Jump to Section Disclaimer Scope Methods Definition Introduction Systems for the grading and classification of acne Microbiologic testing Endocrinologic testing Topical therapies Systemic antibiotics Hormonal agents Isotretinoin Miscellaneous therapies/physical modalities Complementary/alternative therapies Role of diet in acne Gaps in research/knowledge Appendix References

Combination oral contraceptive pills (COCs) contain both an estrogen and a progestin component. COCs were first approved by the FDA for contraception in the United States in 1960. They prevent ovulation and pregnancy by inhibiting gonadotropin-releasing hormone and, subsequently, follicle-stimulating and luteinizing hormones. These hormones are needed to begin follicular maturation and for ovulation; in their absence, ovulation does not occur. Recommendations for hormonal agents are shown in Table VIITable VII, and the strength of recommendations for the treatment of acne with hormonal agents is shown in Table IIITable III. World Health Organization (WHO) recommendations for COC usage eligibility are listed in Table VIIITable VIII. Prescribing information for hormonal therapies is located in Supplemental Table XXIII, Supplemental Table XIV, Supplemental Table XXV, Supplemental Table XXVI, Supplemental Table XXVII, Supplemental Table XXVIII.

Table VII Recommendations for hormonal agents Estrogen-containing combined oral contraceptives are effective and recommended in the treatment of inflammatory acne in females Spironolactone is useful in the treatment of acne in select females Oral corticosteroid therapy can be of temporary benefit in patients who have severe inflammatory acne while starting standard acne treatment In patients who have well documented adrenal hyperandrogenism, low-dose oral corticosteroids are recommended in treatment of acne View Table in HTML

Table VIII World Health Organization recommendations for combined oral contraceptive usage eligibility COC use not recommended Caution or special monitoring Pregnancy Breastfeeding (6 weeks-6 months postpartum) Current breast cancer Postpartum (<21 days) Breastfeeding <6 weeks postpartum Age ≥35 years and light smoker (<15 cigarettes per day) Age ≥35 years and heavy smoker (≥15 cigarettes per day) History of hypertension (including pregnancy) or if monitoring is not feasible Hypertension: systolic, ≥160 mm Hg; diastolic, ≥100 mm Hg Hypertension: systolic, 140-159 mm Hg; diastolic, 90-99 mm Hg; or controlled and monitored Diabetes with end-organ damage Headaches: migraine without focal neurologic symptoms <35 years Diabetes >20 years duration Known hyperlipidemia should be assessed (eg, type and severity) History of or current deep vein thrombosis or pulmonary embolism History of breast cancer with ≥5 years of no disease Major surgery with prolonged immobilization Biliary tract disease Ischemic heart disease (history or current); valvular heart disease with complications Mild compensated cirrhosis History of cerebrovascular accident History of cholestasis related to COC use Headaches (eg, migraine with focal neurologic symptoms at any age, or without aura if ≥35 years) Concurrent use of drugs that affect liver enzymes Active viral hepatitis Severe decompensated cirrhosis Liver tumor (benign or malignant) View Table in HTML

COCs have evolved since 1960. Ethinyl estradiol levels have gradually decreased from around 50 to 150 μg per pill to as low as 10 μg. A variety of different progestational moieties have been used, beginning with the first-generation progestins, the estranes (ie, norethindrone and ethynodiol diacetate). Second-generation progestins include levonorgestrel and norgestimate; these progestins are referred to as the gonanes. Third-generation progestins include less androgenic gonane progestins, such as desogestrel and gestodene. First-, second-, and third-generation progestins are derived from testosterone and alone have androgenic potential. Fourth-generation progestins are not derived from testosterone and include the antiandrogenic progestin drospirenone. While progestins vary in their androgenic potential, evidence suggests that when combined with ethinyl estradiol, the net effect of all COCs is antiandrogenic.219x219Arrington, E.A., Patel, N.S., Gerancher, K., and Feldman, S.R. Combined oral contraceptives for the treatment of acne: a practical guide. Cutis. ; 90: 83–90

Google ScholarSee all References, 220x220Davtyan, C. Four generations of progestins in oral contraceptives. Proceedings of UCLA Healthcare. ; 16 ( )www.med.ucla.edu/modules/xfsection/download.php?fileid=638. ( )

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There are currently 4 COCs approved by the FDA for the treatment of acne. They are ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/ferrous fumarate, ethinyl estradiol/drospirenone, and ethinyl estradiol/drospirenone/levomefolate. The mechanism of action of COCs in the treatment of acne is based on their antiandrogenic properties. These pills decrease androgen production at the level of the ovary and also increase sex hormone–binding globulin, binding free circulating testosterone and rendering it unavailable to bind and activate the androgen receptor. In addition, COCs reduce 5-alfa-reductase activity and block the androgen receptor.219x219Arrington, E.A., Patel, N.S., Gerancher, K., and Feldman, S.R. Combined oral contraceptives for the treatment of acne: a practical guide. Cutis. ; 90: 83–90

