Persistent Acne in Women

Am J Clin Dermatol 2006; 7 (5): 281-290THERAPY IN PRACTICE 1175-0561/06/0005-0281/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Persistent Acne in WomenImplications for the Patient and for Therapy

Christina Williams and Alison M. Layton

Department of Dermatology, Harrogate and District Foundation Trust, Harrogate, UK

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2811. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2822. Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2823. Implications of Persistent Acne for the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2844. Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2845. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

5.1 Topical Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2845.2 Systemic Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

5.2.1 Systemic Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2865.2.2 Hormonal Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2865.2.3 Oral Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2865.2.4 Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2875.2.5 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2875.2.6 Isotretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2875.2.7 Adjunctive Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288

Acne is traditionally regarded as a skin disorder of the teenage years. However, recent epidemiologic studiesAbstracthave shown that a significant number of female patients aged >25 years experience acne. One recentcommunity-based UK study estimated the prevalence of facial acne in adult women aged between 26 and 44years to be 14%. It is not clear whether there is a true increase in acne in this age group or whether these patientsare less tolerant of their acne and/or better informed of available therapies and so seek advice. The reasons forpersistent acne are not fully understood. External factors such as use of certain cosmetics, ingestion of drugs, andendocrine abnormalities should all be considered when managing these patients. Post-adolescent acne in femalescan be divided into ‘persistent acne’, which represents a continuation of acne from adolescence into adult life,and ‘late-onset’ acne, which describes significant acne occurring sometimes for the first time after the age of 25years. The clinical picture of each of these forms of acne in adult females can differ slightly from conventionaladolescent disease. The course of each form is more indolent. Because of these variations, the approach toinvestigation and management of these cases may have subtle differences when compared with that for teenagedisease. Acne treatment should aim to reduce sebum, comedogenesis, propionibacteria population, and inflam-mation. Treatment selection will depend on the acne grade and site as well as the patient’s preference and abilityto comply with therapy. Maintenance therapy plays an important role in managing this group of patients. As theresponse to treatment is inevitably slow, patients must be encouraged to adhere to the chosen treatment regimen.

282 Williams & Layton

This article reviews the literature on persistent acne in women in terms of clinical presentation and possibleetiologic factors, and outlines principles of therapy related to managing these cases.

Acne is one of the most common skin diseases encountered by perioral distribution. Comedonal lesions are typically absent orcommunity physicians and dermatologists. It can present at any sparse, but if present they frequently present as macrocomedones.age, from neonates to mature adults, but is most prevalent and The tender inflammatory lesions flare premenstrually on a regularmost severe during adolescence, reaching a peak at the age of basis and can be very resistant to treatment. They frequently14–17 years in females and 16–19 years in males.[1] The face and/ produce post-inflammatory erythema, hyper- and/or hypopig-or trunk may be affected. Clinical acne was previously said to mentation, and scarring, all of which are cosmetically disfiguringresolve slowly by the age of 20–25 years. However, there is a to the patient.significant and growing body of literature that now suggests that Sporadic late-onset acne represents an acute, unpredictablepost-adolescent acne is increasing in incidence.[2-4] Goulden et flare of acne in later life that can coincide with a systemic illness.al.[4] have indicated that the mean age of acne patients in their The acne frequently embraces inflammatory papules and pustulesdepartment increased from 20.5 years in 1984 to 26.5 years in with very few comedones and can affect one or more acne sites. In1994. In a further study, these investigators showed that the older patients, i.e. those aged >60 years, the acne is seen moreprevalence of acne remained constant between 24 and 44 years of commonly on the trunk than on the face.[5] As with other forms ofage and did not decrease significantly until after 44 years of age.[2] persistent acne, sporadic late-onset acne is more recalcitrant and

