Demystifying retinoids for skincare: Retinol? Retinal? Retinoic Acid? Retinoids? What’s the difference, and what should I use in my skincare?

David L Stachura and Kristen F Rueb

Like most consumers who care about skin health, you probably see products advertised as containing “retinol.” Most people have at least an inkling that these products are part of a normal skincare routine, but it is hard for most consumers to sort through all the different “versions” of retinoids that companies advertise. Few people understand the differences between these molecules, but fret not! You don’t need to be a biochemist to understand what retinol is and why you should incorporate it into your skincare routine.

The science behind retinoids and vitamin A

First, some nomenclature discussion. It’s more accurate to refer to “retinoids,” which is a fancy way of saying a chemical compound that is either a natural derivative of vitamin A or chemically related to it. In other words, “retinoid” is a catch-all term that refers to anything related to vitamin A. Some people use the term “vitamin A” in a similar way- to include all versions of these compounds, but “retinoid” is more accurate.

What is vitamin A? Vitamin A is an essential, fat-soluble vitamin that your body needs to function (reviewed in [1]). That’s right- the human body can’t make vitamin A- you need to get it from somewhere else (hence the term “essential”). It is necessary for the immune system, reproduction, organ function, and growth and development. It’s also important for your vision. Fun fact? Retinol’s name is derived from “retina,” due to its role in your eye. We’ll talk more about the different versions of retinoids later on.

How do most people get vitamin A? Mostly it is obtained from the diet. You can get vitamin A from animal-based foods like dairy products, meat, eggs, and fish. You also get vitamin A in the form of retinoid precursors (like beta carotene) from fruits and vegetables- these substances are converted to retinoids in your body by special enzymes. Want to make sure you are getting plenty of vitamin A in your diet? Think about this- vitamin A is stored in fat, so the amount of fat in your milk or dairy product directly translates to its vitamin A content. Additionally, it’s better to eat meat from animals that have been fed a higher concentration of feed with beta carotene- they are richer in vitamin A due to their bodies metabolizing the compound before you consume it. In terms of vegetables and plants? Beta carotene is the main source of vitamin A precursor in the human diet, and that is easily obtained from eating red and orange vegetables and fruit. Carrots, tomatoes, and spinach (one of the green vegetables with high concentration of vitamin A precursor) are the main contributors in the human diet, although citrus fruit and juice also contain large amounts. These retinoids are absorbed by your body and accumulate in the liver and in adipose tissue (fat). We’ll describe a little bit more of the chemistry involved in these processes below, but in essence, you take retinoids into your body as either retinyl esters and retinol (from animal products) or as vitamin A precursor (from vegetables). They are converted to other substances in your body by a multitude of enzymes. The main active retinoid molecules are retinal and retinoic acid (RA).

Ok. Already it’s getting confusing. So, let’s look at Figure 1, which shows all the retinoids we’re talking about here (modified from [2]). I’ve drawn arrows in between the versions of retinoids to show you what can be converted into different versions of vitamin A. Let’s say you eat some meat, and ingest some retinyl esters (like retinyl linoleate). That substance can be converted into retinol. That retinol can either be used by your body, or converted to retinal. That retinal can either be used by your body or converted into RA. Note that all of the arrows go both ways, except for the one that points to RA. That means that, depending on the need, you can convert the retinoids back and forth (using different enzymes). For example, you can convert retinol into retinal, and then back again into retinol. There’s a lot of metabolism and chemistry involved here, but the simplest way to think about it is this: the main retinoid your body uses is RA. That comes from retinal. And retinal comes from retinol. And retinol comes from retinyl lineolate. So, retinyl lineolate is three steps away from being the most potent retinoid, RA.

Figure 1: Common retinoids for skincare and their relative strength. The strongest retinoids (retinoic acid isomers all-trans-retinoic acid and 13-cis-retinoic acid) are listed at the top, and the weakest are at the bottom, which inversely correlates with how mild they are for skincare applications. Structure diagrams used and modified from [2]. Arrows in between the retinoids show what chemical structure can be converted into what other structure (i.e. retinol can be converted into retinal and into retinyl esters, although different enzymes are involved); see text for a full explanation.

In the above example, I highlighted an animal product with a retinyl ester. If you do the same exercise with vegetables, you start off at a different step in the process. Beta carotene is converted to retinal. Then your body has the option to store it as retinol (and further down the storage path as a retinyl ester), use it at retinal, or make more RA. It’s the same idea, just a different step in the process.

