- Email: [email protected]
Contraception and the dermatologist
REVIEW
Contraception and the dermatologist Kelly H. Tyler, MD, FACOG, and Matthew J. Zirwas, MD, FAAD Columbus, Ohio Contraceptives are pertinent to dermatologists in 3 major instances: (1) prescribing combined oral contraceptives for the treatment of acne; (2) ensuring that women being treated with potential teratogens are on adequate contraception; and (3) counseling female patients regarding contraceptives that can worsen acne. Most modern combined oral contraceptives will benefit acne; however, there are some agents that may be more effective than others, primarily because of the progestin used in the agent. Long-acting reversible contraceptives should be first line for women on teratogenic medications, but some of these agents can worsen acne because they release progestins. ( J Am Acad Dermatol 2013;68:1022-9.) Key words: acne; combined oral contraceptives; contraception; depot medroxyprogesterone acetate; etonogestrel implant; intrauterine device; nickel hypersensitivity.
C
ontraceptive methods are of particular interest to the dermatologist for a variety of reasons. Oral contraceptives are a wellknown treatment option for acne and hirsutism, whereas other contraceptive methods, such as medroxyprogesterone acetate (Depo-Provera, Pfizer Inc, New York, NY), implantable etonogestrel (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ), and the levonorgestrel intrauterine device (IUD) (Mirena, Bayer HealthCare, Montville, NJ) can cause acne to flare. In addition, the dermatologist should be familiar with the various methods of contraception and the side effects, contraindications, and effectiveness of each, especially when prescribing potentially teratogenic medications to women of childbearing age.
Abbreviations used: COC: EE: FDA: IUD: SMART:
combined oral contraceptive ethinyl estradiol Food and Drug Administration intrauterine device system to manage Accutane-related teratogenicity
Half of pregnancies in the United States are unplanned, and more than half of the women with unplanned pregnancies are on contraception at the time of conception.1 In light of this, there has been a re-examination of contraceptive methods, which are now grouped based on effectiveness rather than type.1 First-tier contraceptives, including vasectomy, sterilization, IUDs, and subcutaneous implants, are the most effective, easy to use, and have a pregnancy rate of less than 2 per 100 women in the first year of use.1 By increasing the use of first-tier methods, physicians can decrease the number of unintended
pregnancies for women on contraception. A list of currently available contraceptive methods and of the efficacy and tier classification of each is outlined in Table I.1-3 The most recent studies on contraception, such as one recently published in the New England Journal of Medicine, have highlighted the first-tier longacting reversible contraceptive methods, such as IUDs and subcutaneous implants, in reducing the number of unintended pregnancies.4 In addition, a 2002 survey conducted by the Guttmacher Institute showed that the discontinuation rates for shortacting contraceptive methods in the first year was as high as 57% for male condoms, 33% for oral contraceptives, and 44% for injectables (eg, DepoProvera, Pfizer Inc),5 which further highlights the need for increased use of first-tier contraceptives. Contraception is commonly prescribed by dermatologists when initiating therapy with the teratogen isotretinoin. The iPledge program was implemented in 2006 with the goal of reducing fetal exposure to
From the Division of Dermatology, Ohio State University. Funding sources: None. Disclosure: Dr Zirwas has acted as a consultant for Smart Practice, Onset, Taro, and Valeant. Dr Tyler has no conflicts of interest to declare. Accepted for publication November 23, 2012.
Reprint requests: Kelly H. Tyler, MD, FACOG, 911 Neil Ave, Columbus, OH 43215. E-mail: [email protected]. Published online January 21, 2013. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.11.018
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isotretinoin, but a recent study by Shin et al6 showed androgen receptor and therefore more benefit in that fetal exposure has not significantly decreased acne and hirsutism.9 Drospirenone, a fourthwhen compared with the previously implemented generation progestin and analogue of spironolacsystem to manage Accutane-related teratogenicity tone, blocks androgens from binding to the receptor, (SMART) program. The most common reasons for making it an effective COC for treating acne.9 For all COCs, however, the effects of the estrogen outweigh this failure are patient noncompliance with contrathe effects of the progesterone, so androgen levels ception or contraceptive failure.6 In fact, a recent study by Steinkellner et al7 decrease overall.9 In fact, a showed that both taking 1 or recent Cochrane review of 23 CAPSULE SUMMARY more category X medications trials on the effectiveness of and taking contraception COCs for acne showed that All combined oral contraceptives treat prescribed by a dermatolothey all reduced noninflamacne, but some may be more effective gist were independent risk matory and inflammatory fabecause of the particular progestin in factors for noncompliance cial acne lesions. Some of the the agent. When prescribing oral with oral contraception. trials showed that antiandrocontraceptives, patients should be Given all the recent data, genic progestins such as cyscreened for contraindications. when considering therapy proterone acetate (not Progestin-only contraceptive methods with a potentially teratoavailable in the United frequently worsen acne. genic medication such as States) and drospirenone oral isotretinoin in a woman were superior, but overall Dermatologists should consider longof childbearing age who has few differences were found acting reversible contraceptives first line not undergone sterilization, between types of COCs.11 for women on teratogenic medications Despite the fact that all it is the opinion of the aubecause of high failure rates with other COCs are effective in treating thors that long-acting reversmethods. acne, certain COCs have an ible contraceptive methods FDA-approved indication. should be first line. Ethinyl estradiol (EE) 20/30/35 g plus norethinCOMBINED ORAL CONTRACEPTIVES AND drone 1 mg (Estrostep FE, Warner Chilcott, ACNE Rockaway, NJ), EE 35 g plus norgestimate 180/ All combined oral contraceptives (COCs) have the 215/250 g (Ortho Tri-Cylcen, Ortho-McNeilability to improve acne and hirsutism, although not Janssen, Raritan, NJ), and EE 20 g plus drospireall have a Food and Drug Administration (FDA)none 3 mg (Yaz, Bayer HealthCare) have all been approved indication to treat these conditions. All approved for the treatment of moderate acne based COCs suppress luteinizing hormone-driven androon clinical trial evidence.12 A multicenter randomized, double-blind, placebogen production and increase sex hormone binding controlled trial on the effectiveness of EE 35 g plus globulin. The result is a decrease in the levels of free norgestimate 180/215/250 g (Ortho Tri-Cylcen, androgen, leading to a reduction in excess hair Ortho-McNeil-Janssen) in treating moderate acne growth and an improvement in acne.8 Sex hormone binding globulin is produced by the liver and nonshowed a statistically