resistant to therapy.1. Clinical Presentation

2. EtiologyObservations of post-adolescent acne confirm the presence of

two clinical groups: There are four major factors implicated in the etiology of1. ‘Persistent acne’ represents a continuum from adolescence into adolescent acne: increased sebum production, follicular hyperker-adult and middle-aged life. Patients have lesions most days and atinization, increased Propionibacterium acnes within the follicle,may experience a premenstrual flare of their acne. and production of inflammation.[6] Persistent acne as a continua-2. ‘Late-onset acne’ represents acne that occurs sometimes for the tion of adolescent acne appears to share these pathogenic features.first time well after puberty and can be subdivided further into: There is a significantly higher sebum excretion rate among adult• ‘chin acne’, which is inflammatory acne that occurs in mature women with persistent acne, compared with adult women without

females, flares premenstrually, and is distributed around the acne, suggesting that there may be an underlying increase inchin and perioral region; and sebogenesis in the former group.[7] The sebaceous gland is under

• ‘sporadic acne’, which occurs suddenly in later life for no androgenic control, and hormonal abnormalities have been exten-apparent reason, although it may be associated with systemic sively investigated in acne. However, studies of both ovarian anddisease. adrenal androgenic hormone levels have shown no clear pattern ofBoth persistent and late-onset acne appear more commonly on abnormality.[8] A local abnormality of androgen metabolism, in

the face than elsewhere in women, and persistent acne appears to particular the conversion of dihydrotestosterone to testosterone bybe more common than late-onset acne.[2] type 1 5α-reductase in acne-prone follicles, is more likely to be

The lesions of persistent acne are usually deep-seated, tender, important. It has been suggested that this may lead to abnormalinflammatory papules and nodules, frequently involving the lower follicular keratinization, as well as increased sebum production.[9]

third of the face, jaw line, and neck. The shoulders and upper back However, it is more difficult to explain premenstrual and sporadicmay be involved. Comedonal lesions may also involve the fore- late-onset acne, which both present well after the hormonalhead or lateral margins of the face, but they are not always changes that accompany puberty.prominent. The role of circulating androgens in adult acne has been exten-

The clinical variant seen in perimenopausal mature women, sively investigated but remains controversial. Levels of total andalso sometimes referred to as ‘chin acne’, embraces deep-seated free testosterone and sex hormone-binding globulin in acne pa-inflamed papules and nodules, particularly on the chin and in a tients have been reported as being both elevated and within the

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (5)

Persistent Acne in Women 283

normal range.[10-14] However, many of these studies have com- increased significantly over the last decade.[19] Carriage of resis-pared patients with different acne grades, patients with isolated tant P. acnes may result in reduced response to antibacterialacne, and patients with acne combined with features of hyperan- therapy, as has been demonstrated with erythromycin[20] and tetra-drogenicity. These inconsistencies may well account for the dis- cycline.[21] It has therefore been postulated that the increase increpancies in the results. adult acne may relate to an increased carriage of antibacterial-

resistant bacteria.[4] However, when the cutaneous microbiologyIt has also been suggested that target tissue androgens may playof patients with adult acne was compared with that of individualsa role in the pathogenesis of female acne. The gonads and adrenalwith adolescent acne or control patients, no underlying differencesgland produce the majority of circulating androgens. Androgensin the microbiology of the skin were noted.[22] It has been suggest-can also be produced locally within the sebaceous gland from theed that more severe forms of post-adolescent acne could relate to aadrenal precursor hormone dehydroepiandrosterone sulfatehigh level of antibodies to P. acnes, especially as there appears to(DHEAS). Several studies have shown that women with acne whobe a large inflammatory component in adult acne. Adolescentshave normal circulating androgen levels have increased levels ofwith moderate acne have antibody levels to P. acnes similar tothe tissue-derived androgens 3α-androstanediol glucuronide[15]

those of age-matched unaffected controls, but more severe acneand androsterone glucuronide.[16] A trend has been noted towardsufferers have significantly higher levels of antibodies to P. ac-higher levels of type 1 5α-reductase activity, the enzyme thatnes.[22] However, investigations into this hypothesis have notconverts testosterone to the more androgenic dihydrotestosterone,provided any evidence to suggest that a higher antibody titer toin the sebaceous glands of women with acne compared with thoseP. acnes is involved in the etiology of persistent acne.[22]without acne.[17] In addition, the mean serum androgen levels of

