Hormonal therapies serve as key adjunct acne treatment
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Dermatologists have known for years that hormonal therapies, such as oral contraceptives (OCs), are an effective treatment for acne, particularly for resistant acne in adult women. Despite that, they are not a first line of therapy and are commonly used in combination with traditional treatments. Other hormonal therapies, namely spironolactone, are increasingly being used to treat this subset of acne patients, as well.

For nearly 50 years, birth control pills have been used off-label to treat largely resistant acne in adult women, noted Alan Shalita, MD, distinguished teaching professor and chair of the department of dermatology at the SUNY Downstate Medical Center in Brooklyn. Oral contraceptives containing both estrogen and progestin decrease ovulatory-related ovarian androgen production and free testosterone, the latter of which drives the sebaceous glands, while increasing sex hormone-binding globulin (SHBG). Estrogen may play a more extensive role, he added, noting it is possible that androgen receptors are in the follicle wall. Using a different mechanism of action, spironolactone is an antiandrogen and aldosterone antagonist that competes with 5-a dihydrotestosterone for androgen receptors in the skin. Thus, spironolactone inhibits testosterone and 5-a dihydrotestosterone binding and also increases SHBG.

In the past decade, the use of OCs has most likely increased, particularly among dermatologists, as a result of the Food and Drug Administration’s approval of four OCs for acne treatment. But as Julie Harper, MD, clinical associate professor at the University of Alabama in Birmingham, points out, the use of all combination estrogen and progestin OCs results in an increase in SHBG and a resultant decrease in free testosterone.[pagebreak]

Some of the newer OCs contain drospirenone (DRSP), which differs from the classic progestins in its derivation from spironolactone, noted Aleksandar L. Krunic, MD, PhD, associate professor of dermatology and director of dermatologic surgery at the University of Illinois College of Medicine, adjunct associate professor of dermatology at Northwestern University’s Feinberg School of Medicine in Chicago, and one of the authors of a study on DRSP and spironolactone (J Am Acad Dermatol 2008;58:60-2.). These DRSP-containing OCs exhibit partial antiandrogenic activity, but lack androgenic effect, he explained. They regulate the menstrual cycle and result in lighter, less painful periods as well as reduced sebum production and hair growth, and often improve acne by the third cycle. (On April 11, the FDA announced additional warnings for some DRSP-containing OCs because a review indicated they have three times the risk of other OCs of causing blood clots.)

Subset of patients

Candidates for hormonal therapy are women beyond menarche with evidence of hormone-related acne, late-onset acne, and/or menstrual flares. Those who are unresponsive to conventional therapies and need oral contraception for gynecologic/birth control reasons also are good candidates.

“The use of OCs in acne is a very effective treatment option for women who have either clear signs of hormonal acne or have been on traditional therapies without an improvement,” Dr. Harper said. “But it is very seldom the first line of therapy unless they have signs of androgen-related acne right away and they need contraception.”

The classic example of hormonal acne is a concentration of lesions along the chin, jawline, lower face, and neck, according to Diane Berson, MD, assistant clinical professor on faculty at the Weill Medical College of Cornell University at New York Presbyterian Hospital. These women tend to have premenstrual breakouts with or without menstrual irregularities and hirsutism.

Jim Leyden, MD, emeritus professor of dermatology at the University of Pennsylvania’s School of Medicine, prescribes OCs more freely in women with hormone-related acne in their late teens and 20s. But if a younger teenager is not responding to the traditional therapies, he will consider it an option. The same is true of spironolactone. Prescribing the latter is an easy way of offering hormonal treatment without getting into dicey questions about “the pill” with mothers and daughters, he said. Dr. Krunic said he will prescribe hormonal therapy for 12 to 24 menstrual cycles, then slowly start to wean patients off the treatment — unless the patient desires to continue birth control pills for contraception, in which case he refers them to their gynecologist for further prescriptions and follow-up.

Women with endocrine disorders, such as polycystic ovarian syndrome (PCOS) and congenital adrenal hyperplasia (CAH), may benefit from hormonal therapies, as well.

Patients who frequently skip menstrual cycles, with or without hirsutism, may have an abnormal hormonal status or PCOS, Dr. Leyden said. When taking a history, instead of asking the patient if her menstrual cycle is regular, he said it’s better to ask how often she gets a period, pointing out that “being regular” is not the same as having a normal cycle. Even if the patient lacks facial hair, he said, ask about it because most women have excess hair removed. Depending on the patient’s age, you may want to ask about pregnancies and their outcomes, Dr. Harper added. Asking about her response to previous acne treatments may also be helpful. “If a person has been on isotretinoin many times and the acne always comes back that might be an indication there’s an underlying problem that needs to be addressed,” she said.