significant mean percent oral hormonal methods, such as the vaginal contradecrease in total lesion count from baseline to cycle ceptive ring and the contraceptive patch, bypass the 6 of 53.1% (COC) versus 26.8% (placebo).13 Comparatively, 2 randomized, double-blind, first-pass liver effects that occur with oral ingestion of placebo-controlled trials of EE 20 g plus drospirhormonal agents. This leads to less of an increase in enone 3 mg (Yaz, Bayer HealthCare) showed statissex hormone binding globulin and subsequently less tically significant mean percent decreases in total of an effect on acne and hirsutism.8 COCs, by definition, include a combination of a lesion count from baseline to cycle 6 of 79.9% (COC) progestin and an estrogen.9 Older synthetic firstversus an unusually high placebo response of generation progestins, such as the gonane norethin79.8%14 and 46.3% (COC) versus 30.6% (placebo).15 Similarly, a multicenter, randomized, double-blind, drone, and second-generation estranges, such as placebo-controlled trial of 100 g levonorgestrel/ levonorgestrel and norgestrel, are derived from pro20g EE (Alesse, Wyeth Ayerst, Madison, NJ) revealed gesterone and may activate the androgen receptor, a statistically significant mean percent decrease in theoretically lessening the beneficial effects of these total lesion count from baseline to cycle 6 of 39.9% agents for acne and hirsutism.10 Desogestrel and norgestimate are newer third-generation gonanes or (COC) versus 23.4% (placebo).16 Finally, pooled data from 2 multicenter placebo-controlled trials of synthetic progestins that have less activity at the d
d
d
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Table I. Contraceptive failure rates during first year of use Women with pregnancy Perfect use (%)
Method
None1 First-tier methodsemost effective Levonorgestrel IUD1 (Mirena, Bayer HealthCare, Montville, NJ) Copper IUD1 (ParaGard T 380A, Teva Pharmaceutical Industries, Ltd, Petah Tikva, Israel) Etonogestrel implant3 (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ) Laparoscopic tubal ligation1 Essure hysteroscopic sterilization2 Male sterilization1 Second-tier methodsevery effective Combination pill1 Progestin-only pill1 Depot medroxyprogesterone1 (Depo-Provera, Pfizer Inc, New York, NY) Contraceptive vaginal ring1 (Nuvaring, Merck & Co, Inc, Whitehouse Station, NJ) Combination patch1 (Ortho Evra, Janssen Pharmaceuticals Inc, Ortho-McNeil-Janssen, Raritan, NJ) Third-tier methodsemoderately effective Diaphragm and spermicides1 Male condom1 Female condom1 Fourth-tier methodseless effective Spermicides1 Spongeeparous women1 Spongeenulliparous women1
85
Typical use (%)
85
0.1 0.6 0.05 0.5 0.2 0.1
0.1 0.8 0.05 0.5 0.2 0.15
0.3 0.5 0.3 0.3 0.3
8 8 3.1 8 8
6 2 5
16 15 21
18 20 9
29 32 16
IUD, Intrauterine device.
EE 20/30/35 g plus norethindrone 1 mg (Estrostep FE, Warner Chilcott) showed a statistically significant mean percent decrease in total lesion count from baseline to cycle 6 of 43% (COC) versus 31% (placebo).17
COCs AND THROMBOEMBOLISM A controversy has arisen regarding a possible increased risk of venous thromboembolism associated with COCs containing drospirenone. A recent article by Raymond et al18 reviewed the current studies of venous thromboembolism in users of drospirenone-containing COCs compared with users of nondrospirenone-containing COCs. Of the 9 studies evaluated, 4 found no difference in venous thromboembolism risk,19-22 and 5 found significant risk elevations in patients using drospirenonecontaining COCs.23-27 Two of the studies that appear more credible, both by Dinger et al,19,20 obtained data via patient questionnaires and medical records review. These 2 studies compared drospirenone with levonorgestrel and both found no increased risk of thromboembolism. Interestingly, these 2 studies and a third that showed no increased risk were funded by the pharmaceutical companies.19-21 The third study in this group by Seeger et al21 obtained data from
insurance claim databases, included a medical records review, and compared drospirenone with various progestins. This study compares drospirenone with other progestins as a group, so it is difficult to say how drospirenone compares with the individual types of progestins. In contrast, the last study that technically found no increased risk was the study by Van Hylckama Vlieg et al,22 but this study compared drospirenone with levonorgestrel, gestodene, desogestrel, and cyproterone acetate. Whereas the risk of thromboembolism was not significantly different when drospirenone was compared with gestodene, desogestrel, and cyproterone acetate, the risk of thromboembolism was increased when drospirenone was compared with levonorgestrel (odds ratio 1.7). Of the studies that showed an increased risk of thromboembolism, all used data from insurance claim databases and national registries, which are not designed for epidemiologic research.28 Four of these 5 studies compared drospirenone with levonorgestrel,23-26 but the FDA study compared drospirenone with 0.15 mg of levonorgestrel and a group of 4 progestins, making it difficult to determine how the risk of thromboembolism with drospirenone compares to the risk with progestins other than levonorgestrel.27 In these studies, the measures of
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association (incidence rate ratios, odds ratios, or hazard ratios) ranged from 1.7 to 3.3.23-27 All of the studies had weaknesses that complicate the interpretation of the data. As mentioned above, most of the studies, including all of the studies showing positive associations, used data from insurance claim databases and national registries. The actual use of a prescribed or dispensed COC was not confirmed, and data about other risk factors for thromboembolism, such as a family history of thromboembolism, were incomplete.18 All but 1 of the studies23 evaluated only drospirenone-containing products with 21 days of active pills and 30 g of EE (Yasmin, Bayer HealthCare), so it is unknown whether the results would be the same with the newer product containing 24 days of active pills and 20 g of EE (Yaz, Bayer HealthCare).18 In any case, venous thromboembolism is very rare in young women, and if a small increase in risk exists, at the very most it would impact only 0.05% to 0.1% of users.18 When put into perspective, the risk of venous thromboembolism is 0.5% in the postpartum period and 0.1% during pregnancy,29 so women on drospirenone-containing COCs are at lower risk for thromboembolism than they would be if they became pregnant. In addition, there are other benefits studied specifically in drospirenone-containing COCs including improvement in premenstrual dysphoric disorder.18 In fact, the FDA has recently endorsed product labeling for a drospirenonecontaining COC that addresses one of the studies and concludes that the risk estimates for venous thromboembolism may not be reliable because the analysis may have included women of varying risk levels.30 When considering treating a patient with drospirenone-containing COCs, it is important to consider the patient’s other risk factors, discuss the conflicting data, and decide whether any potential small increase in the risk of venous thromboembolism outweighs the other benefits of therapy, including improvement of acne. Although most data regarding thromboembolism have assessed the risk of venous thromboembolism, a recent Danish cohort study by Lidegaard et al31 examined the risk of thrombotic stroke and myocardial infarction with hormonal contraception. They examined the risk according to progestin (norethindrone, levonorgestrel, norgestimate, desogestrel, gestodene, and drospirenone) and the dose of EE (20 g vs 30-45 g). The risk of thrombotic stroke and myocardial infarction was low overall, and there were very small differences in risk according to the progestin type. The risk was increased by a factor of 0.9 to 1.7 for COCs with 20 g of EE and by a factor of 1.3 to 2.3 with 30 to 45 g of EE. As an example, the