these women with acne were significantly and relatively higher The role of cosmetics in persistent acne is continually debat-but still within the normal range. These investigators suggested ed.[23] Kligman and Mills[24] coined the term ‘acne cosmetica’ tothat serum levels of androgens might play a role in the develop- describe persistent low-grade acne in adults. There is clear evi-ment of acne in women by acting directly at the level of the dence that various cosmetic ingredients – particularly lanolins,sebaceous glands to stimulate local tissue enzyme activity. Alter- petrolatum, and certain vegetable oils – do elicit comedones innatively, the sebaceous glands of patients with acne may be more both animal and human studies.[24,25] In addition, acneiform erup-sensitive to the effects of androgens. It is unclear as to whether tions after facial beauty treatments that include massage have beenacne is mediated by serum androgens, locally produced androgens, described, the lesions being predominantly inflammatory and in-or a combination of both. dolent, and often producing post-inflammatory hyperpigmenta-

tion.[25] However, Cunliffe[26] found no correlation between theFollicular pore diameter increases as a function of age. Oneduration of cosmetic use and the severity of acne, and confirmedstudy showed that patients with late-onset acne had larger poresthat stopping use of the suspected cosmetic product did not pro-than those of the same age with no acne.[18]

duce an improvement in post-adolescent acne.Other possible etiologic factors that have been consideredinclude genetic predisposition, smoking, antibacterial-resistant Stress is frequently reported as a possible trigger for thesepropionibacteria, use of cosmetics, and/or stress. forms of acne seen in females. Emotional factors presumably

With regard to genetic predisposition, one study revealed that affect acne by altering the adrenal-pituitary axis. Stress could be50% of acne sufferers had a first-degree relative with post-adoles- associated with increased adrenal androgen production and subse-cent acne, a finding that suggests that there may be a familial quent sebum production and comedogenesis.[27] A clear relation-tendency to the disease in some individuals.[4] ship has been observed between increasing stress levels, androgen

hormones, and increasing levels of acne in women with fast-pacedSmoking has also been cited as a possible contributory factor toprofessional careers.[28]acne. It has been suggested that smokers have acne more frequent-

ly and severely than non-smokers, and that the correlation appears In summary, the causes of persistent post-adolescent acne into be dose dependent. This finding may have been confounded, women remain to be determined. It would appear that certainhowever, as the data collected did not indicate whether smoking individuals have increased levels of androgens, which could ex-started before the onset of acne or was a consequence of having plain the increase in their acne. However, the relationship betweenacne.[3] levels of circulating androgens and the severity of acne has not

P. acnes plays an important role in the pathogenesis of adoles- been proven, and locally produced androgens and/or end-organcent acne. The incidence of antibacterial-resistant P. acnes has hyper-responsiveness may be contributing factors.



3. Implications of Persistent Acne for the Patient do, acanthosis nigricans, and deepening of the voice. These pa-tients frequently have insulin resistance and are at increased risk of

Acne vulgaris and the potential scarring it can cause signifi- developing diabetes mellitus and cardiovascular disease.[33] It iscantly impact on a patient’s quality of life. Adults may be affected therefore important for the long-term health of these patients toby acne in many ways, e.g. in social functioning, education, or identify hyperandrogenism so that they can receive appropriateemployment. In a sample of 1250 subjects, Cunliffe[29] found that therapy to avoid these long-term complications. It is also impor-the unemployment rate was 7% higher for adults with acne. The tant to consider investigating patients with true late-onset acne.duration of disease has been shown to correlate with psychosocial One study demonstrated that one in ten patients with late-onsetdisability.[30] In a multivariate analysis, older adults with acne acne have either polycystic ovaries or late-onset adrenal hyperpla-vulgaris reported significantly greater overall effects on their sia.[34]

quality of life than did younger patients, even when controlling forFurther screening tests may include measurement of serum

