BFF: Vitamin A and your skin

Okay, the Bugs Bunny part is a stretch, but not the relationship between carrots and skin care. And it has nothing to do with the ancient “root” word for carrot, ker, which translates into the word “horn”, which a carrot resembles. Nor is it because ker is also the basis of the word keratin, which is the protein that makes up animal horns, hoofs, claws, and fur – as well as our own hair, fingernails, and is the major protein in the keratinocytes of the stratum corneum layer of our epidermis. There is a different reason.

Actually, carrots are high in β-carotene (itself named after carrots) and something found in other fruits and vegetables and responsible for the orange color of carrots. Here comes the hook:  β-carotene is composed of two retinyl groups which are converted in the small intestine into two molecules of retinal, a form of Vitamin A.

“Eat Your Carrots; they’re Good for Your Eyes.”

Turns out that is a true statement. It was discovered long ago that vitamin A deficiency is one of the causes of night blindness, in this case because of an abnormality in the functioning of the cells of the retina. It was the search for the cause of night blindness that led to the discovery of vitamin A. (Other non-nutritional causes include severe myopia, glaucoma medications that constrict the pupil, cataracts, and retinitis pigmentosa.)

There are, in fact, many “forms” of Vitamin A , collectively known as retinoids, including retinal, retinol, retinaldyhyde, retinyl palmitate, and retinoic acid.  All have retina as their root word and enzymes within the body, including in the skin, can transition one compound into another. Retinoic acid is the “active” form and an important hormone-like growth factor for epithelial (e.g. skin) and other cells.

Not surprisingly, vitamin A has many functions besides being absolutely necessary for vision, including gene transcription, immune function, embryogenesis, bone metabolism, and blood cell production. Too little or too much causes problems.

OK, so what about the skin? 

Vitamin A deficiency not only leads to vision issues, it is also the cause of skin disorders in which too much keratin is synthesized. In decades past, oral administration of vitamin A was used to treat such conditions but with only marginal success.  Instead, cumulative vitamin A overdosing was found to carry risks of bone, liver, and neurologic injury and congenital malformations (more on the last issue later.)

Because vitamin A is a fat soluble vitamin, and the epidermis is lipophilic (“fat loving”), vitamin A is able to penetrate the stratum corneum and exert effect in deeper layers. As opposed to many other vitamins, vitamin A as found in the diet does not have much direct biological effect but works instead via the active metabolite (biochemical derivative) retinoic acid.

Retinoic acid has direct effect on skin cells through modulation of gene expression within the interior of the cell, in effect, “adjusting” rates of cellular differentiation and proliferation resulting in a more youthful looking state.  

Retinoic acid, also known as tretinoin, is the active ingredient in Retin A, and is clinically proved to favorably impact skin in the following ways:

  • Reduction of both wrinkles and fine lines
  • Increases collagen production
  • Smoothes skin texture
  • Increases skin thickness
  • Improves elasticity
  • Diminishes acne
  • Improves overall skin tone
  • Diminishes mottled pigmentation
  • Increases skin hydration
  • Stimulates skin repair
  • Decreases enlarged pores

Tretinoin can be drying and increase sensitivity to sunlight. More sensitive people may experience redness, scaling, itching, and burning. Physicians recommend gradually increasing use to allow acclimating to the drug over time.

Isotretinoin is the prescription drug Accutane, and oral formulation used to control severe cystic acne vulgaris. It is a powerful drug with potential to cause a variety of birth defects. For that reason, its use is strictly limited and females taking the drug are instructed to use two means of contraception one month before, during, and one month after discontinuing its use.

Skin benefits of retinyl palmitate,  retinol, and retinaldehyde

The related metabolic pathway among these related vitamin A compounds is below:

Retinyl palmitate <=> Retinol <=> Retinaldehyde => Retinoic acid

Retinol and retinyl palmitate are among the most widely used active ingredients in skin care products.  Both are forms of vitamin A that can be converted into retinoic acid by enzymes found within the skin.  When sufficient amounts of retinol and retinyl palmitate are added to skin cell culture, the amount of retinoic acid in the cells increases. Therefore, at least in theory, topical vitamin A may deliver at least some of the well-established skin benefits of retinoic acid while producing fewer side effects.

