Oral Contraceptives: Current Status

The turn of this century marked the fourth decade of oral contraceptive use. Although there has been a wealth of literature that has shown “the pill” to be safe and effective, there continues to be some controversy about some aspects of safety. In addition, because of persistence of nuisance side effects such as abnormal bleeding and nausea, new agents have been introduced during the past several years. This article reviews the current status of the oral contraceptive including new developments, efficacy, major sequelae, selected side effects, and noncontraceptive benefits. New Developments The major new developments in the past two decades include introduction of new progestins, ie, desogestrel and norgestimate, and reduction in the dosage of ethinyl estradiol from 35 μg to 20 μg per pill. More recent innovations have focused on shortening the hormone-free interval. For example, one preparation provides 10 μg of estradiol for 5 days after completion of the 21 days of estrogen–progestin combination dosage. Another preparation awaiting Food and Drug Administration approval provides a continuous combination dosage for 84 days. The major impetus for these changes has been to improve safety and to reduce side effects. Although there is some evidence that the newer progestins may have less androgenicity, desogestel has been embroiled in a controversy about whether its use increases the risk for thromboembolism. There are little data to indicate whether reduction of the estrogen dose to 20 μg is associated with decreased risk of serious sequelae, primarily because of lack of data. Relative to alterations in side effects, as will be presented later, the data are mixed. Finally, shortening the pill-free interval, although helpful for some users, does not appear to be the solution that markedly reduces nuisance side effects. 1 Contraceptive Effects Combined oral contraceptives suppress ovulation by diminishing the frequency of gonadotropin-releasing hormone pulses and halting the luteinizing hormone surge. They also alter the consistency of cervical mucous, affect the endometrial lining, and alter tubal transport. When administered correctly and consistently, they confer a greater than 99% method effectiveness in preventing pregnancy. 2 Unfortunately, problems with compliance, frequently secondary to side effects such as abnormal bleeding, have led to a significantly reduced use-effectiveness. Overall, the use-effectiveness, because of these factors, ranges between 94–97%. 2 Although overall efficacy may not be affected by recent dosage alterations, some data examining ovarian follicle changes suggest that there may be less margin for error with low-dose preparations such that missing pills for 2 or more days may be more likely to result in break-through ovulation. 3 Major Sequelae By the 1970s, it had been established that oral contraceptives were associated with various types of cardiovascular risks. As time progressed, additional concerns were raised, particularly risk for breast cancer. Both of these major issues will be examined in this section because with the significant reduction in estrogen and progestin dosages and the introduction of new formulations, many of the original estimates may require modification. VENOUS THROMBOEMBOLISM The lowering of the estrogen dose in oral contraceptives is associated with a reduction in risk for venous thromboembolism. For example, a pharmacy-based study demonstrated a dose–response effect with rates of venous thromboembolism ranging from 10 events per 10,000 woman-years for greater than 50-μg estrogen pills to 4.2 events per 10,000 woman-years for less than 50-μg estrogen pills. 4 Little significant new information evolved about oral contraceptive components or dosages until studies published in late 1995 and early 1996 suggested that two of the newer progestins, gestodene and desogestrel, had a greater risk for venous thromboembolism than older progestins such as levonorgestrel. 5,6 As shown in Table 1, use of most oral contraceptives approximately triples one’s risk of venous thromboembolism, although some studies with formulations containing gestodene or desogestrel have shown approximately a seven-fold increased risk compared with nonusers of oral contraceptives. These findings have been discussed in several publications, with concerns being raised about possible sources of bias and confounding and lack of biologic plausibility. 7 It is important to recognize, however, that even with the worst case scenario, the attributable risk annually is approximately 18 additional cases of the disorder per 100,000 users of gestodene or desogestrel containing oral contraceptives compared with nonusers of oral contraceptives. In addition, the mortality caused by venous thromboembolism among oral contraceptive users is quite low. Age does affect mortality; for women age 35 to 44 years, the mortality rates double. In a recent World Health Organization study, obesity and age also were found to be risk factors for venous thromboembolism, although the former is not a consistent finding in all studies. 6 Finally, there is no evidence that smoking or the presence of varicose veins among users of oral contraceptives appreciably affects their relative risk for venous thromboembolism. 6Table 1: Incidence* of Cardiovascular Disease Among Low-Dose Oral Contraceptive†-Users by Progestin Type, Ages 20–24 YearsThe identification of the factor V Leiden mutation in 1993 introduced another consideration about the relation between oral contraceptive use and venous thromboembolism. A single amino acid substitution results in a variant of factor V that is resistant to activated protein-C, which leads to enhancement of clot formation and an increased risk of venous thromboembolism. This mutation, which is known as either factor V Leiden or activated protein-C resistance, has a prevalence in the general population of approximately 5% in US white women, 2.2% in Hispanic women, and 1.2% in black women, making it the most commonly occurring natural anticoagulant deficiency. 