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NEW YORK -- An old cardiovascular drug has emerged as a key option for hormonal management of acne -- with recognized safety caveats.

Studies dating back to the 1980s have demonstrated the efficacy of spironolactone for acne in women, particularly acne unresponsive to nonhormonal therapies. However, the drug comes with an FDA-mandated black-box warning about tumorigenic potential and the caution that "Unnecessary use of this drug should be avoided."

Spironolactone also is contraindicated in patients with renal insufficiency, pregnancy, abnormal uterine bleeding, estrogen-dependent malignancy, and in combination with drugs that could lead to hyperkalemia.

Keeping the safety issues at the forefront, spironolactone has well documented efficacy in difficult cases of acne, , of Northwestern University, said here at the American Academy of Dermatology summer meeting. Though spironolactone is widely used by many dermatologists to treat acne, the application remains off label.

A colleague once told Schlosser that if he could have only three therapies for acne, he would choose a fixed-dose topical agent, isotretinoin, and spironolactone. Acknowledging her respect for the colleague, Schlosser said, "I thought, if that's good enough for him, then it's good enough for me, too."

Hormonal approaches to acne in women warrant consideration under certain circumstances: hyperandrogenemia, late-onset (>25) or persistent acne, predominant distribution on the lower face or neck, perimenstrual acne flares, comedonal acne with seborrhea, resistance to conventional therapies, and as an alternative to repeat isotretinoin.

Schlosser suggested considering an endocrinology workup in adult women who exhibit hirsutism, androgenetic alopecia, signs of virilization (deep voice, increased muscularity), acanthosis nigricans, central or abdominal obesity, oligomenorrhea/amenorrhea, and infertility. Those circumstances are in addition to the general tipoffs to something out of the ordinary: sudden onset, severe or extensive disease, and resistance to conventional therapies.

As a cardiovascular medication, spironolactone is an aldosterone antagonist and diuretic. Beyond those effects, the drug also is a competitive inhibitor of the androgen receptor and an inhibitor of 5-alpha reductase. The molecule has some affinity for the progesterone receptor, said Schlosser.

With respect to its application to the treatment of acne, spironolactone offers dose-dependent reductions in sebum excretion and has a variable effect on serum androgen levels. The drug has been used in the treatment of acne, hirsutism, and female pattern alopecia. The range of effective doses is 50 to 200 mg.

The medical literature on spironolactone for acne shows generally positive results with respect to efficacy. One involved 116 Asian women, 64 of whom completed 20 weeks of treatment. The results showed that 53% of the patients achieved excellent responses and the remaining 47% had good responses.

Another study involved , 79% of whom had disease that failed treatment with an oral antibiotic and 14% had disease that failed isotretinoin. The patients received 50 to 100 mg/day for an average of 10 months. A third of the patients had complete clearance of acne, another third had marked improvement, and 27% had partial improvement. A majority of patients reported no adverse effects associated with spironolactone therapy.

In general, spironolactone is well tolerated, and side effects tend to be dose-dependent, said Schlosser. A who received spironolactone for acne showed that the most common adverse events were diuresis (29%) and menstrual irregularities (22%), followed by breast tenderness (17%), fatigue (15%), and dizziness and lightheadedness (11% to 12%).

Patients who receive spironolactone for acne should have periodic laboratory tests to monitor renal function, electrolytes, and complete blood count, said Schlosser. Patients' adherence to contraception should be monitored, along with pregnancy testing.

Treatment with spironolactone may lead to elevated potassium levels, particularly in patients who are predisposed to hyperkalemia. Whether ongoing monitoring is necessary for women treated for acne remains an unresolved issue. In , investigators retrospectively evaluated the effect of spironolactone on potassium levels in 974 healthy women who took the drug for acne from 2000 to 2014. The data showed that 0.76% of the patients had elevated potassium at baseline, which was virtually unchanged at 0.72% during treatment with the aldosterone inhibitor.

The black-box warning for spironolactone is based on preclinical studies involving doses 10 to 500 times higher than those typically given to humans. The studies showed an association with the high doses of spironolactone and several types of tumors. Several retrospective and case-control studies have yielded little or no evidence of a cause-and-effect relationship between spironolactone and cancer, said Schlosser.

Studies of the cancer potential included an analysis of a that included 2.3 million adult women who took spironolactone during 1995 to 2010. The authors concluded that "with respect to breast, uterus, ovarian, and cervical cancer, there is no evidence of increased risk with spironolactone."

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