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Table II. Risk factors in women for whom combined oral contraceptive risks may outweigh benefits Hypertension and age [35 y Hypertension with vascular disease Cerebrovascular disease Cigarette smoking and age [35 y Congestive heart failure Obesity and age [35 y Hypertriglyceridemia Coronary artery disease Systemic lupus erythematous with vascular disease Systemic lupus erythematous with nephritis Systemic lupus erythematous with antiphospholipid antibodies History of thromboembolic disease Migraine headaches with focal neurologic signs Migraine headaches (any type) and age [35 y Women \3 wk postpartum
authors translated these risks to mean that only 2 of 10,000 women taking COCs with desogestrel/20 g EE would have an arterial thrombosis versus venous thrombosis in 6.8 women of 10,000 taking the same COC; therefore, the risk of arterial thrombosis is much lower than the risk of venous thrombosis on COCs.31
COCs AND PATIENT SELECTION Patients with acne who may benefit from treatment with COCs include women with clinical signs of hyperandrogenism, proven ovarian or adrenal hyperandrogenism, acne tarda, polycystic ovarian syndrome, premenstrual flares of acne, and women whose acne has not responded to other conventional therapies. In addition, COCs may be a good choice for the treatment of acne in women who are in need of contraception or who are already being considered for treatment with isotretinoin for acne.32 Patients who are not good candidates for COCs are those with risk factors for known side effects, such as women with a personal or strong family history of cerebrovascular disease, coronary artery disease, congestive heart failure, hypertriglyceridemia, migraine headaches with focal neurologic signs such as aura, thromboembolic disease, hypertension with vascular disease, or systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies. In addition, women older than 35 years who have hypertension, smoke, have any type of migraine, or are obese should not be treated with COCs (Table II).33
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Before starting COCs, patients should be questioned regarding any possible contraindications to COCs and counseled regarding the side effects including nausea, breast tenderness, menstrual irregularity or breakthrough bleeding, and risks such as increased blood pressure and venous thromboembolism.9 Most of the side effects occur when first starting COCs, so patients should be counseled to continue the medication as prescribed if they experience nausea, breast tenderness, or irregular bleeding. They should also ensure that they are taking it daily at the same time because missing doses or taking doses late can contribute to breakthrough bleeding and decreased efficacy. A potential side effect of particular concern to the dermatologist is hair loss upon discontinuation of the pill. Telogen effluvium may occur 6 weeks to 3 months after discontinuation of COCs, but normal hair growth usually returns within 3 to 6 months.34 When starting COCs, the 2 most frequent methods used by gynecologists are the Sunday start and the first-day start. With the first-day start, the patient starts the pills on the first day of menses and does not need to use backup contraception, such as condoms, although some practitioners do still advise patients to use backup contraception for the first week. With Sunday start, the patient starts the pills the first Sunday after the onset of menses and does need to use backup contraception for the first week. There has been some debate as to whether antibiotics decrease the effectiveness of COCs. The only antibiotic that is proven to reduce the effectiveness of COCs is rifampin. Studies have failed to show that estrogen levels are affected by other antibiotics such as penicillins, tetracycline, and doxycycline.1,9 Side effects such as vomiting and diarrhea can decrease absorption, but there are no randomized controlled trials showing that simply taking antibiotics, other than rifampin, with COCs make them less effective.1,9 Regarding gynecologic examinations in patients using COCs or other birth control methods, the newest guidelines recommend initiating Pap smears at age 21 years, regardless of the age of onset of sexual activity or use of COCs. Sexually active women younger than 21 years should be screened for sexually transmitted diseases and counseled regarding safe sex and contraception.35
PROGESTERONE-ONLY CONTRACEPTIVES AND ACNE Progesterone-only options for contraception come in various forms. Progestineonly pills containing only norethindrone or norgestrel are prescribed primarily for breast-feeding mothers or women in
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whom estrogen-containing COCs are contraindicated because of thromboembolic disease or other risk factors outlined in Table II. Because these contain older progestins, they could potentially worsen acne, and they are generally less effective for contraception than COCs, as shown in Table I. Three other available progesterone-only options are depot medroxyprogesterone acetate (Depo-Provera, Pfizer Inc), implantable etonogestrel (Nexplanon, Merck & Co, Inc), and the levonorgestrel IUD (Mirena, Bayer HealthCare). Side effects such as acne, hirsutism, and hair loss have been attributed to the androgenic effect of progestins in all of these contraceptives.36 Depot medroxyprogesterone acetate is given every 12 weeks as an intramuscular injection, and there is a newer product available as a subcutaneous injection (Depo-subQ Provera, Pfizer Inc, New York, NY). Although the major side effects include unscheduled bleeding and weight gain, acne and hair loss have been reported as minor side effects.37 In a recent study, only 5% of women reported hair loss, and acne was not reported as an undesirable side effect.37 In 2 studies of the newer 3-year etonogestrel implant (Nexplanon, Merck & Co, Inc), 14.5% and 18.5% of patients reported acne, but hair loss and hirsutism were not among the reported side effects.36,38 Similarly, acne was reported as a transient side effect of the levonorgestrel-releasing IUD in the first few months after placement, causing 2.3% of patients to discontinue it.39 The side effect subjectively decreased in patients over time, likely because of the gradual decline in levonorgestrel release from 20 to 10 g a day near the end of the 5-year period of effectiveness.40 Findings of various studies on progesterone-only contraception illustrate the increase in androgen-related side effects, so it is important to weigh the small risk of worsening acne against the need for effective contraception in certain patients who may not be candidates for other forms of birth control.