For patients suspected of having hormonal abnormalities, dermatologists typically test for levels of total and free testosterone, dehydroepiandrosterone sulfate (DHEAS), and luteinizing hormone/follicle stimulating hormone (LH/FSH). If the lab results come back abnormal, Dr. Harper will test for 17 hydroxyprogesterone. In general, a modestly high DHEAS level may indicate CAH, but higher levels should trigger evaluation for an adrenal tumor. Higher total testosterone levels may be seen in ovarian tumors, but mild increases are indicative of PCOS as are LH/FSH ratios greater than two to three. Levels of 17 hydroxyprogesterone have been used to confirm adult-onset CAH. Even when the lab workup is normal, which is most of the time, these patients can still benefit from hormonal treatment, she noted.[pagebreak]

In combination, alone

Many dermatologists use spironolactone in conjunction with OCs to minimize its side effects, which commonly include menstrual irregularities and breast tenderness, Dr. Shalita explained. A typical treatment dose of spironolactone is 50 to 100 mg daily. At higher doses, the side effects are more prominent.

The other advantage to combining these hormonal therapies is that they treat acne using two mechanisms of action, essentially doubling the effect, Dr. Berson said. If the acne is not being adequately controlled with OCs, she may add spironolactone. “Birth control pills can take two to three months to show an effect, but with spironolactone, most patients notice decreased outbreaks and oiliness in a couple of weeks,” Dr. Berson added.

Some dermatologists believe that spironolactone shouldn’t be prescribed in the absence of OCs because it is associated with hypospadias and feminization of the male fetus, Dr. Leyden said.

But as Dr. Harper points out, spironolactone is one of several medications that patients shouldn’t become pregnant while taking. Although she generally prescribes it in combination with OCs to help minimize side effects, Dr. Harper will prescribe spironolactone alone after thoroughly explaining the potentially serious risks of becoming pregnant. Like her counterparts, she also prescribes spironolactone without OCs for patients in whom the use of estrogen is contraindicated, or in post-menopausal women or those who have had a hysterectomy, or smokers.

Moreover, patients are not candidates for combined therapy with OCs if they have risk factors such as obesity, high blood pressure, stroke, deep vein thrombosis (DVT), migraines, or a family history of breast/endometrial cancer, Dr. Krunic noted.

Used with traditional therapies

Hormonal therapies are typically used in combination with traditional acne therapies, including topical or systemic retinoids, topical benzoyl peroxide, and topical or systemic antibiotics. As Dr. Shalita points out, the consensus of the Global Alliance for Improving Outcomes in Acne is that a topical retinoid should be used to treat all but the most severe forms of acne.

As the patient responds to treatment, Dr. Berson may stop the oral antibiotics or topical antimicrobials while continuing the hormonal therapy. “But even when the patient is clear, I tend to keep her on retinoids because they treat existing acne and help prevent future breakouts,” she said.

Dr. Harper frequently overlaps hormonal and traditional therapies because she gets faster results that way. She may use both for two to three months and then discontinue the traditional therapy. “When hormone therapy is effective, patients are on them for a long time,” she noted.

Dr. Krunic has found that most of these patients are just partially responsive to retinoids. In addition, their skin is often more sensitive to the drying effect of topical retinoids or irritation from benzoyl peroxide. As a result, he commonly combines antiandrogen therapy with systemic antibiotics, often in the beta-lactam or cephalosporin group. Topically, he prefers lotions or water-based vehicles like cleansing cloths containing sodium sulfacetamide and sulfur.

Dr. Leyden has a slightly different approach. For patients who are unresponsive to several conventional therapies, he will stop all of them and prescribe spironolactone, and assess their progress in six weeks. “Many times, spironolactone is enough,” Dr. Leyden said. But for a teenager with blackheads, non-inflammatory lesions, pustules, and papules, he will use a topical antibiotic and retinoid and add spironolactone. Assuming the patient comes under control fairly quickly, he will slowly stop the antibiotics, but will continue the retinoids because of the blackheads.

“Many times, you can get away without oral antibiotics,” he noted.[pagebreak]

Risks, concerns

Using OCs is associated with an increased risk of DVT, stroke, and myocardial infarction, among others. But Dr. Berson points out that there is a decreased risk and fewer side effects associated with today’s OCs due to the smaller amounts of estrogen in them. Newer OCs contain 20 to 35 mcg of estrogen compared with 100 mcg in the first-generation OCs. She informs her patients about the signs of DVT, that it can be pains and cramping in both the legs and/or arms, and tells them to contact her if they develop any symptoms. Dr. Berson also recommends that they stay active and drink a lot of water as immobility and dehydration will increase one’s potential to develop DVT.

Stroke, myocardial infarction, and DVT are also very strongly linked to other risk factors, such as smoking, Dr. Harper noted. Although a slight increased risk of developing breast cancer has been raised, she questions that. Regarding the FDA’s investigation of DRSP-containing OCs, she said two studies suggest that these birth control pills are associated with twice the risk of developing DVT than those containing levonorgestrel. “When the lay population hears that there is a double risk, it sounds frightening,” she said. “But when you look at the absolute risk, it increases from six out of 10,000 events to 10 out of 10,000 events. It’s really important that dermatologists understand those numbers because we’re the ones our patients will ask.”