Google ScholarSee all References, 221x221Arowojolu, A.O., Gallo, M.F., Lopez, L.M., and Grimes, D.A. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. ; : CD004425

Google ScholarSee all References, 222x222Harper, J.C. Should dermatologists prescribe hormonal contraceptives for acne?. Dermatol Ther. ; 22: 452–457

Crossref | PubMed | Scopus (10) | Google ScholarSee all References, 223x223Rabe, T., Kowald, A., Ortmann, J., and Rehberger-Schneider, S. Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro. Gynecol Endocrinol. ; 14: 223–230

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Numerous randomized controlled clinical trials have assessed the efficacy of COCs in the management of acne.98x98Lucky, A.W., Koltun, W., Thiboutot, D. et al. A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment. Cutis. ; 82: 143–150

PubMed | Google ScholarSee all References, 99x99Maloney, J.M., Dietze, P. Jr., 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. ; 112: 773–781

Crossref | PubMed | Scopus (39) | Google ScholarSee all References, 100x100Maloney, J.M., Dietze, P. Jr., Watson, D. et al. A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. J Drugs Dermatol. ; 8: 837–844

PubMed | Google ScholarSee all References, 101x101Plewig, G., Cunliffe, W.J., Binder, N., and Hoschen, K. Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial. Contraception. ; 80: 25–33

Abstract | Full Text | Full Text PDF | PubMed | Scopus (21) | Google ScholarSee all References, 221x221Arowojolu, A.O., Gallo, M.F., Lopez, L.M., and Grimes, D.A. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. ; : CD004425

Google ScholarSee all References, 224x224Koltun, W., Lucky, A.W., Thiboutot, D. et al. Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial. Contraception. ; 77: 249–256

Abstract | Full Text | Full Text PDF | PubMed | Scopus (53) | Google ScholarSee all References, 225x225Koltun, W., Maloney, J.M., Marr, J., and Kunz, M. Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 mug plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis. Eur J Obstet Gynecol Reprod Biol. ; 155: 171–175

Abstract | Full Text | Full Text PDF | PubMed | Scopus (10) | Google ScholarSee all References, 226x226Jaisamrarn, U., Chaovisitsaree, S., Angsuwathana, S., and Nerapusee, O. A comparison of multiphasic oral contraceptives containing norgestimate or desogestrel in acne treatment: a randomized trial. Contraception. ; 90: 535–541

Abstract | Full Text | Full Text PDF | Google ScholarSee all References It is evident from these trials that COCs reduce acne—both inflammatory and comedonal lesion counts. It is more difficult to determine which, if any, COC is consistently superior in the treatment of acne. A 2012 Cochrane metaanalysis assessed the effect of birth control pills on acne in women and included 31 trials with a total of 12,579 women. Nine trials compared a COC to placebo, and all of these COCs worked well to reduce acne. The progestins included in these 9 trials were levonorgestrel, norethindrone acetate, norgestimate, drospirenone, dienogest, and chlormadinone acetate. Seventeen trials compared 2 COCs, but no consistent differences in acne reduction were appreciated based on formulation or dosage of the COC. Only 1 small study compared a COC to an oral antibiotic; no significant difference in self-assessed acne improvement was identified.221x221Arowojolu, A.O., Gallo, M.F., Lopez, L.M., and Grimes, D.A. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev. ; : CD004425

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A recent publication evaluated the effectiveness of drospirenone 3 mg/ethinyl estradiol 20 μg in the treatment of moderate truncal AV. The COC showed significant reductions in inflammatory, noninflammatory, and total acne lesions compared to placebo.227x227Palli, M.B., Reyes-Habito, C.M., Lima, X.T., and Kimball, A.B. A single-center, randomized double-blind, parallel-group study to examine the safety and efficacy of 3mg drospirenone/0.02 mg ethinyl estradiol compared with placebo in the treatment of moderate truncal acne vulgaris. J Drugs Dermatol. ; 12: 633–637

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The risks of COCs must be weighed against the risks of the condition that they are treating or preventing. When COCs are used for contraception, their risks must be compared to the risks of pregnancy. If COCs are used exclusively for acne, their risks must be compared to the risks of acne. It is important to remember that FDA approval of all COCs for acne specifies that they are approved for the treatment of acne in women who also desire contraception.

