Advertisement

What the Pediatric and Adolescent Gynecology Clinician Needs to Know about Acne

  • Amanda Rusk
    Correspondence
    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.
    Affiliations
    University of Cincinnati Medical Center, Department of Dermatology, Cincinnati, Ohio
    Search for articles by this author
  • Kalyani Marathe
    Affiliations
    University of Cincinnati Medical Center, Department of Dermatology, Cincinnati, Ohio

    Cincinnati Children's Hospital Medical Center, Department of Dermatology, Cincinnati, Ohio
    Search for articles by this author
  • Anne W. Lucky
    Affiliations
    University of Cincinnati Medical Center, Department of Dermatology, Cincinnati, Ohio

    Cincinnati Children's Hospital Medical Center, Department of Dermatology, Cincinnati, Ohio
    Search for articles by this author
Published:March 13, 2021DOI:https://doi.org/10.1016/j.jpag.2021.03.002

      ABSTRACT

      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.

      Key Words

      Brief Review of Pathophysiology

      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.
      • Dreno B
      • Gollnick HPM
      • Kang S
      • et al.
      Understanding innate immunity and inflammation in acne: implications for management.
      ,
      • Harper JC
      Acne vulgaris: what's new in our 40th year.
      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.
      • Ceruti JM
      • Leirós GJ
      • Balañá ME
      Androgens and androgen receptor action in skin and hair follicles.
      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.
      • Lee WJ
      • Jung HD
      • Chi SG
      • et al.
      Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured 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.
      • New MI
      An update of congenital adrenal hyperplasia.
      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.
      • Dréno B
      What is new in the pathophysiology of acne, an overview.
      In a sebum-rich environment, more pathogenic strains of C acnes might disrupt the microbiome.
      • O'Neill AM
      • Gallo RL
      Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris.
      C acnes interacts with toll-like receptor 2, defensins, and matrix metalloproteinases, leading to hyperkeratinization of the sebaceous unit and activation of innate immunity.
      • Dreno B
      • Gollnick HPM
      • Kang S
      • et al.
      Understanding innate immunity and inflammation in acne: implications for management.
      ,
      • Dréno B
      What is new in the pathophysiology of acne, an overview.
      ,
      • Jugeau S
      • Tenaud I
      • Knol AC
      • et al.
      Induction of toll-like receptors by Propionibacterium acnes.
      ,
      • Kim J
      Review of the innate immune response in acne vulgaris: activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.
      C acnes also stimulates monocytes to produce interleukin-8, a chemotaxin, pulling neutrophils into the follicle.
      • Kim J
      Review of the innate immune response in acne vulgaris: activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.
      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.
      • Woo TE
      • Sibley CD
      The emerging utility of the cutaneous microbiome in the treatment of acne and atopic dermatitis.
      Therapies that support the cutaneous microbiome including prebiotics, probiotics, and cutaneous microbiota transplants might be valuable as well.
      • Woo TE
      • Sibley CD
      The emerging utility of the cutaneous microbiome in the treatment of acne and atopic dermatitis.
      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.
      • Eichenfield LF
      • Krakowski AC
      • Piggott C
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      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.
      • Uslu G
      • Şendur N
      • Uslu M
      • et al.
      Acne: prevalence, perceptions and effects on psychological health among adolescents in Aydin, Turkey.
      Several studies have been performed, which showed the effect of acne on self-esteem, personality, mood, and quality of life using various questionnaires.
      • Dunn LK
      • O'Neill JL
      • Feldman SR
      Acne in adolescents: quality of life, self-esteem, mood, and psychological disorders.
      Patients exhibit increased incidence of anxiety, depression, and suicidal ideation.
      • Dunn LK
      • O'Neill JL
      • Feldman SR
      Acne in adolescents: quality of life, self-esteem, mood, and psychological disorders.
      One review showed that effective treatment of acne, especially with isotretinoin, led to improvement in psychologic abnormalities.
      • Tan JK
      Psychosocial impact of acne vulgaris: evaluating the evidence.
      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.
      • Eichenfield LF
      • Krakowski AC
      • Piggott C
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      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 1
      Fig. 1Scattered closed and open comedones on the forehead.
      Fig 2
      Fig. 2Inflammatory erythematous papules and pustules on Fitzpatrick type II skin (a) and Fitzpatrick type V skin (b).