Numerous products with retinol and retinyl palmitate are touted as equivalent to retinoic acid in effectiveness yet devoid of its side effects. The reality is a bit more complicated. Many of these products contain too little retinol / retinyl palmitate to have any noticeable effect. The fact that these agents are in the list of ingredients is not enough. Products with high concentrations do exist but may still not deliver the purported benefits for a number of reasons. In particular, a product with highly concentrated retinol may cause skin irritation, especially in people with sensitive skin. Highly concentrated retinyl palmitate is less irritating than retinol (at equivalent levels) but is also less effective. (After all retinyl palmitate is the farthest away from retinoic acid in the metabolic pathway.) Furthermore, conversion rates of various forms of vitamin A to retinoic acid vary among individuals – the same product/concentration may yield visible benefits in some people and little or none in others. Further still, retinol, and to a lesser degree retinyl palmitate, can be degraded by oxidation if formulated, stored and/or used improperly.

Among retinoids precursors, retinaldehyde is the nearest (on the metabolic pathway) to retinoic acid and is likely to match its benefits more closely. However, well-designed products containing retinol and/or retinyl palmitate provide an additional alternative that may be cheaper and, at least for some people, less irritating.

Are there other downsides to these skin care ingredients to consider?

Aside from irritation, drying, and photosensitivity, there remains an open  question as to the possible carcinogenic potential of retinyl palmitate.  A recent study made public last January (by an interagency group within the NIH) demonstrated that retinyl palmitate speeds photo-carcinogenic effects on hairless mice. The study, entitled Photococarcinogenesis Study Of Retinoic Acid And Retinyl Palmitate and conducted at a federal research center found that animals treated with small doses of retinyl palmitate and ultraviolet light developed skin tumors faster than untreated, light-exposed mice or those treated only with a control cream. To date, however, there is no prohibition against use of retinyl palmitate.

Retinol has been used in topical application for more than 25 years without evidence of increased incidence of carcinoma.  In fact, a 1997 study by Moon et al in Cancer Epidemiology showed oral administration of retinol was preventative of squamous cell carcinoma but not basal cell carcinoma.

Overall, the evidence is as yet not clearly conclusive. What many dermatologists recommend is use of retinoid containing skin products along with sun protection if used during the day or, more preferable, use of the products during the nighttime hours.

 

20 Comments

  1. drjohn says:

    Dr George, Astaxanthin is one of the most abundant carotenoids in nature, particularly in marine based life. Given their instability in light, do you think it might have any role as a cosmeceutical active? DrJohn

  2. Drgeorge says:

    Astaxanthin is a carotenoid that belongs to a class of phytochemicals called terpenes. The nomenclature is derived from a word meaning “yellow leaves”. Like many carotenoids, astaxanthin is a colorful, lipid-soluble pigment. This color is due to the extended chain of conjugated (alternating double and single) double bonds at the center of the compound. Similar to other carotenoids, this chain of conjugated double bonds is responsible for the pronounced antioxidant function of astaxanthin,

    Astaxanthin is found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds. It provides the red color of salmon meat and the red color of cooked shellfish. Astaxanthin is not converted to vitamin A (retinol) in the human body and thus would not be suitable as a vitamin A precursor in skin applications. It might, however, have significant antioxidant value although it is so highly colored that it is used as a food colorant which may make its use in cosmeceuticals, especially ones not intended to have a significant color component, an insurmountable problem.

  3. lyonella says:

    I tried adding a bit of it to a sunscreen I was making and it made it a lovely peach color but couldnt even add enough to reach therapeutic levels – too orange for that unless applying for OompaLoompa role. And stained my gloves in the trying.

    • drjohn says:

      Oompa Loompas in the original Willy Wonka movie were orange, but just kind of tan in the newer version. I liked the original better.

