Combined Oral Contraceptives for the Treatment of Acne: A Practical Guide

Hormonal therapy in the form of combined oral contraceptives (COCs) can be a useful tool in the treatment of patients with mild, moderate, or severe acne vulgaris.^1,2 Eligible patients include postmenarcheal to premenopausal women who desire contraception or simply do not intend to become pregnant. Combined oral contraceptives may be used in combination with other acne treatments, and they can be considered as first-line agents in patients with a strong association between acne severity and their menstrual cycle or in the presence of menstrual cycle irregularities. Although there has been concern that the contraceptive ability of COCs is decreased by concomitant use of antibiotics, failure rates were no higher than the typical COC failure rates of 1% to 3%.³ There is no pharmacokinetic evidence to indicate that any antibiotics other than rifampin lower levels of COCs.⁴

Adrenal or ovarian neoplasms should be excluded by history and physical examination prior to initiating treatment with COCs. Hirsutism, alopecia, acanthosis nigricans, cushingoid symptoms, irregular menses, clitoromegaly, or severe acne of sudden onset warrant further endocrinologic testing.^5-7 Menstrual irregularity in the first 2 to 3 years of postmenarcheal females is common and usually does not require further workup.⁸

Drug Selection

Combined oral contraceptives are effective in the treatment of acne but vary in their formulation.^9-12 All COCs combine an estrogen, typically ethinyl estradiol (EE), and a progestin. First-generation COCs consisted of 50 to 150 µg of estrogens as well as progestins called estranes (eg, norethindrone, ethynodiol diacetate). Second-generation COCs dosed estrogen at less than 50 µg combined with gonane progestins (eg, levonorgestrel, norgestimate). Third-generation COCs also used less androgenic gonane progestins (eg, desogestrel, gestodene). A fourth generation has been proposed that consists of COCs using progestins, such as drospirenone (DRSP) and chlormadinone acetate, which are not testosterone derived.¹³ Theoretically, less androgenic COCs should be better acne treatments.^5,14-16 However, all COCs effectively treat acne, and there is little evidence to suggest one is substantially more effective than the next.^17-19 Therefore, it is believed that the estrogen component may be more responsible for the therapeutic effects of COCs via their ability to decrease androgen secretion from the ovaries and adrenal glands, reduce 5 α-reductase activity, and increase sex hormone–binding globulin.^1,5,7,17,20

With more than 40 COCs now on the market, choosing the right one for a patient can be daunting.

There are 3 COCs that have been approved by the US Food and Drug Administration (FDA) to treat acne vulgaris: (1) Ortho Tri-Cyclen®: norgestimate (white tablets, 0.180 mg; light blue tablets, 0.215 mg; blue tablets, 0.250 mg); EE (0.035 mg); (2) Yaz®: DRSP (3 mg) combined with EE (0.02 mg); and (3) Estrostep® Fe: norethindrone acetate (1 mg) combined with EE (white triangular tablets, 20 µg; white square tablets, 30 µg; white round tablets, 35 µg) and ferrous fumarate (75 mg).²¹ Because most COCs are effective for most women, drug selection may be more appropriately determined by cost, side-effect profile, lifestyle, and patient preference (Tables 1 and 2, see PDF). Tolerability of the traditional 7-day placebo hormone-free interval (HFI) plays a critical role. Women who do not have difficulty with this HFI and who are affected by dysmenorrhea and other menstrual irregularities may benefit from traditional, less expensive COCs that simply combine 20 to 50 µg EE and a progestin in a 21 active-tablet and 7 placebo-tablet combination.²¹

Women who experience exaggerated premenstrual symptoms or menstrual headaches during the HFI may be better served by the newest generation of COCs, which have a shorter HFI (Tables 1and 2, see PDF). This group of COCs tends to be more expensive than traditional COCs but provides less frequent withdrawal bleeds and similar protection. Specifically, Lybrel® (levonorgestrel [90 µg] combined with EE [20 µg]) entirely eliminates monthly menses and is the first FDA-approved yearlong COC. Yasmin® (DRSP [3 mg] and EE [0.03 mg]) and Yaz are particularly unique because they use antiandrogenic DRSP, a spironolactone analogue, and specifically are marketed to have antiacne effects.²² Drospirenone is the only FDA-approved progestin with direct androgen receptor–blocking properties.²¹ Although the majority of women do well with their first COC, switching drugs occasionally is helpful.¹⁶

Associated Risks

All COCs have associated risks, but the risks can be minimized with careful patient screening (Tables 3 and 4, see PDF).^19,23 Although serious adverse events are possible, overall risks for adverse events from COCs are low.^9,19,24-26 Given the low age and generally good health of the patient population for which COCs typically are prescribed, even an elevated relative risk translates into a low absolute risk for notable side effects.¹⁹

The most substantial risks are cardiovascular.²⁵ The risk for venous thromboembolism (VTE), deep vein thrombosis, and pulmonary embolism increases with age and is dose related.^9,24 There is a 10-fold increased risk for VTE in the first year and a 2-fold risk in the second year of use and beyond.^26,27 Additionally, there have been concerns that DRSP-containing COCs place patients at a higher risk for VTE compared to traditional COCs, but these concerns have not been supported by more recent studies.²⁸ Discontinuation of the COC returns a patient to baseline risk within 3 months.²⁹ Although the risk for VTE while using COCs is widely noted in the literature, the overall risk is relatively low.^9,19