      Treatment

      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.
      • Berry K
      • Lim J
      • Zaenglein AL
      Acne vulgaris: treatment made easy for the primary care physician.
      Table 1Topical Acne Treatments.
      Topical medicationAvailable strengthAvailable vehiclesAvailable OTC
      Inflammatory lesions
       BPO2.5%-10%Gel, cream, pad, cleanser, foamYes
       Salicylic acid0.5%-5%Gel, cream, pad, cleanser, foam, solution, lotionYes
       Dapsone5%, 7.5%GelNo
       Clindamycin1%Solution, gel, pad, creamNo
       Erythromycin2%Solution, gel, pad, lotionNo
      Minocycline4%FoamNo
      Comedonal lesions
       Adapalene0.1%Gel, cream, lotionYes
      0.3%GelNo
      Tretinoin0.025%Cream, gel,No
      0.05%Cream, liquidNo
      0.1%CreamNo
      0.04%, 0.06%, 0.08%, 0.1%Micro gelsNo
       Tazarotene0.045%LotionNo
      0.05%, 0.1%Gel, cream, foamNo
       Trifarotene50 µg/gCreamNo
      Other and combination
       Azelaic Acid10%SuspensionYes
      15%Gel, foamNo
      20%CreamNo
       Sulfur/sodium sulfacetamide5%, 10%Lotion, wash, suspensionYes
       BPO/erythromycin5%/1%GelNo
       BPO/clindamycin2.5%, 3.75%, 5%/1%, 1.2%GelNo
       BPO/adapalene2.5%/0.1%, 0.3%GelNo
       Clindamycin/tretinoin1.2%/0.025%GelNo
      Hormonal
       Clascoterone1%CreamNo
      BPO, benzoyl peroxide; OTC, over-the-counter.
      Table 2Algorithm for the Management of Acne Vulgaris in Female Patients on the Basis of Severity.
      SeverityTry firstCombine with
      Mild comedonalTopical retinoid
      Mild inflammatory/mixedBenzoyl peroxide
      May use topical dapsone, azelaic acid, or sodium sulfacetamide if benzoyl peroxide is not tolerated.
      with topical retinoid
      Topical antibiotic
      ModerateTopical retinoid with benzoyl peroxide with or without oral antibiotic or hormonal therapy
      Currently combined oral contraceptives with or without spironolactone. The role of topical antiandrogens not yet established.
      Isotretinoin
      SevereTopical retinoid with benzoyl peroxide and oral antibiotic with or without hormonal therapyIsotretinoin
      Very severe/nodulocysticIsotretinoin
      low asterisk May use topical dapsone, azelaic acid, or sodium sulfacetamide if benzoyl peroxide is not tolerated.
      Currently combined oral contraceptives with or without spironolactone. The role of topical antiandrogens not yet established.
      Benzoyl peroxide is antibacterial against C acnes and has mild comedolytic abilities.
      • Fulton JE
      • Farzad-Bakshandeh A
      • Bradley S
      Studies on the mechanism of action of topical benzoyl peroxide and vitamin A acid in acne vulgaris.
      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.
      • Marson JW
      • Baldwin HE
      An overview of acne therapy, part 1: topical therapy, oral antibiotics, laser and light therapy, and dietary interventions.
      ,
      • Yang Z
      • Zhang Y
      • Lazic Mosler E
      • et al.
      Topical benzoyl peroxide for acne.
      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.
      • Yang Z
      • Zhang Y
      • Lazic Mosler E
      • et al.
      Topical benzoyl peroxide for acne.
      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.
      • Lu J
      • Cong T
      • Wen X
      • et al.
      Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes.
      Sulfur, available as sulfur 5% with sodium sulfacetamide 10%, has keratolytic properties as well as antibacterial activity.
      • Gupta AK
      • Nicol K
      The use of sulfur in dermatology.
      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.
      • Schulte BC
      • Wu W
      • Rosen T
      Azelaic acid: evidence-based update on mechanism of action and clinical application.
      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.
      • Eichenfield LF
      • Krakowski AC
      • Piggott C
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      Four US Food and Drug Administration (FDA)-approved topical retinoids are available including adapalene, tretinoin, tazarotene, and most recently trifarotene.
      • Tan J
      • Miklas M
