What Kind, When, and for Whom?
Background: In Germany today, one-third of the 20 million women of child-bearing age use combined oral contraceptives (COCs). In this article, we summarize the current knowledge of the mode of action, wanted and unwanted side effects, and long-term risks of COCs. The levonorgestrel intrauterine device (IUD) and long-acting injectable or implantable monophasic progestogen preparations offer comparable contraceptive efficacy to COCs. Nonetheless, they are less frequently used in Germany than COCs, because of their propensity to cause breakthrough bleeding.
Method: Selective review of the literature.
Results: COCs suppress gonadotropin secretion and thereby inhibit follicular maturation and ovulation. Their correct use is associated with 0.3 pregnancies per 100 women per year, their typical use, with 1 pregnancy per 100 women per year (Pearl index). COCs have effects on the cardiovascular and hemostatic systems as well as on lipid and carbohydrate metabolism. When given in the presence of specific risk factors, they significantly increase the likelihood of cardiovascular disease and thromboembolism. Women with persistent human papilloma virus (HPV) infection who take COCs are at increased risk of developing invasive cervical cancer. On the other hand, COCs lower the cumulative incidence of endometrial and ovarian cancer by 30% to 50%, and that of colorectal cancer by 20% to 30%. Other malignancies seem to be unaffected by COC use.
Conclusion: As long as personal and familial risk factors are carefully considered, COCs constitute a safe, reversible, and well-tolerated method of contraception..
Hormonal contraceptives are among the most reliable reversible methods of contraception (Table 1 gif ppt) (1). Their composition, dosage and usage varies, leading to differing rates of risk, side effects and advantages. The wide range of available preparations offers individual choice, tailored to a woman’s priorities regarding effectiveness, cycle control, side effects and risks, as well as therapeutic and preventive effects.
It was 50 years ago in 1961 that the first hormonal contraceptive was introduced to the German market. Today, a third of Germany’s 20 million women of reproductive age take a combined pill (e1), while other hormonal methods such as the progestagen only pill (POP), the levonorgesterol-bearing intrauterine device (IUD), and transdermal and vaginal contraceptives, play a lesser role.
For this reason, this article will focus solely on combined oral contraceptives. It should however be noted at this point that the IUDs, long acting progestagen-only implants and injectables—containing 104 or 150 mg of medroxyprogesterone acetate, 200 mg norethisterone enantate or 68 mg etonorgestrel respectively—offer equal contraceptive efficacy (ideal use). They are also associated with reduced thrombotic risk due to the absence of an estrogen component which reduces the effect on the clotting system, but bleeding abnormalities are commoner than with combined oral contraceptives, especially at the beginning of treatment.
The learning objectives for the reader are:
- to increase awareness of the mode of action and contraceptive efficacy of the combined pill
- to understand and assess its risks and side effects
- to be aware of the additional uses and indications for combined hormonal preparations.
This review article is based on a selective review of the literature.
Composition of combined oral contraceptives
Combined oral contraceptives (COCs) consist of a combination of estrogen and progestagen. Most preparations are taken daily for 21 days, followed by a seven day break (hormone-free interval or pill-free interval, PFI) during which a withdrawal bleed occurs two to three days after the last tablet taken (conventional regimen, 21/7) (Figure 1 gif ppt). Ethinylestradiol (EE) is the estrogen used in almost all preparations, with the exception of one which uses estradiol valerate. These are combined with one of a variety of synthetic progestagens (eTable 1 gif ppt) (2) (e2–e4).
To minimize the risk of serious side effects such as thromboembolic events, only low dose preparations, so-called micro-pills with 15–35 µg EE, or else the combination with estradiol valerate, should be prescribed routinely. Because the progestagens vary as to their efficacy and spectrum of action, the daily doses of these varies considerably (eTable 1).
Monophasic combined pills contain constant daily doses of contraceptive steroids, while biphasic or triphasic preparations have a daiy dose which varies in a stepwise fashion (Figure 1) (e4). During the pill-free interval, follicular maturation begins due to the loss of pituitary suppression via the contraceptive steroids. This is then suppressed once more in the course of the first week of the new pill cycle (e2, e4). The contraceptive vaginal ring and patch work like oral combined preparations, with a 21 day hormone phase and a seven day pill-free interval, during which a withdrawal bleed occurs. Their efficacy, side effect profile and hepatic effects are broadly equivalent to those of low dose oral contraceptives.
