EFFECT OF NORETHISTERONE ACETATE ON SERUM-LIPID AND LIPOPROTEIN PARAMETERS AS WELL AS ON BLOOD-COAGULATION IN FEMALE MONKEYS (MACACA-FASCICULARIS)

The effects of daily oral administration of a high dose of 10 mg noret histerone acetate (NET-Ac.)/kg/day over 14 weeks on serum lipid and li poprotein parameters as well as on blood coagulation were investigated in female monkeys (M. fascicularis). Measurements of lipids and lipop rotein cholesterol were performed in weeks -5 and -1 before treatment and in weeks 4, 8 and 12 after treatment. In addition, various blood c oagulation and fibrinolytic parameters were determined in weeks 11-14 after treatment with NET-Ac. Furthermore, the serum levels of norethis terone (NET) were determined in order to monitor the real systemic com pound exposure and revealed that C-max and AUC (0-3 h) values reached for norethisterone in this experiment in monkeys were about 25 times h igher than those obtained after an oral contraceptive dose of NET-Ac. in women. The results of lipid and lipoprotein cholesterol determinati ons showed decreases in serum total lipids, phospholipids, triglycerid es and total cholesterol associated with similar decreases in HDL-, LD L- and VLDL-cholesterol fractions after NET-Ac.-treatment in monkeys. These effects were observed from week 4 onwards and maintained their m agnitude up to week 12 after treatment. Since both HDL- and LDL-choles terol fractions decreased, the HDL/LDL-ratio remained almost unchanged . Thus, the results obtained in this study after high-dose treatment w ith NET-Ac. in monkeys did not indicate any changes of lipid and lipop rotein parameters which in humans are supposed to be associated with a n increased risk of cardiovascular lesions, namely a decrease in HDL- and increase in LDL-cholesterol fractions. The results of blood coagul ation and fibrinolytic parameters showed increased antithrombin-III an d plasminogen levels besides minor changes in other parameters, thus i ndicating that NET-Ac.-treatment does not contribute to an increased r isk of cardiovascular thrombotic events in the cynomolgus monkey.