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What is retinol

What is retinol

Retinol also called preformed vitamin A or retinoid, is the alcohol form of vitamin A 1. Retinol is a form of vitamin A found only in foods that come from animal sources such as organ meats (such as liver), dairy products, fish, eggs and some fortified food products such as breakfast cereals. Retinol is the immediate precursor to two important active metabolites: retinal, which plays a critical role in vision, and retinoic acid, which serves as an intracellular messenger that affects transcription of a number of genes. Vitamin A cannot be synthesized by the body; hence it needs to be supplied to the body. The body can use retinol to make retinal and retinoic acid (other forms of vitamin A).

Naturally, vitamin A is obtained through the diet in two forms:

  • Preformed vitamin A (retinol and retinyl ester) is derived from animal sources such as organ meats (such as liver), dairy products, fish and eggs. The retinyl esters are converted to retinol before absorption from food in the small intestine and back to retinyl esters for storage in the liver. 
  • Provitamin A (carotenoids) are derived from colorful fruits, vegetables and other plant-based products. Carotenoids are yellow- to orange-colored organic pigments found in several fruit and vegetables. In addition to their relationship to vitamin A, they are known for their antioxidant activities. Some of the most well-known carotenoids are beta-carotene (β-carotene), alpha-carotene (α-carotene), lutein, lycopene and cryptoxanthin. The most common provitamin A carotenoid in foods and dietary supplements is beta-carotene (β-carotene). Provitamin A (carotenoids) are turned into vitamin A by your body.

Both ingested forms of vitamin A must be converted to retinal and retinoic acid after absorption to support biological processes 2. The various forms of vitamin A are solubilized into micelles (molecules dispersed in a liquid, forming a colloidal suspension) in the intestinal lumen and absorbed by duodenal mucosal cells 3. Retinyl esters and provitamin A carotenoids (beta-carotenoids) are converted to retinol after uptake into the lumen (for retinyl esters) or absorption (for provitamin A carotenoids). Retinol is then oxidized to retinal and retinoic acid, the two main active vitamin A metabolites in the body 4. Most of the body’s vitamin A is stored in the liver in the form of retinyl esters 4.

Vitamin A is a fat soluble vitamin that has multiple functions for the human body: vitamin A is important for growth and development of bone growth, tooth development, vision (especially in the dark by helping the eyes to adjust to light changes), reproduction, cell division, gene expression, and for the maintenance of the immune system 5, 6. Essentially, the skin, eyes, and mucous membranes of the mouth, nose, throat and lungs depend on vitamin A to remain moist 7. Vitamin A is also an important antioxidant compound that may play a role in the prevention of certain cancers 8.

The recommended daily allowance for vitamin A is 300 to 700 microgram (μg) for children and approximately 700 to 900 microgram (μg) for adults (900 micrograms/day for adult males and 700 micrograms/day for adult females), amounts which can be provided by a normal diet 9. Higher doses of vitamin A can be toxic, leading to a constellation of signs and symptoms as well as liver injury, jaundice, enlargement of the liver and spleen, portal hypertension and cirrhosis.

Good sources of vitamin A (retinol) include:

  • cheese
  • eggs
  • oily fish
  • fortified low-fat spreads
  • milk and yoghurt
  • liver and liver products such as liver pâté – this is a particularly rich source of vitamin A, so you may be at risk of having too much vitamin A if you have it more than once a week (if you’re pregnant you should avoid eating liver or liver products)

You can also get vitamin A by including good sources of beta-carotene in your diet, as the body can convert this into retinol.

The main food sources of beta-carotene are:

  • yellow, red and green (leafy) vegetables, such as spinach, carrots, sweet potatoes and red peppers
  • yellow fruit, such as mango, papaya and apricots

Retinol/vitamin A is generally stored in the liver from where it is mobilized into blood circulation bound to retinol binding protein (RBP) also known as RBP4. Liver exhibits high affinity binding sites for RBP4 10. The stored vitamin A/retinol is mobilized into blood plasma by the enzymes retinyl ester hydrolases 11. The normal concentration of retinol in blood plasma varies between 1.0 and 2.0 μM 12.

The mechanism/s by which retinol executes its function however, remain poorly understood.

Retinol is metabolized into four important products:

  1. Retinyl esters,
  2. All-trans retinoic acid,
  3. 14-hydroxy-4, 14-retro retinol, and
  4. All-trans 3, 4-didehydroretinol, and its esters.

Retinoids are required for a vast number of biological processes. In particular, they are involved in embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. Retinal is an essential part of the rhodopsin pigment, necessary for vision 13. Retinoids are found in the keratinocytes in two forms: retinol and retinyl esters – probably the storage form.

Studies of the past two decades have shown that retinol is associated with cell differentiation via its most potent metabolite retinoic acid 1. Retinol (vitamin A) executes its function via retinoic acid and regulates the function of >500 genes involved in development and cell differentiation 14. The circulating retinol in blood plasma binds to a 21 kDa retinol binding protein (RBP) also known as RBP4 and thyroxine binding-protein transthyretin (TTR) to form a ternary retinol-RBP-TTR complex in 1:1:1 molar proportion that binds to the target cell via cell surface receptor STRA6 (stimulated by retinoic acid 6) for transport into the target cell 15.

Inside the cytoplasm, retinol/vitamin A binds to a 15 kDa cellular retinol binding protein (CRBP) and is converted into retinoic acid by two sequential oxidation steps that convert first retinol into retinaldehyde and then to retinoic acid. Though the conversion of retinol into retinaldehyde is reversible, the retinoic acid cannot be reduced back to retinol. Retinol is converted into retinaldehyde by retinol dehydrogenases (Rdh10) whereas the enzymes that metabolize retinaldehyde into retinoic acid include retinaldehyde dehydrogenases Ralhd1 (Aldhd1), Ralhd2 (Alhd1A2) and Ralhd3 (Alhd1A3) 16.

Retinoic acid is then transported to the nucleus where it binds to heterodimer receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR) which belong to the superfamily of ligand-inducible transcriptional regulators that include steroid hormone receptors, thyroid hormone receptors, and vitamin D3 receptors. This complex then binds to the retinoic acid responsive elements (RARE) in the promoter region of the retinoic acid-responsive genes to activate their expression 17.

Table 1. Commonly used names and abbreviations for vitamin A and its derivative

RetinoidAlso Known As
Vitamin ARetinol
TretinoinAll-trans-retinoic acid
Isotretinoin13-cis-retinoic acid
Alitretinoin9-cis-retinoic acid
[Source 18 ]

Table 2. Recommendations for vitamin A intake by age or population group by the Institute of Medicine 19 and the Food and Agriculture Organization of the United Nations (FAO) 20

US Institute of Medicine
Food and Agriculture Organization of the United Nations (FAO)
Life-stage groupEAR, μg RAEs/dAI or RDA, μg RAEs/dUL,2 μg REs/dMean requirement, μg REs/dRecommended safe intake, μg REs/d
 0–6 months400600180375
 7–12 months500600190400
 1–3 years210300600200400
 4–6 years200450
 4–8 years275400900
 7–9 years250500
 9–13 years
Adolescents aged 10–18 years
  14–18 years4857002800
  ≥19 years5007003000270–300500–600
  14–18 years6309002800300600
  ≥19 years6259003000300600
  14–18 years5307502800370800
  19–50 years5507703000370800
  14–18 years88512002800450850
  19–50 years90013003000450850

Footnote: 1RAEs are based on preformed retinol and a bioconversion factor of 12 μg beta-carotene to 1 μg retinol and REs are based on preformed retinol and a bioconversion factor of 6 μg beta-carotene to 1 μg retinol. 2The Tolerable Upper Intake Level (UL) is based on preformed retinol alone.

  • Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
  • Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
  • Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
  • Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

Abbreviations: AI = Adequate Intake; EAR = Estimated Average Requirement; RAE = retinol activity equivalent; RE = retinol equivalent; UL = Tolerable Upper Intake Level.

[Source 21 ]

Table 3. Vitamin A content of selected foods

Foodmcg RAE per servingPercent DV*
Beef liver, pan fried, 3 ounces6582731
Sweet potato, baked in skin, 1 whole1403156
Spinach, frozen, boiled, ½ cup57364
Pumpkin pie, commercially prepared, 1 piece48854
Carrots, raw, ½ cup45951
Herring, Atlantic, pickled, 3 ounces21924
Ice cream, French vanilla, soft serve, ⅔ cup18521
Milk, skim, with added vitamin A and vitamin D, 1 cup14917
Cantaloupe, raw, ½ cup13515
Cheese, ricotta, part skim, ½ cup13315
Peppers, sweet, red, raw, ½ cup11713
Mangos, raw, 1 whole11212
Breakfast cereals, fortified with 10% of the DV for vitamin A, 1 serving9010
Egg, hard boiled, 1 large758
Black-eyed peas (cowpeas), boiled, 1 cup667
Apricots, dried, sulfured, 5 apricots637
Broccoli, boiled, ½ cup607
Salmon, sockeye, cooked, 3 ounces597
Tomato juice, canned, ¾ cup425
Yogurt, plain, low fat, 1 cup324
Tuna, light, canned in oil, drained solids, 3 ounces202
Baked beans, canned, plain or vegetarian, 1 cup131
Summer squash, all varieties, boiled, ½ cup101
Chicken, breast meat and skin, roasted, ½ breast51
Pistachio nuts, dry roasted, 1 ounce40

Footnotes: *DV = Daily Value; RAE = retinol activity equivalent. FDA developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin A is 900 mcg RAE for adults and children age 4 years and older, where 1 mcg RAE = 1 mcg retinol, 2 mcg beta-carotene from supplements, 12 mcg beta-carotene from foods, 24 mcg alpha-carotene, or 24 mcg beta-cryptoxanthin. FDA does not require food labels to list vitamin A content unless vitamin A has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source 22 ]

Figure 1. Retinol

retinol chemical structure

Figure 2. Vitamin A and retinoids structures

Vitamin A and retinoids structures

Footnote: The structure of vitamin A and retinoids. The retinoids represented belong to the four described generations. First-generation compounds are found in the diet, except for some natural metabolites formed in the body. Members of the 2nd, 3rd and 4th generations are synthetic derivates based on the original retinoic structure and are used in treating different diseases. All retinoids possess a common structure and similar physicochemical properties, although their effects on the human body can vary greatly.

[Source 23 ]

Figure 3. Major dietary forms of vitamin A

major dietary forms of vitamin A

Footnotes: The structures of the major dietary forms of vitamin A. Preformed retinol is primarily found as retinyl palmitate in most animal livers, fortificants, and supplements. From ∼50 provitamin A carotenoids in plants, the common ones include α-carotene, β-carotene, and β-cryptoxanthin. These forms of provitamin A carotenoids are often quantified in human serum.

[Source 24 ]

What does retinol do?

The importance of retinol (vitamin A) was discovered during World War I and subsequent research showed that its deficiency gives rise to xerosis (dry skin) and follicular hyperkeratosis (skin condition characterized by excessive development of keratin in hair follicles, resulting in rough, cone-shaped, elevated papules) 25. These observations were followed by numerous studies focused on the metabolism and pharmacological action of retinoids in the skin leading to the establishment of retinoic acid treatment for various skin diseases 26.