      A novel topical retinoid for acne: trifarotene 50 μg/g cream.
      Retinoids are vitamin A derivatives that reduce occlusion of the follicle by normalizing keratinization and decreasing cohesiveness of keratinocytes.
      • Khalil S
      • Bardawil T
      • Stephan C
      • et al.
      Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects.
      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.
      • Thiboutot D
      • Arsonnaud S
      • Soto P
      • et al.
      Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris.
      • Gold LS
      • Colon LE
      • Johnson LA
      • et al.
      Is switching retinoids a sound strategy for the treatment of acne vulgaris?.
      • Tanghetti E
      • Dhawan S
      • Green L
      • et al.
      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.
      • Pariser D
      • Colon LE
      • Johnson LA
      • et al.
      Adapalene 0.1% gel compared to tazarotene 0.1% cream in the treatment of acne vulgaris.
      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.
      • Kircik LH
      Tretinoin microsphere gel pump 0.04% versus tazarotene cream 0.05% in the treatment of mild-to-moderate facial acne vulgari.
      A new formulation of tazarotene, 0.045% lotion, recently underwent phase III trials and was well tolerated.
      • Tanghetti EA
      • Werschler WP
      • Lain T
      • et al.
      Tazarotene 0.045% lotion for once-daily treatment of moderate-to-severe acne vulgaris: results from two phase 3 trials.
      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.
      • Tan J
      • Miklas M
      A novel topical retinoid for acne: trifarotene 50 μg/g cream.
      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.
      • Marson JW
      • Baldwin HE
      An overview of acne therapy, part 1: topical therapy, oral antibiotics, laser and light therapy, and dietary interventions.
      Combination products stabilize benzoyl peroxide and topical retinoid combinations, preventing the oxidation of the retinoid.
      • Yang Z
      • Zhang Y
      • Lazic Mosler E
      • et al.
      Topical benzoyl peroxide for acne.
      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.
      • Berry K
      • Lim J
      • Zaenglein AL
      Acne vulgaris: treatment made easy for the primary care physician.
      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.
      • Zaenglein AL
      • Pathy AL
      • Schlosser BJ
      • et al.
      Guidelines of care for the management of acne vulgaris.
      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.
      • Zaenglein AL
      • Pathy AL
      • Schlosser BJ
      • et al.
      Guidelines of care for the management of acne vulgaris.
      Oral antibiotic use should be limited to 3-6 months to prevent resistance, and should be combined with topical or other systemic therapy.
      • Zaenglein AL
      • Pathy AL
      • Schlosser BJ
      • et al.
      Guidelines of care for the management of acne vulgaris.
      ,
      • Barbieri JS
      • Spaccarelli N
      • Margolis DJ
      • et al.
      Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
      When acne is under control, oral antibiotics should be discontinued and control should be maintained with a topical regimen.
      • Eichenfield LF
      • Krakowski AC
      • Piggott C
      • et al.
      Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
      Optimizing topical regimens, using hormonal therapy for female patients, and using isotretinoin are important to prevent the overuse of systemic antibiotics.
      • Thiboutot D
      • Dréno B
      • Sanders V
      • et al.
      Changes in the management of acne: 2009-2019.
      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.
      • Blasiak RC
      • Stamey CR
      • Burkhart CN
      • et al.
      High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris.
      Evidence supports decreased relapse rates with higher total doses of up to 220 mg/kg.
      • Blasiak RC
      • Stamey CR
      • Burkhart CN
      • et al.
      High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris.
      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.

