Int J Gynaecol Obstet 16: 394-397, 1979
Studies on Liver Function Under the Influence of Oral Contraceptives E. Briigmann 1 , G. Goretzlehner 2 , J. Dabels 1 and J. Tòwe 3 Department of Gastroenterology of the Internal Medicine Clinic*, Department of Obstetrics and Gynecology"1 and Department of Medical Documentation and Statistics , Medical Faculty, Wilhelm Pieck University Rostock, Rostock, German Democratic Republic
ABSTRACT Briigmann E, Goretzlehner G, Dabels J, ToweJ (Depts of Gastroenterology of the Internal Medicine Clinic, Medical Documentation and Statistics and Obstetrics and Gynecology, Medical Faculty, Wilhelm Pieck University Rostock, Rostock, German Democratic Republic). Studies on liverfunction under the influence of oral contraceptives. Int J Gynaecol Obstet 16: 394-397, 1979 The effects of two sequential therapies using mestranol as an estrogen and chlormadinone acetate and norethisterone acetate, respectively, as a gestagen on the aminotransferase (GOT and GPT), alkaline phosphatase and a-amylase activities, the cholesterol, total bilirubin and total protein contents and the indocyanine green (Ujoviridin, VEB Chemiekombinat Bitterfeld) half-life were studied in two groups, each comprising 12 women of fertile age. The serum protein was separated by paper electrophoresis and both the thymol turbidity and zinc sulphate tests were performed during the first treatment cycle. An estrogen-induced rise in alanine aminotransferase (GPT) activity from 6.31 U/liter to 12.14 UI liter was observed during application of the mestranol/chlormadinone acetate therapy. The value dropped to 5.34 I)/liter when chlormadinone acetate was administered as a gestagen in addition to the estrogen. No significant changes were noted in the other biochemical parameters.
canals which have not been accompanied by clinical signs of an illness. Modifications of biochemical parameters have also been observed (1, 5, 10, 11, 17, 19, 20, 24). In the following, we shall report on possible effects of mestranol administered alone and combined with norethisterone acetate and chlormadinone acetate in the course of sequential treatment on biochemical parameters, particular attention being paid to the indocyanine green (ICG) half-life.
MATERIALS A N D M E T H O D S
Sequential therapies involving the application of mestranol as an estrogen and norethisterone acetate and chlormadinone acetate, respectively, as gestagens were undertaken on 24 healthy fertile women between the ages of 17 and 41 who had been divided into two groups of identical size for the purposes of this study. T h e first group was comprised of 12 women, aged 17 to 41 (average, 25.0 years), who received 0.08 mg of mestranol daily from the fifth to the 24th day of the cycle and 2 mg of chlormadinone acetate daily in addition from the 15th to the 25th day of the Sequential therapy involving application of mestranol and cycle. T h e second group of 12 women, aged 18 to 41 norethisterone acetate produced only statistically secured rises (average, 26.9 years), also received 0.08 m g of mesin the OLi-globulin content and the GPT activity. All other tranol from the fifth to the 24th day of the cycle, changes in the different parameters remained within the but 1 mg of norethisterone acetate in addition from normal range and were statistically insignificant. the 15th to the 24th day of the cycle. Blood samples were taken and the ICG tests were performed three times under standardized conditions in both groups during the first treatment cycle, INTRODUCTION in this manner: (a) on the 3rd day of the cycle, ie, prior to steroid application; (b) on the morning of the 15th day of the cycle in order to register the T h e number of reports on undesirable side effects effect of estrogen, ie, prior to gestagen application; during the use of oral contraceptives has steadily and (c) on the morning of the 25th day of the cycle increased during recent years. Such reports have upon completion of estrogen-gestagen application. mentioned effects on the cardiovascular system, blood clotting and the gastrointestinal and genital T h e clinicochemical studies involved determina-