the clinical severity of the acne. Myhill et al.[31] also found that theDHEAS, total testosterone, free testosterone, luteinising hor-

effect of acne on patients’ lives may be related to their age. In theirmone : follicle-stimulating hormone ratio, prolactin, androstene-

study, adults ≥21 years of age with acne were less likely thandione, and sex hormone-binding globulin. These tests should be

younger patients with acne to demonstrate improvements on mea-obtained during days 1–5 of the menstrual cycle. Either the adrenal

sures of social appraisal and social assertiveness following treat-or the ovary may produce excess androgens. Serum DHEAS and

ment with isotretinoin.17-hydroxyprogesterone can be used to screen for an adrenal

Because acne is not always considered to be a chronic inflam- source of excess androgen production. An ovarian source ofmatory disorder, its psychosocial impact is not always considered excess androgens can be suspected in cases where the total testos-to be as significant as that of other inflammatory dermatoses. In a terone level is elevated. Table II summarizes these investigations.study of 60 adult patients with acne, Lasek and Chren[32] found thatpatients reported emotional effects of their skin condition that 5. Managementwere similar in magnitude to those reported by patients with

Acne can cause significant embarrassment and anxiety in anypsoriasis, which is traditionally regarded as a skin condition caus-patient. It is important for physicians to educate patients about theing significant disability.available treatment options and their expected outcomes. ThePersistent and late-onset acne frequently cause discomfort andresponse to treatment in this particular group of patients can becosmetic disability with inflammation, pigmentary changes, andslow, and patients must be encouraged to adhere to the chosenscarring. Physicians should be sensitive to all of these issues andtreatment regimen.should carefully consider the implications of psychosocial disabil-

The general principles of treatment of acne (figure 1) in theity caused by acne when managing these patients.mature female do not differ significantly from those in other age

4. Investigations groups, but there are some subtle differences that should beconsidered.

Development of acne outside what was previously consideredA combination of topical and systemic treatments should be

to be the usual age group warrants a thorough medical history,considered in patients with persistent/late-onset acne. However,

including family history, and exclusion of precipitating causesolder skin does appear to be more sensitive to topical therapies.

such as exposure to comedogenic substances or drugs (table I).This should be followed by a physical examination.

5.1 Topical TherapiesAlthough hormones influence acne, it is clear that the majority

of acne patients do not have an endocrine disorder. Nevertheless, Older skin displays increased irritancy to topical retinoids andconsideration should be given to endocrine causes. Hyperan- antibacterials but is resistant to the irritant effects of benzoyldrogenism, including polycystic ovary syndrome, should be con- peroxide.[5] Benzoyl peroxide is a powerful antimicrobial agentsidered in women whose acne is severe, is of sudden or late onset, that rapidly destroys both bacterial organisms and yeasts. It pro-is refractory to therapy, and/or is associated with other signs of vides good efficacy against superficial inflammatory lesions, withhyperandrogenism such as hirsutism, irregular menses, or infertili- rapid bacteriostatic and possibly bactericidal action. It also has thety. Additional clinical signs or symptoms of hyperandrogenism advantage of not being associated with antimicrobial resistanceinclude cushingoid features, androgenetic alopecia, increased libi- and is active against both fully sensitive and resistant strains of



Table I. Drug classes or types that may exacerbate or cause acne

Drug class or type Examples Indications

Corticosteroid

topical Betamethasone Atopic eczema, psoriasis

oral Prednisolone Immunosuppression

inhaled Budesonide Asthma

Anabolic steroid/synthetic androgen Danazol, nandrolone, stanozolol Body building, endometriosis

Antiepileptic Carbamazepine, phenytoin, gabapentin, topiramate Epilepsy

Antidepressant Lithium, sertraline Depression, anxiety

Antipsychotic Pimozide, risperidone Schizophrenia, mania

Antitubercular drug Isoniazid, pyrazinamide Tuberculosis

Antineoplastic drug Dactinomycin, pentostatin Cancer

Antiviral drug Ritonavir, ganciclovir HIV/AIDS, cytomegalovirus infection

Corticotropin Corticotropin, synthetic corticotropin Adrenocortical malfunction

Calcium channel antagonist Nilvadipine, nimodipine Hypertension

Halogen Sodium fluoride, potassium iodide Fluoride supplementation, hyperthyroidism

