5B.1 Epidemiology of hormonal therapy related thrombosis

Abstract

In this abstract some additional background data are provided for the presentation during the symposium. Venous and arterial thromboses have different risk factors [1] (see Table 1). There are single preparations that only contain a progestin or progestogen (progestogen-only contraceptives, POC), which also can be orally, subcutaneously, intramuscularly (depot) and intrauterinely (levonorgestrel containing IUD) administered. The levonorgestrel containing IUD acts predominantly locally. The contraceptive action is mainly due to the progestogen component by suppressing the luteinizing hormone (LH) that thus prevents the ovulation process. Nowadays the estrogen is added to the progestogen in order to avoid blood loss during the cycle (spotting and breakthrough bleeding), which often occurs in POCs or combination preparations with a very low estrogen content. Avoiding intermenstrual blood loss during hormonal contraception increases compliance and restrains pregnancy failure. Combination preparations are by far the most used. Since oral contraceptives first became licensed in 1959, the estrogen dose has been reduced. Early preparations contained 150mg mestranol or ethinylestradiol (EE2), the latter is currently used in virtually all combination preparations. Ethinylestradiol is a synthetic, slightly altered version of the naturally occurring estradiol, which is inactive when taken orally and becomes effective after the liver passage. The dose of EE2 has been stepwise reduced over the years, and nowadays most preparations contain 50mg (nearly used) or generally 30mg EE2, while some recently introduced brands hold even less, i.e. 20 or even 15mg EE2. The chemical composition of the progestogen content rather than the dose has also changed over time. In historical perspective three generations of progestogens have been categorized. Henzl and Edwards [6] provided the chemical base for this classification. Early preparations contained lynestrenol or norethynodrel, derivatives of norethindrone or nethisterone (testosterone like steroids) that are also known as first-generation progestogens or estranes, and are still used in short term (12 days) treatments, but not much in combined oral contraceptives anymore. Second-generation progestogens are gonanes, include norgestrel and levonorgestrel, of which levonorgestrel is widely used. Third-generation progestogens, which have the same basic steroid molecule as the gonanes, are desogestrel and gestodene. Both are also widely prescribed, despite their increased venous thrombogenicity [7], if combined with EE2. Finally, some progestogens are difficult to classify: norgestimate is categorized as a third-generation gonane, but because after uptake it is in part rapidly converted to levonorgestrel, it may metabolically belong among the second-generation progestogens. Two substances used in oral contraceptives in combination with an estrogen need to be treated separately, since they are not classified in a generation. First, cyproteronacetate (CPA; a gonane skeleton with extra carbons on the 17, 18 and 19 positions and designated as pregnane, consisting of in total 21 carbons) a derivative of progesterone, is also used for treatment of acne vulgaris, seborrhoea or mild hirsutism, however not more effective than other COCs [8 10]. Secondly, drospirenone (DRSP) is an anti-mineralocorticoid with anti-aldosterone effects [11,12). In combination with ethinylestradiol, CPA and DRSP have similar thrombogenic characteristics as thirdgeneration progestogens [13]. Finally, I mention the pregnanes, medroxyprogesteron used in depot form and the recently introduced chlormadinone acetate predominantly used in combination with EE2 [8,12].