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Address correspondence to: Amanda Rusk, MD, University of Cincinnati Medical Center, Department of Dermatology, 231 Albert Sabin Way, Cincinnati, OH 45267-2827; Phone (330) 388-0824.
University of Cincinnati Medical Center, Department of Dermatology, Cincinnati, OhioCincinnati Children's Hospital Medical Center, Department of Dermatology, Cincinnati, Ohio
University of Cincinnati Medical Center, Department of Dermatology, Cincinnati, OhioCincinnati Children's Hospital Medical Center, Department of Dermatology, Cincinnati, Ohio
Acne vulgaris is a common skin condition encountered in specialties outside of dermatology, including obstetrics and gynecology. The pathophysiology of acne is complex and includes disruption of the cutaneous microbiome, abnormal keratinization, inflammation, and hormonal influences. Various topical and systemic treatment modalities target each component of acne pathophysiology. Clinically, acne can be broken down into noninflammatory, inflammatory, or mixed subtypes. The age of the patient at presentation and signs and symptoms of hormonal imbalance might prompt workup for underlying disorders. The severity as well as type of acne dictates the type of treatment.
Acne is a common skin disorder encountered in various specialties beyond dermatology, including obstetrics and gynecology. The pathophysiology of acne can be broken down into 4 categories including follicular microbiome, abnormal keratinization, inflammation/innate immunity, and hormonal influences on sebum and immunity. Each of these can be targeted with different therapeutic approaches.
Early adolescence heralds an increase in sebum production as well as changes in sebum composition including decreased linoleic acid and sebocyte cytokine production, leading to upregulation of interleukin-1 and stimulation of the inflammatory cascade and endothelial cell activation.
These changes are in response to rising levels of adrenal androgens, especially dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS).
Androgens, including testosterone and dihydrotestosterone, and estrogens are hormones synthesized in the testes, ovaries, adrenal glands, placenta, and brain that act via intracellular receptors.
In the skin, androgens play a role in sebum production and barrier integrity. Dihydrotestosterone plays a role in sebum production and the production of proinflammatory cytokines by sebocytes.
Antiandrogens and estrogens are used to treat the hormonal component of acne.
Acne might be one of the earliest signs of adrenarche as the adrenal glands mature and begin to produce androgens. Adrenal androgens are responsible for infantile acne and prepubertal acne. Adrenal androgens might also be increased in patients with congenital adrenal hyperplasia, and benign or malignant adrenal tumors. In congenital adrenal hyperplasia, including atypical/late-onset types more frequently seen after the newborn period, low cortisol levels induce high levels of adrenocorticotrophic hormone, which can lead to severe acne.
Ovarian sources of androgens include ovarian tumors and polycystic ovarian syndrome (PCOS). Locally in the skin within the sebaceous glands, androgens are produced via the β-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, and 5α-reductase pathways.
The microbiome also plays a role in the pathophysiology of acne. In a balanced microbiome, Cutibacterium acnes (formerly Propionibacterium acnes) colonization is kept in check by Staphylococcus epidermidis via release of succinic acid.
C acnes interacts with toll-like receptor 2, defensins, and matrix metalloproteinases, leading to hyperkeratinization of the sebaceous unit and activation of innate immunity.
Targeting C acnes therapeutically with topical or oral antibiotics helps reduce this inflammation and restore the natural skin barrier. Selective therapies that do not disturb commensal organisms, such as bacteriophage endolysin specifically targeting C acnes, show promise in the treatment of acne vulgaris.
Hyperkeratinization of the follicular epithelium leads to formation of a microcomedone, the earliest finding in an acne lesion. Topical and systemic retinoids help regulate keratinization to prevent the initial plugging of the follicle.
History
It is important to take a detailed history of the patient's acne timeline including age of onset, relationship to adrenarche and menarche, and relationship to menstrual cycles. According to a consensus by the American Acne and Rosacea Society and endorsed by the American Academy of Pediatrics, mid-childhood acne occurring between the ages of 1 and 7 years old is uncommon and warrants workup by a pediatric endocrinologist for causes of hyperandrogenism, whereas preadolescent acne occurring between the ages of 7 and 12 years is common and might precede other signs of pubertal maturation.