      iPledge REMS [prescribing information]. Available: https://www.ipledgeprogram.com/iPledgeUI/prInfo.u . Accessed August 18, 2020

      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.
      • Barbieri JS
      • Shin DB
      • Wang S
      • et al.
      The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time.
      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.
      • Barbieri JS
      • Shin DB
      • Wang S
      • et al.
      The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time.
      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.
      • Hebert A
      • Thiboutot D
      • Stein Gold L
      • et al.
      Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials.
      It is supposed to be available in 2021.
      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.
      • Thorneycroft IH
      • Stanczyk FZ
      • Bradshaw KD
      • et al.
      Effect of low-dose oral contraceptives on androgenic markers and acne.
      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.
      • Kelly S
      • Davies E
      • Fearns S
      • et al.
      Effects of oral contraceptives containing ethinylestradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women.
      ,
      • Arowojolu AO
      • Gallo MF
      • Lopez LM
      • et al.
      Combined oral contraceptive pills for treatment of acne.
      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.

      FDA. US Food and Drug Administration: YAZ ® (Drospirenone and Ethinyl Estradiol) Tablets package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; Revised 2012. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021676s012lbl.pdf. Accessed April 1, 2021.

      • Redmond GP
      • Olson WH
      • Lippman JS
      • et al.
      Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial.
      • Maloney JM
      • Dietze P
      • Watson D
      • et al.
      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.
      • Akamatsu H
      • Zouboulis CC
      • Orfanos CE
      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.
      • Barbieri JS
      • Spaccarelli N
      • Margolis DJ
      • et al.
      Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
      ,
      • Blasiak RC
      • Stamey CR
      • Burkhart CN
      • et al.
      High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris.
      ,
      • Barbieri JS
      • Choi JK
      • Mitra N
      • et al.
      Frequency of treatment switching for spironolactone compared to oral tetracycline-class antibiotics for women with acne: a retrospective cohort study 2010-2016.
      • Park JH
      • Bienenfeld A
      • Orlow SJ
      • et al.
      The use of hormonal antiandrogen therapy in female patients with acne: a 10-year retrospective study.
      • Isvy-Joubert A
      • Nguyen JM
      • Gaultier A
      • et al.
      Adult female acne treated with spironolactone: a retrospective data review of 70 cases.
      • Roberts EE
      • Nowsheen S
      • Davis MDP
      • et al.
      Treatment of acne with spironolactone: a retrospective review of 395 adult patients at Mayo Clinic, 2007-2017.
      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.
      • Roberts EE
      • Nowsheen S
      • Davis MDP
      • et al.
      Treatment of acne with spironolactone: a retrospective review of 395 adult patients at Mayo Clinic, 2007-2017.
      There is no evidence of hyperkalemia in young and otherwise healthy women, and monitoring of potassium is not required in this population.
      • Plovanich M
      • YuWeng Q
      • Mostaghimi A
      Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne.
      ,
      • Barker RA
      • Wilcox C
      • Layton AM
      Oral spironolactone for acne vulgaris in adult females: an update of the literature.
      In animals, male fetuses exposed to spironolactone showed feminization and the severity of genital dysmorphism was dose-dependent.
      • Liszewski W
      • Boull C
      Lack of evidence for feminization of males exposed to spironolactone in utero: a systematic review.
      ,

      Pfizer: Aldactone package insert. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf . Accessed August 18, 2020

      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.
      • Berry K
      • Lim J
      • Zaenglein AL
      Acne vulgaris: treatment made easy for the primary care physician.
      ,
      • McEvoy B
      • Nydegger R
      • Williams G
      Factors related to patient compliance in the treatment of acne vulgaris.