ESSURE AND NICKEL ALLERGY The Essure hysteroscopic tubal sterilization system (Conseptus, San Carlos, CA) was launched in 2001 as a permanent female birth control method.41 It is composed of a delivery catheter and a fallopian tube implant consisting of a nickel titanium (nitinol) elastic outer coil, a stainless steel inner coil, and polyethylene fibers.41 This is of particular interest to the dermatologist because nickel is the leading cause of contact dermatitis, especially in women, and implanted devices that contain nickel are known to cause allergic reactions in some patients.42
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Table III. Dermatologic side effects of contraceptive methods Contraceptive
Dermatologic side effect
Comments
COCs Progestin-only pill
Improved acne and hirsutism Potentially worsens acne
Contraceptive ring (Nuvaring, Merck & Co, Inc, Whitehouse Station, NJ) Contraceptive patch (Ortho Evra, Ortho-McNeil-Janssen, Raritan, NJ) Depot medroxyprogesterone acetate (Depo-Provera, Pfizer Inc, New York, NY) Etonogestrel implant (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ) Levonorgestrel IUD (Mirena, Bayer HealthCare, Montville, NJ)
Less effect on acne and hirsutism
Hair loss can occur on discontinuation Slightly less effective for contraception than COCs Lacks first-pass liver effect of COCs
Less effect on acne and hirsutism
Lacks first-pass liver effect of COCs
Acne and hair loss are minor side effects
Major side effects are unscheduled bleeding and weight gain
Acne has been reported in studies
Hair loss and hirsutism not among reported side effects in studies
Transient worsening of acne
Acne decreases as levonorgestrel release declines near end of 5-y period of effectiveness 2 Case reports of renal transplant recipients conceiving on cyclophosphamide and chlorambucil, perhaps because intact immune system is required for IUD to function47 Minimal reports of possible nickel hypersensitivity in studies; contraindication has been removed by manufacturer
Copper IUD (ParaGard T 380A, Teva Pharmaceutical Industries, Ltd, Petah Tikva, Israel)
Possible failures in patients on immunosuppressive therapy
Essure hysteroscopic sterilization (Conseptus, San Carlos, CA)
Potential nickel hypersensitivity reaction
COC, Combined oral contraceptive; IUD, intrauterine device.
When Essure was first introduced, the manufacturer (Conseptus) listed nickel allergy as a contraindication, but they have since removed that contraindication. At the time of a 2011 study by Zurawin and Zurawin,42 436,937 Essure kits had been sold and there had been no reports of nickel hypersensitivity in clinical trials and only 63 reported cases of suspected nickel hypersensitivity (0.014%). A European study analyzing 4000 Essure procedures reported only 2 patients or 0.05% with a suspected nickel sensitivity that underwent subsequent laparoscopic salpingectomy to remove the implants.43 In addition, 25 patients in the same study with proven nickel allergy received Essure implants without adverse reactions.43 Current data show that there is not a reliable test to predict nickel hypersensitivity from implanted devices, so positive patch testing for a nickel allergy should not be considered an absolute contraindication to placing such devices.44 If a nickel-sensitive patient experiences prolonged abdominal pain or a generalized pruritic rash, a reaction to the device, although unlikely, should be considered. Such patients may be treated initially with a short course of systemic corticosteroids and antihistamines without removing the device.45,46 If the steroids and
antihistamines are effective and then symptoms recur upon cessation, it supports the possibility that an allergic reaction to the device could be the cause. If the symptoms become chronic, lasting several months, then laparoscopic salpingectomy could be considered, but the patient should be counseled that it is not certain that it will lead to resolution of symptoms.
SUMMARY Dermatologists should be familiar with the various contraceptive options for female patients and the effectiveness of each, especially when prescribing potential teratogens. All COCs also have the potential to improve acne, although certain COCs have the FDA-approved indication. Progesteroneonly contraceptive methods, on the other hand, can have androgenic effects and may not be the best choice in patients struggling with acne or hirsutism. Finally, if a patient presents with suspected nickel sensitivity after placement of the nitinol-containing Essure implant, initial conservative treatment is recommended. Table III summarizes the dermatologic side effects of common contraceptive methods.
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German case-control study. J Fam Plann Reprod Health Care 2010;36:123-9. Dinger JC, Heinemann LA, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European active surveillance study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-54. Seeger JD, Loughlin J, Eng PM, Clifford CR, Cutone J, Walker AM. Risk of thromboembolism in women taking ethinyl estradiol/drospirenone and other oral contraceptives. Obstet Gynecol 2007;110:587-93. Van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of estrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009;339: b2921. Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and estrogen doses: Danish cohort study, 2001-9. BMJ 2011;343: d6423. Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011;342:d2151. Parkin L, Sharples K, Hernandez RK, Jick SS. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK general practice research database. BMJ 2011; 342:d2139. Gronich N, Lavi I, Rennert G. Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ 2011;183:E1319-25. FDA Office of Surveillance and Epidemiology. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints, 2011. Available from: URL:http://www.fda. gov/downloads/Drugs/DrugSafety/UCM277384.pdf. Accessed May 22, 2012. Grimes DA. Epidemiologic research using administration databases: garbage in, garbage out. Obstet Gynecol 2010;116: 1018-9. Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697-706. Reid R, Leyland N, Wolfman W, Allaire C, Awadalla A, Best C, et al. SOGC clinical practice guidelines: oral contraceptives and the risk of venous thromboembolism; an update, No. 252, December 2010. Int J Gynaecol Obstet 2011;112:252-6. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012;366:2257-66. Leyden J, Shalita A, Hordinsky M, Swinyer L, Stanczyk FZ, Weber ME. Efficacy of a low-dose oral contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for the treatment of moderate acne: a randomized, placebo-controlled trial. J Am Acad Dermatol 2002; 47:399-409. ACOG Committee on Practice Bulletins-Gynecology. ACOG practice bulletin 73: use of hormonal contraception in women with coexisting medical conditions. Obstet Gynecol 2006;107: 1453-72. Morelli JG. Disorders of hair. In: Kleigman RM, Bonita MD, Stanton J, St Geme J, Schor N, Behrman RE, editors. Nelson
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35.
36.
37.
38.
39.