      • lyonella says:

        LOL! You might like this SS that has astaxanthin but probably isnt orange enough for you:

        SUNTEGRITY

        Size: 1.7 oz / 50 ml $45

        ACTIVE INGREDIENT: Zinc oxide 20%

        OTHER INGREDIENTS: OTHER INGREDIENTS: Water (Purified), Aloe Barbadensis Leaf Juice**, Capric Caprylic Triglycerides, Sorbitan Stearate, Glyceryl Stearate, Polyglyceryl-4 Isostearate, Hexyl Laurate, Jojoba Oil**, Cetyl Dimethicone, Dimethicone, Magnesium Sulfate (Epsom Salt), Sunflower Oil**, Cucumber Extract**, Hyaluronic Acid, Green Tea Extract**, Pomegranate Oil**, Red Algae Extract, Astaxanthin, Citrus Sinensis (Sweet Orange) Essential Oil,Citrus Reticulata Blanco (Tangerine) Essential Oil, Citrus Paradisi (Grapefruit) Essential Oil, Polyaminopropyl Biguanide*, Ethylhexylglycerin*

        *Paraben-free anti-microbial agent.
        **Certified Organic Ingredients

        What say you? yay or nay?

        I asked the company why they use citrus oils (I always thought they are photosensitizers) and the response was that @<1% in the products, they arent a problem.

        • drjohn says:

          A bit complicated for a SS. I suspect the astaxanthin is in “subclinical” concentration as well. :Let’s call it “approved for anyone with skin type O (“Oompa Loompa”).

  4. lifebythedrop says:

    Hello Dr’s, I am extremely happy to have found your website. I have been using tretinion .025 %, mostly to keep acne at bay, and was just curious if the different percentages of tretinion do different purposes? Would someone trying to prevent, and get rid of wrinkles benefit better from a tretinion of .1 % over .025 %?
    Thank you for your time.

  5. Drgeorge says:

    In addition to acne control, topical Tretinoin is commonly used (among other things) in the amelioration of fine wrinkles, mottled hyperpigmentation, and tactile roughness of facial skin. Formula concentrations in the United States are limited to 0.1% or less and absorption of the drug is greatly affected by the condition of the skin to which it is applied. For this reason, it is not recommended to be used on sunburned, eczematous, abraded,or dermatitic skin. It is, in fact, a photosensitizer so adequate precautions are necessary if sun exposure is contemplated. In addition, it can lead to burning, stinging, redness, and skin peeling with excessive use or concentration.

    Transcutaneous absorption is highly variable. In a study of 14 healthy men, dermal absorption of Tretinoin from various topical formulations ranged from 1% to 31% of applied dose, depending on whether it was applied to healthy or unhealthy skin. For these reasons, the recommendation is to use the least concentration required to achieve the desire effect and to ramp up use slowly to acclimatize the skin in order to avoid side effects. There is no fast and hard rule for a given individual. Slowly increasing frequency of application is recommended. If you do opt for a higher strength formula, it makes sense to back off the amount and interval of application and again approach from the side of “too little” at first. In my decades of practicing anesthesia I learned early on that it’s much wiser to give multiple small doses of a drug to obtain the desired effect. One can alway give more; iIt’s impossible to get it back if you give too much.

  6. Susan Dent says:

    Do you know if retinoids/retinol products just simply don’t work on some people? I’ve heard some tales of it not working, or going badly awry – the badly awry one was someone who I felt probably did take adequate care and got her product from a reputable source.

    The other concern I have about this ingredient is that if possible I would like to favour collagen type III creation over collagen type I, and that retinoids (along with many other ingredients) create collagen type I.
    (That’s if what I’ve heard about coll III and coll I isn’t total baloney!)

    • drjohn says:

      Retin A (tretinoin) is effective but tricky to use. Almost anyone can become sensitized to it, and develop side effects. Other retinols are less likely to cause such problems. Recent research suggests that they are as effective in the longer term as tretinoin, So even though tretinoin is the most strongly evidenced (for efficacy) topical we have, I believe we will see other retinoids becoming more widely used in the future. Wait for that Dr George article to address the collagen type question.

  7. Susan Dent says:

    Thank you very much for your replies Dr John – will wait quietly for the Collgen & matrix protein article. It was Retin A that the person in question used, too.

    Interesting that the ‘lower’ or further removed types of retinol actually may work just as well, just over a longer period of time. All consumers like to see quick results from a potion, but with this knowledge, some might be prepared to wait and possibly avoid side effects.