COC use is associated with cardiovascular risks. Venous thromboembolic events (VTEs) have been the center of an ongoing debate regarding COCs. Traditionally, higher doses of ethinyl estradiol have been linked to increased risks of VTE. However, in recent years, some progestins have been implicated as risk factors for VTE. A recent Cochrane metaanalysis evaluated 25 publications reporting on 26 studies focused on oral contraceptives and venous thrombosis. The analysis concluded that all COC use increases the risk of VTE compared to nonusers. The relative risk of venous thrombosis for COCs with 30 to 35 μg of ethinyl estradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone was similar and about 50% to 80% higher than for COCs with levonorgestrel.228x228George, R., Clarke, S., and Thiboutot, D. Hormonal therapy for acne. Semin Cutan Med Surg. ; 27: 188–196

Crossref | PubMed | Scopus (46) | Google ScholarSee all References To put this increased risk into perspective, it is important to note that the baseline risk of VTE in nonpregnant, nonusers of COCs is 1 to 5 per 10,000 woman-years. Users of COCs have a VTE risk of 3 to 9 per 10,000 woman-years. Users of drospirenone-containing COCs have a VTE risk of about 10 per 10,000 woman-years. Pregnant women have a VTE risk between 5 and 20 per 10,000 woman-years, and women within 12 weeks postpartum have a VTE risk of between 40 and 65 per 10,000 woman-years.229x229The American College of Obstetricians and Gynecologists website. Committee opinion 540. Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. Available at: http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Gynecologic-Practice/Risk-of-Venous-Thromboembolism. Accessed January 6, 2016.

Google ScholarSee all References, 230x230US Food and Drug Administration website. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed January 6, 2016.

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Myocardial infarction (MI) risks are also increased in COC users. This risk is strongly associated with cigarette smoking and other risk factors, such as diabetes mellitus and hypertension. The WHO reports that COCs are not associated with an increased risk of MI in healthy, normotensive, nondiabetic, nonsmokers at any age.231x231Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. ; 349: 1202–1209

Abstract | Full Text | Full Text PDF | PubMed | Google ScholarSee all References There is also an increased risk of both ischemic and hemorrhagic stroke in COC users. Cigarette smoking and hypertension contribute to this increased risk, as do higher doses of ethinyl estradiol and age >35 years. While these are serious potential adverse events, these cardiovascular events are uncommon in women of reproductive age. An increased relative risk still translates to an overall low absolute risk.219x219Arrington, E.A., Patel, N.S., Gerancher, K., and Feldman, S.R. Combined oral contraceptives for the treatment of acne: a practical guide. Cutis. ; 90: 83–90

Google ScholarSee all References, 222x222Harper, J.C. Should dermatologists prescribe hormonal contraceptives for acne?. Dermatol Ther. ; 22: 452–457

Crossref | PubMed | Scopus (10) | Google ScholarSee all References, 232x232Katsambas, A.D. and Dessinioti, C. Hormonal therapy for acne: why not as first line therapy? facts and controversies. Clin Dermatol. ; 28: 17–23

Abstract | Full Text | Full Text PDF | PubMed | Scopus (38) | Google ScholarSee all References

COC use may be associated with an increased risk of breast cancer in some women. A large metaanalysis including data from 53,297 women with breast cancer and 100,239 controls showed an increased risk of breast cancer in current users of COCs. The relative risk of breast cancer in current COC users was 1.24 (95% confidence interval [CI], 1.15-1.33). This increased risk disappeared 10 years after COC discontinuation. Age at first use of a COC was the only factor that was associated with an overall increased risk. Risk did not appear to correlate with the duration of use of the COC or family history of breast cancer.233x233Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. ; 350: 1047–1059

Abstract | Full Text | Full Text PDF | PubMed | Scopus (2109) | Google ScholarSee all References A more recent systematic review of cancer risks associated with oral contraceptive use also showed an increased relative risk (1.08; 95% CI, 1.00-1.17) of breast cancer in COC users, and higher risk was associated with more recent use of a COC.234x234Gierisch, J.M., Coeytaux, R.R., Urrutia, R.P. et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. ; 22: 1931–1943

Crossref | PubMed | Scopus (41) | Google ScholarSee all References Notably, this increased risk of breast cancer is greatest in women <34 years of age, when the overall incidence of breast cancer is at its lowest.233x233Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. ; 350: 1047–1059

Abstract | Full Text | Full Text PDF | PubMed | Scopus (2109) | Google ScholarSee all References

The risk of cervical cancer may be increased in women who use COCs. An analysis of 24 observational studies found that the risk of cervical cancer increases with an increased duration of COC use. The risk declines after the COC is discontinued and the increase in risk disappears after 10 years of nonuse.235x235International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby, P., Beral, V., Berrington de González, A. et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet. ; 370: 1609–1621