IntJ Gynaecol Obstet 16
Oral contraceptives and liver function
tion of the following serum parameters: (a) aminotransferase activity, (b) alkaline phosphatase activity, (c) a-amylase activity, (d) ICG half-life, (e) cholesterol content, (f) total protein content and paper-electrophoretic separation, (g) total bilirubin content, (h) thymol turbidity and (i) zinc sulphate content. T h e aminotransferase activity was gauged by spectral photometric means. Except for the ICG half-life, the remaining biochemical parameters were determined in accordance with the Deutsches Arzneibuch (DAB) 7 (9). T h e ICG was arrived at as follows: T h e ICG load was 0.5 m g / k g body weight. This was obtained by means of Ujoviridin ampules (VEB Chemiekombinat Bitterfeld) containing 25 mg of ICG dissolved in 1 ml of 1.2 propandiol. Prior to intravenous application, the contents of each ampule were diluted with 4 ml of distilled water for injection purposes so that the solution used contained 5 m g of ICG. An indwelling cannula was inserted into the left cubital vein and 4 ml of blood was extracted in order to determine background values. The calculated amount of stain was injected over a period of 15 seconds a n d 5-7 ml of blood was extracted at 4, 6, 8, 10, 15 and 20 minutes after the injection had been completed. In order to remove adhering stain and to obviate analytic errors due to residual blood from the preceding sampling, the cannula was
395
cleaned by allowing a few drops of blood to emerge and rinsing with an isotonic salt solution (0.9 g m / 100 ml) after the stain had been injected and between the different blood samplings. When the blood samples had been centrifuged, the extinction was measured against the background serums by spectral photometry, using a wave length of 814 n m and a layer thickness of 10 mm (7). T h e extinction values obtained for the different sampling times were matched to an exponential curve logarithmically (quasilinear regression principle) and the half-life was determined from the constants of the e-function. T h e normal range for the half-life depends on the evaluation technique. T h e parameters measured were analyzed by means of simple factorial analysis followed by Fisher's homogeneity test. Since, in our case, the changes in the clinical parameters at discrete time intervals were of interest, pair comparisons were used to assess these changes (8).
RESULTS T h e mean values and standard deviations for the mestranol/chlormadinone acetate sequential therapy are presented in Table I. During this medication, the G P T was observed to rise from 6.31 U/liter to 12.4 U/liter under the effect of estrogen. T h e
Table I. Biochemical parameter values (mean ± standard deviation) for 12 women during mestranol/ chlormadinone acetate application. Ia II Parameter III Blood sedimentation rate, 1 st hour (mm) Blood sedimentation rate, 2nd hour (mm) SGOT b (U/liter) SGPTC (U/liter) Zinc sulphate (Te) Thymol turbidity (Mu) Total bilirubin ( m g / 1 0 0 ml) a-amylase ( U / 1 0 0 0 ml) Alkaline phosphatase ( U / 1 0 0 0 ml) Cholesterol ( m g / 1 0 0 ml) Total protein ( m g / 1 0 0 ml) Albumin (%) «i-globulin a z -globulin /?-globuiin y-globulin Ujoviridin ICG half-life (min)
13.08 ± 12.75
5.10 ±
5.17
19.63 ± 25.92 ± 13.67 20.86 ± 17.14 ± 18.99 5.43 ± 12.14 ± 9.70 2.71 ± 3.21 ± 1.31 1.46 ± 1.50 ± 0.79 0.59 ± 0.52 ± 0.20 8.30 ± 7.45 ± 4.15 26.04 ± 30.38 ± 14.41 225.70 ± 219.00 ± 82.22 6.74 ± 6.68 ± 0.47 55.08 ± 60.23 ± 8.59 6.15 ± 5.54 ± 1.66 11.92± 9.55 ± 2.90 13.92 ± 12.69 ± 2.75 12.15 ± 12.00 ± 3.61 3.40 ± 3.19 ± 0.59 a Key to headings: I = prior to treatment (3rd day of cycle); II = after 10 x 0.08 mg of mestranol (15th day of = after 20 x 0.08 mg of mestranol and 10 x 2 mg of chlormadinone acetate (25th day of cycle). " Aspartate aminotransferase. c Alanine aminotransferase.