8,9 A recent study estimated the risk of venous thromboembolism among oral contraceptive users with factor V Leiden. 8 With the mutation at a prevalence of approximately 5%, the risk for reproductive-aged women who were not using oral contraceptives was 5.7 venous thromboembolism events per 10,000 woman-years. In contrast, among oral contraceptive users with the mutation, the rate increased to 28.5 events per 10,000 woman-years. However the absolute risk of venous thromboembolism among such women is quite low. For example, one investigator determined that screening one million potential users for all known coagulation factor deficiencies or mutations would identify approximately 50 women at risk, but also would result in approximately 62,000 women having false-positive results. 9 STROKE Stroke often is divided into two major categories: ischemic or thrombotic and hemorrhagic. Although earlier studies focused most of their attention on estrogen dose, more recent studies of low-dose oral contraceptives have better recognized the role of confounders and have used more rigorous approaches to both design and analysis, such that current risk estimates are probably more accurate. Iscemic Stroke The risk of thrombotic or ischemic stroke among current users of low-dose oral contraceptives appears to be relatively low. As shown in Table 1, among women age 20 to 24 years, the overall risk among oral contraceptive users is increased by approximately two and one-half-times compared with that of nonusers. 5 There is no evidence that type of progestin influences risk or mortality associated with ischemic stroke. 5,6 The risk of ischemic stroke does appear to be directly proportional to estrogen dose, based on studies completed in developed as opposed to less developed countries. 6 Age appears to be a risk factor relatively independent of oral contraceptive use, with the relative risk of ischemic stroke doubling as women reach age 40 to 44 years. It is unclear in some studies whether this increment actually represents an increased likelihood of the presence of an undetected risk factor such as hypertension. 6 Hypertension, cigarette smoking, and migraine headaches also interact with oral contraceptive use to substantially increase the risk of ischemic stroke. Of importance is the finding in at least three studies that women administered oral contraceptives containing less than 50 μg of estrogen who have their blood pressure checked regularly do not have a significantly increased risk for ischemic stroke. 6 Hemorrhagic Stroke As shown in Table 1, the risk of hemorrhagic stroke in young women is low and is not increased by use of oral contraceptives in the absence of risk factors. 5,6 Although age independently increases the risk in both users and nonusers, there appears to be no relation between the components of oral contraceptives, their dosages, or duration of use and the risk of hemorrhagic stroke. In addition to age, the major risk factors for hemorrhagic stroke are cigarette smoking and hypertension. Smoking increases the risk of hemorrhagic stroke approximately two-fold among non-oral contraceptive users and three-fold among oral contraceptive users. 6 In one study, history of hypertension increased the risk by approximately five-fold among women in Europe who were not oral contraceptive users compared with non-oral contraceptive using women who were normotensive; among women with hypertension in developing countries, the relative risk increased to 9.4. 6 With current oral contraceptive use, in the absence of hypertension, the risk of hemorrhagic stroke is not increased, but with a history of hypertension, the relative risk among users increases to 10.2 in Europe and to 14.2 in developing countries. 6 Overall, for women younger than 35-years-old who do not smoke and who are normotensive, the risk of hemorrhagic stroke is not affected by oral contraceptive use. MYOCARDIAL INFARCTION As shown in Table 1, myocardial infarction is a rare condition among reproductive-aged women. Age influences this risk in an exponential fashion, with the incidence of myocardial infarction increasing to 30 cases per 100,000 annually among women age 40 to 44 years. 5 The presence of other risk factors such as cigarette smoking, hypertension, and diabetes strongly influences the risk of myocardial infarction. The more recent studies of oral contraceptive use and myocardial infarction have shown some increase in risk with oral contraceptive use for those women with risk factors. 6 Thus, as shown in Table 1, although oral contraceptive users overall have some increased risk, it is estimated that 80% of the cases among oral contraceptive users are attributable to cigarette smoking, with the remainder occurring in users with other risk factors such as hypertension or diabetes. There is no increased risk for myocardial infarction associated with increasing duration of oral contraceptive use or with past use. 6 Nonsmoking oral contraceptive users who have regular blood pressure examinations and who do not have diabetes have no increased risk of myocardial infarction. There is no evidence that use of new low-dose oral contraceptives modifies risk for myocardial infraction, although one study has suggested that users of oral contraceptives containing gestodene or desogestrel have a reduced risk for myocardial infarction compared with users of preparations containing the progestin levonorgestrel;10 however, this has not been confirmed in other studies. BREAST CANCER RISK For several decades, there has been concern about the possible association between oral contraceptive use and breast cancer. Unfortunately, many epidemiologic studies reported conflicting results, with the discrepancies probably related to how well potential biases and confounding were addressed in the individual studies. To address the concerns with earlier publications, a meta-analysis of most of the better epidemiologic studies in the literature was published in 1996. 