Abstract | Full Text | Full Text PDF | PubMed | Scopus (184) | Google ScholarSee all References Another systematic review found no significant increase in the risk of cervical cancer among ever-users of COCs and never-users from 9 pooled studies. This study did show an increased risk of cervical cancer in women with >5 years of COC use compared with never-users, but the difference was not statistically significant.234x234Gierisch, J.M., Coeytaux, R.R., Urrutia, R.P. et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. ; 22: 1931–1943

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There is additional concern regarding COC use in younger adolescent populations given the adverse effects of low estrogen on bone mass. Peak bone mass development occurs during adolescence and young adulthood. The addition of low-dose estrogen COCs early in the teen years may undermine the accrual of bone mass.236x236Lloyd, T., Rollings, N., Andon, M.B. et al. Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females. J Clin Endocrinol Metab. ; 75: 383–387

Crossref | PubMed | Scopus (84) | Google ScholarSee all References Osteopenia or decreased bone mineral density with COC use has not been shown.237x237Cromer, B.A., Bonny, A.E., Stager, M. et al. Bone mineral density in adolescent females using injectable or oral contraceptives: a 24-month prospective study. Fertil Steril. ; 90: 2060–2067

Abstract | Full Text | Full Text PDF | PubMed | Scopus (59) | Google ScholarSee all References, 238x238Lloyd, T., Petit, M.A., Lin, H.M., and Beck, T.J. Lifestyle factors and the development of bone mass and bone strength in young women. J Pediatr. ; 144: 776–782

Abstract | Full Text | Full Text PDF | PubMed | Scopus (60) | Google ScholarSee all References However, definitive conclusions are yet to be made. In general, the use of COC for acne should be avoided within 2 years of first starting menses or in patients who are <14 years of age unless it is clinically warranted. The FDA has approved COC use for females 14 years (eg, drospirenone and drosperinone/levomefolate) or 15 years (eg, norgestimate and norethindrone/ferrous fumarate) and older (and desiring use of a COC as mentioned above).

There are many noncontraceptive benefits of COCs in addition to the improvement of acne. These include regulation of the menstrual cycle, lessening of menorrhagia and associated anemia, and a reduction in the formation of benign ovarian tumors. Decreased risks of colorectal, ovarian, and endometrial cancers have been shown in COC users.222x222Harper, J.C. Should dermatologists prescribe hormonal contraceptives for acne?. Dermatol Ther. ; 22: 452–457

Crossref | PubMed | Scopus (10) | Google ScholarSee all References, 239x239Maguire, K. and Westhoff, C. The state of hormonal contraception today: established and emerging noncontraceptive health benefits. Am J Obstet Gynecol. ; 205: S4–S8

Abstract | Full Text | Full Text PDF | PubMed | Scopus (31) | Google ScholarSee all References

Oral contraceptives may improve acne for many women. They may be used alone or in combination with other acne treatments. While some women present with signs or symptoms suggestive of a hormonally induced worsening of acne (ie, premenstrual flares or hirsutism), the use of COCs is not limited to these individuals. Any woman with signs or symptoms of hyperandrogenism should be evaluated appropriately for an underlying cause. However, COCs may be beneficial to women with clinical and laboratory findings of hyperandrogenism and in women without these findings.

COCs may be included as part of a comprehensive acne treatment regimen. Women who desire contraception or who suffer from menorrhagia may choose to begin a COC early in their acne treatment. In other women, COCs may be added to a treatment regimen when results with other agents have been limited. COCs may be used in combination with other oral acne medications, including the tetracycline class of antibiotics and spironolactone. There is much misunderstanding regarding the concomitant use of oral antibiotics and COCs and putative contraceptive failure. Rifampin and griseofulvin are the only antiinfectives that interact with COCs, lessening their effectiveness.240x240ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin. No. 73: Use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol. ; 107: 1453–1472

Crossref | PubMed | Google ScholarSee all References The tetracycline class of antibiotics has not been shown to reduce the effectiveness of COCs when taken concomitantly.222x222Harper, J.C. Should dermatologists prescribe hormonal contraceptives for acne?. Dermatol Ther. ; 22: 452–457

Crossref | PubMed | Scopus (10) | Google ScholarSee all References, 232x232Katsambas, A.D. and Dessinioti, C. Hormonal therapy for acne: why not as first line therapy? facts and controversies. Clin Dermatol. ; 28: 17–23

Abstract | Full Text | Full Text PDF | PubMed | Scopus (38) | Google ScholarSee all References, 241x241Helms, S.E., Bredle, D.L., Zajic, J., Jarjoura, D., Brodell, R.T., and Krishnarao, I. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol. ; 36: 705–710

Abstract | Full Text PDF | PubMed | Scopus (66) | Google ScholarSee all References, 242x242London, B.M. and Lookingbill, D.P. Frequency of pregnancy in acne patients taking oral antibiotics and oral contraceptives. Arch Dermatol. ; 130: 392–393