      Treatment of Scars

      Acne scars can be categorized as atrophic (boxcar, icepick, or rolling), hypertrophic, or keloidal, and treatment should be tailored to the type of scar.
      • Zaleski-Larsen LA
      • Fabi SG
      • McGraw T
      • et al.
      Acne scar treatment: a multimodality approach tailored to scar type.
      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.
      • Zaleski-Larsen LA
      • Fabi SG
      • McGraw T
      • et al.
      Acne scar treatment: a multimodality approach tailored to scar type.
      Topical azelaic acid may also be used to treat postinflammatory hyperpigmentation because of its antityrosinase activity.
      • Kircik LH
      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.
      • Boen M
      • Jacob C
      A review and update of treatment options using the Acne Scar Classification System.
      Deeper boxcar scars and icepick scars can be excised if larger or punched out if smaller.
      • Zaleski-Larsen LA
      • Fabi SG
      • McGraw T
      • et al.
      Acne scar treatment: a multimodality approach tailored to scar type.
      Hypertrophic or keloidal scars caused by excess collagen deposition can be treated with serial intralesional 10-40 mg/mL triamcinolone injections.
      • Zaleski-Larsen LA
      • Fabi SG
      • McGraw T
      • et al.
      Acne scar treatment: a multimodality approach tailored to scar type.
      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.
      • Chung HJ
      • Al Janahi S
      • Cho SB
      • et al.
      Chemical reconstruction of skin scars (CROSS) method for atrophic scars: a comprehensive review.
      Other treatment modalities include laser resurfacing, microneedling, chemical peels, platelet-rich plasma, and dermal fillers.
      • Boen M
      • Jacob C
      A review and update of treatment options using the Acne Scar Classification System.
      ,
      • Soliman YS
      • Horowitz R
      • Hashim PW
      • et al.
      Update on acne scar treatment.
      ,
      • Xu Y
      • Deng Y
      Ablative fractional CO 2 laser for facial atrophic acne scars.