  8. Bess Gallanis says:

    Interesting work that you are doing on this site. What is your opinion about using Renova and stem cell derived product simultaneously? Not necessarily in the same application, but say one in the AM and Renova in the PM. I have used both treatments and tolerate them well, but have taken the precaution of using Renova in the winter and growth factors (AQ Skin Serum) in the summer.

    • drjohn says:

      Yes, there are perfectly compatible. We have now heard from many people using this combination, and it seems to be totally complimentary. In fact, with bone marrow derived stem cell based products (but not adipose tissue derived ones) the abundance of anti-inflammatory cytokines creates such a tolerance for tretinoin that people find they can increase their dose without any irritation. Heck, you can even throw in some dermabrasion or dermarolling. We have seen some amazing pictures.

  9. Chavy says:

    Is it possible that tretinoin can be damaging to the skin? At first, it was doing wonders evening out my skin tone and preventing acne but now that I’m 7 months in, I’ve recently been noticing new moles that are small and very light in color, a single dot on the skin under my right eye that I presume to be consistent with petechiae, and even broken capillaries on my cheeks! Say it ain’t so!! I currently use a 0.025% formulation and wear sunscreen religiously. Could it be from overuse of the tretinoin (I use more than about two pea sized amount for my face) causing accelerated photo damage by thinning my epidermis? Or could it be my sunscreen? I use Aveenos protect + hydrate spf 30. I’ve seen a lot of other users’ complaints online of tretinoin “ruining” their skin and am a bit concerned I may be in the same boat. Thanks in advance for your appreciated knowledge!!

    • drgeorge says:

      Chavy, in poking around the literature, I see nothing that links topical retinoic acid (tretinoin) to the changes you are describing. You can back off your dosage but the usual indication is redness and flaking, which you are not describing. Petechiae represent microhemorrhages and can be seen in bleeding disorders or excessive anticoagulation. A single one is highly unlikely. With aging, the “lesions” you describe occur through the years. Ask your prescribing dermatologist for his/her opinion. BTW, complaints of retinoic acid “ruining” skin are not borne out in the medical literature.

  10. anna says:

    This is an old study, but I would love to hear your thoughts on this. It concerns tretinoin and harmful tretinoin metabolites.Last paragraph.
    http://jamanetwork.com/journals/jamadermatology/article-abstract/419802

    The last paragraph posed a hypothetical that questioned whether metabolites of tretinoin might contribute to cancer in lung tissue – without offering evidence that such a relationship indeed exists.

    • drgeorge says:

      This is far from an indictment, and quite common in medical literature where “may” and “might” are some of the favorite words used. BFT could find nothing additional that discussed this particular question regarding tretinoin and lung cancer. BFT did find other articles with the opposite conclusion. (See below.) One suspects that a problem, if it did indeed exist, would by now have declarative and final conclusions. Nothing was found in multiple searches. Article snippets below.

      “We evaluated the baseline serum levels of beta carotene, total carotenoids, vitamin A and E, and retinol-binding protein among 156 initially healthy men who participated in the Multiple Risk Factor Intervention Trial (MRFIT) and who subsequently died of cancer and 311 controls individually matched for age, smoking status, randomization group, date of randomization, and clinical center. Both total carotenoids and beta carotene levels were lower in the 66 lung cancer cases than in their matched controls. For all cancer deaths combined, there were no significant differences in total carotenoids or beta carotene between cases and controls. The relationship between lower serum carotenoid levels and lung cancer persisted after adjusting for the number of cigarettes, alcohol intake, serum thiocyanate levels, and cholesterol levels in the blood. Serum levels of retinol, alpha tocopherol, and retinol-binding protein were not related to any cancer site. The results of this study provide further evidence for a possible protective effect of beta carotene against lung cancer among cigarette smokers.”