40.
textbook of pediatrics. 19th ed. Philadelphia: Saunders; 2011. pp. 2289-93. ACOG Committee on Practice BulletinseGynecology. ACOG practice bulletin 109: cervical cytology screening. Obstet Gynecol 2009;114:1409-20. Brache V, Faundes A, Alvarez F, Cochon L. Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials. Contraception 2002;65: 63-74. Wanyonyi SZ, Stones WR, Sequeira E. Health-related quality of life changes among users of depot medroxyprogesterone acetate for contraception. Contraception 2011;84:e17-22. Funk S, Miller MM, Mishell DR, Archer DF, Poindexter A, Schmidt J, et al. Safety and efficacy of Implanon, a single-rod implantable contraceptive containing etonogestrel. Contraception 2005;71:319-26. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: a randomized comparative trial. Contraception 1994;49:56-72. Mansour D. The benefits and risks of using a levonorgestrel-releasing intrauterine system for contraception. Contraception 2012;85:224-34.
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41. Hurskainen R, Hovi SL, Gissler M, Grahn R, Kukkonen-Harjula K, Nord-Saari M, et al. Hysteroscopic tubal sterilization: a systematic review of the Essure system. Fertil Steril 2010;94:16-9. 42. Zurawin RK, Zurawin JL. Adverse events due to suspected nickel hypersensitivity in patients with Essure micro-inserts. J Minim Invasive Gynecol 2011;18:475-82. 43. Arjona Berral JE, Velasco Sanches E, Povedano Canizares B, Castillo R, Davalos S. Complications associated with Essure device: analysis after 4000 procedures. Gynecol Surg 2010; 7(Suppl):S89. 44. Anselmino M, Ribezzo M, Orzan F. Nickel allergy: how deep? Acta Cardiol 2009;64:104-6. 45. Honari G, Ellis SG, Wilkoff BL, Aronica MA, Svensson LG, Taylor JS. Hypersensitivity reactions associated with endovascular devices. Contact Dermatitis 2008;59:7-22. 46. Rigatelli G, Cardaioli P, Giordan M, Aggio S, Chinaglia M, Braggin G, et al. Nickel allergy in interatrial shunt device-based closure patients. Congenit Heart Dis 2007;2: 416-20. 47. Zerner J, Doil KL, Drewry J, Leeber DA. Intrauterine contraceptive device failures in renal transplant patients. J Reprod Med 1981;26:99-102.
Contraception and the dermatologist Kelly H. Tyler, MD, FACOG, and Matthew J. Zirwas, MD, FAAD Columbus, Ohio Contraceptives are pertinent to dermatologists in 3 major instances: (1) prescribing combined oral contraceptives for the treatment of acne; (2) ensuring that women being treated with potential teratogens are on adequate contraception; and (3) counseling female patients regarding contraceptives that can worsen acne. Most modern combined oral contraceptives will benefit acne; however, there are some agents that may be more effective than others, primarily because of the progestin used in the agent. Long-acting reversible contraceptives should be first line for women on teratogenic medications, but some of these agents can worsen acne because they release progestins. ( J Am Acad Dermatol 2013;68:1022-9.) Key words: acne; combined oral contraceptives; contraception; depot medroxyprogesterone acetate; etonogestrel implant; intrauterine device; nickel hypersensitivity.
C
ontraceptive methods are of particular interest to the dermatologist for a variety of reasons. Oral contraceptives are a wellknown treatment option for acne and hirsutism, whereas other contraceptive methods, such as medroxyprogesterone acetate (Depo-Provera, Pfizer Inc, New York, NY), implantable etonogestrel (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ), and the levonorgestrel intrauterine device (IUD) (Mirena, Bayer HealthCare, Montville, NJ) can cause acne to flare. In addition, the dermatologist should be familiar with the various methods of contraception and the side effects, contraindications, and effectiveness of each, especially when prescribing potentially teratogenic medications to women of childbearing age.
Abbreviations used: COC: EE: FDA: IUD: SMART:
combined oral contraceptive ethinyl estradiol Food and Drug Administration intrauterine device system to manage Accutane-related teratogenicity
Half of pregnancies in the United States are unplanned, and more than half of the women with unplanned pregnancies are on contraception at the time of conception.1 In light of this, there has been a re-examination of contraceptive methods, which are now grouped based on effectiveness rather than type.1 First-tier contraceptives, including vasectomy, sterilization, IUDs, and subcutaneous implants, are the most effective, easy to use, and have a pregnancy rate of less than 2 per 100 women in the first year of use.1 By increasing the use of first-tier methods, physicians can decrease the number of unintended
pregnancies for women on contraception. A list of currently available contraceptive methods and of the efficacy and tier classification of each is outlined in Table I.1-3 The most recent studies on contraception, such as one recently published in the New England Journal of Medicine, have highlighted the first-tier longacting reversible contraceptive methods, such as IUDs and subcutaneous implants, in reducing the number of unintended pregnancies.4 In addition, a 2002 survey conducted by the Guttmacher Institute showed that the discontinuation rates for shortacting contraceptive methods in the first year was as high as 57% for male condoms, 33% for oral contraceptives, and 44% for injectables (eg, DepoProvera, Pfizer Inc),5 which further highlights the need for increased use of first-tier contraceptives. Contraception is commonly prescribed by dermatologists when initiating therapy with the teratogen isotretinoin. The iPledge program was implemented in 2006 with the goal of reducing fetal exposure to
From the Division of Dermatology, Ohio State University. Funding sources: None. Disclosure: Dr Zirwas has acted as a consultant for Smart Practice, Onset, Taro, and Valeant. Dr Tyler has no conflicts of interest to declare. Accepted for publication November 23, 2012.