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Because the progestin drospirenone is an analog of spironolactone, there has been some concern that using a drospirenone-containing COC and spironolactone together might increase the risk of hyperkalemia. In 1 study, 27 women with acne were treated with a COC containing drospirenone 3 mg and ethinyl estradiol 30 μg and spironolactone 100 mg each day. There were no significant elevations of serum potassium and there were no additional side effects significant enough to discontinue treatment.243x243Krunic, A., Ciurea, A., and Scheman, A. Efficacy and tolerance of acne treatment using both spironolactone and a combined contraceptive containing drospirenone. J Am Acad Dermatol. ; 58: 60–62

Abstract | Full Text | Full Text PDF | PubMed | Scopus (23) | Google ScholarSee all References

Acne reduction with COC use takes time. Randomized controlled trials consistently show a statistically significant improvement in acne with COCs compared to placebo by the end of cycle 3.98x98Lucky, A.W., Koltun, W., Thiboutot, D. et al. A combined oral contraceptive containing 3-mg drospirenone/20-microg ethinyl estradiol in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled study evaluating lesion counts and participant self-assessment. Cutis. ; 82: 143–150

PubMed | Google ScholarSee all References, 99x99Maloney, J.M., Dietze, P. Jr., 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. ; 112: 773–781

Crossref | PubMed | Scopus (39) | Google ScholarSee all References, 100x100Maloney, J.M., Dietze, P. Jr., Watson, D. et al. A randomized controlled trial of a low-dose combined oral contraceptive containing 3 mg drospirenone plus 20 microg ethinylestradiol in the treatment of acne vulgaris: lesion counts, investigator ratings and subject self-assessment. J Drugs Dermatol. ; 8: 837–844

PubMed | Google ScholarSee all References, 101x101Plewig, G., Cunliffe, W.J., Binder, N., and Hoschen, K. Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled phase III trial. Contraception. ; 80: 25–33

Abstract | Full Text | Full Text PDF | PubMed | Scopus (21) | Google ScholarSee all References, 224x224Koltun, W., Lucky, A.W., Thiboutot, D. et al. Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial. Contraception. ; 77: 249–256

Abstract | Full Text | Full Text PDF | PubMed | Scopus (53) | Google ScholarSee all References, 225x225Koltun, W., Maloney, J.M., Marr, J., and Kunz, M. Treatment of moderate acne vulgaris using a combined oral contraceptive containing ethinylestradiol 20 mug plus drospirenone 3 mg administered in a 24/4 regimen: a pooled analysis. Eur J Obstet Gynecol Reprod Biol. ; 155: 171–175

Abstract | Full Text | Full Text PDF | PubMed | Scopus (10) | Google ScholarSee all References Those treated with COCs for acne should be educated that acne reduction may not be appreciated for the first few months of treatment. Therefore, combining COCs with other acne medications early in treatment may be appropriate.

A Papanicolaou smear and a bimanual pelvic examination are no longer deemed mandatory before initiating the use of a COC. While these screening examinations may offer valuable information, they do not identify women who should not take a COC and should not be required before initiating treatment with a COC. Obtaining a thorough medical history and a blood pressure measurement are important before prescribing a COC.244x244Stewart, F.H., Harper, C.C., Ellertson, C.E., Grimes, D.A., Sawaya, G.F., and Trussell, J. Clinical breast and pelvic examination requirements for hormonal contraception: current practice vs evidence. JAMA. ; 285: 2232–2239

Crossref | PubMed | Google ScholarSee all References Proper patient selection is imperative to minimize risks associated with COC use. The WHO has published contraindications for the use of COCs.245x245Cusan, L., Dupont, A., Gomez, J.L., Tremblay, R.R., and Labrie, F. Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril. ; 61: 281–287

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Spironolactone is an aldosterone receptor antagonist that exhibits potent antiandrogen activity by decreasing testosterone production and by competitively inhibiting binding of testosterone and dihydrotestosterone to androgen receptors in the skin.246x246Boisselle, A., Dionne, F.T., and Tremblay, R.R. Interaction of spironolactone with rat skin androgen receptor. Can J Biochem. ; 57: 1042–1046

Crossref | PubMed | Google ScholarSee all References, 247x247Menard, R.H., Martin, H.F., Stripp, B., Gillette, J.R., and Bartter, F.C. Spironolactone and cytochrome P-450: impairment of steroid hydroxylation in the adrenal cortex. Life Sci. ; 15: 1639–1648

Crossref | PubMed | Google ScholarSee all References, 248x248Menard, R.H., Stripp, B., and Gillette, J.R. Spironolactone and testicular cytochrome P-450: decreased testosterone formation in several species and changes in hepatic drug metabolism. Endocrinology. ; 94: 1628–1636

