Acne vulgaris may be effectively treated with combination oral contraceptive pills (COCs) in women. COCs may be useful in any woman with acne in the absence of known contraindications. When prescribing a COC to a woman who also desires contraception, the risks of the COC are compared with the risks associated with pregnancy. When prescribing a COC to a woman who does not desire contraception, the risks of the COC must be weighed against the risks associated with acne. COCs may take 3 cycles of use to show an effect in acne lesion count reductions.
Key points
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Combination oral contraceptive pills (COCs) are effective at reducing acne in women.
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COCs are useful for women with and without clinical and/or laboratory signs of hyperandrogenism. It is important to do an appropriate hormonal laboratory work-up in women with clinical signs or symptoms of hyperandrogenism to exclude underlying conditions such as late-onset congenital adrenal hyperplasia, polycystic ovary syndrome, and adrenal or ovarian androgen-secreting tumors.
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All COCs are associated with an increased risk of venous thromboembolism compared to the age-matched population.
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Blood pressure measurement should be performed prior to initiating therapy with a COC. Papanicolaou smears and bimanual pelvic examinations are not required to initiate treatment with a COC.
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There are contraindications to COC use including pregnancy, hypertension, migraine headaches, and cigarette smoking in women over the age of 35.
The pathogenesis of acne is complex and multifactorial. Androgen hormones and excess sebum may contribute to the development of acne and are potential targets for treatment. Combination oral contraceptive pills (COC’s) are indirectly anti-androgenic and they have been used with success in the treatment of acne. It is important that dermatology providers understand when and how to prescribe these medications safely and effectively.
Combination oral contraceptive pills
Combination oral contraceptives contain a combination of ethinyl estradiol and a progestin. The ethinyl estradiol dose ranges from 10 μg to 50 μg per day. The progestational agent employed in COCs varies widely from pill to pill. Most of the first- and second-generation progestins (ie, norethindrone, norethindrone acetate, levonorgestrel) are derived from testosterone and may interact with the progesterone receptor, the androgen receptor, the estrogen receptor, the glucocorticoid receptor, and the mineralocorticoid receptor. Although these progestins are successful at preventing pregnancy, they may produce adverse effects related to this nonspecific receptor selectivity. Third-generation progestins, including desogestrel, norgestimate, and gestodene, are also derived from testosterone but have been modified to be less androgenic. Fourth-generation progestins, including drospirenone, bind specifically to the progesterone receptor and not to the other steroid receptors, resulting in no androgenic adverse effects. Drospirenone is derived from 17-alpha spironolactone and has antiandrogenic and antimineralocorticoid effects.
The overall androgenic effect of a COC may be influenced by the type and dose of progestin, by the dose of estrogen, and by its overall suppressive effects on the ovary. Although fourth-generation progestins are, by themselves, antiandrogenic, there is evidence that COCs containing first-, second-, third-, and fourth-generation progestins result in a net increase in sex hormone binding globulin (SHBG) and a net decrease in free testosterone.
Combination oral contraceptive pills
Combination oral contraceptives contain a combination of ethinyl estradiol and a progestin. The ethinyl estradiol dose ranges from 10 μg to 50 μg per day. The progestational agent employed in COCs varies widely from pill to pill. Most of the first- and second-generation progestins (ie, norethindrone, norethindrone acetate, levonorgestrel) are derived from testosterone and may interact with the progesterone receptor, the androgen receptor, the estrogen receptor, the glucocorticoid receptor, and the mineralocorticoid receptor. Although these progestins are successful at preventing pregnancy, they may produce adverse effects related to this nonspecific receptor selectivity. Third-generation progestins, including desogestrel, norgestimate, and gestodene, are also derived from testosterone but have been modified to be less androgenic. Fourth-generation progestins, including drospirenone, bind specifically to the progesterone receptor and not to the other steroid receptors, resulting in no androgenic adverse effects. Drospirenone is derived from 17-alpha spironolactone and has antiandrogenic and antimineralocorticoid effects.
The overall androgenic effect of a COC may be influenced by the type and dose of progestin, by the dose of estrogen, and by its overall suppressive effects on the ovary. Although fourth-generation progestins are, by themselves, antiandrogenic, there is evidence that COCs containing first-, second-, third-, and fourth-generation progestins result in a net increase in sex hormone binding globulin (SHBG) and a net decrease in free testosterone.
