Ovulationshemmer: Die Bedeutung der Östrogendosis

Abstract

The large prospective studies on adverse effects of oral contraceptives have unanimously revealed an increased risk of thromboembolic diseases, which seem to be associated with the dose of ethinylestradiol (EE). According to the recommendations of several medical committees, the dose of EE has, therefore, been more and more reduced; in some countries there are now ovulation inhibitors containing 20 micrograms EE. Since serious reactions, which have a relatively low incidence, are highly underreported (less than 10%), it is difficult to prove dose-dependent differences in the rates of cardiovascular diseases. There is, however, virtually no doubt that not only the incidence of thromboembolic diseases and stroke, but also that of benign liver tumours and gall bladder diseases is increased in relation to the EE-dose. A series of metabolic serum parameters, e.g. serum binding proteins, coagulation and fibrinolysis factors, angiotensinogen, is changed by EE in a dose-dependent manner which is, however, limited when the effects are receptor-mediated. Higher doses of EE have been shown to facilitate fibrin deposits on vascular subendothelium. The pharmacological effects of EE are to a large extent dependent on the dose, e.g. the irreversible reactions of EE and other ethinylated steroids with hepatic enzymes which are involved in the metabolism of steroids, drugs and toxic compounds. After long-term treatment with combinations containing 50 micrograms EE, in half of the women, abnormal liver function tests with pathological morphological alterations have been found. As combinations with low EE doses and a sufficiently effective progestogen component do not differ from higher dosed oral contraceptives in their contraceptive safety and cycle control, there are no indications for pills containing 50 micrograms EE, except the normophasic sequential preparations for women with sustained irregular bleedings when taking low dose combinations.

Inhibiting effect of ethinylestradiol/levonorgestrel combination on microsomal enzymatic activities in rat liver and kidney

“…Steroid metabolism leads to the formation of reactive derivatives, which inhibit the function of P450 via negative feedback (10,11). Some synthetic gestagens containing the ethinyl group (gestodene, 3-keto-desogestrel), and estrogen metabolites cause the time-dependent loss of cytochrome P450 and irreversibly inhibit monooxygenase activity in vitro and in vivo, thus leading to a rise in the serum levels of contraceptive steroids (12)(13)(14). Thus synthetic steroids used in contraception or in treating some gynecological diseases may interfere with: (i) metabolism of other drugs and endogenous substances by monooxygenases (15,16); and (ii) P450-dependent synthesis, e.g.…”

“…Contemporary contraceptives contain estrogen (EE) in a dose below 50 mg and gestagens of minimal androgenic activity in order to prevent adverse effects of steroids or their derivatives (14,22,23). Triphasic contraceptives contain a constant dose of EE (30-40 mg), and gestagen whose dose is dependent on the phase of sexual cycle (24)(25)(26).…”