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.²²⁷

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.²²⁸ 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.^229,230

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.²³¹ 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.^219,222,232

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.²³³ 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.²³⁴ 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.²³³

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.²³⁵ 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.²³⁴

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.²³⁶ Osteopenia or decreased bone mineral density with COC use has not been shown.^237,238 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 (e.g., drospirenone and drosperinone/levomefolate) or 15 years (e.g., 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.^222,239

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 (i.e., 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.²⁴⁰ The tetracycline class of antibiotics has not been shown to reduce the effectiveness of COCs when taken concomitantly.^{222,232,241,242}

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.²⁴³

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.^{98-101,224,225} 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.²⁴⁴ Proper patient selection is imperative to minimize risks associated with COC use. The WHO has published contraindications for the use of COCs.²⁴⁵

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.^246-249 It may also inhibit 5-alfa-reductase and increase steroid hormone–binding globulin.^250,251 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.^252,253 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.¹⁰² 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.103 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.²⁵⁴ 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.255 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.²²⁸ 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.²⁵⁶ 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.²⁵⁷ 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.²⁴³

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 medications²⁵⁸; however, subsequent longitudinal and retrospective studies found no association.^255,259,260 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.²⁶¹ 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.²⁶²

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.^104,263-267 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.²⁴⁵

Common side effects associated with flutamide include gastrointestinal distress, breast tenderness, hot flashes, headache, xerosis, and decreased libido.^228,267 High rates of side effects among users may decrease compliance with use.105 In 1 prospective randomized trial of 131 women, side effects at a dose of 125 mg daily were comparable to placebo.²⁶⁷ Importantly, flutamide use has been associated with idiosyncratic fatal hepatotoxicity, which appears to be dose- and age-related.^268,269 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.^106,270,271 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.^272,273

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