AHA Structure

AHAs are among the most widely studied and commonly used ingredients in cosmetic skin care products. The simplest of the hydroxy acid compounds, these organic carboxylic acids feature one hydroxyl group attached to the alpha position of the carboxyl group. The hydroxyl and carboxyl groups are both directly attached to an aliphatic or alicyclic carbon atom, rendering the hydroxyl group chemically neutral, and only the carboxyl group provides an acidic property. Many AHAs are naturally present in foods and fruits.

Glycolic acid, the smallest (MW 76 g/mol) and the most commonly used AHA, is found in sugarcane. Lactic acid, found naturally in tomatoes, is another small AHA molecule (MW 90 g/mol) that is widely used in topical formulations to exfoliate and provide antiaging benefits. It is also part of skin’s natural moisturizing factor (NMF) in the lactate form as a naturally occurring, endogenous humectant. Ubiquitous in nature as an intermediate in the Kreb’s cycle and found naturally in many citrus fruits (at a concentration of 5–9%), citric acid is both an alpha- and beta-hydroxy acid. It possesses a single hydroxyl moiety that is located in a position that is both alpha and beta relative to the acidic carboxyl group. Aside from its various industrial and food uses, citric acid has profound effects on skin morphology, delivering significant antiaging benefits including reduction in melanin for pigment evening ( Fig. 13.1 ).

Brightening effect observed with citric acid in vitro . Citric acid significantly reduced melanin content in the melanoderm in vitro skin equivalent model relative to the water control, p = 0.01.

Some AHAs contain a phenyl group as a side-chain substituent changing the solubility profile of the AHA, providing increased lipophilicity. This property makes them well suited to target oily and acne-prone skin versus conventional water-soluble AHAs. Mandelic acid (phenyl glycolic acid) and benzilic acid (diphenyl glycolic acid) are examples of this class of AHAs. Mandelic acid has been shown to significantly reduce sebaceous neutral lipid production (e.g., squalene and wax esters) in cultured sebocytes ( p < 0.05 vs. untreated control), which corresponds to clinical improvement in skin oiliness and shine in as little as 1 week ( p < 0.001) ( ).

Histologic Effects of AHAs

Drs. Van Scott and Yu made a novel discovery when they demonstrated the benefits of AHAs on normalizing the process of skin keratinization in severe hyperkeratotic conditions such as lamellar ichthyosis. They published their pioneering findings in 1974 clearly demonstrating the clinical and histologic effects of topically applied AHAs on skin desquamation. Their early research showed concentration-dependent effects on skin; continuous application of low concentrations (i.e., 10% glycolic acid) caused a profound normalizing effect on ichthyotic skin. Conversely, short discontinuous applications of high concentrations at low pH (e.g., topical peel strength) provoked epidermolysis.

Further research by Van Scott and Yu revealed benefits beyond exfoliation, securing a significant role for these compounds in antiaging skin care. Topical application of AHAs at concentrations of 10–25% caused increased biosynthesis of dermal GAGs and collagen fibers and improved the quality of photoaged elastic fibers. Additional development work revealed that twice-daily application of AHA cream formulations (10–35%) to forearms for 1–9 months versus a control cream caused a measurable increase in skin thickness using calipers. Corresponding histologic analysis revealed increased biosynthesis of GAGs and collagen fibers, which explained the significant increase in skin thickness that was observed. After these initial findings, decades of clinical, histologic, and cellular research have further supported the antiaging effects of glycolic acid and other AHAs on SC desquamation, epidermal proliferation, dermal matrix remodeling, and melanin distribution. For example, a study done by showed the effects of AHAs on photoaged human skin by both clinical and microanalytic methods. Glycolic, lactic, or citric acid containing lotion (25%) was applied to one forearm versus a placebo lotion that was applied to the contralateral forearm over a period of 6 months. Forearm thickness measurements were conducted throughout the study using digital micrometers, and biopsy specimens were collected from both arms for endpoint analysis. Results demonstrated a 25% increase in skin thickness in the AHA-treated forearms, which was significantly greater than the vehicle control arm. Specifically, epidermal and papillary dermal thickness increased with AHA treatment compared with vehicle ( p < 0.05); other dermal changes included increased acid mucopolysaccharides, improved quality of elastic fibers, and increased density of collagen with no evidence of inflammation. A decrease in epidermal melanin clumping was also observed. This pivotal study clearly demonstrated the manifold antiaging effects of AHAs.