11 A total of 54 studies were included in the analysis, representing 53,297 women with breast cancer and 100,239 control patients. To be included, studies had to have had at least 100 women with breast cancer diagnosed, and the original data had to be available for reanalysis. In all, there were 11 cohort studies, 28 case-control studies with population-based controls, and 15 case-control studies with hospital-based control patients. In addition, approximately one-third of the cancers were diagnosed in women younger than 45-years-old, and approximately one-half had cancer diagnosed after 1985. Figure 1 provides the major findings from this meta-analysis. For current users of oral contraceptives, the relative risk of breast cancer compared with never-users was 1.24. As shown, this small increase in risk persisted for approximately 10 years, but the risk essentially disappeared after that time period. In addition, there was no overall effect of oral contraceptive use by dosage, specific formulation, duration of use, age at first use, age at time of cancer diagnosis, or by family history of breast cancer. The comparison of ever-users of oral contraceptives with never-users revealed that the relative risk for tumors that had spread as opposed to localized disease was 0.88. Thus, although oral contraceptive users have a modest increase in risk of breast cancer, the disease tends to be localized. Also, the pattern of disappearance of risk after 10 years coupled with the tendency toward localized disease suggests that the overall effect may represent detection bias or perhaps a promotional effect. For example, if oral contraceptive users undergo more frequent breast examinations because they are required to see a clinician to get their prescriptions refilled compared with users of other methods, the findings may be because of users having a better chance of earlier detection. A promotional effect would occur if the hormones in oral contraceptives, especially estrogen, cause growth of cells that already have been transformed into a neoplasia, leading to earlier detection. Although most of the available data indicate little concern for most oral contraceptive users relative to breast cancer, an historic cohort study suggests that oral contraceptive use before 1975 among women with a first-degree relative with breast cancer increases one’s risk by approximately three-fold. 12FIG. 1: Horizontal bars are point estimates; vertical bars are 95% confidence intervals. Relative risk calculated versus never-use. Adapted from Collaborative Group on Hormonal Factors in Breast Cancer: Breast cancer and hormonal contraceptives: Further results. Contraception. 1996;54:1s–106s.Compliance and Selected Side Effects A number of authors have examined oral contraceptive compliance in various patient populations during the past two decades. In a study of 1,657 oral contraceptive users completed in the United States, women were surveyed at 2 and 6 after or to the use of a new oral contraceptive Although the results are by the low rate of of the they some about issues that affect oral contraceptive to one’s at the time having a and not the information were associated with missing two or more pills per the before was associated with the risk of missing pills during a and or also were associated with missing pills during a Overall, in this study, of oral contraceptive users reported missing one or more pills during a and two or Side effects were the most important women using oral contraceptives in this of women their preparation for this this increased to to for some side is included in the was the side effect most frequently as being associated with oral contraceptive side effects included nausea, and breast was the finding that among study who to oral contraceptives but not to no and approximately selected a less or Although the of to the study to be into approximately of women who were oral contraceptive users and approximately of women to another oral contraceptive had by the of the among all women who to oral contraceptive use, first their of recent data the frequency of side effects among users of newer formulations indicate that the estrogen dose some but not all For example, a a ethinyl estradiol and preparation with a ethinyl estradiol preparation demonstrated an incidence of bleeding during 6 of among those using the oral compared with a of among those using the oral Another a ethinyl estradiol a ethinyl estradiol with 10 μg during days desogestrel and a ethinyl estradiol preparation demonstrated in particularly for the but with control for all preparations by 6 of use. 15 This also and breast was in of all users, but by 6 approximately of those using ethinyl estradiol versus approximately of those using breast was in a of by 6 approximately of users of ethinyl estradiol the compared with approximately among the users of the pill. Thus, it appears that the dose of estrogen reduces the frequency of side effects for the most is less in Health There are a number of noncontraceptive associated with oral contraceptive use. This section reviews some of the major reported including such as and cancer. Although not a noncontraceptive has important on a number of epidemiologic studies, oral contraceptives an approximately reduction in risk of pregnancy. The likely is of an effect that all types of and that be with low-dose oral contraceptives as RISK CANCER Although ovarian cancer is relatively it has a case least case-control studies and three cohort studies have examined the relation between oral contraceptive use and ovarian cancer. but two of these studies have shown a effect for oral contraceptives. There appears to be a overall in risk among users, with approximately 1 after use, with a annually in risk for of use. In addition, between 15 to 20 years after oral contraceptive There are also data to suggest that oral contraceptive use reduces the risk of ovarian cancer among women who are at for the A recent study that this with the use of the newer low-dose oral contraceptives as data from one study also suggest that oral contraceptive use may women with the or however, this study is by its small 18 The by which oral contraceptives may their effects include