Skincare and retinoids

As mentioned above, vitamin A is essential for a multitude of different processes in the body, due to the fact that it has several biologically active forms (retinol, retinal, and RA). As you probably guessed, vitamin A is also important for your skin (reviewed in [3,4,5]). In fact, retinoids are widely used in dermatology due to the fact that there is solid clinical evidence that they induce skin repair. Tretinoin, which is the prescription form of RA, has been widely studied and is a treatment for acne vulgaris (the common form of acne). Importantly, it is the “gold standard” for skin rejuvenation due to its effect of reducing fine lines, deep wrinkles, and hyperpigmentation. It also improves skin texture and is used to treat photoaging. Importantly, these aren’t just cosmetic claims- tretinoin is a prescription drug that has years of clinical trial data to support these statements.

As a brief review, your skin is composed of three major layers; the outer epidermis, the middle dermis, and the lower hypodermis (Figure 2). On the surface of the epidermis are actually dead epithelial cells known as the stratum corneum. The cells present in these layers are held together by lots of proteins known collectively as the extracellular matrix (ECM). The ECM is mostly made of collagen and elastin, which help give your skin shape, structure, and elasticity. It’s important to note that you are constantly producing more skin cells- there are adult stem cells located in the hypodermis and dermis that make more cells and push the old one’s further towards the surface, where they are eventually sloughed off. On average, you replace the epidermis of your skin every month. Vitamin A is a huge component of how your skin performs this process.

Figure 2: Retinoids can reverse the aging process that naturally occurs in skin. Healthy skin (left) has thicker epidermis, dermis, and hypodermis due to more healthy cell turnover and ECM production. Older skin (right) begins to thin and becomes less elastic over time. Additionally, inappropriate pigmentation occurs, blood flow is reduced to these tissues, and the production of cells and their ECM is reduced. Adding retinoids to older skin can’t reverse all the issues that come along with aging, but it promotes sloughing off of the stratum corneum (the upper layer of the epidermis), epidermal cell turnover, and ECM production to thicken the skin and reduce wrinkles. Image modified from Kristine Cordy

Tretinoin stimulates epidermal cells to proliferate and grow and also remodels ECM proteins in the dermis. ECM protein homeostasis is super important for how your skin ages- the balance of collagen production, destruction, and rearrangement is essential for the skin’s tone and elasticity. In essence, tretinoin stimulates the production of more collagen, while reducing the activity of enzymes that break down collagen called matrix metalloproteinases (MMPs). It also stimulates tissue inhibitors of MMPs (called TIMPs), which again help maintain healthy ECM homeostasis. Although this is a very simplified description, vitamin A is an important molecule that regulates cell growth and proper ECM homeostasis. In essence, RA helps reverse the negative effects of aging that make aging skin thin and less elastic.

What is the strongest retinoid?

Great question! Let’s order the common retinoids starting with the strongest version. Basically every step down in strength is a different modified form of vitamin A. Although it may be too much chemistry for some, I’ve adapted an image from [2] that helps explain the difference in these molecules (Figure 1).

Basically, in chemical terms, there are four core versions of retinoids. All of them are very similar; they vary in their terminal polar end group (in Figure 1, look at the right side of the chemical molecules- note that they are all slightly different).

1. Retinoic Acid (RA)

The strongest retinoid is RA. This is the most biologically active retinoid and a powerful signaling molecule. All forms of retinoids can be converted to this metabolite, which exerts its effects by binding to a specific receptor in cells called, conveniently, the retinoic acid receptor (RAR). RAR is essential for either turning on or turning off specific gene sequences. Without getting into too much biology, you can think of RA directly affecting the expression of genes and therefore production of proteins in your body. As mentioned before, RA is essential for lots of processes in your body. It’s even required for the patterning of the anterior/posterior axis (how your body is arranged head-to-toe) in early embryonic development.