5.07 11.09 5.08 1.07 0.66 0.24 2.70 10.08 99.76 0.69 7.13 2.34 2.69 2.36 3.31 0.91
23.54 18.38 6.38 2.71 1.27 0.68 7.00 29.71 213.86 6.91 57.38 5.23 10.76 12.31 14.31 3.81
± 16.76 ± 7.00 ± 4.56 ± 1.27 ± 0.83 ± 0.52 ± 3.27 ± 6.86 ± 38.40 ± 0.83 ± 9.61 ± 1.17 ± 3.65 ± 3.22 ± 3.61 ± 1.16
11.23 ±
7.36
cycle); and III
IntJ Gynaecol Obslet 16
396
Briigmann et al
Table II. Biochemical parameter values (mean ± standard deviation) for 12 women during mestranol/ norethisterone acetate application. Ia
Parameter Blood sedimentation rate, 1 st hour (mm) Blood sedimentation rate, 2nd hour (mm) SGOT a (U/liter) SGPT" (U/liter) Zinc sulphate (Te) Thymol turbidity (Mu) Total bilirubin ( m g / 1 0 0 ml) a-amylase ( U / 1 0 0 0 ml) Alkaline phosphatase ( U / 1 0 0 0 ml) Cholesterol ( m g / 1 0 0 ml) Total protein ( m g / 1 0 0 ml) Albumin (%) a t -globulin a 2 -globulin /?-globulin y-globulin Ujoviridin ICG half-life (min)
10.88 ±
III
II 6.16
23.63 ± 9.46 23.50 ± 1 3 . 1 0 11.00 ± 10.86 3.56 ± 1.09 1.40 ± 0.56 0.45 ± 0.28 6.32 ± 2.29 28.22 ± 8.81 222.44 ± 37.91 7.03 ± 0.49 55.56 ± 6.68 5.31 ± 1.14 11.38± 2.63 12.69 ± 2.06 12.56 ± 20.32 3.49 ± 0.61
9.27 ±
4.32
20.60 ± 10.91 25.88 ± 10.62 15.75 ± 10.69 3.38 ± 1.02 1.75 ± 0.45 0.43 ± 0.18 7.02 ± 2.35 29.31 ± 1 1 . 0 2 214.31 ± 5 6 . 2 0 6.68 ± 0.45 54.74 ± 5.19 7.27 ± 1.16 11.53± 1.73 13.27 ± 2.66 13.13 ± 2.85 3.39 ± 0.71
9.08 ± 22.46 21.06 7.44 2.81 1.75 0.53 7.67 22.72 202.19 6.69 54.69 6.38 11.56 14.44 12.94 3.44
4.89
± 10.00 ± 10.00 ± 4.62 ± 1.22 ± 0.85 ± 0.20 ± 2.95 ± 6.53 ± 45.33 ± 0.52 ± 5.06 ± 1.41 ± 1.71 ± 2.00 ± 3.17 ± 0.82
' Key to headings: I = prior treatment (3rd day of cycle); II = after 10 x 0.08 mg of mestranol (15th day of cycle); and III after 20 x 0.08 mg of mestranol and 10 x 1 mg of norethisterone acetate (25th day of cycle). ' Aspartate aminotransferase. : Alanine aminotransferase.
administration of chlormadinone acetate as a gestagen in addition to the estrogen caused this value to drop to 5.43 U/liter. No statistically secured changes were noted at the different examination times for the other biochemical parameters, including the Ujoviridin ICG half-life. T a b l e II shows the mean values and standard deviations observed during the sequential therapy involving mestranol and norethisterone acetate administration. Statistically significant changes in the values during the first phase of treatment were found only in connection with rises in the aj-globulin content a n d the G P T activity. T h e changes in all other parameters were insignificant and remained within the normal range. This applies also to the Ujoviridin ICG half-life. Comparison of the two sequential therapies by means of simple factorial analysis and the comparison of the mean values of the biochemical parameters at the different examination times produced no statistically secured differences between the two gestagen phases involving the use of chlormadinone acetate a n d norethisterone acetate, respectively.