      Conclusion

      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.
        J Eur Acad Dermatol Venereol. 2015; 29: 3
        • Harper JC
        Acne vulgaris: what's new in our 40th year.
        J Am Acad Dermatol. 2020; 82: 526
        • Ceruti JM
        • Leirós GJ
        • Balañá ME
        Androgens and androgen receptor action in skin and hair follicles.
        Mol Cell Endocrinol. 2018; 465: 122
        • Lee WJ
        • Jung HD
        • Chi SG
        • et al.
        Effect of dihydrotestosterone on the upregulation of inflammatory cytokines in cultured sebocytes.
        Arch Dermatol Res. 2010; 302: 429
        • New MI
        An update of congenital adrenal hyperplasia.
        Ann N Y Acad Sci. 2004; 1038: 14
        • Dréno B
        What is new in the pathophysiology of acne, an overview.
        J Eur Acad Dermatol Venereol. 2017; 31: 8
        • O'Neill AM
        • Gallo RL
        Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris.
        Microbiome. 2018; 6: 177
        • Jugeau S
        • Tenaud I
        • Knol AC
        • et al.
        Induction of toll-like receptors by Propionibacterium acnes.
        Br J Dermatol. 2005; 153: 1105
        • Kim J
        Review of the innate immune response in acne vulgaris: activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses.
        Dermatology. 2005; 211: 193
        • Woo TE
        • Sibley CD
        The emerging utility of the cutaneous microbiome in the treatment of acne and atopic dermatitis.
        J Am Acad Dermatol. 2020; 82: 222
        • Eichenfield LF
        • Krakowski AC
        • Piggott C
        • et al.
        Evidence-based recommendations for the diagnosis and treatment of pediatric acne.
        Pediatrics. 2013; 131: S163
        • Uslu G
        • Şendur N
        • Uslu M
        • et al.
        Acne: prevalence, perceptions and effects on psychological health among adolescents in Aydin, Turkey.
        J Eur Acad Dermatol Venereol. 2008; 22: 462
        • Dunn LK
        • O'Neill JL
        • Feldman SR
        Acne in adolescents: quality of life, self-esteem, mood, and psychological disorders.
        Dermatol Online J. 2011; 17: 1
        • Tan JK
        Psychosocial impact of acne vulgaris: evaluating the evidence.
        Skin Therapy Lett. 2004; 9: 1
        • Berry K
        • Lim J
        • Zaenglein AL
        Acne vulgaris: treatment made easy for the primary care physician.
        Pediatr Ann. 2020; 49: e109
        • Fulton JE
        • Farzad-Bakshandeh A
        • Bradley S
        Studies on the mechanism of action of topical benzoyl peroxide and vitamin A acid in acne vulgaris.
        J Cutan Pathol. 1974; 1: 191
        • Marson JW
        • Baldwin HE
        An overview of acne therapy, part 1: topical therapy, oral antibiotics, laser and light therapy, and dietary interventions.
        Dermatol Clin. 2019; 37: 183
        • Yang Z
        • Zhang Y
        • Lazic Mosler E
        • et al.
        Topical benzoyl peroxide for acne.
        Cochrane Database Syst Rev. 2020; 3CD011154
        • Lu J
        • Cong T
        • Wen X
        • et al.
        Salicylic acid treats acne vulgaris by suppressing AMPK/SREBP1 pathway in sebocytes.
        Exp Dermatol. 2019; 28: 786
        • Gupta AK
        • Nicol K
        The use of sulfur in dermatology.
        J Drugs Dermatol. 2004; 3: 427
        • Schulte BC
        • Wu W
        • Rosen T
        Azelaic acid: evidence-based update on mechanism of action and clinical application.
        J Drugs Dermatol. 2015; 14: 964
        • Tan J
        • Miklas M
        A novel topical retinoid for acne: trifarotene 50 μg/g cream.
        Skin Therapy Lett. 2020; 25: 1
        • Khalil S
        • Bardawil T
        • Stephan C
        • et al.
        Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects.
        J Dermatolog Treat. 2017; 28: 684
        • Thiboutot D
        • Arsonnaud S
        • Soto P
        • et al.
        Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris.
        J Drugs Dermatol. 2008; 7: s3
        • Gold LS
        • Colon LE
        • Johnson LA
        • et al.
        Is switching retinoids a sound strategy for the treatment of acne vulgaris?.
        J Drugs Dermatol. 2008; 7: s1
        • Tanghetti E
        • Dhawan S
        • Green L
        • et al.
        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.
        J Drugs Dermatol. 2010; 9: 549
        • Pariser D
        • Colon LE
        • Johnson LA
        • et al.
        Adapalene 0.1% gel compared to tazarotene 0.1% cream in the treatment of acne vulgaris.
        J Drugs Dermatol. 2008; 7: s18
        • Kircik LH
        Tretinoin microsphere gel pump 0.04% versus tazarotene cream 0.05% in the treatment of mild-to-moderate facial acne vulgari.
        J Drugs Dermatol. 2009; 8: 650
        • Tanghetti EA
        • Werschler WP
        • Lain T
        • et al.
        Tazarotene 0.045% lotion for once-daily treatment of moderate-to-severe acne vulgaris: results from two phase 3 trials.
        J Drugs Dermatol. 2020; 19: 70
        • Zaenglein AL
        • Pathy AL
        • Schlosser BJ
        • et al.
        Guidelines of care for the management of acne vulgaris.
        J Am Acad Dermatol. 2016; 74: 945
        • Barbieri JS
        • Spaccarelli N
        • Margolis DJ
        • et al.
        Approaches to limit systemic antibiotic use in acne: systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments.
        J Am Acad Dermatol. 2019; 80: 538
        • Thiboutot D
        • Dréno B
        • Sanders V
        • et al.
        Changes in the management of acne: 2009-2019.
        J Am Acad Dermatol. 2020; 82: 1268
        • Blasiak RC
        • Stamey CR
        • Burkhart CN
        • et al.
        High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris.
        JAMA Dermatol. 2013; 149: 1392
      1. iPledge REMS [prescribing information]. Available: https://www.ipledgeprogram.com/iPledgeUI/prInfo.u . Accessed August 18, 2020

        • Barbieri JS
        • Shin DB
        • Wang S
        • et al.
        The clinical utility of laboratory monitoring during isotretinoin therapy for acne and changes to monitoring practices over time.
        J Am Acad Dermatol. 2020; 82: 72
        • Hebert A
        • Thiboutot D
        • Stein Gold L
        • et al.
        Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials.
        JAMA Dermatol. 2020; 156: 621
        • Thorneycroft IH
        • Stanczyk FZ
        • Bradshaw KD
        • et al.
        Effect of low-dose oral contraceptives on androgenic markers and acne.
        Contraception. 1999; 60: 255
        • Kelly S
        • Davies E
        • Fearns S
        • et al.
        Effects of oral contraceptives containing ethinylestradiol with either drospirenone or levonorgestrel on various parameters associated with well-being in healthy women.
        Clin Drug Investig. 2010; 30: 325
        • Arowojolu AO
        • Gallo MF
        • Lopez LM
        • et al.
        Combined oral contraceptive pills for treatment of acne.
        Cochrane Database Syst Rev. 2012; 7CD004425
      2. 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

      3. 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.