Human growth hormone Genetically engineered human growth hormone Muscle wasting, e.g. HIV/AIDS

Vitamins Vitamin B12 (cyanocobalamin), possibly other B vitamins Dietary supplementation

Miscellaneous Buserelin Endometriosis, prostate cancer

Cabergoline Hyperprolactinemia, suppression of lactation

Clofazimine Leprosy

Ciclosporine (ciclosporin) Transplant rejection, severe eczema

Dantrolene Malignant hyperthermia, muscle spasm or

spasticity associated with multiple sclerosis/

other neurologic damage

Famotidine Gastric and duodenal ulcers

Follitropin alfa Female infertility, assisted conception

Isosorbide mononitrate Prophylaxis of angina

Medroxyprogesterone Endometrial cancer, menopause,

contraception

Mesalazine Ulcerative colitis

Ramipril Hypertension, heart failure

P. acnes. Hence, benzoyl peroxide can be combined very effec- antimicrobials used alone.[6] The antibacterial should be discontin-tively with topical or systemic antibacterials.[6] ued when inflammatory lesions resolve adequately, whereas the

topical retinoid should be continued in an attempt to maintain theTopical retinoids target the microcomedo, which is the precur-remission.sor of acne lesions. There is now consensus that topical retinoids

should be considered as a first-line therapy for mild to moderate Topical antibacterial therapies containing clindamycin andinflammatory acne as well as comedonal acne.[6] However, since erythromycin are available, and their impact is predominantly anti-topical retinoids can be particularly problematic in older skin, inflammatory. They should not be used as monotherapy because ofproducing significant irritancy, short durations of application their relatively slow onset of action and potential for bacterialshould be adopted in the first instance, with gradual increments in resistance if used for prolonged periods.[35] In the authors’ experi-application time as tolerated. Retinoids used in combination with a ence, topical antibacterials do not achieve very effective results intopical or oral antimicrobial agent apparently achieve more rapid patients with persistent or late-onset acne, who frequently requireefficacy and significantly greater reductions in acne lesions than prolonged treatment regimens.



are to be incorporated into a regimen containing an oral contracep-tive, the patient should be warned about the possible decreasedefficacy of the oral contraceptive, although, with the exception ofrifampin (rifampicin)-like drugs, there is a lack of scientific evi-dence supporting the ability of commonly prescribed antibacterialsto reduce either blood levels and/or the effectiveness of oralcontraceptives.[40]

5.2.2 Hormonal Therapies

Hormonal treatments may be another therapeutic approach foradult females with acne. Women with acne may have higher serumandrogen levels than women without acne, but these levels are stilloften within the normal range. However, it is important to note thathormonal therapy can be effective in women with acne whether or

Table II. Investigating for endocrine abnormalities in women with persistent

acne

Cause Investigations

Iatrogenic Thorough medical history including drugs

Polycystic ovary syndrome Total and free testosterone, luteinizing

hormone : follicle-stimulating hormone

ratio

Congenital adrenal Serum DHEAS, 17-hydroxyprogesterone

hyperplasia

Cushing syndrome Dexamethasone suppression test will

help identify Cushing syndrome or

congenital adrenal hyperplasia

Gonadal or adrenal tumors Total and free testosterone, DHEAS

DHEAS = dehydroepiandrosterone sulfate.

not their serum androgen levels are abnormal.[41] Hormonal treat-Topical 4% nicotinamide gel represents an alternative topical ment of hyperandrogenism centers on reducing circulating andro-

anti-inflammatory therapy that has been used successfully as a gen levels and/or androgen receptor blockade. This can be accom-twice-daily application in some older acne patients in a vehicle- plished by estrogens, androgen receptor antagonists, or agentscontrolled study.[36] This agent has been shown to be as effective designed to decrease the endogenous production of androgens byas 1% clindamycin gel and has the advantage of not promoting the ovary or adrenal gland, such as oral contraceptives, corticoste-bacterial resistance in cases that may require longer-term treat- roids, or gonadotrophin-releasing hormone.ment.