Mechanism of action in acne
The antiandrogenic effects of COCs may be useful in the treatment of acne. COCs decrease production and activity of androgens through several mechanisms. First, COCs suppress the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). This suppresses ovarian production of androgen and ovulation. Second, ethinyl estradiol increases hepatic synthesis of SHBG. SHBG binds free testosterone (T) and prevents it from binding to the androgen receptor or from being converted to the more potent dihydrotestosterone (DHT). Third, some progestins inhibit 5-alpha reductase, which converts T to DHT.
Efficacy in acne
There have been numerous studies that evaluate the efficacy of COCs in the treatment of acne. A large Cochrane meta-analysis recently evaluated 31 of these studies. Of 10 trials that included a placebo group, 9 trials showed improvements in acne, and 1 trial had insufficient data to analyze. The progestins included in these placebo-controlled trials included levonorgestrel (LNG), norethindrone acetate (NA), norgestimate (NGM), drospirenone (DRSP), dienogest, and chlormadinone acetate (CMA). Seventeen of the remaining trials compared 2 COCs in the treatment of acne. COCs containing CMA or cyproterone acetate, neither of which are available in the United States, seem to work better for acne than those containing LNG. COCs containing DRSP seem to work better than those containing NGM or nomegestrel acetate. The authors concluded that comparisons between other COCs were either conflicting or showed no significant difference in acne reduction.
The usefulness of COCs in truncal acne has also been evaluated. DRSP/ethinyl estradiol 20 μg was shown to be superior to placebo for truncal acne in a 24-week study. Noninflammatory, inflammatory, and total lesion counts diminished by 52.1%, 53.2%, and 57.3% with DRSP/ethinyl estradiol 20 μg compared with -9.2%, 18.2%, and 17% with placebo ( P =.02, .05, and .02, respectively).
Four COCs are currently US Food and Drug Administration (FDA)-approved for the treatment of acne. They are Ortho Tri-Cyclen (norgestimate 0.180 mg, 0.215 mg, 0.250 mg/ethinyl estradiol 35 μg), Estrostep Fe (norethindrone acetate 1 mg/ethinyl estradiol 20 μg, 30 μg, 35 μg and ferrous fumurate), Yaz (drospirenone 3 mg/ethinyl estradiol 20 μg) and Beyaz (drospirenone 3 mg/ethinyl estradiol 20 μg and levomefolate calcium). It is important to understand the nuances of these FDA indications. All of the COCs FDA-approved for acne are FDA-approved for acne in women who also desire contraception. Balancing the risks of COCs against the risks of pregnancy is quite different from balancing the risks of COCs against the risks of acne.
Benefits
COCs offer many noncontraceptive benefits. They normalize the menstrual cycle, reduce anemia, reduce the risk of ectopic pregnancy, reduce pelvic inflammatory disease, and decrease endometrial, ovarian, and colorectal cancer risks. Ovarian cancer risks are decreased by 40% in women 20 to 54 years of age who have taken a COC for even just a few months versus women who have never taken a COC. This protective effect persists long after the COC is discontinued. Endometrial cancer risk is decreased by about 50% in COC users versus never users.
Premenstrual dysphoric disorder symptoms may also be lessened with COCs. In particular, a Cochrane meta-analysis concluded that COCs containing drospirenone 3 mg and ethinyl estradiol 20 μg may help reduce the symptoms of premenstrual dysphoric disorder.
Risks
COCs are not without risks. They increase the risk of venous thromboembolism (VTE), myocardial infarction, and stroke. They also have an impact on cervical and breast cancer risks. There is ongoing debate about their role in bone mineral density and bone mass accrual.