Myocardial infarction (MI) and ischemic stroke also are rare, even more so than venous events. There is an approximate 2-fold increase in risk for MI and ischemic stroke in women using COCs,²⁴ but these adverse events are rare in reproductive-aged women, making the incidence low.^9,24 The newer third-generation COCs have no increased risk for MI; some studies even showed a slight reduction in risk.^13,30 However, the risk for MI increases 10-fold in women who smoke and also is higher for women older than 35 years.²⁴ Guidelines caution physicians against prescribing COCs to women who smoke and are older than 35 years.¹³

The risk for localized breast cancer in patients taking COCs has been debated.^9,19,20,24 One study found a relative risk for breast cancer of 1.24 while taking the drug and an increased risk for up to 4 years following cessation of treatment.³¹ However, the risk completely disappeared within 10 years, there was no increased lifetime risk, and the type of cancer was less advanced.²⁴ None of the data show an increased risk for breast cancer in women aged 35 to 64 years who previously used or currently use COCs.³² Mortality rates from breast cancer do not increase with the use of COCs.³³

Combined oral contraceptives only increase the risk for cervical cancer after 5 years of use.^19,24 The risk for cervical cancer immediately begins to decline following cessation of use and is returned to baseline by 10 years.³⁴ One study found no association between the use of COCs and cervical intraepithelial neoplasia grades 1 or higher among women with human papillomavirus, even beyond 5 years of COC use.³⁵

It is important to stress to patients that the risks for COCs have been fairly well elucidated and are substantially less concerning than previously believed if the patient is otherwise healthy.⁴ Both patients and physicians may believe that these medications are inherently unsafe,^16,36,37 but these fears are unfounded and contribute to the underutilization of COCs.

Benefits

There also are benefits of COCs that extend beyond their positive effect on acne.¹⁹ Combined oral contraceptives decrease the risk for endometrial and ovarian cancer.²⁴ This protection continues for at least 20 years following discontinuation of the medication.

Combined oral contraceptives also may protect women from colorectal cancer.^9,37 Additionally, there is less risk for symptomatic pelvic inflammatory disease, ectopic pregnancy, and benign breast disease, along with improved cycle control, less frequent instances of dysmenorrhea, and increased bone density. Combined oral contraceptives prevent unintended pregnancy, which can pose a substantial health risk, as well as psychologic, social, and financial distress.^{9,19,24,25,38}

Another benefit of COCs is for women with severe acne who may be future candidates for isotretinoin therapy. In this situation, COCs arguably are the appropriate preceding step, considering the requirement of 2 forms of contraception while taking isotretinoin. By exclusively trying a patient on COCs prior to initiation of isotretinoin therapy, the physician may be better equipped to differentiate the causal medication of mood symptoms, as both medications are cited to produce mood-related side effects.^39,40 In addition, a sufficiently satisfactory response to COCs could occur, which would render treatment with isotretinoin unnecessary.

Initial Evaluation and Monitoring

Initial evaluation should include a measurement of blood pressure and a detailed patient history.^19,23 Physical examination that extends beyond the skin is not necessary or indicated.^16,25,41 Pelvic examination, screening for cervical intraepithelial neoplasia, and breast examination are not required. Although these examinations are valuable as screening tools, they are not helpful in determining which patients should or should not undergo treatment with COCs.^41-44 The American Congress of Obstetricians and Gynecologists guidelines recommend that patients initiate pelvic examination screening at 21 years of age and biennially thereafter, irrespective of the onset of sexual activity or contraception use.⁴⁵ Therefore, there is no need for follow-up with a gynecologist after initiation of COCs for acne vulgaris. However, with any medication, return visits to the dermatologist should be scheduled to monitor clinical progress and side effects. Periodic blood pressure measurements also are recommended.¹⁹

The dermatologist may elect to perform a pregnancy test to enable the patient to start the medication that same day.^16,38 Described as the quick-start approach, beginning to use COCs in the health care provider’s office under direct observation has been found to improve short-term compliance compared to initiation after next menses. The rate of pregnancy within the first 6 months of initiation of COCs was lower for those who used the quick-start approach.⁴⁶ However, patients must be advised to use a separate method of contraception for the first week to avoid an unintended pregnancy.¹⁶ Alternatively, if the clinician and patient decide to initiate treatment at or immediately after the onset of the next menstrual cycle, a pregnancy test is not needed.³⁸ The longer the patient delays the initiation of the COC, the less chance she will be adherent.^38,41 No other routine laboratory testing is indicated in an otherwise healthy patient with an unremarkable personal and family history.¹⁶

Counseling

When prescribing COCs, appropriate counseling regarding when to start is critical. The patient must take the pill each day and be aware of what to do if she skips 1 or more pills (Figure, see PDF).⁴⁷ The chance of pregnancy (1%–3%), the lack of protection against sexually transmitted diseases, and the dangers of concomitant smoking should be discussed.^16,19 Patients should establish a daily routine for taking the COC to maximize compliance.⁴⁸ Misconceptions surrounding COCs and pelvic examinations, future fertility or teratogenicity, and risk for weight gain should be dispelled.^16,36,38,49 Finally, the patient should know that it might take several months to see antiacne results,^5,7 and she should not discontinue the medication if it does not work right away. The patient should be given ample time to ask questions and the issues discussed should be documented.

Conclusion

Although some dermatologists may be hesitant to prescribe hormonal therapies, COCs can be safely and appropriately used in eligible female patients with acne. We provided guidelines for the selection of COCs, reviewed the risks and benefits, and described ways to monitor and counsel patients.