5.2.3 Oral Contraceptives

Hormonal therapy can be initiated with the use of oral contra-5.2 Systemic Therapiesceptives in patients with no contraindications to use of theseagents. This approach may not be appropriate in mature femalesAs most patients with persistent or late-onset acne have deep-because of increasing thromboembolic risks. The estrogen in oralseated inflammatory lesions, they will require some systemiccontraceptives reduces the androgen effect by suppressing gona-therapy. The options are systemic antibacterials, hormonal thera-dotrophin release, resulting in reduced ovarian androgen produc-pies, and oral isotretinoin.tion. A secondary antiandrogen effect of oral contraceptives is the

5.2.1 Systemic Antibacterials estrogen-induced increase in sex hormone-binding globulin,Oral antibacterials should be considered in women with persis-

tent acne, and the preferred agents are second-generation tetracy-clines.[37] Systemic antibacterials reduce P. acnes and Staphylo-

coccus epidermidis levels and also have anti-inflammatory activi-ty.[38] However, the response to oral antibacterials can be veryslow in this group of patients. Table III outlines recommendeddoses and potential adverse effects of systemic antibacterial ther-apy. Once the appearance of new inflammatory lesions has de-creased or stopped, the dose may be gradually tapered or with-drawn. Topical retinoid therapy should then be considered in anattempt to maintain remission.[6]

Treatment failures with systemic antibacterials occur in up to80% of adult women[39] and, to avoid antibacterial resistance,general guidelines have been published that recommend avoidingantibacterial monotherapy and adding benzoyl peroxide if antibac-terials must be used for prolonged periods.[37] If oral antibacterials

Success

Failure

Failure

Success

Success

Mild acne(comedones ±inflammatory

lesions)

Moderate acne(mild-moderate

papular/pustular)

Severe acne(severe

nodulocystic)

Topical retinoidsor

topical retinoid+ BPO

Combination therapyoral antibacterial +

topical retinoid ± BPO

Acne grade Maintenancetherapy

Choice of treatment

Topical retinoidsor

topical retinoid + BPO/topical antibacterial

Systemic isotretinoinor

hormonal therapy(in females, especially

if signs ofhyperandrogenism)

Fig. 1. Guidance for the treatment of acne vulgaris. BPO = benzoyl perox-ide.



and hirsutism in numerous open studies.[43] Chlormadinone isavailable in several European countries and can also be combinedwith ethinyl estradiol in a contraceptive formulation.[6]

Spironolactone

Spironolactone functions both as an androgen receptor antago-nist and as an inhibitor of 5α-reductase. It is not licensed for use inacne. However, in dosages of 50–100mg twice daily, spirono-lactone has been shown to reduce sebum production and improveacne.[44] It can be considered if there is failure to respond tostandard therapies and/or there are features of hyperandrogenismin adult women.[45] The adverse effects of spironolactone are doserelated and include potential hyperkalemia, irregular menstrualperiods, breast tenderness, headache, and fatigue.[46] Becausespironolactone is an antiandrogen, there is a risk of feminization ofa male fetus and thus pregnancy should be avoided. A response in

Table III. Systemic antibacterials in the treatment of acne vulgaris

Antibacterial Dosage Adverse effects

Oxytetracycline 500mg twice daily Rare onycholysis,

photosensitivity, benign

intracranial hypertension

Minocycline 100–200 mg/day Headaches, dizziness,

pigmentary changes,

autoimmune hepatitis/lupus

erythematosus-like syndrome

Doxycycline 100–200 mg/day Photosensitivity

Lymecycline 300–600 mg/day Less than minocycline

(not available

in the US)