Vitamin A is required for the regulation of numerous key biological processes including roles in the following:

  • vision (proper functioning of the retina),
  • growth and differentiation of target tissues,
  • maintenance of epithelial surfaces,
  • modulation of immune function,
  • reproduction and proper functioning of the reproductive organs,
  • embryonic growth and development.

Retinol is the precursor for ≥2 essential biologically active molecules: all-trans retinoic acid as the ligand of nuclear receptors, such as RARs 27, and 11-cis-retinal required in the visual cycle 28.

Critical Steps in the Functions of Vitamin A

Vision 28

  • 11-cis Retinal binds to opsin to form rhodopsin, which can absorb light within the visible spectrum.
  • When 11-cis retinal absorbs a photon, it isomerizes to all-trans retinal through several intermediate species and is rapidly released from opsin.
  • The isomerization of 11-cis retinal is the initial step in vision. An excited intermediate of rhodopsin greatly amplifies light-induced hyperpolarization of the rod membrane, resulting in generation of the nerve impulses for vision.

Nuclear receptors/gene regulation

  • All-trans retinoic acid is the most biologically relevant metabolite of vitamin A.
  • Retinoic acid binds and activates several nuclear receptors, i.e., RARs, retinoid X receptor, and PPARs 29.
  • Upon ligand binding, RAR dimerizes with a retinoid X receptor to form a heterodimer, which then initiates gene transcription by binding to the retinoic acid response element in the promoter region of >500 target genes 30.
Functional Roles of Vitamin A


In the eye, the retina is the structure responsible for visual perception, including its transmission to the brain. This perception is mediated by specific structures in the retina: rods and cones. Rods are sensitive to low light and hence are crucial for vision in dark situations (e.g., night vision), whereas cones are responsible for high-intensity light (color vision). A deficiency in retinol leads to low light vision impairment due to deficient rhodopsin formation 23. This situation causes night blindness, which is also called nyctalopia 31. Low light vision can be recovered after the normalization of plasma retinol levels. However, it takes several weeks until the normal function is completely restored.


Vitamin A deficiency negatively affects hemoglobin concentrations. Supplementing women with vitamin A and iron enhanced hemoglobin concentrations more than either nutrient alone 32.

Immune Function

  • The regulatory roles of vitamin A in mammals include the maintenance of epithelial cell differentiation and immune competence 33.
  • Vitamin A supports innate immune function by supporting regeneration of mucosal barriers damaged by infection in children and by enhancing the function of neutrophils, macrophages, and NK cells, as described primarily in rodents 33.
  • Vitamin A is required for adaptive immunity and plays a role in the development of T-helper (Th), T-regulatory, and B cells, but more in vivo work is needed 33.
  • All-trans retinoic acid is a potent regulator of gene expression, and it controls leukocyte homing and T-regulatory function 34. Its production by cells of the immune system is regulated during an immune response in a manner that is still being elucidated 35.
  • In human T lymphocytes, all-trans retinoic acid inhibited the production of cytokines that favor the generation of Th1-type T cells and enhanced the production of cytokines favoring the Th2-type T cells 36.


  • Meta-analyses of human studies have shown an inverse relation between dietary amounts of vitamin A and various cancers, for example, bladder 37, breast 38, cervical 39, and gastric 40.
  • Synthetic retinoids and some naturally occurring retinoids (e.g., all-trans retinoic acid, 9-cis retinoic acid, 13-cis retinoic acid) have been used in clinical studies 41.
  • Certain retinoids inhibit the growth of various tumors (e.g., lung, gastrointestinal, breast) and may have chemopreventive and/or chemotherapeutic properties 42.
  • All-trans retinoic acid is used as a chemotherapeutic agent to treat acute promyelocytic leukemia, and in the vast majority of these patients this treatment leads to a complete remission 43.

Retinoids, the natural and synthetic analogues of retinol, have been of significant interest as cancer preventive agents since late 1970s 44. They have been used in many clinical trials to assess the role of β-carotene in cancer prevention. Almost 27 years ago, the first phase of β-Carotene and Retinol Efficacy Trial (CARET) among men and women at high risk of lung cancer was stopped early primarily due to an increased risk of lung cancer 45. Similarly α-tocopherol and β-carotene (ATBC) and CARET study found an increased risk of lung cancer among those assigned to active β-carotene treatment 46 or no significant benefit of β-carotene 47. On the other hand, β-carotene alone was found to be associated with an increased risk of aggressive prostate cancer in a nested case-control study 48. The outcome of these trials therefore, led some to question the safety of β-carotene supplementation for cancer prevention.


  • Type 1 diabetes has been associated with lower concentrations of serum retinol and its carrier proteins (RBP and transthyretin) in patients 49.
  • Type 2 diabetes has a less-clear relation with serum retinol and carrier proteins, with some studies showing no change and others showing reductions in type 2 diabetes 50.
  • Vitamin A deficiency and excess have varying and discordant effects on macronutrient metabolism in various tissues and cell types 51.
  • Vitamin A is involved in pancreatic development and function: deficiency caused reduced β cell mass in fetal islets 52 and reduced glucagon and insulin secretion from pancreatic α and β cells, respectively 53.
  • Retinol Binding Protein secreted by adipose tissue has been implicated as a link between obesity and insulin resistance by interrupting insulin signaling in muscle and increasing hepatic glucose output 54.
  • In human macrophages, Retinol Binding Protein may cause insulin resistance by contributing to adipocyte inflammation through proinflammatory cytokine activation, and the mechanism is retinol- and STRA6-independent 55.
  • The public health link of vitamin A status to diabetes needs further investigation.

Energy metabolism and obesity

  • Evidence in animals exists for a role of vitamin A in maintaining energy metabolism; however, more research is needed.
  • Retinoic acid exerts its broad range of biological effects in large part by controlling gene expression. Early in adipogenesis, retinoic acid blocks differentiation, whereas after 48 h of differentiation, it promotes fat cell formation 56.
  • Mice lacking retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance. Administration of retinal or an Raldh1 inhibitor to obesity-susceptible mice reduced fat accumulation and increased insulin sensitivity 56.
  • In mice with active protein kinase C, retinol supplementation showed that retinol is a metabolic cofactor involved in the regulation of mitochondrial fuel utilization 57.

HIV and pregnancy

  • Currently, no conclusive evidence of vitamin A supplementation on vertical HIV transmission exists; therefore, the WHO does not recommend supplementation in HIV-positive pregnant women to reduce the risk of mother-to-child transmission 58, 59.
  • Cochrane reviews indicated that vitamin A alone 60 and micronutrient supplementation 61 should not be used as a substitute for recommended antiretroviral medication.
  • In infants with mannose-binding lectin-2 variants, vitamin A supplementation to mothers at delivery was associated with a decreased risk of HIV transmission 62.
  • Future work is needed on the effect of vitamin A supplementation on HIV transmission from mother to child that accounts for the potential effect of an innate immune deficiency.


  • On the basis of a randomized, placebo-controlled clinical trial in children with measles, along with other clinical research, the WHO recommends that age-appropriate doses of vitamin A be given twice 24 h apart to infants and children with measles in populations in whom vitamin A deficiency may be present to decrease the risk of death from measles 63. Recommended doses are 30,000 mcg RAE (100,000 IU) of vitamin A once for infants ages 6–11 months and 60,000 mcg RAE (200,000 IU) every 4–6 months for ages 1–5 years 64.
  • Prevention of vitamin A deficiency by using periodic, high-dose supplements in communities in which vitamin A deficiency is a public health problem decreases the risk of developing measles in children 6–59 mo of age 65.

Serum retinol concentrations

Serum retinol concentration measurements by high-performance liquid chromatography are a common method used to assess vitamin A status of populations 66. The current cutoff used to define a severe public health problem for vitamin A deficiency is when 20% of children aged 6–71 months have a serum retinol concentration <0.7 μmol/L 67. Although currently recommended for use by the WHO, serum retinol concentrations should not be used alone to define the degree of public health significance but should be used in conjunction with another biological indicator or when ≥4 of the following risk factors are found in the population being evaluated 67:

  • infant mortality rate >75 of 1000 live births and under-5-y mortality rate of >100 of 1000 live births;
  • full immunization coverage in <50% of children at 12–23 mo of age;
  • <50% prevalence of breastfeeding in 6-mo-old infants;
  • median dietary intakes <50% of recommended safe levels of intake among 75% of children 1–6 y of age;
  • 2-wk period prevalence of diarrhea of ≥20%;
  • measles case fatality rate of ≥1%;
  • no formal schooling for ≥50% of women 15–44 y of age; and
  • <50% of households with a safe water source (e.g., boiled, treated, filtered, properly stored).

Serum retinol and retinol-binding protein tend to be lower in infants and young children than in adults, even in vitamin A–adequate populations. Therefore, the same cutoff cannot be used for infants <6 mo of age 68. However, the relative concentration to define vitamin A deficiency in infants has not been determined and is a research question that needs to be addressed. Serum retinol concentration tends to increase through middle-age in the US population (particularly in men but also in women >60 y of age) and may represent a continuing, although less pronounced, association of liver vitamin A stores 69.

Retinol-binding protein concentrations do not vary by sex, generally speaking, and the lower serum retinol concentrations in women than in men in middle-age may be due to differences in liver stores or to the higher prevalence of inflammation in women 69. The cutoff used for deficiency in adults varies, and some researchers choose to use 0.7 μmol/L whereas others suggest 1.05 μmol/L 68. The hepatic synthesis of retinol-binding protein is depressed during zinc deficiency 70, which results in lower plasma retinol concentrations that confound measurements in zinc-deficient individuals. Pregnancy lowers serum retinol concentrations through hemodilution.

Serum Retinol Concentration Use in Clinical Application

Serum retinol concentrations are affected by infection status. Retinol-binding protein is a negative acute-phase protein, and thus retinol and retinol-binding protein concentrations decrease during the acute-phase response 71. Therefore, serum retinol has very little utility to diagnose vitamin A deficiency when individuals have an infection. In addition, serum retinol concentrations are homeostatically controlled over a broad range of liver reserves and thus are best used at the population level as detailed above.

Use of serum retinol concentrations in epidemiologic studies

Serum retinol concentrations are determined and have been evaluated in epidemiologic surveys. A recent evaluation of NHANES III data in adults ≥50 y of age determined that serum retinol concentrations that were either <1 μmol/L or >2.8 μmol/L were associated with increased risk of all-cause and cardiovascular or coronary artery disease–related mortality 71. The significance of these findings is not entirely known. In otherwise well-nourished individuals who are not experiencing inflammation, serum retinol concentrations <1 μmol/L may reflect vitamin A deficiency 68. It appears that serum retinol concentrations are increasing over time in well-nourished Americans, which may be associated with increased catabolism 72 due to the fortification of a variety of foods and multivitamin supplement use that increase total body stores over time 73.