of in a reduced frequency of to the ovarian and the of Although the is data about how are associated with ovarian cancer in and that have been shown to some ovarian cancer RISK CANCER cancer is more than ovarian cancer, and the rates are least 11 case-control studies and one cohort study have demonstrated that use of oral contraceptives endometrial cancer. Overall, the studies suggest to a reduction in risk approximately 1 after of use, that increases with duration of use, and that to 20 years after oral contraceptive use is has been demonstrated for and The effect in studies for women with potential risk factors such as obesity and The of is likely reduction in the of endometrial cells because of effects. current low-dose preparations use progestins that have the endometrial effects as older this effect is likely to occur with their use as A number of epidemiologic studies that use of oral contraceptives will reduce the risk of by compared with the risk to women not using or who use a there is no effect the of including and of the The for include and increased of cervical that of is substantially include reduced in less to the an less likely to growth of and possible changes in that the of current oral contraceptives these effects, it is likely they also will BREAST The results of several studies a in the incidence of with oral contraceptive use. 20 of is decreased among women younger than age These effects are in current and recent users of oral contraceptives. The likely is of ovulation and of the breast that in the first of a This effect to be with the estrogen of 30 to 35 although the effect may not be as significant with the newer in which more frequent or increased of progestins may improve the risk Oral contraceptive use also has been demonstrated to the incidence of studies have the effects of current low-dose oral contraceptives on and a demonstrated that women with bleeding using a ethinyl estradiol oral contraceptive an in bleeding during 3 compared with a in the 21 As a of it is that the combination of estrogen and progestin in oral contraceptives essentially the with the progestins in oral contraceptives are they are in their effect on endometrial Although there is information about oral contraceptives as for a number of their Oral contraceptives likely the by the of leading to less endometrial and and by RISK are the most and are found in to of women. of a reduced risk of in oral contraceptive users, a case-control study from found no relation between oral contraceptive use and risk of these estrogen do appear to the incidence of such that the effect may be in Oral contraceptive use also has been shown to reduce blood in women with The frequency of ovarian among oral contraceptive users is on the dosages in oral contraceptive Although the data are there is a that contraceptives, 50 μg or greater of ethinyl In contrast, current formulations appear to have no effect on ovarian 3 It is important to that many of the recent studies this use of as opposed to in which some type of may be many of these in such studies with Thus, it appears that current low-dose oral contraceptives reduce the frequency of ovulation but may early of that do not to the of ovulation. during a demonstrated that approximately one-half of women demonstrated of their a containing the progestin approximately of women a preparation also Overall, the rate to the oral contraceptive in these two studies is to that by women using agents such as or or There are several of by which oral contraceptives reduce Oral contraceptives increase the of which in turn and suppress both of these effects reduce of ovarian In addition, it appears that progestins also have the to which is to to at the of the in women between the of 20 and years, for approximately 10 years, and in the years. studies have revealed a effect on and studies no effect on among oral contraceptive users. studies have demonstrated a effect on a population-based control study revealed a reduction in It appears that oral contraceptives are most during of low estrogen and with increased duration of use. on by increasing and directly of the estrogen of oral contraceptives is for these effects, it is that this would be with the RISK CANCER There is epidemiologic evidence that oral contraceptives may women from having cancer in There have been several case-control studies and at least one cohort study that have demonstrated a effect cancer in ever-users of oral contraceptives 28 In some studies, this effect appears to be directly proportional to duration of use, although this has not been a consistent finding in all studies. there are other studies that no effect of oral contraceptive use on the of this The of for this possible effect is essentially although some that oral contraceptives this by acid and by by having a effect on or by having some type of most of these findings are related to use of oral contraceptives, it is unclear whether users of preparations will effect. RISK studies published before suggested a reduction in the risk of in oral contraceptive users. More a meta-analysis a studies found no evidence of a effect of oral contraceptive use, one other potential of with current oral contraceptive use. The cause of the disease is although most it among the hormones in interact with a disorder with this type of cause is the past decades, oral contraceptives have a safe and method of in the estrogen and progestin dosages have significantly decreased the incidence of cardiovascular The association between oral contraceptives and breast cancer appears to be primarily because of detection bias or a promotional effect. the changes in formulation, the problems related to side effects have not been compliance and use is strongly affected by side effects, in this is probably the by of oral contraceptives. It is also that there are a number of significant noncontraceptive that in oral contraceptive users. Unfortunately, many women do not about these benefits. Thus, one of the issues that to to address is how to better information about oral contraceptives and in general to patients.