Erythromycin 500mg twice daily Gastrointestinal upset, nausea,

diarrhea

Trimethoprim 200–300mg twice Rare hepatic/renal toxicity

dailypatients with acne may take 3–6 months,[45] as with other hormo-nal therapies.

which lowers circulating serum testosterone levels. The estrogen isFlutamidemost commonly combined with a progestin (progestogen) to avoidFlutamide blocks the androgen receptor and is approved for thethe risk of endometrial cancer. Some progestins may have intrinsic

treatment of prostate cancer. It has also been used at dosages ofandrogenic activity, which may aggravate acne; however, the250mg twice daily in combination with oral contraceptives for thethird-generation progestins, e.g. desogestrel and norgestimate,treatment of acne or hirsutism in females.[47] Dosages of >500 mg/have the lowest intrinsic androgenic activity. A new combined pillday are associated with a 1–5% risk of hepatotoxicity,[48] andcontaining the progestin drospirenone and ethinyl estradiol, Yas-monitoring of liver function is necessary at all dosages. As with allmin® 1 (Berlex Inc., Wayne, NJ, USA), is now available in theantiandrogens, pregnancy should be avoided because of the risk ofUK. This product has been compared with a third-generationfeminization of a male fetus.combined pill in a 1-year study, which suggested that Yasmin®

had superior beneficial effects on acne lesions.[42]

5.2.5 CorticosteroidsIf the patient’s acne has not significantly improved with an oral

Corticosteroids in low doses can suppress adrenal production ofcontraceptive after three to six cycles, an androgen receptor antag-

androgens.[49] They are indicated in patients who have an elevatedonist can be added. Androgen receptor antagonists currently in use

serum DHEAS or 17-hydroxyprogesterone level associated withinclude cyproterone, spironolactone, and flutamide.

an 11- or 21-hydroxylase deficiency. Deficiency of 21-hydroxy-lase is present in approximately 3% of hirsute women, and muta-5.2.4 Antiandrogens

tions in the 21-hydroxylase gene are found more frequently inCyproterone

women with acne than in those without acne.[50] A combination ofCyproterone is a progestational antiandrogen that blocks the

corticosteroids and estrogens has been used for recalcitrant acne inandrogen receptor. It is combined with ethinyl estradiol in an oral

women, based on inhibition of sebum production by this combina-contraceptive formulation (Dianette®; Schering AG, Berlin, Ger-

tion.[51,52] The mechanism of action is probably related to a greatermany). This product is licensed in the UK as a treatment for severe

reduction in plasma androgen levels with combined therapy than isacne that has not responded to oral antibacterials, or for moderate

produced by either drug alone.or severe hirsutism. Treatment is often required for up to six

5.2.6 Isotretinoinmenstrual cycles before a response is seen. Dianette® andcyproterone are not available in the US. Cyproterone alone has If the acne is severe and refractory to therapy, oral isotretinoinbeen shown to be effective at a dosage of 50–100 mg/day in acne can be considered for use, provided there are no contraindications.

1 The use of trade names is for product identification purposes only and does not imply endorsement.



Patients with very persistent disease that is unresponsive to stan- relapse rate post-therapy is high, but maintenance therapy withdard therapy with antibacterials and topical retinoids, patients with topical retinoids may help to reduce this.[60]

psychological problems, and/or those at risk of scarring should be For those cases in which remission cannot be achieved withseriously considered for oral isotretinoin treatment.[6,53] Isotreti- topical retinoids, it has been demonstrated that low-dose intermit-noin decreases the size and secretion of the sebaceous glands, tent therapy with isotretinoin can be very helpful for maintainingnormalizes follicular keratinization (thereby preventing the forma- improvement in a carefully selected group of adult patients.[61]