Crossref | PubMed | Google ScholarSee all References, 249x249Rifka, S.M., Pita, J.C., Vigersky, R.A., Wilson, Y.A., and Loriaux, D.L. Interaction of digitalis and spironolactone with human sex steroid receptors. J Clin Endocrinol Metab. ; 46: 338–344

Crossref | PubMed | Google ScholarSee all References It may also inhibit 5-alfa-reductase and increase steroid hormone–binding globulin.250x250Zouboulis, C.C., Akamatsu, H., Stephanek, K., and Orfanos, C.E. Androgens affect the activity of human sebocytes in culture in a manner dependent on the localization of the sebaceous glands and their effect is antagonized by spironolactone. Skin Pharmacol. ; 7: 33–40

Crossref | PubMed | Google ScholarSee all References, 251x251Serafini, P.C., Catalino, J., and Lobo, R.A. The effect of spironolactone on genital skin 5 alpha-reductase activity. J Steroid Biochem. ; 23: 191–194

Crossref | PubMed | Scopus (25) | Google ScholarSee all References Its use as an antiandrogen is not approved by the FDA for the treatment of acne. Two small, placebo-controlled prospective studies showed statistically significant improvement in acne severity and sebum production at doses ranging from 50 to 200 mg daily.252x252Muhlemann, M.F., Carter, G.D., Cream, J.J., and Wise, P. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. ; 115: 227–232

Crossref | PubMed | Google ScholarSee all References, 253x253Goodfellow, A., Alaghband-Zadeh, J., Carter, G. et al. Oral spironolactone improves acne vulgaris and reduces sebum excretion. Br J Dermatol. ; 111: 209–214

Crossref | PubMed | Google ScholarSee all References A retrospective chart review of 85 patients treated with spironolactone 50 to 100 mg daily, either as monotherapy or as adjunctive therapy, revealed that 66% of women were clear or markedly improved with favorable tolerability at these lower doses.102x102Shaw, J.C. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol. ; 43: 498–502

Abstract | Full Text | Full Text PDF | PubMed | Google ScholarSee all References More recently, a Japanese study investigated the efficacy of spironolactone in Asian patients. One hundred thirty-nine Japanese patients (116 women and 23 men) were treated with spironolactone 200 mg daily for 8 weeks, followed by a taper of 50 mg every 4 weeks over a total of 20 weeks. All 64 women who completed the study had clinical improvement ranging from good to excellent. The study was discontinued prematurely in the male patients because of the development of gynecomastia.103x103Sato, K., Matsumoto, D., Iizuka, F. et al. Anti-androgenic therapy using oral spironolactone for acne vulgaris in Asians. Aesthetic Plast Surg. ; 30: 689–694

Crossref | PubMed | Scopus (0) | Google ScholarSee all References Given the small number and size of available studies, a recent Cochrane database review concluded that there are insufficient data to support the efficacy of spironolactone in the treatment of acne.254x254Brown, J., Farquhar, C., Lee, O., Toomath, R., and Jepson, R.G. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database Syst Rev. ; : CD000194

PubMed | Google ScholarSee all References Despite the lack of published data, relying on available evidence, experience, and expert opinion, the work group supports the use of spironolactone in the management of acne in select women.

Spironolactone is well tolerated overall, and its side effects are dose-related. Common side effects include diuresis (29%), menstrual irregularities (22%), breast tenderness (17%), breast enlargement, fatigue, headache, and dizziness.255x255Shaw, J.C. and White, L.E. Long-term safety of spironolactone in acne: results of an 8-year followup study. J Cutan Med Surg. ; 6: 541–545

Crossref | PubMed | Scopus (35) | Google ScholarSee all References Spironolactone is also pregnancy category C; animal studies have shown feminization of a male fetus early in gestation. Therefore, concomitant use of a COC is often recommended to both regulate menses and prevent pregnancy in many patients. Hyperkalemia is a potentially serious side effect that, fortunately, is rare in young healthy individuals with normal hepatic, adrenal, and renal function. Non–clinically relevant elevations may occur in about 13.7% of patients.228x228George, R., Clarke, S., and Thiboutot, D. Hormonal therapy for acne. Semin Cutan Med Surg. ; 27: 188–196

Crossref | PubMed | Scopus (46) | Google ScholarSee all References A recent retrospective database review identifying 967 women between 18 and 45 years of age taking spironolactone 50 to 200 mg daily for acne found that only 0.75% of the 1723 associated potassium measurements exceeded 5.0 mmol/L. Six of the 13 abnormal tests were normal upon repeat testing. Patients with renal or cardiovascular disease and those taking angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were excluded. Based on these findings, the authors concluded that testing for potassium in young healthy women taking spironolactone for acne is unnecessary.256x256Plovanich, M., Weng, Q.Y., and Mostaghimi, A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. ; 151: 941–944