Effect of infection or inflammation on serum retinol concentrations

The acute-phase response to either infection or inflammation affects retinol homeostasis. The acute-phase response on micronutrient status markers has been reviewed 74. Currently, concentrations of C-reactive protein (CRP) and α1-acid glycoprotein (AGP) have been used to identify infection stage according to a proposed published paradigm: elevated CRP alone indicates the incubation or early phase of an acute infection, elevated CRP and AGP indicate early convalescence, and elevated AGP only indicates late convalescence. These inflammation stages have been used to correct serum retinol concentrations or to choose lower cutoffs for serum retinol as a marker of deficiency 75. During early convalescence, serum retinol concentrations are shifted further to the left than during late convalescence or incubation 71.

Retinol for skin

Many epithelial cells appear to require vitamin A for proper differentiation and maintenance. Lack of vitamin A leads to dysfunction of many epithelia – the skin becomes keratinized and scaly, and mucus secretion is suppressed 76. It seems likely that many of these effects are due to impaired transcriptional regulation due to deficits in retinoic acid signalling.

Dietary retinyl esters and β-carotene are converted to retinol by the liver. In the liver, retinol is either reesterified to retinyl ester for storage or released into the circulation 77. Bound to retinol-binding protein, retinol reaches the skin via capillaries in the dermis 78. Cellular uptake of retinol from plasma is thought to occur via receptor-mediated uptake or endocytosis 79. Cells in both the epidermis and dermis are targets for retinoid action. Keratinocytes and fibroblasts convert retinol first to retinaldehyde and then to all-trans-retinoic acid (tretinoin) 80.

The physiological actions of retinoids in the skin are mediated primarily through their interactions with retinoic acid receptor (RAR) and retinoid X receptor (RXR), members of a superfamily of ligand-activated transcription factors 78. The primary isoforms present in human epidermis are RAR-α and RXR-γ. More specifically, mRNA and protein levels of total and isoform-specific RXR and RAR were measured in human epidermal biopsies 81. There is approximately 5-fold more total RXR than total RAR protein. Of these totals, the isoforms present are: 90% RXR-α and no detectable RXR-β or RXR–γ and 87% RAR-γ, 12-14% RAR-α, and no detectable RAR-β. RAR-β is present only in the dermis and not in keratinocytes 82.

Human epidermal cells preferentially bind tretinoin 83. In skin cells, other retinoids (alitretinoin, isotretinoin and all-trans-retinol) isomerize to tretinoin, the primary ligand that mediates RAR-dependent responses in human skin 84, 85. Skin cells also have the capacity to convert β-carotene into vitamin A metabolites. Incubation with radiolabelled β-carotene increased retinol concentration in cultures of human keratinocytes and melanocytes 86. Topically applied β-carotene increased the retinyl ester content in excised human skin samples in hairless mouse skin, demonstrating that β-carotene can serve as a precursor to epidermal vitamin A 87.

Figure 4. Retinoids in dermatological therapy

retinoids in dermatological therapy


In addition to their known role in the treatment of photodamaged skin (photoaging), pretreatment with retinoids might prevent ultraviolet (UV)-induced damage in the first place.

Ultraviolet radiation (UVR) damages skin via many mechanisms. One way ultraviolet radiation contributes to photodamage is by modulating signaling pathways that influence collagen homeostasis in skin cells (4, 25). For example, ultraviolet radiation induces the transcription factor AP-1, which increases the expression of several matrix metalloproteinases (MMPs) (collagenase, gelatinase, stromelysin), proteolytic enzymes that degrade dermal collagen and fibrillin 80.

In a small sampling of adult subjects (N=6), biopsies of irradiated and non-irradiated buttock skin were compared before and after pretreatment with tretinoin 88. UV-B (2X Minimal Erythemal Dose [MED], which is the lowest dose of ultraviolet radiation that will produce a detectable erythema 24 hours after ultraviolet radiation exposure) increased DNA binding of the transcription factors AP-1 and NF-kappa-B followed by increased mRNA, protein, and activity levels of collagenase, stomelysin, and gelatinase—matrix-degrading metalloproteinases (MMPs) regulated by these transcription factors. Pretreatment with tretinoin inhibited UVB-induced AP-1 DNA-binding activity (a process call transrepression), as well as MMP expression and activity by 50-80% 89. In a second human study, skin samples were obtained in irradiated and non-irradiated buttock skin from 59 white subjects (mean age, 35 years) who were pretreated with tretinoin or vehicle 48 hours prior to UV exposure 90. Notably, the ultraviolet radiation dose used in this study did not cause erythema and was equivalent to five to 15 minutes of exposure to noonday sun. The authors demonstrated that ultraviolet radiation induced three MMPs, collagenase, gelatinase, and stromelysin, in the epidermis and dermis. Pretreatment with tretinoin inhibited UV-induced MMP expression and activity by 70-80% without affecting the expression of their inhibitor (tissue inhibitor of MMP type I [TIMP]). In a separate study with the same study design, pretreatment with retinoic acid prevented UV-induced reductions in RXR-α and RAR-γ protein levels and transcriptional activity in buttock skin compared to non-irradiated sites on the same individual (N=70) 91. Overall, retinoids appear to prevent photodamage by interfering with ultraviolet radiation-mediated activation of signaling pathways that damage dermal collagen.


Clinical signs of photoaging include fine and coarse wrinkles, mottled hyperpigmentation, actinic lentigines, freckles, roughness, telangiectasia, and sallowness 92. These traits are reflective of histological changes in both the epidermis and dermis in sun-exposed skin.

Topical retinoids lead to visible improvement in fine wrinkling, smoothness, and hyperpigmentation of photodamaged skin 93, 88, 94. Topical retinoids induce a number of histological changes in both the epidermis and dermis, and it is thought that changes in dermal collagen underlie the observed clinical improvements 95, 96. Both clinical and histological skin parameters return to baseline upon discontinuation of topical application of retinoids; thus, a long-term maintenance regimen is necessary to sustain retinoid-induced improvements 97.


In a vehicle-controlled trial, the activity between all-trans-retinol and all-trans-retinoic acid (tretinoin) was compared in human skin 98. Vehicle, all-trans-retinol (1.6%), and tretinoin (0.025%) were applied to different sites on the buttock skin of seven subjects and compared after four days of continuous occlusion. Although a much higher concentration of retinol was needed to achieve similar results (retinol was ~20-fold less potent than retinoic acid), retinol induced the same histological changes (hyperplasia and spongiosis) as tretinoin without causing erythema.

Retinol has also been evaluated in the treatment of naturally aged human skin. Although the features of naturally aged and photodamaged skin differ, disrupted collagen homeostasis is thought to contribute to wrinkling in both situations 92. Skin biopsies from 72 individuals from four age groups (18-29 years, 30-59 years, 60-79 years, and ≥80 years) were compared 99. Naturally aged skin exhibits reduced fibroblast proliferation, increased metalloproteinase (MMP) expression, and reduced collagen synthesis. In a separate analysis, 53 individuals (80 years and older) were treated with 1% topical retinol or vehicle on buttock skin for seven days 99. Topical retinol increased dermal fibroblast number, reduced MMP expression, and increased collagen synthesis compared to vehicle-treated sites. Thus, even after only seven days of application, topical retinol partially reversed some of the cellular abnormalities present in naturally aged skin. In a randomized, double-blind, vehicle-controlled study, 36 elderly subjects (mean age, 87 years) received topical 0.4% retinol (retinol) lotion or vehicle to their left or right upper, inner arm 3 times/week for 24 weeks 100. Topical retinol improved clinical appearance (fine wrinkling) and increased the expression of two matrix molecules, glycosaminoglycan and procollagen 1, compared to vehicle-treated skin. Most subjects reported mild cutaneous irritation on the retinol-treated arm, including erythema, peeling, pruritis, dryness, and burning/stinging.


In a randomized, double-blind, vehicle-controlled trial, 800 adults (mean age 53.5 years) with moderate to severe photodamage applied topical 0.1% isotretinoin (13-cis-retinoic acid) or vehicle to the face, forearms, and hands nightly for 36 weeks 101. According to physician and patient assessment, isotretinoin treatment resulted in significant improvements in overall appearance, fine and coarse wrinkling, texture and hyperpigmentation compared to baseline. Computer image analysis revealed a 20% reduction in facial wrinkle length following isotretinoin treatment compared to baseline; no change was observed in vehicle-treated skin. Most patients reported adverse events (erythema, peeling/scaling, burning, pruritis) as mild to moderate, though 5-10% of patients graded them as severe. Punch biopsies (N=120) from forearm skin showed that isotretinoin increased epidermal thickness but did not alter any other histological parameters. Consistent with other reports, there was no change in plasma retinoid levels throughout the study period.


Among the retinoids, tretinoin (all-trans-retinoic acid) is the most extensively studied topical agent for skin health 78, 94. Topical tretinoin is most effective for treating fine facial wrinkles, rough texture associated with photodamage, and mottled epidermal pigmentation.

In one of the earliest evaluations of the efficacy of topical tretinoin on photodamaged skin, punch biopsies were obtained before and after treatment with 0.05% tretinoin cream or vehicle to photodamaged forearm and facial skin in a small sampling of elderly volunteers (aged 66-77 years) 102. After three months (forearms, N=16) or six to 12 months (face; N=8), histological abnormalities characteristic of end-stage epidermal photoaging (fewer cell layers, smaller cells, flattening of the dermatoepithelial junction, dense perinuclear clustering of large melanocytes, and hyperkeratosis) were corrected in tretinoin-treated skin. Dermal changes were not obvious, and the permanence of the tretinoin-induced changes was not evaluated 102.

These observations set the stage for subsequent randomized controlled trials (RCTs) evaluating the safety and efficacy of topical retinoids in the treatment of photodamaged skin. In an early randomized, double-blind, vehicle-controlled trial, 30 patients (mean age, 50 years) with photodamaged skin applied 0.1% tretinoin cream or vehicle once nightly for four months to photodamaged facial and forearm skin 103. Significant improvement in fine facial wrinkling, coarse wrinkles, sallowness, roughness, and actinic lentigines was observed following topical tretinoin treatment. Ninety-two % of patients experienced “retinoid dermatitis” that lasted from two weeks to three months. Histologic data showed that tretinoin-treated forearm skin exhibited increased epidermal thickness, compaction of the stratum corneum (SC), and increased vascularity in the papillary dermis compared to vehicle-treated skin. A subset of subjects continued in an open-label format for a total of 10 months (N=21) or 22 months (N=16) of topical tretinoin treatment 104. Clinical changes in fine wrinkling and texture of facial skin were sustained despite reduced dose (0.05%) or frequency (every other day) of tretinoin application.

Biopsies obtained from photodamaged forearm skin and sun-protected buttock skin were compared in 26 healthy, white subjects (mean age, 56 years) 105. Collagen 1 formation (detected immunohistochemically) was 56% lower in the papillary dermis in photodamaged skin. In a separate analysis, 29 healthy subjects (mean age, 63 years) were randomly assigned to receive daily application of 0.1% tretinoin cream or vehicle for 10 to 12 months on photodamaged skin 105. Tretinoin treatment resulted in an 80% increase in collagen 1 formation compared to baseline. Thus, topical tretinoin partially restored collagen formation in the dermis of photodamaged skin.

These trials provided abundant information regarding the effect of topical tretinoin on photodamaged skin, but they are somewhat limited by small sample sizes. As a result, a number of larger, long-term, randomized controlled trials have been conducted that corroborate the efficacy of topical tretinoin in the treatment of clinical and histological features of photoaging.