Reprint requests: Kelly H. Tyler, MD, FACOG, 911 Neil Ave, Columbus, OH 43215. E-mail: [email protected]. Published online January 21, 2013. 0190-9622/$36.00 Ó 2012 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2012.11.018
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isotretinoin, but a recent study by Shin et al6 showed androgen receptor and therefore more benefit in that fetal exposure has not significantly decreased acne and hirsutism.9 Drospirenone, a fourthwhen compared with the previously implemented generation progestin and analogue of spironolacsystem to manage Accutane-related teratogenicity tone, blocks androgens from binding to the receptor, (SMART) program. The most common reasons for making it an effective COC for treating acne.9 For all COCs, however, the effects of the estrogen outweigh this failure are patient noncompliance with contrathe effects of the progesterone, so androgen levels ception or contraceptive failure.6 In fact, a recent study by Steinkellner et al7 decrease overall.9 In fact, a showed that both taking 1 or recent Cochrane review of 23 CAPSULE SUMMARY more category X medications trials on the effectiveness of and taking contraception COCs for acne showed that All combined oral contraceptives treat prescribed by a dermatolothey all reduced noninflamacne, but some may be more effective gist were independent risk matory and inflammatory fabecause of the particular progestin in factors for noncompliance cial acne lesions. Some of the the agent. When prescribing oral with oral contraception. trials showed that antiandrocontraceptives, patients should be Given all the recent data, genic progestins such as cyscreened for contraindications. when considering therapy proterone acetate (not Progestin-only contraceptive methods with a potentially teratoavailable in the United frequently worsen acne. genic medication such as States) and drospirenone oral isotretinoin in a woman were superior, but overall Dermatologists should consider longof childbearing age who has few differences were found acting reversible contraceptives first line not undergone sterilization, between types of COCs.11 for women on teratogenic medications Despite the fact that all it is the opinion of the aubecause of high failure rates with other COCs are effective in treating thors that long-acting reversmethods. acne, certain COCs have an ible contraceptive methods FDA-approved indication. should be first line. Ethinyl estradiol (EE) 20/30/35 g plus norethinCOMBINED ORAL CONTRACEPTIVES AND drone 1 mg (Estrostep FE, Warner Chilcott, ACNE Rockaway, NJ), EE 35 g plus norgestimate 180/ All combined oral contraceptives (COCs) have the 215/250 g (Ortho Tri-Cylcen, Ortho-McNeilability to improve acne and hirsutism, although not Janssen, Raritan, NJ), and EE 20 g plus drospireall have a Food and Drug Administration (FDA)none 3 mg (Yaz, Bayer HealthCare) have all been approved indication to treat these conditions. All approved for the treatment of moderate acne based COCs suppress luteinizing hormone-driven androon clinical trial evidence.12 A multicenter randomized, double-blind, placebogen production and increase sex hormone binding controlled trial on the effectiveness of EE 35 g plus globulin. The result is a decrease in the levels of free norgestimate 180/215/250 g (Ortho Tri-Cylcen, androgen, leading to a reduction in excess hair Ortho-McNeil-Janssen) in treating moderate acne growth and an improvement in acne.8 Sex hormone binding globulin is produced by the liver and nonshowed a statistically significant mean percent oral hormonal methods, such as the vaginal contradecrease in total lesion count from baseline to cycle ceptive ring and the contraceptive patch, bypass the 6 of 53.1% (COC) versus 26.8% (placebo).13 Comparatively, 2 randomized, double-blind, first-pass liver effects that occur with oral ingestion of placebo-controlled trials of EE 20 g plus drospirhormonal agents. This leads to less of an increase in enone 3 mg (Yaz, Bayer HealthCare) showed statissex hormone binding globulin and subsequently less tically significant mean percent decreases in total of an effect on acne and hirsutism.8 COCs, by definition, include a combination of a lesion count from baseline to cycle 6 of 79.9% (COC) progestin and an estrogen.9 Older synthetic firstversus an unusually high placebo response of generation progestins, such as the gonane norethin79.8%14 and 46.3% (COC) versus 30.6% (placebo).15 Similarly, a multicenter, randomized, double-blind, drone, and second-generation estranges, such as placebo-controlled trial of 100 g levonorgestrel/ levonorgestrel and norgestrel, are derived from pro20g EE (Alesse, Wyeth Ayerst, Madison, NJ) revealed gesterone and may activate the androgen receptor, a statistically significant mean percent decrease in theoretically lessening the beneficial effects of these total lesion count from baseline to cycle 6 of 39.9% agents for acne and hirsutism.10 Desogestrel and norgestimate are newer third-generation gonanes or (COC) versus 23.4% (placebo).16 Finally, pooled data from 2 multicenter placebo-controlled trials of synthetic progestins that have less activity at the d
d
d
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Table I. Contraceptive failure rates during first year of use Women with pregnancy Perfect use (%)
Method
None1 First-tier methodsemost effective Levonorgestrel IUD1 (Mirena, Bayer HealthCare, Montville, NJ) Copper IUD1 (ParaGard T 380A, Teva Pharmaceutical Industries, Ltd, Petah Tikva, Israel) Etonogestrel implant3 (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ) Laparoscopic tubal ligation1 Essure hysteroscopic sterilization2 Male sterilization1 Second-tier methodsevery effective Combination pill1 Progestin-only pill1 Depot medroxyprogesterone1 (Depo-Provera, Pfizer Inc, New York, NY) Contraceptive vaginal ring1 (Nuvaring, Merck & Co, Inc, Whitehouse Station, NJ) Combination patch1 (Ortho Evra, Janssen Pharmaceuticals Inc, Ortho-McNeil-Janssen, Raritan, NJ) Third-tier methodsemoderately effective Diaphragm and spermicides1 Male condom1 Female condom1 Fourth-tier methodseless effective Spermicides1 Spongeeparous women1 Spongeenulliparous women1
85
Typical use (%)
85
0.1 0.6 0.05 0.5 0.2 0.1
0.1 0.8 0.05 0.5 0.2 0.15
0.3 0.5 0.3 0.3 0.3
8 8 3.1 8 8
6 2 5
16 15 21
18 20 9
29 32 16
IUD, Intrauterine device.