In addition, an increased risk of hyperkalemia when DRSP-containing OCs are combined with spironolactone was not demonstrated in recent studies, Dr. Krunic noted. Despite the hyperkalemia warning, physicians are using OCs containing DRSP with spironolactone preferentially and they are not following the recommended potassium monitoring requirements, he said.

There is, however, some concern regarding the use of OCs hindering bone density in young adolescents. The body relies on estrogen for bone development, much of which occurs within four years after menarche. By the late teens and early 20s, however, peak bone mass is formed. “When you give someone the birth control pill, you’re choosing how much estrogen that person will have because you’re suppressing the amount the body will make,” Dr. Harper said. “The concern is that estrogen levels in the pill are too low to support enough bone formation to prevent osteoporosis and bone fractures later in life. After reviewing the literature, I’m not sure that we know the answer to that.” There is evidence showing that the combination OCs with 30 mcg of ethinyl estradiol are adequate to ensure sufficient bone accrual during adolescence and normal bone health into adulthood. Still, Dr. Harper cautions dermatologists to be aware that lower levels of estrogen may not always be better, especially for young adolescents.

Regarding antibiotics decreasing the effectiveness of OCs, Dr. Harper said that there is no evidence to support that with the antibiotics used to treat acne. The hypothesis is that antibiotics decrease the gut flora needed to further degrade inactive metabolites of the OCs to active drug during enterohepatic recirculation. Dr. Berson points out that the failure rate of OCs is 3 percent, which remains the same with antibiotic use. Moreover, it takes one month for birth control pills to take effect, the same amount of time it takes the gut flora to normalize, she said. Women are told to use appropriate precautions to prevent pregnancy during that time.

They may not be the first line of therapy, but hormonal therapies are an effective secondary adjunctive treatment that will, no doubt, continue to grow in popularity. “Women are asking for it by name,” Dr. Leyden said. “They want the pill that doesn’t make them break out.”

Dermatologists prescribing more OCs, but numbers still low

Oral contraceptives (OCs) are rarely prescribed for acne despite their efficacy for treating it, according to a study presented by Steven Feldman, MD, PhD, of Wake Forest University, at the AAD’s recent Annual Meeting in San Diego.

Overall, physicians prescribed OCs at 2.58 percent of acne visits, with dermatologists prescribing them at 2.03 percent of visits. In recent years, such prescriptions increased by 0.9 percentage points among dermatologists. Dr. Feldman suggested that the low rate of OC prescriptions among dermatologists is likely due to their lack of experience with birth control pills in routine practice.

Some dermatologists may be reluctant to prescribe OCs because they tend to think of them as falling under the purview of a gynecologist. Part of that could be that dermatologists have the mistaken impression that patients going on the birth control pill must get a pap smear, Dr. Shalita said. But several years ago, the American Congress of Obstretricians and Gynecologists came out with a report saying that women who are not sexually active don’t need to see a gynecologist for a year after being on the birth control pill, he said. If they are sexually active, they should be getting a routine pap smear anyway.

Then there is the awkward conversation that can ensue when discussing OCs for teenagers. “I never use the words birth control pill’ with mothers,” Dr. Leyden said. “I always talk about estrogen therapy, which if you take it every day will help prevent you from getting pregnant.” Dr. Berson similarly discusses hormone treatment, especially when speaking with a 16-year-old girl who is there with her mom. “You don’t want to say we’re putting your daughter on the birth control pill because it can open a Pandora’s Box,” she said.

Younger dermatologists are probably more comfortable than older ones prescribing OCs, Dr. Harper said. She speculates that this is because they are coming out of residency training learning about them. In addition, FDA approval has had an impact. “Oral contraceptives were being used off-label. But now that the FDA has approved them for the treatment of acne, more dermatologists can feel comfortable with prescribing them,” Dr. Berson said. When she first started prescribing OCs, Dr. Berson always recommended that patients go to the gynecologist, but that is unnecessary unless the patient has an underlying endocrinopathy or is at risk of complication. Nowadays, she gives patients a three-month prescription and recommends that they see a gynecologist annually because the assumption is that a patient on OCs is more likely to be sexually active, which puts them at risk for sexually transmitted diseases.

“Oral contraceptives and spironolactone have been very helpful additions to our therapeutic armamentarium for acne,” Dr. Berson said. “Dermatologists are getting more comfortable with giving women this form of treatment as an adjunct to traditional treatments.”

Passing the test

Dermatologists treating patients for acne who suspect hormonal abnormalities should test them to rule out other conditions. Julie Harper, MD, clinical associate professor at the University of Alabama in Birmingham, recommends following the steps below.



Dermatologists prescribing more OCs, but numbers still low
Passing the test