Additional clinical and skin biology studies have validated the early research findings of Van Scott, Yu, and Ditre. For example, a study of human skin explants treated topically with 8%, 10%, 15%, or 25% glycolic acid (pH 4) daily for 5 days demonstrated increased desquamation in a concentration-dependent manner. Similarly, total collagen levels were increased with all glycolic acid treatments, and greater effects were observed at higher concentrations—all without impact to tumor necrosis factor-alpha (TNF-α) expression as a measure of irritation ( ).

Clinical Effects of Cosmetic AHAs

Antiaging effects of cosmetic AHAs have been demonstrated in rigorous clinical studies that have been published in peer-reviewed journals. For example, in a randomized, double-blind, vehicle-controlled study conducted by , photodamaged skin of 74 females was treated for 22 weeks with topical glycolic acid or lactic acid creams (8%). The AHA cream was applied monadically to the face and in a paired comparison to one forearm, leaving the remaining forearm for the vehicle control. Results showed the AHA creams were well tolerated and significantly improved photodamaged skin. Both glycolic and lactic acid significantly reduced mottled hyperpigmentation and/or sallowness on the forearms in comparison to the vehicle control ( p < 0.05). Subject self-assessment supported the clinical-grading result findings, noting improvements from baseline in reduction of fine lines, firmness of skin, reduction of age spots, and evenness of pigmentation.

Another randomized, double-blind, vehicle-controlled face and neck study, conducted by , compared a 5% unneutralized formulation of glycolic acid to its vehicle control over a period of 12 weeks. Glycolic acid treatment showed significant improvement in physician-assessed skin texture and a trend toward overall improvement in discoloration versus vehicle control. The effects of topical glycolic acid creams (8%, pH 3.8) were assessed compared to vehicle control creams in several studies using the photodamaged arm model. Antiaging benefits following AHA use were found to be reproducible. Notably, glycolic acid provided significantly greater improvement to crepe-like skin appearance than its vehicle control after 8 and 12 weeks of use ( ). A split-face study by compared 8% glycolic acid cream (pH 3.8) to vehicle and incorporated objective instrumental assessments including digital photography, ballistometry, and three-dimensional facial scanning. These instruments measured signs of photodamage including elasticity and firmness and captured an overall three-dimensional image of length and depth of fine lines and wrinkles. The measures provide a quantitative method to assess early changes in periorbital, glabellar, and nasolabial target benefit areas. Fine lines and wrinkles were fewer and less deep in the periorbital area after 8 weeks of treatment with glycolic acid. Skin tone was also noticeably improved and the overall texture of the skin was smoother. AHAs have clearly demonstrated significant clinical benefits to photodamaged skin both qualitatively and quantitatively, including improvements to skin tone, aged appearance, crepiness, discoloration, smoothness, and fine lines and wrinkles.

Mechanisms of Action of AHAs

The exact mechanisms by which AHAs exert their effects on skin are not completely understood. Insights into possible mechanisms are based on available in vitro and clinical data. Early ultrastructural evaluations have revealed the clues in determining potential mechanisms of action, including diminished corneocyte cohesion at the lower level of the SC; diminished number and strength of desmosomal attachments between adjacent corneocytes; and increased epidermal and dermal skin thickness in photoaged skin, which may correspond with in vitro observations of increased keratinocyte and fibroblast proliferation ( ; ) as well as increased dermal synthesis of GAGs and collagen fibers. Investigative work by suggests an inverse relationship between SC acidification (glycolic acid solution, pH 3.8) and concentration of calcium and ammonium ions essential to various skin functions and enzymatic activity including transglutaminase, critical to epidermal cell differentiation.