      4. FDA. US Food and Drug Administration: YAZ ® (Drospirenone and Ethinyl Estradiol) Tablets package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; Revised 2012. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021676s012lbl.pdf. Accessed April 1, 2021.

        • Redmond GP
        • Olson WH
        • Lippman JS
        • et al.
        Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial.
        Obstet Gynecol. 1997; 89: 615
        • Maloney JM
        • Dietze P
        • Watson D
        • et al.
        Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial.
        Obstet Gynecol. 2008; 112: 773
        • Akamatsu H
        • Zouboulis CC
        • Orfanos CE
        Spironolactone directly inhibits proliferation of cultured human facial sebocytes and acts antagonistically to testosterone and 5α-dihydrotestosterone in vitro.
        J Invest Dermatol. 1993; 100: 660
        • Barbieri JS
        • Choi JK
        • Mitra N
        • et al.
        Frequency of treatment switching for spironolactone compared to oral tetracycline-class antibiotics for women with acne: a retrospective cohort study 2010-2016.
        J Drugs Dermatol. 2018; 17: 632
        • Park JH
        • Bienenfeld A
        • Orlow SJ
        • et al.
        The use of hormonal antiandrogen therapy in female patients with acne: a 10-year retrospective study.
        Am J Clin Dermatol. 2018; 19: 449
        • Isvy-Joubert A
        • Nguyen JM
        • Gaultier A
        • et al.
        Adult female acne treated with spironolactone: a retrospective data review of 70 cases.
        Eur J Dermatol. 2017; 27: 393
        • Roberts EE
        • Nowsheen S
        • Davis MDP
        • et al.
        Treatment of acne with spironolactone: a retrospective review of 395 adult patients at Mayo Clinic, 2007-2017.
        J Eur Acad Dermatol Venereol. 2020; 34: 2106
        • Plovanich M
        • YuWeng Q
        • Mostaghimi A
        Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne.
        JAMA Dermatol. 2015; 151: 941
        • Barker RA
        • Wilcox C
        • Layton AM
        Oral spironolactone for acne vulgaris in adult females: an update of the literature.
        Am J Clin Dermatol. 2020; 21: 303
        • Liszewski W
        • Boull C
        Lack of evidence for feminization of males exposed to spironolactone in utero: a systematic review.
        J Am Acad Dermatol. 2019; 80: 1147
      5. Pfizer: Aldactone package insert. Available: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/012151s062lbl.pdf . Accessed August 18, 2020

        • McEvoy B
        • Nydegger R
        • Williams G
        Factors related to patient compliance in the treatment of acne vulgaris.
        Int J Dermatol. 2003; 42: 274
        • Zaleski-Larsen LA
        • Fabi SG
        • McGraw T
        • et al.
        Acne scar treatment: a multimodality approach tailored to scar type.
        Dermatol Surg. 2016; 42: S139
        • Kircik LH
        Efficacy and safety of azelaic acid (AzA) gel 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study.
        J Drugs Dermatol. 2011; 10: 586
        • Boen M
        • Jacob C
        A review and update of treatment options using the Acne Scar Classification System.
        Dermatol Surg. 2019; 45: 411
        • Chung HJ
        • Al Janahi S
        • Cho SB
        • et al.
        Chemical reconstruction of skin scars (CROSS) method for atrophic scars: a comprehensive review.
        J Cosmet Dermatol. 2021; 20: 18
        • Soliman YS
        • Horowitz R
        • Hashim PW
        • et al.
        Update on acne scar treatment.
        Cutis. 2018; 102: 21
        • Xu Y
        • Deng Y
        Ablative fractional CO 2 laser for facial atrophic acne scars.
        Facial Plast Surg. 2018; 34: 205