Spontaneous occurrence of thrombosis is rare in young individuals. The risk increases with age and in women not taking hormone preparations is 2 per 10 000 per year in the 15–19 year age group and 7/10 000/y among those aged 45–49 years (1). Taking ethinylestradiol (EE)-containing combined oral contraceptives (COCs) of all generations undoubtedly increases the baseline risk. The risk increase depends primarily on the dosage of the EE component, but also that of the progestogen component. With regard to the influence of the combination of estradiol valerate and dienogest on the risk of thrombosis, data are so far lacking; for this reason this preparation was omitted from the following discussion.
Important desired and undesired effects of any COC depend on the estrogen dosage. Compared with preparations containing 30–35 µg EE, the thrombosis risk is 40% lower for a dosage of 20 µg and 60% higher for a dosage of 50 µg (2). In spite of this, combinations containing 30 µg EE remain the medication of choice for many women, including very young women, because of the poorer cycle control with 20 µg EE preparations. In view of the dose-dependent procoagulatory effects of EE, patients with a raised risk of thrombosis should be prescribed a gestagen mono-preparation.
According to what is currently known, progestogen only therapy probably does not affect the risk of thrombosis (1). However, progestogens may modify the EE-induced increase in the thrombosis risk. Many studies have shown that differences exist for the different progestogens. COCs containing levonorgestrel (LNG), for example, double the baseline risk. Compared with EE/LNG combinations, the risk for combinations containing gestodene (GSD), desogestrel (DSG), and cyproterone acetate may be raised by up to 80%. Study results are contradictory regarding combinations containing drospirenone (DRSP); this is the reason why we did not explicitly include DRSP in our article (3, 4, 5, 6). Although it is indisputable that the absolute risk is low for all COCs, COCs are contraindicated in patients with relevant increases in the individual thrombosis risk—independently of the progestogen component involved.
Gundert-Remy and Stammschulte cite a report from the European Medicines Agency (EMA), which categorizes the risk for DRSP preparations as higher than that for LNG preparations, and compared with GSD- or DSG-combinations, the risk is reportedly similar (exact wording: “… may be similar”). Furthermore the EMA explicitly points out that the absolute risk is low and that there is thus no reason to stop taking EE/DRSP combinations.
The concluding question is whether on the basis of the available data all women should be treated primarily with EE/LNG preparations. Since the progestogen LNG exerts partially androgenic effects, patients with a predisposition may develop undesirable adverse effects when taking EE/LNG preparations—such as acne or seborrhea. The combination also seems to lack benefit in women who already have symptoms of androgenization and therefore require a COC with an anti-androgenic progestogen. Women who have premenstrual dysphoric disorder (PMDD) have been found to benefit from taking EE/DRSP with a shortened hormone-free interval.
On this background of the very low incidence of venous thrombosis we think it is acceptable to prescribe, without further restrictions, the individually best tolerated COC to healthy young women without risk factors. General thrombophilia screening before prescribing COCs—of whatever generation—is not justified as its cost-benefit profile is not favorable, and no specialist professional society therefore recommends such screening.
What is far more important is to take a detailed history and undertake a thorough examination to assess risk factors before issuing the first prescription, and annual regular controls afterwards. Furthermore, all women—especially those about to be issued with their first ever prescription—should receive comprehensive information about the possible symptoms of thrombosis and pulmonary embolism, to ensure that they seek medical treatment immediately should such an event occur. Additionally, the women should be informed that the risk of thrombosis is substantially higher during the first 3–6 months of treatment than in the time afterwards. Women with relevant risk factors should not receive any COCs, not even those of the so-called second generation.
Because of space restrictions we were not able to discuss in detail the use and risks associated with progestogen only preparations, even though they are the preferred option in certain risk groups. The same is the case for individual side effects of the pill for which satisfactory epidemiological data are lacking.
Prof. Dr. med. Inka Wiegratz
Klinik für Gynäkologie und Geburtshilfe
Schwerpunkt Gynäkologische Endokrinologie u.
Klinikum der Johann Wolfgang Goethe Universität Frankfurt
Prof. Dr. med. Christian Thaler
Hormon und Kinderwunschzentrum, Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Klinikum der Ludwig-Maximilian-Universität München, Campus Großhadern.
Conflict of interest statement
Professor Wiegratz has received honoraria for acting as an adviser from Bayer Healthcare. She has received travel expenses and conference participation fees from Serono, Essex, and Jenapharm. She has received honoraria for scientific presentations and expert meetings from Jenapharm, Bayer Schering Pharma, Dr Kade/Besins Pharma, Essex Pharma, and Merck-Serono. She has received honoraria for conducting commissioned clinical studies as third-party funding from Jenapharm and Bayer Healthcare.
Professor Thaler has received honoraria for acting as an adviser from Wyeth, Pfizer, MSD, and Bayer Healthcare. He has received honoraria for acting as an expert consultant from MSD and Sandoz. He has received travel expenses and hotel expenses from von MSD, Wyeth, Jenapharm, Bayer Healthcare, Merck-Serono, and Ferring. He has received funding for a research project into a third-party funds account from MSD, Merck-Serono, Baxter, and Ferring.
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