RA basically comes in two versions, which are all-trans-retinoic acid and 13-cis-retinoic acid (there is another version called 9-cis-retinoic acid that I have omitted due to it not being super popular for skincare applications). These are two isomers of each other, which is a fancy way of saying that their atoms are arranged in a slightly different way (see Figure 1). Effectively they do the same thing biologically, though. You probably know all-trans-retinoic acid as tretinoin, and 13-cis-retinoic acid as isotretinoin. Or, you’ve heard of their more popular prescription drug names, Retin-A and Accutane, respectively. These are prescription drugs, and you need to have a doctor evaluate your skin condition and write a prescription for them. They are primarily used to treat severe acne, but also are useful for treating photoaging of the skin, significantly reducing fine lines and hyperpigmentation. If you’ve ever used RA, you know that it sometimes has pretty visible side effects, such as skin redness, irritation, peeling, and sun sensitivity. This is due to the remodeling and rejuvenation of the skin that it induces. And although it eventually causes thickening of the skin, at first the effect is to clear dead skin cells from the epidermis, causing the skin to be more sensitive to UV radiation from the sun. If you use RA on a daily basis, you need a good SPF to protect yourself. Another important issue to consider is that RA is a powerful signaling molecule that is essential for patterning the early embryo. That means you cannot use RA when you are pregnant. In fact, most doctors will want female patients to be on at least two forms of birth control if they are using RA; it’s that powerful and the detrimental effects to a developing fetus would be catastrophic.

2. Retinaldehyde (retinal)

Second in line is retinal, also called retinaldehyde. It’s one enzymatic reaction away from RA, and can also be converted into retinol. When you eat beta carotene from vegetables, that molecule actually gets enzymatically converted into retinal. Retinal is also a signaling molecule in your body and is the basis of vertebrate sight. When bound to opsins, retinal forms the chemical basis for light detection in your eyes (it triggers a chemical signaling cascade in the retina, which is interpreted by the brain).

Retinal is the strongest of the over-the-counter (OTC) retinoids but it is still gentler than RA itself. When formulated in skincare products, retinal promotes cell turnover to even skin tone and texture, and smooths wrinkles and fine lines. It also helps with acne. Some people will still experience irritation and dryness when using retinal, but less so than pure RA. Retinal isn’t super common in skincare formulations, though. In general, it is pretty unstable, and is easily oxidized. Although it converts quickly to RA and is fairly efficacious in skincare, to make a stable product with retinal is difficult, so the products are relatively expensive.

3. Retinol

Next in line strength-wise is retinol, which is more common in skincare products. It is two enzymatic steps away from pure RA, and so is more mild than retinal or RA. Most retinol is obtained from your diet by consuming foods from animal sources, including dairy products, eggs, fish, and organ meats. Once in your body, it can be converted to retinal or retinyl esters (which is the form of most of your body’s retinoid storage).

Retinol, like its other retinoid relatives, regulates cell turnover, promotes effective exfoliation, prevents acne, helps with hyperpigmentation, smooths fine lines and wrinkles, increases hyaluronic acid production, produces collagen, and helps to reduce oil production and unclog pores. Like its relatives, it also can cause irritation, drying, and peeling. However, its effects are much more mild than retinal or RA. Retinol is more stable than retinal, but it isn’t always the easiest to formulate skincare products with. Retinol is sensitive to light, heat, and oxygen, and studies indicate that many cosmetic products containing retinol are extremely unstable [6]. In fact, long-term stability testing of retinol-containing products indicates that most products have less retinol than they claim, likely due to degradation of the molecule [7].

4. Retinyl esters

Finally, you have retinyl esters, which are the oil-soluble versions of Vitamin A. They are the furthest removed from RA and take three enzymatic steps to be converted into it. Hence, retinyl esters are the most mild of the retinoids. Like retinol, retinyl esters are mainly obtained by eating animal products, and most of the body’s vitamin A is stored in the liver in the form of retinyl esters.

There are a few retinyl esters used in skincare, including retinyl palmitate, retinyl propionate, retinyl acetate, and retinyl linoleate. These are all ester forms of retinoids, which is a fancy way of saying that the retinol molecule is bound to something that makes it “fatty” and oil-soluble (hence the reason vitamin A is fat soluble). Take a peek at Figure 1, and you’ll see the “R” groups at the right end of the molecules. Each different retinyl ester has a different one attached. Retinyl linoleate is retinol plus linoleic acid (also called vitamin F), retinyl palmitate is retinol + palmitic acid, retinyl propionate is retinol bound to propionic acid, and retinyl acetate is retinol + acetic acid. So, when you apply these versions of retinoids to the skin, they de-esterify, turning into retinol and whatever R group is attached. One of the main benefits of the retinyl esters in skincare is their stability. Because they are linked to other molecules, they are generally more stable and easy to formulate with.