DISCUSSION O u r studies have shown that the sequential therapies involving the use of mestranol as an estrogen
IntJ Gynaecol Obstet 16
and chlormadinone acetate and norethisterone acetate, respectively, as gestagens led to no significant changes in the biochemical parameters, including the Ujoviridin ICG half-life, during the acute adaptation phase in the course of the first cycle of clinical treatment. Similar results were obtained during the application of ethynyl estradiol as an estrogen and chlormadinone acetate or norethisterone acetate as a gestagen (2). This can probably be attributed to the ten-day estrogen phase and the estrogen-gestagen phase of identical length. Plotz (22) came to the conclusion that pathologic aminotransferase values occur in women virtually only after the menopause upon application of estrogen and rarely in younger women of fertile age. In the course of continuous treatment, these elevated aminotransferase activity values return to the normal range. Oldershausen observed a swelling of the liver but no inflammatory reaction upon lynostrenol and mestranol application (18). Eisenstadt (13) and Larsson-Cohn (16) have reported similar findings. O u r studies naturally permit no conclusions to be drawn regarding the reactions of the enzymes to the same therapies during long courses of treatment. Piel and his co-workers (21) observed a rise in the numbers of mitochondria and lysosomes during electron microscopic investigation of liver samples taken by biopsy during the application of contraceptive steroids. Forker (14) was able to show that bile secretion in rats can be reduced by more than 50%
Oral contraceptives and liver function
upon application of ethynyl estradiol, with the result that estrogen production is reduced. This might also explain why cholostasia occurs in man, although it must be stressed that the estrogen-gestagen concentrations used in man are substantially lower than those used in animal experiments. It can thus be suspected that genetic factors play some role in the occurence of this jaundice form (8).
REFERENCES 1. Adlercreutz H, T e n h u n e n R: Some aspect of the interaction between natural a n d synthetic female sexual hormones and the liver. Am J M e d 49:630, 1970. 2. Akpowowo H : Leberfunktionsuntersuchungen unter dem Einfluss unterschiedlicher Sequentialtherapieformen mit synthetischen Sexualsteroiden. Diplomarbeit, Bereich Medizin der Universitát Rostock, Rostock, G D R , 1975. 3. Battelle C o l u m b u s Laboratories: Interaction of Science and Technology in the Innovative Processing of Case Studies: Final Report Prepared for the National Science Foundation. Battelle C o l u m b u s Laboratories, Columbus, O H , 1973. 4. Berg I W , Ketelaar R I , Rose EF, Vernon R I : H e p a t o m a s a n d oral contraceptives. Lancet 2:349, 1974. 5. Boake W C : Effects of natural a n d synthetic estrogens and progestérones on hepaticofunctions. Acta Endocrinol [Suppl] (Kbh) 56.119, 1967. 6. Brohult I, Westgren A: Liver reaction in connection with oral contraceptive steroids. Acta Obstet Gynecol Scand 48: 242, 1969. 7. B r u g m a n n E: Uber die unterschiedliche Eliminationsgeschwindigkeit von Indozyaningriin bei Lebererkrankungen verschiedener Schweregrade. Z Gesamte Inn Med 28:523, 1973. 8. B r u g m a n n E, Tòwe J : Dissertation zur Erlangung des akademischen Grades, Doktor der Wissenschaften, Wilhelm Pieck Universitát Rostock, Rostock, G D R , 1976. 9. Deutsches Arzneibuch 7 (DL): 1. DDR-Ausgabe: Diagnostische Laboratoriumsmethoden. Akademie-Verlag, Berlin, 1968. 10. Drill, VA: Pharmacology of hepatotoxic agents. Ann NY Sei 104:858, 1963. 11. Eisalon A, Konttinen A, Hietala O : Oral contraceptives
397