Method of action
The contraceptive effect of the COCs depends primarily on the suppression of gonadotrophin release. This leads to the arrest of follicular maturation, of the preovulatory luteinizing hormone surge, and of ovulation. Most COCs have a progestagen dose which is significantly above the threshold for ovulation suppression (eTable 1), so that even without the estrogen component, the contraceptive effect would be achieved. Additional effects include the peripheral action of progestagens on cervical mucus, tubular function and the endometrium. However, cycle control depends on the effects of the estrogen component (e2, e4).
The efficacy of a method of contraception is represented using the Pearl Index (PI), i.e. the number of unwanted pregnancies per 1300 cycles of use (100 woman-years) (e5). User errors and compliance problems lead to an increase in the Pearl Index. With ideal use (no missed pills), the PI is around 0.3 (Table 1) (1, 3). However, half of women miss at least one and a quarter at least two pills per cycle (actual use), which raises the PI (4). The failure rate of COCs appears to be somewhat lower (PI around 1) in Europe than the USA (PI around 8) (Table 1) (3, 5). This may relate to more careful instruction in reliable use, or to differing attitudes to safe contraception between European and American women (e6). The risk of pregnancy is highest when pills are missed at the beginning of the first week of pills, or the end of the last one, because these prolong the pill-free interval during which follicular maturation resumes. Appropriate measures to prevent unwanted pregnancy where pills have been missed are presented in Figure 2 (gif ppt) (6, e7). These measures apply only to monophasic combined preparations taken conventionally, i.e. for 21 days with a 7 day pill-free interval. With mistakes using the following preparations, these measures must be adapted accordingly (6):
- where the pill-free interval is shorter than seven days
- where the preparation uses placebo tablets in the pill-free interval
- where the route of administration is vaginal or transdermal
- with progestagen only methods.
COCs with 20 µg EE per day are as effective as ≥30 µg preparations, since ovulation inhibition depends primarily on the progestagen component (e8). Extending the pill cycle from 21 to 24 days (24/4) increases the suppression of follicular maturation and hence allows for a dose reduction in the contraceptive steroids (3). The use of extended cycle regimens with a seven day PFI after for example 84 days (84/7), or continuous COC use, suppress ovarian function even more effectively. The number of withdrawal bleeds is also reduced, which many women view positively (Figure1) (7, e9).
The efficacy of the COC can be compromised by gastrointestinal disturbance or antibiotic use (e10). Although a recently published study found no influence of antibiotics (e11), the recommendation is still to use additional, alternative methods of contraception (barrier methods) during antibiotic use and for a further seven days.
Intercurrent use of liver enzyme inducing medications such as rifampicin and rifabutin can reduce the efficacy of hormonal contraceptives. By contrast, oral contraceptives can also influence the efficacy of other medications. Hence COC administration can reduce serum levels of lamotrigine resulting in increased seizure risk, with a subsequent rise in the pill-free interval (8, e12). Extended cycle or continuous use of the COC can avoid these fluctuations.
Side effects and risks
Hormonal contraceptives affect the whole body and some of these effects are beneficial or therapeutic (Box gif ppt) (9, e13). On the other hand, unwanted drug effects can represent a health risk, depending on a woman’s pre-existing risk factors. The majority of side effects reported during COC use are equivalent in frequency to those reported in placebo groups (e14–e16).
Hormonal contraceptives affect cardiac function, the circulation, blood pressure, fat and carbohydrate metabolism and blood clotting, and have direct effects on the vascular wall. In the presence of pre-existing cardiovascular risk factors, the COC can increase the risk of vascular disease.
The incidence of venous thromboembolic disease (VTE) in healthy women of reproductive age is very low, at around 4 to 5/10 000 women per year (10). COC use alters clotting factors and fibrinolysis via its effect on liver metabolism, and can lead to a reversible activate protein C resistance (e17). These effects contribute to an increased VTE risk with COC use of 9 to 10/10 000 woman years, a risk which is proportionate to the estradiol dose, and highest at the beginning of treatment. By comparison, this risk during pregnancy is around 29/10 000, and in the postpartum period, around 300–400/10 000 woman years (e18–e20).
