: tretinoin for mild to moderate acne, comedones, pigment spots and photoaging, isotretinoin for severe, scarring acne. Used together on the skin the two add up dryness and irritation, which is why the literature advises against continuing topical retinoids during an isotretinoin course.

Adapalene, a synthetic third-generation retinoid, binds the receptors more selectively and is stable in light. It irritates less, but has far fewer data in photoaging than tretinoin.

• Retinoid dermatitis: redness, flaking, burning, dryness and tightness, mainly in the first 2 to 4 weeks. It is the most common effect by far and the reason for the slow start. In Griffiths and colleagues, irritation was significantly more frequent at 0.1% than at 0.025% with no difference in effect. If it gets too much: skip a night, moisturise, do not increase the amount.
• Initial acne flare: more spots can appear in the first weeks as blocked follicles empty out. It usually settles by week 6 to 8.
• Photosensitivity: skin under tretinoin burns faster. Sunscreen is not optional, it is part of the application.
• Pigment changes: occasionally lighter or darker patches, mostly temporary, more often in darker skin types and where the skin is irritated.
• Pregnancy: retinoids are regarded as off limits in pregnancy. A meta-analysis in the British Journal of Dermatology (2015) found no significant rise in malformations across 654 exposed pregnancies, but stated itself that it was too small to prove safety. The rule therefore stands: not in pregnancy, not when trying to conceive.
• Interactions on the skin: benzoyl peroxide can oxidise tretinoin; alcohol-based toners, exfoliants and scrubs amplify irritation. Avoid waxing and laser on the areas you apply tretinoin to in the days before and after.

Keep the tube tightly closed at room temperature, 15 to 25 °C, protected from light and heat. Tretinoin is sensitive to light and oxidation, so the tube does not belong on a windowsill or next to the bathroom radiator. Do not freeze. After opening, use within the period printed on the pack. Keep out of reach of children.