Preadolescent acne does not require further workup unless there are other signs of androgen excess or PCOS on history or exam. Because androgen output is very low in patients with pre- and early adolescent acne, and there are few good standards for normal at these ages, elevated but not “abnormal” androgen levels might be difficult to interpret. Ovarian ultrasound is rarely used because benign ovarian cysts in childhood might be confounding.
Psychological Effects of Acne
The psychological effects of acne might be under-recognized but might be present in patients being treated for acne. In one cross-sectional analysis of high school students, acne was self-reported in approximately 85% of participants and there was a direct correlation between severity of acne and symptoms of anxiety, depression, and lower self-esteem.
Several studies have been performed, which showed the effect of acne on self-esteem, personality, mood, and quality of life using various questionnaires.
It is important to monitor patients with acne for any of these symptoms and treat or refer as appropriate.
Physical Exam
Acne can be classified as mild, moderate, or severe depending on the number of lesions, type of lesions, and amount of skin involved as well as by predominant morphology.
Acne morphology is broken down into 2 basic types: noninflammatory lesions and inflammatory lesions. Noninflammatory lesions are characterized by closed comedones (whiteheads) that do not have surrounding erythema or an apparent follicular opening, and open comedones (blackheads), which have a follicular opening filled with a keratinaceous core (Fig. 1). The keratin appears black because of melanin deposition and lipid oxidation, not dirt. Papules, pustules, and nodules are examples of inflammatory acne (Fig. 2). Lesions can begin to coalesce in more severe nodulocystic acne to form large nodules (Fig. 3). Although nodules used to be called cysts, they do not have epithelial linings and therefore are not true cysts. Even after resolution of inflammatory lesions, postinflammatory pigment changes and erythema might persist. Typically, this fades over many months, but occasionally pigment alteration might be permanent. Severe nodulocystic acne might leave pitted or hypertrophic scars. Hirsutism, alopecia, acanthosis nigricans, and obesity might be other features of elevated androgen levels, such as in metabolic syndrome and/or PCOS.
Fig. 1Scattered closed and open comedones on the forehead.
Treatment of acne is according to the type (inflammatory vs noninflammatory) and the severity of acne (Table 1). Many patients will have tried at least 1 over-the-counter (OTC) product and for early or mild disease, these might be effective. Various products available OTC include benzoyl peroxide 2.5%-10%, adapalene 0.1% gel, salicylic acid 0.5%-2%, and sulfur sulfacetamide.
Topical prescription therapies include topical retinoids, benzoyl peroxide wash or gel, topical dapsone, topical antibiotics, azelaic acid, and various combination products (Table 2). For mild disease, topical therapy alone might be sufficient whereas moderate to severe disease typically requires additional use of systemic agents. In most cases, a combination of benzoyl peroxide and a topical retinoid is sufficient and a great starting point.
It comes in strengths ranging between 2.5% and 10% and is formulated as a gel, lotion, cream, pad, cleanser, and foam, all of which are available OTC as well as by prescription in some cases. Although effective as a monotherapy, benzoyl peroxide is often used in conjunction with topical retinoids or topical antibiotics to improve effectiveness.
It is important to note that benzoyl peroxide might bleach clothing and linens, and can be irritating to the skin in a concentration-dependent manner. True allergic contact dermatitis occurs but is rare. Benzoyl peroxide has not been associated with the development of resistant C acnes strains like other antimicrobials and should be used in addition to any regimen using topical antibiotics to reduce the development of resistance.
Salicylic acid, available OTC in strengths from 0.5% to 5%, works by dissolving desmosomes leading to decreased adhesion of corneocytes, increased cell turnover, and breakdown of the microcomedone.
Azelaic acid is available at strengths ranging from 10% to 20% and has several different mechanisms of action. Azelaic acid is bactericidal toward C acnes, anti-inflammatory, and inhibits keratinization.