Crossref | Scopus (0) | Google ScholarSee all References Serum potassium testing is therefore not required, but should be considered in older patients and in patients who are also taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal antiinflammatory drugs, and digoxin. Measurements should be performed at baseline, during therapy, and after dose increases in these patients. Patients should also be educated about avoiding foods that are high in dietary potassium, such as low-sodium processed foods and coconut water.257x257Zeichner, J.A. Evaluating and treating the adult female patient with acne. J Drugs Dermatol. ; 12: 1416–1427

PubMed | Google ScholarSee all References Spironolactone may also be used safely with drospirenone-containing COCs. No elevations in serum potassium were identified in a series of 27 patients treated with spironolactone 100 mg daily in combination with ethinyl estradiol 30 μg/drospirenone 3 mg.243x243Krunic, A., Ciurea, A., and Scheman, A. Efficacy and tolerance of acne treatment using both spironolactone and a combined contraceptive containing drospirenone. J Am Acad Dermatol. ; 58: 60–62

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Animal studies using up to 150 times human doses of spironolactone or its metabolite found the development of thyroid, hepatic, testicular, and breast adenomas, as well as thyroid carcinoma and myelocytic leukemia. These findings contributed to a black box warning stating that the off-label and unnecessary use of spironolactone should be avoided. To date, there has been only 1 human report suggesting carcinogenicity in which the authors identified 5 hospitalized patients with breast cancer who were taking spironolactone among other medications258x258Loube, S.D. and Quirk, R.A. Letter: breast cancer associated with administration of spironolactone. Lancet. ; 1: 1428–1429

Abstract | PubMed | Google ScholarSee all References; however, subsequent longitudinal and retrospective studies found no association.255x255Shaw, J.C. and White, L.E. Long-term safety of spironolactone in acne: results of an 8-year followup study. J Cutan Med Surg. ; 6: 541–545

Crossref | PubMed | Scopus (35) | Google ScholarSee all References, 259x259Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A., and Madsen, S. Nonestrogenic drugs and breast cancer. Am J Epidemiol. ; 116: 329–332

PubMed | Google ScholarSee all References, 260x260Friedman, G.D. and Ury, H.K. Initial screening for carcinogenicity of commonly used drugs. J Natl Cancer Inst. ; 65: 723–733

PubMed | Google ScholarSee all References In addition, a recent large retrospective matched cohort study of 1.29 million women >55 years of age found no association between spironolactone use and breast cancer with 8.4 million patient-years of use, further disproving any causal relationship.261x261Mackenzie, I.S., Macdonald, T.M., Thompson, A., Morant, S., and Wei, L. Spironolactone and risk of incident breast cancer in women older than 55 years: retrospective, matched cohort study. BMJ. ; 345: e4447

Crossref | PubMed | Scopus (13) | Google ScholarSee all References These findings were supported by another large retrospective cohort study of 2.3 million women representing 28.8 million person-years that showed no association between spironolactone use and the development of breast, uterine, cervical, or ovarian cancers.262x262Biggar, R.J., Andersen, E.W., Wohlfahrt, J., and Melbye, M. Spironolactone use and the risk of breast and gynecologic cancers. Cancer Epidemiol. ; 37: 870–875

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Flutamide is a nonsteroidal selective androgen receptor blocker used in the treatment of prostate cancer. It is not approved by the FDA for use in acne. Doses ranging from 250 mg twice daily to as little as 62.5 mg daily have shown efficacy in the treatment of acne in small prospective trials.104x104Wang, H.S., Wang, T.H., and Soong, Y.K. Low dose flutamide in the treatment of acne vulgaris in women with or without oligomenorrhea or amenorrhea. Changgeng Yi Xue Za Zhi. ; 22: 423–432

PubMed | Google ScholarSee all References, 263x263Cusan, L., Dupont, A., Belanger, A., Tremblay, R.R., Manhes, G., and Labrie, F. Treatment of hirsutism with the pure antiandrogen flutamide. J Am Acad Dermatol. ; 23: 462–469

Abstract | Full Text PDF | PubMed | Google ScholarSee all References, 264x264Muderris II, Bayram, F., and Guven, M. Treatment of hirsutism with lowest-dose flutamide (62.5 mg/day). Gynecol Endocrinol. ; 14: 38–41

Crossref | PubMed | Google ScholarSee all References, 265x265Carmina, E. and Lobo, R.A. A comparison of the relative efficacy of antiandrogens for the treatment of acne in hyperandrogenic women. Clin Endocrinol. ; 57: 231–234