There is a suggestion that the progestagen component modifies the estradiol related VTE risk. Desogestrel, gestodene and cyproterone acetate are associated with a higher risk than levonorgestrel-based COCs (11). There are however contradictory data on this point (e21). Additional factors which further increase the risk of VTE during COC use include age, high BMI, immobility, vasculitis and smoking, while moderate alcohol consumption reduces the risk (e22, e23). The contraceptive patch carries a higher VTE risk than other contraceptives, presumably due to its heavier estradiol burden on the liver, while the vaginal ring carries similar risks to those of oral preparations (e4, e24). The presence of a positive family or personal history of thromboembolic disease, or of genetic or acquired thrombophilia, increases baseline VTE risk significantly, a risk which is increased still further with COC use. Hence a woman with a heterozygous Factor-V-Leiden-Mutation (prevalence of around 5%) or a perthrombin mutation has a 7- to 10-fold VTE risk with COC use (12). Nevertheless, general screening for these conditions has not been found to be cost effective (1, e17, e25, e26). In order to prevent one venous thromboembolic event, around 8000 women would need to undergo screening, of whom 400 would stop taking the COC (13, e27).
Where surgical procedures with a high thromboembolic risk are planned, the COC should be discontinued four to six weeks preoperatively in order to normalize clotting. By contrast with the COC, progestagen only methods (progestagen only pill/POP containing levonorgestrel or desogestrel, or the levonorgestrel-bearing IUD), appear not to increase this risk (1, 11, e28).
The increased risk of myocardial infarction in young women taking the COC is marginal. Additional risk factors such as age, hypertension, smoking, diabetes, hyperlipidemia, and high BMI must also be taken into account (14, e4, e26, e29) (Table 2 gif ppt). Progestagen only methods appear not to affect the risk of myocardial infarction. (e30).
The risk of ischemic stroke is extremely small in young women, but rises with a history of focal migraine (15, e26, e31, e32). COC use doubles this pre-existing risk, and smoking increases it seven fold (e33) (Table 2). COC does not affect the risk of hemorrhagic stroke.
Benign liver tumors
Focal nodular hyperplasia (FNH) is a rare, benign disease (with a prevalence of 0.4% to 3% in the general population), which is usually diagnosed in asymptomatic women and is rarely associated with complications (e34–e36). It is questionable whether COC affects the severity or prevalence of FNH (e37, e38). If FNH is diagnosed during treatment with a low dose COC, it is reasonable to continue treatment with regular monitoring of the lesion(s) (Table 3 gif ppt) (1, e38).
Hepatocellular adenomas are extremely rare in young women, including long term low dose COC users (prevalence: 3 to 4/100 000) (16, e34, e39). The risk appears to depend on duration of use and the EE dose (e40, e41). If hepatocellular adenoma is diagnosed during treatment with a COC, COC treatment should be discontinued (Table 3). No association has been found between COC use and the incidence of meningioma and prolactinoma.
Carcinomas and mortality
Reproductive factors can influence the incidence of a number of malignancies. For example late menarche, early menopause and prolonged breastfeeding are associated with a reduced risk of breast cancer. Two large cohort studies have shown that the COC—with the exception of invasive cervical cancer—are not associated with any increased risk of cancer (eTable 2 gif ppt) (17, 18).
Numerous recent studies have concluded that the COC has either no, or a marginal, influence on breast cancer risk (eTable 3 gif ppt) (17–20, e42–e46). The absolute risk is very small. For example, if women aged 25 use the COC for five years, there will be just five extra breast cancers per 10 000 women during the following 10-year period (49 instead of 44). Most of these would be local, non-metastasized tumors. The increased risk disappears within ten years of discontinuing the pill (19). Even in women with BRCA1 and BRCA2 mutations, either no risk increase or an extremely small risk increase was found (20, e47, e48). Progestagen only methods (progestagen only pill, depot-medroxypergesteronacetate and the levonorgestrel bearing IUD) also have but a small effect (e49).
The cumulative incidence of ovarian cancer in women under 75 is 1.2% and is reduced by the COC in proportion to the length of treatment by 30% to 50%. This protective effect persists for many years after discontinuation (eTable 2) (17, 18, 21, e50, e51). The same is true for women with BRCA1 and BRCA2 mutations (e47). The incidence of endometrial cancer is also reduced with COC use to a half. The risk reduction correlated with the duration of use and persists after discontinuation for at least 15 years (e52).
COCs increase the risk of cervical intraepithelial neoplasia (CIN), in proportion to the duration of use, with a doubling of risk after five years and a quadrupling after 10 years. However, only women with persistent HPV infection are affected (e53). It appears that the progestagen component promotes the progression of cervical dysplasia. Regular cervical cytology allows early detection of these CIN lesions, while immunization, especially prior to first sexual intercourse, provides protection from HPV. HPV infection is also involved in the development of vulval and vaginal cancer, but the COC appears to have no influence on these.