Different doses of topical tretinoin were evaluated in a large, multicenter, double-blind, vehicle-controlled randomized controlled trial involving 533 subjects (mean age 42 years) with mild to moderately photodamaged facial skin (16). Three concentrations of tretinoin were tested: 0.05%, 0.01%, and 0.001%. After six months of treatment, 0.05% and 0.01% tretinoin produced four significant epidermal differences compared to vehicle-treated skin: (1) increased epidermal thickness, (2) increased number of granular cell layers, (3) decreased melanin content, and (4) stratum corneum compaction. The 0.001% tretinoin was no more active than vehicle. A second very similar multicenter randomized controlled trial compared these same doses of topical tretinoin in the treatment of photodamaged facial skin 106. In this trial, 296 subjects (mean age, 42.5 years) applied topical tretinoin emollient cream or vehicle to the entire face nightly for 24 weeks. Significant clinical improvement in mottled hyperpigmentation, fine wrinkling, and roughness, and the same histological changes noted above occurred with 0.05% and 0.01% tretinoin emollient cream compared to vehicle, though 0.05% tretinoin emollient cream was the most effective dose. A third multicenter randomized controlled trial compared 0.05% or 0.01% topical tretinoin applied daily for 24 weeks to photodamaged facial skin in 299 subjects (mean age, 42 years) 107. As above, 0.05% tretinoin improved the same clinical and histological features of photoaging after six months of treatment. 0.01% tretinoin was less effective, only improving fine wrinkling scores.

To assess longer-term clinical and histological effects, a subset of subjects from two of the multicenter trials 107, 106 continued in a 24-week double-blind extension trial 108. All subjects received active treatment of either 0.05% tretinoin emollient cream (N=126) or 0.01% tretinoin emollient cream (N=133), although subjects and investigators were blinded to dose. Clinical improvements in fine wrinkling, roughness, and mottled hyperpigmentation were maintained or enhanced over the extension period. Continued clinical improvement was more evident in the 0.01% tretinoin emollient cream group, with clinical scores approaching those of the 0.05% dose. Histological parameters were more variable. In both groups, reversal of the increase in stratum corneum compaction, epidermal thickness, and number of granular cell layers was observed at the end of the extension period. Melanin content, on the other hand, continued to decrease at both doses of tretinoin emollient cream. After 48 weeks of exposure, new histological changes were observed at both concentrations of tretinoin emollient cream, including increased epidermal mucin content and reduced dermal elastin content.

Twenty-five subjects from two of the previously conducted controlled trials 107, 109 provided punch biopsies from the periorbital region of the face in order to assess ultrastructural changes associated with topical tretinoin treatment 96. While no changes were evident after six months, electron microscopy revealed clear morphological changes in the papillary dermis (replacement of disorganized collagen fibers with well-organized, packed fibers) after 12 months of topical 0.05% tretinoin treatment. A small number of subjects [(N=27) from abovementioned trial 106 were followed even further, up to four years, after varying exposures of 0.001–0.05% tretinoin emollient cream, applied once weekly to once daily 110. As was observed after 48 weeks of tretinoin emollient cream exposure 97, the epidermal changes observed during the initial phases of topical tretinoin treatment were no longer evident, and there was a significant increase in epidermal mucin content and a significant decrease in dermal elastin content. No signs of abnormal cell or tissue morphology were observed. More recently, 204 subjects (mean age, 63 years) with moderate to severe facial photodamage were randomized to apply 0.05% tretinoin emollient cream or vehicle once daily for two years 111. Topical tretinoin resulted in a significant improvement in clinical signs of photodamage (fine and coarse wrinkling, mottled hyperpigmentation, lentigines, and sallowness) compared to placebo after 24 months of treatment. Mild cutaneous irritation was higher in the tretinoin group and peaked in the first two months, but the overall incidence of adverse events was similar in the tretinoin and placebo groups at the end of the study.

Consistent with these changes in human skin, studies in hairless mice demonstrate that topical tretinoin induces a “zone of repair” in the subepidermal dermis in UV-damaged skin. After inducing connective tissue damage by exposing hairless mice to ultraviolet radiation for 10 weeks, treatment with topical tretinoin (0.05%) for 10 weeks significantly increased dermal vascularity and the size of the subepidermal repair zone (i.e., newly formed and organized collagen bundles) compared to untreated control mice 112. Topical tretinoin also leads to stimulation of collagen synthesis and the effacement of UV-induced surface wrinkles in hairless mice 95, 113.

Overall, long-term, continuous exposure to topical tretinoin results in significant improvement in clinical parameters, though histological changes vary over time 114. With continued application, some early epidermal changes (stratum corneum compaction, increased epidermal and granular layer thickness) return to baseline while other histological changes (increased epidermal mucin content, increased dermal collagen synthesis) become evident. Due to technical limitations of the employed methodologies (i.e., H&E staining) in the human trials, retinoid-induced epidermal changes are well described while dermal changes often go undetected. Nonetheless, due to the weight of evidence from studies in hairless mice and electron microscopic analysis of human skin samples, it is thought that clinical improvement to photodamaged skin is a consequence of increased collagen synthesis induced by tretinoin.

Retinol for acne

Acne is a common skin condition affecting the hair follicle and sebaceous gland, in which there is expansion and blockage of the follicle and inflammation. Acne causes bumps on the skin known as pimples. Pimples form when the tiny hair follicles in your skin are blocked by dead skin and oil. This causes bacteria to grow and irritate the skin. Pimples commonly appear on the face. However, they can appear on the back, chest, arms, and neck. Acne usually starts in your early teen years. It can last into or begin in adulthood. Both boys and girls get it. Family history contributes to acne. If your parents had bad acne, you may have it too. Your immune system plays a role too. Some people are extra sensitive to the bacteria that get trapped in their hair follicles.

There are several types of acne:

  • Whitehead: The tiny hair follicles in your skin becomes blocked with oil and dead skin. A “whitehead” forms at the tip of each pimple.
  • Blackhead: The hair follicle is blocked near the surface of the skin. It turns black when it is exposed to air.
  • Cystic acne: This occurs when cysts form deep in the skin around the hair follicle.

Acne severity is classified as mild, moderate, or severe:

  • Mild acne: total lesion count <30
  • Moderate acne: total lesion count 30–125
  • Severe acne: total lesion count >125

The treatment for acne depends on acne severity 115:

  • Mild acne
    • Topical antiacne agents, such as benzoyl peroxide and/or tretinoin or adapalene gel. New bioactive proteins may also prove successful.
    • Low-dose combined oral contraceptive
    • Antiseptic or keratolytic washes containing salicylic acid
    • Light/laser therapy
  • Moderate acne
    • As for mild acne plus a tetracycline such as doxycycline 50–200 mg daily for 6 months or so
    • Erythromycin or trimethoprim if doxycycline intolerant
    • Antiandrogen therapy with long-term cyproterone acetate + ethinylestradiol or spironolactone may be considered in women not responding to low-dose combined oral contraceptive, particularly for women with polycystic ovaries
    • Isotretinoin is often used if acne is persistent or treatment-resistant
  • Severe acne
    • Referral to a dermatologist
    • If fever, arthralgia, bone pain, ulcerated or extensive skin lesions, blood count should be arranged and referral is urgent
    • Oral antibiotics are often used in higher doses than normal
    • Oral isotretinoin is usually recommended in suitable patients

Topical retinoids

Topical retinoids are creams, foams, lotions, emulsion, and gels containing one or other of group of medicines derived from Vitamin A. These compounds result in proliferation and reduced keratinisation of skin cells independent of their functions as a vitamin. Many brand-name creams containing the retinoids retinol and retinaldehyde can be obtained over the counter at pharmacies and supermarkets.

Applied to the face once daily at bedtime, topical retinoids such as adapalene, isotretinoin, tretinoin (retinoic acid), and trifarotene can help mild to moderately severe acne. They are effective first-line treatment for comedonal and inflammatory acne, but are not recommended as monotherapy for severe acne, especially if there are pustules with deep nodules and cysts. It may take 12 weeks or longer before improvement is seen.

Topical retinoids may reduce the severity of existing scarring and subsequent acne scarring.

Inflammatory dermatoses including acne vulgaris may resolve with postinflammatory hyperpigmentation particularly in skin of color. Topical retinoids are useful to treat post-inflammatory hyperpigmentation as they inhibit melanosome transfer and facilitate melanin dispersal. They are particularly recommended for the treatment of acne in skin of color.

Approved Topical Retinol creams

Naturally occurring retinoids

  • All-trans retinol (used in over-the-counter cosmeceuticals)
  • All-trans retinoic acid (tretinoin)
  • Alitretinoin (US FDA approved for AIDS-related Kaposi’s sarcoma)

Synthesized retinoids

  • Adapalene
  • Tazarotene
  • Bexarotene (US FDA approved for cutaneous lymphoma)

Adapalene gel has received approval from the FDA in the USA for over-the-counter use of acne treatment in patients 12 or older (July 2016).

Adapalene is also available to treat acne in combination with benzoyl peroxide, as Epiduo® gel.

The more potent topical retinoids available on prescription are:

  • ReTrieve™ cream (tretinoin)
  • Retin-A™ Cream (tretinoin or retinoic acid)
  • Retinova™ Cream (tretinoin emollient)
  • Isotrex™ Gel (isotretinoin)
  • Differin™ Gel, Cream (adapalene)

What are they used for?

Topical retinoids are effective treatments for mild to moderately severe acne. The effect is often noticeable within a few weeks, but it may take 6 weeks or longer before improvement occurs.

Tretinoin has also been shown to reverse some of the changes due to photo-aging, i.e. sun damage. If used long term, it may reduce some fine wrinkles, freckles, solar comedones (whiteheads and blackheads), and actinic keratoses (tender, dry sun-spots).

They may also be used in bleaching creams to reduce pigmentation in melasma.

Topical retinoids can be applied to any area but are most often used on the face, the neck and the back of hands.

Do topical retinoids have any side effects?

Topical retinoids can irritate the skin, especially when they are first used. This is more likely in those with sensitive skin, resulting in stinging. Excessive use results in redness, swelling, peeling and blistering in treated areas. It may cause or aggravate eczema, particularly atopic dermatitis.

Side effects and risks of topical retinoids 116:

  • Retinoid dermatitis (erythema, peeling, dry skin)
  • Irritant contact dermatitis
  • Sun sensitivity
  • Allergic contact dermatitis (rare)
  • Teratogenic — potential risk in pregnancy particularly with widespread tazarotene use (pregnancy category X in US)

By peeling off the top layer of skin, they may increase the chance of sunburn. Irritation may also be aggravated by exposure to wind or cold, use of soaps and cleansers, astringents, peeling agents and certain cosmetics.

Some people have reported a flare of acne in the first few weeks of treatment. This usually settles with continued use.

Retinoids taken by mouth may cause birth deformities. Manufacturers recommend that topical retinoids are not used in pregnancy or breastfeeding as negative animal studies are not always predictive of human response.