Crossref | PubMed | Scopus (39) | Google ScholarSee all References, 266x266Adalatkhah, H., Pourfarzi, F., and Sadeghi-Bazargani, H. Flutamide versus a cyproterone acetate-ethinyl estradiol combination in moderate acne: a pilot randomized clinical trial. Clin Cosmet Investig Dermatol. ; 4: 117–121

Crossref | Google ScholarSee all References, 267x267Calaf, J., Lopez, E., Millet, A. et al. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. J Clin Endocrinol Metab. ; 92: 3446–3452

Crossref | PubMed | Scopus (39) | Google ScholarSee all References Flutamide 250 mg twice daily combined with a triphasic COC reduced acne by 80% compared with spironolactone 50 mg twice daily/COC, which reduced acne by only 50% after 3 months of therapy.245x245Cusan, L., Dupont, A., Gomez, J.L., Tremblay, R.R., and Labrie, F. Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertil Steril. ; 61: 281–287

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Common side effects associated with flutamide include gastrointestinal distress, breast tenderness, hot flashes, headache, xerosis, and decreased libido.228x228George, R., Clarke, S., and Thiboutot, D. Hormonal therapy for acne. Semin Cutan Med Surg. ; 27: 188–196

Crossref | PubMed | Scopus (46) | Google ScholarSee all References, 267x267Calaf, J., Lopez, E., Millet, A. et al. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. J Clin Endocrinol Metab. ; 92: 3446–3452

Crossref | PubMed | Scopus (39) | Google ScholarSee all References High rates of side effects among users may decrease compliance with use.105x105Castelo-Branco, C., Moyano, D., Gomez, O., and Balasch, J. Long-term safety and tolerability of flutamide for the treatment of hirsutism. Fertil Steril. ; 91: 1183–1188

Abstract | Full Text | Full Text PDF | PubMed | Scopus (0) | Google ScholarSee all References In 1 prospective randomized trial of 131 women, side effects at a dose of 125 mg daily were comparable to placebo.267x267Calaf, J., Lopez, E., Millet, A. et al. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. J Clin Endocrinol Metab. ; 92: 3446–3452

Crossref | PubMed | Scopus (39) | Google ScholarSee all References Importantly, flutamide use has been associated with idiosyncratic fatal hepatotoxicity, which appears to be dose- and age-related.268x268Wysowski, D.K., Freiman, J.P., Tourtelot, J.B., and Horton, M.L. 3rd. Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med. ; 118: 860–864

Crossref | PubMed | Google ScholarSee all References, 269x269Garcia Cortes, M., Andrade, R.J., Lucena, M.I. et al. Flutamide-induced hepatotoxicity: report of a case series. Rev Esp Enferm Dig. ; 93: 423–432

PubMed | Google ScholarSee all References Therefore, liver function tests need careful monitoring, and the risk of this serious adverse effect must be considered. Use of flutamide in the treatment of acne is discouraged except where benefit warrants the risk.

Low-dose prednisone in doses ranging from 5 to 15 mg daily, administered alone or with high-estrogen containing COCs, has shown efficacy in the treatment of acne and seborrhea.106x106Nader, S., Rodriguez-Rigau, L.J., Smith, K.D., and Steinberger, E. Acne and hyperandrogenism: impact of lowering androgen levels with glucocorticoid treatment. J Am Acad Dermatol. ; 11: 256–259

Abstract | Full Text PDF | PubMed | Google ScholarSee all References, 270x270Saihan, E.M. and Burton, J.L. Sebaceous gland suppression in female acne patients by combined glucocorticoid-oestrogen therapy. Br J Dermatol. ; 103: 139–142

Crossref | PubMed | Google ScholarSee all References, 271x271Darley, C.R., Moore, J.W., Besser, G.M., Munro, D.D., and Kirby, J.D. Low dose prednisolone or oestrogen in the treatment of women with late onset or persistent acne vulgaris. Br J Dermatol. ; 108: 345–353

Crossref | Scopus (5) | Google ScholarSee all References However, long-term adverse effects of corticosteroids prohibit use as a primary therapy for acne. Prednisone in doses of 0.5 to 1 mg/kg/day is indicated for treatment of the systemic and cutaneous manifestations of acne fulminans and for treatment and prevention of isotretinoin-induced acne fulminans–like eruptions. A slow taper over several months is recommended while transitioning to isotretinoin or oral antibiotics in order to minimize relapses.272x272Jansen, T. and Plewig, G. Acne fulminans. Int J Dermatol. ; 37: 254–257

Crossref | PubMed | Scopus (31) | Google ScholarSee all References, 273x273Karvonen, S.L. Acne fulminans: report of clinical findings and treatment of twenty-four patients. J Am Acad Dermatol. ; 28: 572–579

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