Cell culture models have been used to identify other mechanisms of action regarding the role of AHAs in benefiting aged skin. For example, several in vitro studies have evaluated the effects of AHAs on fibroblast cells to better understand the dermal remodeling action of AHAs observed in vivo . Human dermal fibroblast cells exposed to glycolic or L-lactic acid in cell culture produced significantly higher levels of procollagen I in a dose-dependent manner. Similar effects were seen in two other studies that utilized ³ H-Proline labeling as a quantitative measure, suggesting that AHAs have a stimulatory effect on collagen at the level of protein synthesis.

AHAs may also influence epidermal–dermal cellular communication. investigated the effect of glycolic acid on dermal matrix metabolism in both in vitro and ex vivo systems. They found a direct, dose-dependent increase in collagen synthesis following glycolic acid treatment in fibroblast cells. Keratinocytes treated with glycolic acid released higher levels of interleukin 1 alpha (IL-1α), and this effect was also observed ex vivo . Interestingly, when fibroblasts were exposed to conditioned medium from keratinocytes treated with glycolic acid, an upregulation of matrix metalloproteinase-1 (MMP-1) and MMP-3 mRNA expression levels was seen. The effect on MMP levels was most likely mediated by IL-1α, which was upregulated by glycolic acid in keratinocytes. These findings suggest a possible role in cell-to-cell communication with the ability of keratinocyte-treated cells to influence dermal matrix remodeling.

Another study, by , examined the effect of topical application of different concentrations of lactic acid on cytokine secretion profile. At concentrations of 1.5% and 3% there was an increased expression of vascular endothelial growth factor (VEGF) from epidermal skin equivalents. This may in part explain the clinical observation by showing topical application of AHAs can prevent regression of skin microvessels following corticosteroid use.

Topical Uses of AHAs

Descaling Effect

AHAs have long been shown to influence hyperkeratinization by modulating corneocyte attachment at the base of the SC, resulting in a specific desquamation effect unlike the nonspecific effect of traditional keratolytic agents. This effect is clearly visible on hyperkeratotic skin, such as lamellar ichthyosis, and was recently investigated for use on psoriatic plaques. Salicylic acid is the current descaling treatment of choice for psoriatic plaques. However, its use has been shown by Van Scott and Yu to cause dermal thinning, which could exacerbate corticosteroid-induced atrophy, whereas AHAs increase dermal biosynthesis and have been shown to counteract corticosteroid-induced dermal thinning. In a double-blind, active-controlled, bilateral comparison, a 20% AHA/PHA/bionics blend cosmetic cream formulated at pH 3.7 demonstrated a significantly greater descaling effect after 1 week of treatment in comparison to prescription-strength salicylic acid (6%, pH 4.4). Both products were applied twice daily and were equally well tolerated ( Fig. 13.2 ). AHAs are effective descaling agents and may be preferred over salicylic acid to help counteract dermal thinning effects of topical corticosteroids.

Descaling effect observed with 20% alpha-hydroxy acid/polyhydroxy acid/bionic acid formulation. (A) Before treatment. (B) After treatment (2 weeks).

Exfoliating Effects

Glycolic acid is considered to be the gold standard for skin exfoliation in the dansyl chloride cell turnover study model by accelerating the desquamation and removal of dansyl chloride–stained skin. It is important to note, however, that although AHAs increase exfoliation and cell turnover in this model, application of cosmetic-strength AHAs to normal dry skin does not usually cause visibly apparent exfoliation or peeling effects. Furthermore, while dry skin conditions can be temporarily relieved by application of water, humectants, and emollients by attracting water to skin’s surface and/or trapping skin’s natural water, the dry skin condition will persist if the SC barrier is not functioning properly. AHAs have been shown to enhance skin barrier function by increasing ceramides within the SC.