How to use topical retinoids

Follow these instructions carefully:

  • Be cautious if you are using other topical acne treatments – ask your doctor if you should stop these.
  • In general, a cream is less iritating than a gel. If there is a choice, start with a lower concentration product.
  • Use your topical retinoid on alternate nights at first. If you have sensitive skin, wash it off after an hour or so. If it irritates, apply it less often. If it doesn’t, try every night, and if possible twice daily. In most people, the skin gradually gets used to it.
  • To reduce stinging, apply it to dry skin, that is, 30 minutes or longer after washing.
  • Apply a tiny amount to all the areas affected, and spread it as far as it will go.
  • Don’t get it in your eyes or mouth.
  • Apply a sunscreen to exposed skin in the morning.
  • Wear your usual make-up if you wish, and use gentle cleansers (avoid soap) and apply non-greasy moisturisers as often as required.
  • If you have acne, choose oil-free cosmetics.
  • If your skin goes scarlet and peels dramatically even with cautious use, the retinoid may be unsuitable for your sensitive skin.
  • Tolerance to topical retinoids often develops over time.

What is isotretinoin?

Isotretinoin (13-cis retinoic acid) is a vitamin-A derivative (retinoid). The liver naturally makes small quantities of isotretinoin from vitamin-A.

Isotretinoin was developed in the 1950s, but only started being used in the mid 1970s. The original brand names were Accutane® and Roaccutane®, but there are now many generic versions on the market, of varying potency.

What is isotretinoin used for?

Isotretinoin is a very effective medication for the treatment of acne. Originally licensed for use in severe disease, it is increasingly prescribed for all grades of acne.

Isotretinoin is also useful for other follicular conditions, such as:

  • Rosacea
  • Seborrhoea
  • Hidradenitis suppurativa
  • Scalp folliculitis

It is also prescribed for many other skin diseases. Examples include:

  • Discoid lupus erythematosus
  • Granuloma annulare
  • Grover disease
  • Sarcoidosis
  • Extensive actinic keratoses
  • Prevention of squamous cell carcinoma
  • As an adjuvant in neuroblastoma

Contraindications to isotretinoin

  • Isotretinoin must not be taken in pregnancy, or if there is a significant risk of pregnancy.
  • Blood donation by males and females on isotretinoin is not allowed in case the blood is used for a pregnant woman.

Precautions when taking isotretinoin

  • Isotretinoin should be used with caution during breastfeeding.
  • Commercial pilots may be subject to flying restrictions if they take isotretinoin.
  • High dose isotretinoin in very young children has been associated with premature epiphyseal closure, leading to shorter stature (not seen in low dose for the treatment of acne).

How does isotretinoin work?

In acne, isotretinoin:

  • Reduces sebum production
  • Shrinks the sebaceous glands
  • Reduces follicular occlusion
  • Inhibits growth of bacteria
  • Has anti-inflammatory properties

What is the usual dose of isotretinoin?

The range of doses used each day for acne is less than 0.1 to over 1 mg/kg body weight. Some patients may only need a small dose once or twice a week. A course of treatment may be completed in a few months or continue for several years. For acne, some prescribers have targeted a total cumulative dose of 120–140 mg/kg, in the hope of reducing relapse, but the evidence for this remains controversial. The general trend has been to use lower dosages, unrelated to body weight (eg 10 mg/day).

The individual dose prescribed by the dermatologist depends on:

  • Prescriber preference
  • Patient body weight
  • The specific condition being treated
  • Severity of the skin condition
  • Response to treatment
  • Other treatment used at the same time
  • Side effects experienced

Isotretinoin is better taken with water or milk after food to help with its absorption. It may be taken on an empty stomach, but absorption may be halved. There is no particular advantage in splitting the dose over the day. A newer formulation (isotretinoin-lidose) can be taken without food.

For how long is isotretinoin taken?

Most patients should be treated until their skin condition clears and then for a further few months. However, courses have often been restricted to 16–30 weeks (4–7 months) to minimise risk of teratogenicity (risk of congenital abnormalities), and to comply with local regulatory authorities. Isotretinoin may be prescribed for years, usually in low dose or intermittently.

Drug interactions with isotretinoin

Care should be taken with the following medications:

  • Vitamin-A (retinoic acid): side effects are cumulative and could be severe. Beta-carotene (provitamin-A) is permitted.
  • Tetracyclines (including doxycycline, minocycline): these could increase the risk of headaches and blurred vision due to raised intracranial pressure.
  • Warfarin: monitor INR carefully.

What are the side effects and risks of isotretinoin ?

The side effects of isotretinoin are dose dependent; at 1 mg/kg/day, nearly all patients will have some side effects, whereas at 0.1 mg/kg/day, most patients will not. The range and severity of the side effects also depends on personal factors and the disease being treated.

Patients with significant liver or kidney disease, high blood fats, diabetes and depression may be advised not to take isotretinoin or to be on a lower dose than usual and to have regular follow-up visits.

Cutaneous and mucocutaneous side effects

Most of the side effects due to isotretinoin are cutaneous or mucocutaneous and relate to the mode of action of the drug. The most common are listed here. When side effects are troublesome, isotretinoin may need to be withheld or the dose reduced.

  • Acne flare-up (particularly if starting dose is >0.5 mg/kg/day)
  • Dry lips, cheilitis (sore, cracked or scaly lips) (100% of patients on 1 mg/kg/day)
  • Dry skin, fragile skin, eczema/dermatitis (itchy, red patches of skin). Note: atopic eczema may improve.
  • Increased sweating
  • Dry nostrils, epistaxis (nose bleeds)
  • Dry, watery or irritable eyes (especially in contact lens wearers), conjunctivitis, keratitis
  • Dry anal mucosa, bleeding at the time of a bowel motion
  • Dry genitals, dyspareunia (discomfort during intercourse)
  • Facial erythema
  • Sunburn on exposure to the sun
  • Temporary hair loss
  • Brittle nails
  • Skin infections: impetigo, acute paronychia, pyogenic granuloma

Treatment of mucocutaneous side effects

  • Reduce the dosage (eg to 5–10 mg/day)
  • Emollients, lip balm, petroleum jelly, sunscreen, eye drops and lubricants should be applied frequently and liberally when needed
  • Dermatitis can be treated with topical steroids
  • Take short, cool showers without using soap
  • Use mild or diluted shampoo
  • Do not start wearing contact lenses for the first time
  • Do not have elective eye surgery while on isotretinoin or for 6 months afterwards.
  • Do not have ablative laser treatments (eg CO2 resurfacing) while on isotretinoin or for 6 months afterwards. Other laser and light treatments may be performed with care
  • Shave rather than wax
  • Topical and/or oral antibiotics may be prescribed for impetigo

Other common dose-related side effects of isotretinoin

  • Headache
  • Myalgia (muscle aches) and arthralgia (joint aches), especially after exercise
  • Tiredness (lethargy and drowsiness)
  • Disturbed night vision and slow adaptation to the dark. Drivers may experience increased glare from car headlights at night
  • Hypertriglyceridaemia (high levels of triglyceride in the blood), usually of no clinical relevance
  • Irregular or heavy menstrual periods

Rare side effects of isotretinoin

  • Causality of the listed side effects may not have been confirmed
  • Severe headache with blurred vision due to raised intracranial pressure
  • Mood changes and depression. Note: depression is more often related to the skin condition being treated or other health or psychosocial problems.
  • Antidepressant medications may be helpful
  • Corneal opacities and cataracts
  • High-tone deafness
  • Accelerated diffuse interstitial skeletal hyperostosis (bony change)
  • Abnormal liver function tests or symptomatic hepatitis
  • Diarrhea or bleeding from the bowel
  • Pancreatitis
  • Allergy to isotretinoin causing liver disease and a febrile illness

Treatment of systemic side effects

  • Drink minimal alcohol
  • Take paracetamol for headache and for mild aches and pains
  • Seek medical attention early, if unwell

Monitoring isotretinoin

  • Pregnancy must be excluded before and during treatment with isotretinoin.

In an otherwise healthy individual, blood tests are generally not needed. However, consider the following if using high dose (1 mg/kg/day), prolonged courses (>12 months), or if patients have specific risk factors (eg family history of dyslipidaemia, higher risk of viral hepatitis, etc):

  • Cholesterol and triglyceride levels
  • Liver function tests
  • Blood count

Contraception in females considering isotretinoin

  • Isotretinoin must not be taken in pregnancy because of a very high risk of serious congenital abnormalities in the baby. Caution needs to be used during breast-feeding as it enters the breast milk and might affect the baby.

All females who could biologically have a child should take the following precautions during treatment with isotretinoin and for four weeks after the medication has been discontinued:

  • Abstinence. The most reliable method of avoiding pregnancy is not to have sex. No method of contraception is completely reliable. “Natural” family planning is particularly risky.
  • If sexually active, two reliable methods of contraception should be used. Discuss contraception with your doctor (general practitioner, family planning specialist, gynaecologist or dermatologist). The combined oral contraceptive, IUD (intrauterine device), progesterone implant, or medroxyprogesterone injections may be suitable.
  • The low-dose progesterone mini-pill on its own is not recommended.

A prescription for emergency contraception may be available from a medical practitioner (your doctor or family planning clinic) or accredited pharmacy. It prevents 85% of pregnancies if taken within 72 hours of unprotected sexual intercourse.

If contraception fails, termination of pregnancy (an abortion) may be advised if pregnancy arises during treatment with isotretinoin or within a month of discontinuing it.

What happens if a pregnant woman takes isotretinoin?

Isotretinoin has a very high chance of resulting in a spontaneous miscarriage or a severe birth deformity if a fetus is exposed to it during the first half of pregnancy. The deformities affect the growth of tissues developing at the time of exposure to the drug:

  • Cranium (skull and brain)
  • Cardiac (heart)
  • Eye, ear
  • Limbs

No contraceptive precautions are necessary for men

Isotretinoin has no effect on sperm or male fertility and has not been shown to cause birth defects in children fathered by men taking it.

Does acne ever fail to clear on isotretinoin?

Although isotretinoin is usually very effective for acne, occasionally it responds unexpectedly slowly and incompletely. Poor response is associated with:

  • Macrocomedones (large whiteheads)
  • Nodules (large, deep inflammatory lesions)
  • Secondary infection
  • Smoking
  • Polycystic ovarian syndrome
  • Younger age (<14 years)

Options available to slow responders include:

  • Electrocautery of comedones
  • Prolonged course of isotretinoin
  • Additional treatment with oral antibiotics and oral steroids

Can isotretinoin be used again if acne recurs?

At least fifty per cent of patients with acne have a long lasting response after a single adequate course of isotretinoin. In others, acne may recur a few months to a few years after the medication has been discontinued. Relapse is more common in females than in males, and in patients >25 years of age. These patients may receive one or more further courses of isotretinoin.

Long-term treatment (>1 year) is often used for patients with:

  • Persistent acne
  • Seborrhoea
  • Rosacea
  • Scalp folliculitis
  • Skin cancer

Special precautions for pilots considering isotretinoin

Good night vision is important for airline pilots and those flying after dark. Night vision may be affected by isotretinoin. Pilots taking isotretinoin or considering a course of isotretinoin must report to their national aviation authority to discuss how this treatment affects their flying privileges.