EE 20/30/35 g plus norethindrone 1 mg (Estrostep FE, Warner Chilcott) showed a statistically significant mean percent decrease in total lesion count from baseline to cycle 6 of 43% (COC) versus 31% (placebo).17
COCs AND THROMBOEMBOLISM A controversy has arisen regarding a possible increased risk of venous thromboembolism associated with COCs containing drospirenone. A recent article by Raymond et al18 reviewed the current studies of venous thromboembolism in users of drospirenone-containing COCs compared with users of nondrospirenone-containing COCs. Of the 9 studies evaluated, 4 found no difference in venous thromboembolism risk,19-22 and 5 found significant risk elevations in patients using drospirenonecontaining COCs.23-27 Two of the studies that appear more credible, both by Dinger et al,19,20 obtained data via patient questionnaires and medical records review. These 2 studies compared drospirenone with levonorgestrel and both found no increased risk of thromboembolism. Interestingly, these 2 studies and a third that showed no increased risk were funded by the pharmaceutical companies.19-21 The third study in this group by Seeger et al21 obtained data from
insurance claim databases, included a medical records review, and compared drospirenone with various progestins. This study compares drospirenone with other progestins as a group, so it is difficult to say how drospirenone compares with the individual types of progestins. In contrast, the last study that technically found no increased risk was the study by Van Hylckama Vlieg et al,22 but this study compared drospirenone with levonorgestrel, gestodene, desogestrel, and cyproterone acetate. Whereas the risk of thromboembolism was not significantly different when drospirenone was compared with gestodene, desogestrel, and cyproterone acetate, the risk of thromboembolism was increased when drospirenone was compared with levonorgestrel (odds ratio 1.7). Of the studies that showed an increased risk of thromboembolism, all used data from insurance claim databases and national registries, which are not designed for epidemiologic research.28 Four of these 5 studies compared drospirenone with levonorgestrel,23-26 but the FDA study compared drospirenone with 0.15 mg of levonorgestrel and a group of 4 progestins, making it difficult to determine how the risk of thromboembolism with drospirenone compares to the risk with progestins other than levonorgestrel.27 In these studies, the measures of
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association (incidence rate ratios, odds ratios, or hazard ratios) ranged from 1.7 to 3.3.23-27 All of the studies had weaknesses that complicate the interpretation of the data. As mentioned above, most of the studies, including all of the studies showing positive associations, used data from insurance claim databases and national registries. The actual use of a prescribed or dispensed COC was not confirmed, and data about other risk factors for thromboembolism, such as a family history of thromboembolism, were incomplete.18 All but 1 of the studies23 evaluated only drospirenone-containing products with 21 days of active pills and 30 g of EE (Yasmin, Bayer HealthCare), so it is unknown whether the results would be the same with the newer product containing 24 days of active pills and 20 g of EE (Yaz, Bayer HealthCare).18 In any case, venous thromboembolism is very rare in young women, and if a small increase in risk exists, at the very most it would impact only 0.05% to 0.1% of users.18 When put into perspective, the risk of venous thromboembolism is 0.5% in the postpartum period and 0.1% during pregnancy,29 so women on drospirenone-containing COCs are at lower risk for thromboembolism than they would be if they became pregnant. In addition, there are other benefits studied specifically in drospirenone-containing COCs including improvement in premenstrual dysphoric disorder.18 In fact, the FDA has recently endorsed product labeling for a drospirenonecontaining COC that addresses one of the studies and concludes that the risk estimates for venous thromboembolism may not be reliable because the analysis may have included women of varying risk levels.30 When considering treating a patient with drospirenone-containing COCs, it is important to consider the patient’s other risk factors, discuss the conflicting data, and decide whether any potential small increase in the risk of venous thromboembolism outweighs the other benefits of therapy, including improvement of acne. Although most data regarding thromboembolism have assessed the risk of venous thromboembolism, a recent Danish cohort study by Lidegaard et al31 examined the risk of thrombotic stroke and myocardial infarction with hormonal contraception. They examined the risk according to progestin (norethindrone, levonorgestrel, norgestimate, desogestrel, gestodene, and drospirenone) and the dose of EE (20 g vs 30-45 g). The risk of thrombotic stroke and myocardial infarction was low overall, and there were very small differences in risk according to the progestin type. The risk was increased by a factor of 0.9 to 1.7 for COCs with 20 g of EE and by a factor of 1.3 to 2.3 with 30 to 45 g of EE. As an example, the
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Table II. Risk factors in women for whom combined oral contraceptive risks may outweigh benefits Hypertension and age [35 y Hypertension with vascular disease Cerebrovascular disease Cigarette smoking and age [35 y Congestive heart failure Obesity and age [35 y Hypertriglyceridemia Coronary artery disease Systemic lupus erythematous with vascular disease Systemic lupus erythematous with nephritis Systemic lupus erythematous with antiphospholipid antibodies History of thromboembolic disease Migraine headaches with focal neurologic signs Migraine headaches (any type) and age [35 y Women \3 wk postpartum
authors translated these risks to mean that only 2 of 10,000 women taking COCs with desogestrel/20 g EE would have an arterial thrombosis versus venous thrombosis in 6.8 women of 10,000 taking the same COC; therefore, the risk of arterial thrombosis is much lower than the risk of venous thrombosis on COCs.31
COCs AND PATIENT SELECTION Patients with acne who may benefit from treatment with COCs include women with clinical signs of hyperandrogenism, proven ovarian or adrenal hyperandrogenism, acne tarda, polycystic ovarian syndrome, premenstrual flares of acne, and women whose acne has not responded to other conventional therapies. In addition, COCs may be a good choice for the treatment of acne in women who are in need of contraception or who are already being considered for treatment with isotretinoin for acne.32 Patients who are not good candidates for COCs are those with risk factors for known side effects, such as women with a personal or strong family history of cerebrovascular disease, coronary artery disease, congestive heart failure, hypertriglyceridemia, migraine headaches with focal neurologic signs such as aura, thromboembolic disease, hypertension with vascular disease, or systemic lupus erythematosus with vascular disease, nephritis, or antiphospholipid antibodies. In addition, women older than 35 years who have hypertension, smoke, have any type of migraine, or are obese should not be treated with COCs (Table II).33