Topical dapsone gel is available in 5% or 7.5% and has anti-inflammatory and antibiotic properties. Topical antibiotics such as erythromycin, clindamycin, and minocycline may be used, but come with a risk of developing bacterial resistance and therefore should not be used as monotherapy.
Four US Food and Drug Administration (FDA)-approved topical retinoids are available including adapalene, tretinoin, tazarotene, and most recently trifarotene.
In comparison and noninferiority trials, there was no difference between adapalene 0.1% or 0.3% gel and tazarotene 0.1% cream in the decrease of inflammatory or noninflammatory lesions after 12 weeks of treatment.
Randomized comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel in the treatment of patients with at least moderate facial acne vulgari.
In one randomized control trial, tretinoin 0.04% microsphere gel and tazarotene 0.05% cream showed similar efficacy, but tretinoin showed more rapid improvement and less dryness, peeling, or pruritus.
The newest topical retinoid, trifarotene, was FDA-approved in October 2019 for the treatment of facial and truncal acne in those older than 9 years of age.
Often, patients require therapy with combination products to treat inflammatory and noninflammatory lesions. Benzoyl peroxide is available in combination with erythromycin, clindamycin, and adapalene as a single product, which has been shown to be more effective than individual medications alone.
Irritation from topical acne treatments can arise within the first couple of weeks and can deter patients from adhering to their regimen. Over time, irritation improves and can be managed by slowly increasing frequency of application to once a day and with the additional use of a noncomedogenic moisturizer applied after the medication.
For more moderate to severe acne, systemic therapy with antibiotics, isotretinoin, or hormonal therapy may be used. Tetracyclines, including doxycycline and minocycline, are the preferred oral antibiotics for the treatment of acne.
However, tetracycline derivatives should be avoided in children younger than 8 years of age because of tooth staining. Oral erythromycin, azithromycin, or trimethoprim-sulfamethoxazole are alternatives for those who cannot take tetracylines.
Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
Optimizing topical regimens, using hormonal therapy for female patients, and using isotretinoin are important to prevent the overuse of systemic antibiotics.
Isotretinoin is an oral vitamin A derivative approved by the FDA for treatment of severe, recalcitrant acne. It is typically started at 0.5 mg/kg/d and titrated up to 1 mg/kg/d for a total dose of 120-150 mg/kg, usually for a course of 5-6 months.
Because of severe teratogenicity, all patients must register in the iPledge drug monitoring program, and all patients of childbearing potential must receive contraception counseling and must select 2 forms of contraception or abstinence to use during treatment with isotretinoin.
Before isotretinoin initiation, patients of childbearing potential must have 2 negative pregnancy tests 30 days apart and must complete monthly pregnancy tests during treatment. Recommendations vary on laboratory monitoring for hypertriglyceridemia, elevated liver enzymes, leukopenia, and thrombocytopenia.
In one cohort study of 1863 patients who received isotretinoin, significant lab abnormalities were rare and did not change management. Of note, elevated lipid levels occurred during the first few months and then stabilized in most cases.
Hormonal therapy for female patients is an important component in the management of acne vulgaris and is beneficial for the treatment of inflammatory and comedonal acne due to hormonal influences on sebum and keratinization.
Recently, in August 2020, clascoterone cream was FDA-approved for acne, and is the first topical antiandrogen available.
Combined oral contraceptives (COCs) that contain estrogen and progesterone can decrease testosterone levels, inhibit 5α-reductase conversion of testosterone to dihydrotesterone within the pilosebaceous unit, and decrease adrenal and ovarian androgen production, ultimately leading to decreased sebum production.
Drosperinone-containing COCs are generally favored because this progestin has antiandrogenic properties. Although third- and fourth-generation progestins are less androgenic, all COCs are effective for acne. Progestin-only contraceptives, in all forms including oral, injectable, subcutaneous implants, and intrauterine devices can cause worsening of acne.
Effects of oral contraceptives containing ethinylestradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women.