Retinoids as Antiaging

Retinoids are among the most common ingredients found in cosmeceuticals. In fact, they are the most studied and have the most data behind them. They consist of natural and synthetic derivatives of vitamin A that reduce hyperpigmentation and inhibit enzymes from breaking down collagen. Many of their cosmeceutical claims are based on data derived from studies on tretinoin and other classes of retinoid drugs. Some key retinoids include retinoic acid (tretinoin), retinol, retinaldehyde.

Over-The-Counter (OTC) Retinoids

  • They reduce wrinkles and lentigines.
  • Common side-effects include redness, irritation, and an increase in photosensitivity.
  • Certain retinoid analogues within the same class of molecules have been shown to provide less irritation, but maintain comparable levels of efficacy 117.
  • 3 classes of retinoids exhibit distinct properties:
    • Vitamin A metabolites – Trans-retinoic acid, Retinaldehyde, Adapalene, and Tazarotene
    • Vitamin A – Retinol
    • vitamin A esters – retinyl acetate, retinyl propionate, and retinyl palmitate.
    • In randomized, double-blind, placebo-controlled, human studies comparing retinol, retinyl acetate, retinyl propionate and trans-retinoic acid
    • 117
    • propionate exhibited the highest rating when evaluated for efficacy and non-irritation.
    • 0.30% retinyl propionate demonstrated superior reductions in wrinkles, redness and hyper-pigmentation vs. 0.15% retinol.

Retinol (Vitamin A)

Retinol is oxidized into retinaldehyde and then into retinoic acid, the biologically active form of vitamin A. In vivo studies showed that topical retinol had only a modest retinoid-like biologic activity compared with topical retinaldehyde and retinoic acid 118. Two randomized, controlled trials reported significant improvement in fine wrinkles after 12 and 24 weeks of treatment, respectively 119, 120.

  • Cosmeceutical retinol, retinaldehyde, retinyl propionate, retinyl palmitate – in many cases, bioavailability and activity are unproven when formulated.


Retinaldehyde is viewed in a large part as an intermediate form during the conversion of retinol to retinoic acid. Studies have shown that it does have activity in human skin 121. Moreover, some studies have reported that this retinoid can produce significant clinical improvement in the appearance of fine and deep wrinkles 122.

Retinoic Acid (Tretinoin)

Retinoic acid is considered by dermatologists to be the anti-aging gold standard.

  • Available only through a doctor’s prescription.

There is extensive literature on the use of tretinoin, which is considered to be one of the most potent compounds for treating the signs of aging and/or photodamaged skin, including fine lines, hyperpigmented spots, and wrinkles 118. However, side-effects such as burning and scaling have limited its acceptance. In order to minimize these side-effects, various novel drug delivery systems are being developed 123.


  • Exercise care when using with other photosensitizing drugs, e.g., tetracyclines and thiazides.
  • Sun avoidance or sun protection must be encouraged as tretinoin thins the stratum corneum, and allows greater entry of UV light into the skin. People using tretinoin should avoid unnecessary or prolonged exposure to sunlight, and wear sunscreen and protective clothing.
  • Tretinoin can also cause skin irritation and hypo- or hyperpigmentation.

Retinol side effects

Retinol (vitamin A) is a fat soluble retinoid. Retinol (vitamin A) is needed for immunity, visual and dermatological health as well as cell communication and growth. Normal doses of vitamin A are not associated with liver injury or liver test abnormalities, but higher doses (generally more than 40,000 IU daily, ~12,000 μg) can be toxic. In excessive amounts, retinol (vitamin A) can accumulate in the liver and cause a wide array of symptoms. Toxicity is classified as either acute or chronic.

Vitamin A toxicity is also known as hypervitaminosis A.

What causes vitamin A toxicity ?

Acute toxicity

Acute toxicity is caused by a single or a few repeated very high doses – the most common cause of acute vitamin A toxicity is the ingestion (generally accidental) of over 300,000 IU of vitamin A (generally >100 times the Recommended Dietary Allowance [RDA]), arising within days to weeks with a typical symptom complex of severe headache, nausea, vertigo, blurred vision, muscle aches and lack of coordination, followed by skin desquamation and alopecia. Severe overdose can cause increased cerebral spinal fluid pressure, progressive drowsiness and coma.

Chronic toxicity

The most common cause of chronic vitamin A toxicity usually arises 3 months to many years after starting moderately high levels of vitamin A (generally 10 times the Recommended Dietary Allowance) – regular ingestion of over 100,000 IU daily, which is sometimes prescribed for dermatological conditions such as acne. Chronic vitamin A toxicity is marked by dry skin, cheilosis, gingivitis, muscle and joint pains, fatigue, mental dullness, depression and liver test abnormalities. Serum bilirubin is typically only mildly elevated. Serum aminotransferase and alkaline phosphatase levels are variably increased, but usually only 1 to 4 times the upper limit of normal. Serum vitamin A levels are typically, but not invariably elevated. Liver biopsy is diagnostic and shows enlarged, lipid-laden stellate cells with variable degrees of sinusoidal fibrosis. The liver may be hypoechogenic on ultrasound examination and suggest the diagnosis of nonalcoholic fatty liver disease, but the lipid-laden cells found on liver biopsy are not hepatocytes, but rather stellate cells (formerly known as Ito cells or hepatic lipocytes) which contain excess vitamin A.

Chronic, moderately high doses of vitamin A (generally over 1 to 8 years) can lead to portal hypertension with ascites and esophageal varices, even before frank cirrhosis can be shown to be present. While high doses of vitamin A are usually achieved by vitamin A supplements, hypervitaminosis A can also occur with excessive dietary intake of liver, particularly that of carnivores (bears, seals, dogs) or salt-water fish (cod liver oil).

What are the signs and symptoms of vitamin A toxicity?

Signs and symptoms of acute vitamin A toxicity can include:

  • Gastrointestinal: nausea, vomiting, loss of appetite, abdominal pain
  • Neurological: dizziness, irritability, drowsiness, increased intercranial pressure due to cerebral oedema, and headache
  • Dermatological: rash or desquamation (peeling skin)
  • Coma and death

Signs and symptoms of chronic vitamin A toxicity can include:

  • Gastrointestinal symptoms: hepatomegaly, splenomegaly
  • Neurological symptoms: severe headache, pseudotumour cerebri
  • Dermatological symptoms: rash, thin and coarse hair, alopecia of the eyebrows, itch, skin that is dry, rough or cracking, and dry or cracked lips
  • Musculoskeletal: weakness, cortical hyperostosis of the bone, arthralgia, easy fractures

In children, signs and symptoms of vitamin A toxicity are:

  • Neurological: irritability, drowsiness, delirium, coma, increased intercranial pressure, bulging fontanelles (in infants), psychiatric changes, cerebral oedema
  • Ophthamological: bulging eyeballs, swelling of the cortical disc, visual disturbances
  • Dermatological: skin discoloration and/or desquamation, itch

It is also important to note that vitamin A is highly teratogenic if taken during pregnancy (especially in the first 8 weeks) if intake exceeds 10,000 IU daily. Birth defects can also be caused by isotretinoin or other oral retinoids, if taken while pregnant.

Vitamin A and teratogenicity

Excessive intake of Vitamin A during pregnancy has been associated with the following birth defects, collectively known as retinoic acid syndrome:

  • Encephalitis
  • Microcephaly
  • Craniofacial malformations (most commonly a cleft palate)
  • Cardiovascular malformations (most commonly a transposition of the great vessels)
  • Thymus malformation/dysfunction

How is vitamin A toxicity diagnosed?

Diagnosis of vitamin A toxicity is based on signs and symptoms, patient history, lifestyle habits and use of supplements. There is sometimes a poor correspondence between toxicity and serum retinol levels. However, serum levels can sometimes be between 1,000 and 20,000 (with a normal range being 200 to 800 µg/L). The blood sample must be protected from light.

How is vitamin A toxicity treated?

Vitamin a toxicity is treated by stopping the use of vitamin A supplements. Generally, signs and symptoms will resolve on their own with 1–4 weeks, depending on their severity. Birth defects caused by vitamin A toxicity during pregnancy are irreversible.