after liver disease. Br M e d J 5:561, 1971. 12. Eisalon A, Tárvinen PA, Luuhkainen T : Hepatic impairment during the intake of contraceptive pills: clinical trial with postmenopausal women. Br Med J 2:426, 1964. 13. Eisenstadt H B : Abnormal liver function and synthetic estrogens. J A M A 194:933, 1965. 14. Forker EL: T h e effect of estrogen in bile formation in the rat. J Clin Invest 48:645, 1968. 15. Larsson-Cohn U: Oral contraception a n d liver-function tests. Br Med J /.1414, 1965. 16. Larsson-Cohn U: Transaminase activity during oral contraceptive therapy. Acta Obstet Gynecol Scand 45:196, 1966. 17. Linthorst G: Liver function after long-term progestational treatment with and without oestrogen. Br Med J 2:920, 1964. 18. Oldershausen H F v: Arzneimittel und Leberschaden. Therapiewoche 2/:2339, 1971. 19. Oral contraceptives and the liver. Br Med J /:430, 1974. 20. Palva IP, Mustala O D : Oral contraceptives a n d liver damage. Br Med J 2:688, 1964. 21. Piel E, Rais O , Zeuchner E: Functional a n d morphological liver changes in women taking oral contraceptives. Acta C h i r Scand 134:639, 1968. 22. Plotz EJ: Nebenwirkungen antikonzeptioneller Steroide. Geburtshilfe Frauenheilkd 30:193, 1970. 23. Royal College of General Practitioners: Oral Contraceptives a n d Health: An Interim Report from the O r a l Contraception Study of the Royal College of General Practitioners. Pilmann Publishing Corporation, New York, 1974. 24. Tyler E T : Oral contraception and liver d a m a g e . Br Med J 2:1264, 1964. 25. Westerholm B: Oral contraceptives and jaundice. In Sensitization to Drugs, Proceedings of the European Society for the Study of Drug Toxicity, Oxford, April 1968 (ed GB de C Baker, J T r i p o d ) , Vol 10, p 158. Excerpta Medica, Amsterdam, 1969.
Address for reprints: E. Brugmann Internal Medicine Clinic Wilhelm Pieck University Ernst-Heydemann Strasse 6 25 Rostock German Democratic Republic
InlJ Gynaecol Obstet 16
Studies on Liver Function Under the Influence of Oral Contraceptives E. Briigmann 1 , G. Goretzlehner 2 , J. Dabels 1 and J. Tòwe 3 Department of Gastroenterology of the Internal Medicine Clinic*, Department of Obstetrics and Gynecology"1 and Department of Medical Documentation and Statistics , Medical Faculty, Wilhelm Pieck University Rostock, Rostock, German Democratic Republic
ABSTRACT Briigmann E, Goretzlehner G, Dabels J, ToweJ (Depts of Gastroenterology of the Internal Medicine Clinic, Medical Documentation and Statistics and Obstetrics and Gynecology, Medical Faculty, Wilhelm Pieck University Rostock, Rostock, German Democratic Republic). Studies on liverfunction under the influence of oral contraceptives. Int J Gynaecol Obstet 16: 394-397, 1979 The effects of two sequential therapies using mestranol as an estrogen and chlormadinone acetate and norethisterone acetate, respectively, as a gestagen on the aminotransferase (GOT and GPT), alkaline phosphatase and a-amylase activities, the cholesterol, total bilirubin and total protein contents and the indocyanine green (Ujoviridin, VEB Chemiekombinat Bitterfeld) half-life were studied in two groups, each comprising 12 women of fertile age. The serum protein was separated by paper electrophoresis and both the thymol turbidity and zinc sulphate tests were performed during the first treatment cycle. An estrogen-induced rise in alanine aminotransferase (GPT) activity from 6.31 U/liter to 12.14 UI liter was observed during application of the mestranol/chlormadinone acetate therapy. The value dropped to 5.34 I)/liter when chlormadinone acetate was administered as a gestagen in addition to the estrogen. No significant changes were noted in the other biochemical parameters.
canals which have not been accompanied by clinical signs of an illness. Modifications of biochemical parameters have also been observed (1, 5, 10, 11, 17, 19, 20, 24). In the following, we shall report on possible effects of mestranol administered alone and combined with norethisterone acetate and chlormadinone acetate in the course of sequential treatment on biochemical parameters, particular attention being paid to the indocyanine green (ICG) half-life.