Several COC preparations have been FDA-approved for the treatment of acne including Ortho Tri-Cyclen (Janssen; norgestimate/ethinyl estradiol), Estrostep (Allergan; norethindrone acetate/ethinyl estradiol), and Yaz (Bayer; drosperinone/ethinyl estradiol).
FDA. US Food and Drug Administration: MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Available: www.fda.gov/medwatch. Accessed August 18, 2020
FDA. US Food and Drug Administration: ESTROSTEP Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets*) package insert. Irvine, CA: Allergan Inc.; Revised 2017. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020130s018lbl.pdf. Accessed April 1, 2021.
Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
However, most all COCs are effective. Use of COCs in pre- and very early menarchal patients is not indicated. Several months are required to achieve full therapeutic benefit.
Originally used as a potassium-sparing diuretic, spironolactone inhibits sebum production via the androgen receptors on sebocytes and might decrease androgen precursor synthesis in the adrenal glands.
Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5α-dihydrotestosterone in vitro.
Spironolactone is used off-label for the treatment of acne as well as hirsutism and androgenetic alopecia. Although there is a lack of randomized control trials supporting the use of spironolactone, there have been several recent studies showing its effectiveness in the treatment of acne.
Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
Frequency of treatment switching for spironolactone compared to oral tetracycline-class antibiotics for women with acne: a retrospective cohort study 2010-2016.
Several months of therapy with spironolactone are required to reach maximum effectiveness, with a median time to initial response and maximum response of 3 and 5 months in one study.
There are few data on the use of spironolactone, which is off-label for all acne, in pre- and early-adolescence patients. It is important to set expectations for improvement in the treatment of acne vulgaris. In surveys, patients expected significant improvement in acne lesions after only a few weeks. However, treatment for at least 8-12 weeks is necessary to determine effectiveness.
Acne scars can be categorized as atrophic (boxcar, icepick, or rolling), hypertrophic, or keloidal, and treatment should be tailored to the type of scar.
Erythematous scars can be treated with lasers targeting vasculature like 595-nm pulsed-dye laser or intense puled light. Postinflammatory hyperpigmentation can be treated with lasers that target melanin including the Q-switched alexandrite laser.
Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study.
Surgical options include subcision, punch removal, or excision. For subcisions a tribeveled hypodermic needle is used to separate the dermal scar bands and this method can also be performed for atrophic scars. The needle is placed horizontally in the superficial subcutaneous fat and gently advanced back and forth.
Chemical reconstruction of skin scars refers to the application of trichloroacetic acid to atrophic scars. In one review of this technique, 60%-100% of patients demonstrated better than 25%-30% improvement.
Acne is a common dermatologic condition encountered by many different specialties, including obstetrics and gynecology. The pathogenesis is complex and consists of an unbalanced microbiome, hyperkeratinization, inflammation, and hormonal influences, and each of these pathways can be targeted by different therapies. Various topical and oral therapies are used in the treatment of acne depending on severity and whether the acne is inflammatory, comedonal, or both. Acne and resultant scarring might have a negative psychological effect on patients, which improves with successful treatment.
References
Dreno B
Gollnick HPM
Kang S
et al.
Understanding innate immunity and inflammation in acne: implications for management.
Randomized comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel in the treatment of patients with at least moderate facial acne vulgari.
Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
Effects of oral contraceptives containing ethinylestradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women.
FDA. US Food and Drug Administration: MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Available: www.fda.gov/medwatch. Accessed August 18, 2020
FDA. US Food and Drug Administration: ESTROSTEP Fe (Norethindrone Acetate and Ethinyl Estradiol Tablets, USP and Ferrous Fumarate Tablets*) package insert. Irvine, CA: Allergan Inc.; Revised 2017. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020130s018lbl.pdf. Accessed April 1, 2021.
Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5α-dihydrotestosterone in vitro.
Frequency of treatment switching for spironolactone compared to oral tetracycline-class antibiotics for women with acne: a retrospective cohort study 2010-2016.
Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study.
May use topical dapsone, azelaic acid, or sodium sulfacetamide if benzoyl peroxide is not tolerated.
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