Let’s look at retinyl linoleate first. This retinyl ester is very stable and de-esterifies in the skin to retinol and linoleic acid, generating two active ingredients, retinol and vitamin F. Retinol, as we’ve discussed previously, is great for skin turnover and antiaging. Vitamin F is an essential omega-6 fatty acid that is hydrating and helps protect the skin’s barrier, retaining moisture. It’s also useful for brightening the skin. Therefore, it counteracts the negative effects of retinol when used on its own. It also increases hyaluronic acid synthesis (another essential ECM component that moisturizes your skin) and reduces inflammation. Overall, it’s a milder retinoid, but that aids its positive effects on the skin.

Retinyl palmitate is the most abundant endogenous retinyl ester found in the skin, and it is more stable than retinol alone. It is popular in skincare formulations, and separates into retinol and palmitic acid when applied to the skin. Palmitic acid is a fatty acid present in the skin, and it has emollient properties that soften the skin and hydrate it. As such, it is useful to counteract some of the negative properties associated with retinol use.

Retinyl propionate separates into retinol and propionic acid and has stronger retinoid activity than retinyl palmitate [8]. It has the same antiaging effects as the other retinoids, and seems to work best when combined with other ingredients such as niacinamide (vitamin B3) for reversing the negative effects of aging on skin.

Retinyl acetate is a popular retinyl ester used as a commercial cosmetic ingredient in antiaging products. However, clinical studies have not evaluated the antiaging efficacy of retinyl acetate as a single active ingredient in a topical formulation. Instead, it is usually combined with other retinoids in skin formulations.

So, I think the best way to think about this is that RA is the strongest, followed closely by retinal. Retinol is weaker, and retinyl esters are the weakest. If you think about it, your body needs to undergo three enzymatic reactions to make a retinyl ester into RA, while it needs two reactions to convert retinol, and only one to convert retinal. And that is exactly what happens when you add these compounds to your skin- your body converts them to pure RA to affect skin changes. So, the compounds further removed from RA will be weaker, but also less irritating because they need time to convert to RA. They also tend to be more stable, which is important when you formulate a skincare product.

How do I know what retinoid is in a product?

Great question! You need to read the label and interpret this information. See this article that we wrote previously for a great explanation of how to read cosmetic labels and decipher what is in your favorite (or prospective) product.

What retinoid should I use in my skincare regimen?

This is what most people actually want to know, and like most issues, the answer is a little nuanced. Really, it depends on the situation you’re trying to address, your age, and your skin’s sensitivity.

Try not to think about how powerful something is in terms of its efficacy. Think about it like this: a muscle car has a lot of horsepower and is great at going fast in a straight line. But if you are racing on a curvy racetrack, you’ll likely be better off with a more agile car with better handling and less power. It’s good to think about the whole package, and not just “strength.”

If you have severe acne issues, you’ll likely see a doctor and be prescribed the strongest version of retinoid: tretinoin or isotretinoin. But remember- these products are prescription only and are pretty irritating to the skin; you’ll want to pay close attention to using SPF and staying out of the sun (although, everyone should use SPF to protect their skin from UV radiation). If you have sensitive skin and are new to retinoids? Most skincare professionals would probably suggest that you start off with a “weaker” retinoid like a retinyl ester or retinol. Start off slowly, applying every other day, using SPF, and see how your skin reacts. You can always go up in strength, but you can’t easily reduce the strength of your product.

And remember that not all skincare products are created equally. Retin-A and Accutane have other ingredients, but mainly those creams are drugs designed to get RA into your skin as fast as possible. Most commercially available skincare creams have other ingredients that are beneficial for other aspects of your skin. So try and pick a good skincare product that has other high quality ingredients. Peptides, niacinamide, antioxidants, hyaluronic acid, quality emollients, and other ingredients can make a product creamy, luxurious, and more versatile for your skin. You really want something well balanced that makes your skin feel hydrated and look great as opposed to something with the highest amount of retinoids someone can pack into a product. When in doubt, consult a trusted skincare expert for guidance. They have lots of experience with retinoids and should be able to help you get the clear, healthy skin you’ve always wanted.

References

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