COC use significantly reduces the risk of colorectal cancer by 20% to 30% (16, 17, e54, e55). The potential role of COC in the development of hepatocellular carcinoma is as yet not established, but the absolute risk of this illness is extremely small (16, e56).
No effect was found for COC use on thyroid, bronchial, esophageal, gastric, pancreatic carcinoma, or on cholangiocarcinoma, renal cell carcinoma, neuroblastoma, melanoma or Hodgkin’s’ and Non-Hodgkin’s’ lymphoma (16–18, 22, e52, e57, e58).
Mortality is by no means increased in women who have taken the COC, if anything it is reduced (22, 23). The positive effect is largely due to a reduction in cancer related mortality and ischemic heart disease (eTable 4 gif ppt). There was however an increase in mortality in pill users under 45 due to vascular disease. (31 versus 14 cases per 100 000 women per year). This emphasizes the relevance of taking a careful history including family history of vascular risks prior to prescribing the COC.
Implications for practice
COC use does not overall increase cancer risk. On the contrary, two cohort studies found that in pill users, 10 to 45 fewer women developed cancers overall, and mortality was reduced by 52 cases per 100 000 women per year (17, 23).
Additional effects and indications for oral contraceptive use
In addition to their contraceptive effect, COCs have numerous additional benefits which can be used therapeutically (Box). Around 10 % of women of reproductive age suffer from menorrhagia (uterine blood loss of >80 mL/period), affecting particularly older women (e59, e60). In these women, blood loss is reduced by at least 50% (e61). For this reason the pill has long been used as a treatment for menorrhagia. At the end of last year, “treatment of heavy periods” was added as an indication for a specific COC preparation in Germany.
Up to 90% of all young women suffer from dysmenorrhea, which is usually caused by strong uterine contractions (e62). The use of the combined pill leads to a significant improvement in up to 80% of women (e13, e63–e66). A particularly useful strategy is to use an extended cycle or continuous regimen—omitting the pill free interval—to produce amenorrhea. Progestagen implants and the levonorgestrel bearing IUD also have a beneficial effect on dysmenorrhea, although they can be associated with irregular bleeding (e67–e71).
At least 10 % of all women of reproductive age and a large proportion of patients with chronic pelvic pain have endometriosis. The associated symptoms can be treated using continuous or extended cycle use of monophasic COCs (e72). After surgical treatment of endometriotic lesions, COC treatment can offer a long term reduction in disease and symptom recurrence (7, e72–e74).
Women with a fibroid uterus, many of whom suffer menstrual irregularities and dysmenorrhea, often benefit from COC use, particularly extended cycle use. Fears about promoting fibroid growth with COC use appear to be unfounded (e75–e79), although there is a suggestion that COC use in early adolescence (age 13–16) can lead to an increase in their incidence (e80).
COCs are frequently used to treat acne and hirsutism. Their beneficial effect is primarily due to a reduction in ovarian and adrenal androgen production, an increase in sex hormone binding globulin (SHBG) levels, and a reduction in free testosterone. The effect of antiandrogenic progestagens is probably responsible for only a small part of the effect.
Premenstrual syndrome (PMS) is characterized by affective disturbances (irritability, anxiety, aggression, low mood), which are often associated with vegetative symptoms (abdominal distension, headache), weight gain and fluid retention. These symptoms arise in the mid to late luteal phase, and disappear in the first days of menstruation (e81). COC use can reduce the intensity and frequency of individual symptoms, especially with a shortened pill-free interval (24/4), or using an extended or continuous regimen (e82, e83).
Contraception in women over 40
Although fertility is reduced in women over 40, effective contraception is still needed at this age where most women have completed their families, particularly given the increased miscarriage and anomaly risk, as well as increased maternal risks, in this age group (e26). Healthy, low risk women can use all forms of contraception until the menopause (Table 3) (9, e26, e61, e84). Many perimenopausal symptoms can also be improved by COC use. Examples include irregular cycles and other menstrual problems, vasomotor symptoms, loss of bone mineral density, PMS, functional ovarian cysts, bleeding disturbances, or dysmenorrhea (e73, e85). Before commencing treatment, a careful individual risk assessment must be made in order to minimize the risk of harms in this age group already at increased risk (e22, e26). In the presence, for example, of high BMI, smoking, hypertension, diabetes or migraine the COC is contraindicated, and alternative methods should be used.
Fertility following COC discontinuation
The cumulative pregnancy rates of 83% within six months and to 94 % within a year are similar for the COC to figures found with the offset of barrier methods (e86). Long term COC use appears to improve fertility, possibly via protection against ascending genital infection.