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Before starting COCs, patients should be questioned regarding any possible contraindications to COCs and counseled regarding the side effects including nausea, breast tenderness, menstrual irregularity or breakthrough bleeding, and risks such as increased blood pressure and venous thromboembolism.9 Most of the side effects occur when first starting COCs, so patients should be counseled to continue the medication as prescribed if they experience nausea, breast tenderness, or irregular bleeding. They should also ensure that they are taking it daily at the same time because missing doses or taking doses late can contribute to breakthrough bleeding and decreased efficacy. A potential side effect of particular concern to the dermatologist is hair loss upon discontinuation of the pill. Telogen effluvium may occur 6 weeks to 3 months after discontinuation of COCs, but normal hair growth usually returns within 3 to 6 months.34 When starting COCs, the 2 most frequent methods used by gynecologists are the Sunday start and the first-day start. With the first-day start, the patient starts the pills on the first day of menses and does not need to use backup contraception, such as condoms, although some practitioners do still advise patients to use backup contraception for the first week. With Sunday start, the patient starts the pills the first Sunday after the onset of menses and does need to use backup contraception for the first week. There has been some debate as to whether antibiotics decrease the effectiveness of COCs. The only antibiotic that is proven to reduce the effectiveness of COCs is rifampin. Studies have failed to show that estrogen levels are affected by other antibiotics such as penicillins, tetracycline, and doxycycline.1,9 Side effects such as vomiting and diarrhea can decrease absorption, but there are no randomized controlled trials showing that simply taking antibiotics, other than rifampin, with COCs make them less effective.1,9 Regarding gynecologic examinations in patients using COCs or other birth control methods, the newest guidelines recommend initiating Pap smears at age 21 years, regardless of the age of onset of sexual activity or use of COCs. Sexually active women younger than 21 years should be screened for sexually transmitted diseases and counseled regarding safe sex and contraception.35
PROGESTERONE-ONLY CONTRACEPTIVES AND ACNE Progesterone-only options for contraception come in various forms. Progestineonly pills containing only norethindrone or norgestrel are prescribed primarily for breast-feeding mothers or women in
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whom estrogen-containing COCs are contraindicated because of thromboembolic disease or other risk factors outlined in Table II. Because these contain older progestins, they could potentially worsen acne, and they are generally less effective for contraception than COCs, as shown in Table I. Three other available progesterone-only options are depot medroxyprogesterone acetate (Depo-Provera, Pfizer Inc), implantable etonogestrel (Nexplanon, Merck & Co, Inc), and the levonorgestrel IUD (Mirena, Bayer HealthCare). Side effects such as acne, hirsutism, and hair loss have been attributed to the androgenic effect of progestins in all of these contraceptives.36 Depot medroxyprogesterone acetate is given every 12 weeks as an intramuscular injection, and there is a newer product available as a subcutaneous injection (Depo-subQ Provera, Pfizer Inc, New York, NY). Although the major side effects include unscheduled bleeding and weight gain, acne and hair loss have been reported as minor side effects.37 In a recent study, only 5% of women reported hair loss, and acne was not reported as an undesirable side effect.37 In 2 studies of the newer 3-year etonogestrel implant (Nexplanon, Merck & Co, Inc), 14.5% and 18.5% of patients reported acne, but hair loss and hirsutism were not among the reported side effects.36,38 Similarly, acne was reported as a transient side effect of the levonorgestrel-releasing IUD in the first few months after placement, causing 2.3% of patients to discontinue it.39 The side effect subjectively decreased in patients over time, likely because of the gradual decline in levonorgestrel release from 20 to 10 g a day near the end of the 5-year period of effectiveness.40 Findings of various studies on progesterone-only contraception illustrate the increase in androgen-related side effects, so it is important to weigh the small risk of worsening acne against the need for effective contraception in certain patients who may not be candidates for other forms of birth control.
ESSURE AND NICKEL ALLERGY The Essure hysteroscopic tubal sterilization system (Conseptus, San Carlos, CA) was launched in 2001 as a permanent female birth control method.41 It is composed of a delivery catheter and a fallopian tube implant consisting of a nickel titanium (nitinol) elastic outer coil, a stainless steel inner coil, and polyethylene fibers.41 This is of particular interest to the dermatologist because nickel is the leading cause of contact dermatitis, especially in women, and implanted devices that contain nickel are known to cause allergic reactions in some patients.42
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Table III. Dermatologic side effects of contraceptive methods Contraceptive
Dermatologic side effect
Comments
COCs Progestin-only pill
Improved acne and hirsutism Potentially worsens acne
Contraceptive ring (Nuvaring, Merck & Co, Inc, Whitehouse Station, NJ) Contraceptive patch (Ortho Evra, Ortho-McNeil-Janssen, Raritan, NJ) Depot medroxyprogesterone acetate (Depo-Provera, Pfizer Inc, New York, NY) Etonogestrel implant (Nexplanon, Merck & Co, Inc, Whitehouse Station, NJ) Levonorgestrel IUD (Mirena, Bayer HealthCare, Montville, NJ)
Less effect on acne and hirsutism
Hair loss can occur on discontinuation Slightly less effective for contraception than COCs Lacks first-pass liver effect of COCs
Less effect on acne and hirsutism
Lacks first-pass liver effect of COCs
Acne and hair loss are minor side effects
Major side effects are unscheduled bleeding and weight gain
Acne has been reported in studies
Hair loss and hirsutism not among reported side effects in studies
Transient worsening of acne
Acne decreases as levonorgestrel release declines near end of 5-y period of effectiveness 2 Case reports of renal transplant recipients conceiving on cyclophosphamide and chlorambucil, perhaps because intact immune system is required for IUD to function47 Minimal reports of possible nickel hypersensitivity in studies; contraindication has been removed by manufacturer
Copper IUD (ParaGard T 380A, Teva Pharmaceutical Industries, Ltd, Petah Tikva, Israel)
Possible failures in patients on immunosuppressive therapy
Essure hysteroscopic sterilization (Conseptus, San Carlos, CA)
Potential nickel hypersensitivity reaction
COC, Combined oral contraceptive; IUD, intrauterine device.
When Essure was first introduced, the manufacturer (Conseptus) listed nickel allergy as a contraindication, but they have since removed that contraindication. At the time of a 2011 study by Zurawin and Zurawin,42 436,937 Essure kits had been sold and there had been no reports of nickel hypersensitivity in clinical trials and only 63 reported cases of suspected nickel hypersensitivity (0.014%). A European study analyzing 4000 Essure procedures reported only 2 patients or 0.05% with a suspected nickel sensitivity that underwent subsequent laparoscopic salpingectomy to remove the implants.43 In addition, 25 patients in the same study with proven nickel allergy received Essure implants without adverse reactions.43 Current data show that there is not a reliable test to predict nickel hypersensitivity from implanted devices, so positive patch testing for a nickel allergy should not be considered an absolute contraindication to placing such devices.44 If a nickel-sensitive patient experiences prolonged abdominal pain or a generalized pruritic rash, a reaction to the device, although unlikely, should be considered. Such patients may be treated initially with a short course of systemic corticosteroids and antihistamines without removing the device.45,46 If the steroids and
antihistamines are effective and then symptoms recur upon cessation, it supports the possibility that an allergic reaction to the device could be the cause. If the symptoms become chronic, lasting several months, then laparoscopic salpingectomy could be considered, but the patient should be counseled that it is not certain that it will lead to resolution of symptoms.
SUMMARY Dermatologists should be familiar with the various contraceptive options for female patients and the effectiveness of each, especially when prescribing potential teratogens. All COCs also have the potential to improve acne, although certain COCs have the FDA-approved indication. Progesteroneonly contraceptive methods, on the other hand, can have androgenic effects and may not be the best choice in patients struggling with acne or hirsutism. Finally, if a patient presents with suspected nickel sensitivity after placement of the nitinol-containing Essure implant, initial conservative treatment is recommended. Table III summarizes the dermatologic side effects of common contraceptive methods.
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