Recent evidence reveals the activity of low-concentration AHA and PHA leave-on and wash-off formulations in increasing the skin’s natural cell turnover/exfoliation rate. Products contained 1–2% glycolic acid, gluconolactone, or lactobionic acid at pH 3.8–3.9; dansyl chloride fluorescence intensity was used to quantify exfoliation effects versus untreated controls via digital photography and image analysis ( ) ( Fig. 13.3 ).

Enhanced cell turnover effect with wash-off cleansers containing (A) glycolic acid (2%, pH 3.8) or (B) gluconolactone (2%, pH 3.9) demonstrating a statistically significant increase in cell turnover compared to the untreated control based on fluorescence intensity, * p < 0.05, n = 34.

Superficial Skin Peel Procedural Use

Lactic acid and glycolic acid are commonly used superficial peeling agents in the AHA class of compounds. Citric acid and mandelic acid are also found in some peel formulations. AHAs have advantages as peeling agents over other chemical reagents such as trichloroacetic acid (TCA) and salicylic acid (SA). For example, AHA peels can be neutralized using a sodium bicarbonate solution at any time during a peel to terminate the action of the acid, providing an important element of safety. TCA is a powerful denaturant and can cause rapid destruction of the skin; once it is applied to skin, the TCA peel continues until it has fully reacted. SA can be used to target acne-prone skin but, as reported previously, causes a negative dermal thinning effect in skin. Unlike the AHAs, these compounds have no nutritive benefits, and their benefit as peeling agents occurs mainly by the mechanism of wound repair or keratolysis. Conversely, AHAs have been used as superficial peeling agents with demonstrated safety and efficacy profiles on all Fitzpatrick skin types and most therapeutic conditions. In high concentrations of up to 70% without pH adjustment, free-acid AHA peel solutions can be applied for short exposure times (i.e., less than 5 minutes) to the skin to cause desquamation and accelerate epidermal and dermal renewal. These high-strength AHA skin peels are used as topical procedures in physicians’ offices for adjunctive care of many skin types to provide antiaging and skin smoothing benefits. Case studies conducted with physician-strength glycolic acid peels demonstrated improvements to photoaged skin including periocular wrinkling ( Fig. 13.4 ), inflammatory rosacea ( Fig. 13.5 ), and acne plus postinflammatory hyperpigmentation ( Fig. 13.6 ).

(A) Before treatment. (B) After four glycolic acid peels: 1 × 35% (pH 1.3), 1 × 50% (pH 1.2), and 2 × 70% (pH 0.6) demonstrating reduced periocular wrinkles. Includes use of adjunctive antiaging home care products between peels.

Improvement of inflammatory rosacea after nine glycolic acid peels: 2 × 35% (pH 1.3), 2 × 50% (pH 1.2), and 5 × 70% (pH 0.6). (A) Before treatment. (B) After treatment. The patient used a gentle polyhydroxy acid skin care regimen at home between peels and was able to discontinue treatment medication use at the fifth peel (sodium sulfacetamide lotion and oral antibiotic).

Before (A) and after (B) a series of six glycolic acid peels: 2 × 35% (pH 1.3), 3 × 50% (pH 1.2), and 1 × 70% (pH 0.6) demonstrating reduced acne and postinflammatory hyperpigmentation. The patient used a nonfoaming polyhydroxy acid cleanser at home and was able to discontinue medication use (oral antibiotic, at the fourth peel; topical azelaic acid at the sixth peel).

Medium-strength AHA peels (i.e., 30% maximum) have an adjusted pH of at least 3.0 to help ensure safe use by aestheticians in spa and salon settings. The concentration and pH of AHA home peels are adjusted even further to ensure safety for use at home by patients.

Newer dermatologic procedures are often compared to superficial AHA peels as benchmarks to determine efficacy of more invasive procedures. For example, evaluated biweekly microneedling treatments versus 35% glycolic acid peels on 60 patients (Fitzpatrick skin phototypes IV–VI, presence of atrophic acne scars) over 12 weeks. One-third of the peel patients demonstrated clinical improvement in acne scars versus nearly three-quarters of the microneedling patients.