      Relationship between carotenoids and cancer. The multiple risk factor intervention trial (MRFIT) study Cancer Volume 64, Issue 11 July 1989 Pages 126–134

      “Vitamin-A is essential for growth and development of cells and tissues. In its active form, retinoic acid, it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations [Nature 37 (1994) 528; International Review of Cytology. San Diego Academic Press, 1–31]. Vitamin-A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin-A-deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin-A-supplementation [Aust. Paediatr. J. 22 (1986) 95; Lancet 338 (1991) 67]. In addition to the importance of the vitamin for the lung function, vitamin-A is also responsible for the development of many tissues and cells as well as for the embryonic lung development. Recent studies proved that the control occurs by different expressions of retinoid receptors as well as by time-dependent changes of the vitamin-A-metabolism respectively via cellular vitamin-A-binding proteins (CRBP: cytoplasmatic retinol binding protein; CRABP: cytoplasmatic retinoic acid binding protein)”

      Importance of vitamin-A for lung function and development
      Molecular Aspects of Medicine Volume 24, Issue 6, December 2003, Pages 431–440

      “In previously treated head-and-neck cancer patients, p.o. administered isotretinoin (13-cis retinoic acid) reduced the occurrence of second aerodigestive tumors, including lung tumors, but side effects made chronic therapy problematic. We reasoned that inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity, and we proceeded with the pilot study reported here. Male A/J mice were given single i.p. doses of urethane, a common experimental lung carcinogen, or benzo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), putative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 μg/l were initiated. After 2 weeks, the high dose caused severe toxicity on the snout skin, necessitating a reduction of dose frequency to twice a week. As a precaution, the mid dose was reduced to three exposures per week. The weekly total deposited doses after the dose frequency reductions were calculated to be 0.24, 1.6, and 24.9 mg/kg for the low, mid, and high doses, of which 16% was estimated to be deposited in the lungs. The weekly deposited pulmonary drug doses were calculated to be 0.01, 0.07, and 1.1% of a previously reported ineffective oral dose in urethane-treated A/J mice. After 10–16 weeks, mice were sacrificed to count areas of pulmonary hyperplasia and adenomas. For all carcinogens, the mice exposed to the high isotretinoin dose showed reductions of tumor multiplicity ranging from 56 to 80% (P < 0.005). The mid dose was associated with reductions of tumor multiplicity by 67 and 88% (P < 0.005) in BaP- and NNK-treated mice, respectively, and was tolerated until ∼12 weeks, when both these and the high-dose mice began losing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.13) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without any evidence of side effects. For BaP- and NNK-treated mice, numbers of hyperplastic areas directly correlated to dose level and inversely to tumor number, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relative to vehicle-exposed mice, RARα (3.9-fold vehicle), RARβ (3.3-fold), and RARγ (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results from this pilot study suggest that inhaled isotretinoin merits evaluation in people at high risk for lung cancer.” Inhaled Isotretinoin (13-cis Retinoic Acid) Is an Effective Lung Cancer Chemopreventive Agent in A/J Mice at Low doses: A Pilot Study Clinical Cancer Research Aug 2000

  11. Nicole says:

    I currently use tretinoin (1%) every other day and my skin tolerates it well (very mild occaisonal peeling that is easily remedied by a glycolic acid lotion and my Clarisonic). I am considering adding microneedling (0.5 mm) to my routine. How long should I wait after microneedling before resuming applications of tretinoin?

    • drgeorge says:

      Our standard precaution following microneedling is to not apply any product that contains non-physiologic (non-native to the skin) ingredients until the microperforations have had time to seal and close. There is greatly enhanced penetration into the skin because of the thousands of tiny holes. They several hours to close so we recommend waiting 6-8 hours and preferably overnight before applying product other than those made specifically for microneedling. The danger is introducing something that initiates an allergic or inflammatory response which can then lead to fibrosis similar to a foreign body reaction (granulomatous dermatitis), or even post-inflammatory hyperpigmentation in susceptible darker-skinned individuals. We are aware of nasty reactions related to products with so-called snail “growth factors” and even vitamin C and hyaluronic acid products. Snails have 60-70% allergic cross-reactivity to people with dust mites, one of the most common allergies there is. Vit C and HA products may have other ingredients that cause the reaction. We developed a product based on human skin physiology that is now sold by us (AnteAGE, AnteAGE MD, AnteAGE HOME brands) and other major players in the micorneedling space under private label arrangements. Call or email if you care to learn more.

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