There have long been efforts to develop and estradiol based pill, as this estrogen has significantly reduced hepatic effects compared to ehinyl estradiol. However, these attempts have mostly failed due to poor cycle control, as estradiol is broken down in the endometrium far more rapidly than ethinyl estradiol, leading to a higher rate of breakthrough bleeding. Since 2009, the first contraceptive with estradiol valerate has been licensed. Using a complex dosage regimen, efficacy and breakthrough bleeding rates comparable with those of a 20 µg EE pill have been achieved (Figure 1). However, there is an approximately 20% rate of
so-called silent periods—i.e. the lack of a withdrawal bleed (e87–e89). It is possible that fewer serious complications will arise due to the reduced hepatic effects of estradiol, however as long term data are lacking, the contraindications currently remain as for other COCs.
Continuous use of the monophasic COC without a pill-free interval can defer withdrawal bleeding indefinitely. This benefits not only women suffering menstruation-related symptoms, but also women who wish to avoid bleeding for long periods of time for quality of life reasons (7, e9, e90). Although there is in Europe no licensed long term preparation, there is widespread experience with off label long term use (24).
Pill with folate
The prevalence of fetal neural tube defects (NTD), in Germany around 3/10 000 live births, or 9/10 000 pregnancies (e91, e92), can be reduced using preconceptual folate. It is recommended that all women planning pregnancy should take folate (0.4 mg/day) from several weeks prior to conception. The use of a COC with metafolin increases long term folate levels, providing protection in the event of conception shortly after discontinuing the COC. Modelling studies suggest that this might prevent around 600 cases per year, albeit there is currently no folate based pill available in Europe (e93).
Emergency contraception (interception)
Interception is a short acting method of preventing pregnancy where regular contraception has failed or on other particular circumstances. Post coital oral contraceptives are progestagen only methods, containing levonorgestrel (LNG), or a selective progestagen receptor modulator, ulipristal acetate (UPA).
The postcoital contraceptive with 1.2 mg LNG should be used as soon as possible, but at the latest 72 hours after unprotected sex. Their use reduces the unwanted pregnancy rate by 75% to 85%, but the contraceptive efficacy reduces with increasing time interval from unprotected sex (e94–e97). Its use at the time of implantation has no further contraceptive effect, and it does not interrupt an implanted pregnancy (25, e98, e99). The only absolute contraindication is pregnancy, although no teratogenic effects have been demonstrated to date (e100).
The postcoital pill with 30 mg UPA should also be used as soon as possible, but at the latest five days (120 hours) after unprotected sex. Compared with 1.5 mg LNG, 30 mg UPA was found in a meta-analysis to be associated with a significantly reduced pregnancy rate (1.4% versus 2.2%) (e101, e102). The frequency of side effects is comparable for both preparations.
Reliable interception can also be achieved via the insertion of a copper bearing intrauterine device (IUD) within five days of intercourse, which also offers ongoing contraceptive protection (off-label-use) (e4, e103). The pregnancy rarte is around 0.2%
Conflict of interest statement
Perf. Wiegratz has received honoraria for consultancy services from Bayer Healthcare. She has received travel and congress attendance expenses from Serono, Essex and Jenapharm. She has received honoraria for giving scientific lectures and attending expert meetings from Jenapharm GmbH & Co. KG, Bayer Schering Pharma AG, Dr. Kade/Besins Pharma GmbH, Essex Pharma GmbH, and Merck Serono GmbH. She has received honoraria to support clinical studies from Jenapharm and Bayer Healthcare.
Prof. Thaler has received honoraria for consultancy services from Wyeth, Pfizer, MSD and Bayer Healthcare. He has received honoraria for services as a reviewer from MSD and Sandoz. He has received payments in respect of travel and accommodation expenses from MSD, Wyeth, Jenapharm, Bayer Healthcare, Merck-Serono, and Ferring. Prof. Thaler has received honoraria for conducting clinical studies from Pfizer. He has received financial support for research projects into a designated account, from MSD, Merck-Serono, Baxter, and Ferring.
Manuscript submitted on 9 April 2010, revised version accepted on 20 June 2011.
Translated from the original German by Dr. Sandra Goldbeck-Wood.
Prof. Dr. med. Inka Wiegratz
Klinik für Frauenheilkunde und Geburtshilfe
Schwerpunkt Gynäkologische Endokrinologie und Reproduktionsmedizin
Klinikum der Johann Wolfgang Goethe-Universität Frankfurt
60590 Frankfurt am Main, Germany
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