Cardiovascular Risks
Certainly the risk that has garnered the most attention recently is the risk of VTE. All COC use increases the risk of VTE compared with nonuse, and higher estrogen doses are associated with higher risks. A Cochrane meta-analysis of combined oral contraceptives and venous thrombosis found that all COCs investigated were associated with an increased risk of venous thrombosis. This increased risk was dependent on both the progestin and the dose of ethinyl estradiol. COCs with 30 to 35 μg of ethinyl estradiol and gestodene, desogestrel, cyproterone acetate, and drospirenone were similar and 50% to 80% higher than with levonorgestrel. There have been much conflicting data on this topic, but other studies have concluded that newer-generation progestins, including drospirenone, may be associated with a greater risk of VTE than other progestins. Jick and colleagues reported that the risk of nonfatal VTE associated with COCs containing drospirenone is about twice that of COCs containing levonorgestrel. The FDA conducted its own investigation and also found an increased VTE risk associated with drospirenone as compared with various other progestins. It is important, however, to keep this increased risk in perspective. The overall absolute risk of VTE remains small with all COCs. According to a Committee Opinion from The American College of Obstetricians and Gynecologists, the risk of VTE is increased among COC users to 3 to 9 events per 10,000 woman–years compared with 1 to 5 events per 10,000 woman–years in nonusers who are not pregnant. The risk associated with drospirenone containing COCs may be 10.22 events per 10,000 woman–years. This should be weighed against the risk of VTE during pregnancy (5–20 per 10,000 woman–years) and the postpartum period (40–65 per 10,000 woman-years). Again, the risk of VTE associated with a COC may be well worth it when the COC is being used to prevent pregnancy. Consider these risks thoughtfully when prescribing a COC for acne in a woman who does not need contraception.
There are several high-risk factors that may increase the risk of VTE associated with COC use. These include smoking and age 35 years or older, less than 21 days post-partum or 21 to 42 days postpartum with other risk factors, major surgery with prolonged immobilization, history of deep vein thrombosis or pulmonary embolism, hereditary thrombophilia, inflammatory bowel disease with active or extensive disease, surgery, immobilization, corticosteroid use, vitamin deficiencies or fluid depletion, and systemic lupus erythematosus with positive or unknown antiphospholipid antibodies.
The World Health Organization (WHO) states that current or prior use of a COC is not associated with increased risk for myocardial infarction in healthy nonsmokers. Cigarette smoking and COC use may increase the relative risk of myocardial infarction by up to 30-fold. COCs are contraindicated in women 35 years or older who smoke. Hypertension is another independent risk factor for myocardial infarction in COC users.
Both ischemic and hemorrhagic stroke may be increased in COC users. Cigarette smoking, hypertension, and a history of migraine increase the risk of ischemic stroke, as do ethinyl estradiol doses of 50 μg or more. In COC users over the age of 35, smoking and hypertension also increase the risks of hemorrhagic stroke.
Cancer Risks
A large meta-analysis of 54 studies analyzed the role of COCs in the development of breast cancer. The relative risk (RR) of having breast cancer diagnosed in current users was 1.24 (95% confidence interval [CI] 1.15–1.33). The cancers diagnosed in women who had used COCs were less advanced clinically than those diagnosed in never users. There was no significant increased risk of breast cancer diagnosed 10 or more years after stopping the COC. A 2013 review of oral contraceptive use and the risk of breast cancer also concluded that the risk of breast cancer was slightly elevated for women who ever used a COC versus never users. In contradistinction to the risk of VTE, this slight increase risk may translate to a more substantial absolute risk, because the baseline incidence of breast cancer is high.
Cervical cancer risks may be increased in COC users. Results from 24 pooled studies analyzing this potential risk concluded that the RR of cervical cancer in current COC users increases with increasing duration of use. After 5 years of COC use, the risk doubles. This increase in risk vanishes after 10 years without COC use.
Liver cancer risks are increased with COC use, while colorectal cancer risks are decreased.
Bone Risks
Low estrogen (20 μg ethinyl estradiol or less) COCs may result in estrogen levels too low for young adolescents to develop optimal bone mass. This appears to be most important when starting a low estrogen COC within 3 years from menarche and using the COC for more than 2 years continuously. There is strong evidence that COCs containing 30 μg of ethinyl estradiol or more do not have a negative impact on bone accrual during adolescence.
Related posts:
The Relationship of Proper Skin Cleansing to Pathophysiology, Clinical Benefits, and the Concomitant Use of Prescription Topical Therapies in Patients with Acne Vulgaris
Top Ten List of Clinical Pearls in the Treatment of Acne Vulgaris
The Clinical Relevance of Antibiotic Resistance
Evaluation of Acne Scars
Physical Modalities (Devices) in the Management of Acne
When Acne is Not Acne
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