  1. Retinoic acid biosynthesis and metabolism. Napoli JL. FASEB J. 1996 Jul; 10(9):993-1001.
  2. Moise AR, Noy N, Palczewski K, Blaner WS. Delivery of retinoid-based therapies to target tissues. Biochemistry. 2007 Apr 17;46(15):4449-58. doi: 10.1021/bi7003069
  3. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington, DC: National Academy Press; 2001.
  4. Blaner WS. Vitamin A and Provitamin A Carotenoids. In: Marriott BP, Birt DF, Stallings VA, Yates AA, eds. Present Knowledge in Nutrition. 11th ed. Cambridge, Massachusetts: Wiley-Blackwell; 2020:73-91.
  5. Micronutrient Inadequacies in the US Population: an Overview.
  6. Bird JK, Murphy RA, Ciappio ED, McBurney MI. Risk of Deficiency in Multiple Concurrent Micronutrients in Children and Adults in the United States. Nutrients. 2017 Jun 24;9(7):655. doi: 10.3390/nu9070655
  7. Khadim, R & Al-Fartusie, Falah. (2021). Antioxidant vitamins and their effect on immune system. Journal of Physics: Conference Series. 1853. 012065. 10.1088/1742-6596/1853/1/012065
  8. J. W. Alexander, “Specific nutrients and the immune response,” in Nutrition, 1995, vol. 11, no. 2 SUPPL., pp. 229–232.
  9. Trumbo P, Yates AA, Schlicker S, Poos M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc. 2001 Mar;101(3):294-301. doi: 10.1016/S0002-8223(01)00078-5
  10. Kawaguchi R., Yu J., Honda J., Hu J., Whitelegge J., Ping P., Wiita P., Bok D., Sun H. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science. 2007;315:820–825. doi: 10.1126/science.1136244.
  11. Harrison E.H. Mechanisms of digestion and absorption of dietary vitamin A. Annu. Rev. Nutr. 2005;25:87–103. doi: 10.1146/annurev.nutr.25.050304.092614.
  12. Goodman D.S. In: Plasma Retinol Binding Protein in the Retinoids. Sporn M.B., Roberts A.B., Goodman D.S., Orlando F.L., editors. Academic Press; Salt Lake, UT, USA: 1984. pp. 41–88.
  13. Retinoid metabolism in the skin. Roos TC, Jugert FK, Merk HF, Bickers DR. Pharmacol Rev. 1998 Jun; 50(2):315-33.
  14. Retinoids and vertebrate development. Gudas LJ. J Biol Chem. 1994 Jun 3; 269(22):15399-402.
  15. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Kawaguchi R, Yu J, Honda J, Hu J, Whitelegge J, Ping P, Wiita P, Bok D, Sun H. Science. 2007 Feb 9; 315(5813):820-5.
  16. Ocular aldehyde dehydrogenases: protection against ultraviolet damage and maintenance of transparency for vision. Chen Y, Thompson DC, Koppaka V, Jester JV, Vasiliou V. Prog Retin Eye Res. 2013 Mar; 33():28-39.
  17. Transcriptional activities of retinoic acid receptors. Lefebvre P, Martin PJ, Flajollet S, Dedieu S, Billaut X, Lefebvre B. Vitam Horm. 2005; 70():199-264.
  18. Vitamin A and Skin Health.
  19. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington (DC): National Academies Press; 2001.
  20. Joint FAO/WHO Expert Consultation. Vitamin A. In: Vitamin and mineral requirements in human nutrition. 2nd ed. Geneva (Switzerland):WHO/FAO; 2004. p. 17–44.
  21. Tanumihardjo SA, Russell RM, Stephensen CB, et al. Biomarkers of Nutrition for Development (BOND)—Vitamin A Review. The Journal of Nutrition. 2016;146(9):1816S-1848S. doi:10.3945/jn.115.229708.
  22. Vitamin A and Carotenoids.
  23. Carazo A, Macáková K, Matoušová K, Krčmová LK, Protti M, Mladěnka P. Vitamin A Update: Forms, Sources, Kinetics, Detection, Function, Deficiency, Therapeutic Use and Toxicity. Nutrients. 2021 May 18;13(5):1703. doi: 10.3390/nu13051703
  24. Tanumihardjo SA, Russell RM, Stephensen CB, Gannon BM, Craft NE, Haskell MJ, Lietz G, Schulze K, Raiten DJ. Biomarkers of Nutrition for Development (BOND)-Vitamin A Review. J Nutr. 2016 Sep;146(9):1816S-48S. doi: 10.3945/jn.115.229708
  25. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical Interventions in Aging. 2006;1(4):327-348.
  26. Runne U, Orfanos CE, Gartmann H. (1973) Perorale applikation zweier derivate der vitamin A-Säure zur internen psoriasis-therapie (13-cis-beta-vitamin A-Säure und vitamin A-säure-äthylamid). Arch Dermatol Res 247:171–180.
  27. Colors with functions: elucidating the biochemical and molecular basis of carotenoid metabolism. von Lintig J. Annu Rev Nutr. 2010 Aug 21; 30:35-56.
  28. Chemistry of the retinoid (visual) cycle. Kiser PD, Golczak M, Palczewski K. Chem Rev. 2014 Jan 8; 114(1):194-232.
  29. Al Tanoury Z, Piskunov A, Rochette-Egly C. Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res 2013;54:1761–75.
  30. Overview of retinoid metabolism and function. Blomhoff R, Blomhoff HK. J Neurobiol. 2006 Jun; 66(7):606-30.
  31. Wolf G. The discovery of the visual function of vitamin A. J. Nutr. 2001;131:1647–1650. doi: 10.1093/jn/131.6.1647
  32. Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet 1993;342:1325–8.
  33. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr 2001;21:167–92.
  34. Pino-Lagos K, Benson MJ, Noelle RJ. Retinoic acid in the immune system. Ann N Y Acad Sci 2008;1143:170–87.
  35. Raverdeau M, Mills KHG. Modulation of T cell and innate immune responses by retinoic acid. J Immunol 2014;192:2953–8.
  36. Dawson HD, Collins G, Pyle R, Key M, Weeraratna A, Deep-Dixit V, Nadal CN, Taub DD. Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes. BMC Immunol 2006;7:27.
  37. Tang JE, Wang RJ, Zhong H, Yu B, Chen Y. Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies. World J Surg Oncol 2014;12:130.
  38. Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, et al. Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression. Cancer Causes Control 2011;22:1383–96.
  39. Zhang X, Dai B, Zhang B, Wang Z. Vitamin A and risk of cervical cancer: a meta-analysis. Gynecol Oncol 2012;124:366–73.
  40. Wu Y, Ye Y, Shi Y, Li P, Xu J, Chen K, Xu E, Yang J. Association between vitamin A, retinol intake and blood retinol level and gastric cancer risk: a meta-analysis. Clin Nutr 2015;34:620–6.
  41. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer 2001;1:181–93.
  42. Siddikuzzaman GC, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacol Immunotoxicol 2011;33:241–9.
  43. Wang Z-Y, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008;111:2505–15.
  44. Goodman G.E., Alberts D.S., Meyskens F.L. Retinol, vitamins, and cancer prevention: 25 Years of learning and relearning. J. Clin. Oncol. 2008;26:5495–5496. doi: 10.1200/JCO.2008.19.0884.
  45. Goodman G.E., Alberts D.S., Ernest D.L., Meyskens F.L. Phase I trial of retinol in cancer patients. J. Clin. Oncol. 1983;1:394–399.
  46. Lee I.-M., Cook N.R., Manson J.E., Buring J.E., Hennekens C.H. B carotene supplementation and incidence of cancer and cardiovascular disease: The Women’s Health Study. J. Natl. Cancer Inst. 1999;91:2102–2106. doi: 10.1093/jnci/91.24.2102.
  47. Peto R., Doll R., Buckley J.D., Sporn M.B. Can dietary β-carotene materially reduce human cancer rates? Nature. 1981;290:201–208. doi: 10.1038/290201a0.
  48. Leitzmann M.F., Chatterjee N., Peters U., Chatterjee N., Wang Y., Albanes D., Gelmann E.P., Friesen M.D., Riboli E., Hayes R.B. Serum lycopene, other carotenoids, and prostate cancer risk: A nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol. Biomark. Prev. 2007;16:962–968. doi: 10.1158/1055-9965.EPI-06-0861.
  49. Martinoli L, Di Felice M, Seghieri G, Ciuti M, De Giorgio LA, Fazzini A, Gori R, Anichini R, Franconi F. Plasma retinol and alpha-tocopherol concentrations in insulin-dependent diabetes mellitus: their relationship to microvascular complications. Int J Vitam Nutr Res 1993;63:87–92.
  50. Iqbal S, Naseem I. Role of vitamin A in type 2 diabetes mellitus biology: effects of intervention therapy in a deficient state. Nutrition 2015;31:901–7.
  51. Chen W, Chen G. The roles of vitamin A in the regulation of carbohydrate, lipid, and protein metabolism. J Clin Med 2014;3:453–79
  52. Zhao S, Li R, Li Y, Chen W, Zhang Y, Chen G. Roles of vitamin A status and retinoids in glucose and fatty acid metabolism. Biochem Cell Biol 2012;90:142–52.
  53. Brun P-J, Yang KJ, Lee S-A, Yuen JJ, Blaner WS. Retinoids: potent regulators of metabolism. Biofactors 2013;39:151–63.
  54. Graham TE, Kahn BB. Tissue-specific alterations of glucose transport and molecular mechanisms of intertissue communication in obesity and type 2 diabetes. Horm Metab Res 2007;39:717–21.
  55. Norseen J, Hosooka T, Hammarstedt A, Yore MM, Kant S, Aryal P, Kiernan UA, Phillips DA, Maruyama H, Kraus BJ, et al. Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and Toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol 2012;32:2010–9.
  56. Ziouzenkova O, Orasanu G, Sharlach M, Akiyama TE, Berger JP, Viereck J, Hamilton JA, Tang G, Dolnikowski GG, Vogel S, et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med 2007;13:695–702.
  57. Shabrova E, Hoyos B, Vinogradov V, Kim YK, Wassef L, Leitges M, Quadro L, Hammerling U. Retinol as a cofactor for PKCδ-mediated impairment of insulin sensitivity in a mouse model of diet-induced obesity. FASEB J 2016;30:1339–55.
  58. WHO. Guideline: vitamin A supplementation in pregnant women. Geneva (Switzerland): WHO; 2011.
  59. WHO. Guideline: vitamin A supplementation in pregnancy for reducing the risk of mother-to-child transmission of HIV. Geneva (Switzerland): WHO; 2011.
  60. Wiysonge CS, Shey M, Kongnyuy EJ, Sterne JA, Brocklehurst P. Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. Cochrane Database Syst Rev 2011;1:CD003648.
  61. Siegfried N, Irlam JH, Visser ME, Rollins NN. Micronutrient supplementation in pregnant women with HIV infection. Cochrane Database Syst Rev 2012;3:CD009755.
  62. Kuhn L, Coutsoudis A, Trabattoni D, Archary D, Rossi T, Segat L, Clerici M, Crovella S. Synergy between mannose-binding lectin gene polymorphisms and supplementation with vitamin A influences susceptibility to HIV infection in infants born to HIV-positive mothers. Am J Clin Nutr 2006;84:610–5.
  63. WHO. Measles Factsheet, 2016.
  64. Guideline: vitamin A supplementation in infants and children 6-59 months of age.
  65. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA. Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011;343:d5094.
  66. The use and interpretation of serum retinol distributions in evaluating the public health impact of vitamin A programmes. Palmer AC, West KP Jr, Dalmiya N, Schultink W. Public Health Nutr. 2012 Jul; 15(7):1201-15.
  67. WHO. Serum retinol concentrations for determining the prevalence of vitamin A deficiency in populations [Internet]. Geneva (Switzerland); WHO; 2011.
  68. de Pee S, Dary O. Biochemical indicators of vitamin A deficiency: serum retinol and serum retinol binding protein. J Nutr 2002;132(9, Suppl):2895S–901S.
  69. Stephensen CB, Gildengorin G. Serum retinol, the acute phase response, and the apparent misclassification of vitamin A status in the third National Health and Nutrition Examination Survey. Am J Clin Nutr 2000;72:1170–8.
  70. Smith JE, Brown ED, Smith JC Jr. The effect of zinc deficiency on the metabolism of retinol binding protein in the rat. J Lab Clin Med 1974;84:692–7.
