As antibiotic resistance continues to cause concern, one physician recommends that more dermatologists consider hormonal treatments for acne and hirsutism.
Between 2004 and 2013, the number of spironolactone courses per 100 females with acne rose from 2.08 to 8.13 among dermatologists and from 1.43 to 4.09 among nondermatologists. "We are heading in the right direction," said Julie C. Harper, M.D., clinical associate professor of dermatology at the University of at Birmingham. "But we need to continue to get more people to prescribe oral contraceptives if they feel comfortable with them, because it gives us an alternative to antibiotics" for patients with acne.
"We're trying so hard to get away from ongoing antibiotics because of resistance issues, and because of the effect of antibiotics on the gut," which includes reducing helpful bacteria and provoking diarrhea. While spironolactone is not FDA-approved for acne, "we can learn to use it safely and effectively."
Prescribing trends in combined oral contraceptives (COCs) were harder to detect because physicians prescribe oral contraceptives frequently, mainly for acne rather than dermatologic indications, said Dr. Harper. "But when you look at birth-control pills that contain drospirenone, that number had actually decreased in the last 10 years or so," from a peak of 12 per 100 females in 2008 to 5 per 100 in 2013. This decrease likely stems from the fact that such medications have been shown to increase patients' risk of venous thromboembolism (VTE), she said.
"When you use any COC, you're increasing somebody's risk for venous thromboembolism." Per 10,000 woman-years, she noted, a woman's baseline VTE risk is 3. "If she takes a birth control pill of any kind, it doubles to 6. If she takes a fourth-generation progestin like drosperinone, the risk triples, to 9. But if she gets pregnant, it's 12. Statistically, there is an increased risk. But because the risk is so low at baseline, even if we double or triple it, the risk is still very low. And it's always less" than the risk of VTE in pregnancy. So if a patient requires contraception and treatment of acne or hirsutism, "We can feel really good about using oral contraceptives."
Although physicians appear to be getting this message, said Dr. Harper, "There are still many people who are not writing them. The more we get that information out, the better. There are people who don't feel comfortable prescribing the fourth-generation oral contraceptives because they've heard about the increased risk of VTEs. It sounds scary when you hear that the risk is tripled. But you must know what your baseline risk is" to put this number in context.
Additional barriers to increased use of COCs in acne include the fact that both oral and implantable hormonal contraceptives carry an increased risk of breast cancer, said Dr. Harper. "It's not a huge increase, but it's there." In a recent prospective cohort study involving 1.8 Danish million women followed for an average of 10.9 years, investigators found that compared to women who had never used hormonal contraception, the relative risk of breast cancer among current and recent users of hormonal contraception was 1.20 (95% confidence interval/CI: 1.14-1.26). Risk levels ranged from 1.09 for women with less than one year of use to 1.38 for those with more than 10 years of use (p= 0.002).
Spironolactone's black box warning says nothing about breast cancer. "But it says that in chronic toxicity studies in rats, spironolactone was shown to be tumorigenic. But this was all in animal studies," in which researchers used doses at least 25 times the recommended acne dose for humans. Moreover, Dr. Harper said that 2 reviews (one in patients age 20 and older, the other age 55 and older) published since the black box warning debuted have shown no increased breast cancer risk.
Physicians also worry about a possible link between spironolactone, a diuretic, and hyperkalemia. "If we're going to be using this for acne, how often do we need to be checking potassium? Do we need to worry about that?" A 2015 review that compared 974 young, healthy females who took spironolactone for acne to control-group patients showed no increased incidence of hyperkalemia.
Accordingly, said Dr. Harper, "We don't need to be doing routine potassium monitoring in healthy people under age 45 who are taking spironolactone for acne. And I believe we can extrapolate that to hirsutism as well. The trick is that sometimes in hirsutism or alopecia, we're having to use higher doses. And this particular study did not discuss dose." She recommended intermittently checking potassium levels for women taking higher doses, such as 200 mg daily, and those over age 45.
Another barrier to increased spironolactone use is that because it is not FDA-approved for acne, appropriate dosing and regimens remain unclear. "People are confused about what dose to start at, how long patients should stay on it, and if there's a maximum dose – just what to expect from it, because we don't have clinical trials to inform us. I always encourage people to start at a low dose – 25 or 50 mg daily, then titrate up as needed, usually to a maximum of about 100 mg daily."
When patients start the medication, she added, it's crucial to counsel them that they will probably be taking it long-term. "This is not something we use for 3 or 6 months. In fact, the hormonal treatments may not even kick in until about 3 months."
Outside of hormonal treatments, said Dr. Harper, "There are no other great alternatives for acne. In the United States, we're going to use either a COC or spironolactone. There are other antiandrogens out there; for example, flutamide. But the risk is too high in my opinion. There have been instances of fatal hepatitis with that drug, and we have other alternatives including isotretinoin, or anti-androgenic medications like spironolactone and oral contraceptives together to get a synergistic response."
For hirsutism, "I would still limit our treatment to the COCs and spironolactone when it comes to oral drugs," which dermatologists usually couple with devices such as lasers or electrolysis.
For both acne and hirsutism, she said, "Probably all COCs will have some effect. That's because when you combine ethinyl estradiol (EE) with a progesterone, which is what a COC is, the net effect is going to be anti-androgenic. That's what we really trying to do here – have an anti-androgenic effect both in hirsutism and acne." Some evidence suggests that for hirsutism, third or fourth generation progestins work best. Four COCs – Ortho Tri-Cyclen (norgestimate/EE), Estrostep FE (norethindrone acetate/EE), YAZ (drosperinone/EE) and BEYAZ (drosperinone/EE) are FDA-approved for acne.
F008 – Acne, Hair Loss and Hirsutism Evaluation and Management. "Hormonal Treatment of Acne and Hirsutism." Julie C Harper, M.D., 9:30 a.m., February 16, American Academy of Dermatology 2018 annual meeting.