MATERIALS A N D M E T H O D S
Sequential therapies involving the application of mestranol as an estrogen and norethisterone acetate and chlormadinone acetate, respectively, as gestagens were undertaken on 24 healthy fertile women between the ages of 17 and 41 who had been divided into two groups of identical size for the purposes of this study. T h e first group was comprised of 12 women, aged 17 to 41 (average, 25.0 years), who received 0.08 mg of mestranol daily from the fifth to the 24th day of the cycle and 2 mg of chlormadinone acetate daily in addition from the 15th to the 25th day of the Sequential therapy involving application of mestranol and cycle. T h e second group of 12 women, aged 18 to 41 norethisterone acetate produced only statistically secured rises (average, 26.9 years), also received 0.08 m g of mesin the OLi-globulin content and the GPT activity. All other tranol from the fifth to the 24th day of the cycle, changes in the different parameters remained within the but 1 mg of norethisterone acetate in addition from normal range and were statistically insignificant. the 15th to the 24th day of the cycle. Blood samples were taken and the ICG tests were performed three times under standardized conditions in both groups during the first treatment cycle, INTRODUCTION in this manner: (a) on the 3rd day of the cycle, ie, prior to steroid application; (b) on the morning of the 15th day of the cycle in order to register the T h e number of reports on undesirable side effects effect of estrogen, ie, prior to gestagen application; during the use of oral contraceptives has steadily and (c) on the morning of the 25th day of the cycle increased during recent years. Such reports have upon completion of estrogen-gestagen application. mentioned effects on the cardiovascular system, blood clotting and the gastrointestinal and genital T h e clinicochemical studies involved determina-
IntJ Gynaecol Obstet 16
Oral contraceptives and liver function
tion of the following serum parameters: (a) aminotransferase activity, (b) alkaline phosphatase activity, (c) a-amylase activity, (d) ICG half-life, (e) cholesterol content, (f) total protein content and paper-electrophoretic separation, (g) total bilirubin content, (h) thymol turbidity and (i) zinc sulphate content. T h e aminotransferase activity was gauged by spectral photometric means. Except for the ICG half-life, the remaining biochemical parameters were determined in accordance with the Deutsches Arzneibuch (DAB) 7 (9). T h e ICG was arrived at as follows: T h e ICG load was 0.5 m g / k g body weight. This was obtained by means of Ujoviridin ampules (VEB Chemiekombinat Bitterfeld) containing 25 mg of ICG dissolved in 1 ml of 1.2 propandiol. Prior to intravenous application, the contents of each ampule were diluted with 4 ml of distilled water for injection purposes so that the solution used contained 5 m g of ICG. An indwelling cannula was inserted into the left cubital vein and 4 ml of blood was extracted in order to determine background values. The calculated amount of stain was injected over a period of 15 seconds a n d 5-7 ml of blood was extracted at 4, 6, 8, 10, 15 and 20 minutes after the injection had been completed. In order to remove adhering stain and to obviate analytic errors due to residual blood from the preceding sampling, the cannula was
395
cleaned by allowing a few drops of blood to emerge and rinsing with an isotonic salt solution (0.9 g m / 100 ml) after the stain had been injected and between the different blood samplings. When the blood samples had been centrifuged, the extinction was measured against the background serums by spectral photometry, using a wave length of 814 n m and a layer thickness of 10 mm (7). T h e extinction values obtained for the different sampling times were matched to an exponential curve logarithmically (quasilinear regression principle) and the half-life was determined from the constants of the e-function. T h e normal range for the half-life depends on the evaluation technique. T h e parameters measured were analyzed by means of simple factorial analysis followed by Fisher's homogeneity test. Since, in our case, the changes in the clinical parameters at discrete time intervals were of interest, pair comparisons were used to assess these changes (8).