  71. Suri DJ, Tanumihardjo JP, Gannon BM, Pinkaew S, Kaliwile C, Chileshe J, Tanumihardjo SA. Serum retinol concentrations demonstrate high specificity after correcting for inflammation but questionable sensitivity compared with liver stores calculated from isotope dilution in determining vitamin A deficiency in Thai and Zambian children. Am J Clin Nutr 2015;102:1259–65.
  72. Green MH, Green JB. Vitamin A intake and status influence retinol balance, utilization and dynamics in rats. J Nutr 1994;124:2477–85.
  73. Tanumihardjo SA. Vitamin A fortification efforts require accurate monitoring of population vitamin A status to prevent excessive intakes. Procedia Chem 2015;14:398–407.
  74. Raiten DJ, Sakr Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, Brabin BJ, Suchdev P, van Ommen B.; INSPIRE Consultative Group. Inflammation and nutritional science for programs/policies and interpretation of research evidence (INSPIRE). J Nutr 2015;145(Suppl):1039S–108S.
  75. Thurnham D, McCabe GP. Influence of infection and inflammation on biomarkers of nutritional status with an emphasis on vitamin A and iron. WHO report: priorities in the assessment of vitamin A and iron status in populations. Geneva (Switzerland): WHO;2012.
  76. Vitamin A (Retinol).
  77. Blomhoff R. Transport and metabolism of vitamin A. Nutr Rev. 1994 Feb;52(2 Pt 2):S13-23. doi: 10.1111/j.1753-4887.1994.tb01382.x
  78. Fisher GJ, Voorhees JJ. Molecular mechanisms of retinoid actions in skin. FASEB J. 1996 Jul;10(9):1002-13. doi: 10.1096/fasebj.10.9.8801161
  79. Futoryan T, Gilchrest BA. Retinoids and the skin. Nutr Rev. 1994 Sep;52(9):299-310. doi: 10.1111/j.1753-4887.1994.tb01461.x
  80. Fisher GJ, Kang S, Varani J, Bata-Csorgo Z, Wan Y, Datta S, Voorhees JJ. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. 2002 Nov;138(11):1462-70. doi: 10.1001/archderm.138.11.1462
  81. Fisher GJ, Talwar HS, Xiao JH, Datta SC, Reddy AP, Gaub MP, Rochette-Egly C, Chambon P, Voorhees JJ. Immunological identification and functional quantitation of retinoic acid and retinoid X receptor proteins in human skin. J Biol Chem. 1994 Aug 12;269(32):20629-35.
  82. Elder JT, Fisher GJ, Zhang QY, Eisen D, Krust A, Kastner P, Chambon P, Voorhees JJ. Retinoic acid receptor gene expression in human skin. J Invest Dermatol. 1991 Apr;96(4):425-33. doi: 10.1111/1523-1747.ep12469889
  83. Fisher GJ, Datta SC, Voorhees JJ. Retinoic acid receptor-gamma in human epidermis preferentially traps all-trans retinoic acid as its ligand rather than 9-cis retinoic acid. J Invest Dermatol. 1998 Mar;110(3):297-300. doi: 10.1046/j.1523-1747.1998.00112.x
  84. Zouboulis CC. Isotretinoin revisited: pluripotent effects on human sebaceous gland cells. J Invest Dermatol. 2006 Oct;126(10):2154-6. doi: 10.1038/sj.jid.5700418
  85. Tsukada M, Schröder M, Roos TC, Chandraratna RA, Reichert U, Merk HF, Orfanos CE, Zouboulis CC. 13-cis retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoid acid receptors. J Invest Dermatol. 2000 Aug;115(2):321-7. doi: 10.1046/j.1523-1747.2000.00066.x
  86. Andersson E, Vahlquist A, Rosdahl I. Beta-carotene uptake and bioconversion to retinol differ between human melanocytes and keratinocytes. Nutr Cancer. 2001;39(2):300-6. doi: 10.1207/S15327914nc392_21
  87. Antille C, Tran C, Sorg O, Saurat JH. Topical beta-carotene is converted to retinyl esters in human skin ex vivo and mouse skin in vivo. Exp Dermatol. 2004 Sep;13(9):558-61. doi: 10.1111/j.0906-6705.2004.00194.x
  88. Singh M, Griffiths CE. The use of retinoids in the treatment of photoaging. Dermatol Ther. 2006 Sep-Oct;19(5):297-305. doi: 10.1111/j.1529-8019.2006.00087.x
  89. Pfahl M. Signal transduction by retinoid receptors. Skin Pharmacol. 1993;6 Suppl 1:8-16. doi: 10.1159/000211158
  90. Fisher GJ, Wang ZQ, Datta SC, Varani J, Kang S, Voorhees JJ. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med. 1997 Nov 13;337(20):1419-28. doi: 10.1056/NEJM199711133372003
  91. Wang Z, Boudjelal M, Kang S, Voorhees JJ, Fisher GJ. Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med. 1999 Apr;5(4):418-22. doi: 10.1038/7417. Erratum in: Nat Med 1999 Jul;5(7):849.
  92. Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and therapy. Br J Dermatol. 2007 Nov;157(5):874-87. doi: 10.1111/j.1365-2133.2007.08108.x
  93. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006;1(4):327-48. doi: 10.2147/ciia.2006.1.4.327
  94. Darlenski R, Surber C, Fluhr JW. Topical retinoids in the management of photodamaged skin: from theory to evidence-based practical approach. Br J Dermatol. 2010 Dec;163(6):1157-65. doi: 10.1111/j.1365-2133.2010.09936.x
  95. Chaquour B, Seité S, Coutant K, Fourtanier A, Borel JP, Bellon G. Chronic UVB- and all-trans retinoic-acid-induced qualitative and quantitative changes in hairless mouse skin. J Photochem Photobiol B. 1995 May;28(2):125-35. doi: 10.1016/1011-1344(94)07080-8
  96. Yamamoto O, Bhawan J, Solares G, Tsay AW, Gilchrest BA. Ultrastructural effects of topical tretinoin on dermo-epidermal junction and papillary dermis in photodamaged skin. A controlled study. Exp Dermatol. 1995 Jun;4(3):146-54. doi: 10.1111/j.1600-0625.1995.tb00238.x
  97. Olsen EA, Katz HI, Levine N, Nigra TP, Pochi PE, Savin RC, Shupack J, Weinstein GD, Lufrano L, Perry BH. Tretinoin emollient cream for photodamaged skin: results of 48-week, multicenter, double-blind studies. J Am Acad Dermatol. 1997 Aug;37(2 Pt 1):217-26. doi: 10.1016/s0190-9622(97)80128-4
  98. Kang S, Duell EA, Fisher GJ, Datta SC, Wang ZQ, Reddy AP, Tavakkol A, Yi JY, Griffiths CE, Elder JT, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol. 1995 Oct;105(4):549-56. doi: 10.1111/1523-1747.ep12323445
  99. Varani J, Warner RL, Gharaee-Kermani M, Phan SH, Kang S, Chung JH, Wang ZQ, Datta SC, Fisher GJ, Voorhees JJ. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J Invest Dermatol. 2000 Mar;114(3):480-6. doi: 10.1046/j.1523-1747.2000.00902.x
  100. Kafi R, Kwak HS, Schumacher WE, Cho S, Hanft VN, Hamilton TA, King AL, Neal JD, Varani J, Fisher GJ, Voorhees JJ, Kang S. Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol. 2007 May;143(5):606-12. doi: 10.1001/archderm.143.5.606
  101. Maddin S, Lauharanta J, Agache P, Burrows L, Zultak M, Bulger L. Isotretinoin improves the appearance of photodamaged skin: results of a 36-week, multicenter, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2000 Jan;42(1 Pt 1):56-63. doi: 10.1016/s0190-9622(00)90009-4
  102. Kligman AM, Grove GL, Hirose R, Leyden JJ. Topical tretinoin for photoaged skin. J Am Acad Dermatol. 1986 Oct;15(4 Pt 2):836-59. doi: 10.1016/s0190-9622(86)70242-9
  103. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ. Topical tretinoin improves photoaged skin. A double-blind vehicle-controlled study. JAMA. 1988 Jan 22-29;259(4):527-32. Erratum in: JAMA 1988 Aug 19;260(7):926. Erratum in: JAMA 1988 Jun 10;259(22):3274.
  104. Ellis CN, Weiss JS, Hamilton TA, Headington JT, Zelickson AS, Voorhees JJ. Sustained improvement with prolonged topical tretinoin (retinoic acid) for photoaged skin. J Am Acad Dermatol. 1990 Oct;23(4 Pt 1):629-37. doi: 10.1016/0190-9622(90)70265-j
  105. Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid). N Engl J Med. 1993 Aug 19;329(8):530-5. doi: 10.1056/NEJM199308193290803
  106. Olsen EA, Katz HI, Levine N, Shupack J, Billys MM, Prawer S, Gold J, Stiller M, Lufrano L, Thorne EG. Tretinoin emollient cream: a new therapy for photodamaged skin. J Am Acad Dermatol. 1992 Feb;26(2 Pt 1):215-24. doi: 10.1016/0190-9622(92)70030-j
  107. Weinstein GD, Nigra TP, Pochi PE, Savin RC, Allan A, Benik K, Jeffes E, Lufrano L, Thorne EG. Topical tretinoin for treatment of photodamaged skin. A multicenter study. Arch Dermatol. 1991 May;127(5):659-65.
  108. Olsen EA, Katz HI, Levine N, Nigra TP, Pochi PE, Savin RC, Shupack J, Weinstein GD, Lufrano L, Jou HC. Sustained improvement in photodamaged skin with reduced tretinoin emollient cream treatment regimen: effect of once-weekly and three-times-weekly applications. J Am Acad Dermatol. 1997 Aug;37(2 Pt 1):227-30. doi: 10.1016/s0190-9622(97)80129-6
  109. Bhawan J, Gonzalez-Serva A, Nehal K, Labadie R, Lufrano L, Thorne EG, Gilchrest BA. Effects of tretinoin on photodamaged skin. A histologic study. Arch Dermatol. 1991 May;127(5):666-72. Erratum in: Arch Dermatol 1991 Sep;127(9):1382.
  110. Bhawan J, Olsen E, Lufrano L, Thorne EG, Schwab B, Gilchrest BA. Histologic evaluation of the long term effects of tretinoin on photodamaged skin. J Dermatol Sci. 1996 Mar;11(3):177-82. doi: 10.1016/0923-1811(95)00432-7
  111. Kang S, Bergfeld W, Gottlieb AB, Hickman J, Humeniuk J, Kempers S, Lebwohl M, Lowe N, McMichael A, Milbauer J, Phillips T, Powers J, Rodriguez D, Savin R, Shavin J, Sherer D, Silvis N, Weinstein R, Weiss J, Hammerberg C, Fisher GJ, Nighland M, Grossman R, Nyirady J. Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin: a two-year, randomized, placebo-controlled trial. Am J Clin Dermatol. 2005;6(4):245-53. doi: 10.2165/00128071-200506040-00005
  112. Kligman LH. Effects of all-trans-retinoic acid on the dermis of hairless mice. J Am Acad Dermatol. 1986 Oct;15(4 Pt 2):779-85, 884-7. doi: 10.1016/s0190-9622(86)70234-x
  113. Chen S, Kiss I, Tramposch KM. Effects of all-trans retinoic acid on UVB-irradiated and non-irradiated hairless mouse skin. J Invest Dermatol. 1992 Feb;98(2):248-54. doi: 10.1111/1523-1747.ep12556066
  114. Bhawan J. Short- and long-term histologic effects of topical tretinoin on photodamaged skin. Int J Dermatol. 1998 Apr;37(4):286-92. doi: 10.1046/j.1365-4362.1998.00433.x
  115. Acne.
  116. Topical retinoids.
  117. Bissett DL. Topical retinyl priopionate – clinical comparison: a low irritation retinoid for diminishing wrinkles and 5. hyperpigmentation in photoaged human skin. Presented at: The 60th Annual Meeting of the American Academy of Dermatology; New Orleans, LA; February 22-27, 2002.
  118. Sorg O, Antille C, Kaya G, et al. Retinoids in cosmeceuticals. Dermatol Ther 19(5):289-96;2006 Sep-Oct
  119. Piérard-Franchimont C, Castelli D, Van Cromphaut IV, et al. Tensile properties and contours of aging facial skin. A controlled double blind comparative study of the effects of retinol, melibiose-lactose and their association. Skin Res Technol 4:237-43,1998.
  120. Kafi R, Kwak HS, Schumacher WE, et al. Improvement of naturally aged skin with vitamin A (retinol). Arch Dermatol 143(5):606-12;2007 May.
  121. Oblong JE, Bissett DL. Retinoids. In: Draelos ZD, ed. Cosmeceuticals. Philadelphia: Elsevier Saunders pp 36-42;2005.
  122. Creidi P, Vienne MP, Onchonisky S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol 39(6):960-5; 1998 Dec.
  123. Mukherjee S, Date A, Patravale V, et al. Retinoides in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging 1(4):327-48;2006
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