tion of new comedones), indirectly inhibits P. acnes growth via The selection criteria for use of oral isotretinoin in this contextchanges of the follicular milieu, and exerts an anti-inflammatory would include predominantly facial acne, total Leeds grade <1,effect.[54,55] The European Directive for Prescribing Systemic Iso- inflamed lesion count <20, and sebum excretion rate <1.25 μg/tretinoin recommends a starting dosage of oral isotretinoin 0.5 mg/ cm2/minute.[61] In light of the new European Directive for isotreti-kg/day for severe acne.[54,56] The dosage can then be adjusted noin prescribing, including the mandatory pregnancy preventionaccording to efficacy and tolerability, thus ensuring minimal ad- plan, this approach to therapy might now be less attractive toverse effects. Most cases of severe acne respond to a single 4- to prescribers and their female patients.6-month therapeutic course. Because oral isotretinoin is a potent Elderly patients with sporadic acne in their sixth or seventhteratogen, women of childbearing age must not start therapy until a decades have also been successfully treated with oral isotretinoinnegative pregnancy test has been obtained. Adequate contracep- at a dosage of 0.25 mg/kg/day.[5]

tion is essential for fertile, sexually active females before, during,5.2.7 Adjunctive Therapies

and up to 5 weeks post-therapy. Monthly pregnancy testing is nowOccasionally, persistent tender inflammatory nodules or cystsrecommended by the European Directive prior to and throughout

will ensue. These can be treated with an intralesional corticoste-the treatment period. The US FDA requests that users of isotreti-roid injection. This will reduce the likelihood of potential scarringnoin be enrolled into the national iPLEDGE registry before theywhilst rapidly reducing pain and swelling. A 30-gauge needle iscan receive the drug.[57] Women of childbearing age must provideused to inject 1–2 mg/mL of triamcinolone acetonide. One injec-two negative pregnancy tests before their initial prescription,tion site per cyst is usually sufficient, and injections can besupply a negative pregnancy test prior to each monthly repeatrepeated every 3 weeks. Adrenal suppression can be avoided byprescription, and agree to use two forms of contraception through-administering no more than 20mg of corticosteroid at a time.[62]

out therapy and for 30 days after treatment.Post-inflammatory pigmentation, which is a common sequel to

Mood changes, depression, and suicidal ideation have beenthe deep-seated nodular inflammatory lesions seen in persistent

reported as possible idiosyncratic reactions to isotretinoin.[58] Pa-acne, can be treated with topical retinoids or azelaic acid.[63]

tients with persistent and late-onset acne frequently have moreIf macrocomedones are apparent, these should be treated with

psychopathology and so should be well informed of this potentialgentle cautery or low-dose hyfrecation prior to any therapy with

problem and monitored carefully. As some of these patients mayisotretinoin.[64] Glycolic peels have been reported to provide rapid

have insulin resistance, baseline investigations pre-isotretinoinimprovement in comedonal acne when tested on women aged

should include blood sugar, fasting lipid profile, and renal and13–40 years.[65]

liver function. It is now recommended that these indices arerepeated at 1 month and then 3-monthly throughout the treatment

6. Conclusionperiod.[54,55]

Persistent and late-onset acne are frequently refractory to com- Post-adolescent acne in females is not uncommon. The termsbinations of antibacterial and topical therapies. Although many of ‘persistent’ and ‘late-onset’ acne are now generally accepted asthese adult female patients do not have acne of sufficient clinical describing the two types of post-adolescent acne. Persistent acneseverity to warrant use of oral isotretinoin, this form of therapy represents a true continuum of adolescent acne. The distributionshould nevertheless be considered as a treatment option in cases differs slightly, being seen more commonly around the face, jawthat are refractory to all other treatments. Because the grade of line, and upper trunk. Inflammatory lesions predominate, andseverity of disease is low, oral isotretinoin is generally adminis- premenstrual flares may occur. Late-onset acne in female patientstered at a much lower dosage than is recommended for severe acne may be present as the specific entity ‘chin acne’, which flaresand may be required in intermittent dosage regimens.[59] The premenstrually and produces deep-seated inflammatory papulesdosage may be as low as 10–20mg daily for 6–8 months. The and nodules. These frequently result in post-inflammatory erythe-



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Persistent Acne in Women

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