RESULTS T h e mean values and standard deviations for the mestranol/chlormadinone acetate sequential therapy are presented in Table I. During this medication, the G P T was observed to rise from 6.31 U/liter to 12.4 U/liter under the effect of estrogen. T h e
Table I. Biochemical parameter values (mean ± standard deviation) for 12 women during mestranol/ chlormadinone acetate application. Ia II Parameter III Blood sedimentation rate, 1 st hour (mm) Blood sedimentation rate, 2nd hour (mm) SGOT b (U/liter) SGPTC (U/liter) Zinc sulphate (Te) Thymol turbidity (Mu) Total bilirubin ( m g / 1 0 0 ml) a-amylase ( U / 1 0 0 0 ml) Alkaline phosphatase ( U / 1 0 0 0 ml) Cholesterol ( m g / 1 0 0 ml) Total protein ( m g / 1 0 0 ml) Albumin (%) «i-globulin a z -globulin /?-globuiin y-globulin Ujoviridin ICG half-life (min)
13.08 ± 12.75
5.10 ±
5.17
19.63 ± 25.92 ± 13.67 20.86 ± 17.14 ± 18.99 5.43 ± 12.14 ± 9.70 2.71 ± 3.21 ± 1.31 1.46 ± 1.50 ± 0.79 0.59 ± 0.52 ± 0.20 8.30 ± 7.45 ± 4.15 26.04 ± 30.38 ± 14.41 225.70 ± 219.00 ± 82.22 6.74 ± 6.68 ± 0.47 55.08 ± 60.23 ± 8.59 6.15 ± 5.54 ± 1.66 11.92± 9.55 ± 2.90 13.92 ± 12.69 ± 2.75 12.15 ± 12.00 ± 3.61 3.40 ± 3.19 ± 0.59 a Key to headings: I = prior to treatment (3rd day of cycle); II = after 10 x 0.08 mg of mestranol (15th day of = after 20 x 0.08 mg of mestranol and 10 x 2 mg of chlormadinone acetate (25th day of cycle). " Aspartate aminotransferase. c Alanine aminotransferase.
5.07 11.09 5.08 1.07 0.66 0.24 2.70 10.08 99.76 0.69 7.13 2.34 2.69 2.36 3.31 0.91
23.54 18.38 6.38 2.71 1.27 0.68 7.00 29.71 213.86 6.91 57.38 5.23 10.76 12.31 14.31 3.81
± 16.76 ± 7.00 ± 4.56 ± 1.27 ± 0.83 ± 0.52 ± 3.27 ± 6.86 ± 38.40 ± 0.83 ± 9.61 ± 1.17 ± 3.65 ± 3.22 ± 3.61 ± 1.16
11.23 ±
7.36
cycle); and III
IntJ Gynaecol Obslet 16
396
Briigmann et al
Table II. Biochemical parameter values (mean ± standard deviation) for 12 women during mestranol/ norethisterone acetate application. Ia
Parameter Blood sedimentation rate, 1 st hour (mm) Blood sedimentation rate, 2nd hour (mm) SGOT a (U/liter) SGPT" (U/liter) Zinc sulphate (Te) Thymol turbidity (Mu) Total bilirubin ( m g / 1 0 0 ml) a-amylase ( U / 1 0 0 0 ml) Alkaline phosphatase ( U / 1 0 0 0 ml) Cholesterol ( m g / 1 0 0 ml) Total protein ( m g / 1 0 0 ml) Albumin (%) a t -globulin a 2 -globulin /?-globulin y-globulin Ujoviridin ICG half-life (min)
10.88 ±
III
II 6.16
23.63 ± 9.46 23.50 ± 1 3 . 1 0 11.00 ± 10.86 3.56 ± 1.09 1.40 ± 0.56 0.45 ± 0.28 6.32 ± 2.29 28.22 ± 8.81 222.44 ± 37.91 7.03 ± 0.49 55.56 ± 6.68 5.31 ± 1.14 11.38± 2.63 12.69 ± 2.06 12.56 ± 20.32 3.49 ± 0.61
9.27 ±
4.32
20.60 ± 10.91 25.88 ± 10.62 15.75 ± 10.69 3.38 ± 1.02 1.75 ± 0.45 0.43 ± 0.18 7.02 ± 2.35 29.31 ± 1 1 . 0 2 214.31 ± 5 6 . 2 0 6.68 ± 0.45 54.74 ± 5.19 7.27 ± 1.16 11.53± 1.73 13.27 ± 2.66 13.13 ± 2.85 3.39 ± 0.71
9.08 ± 22.46 21.06 7.44 2.81 1.75 0.53 7.67 22.72 202.19 6.69 54.69 6.38 11.56 14.44 12.94 3.44
4.89
± 10.00 ± 10.00 ± 4.62 ± 1.22 ± 0.85 ± 0.20 ± 2.95 ± 6.53 ± 45.33 ± 0.52 ± 5.06 ± 1.41 ± 1.71 ± 2.00 ± 3.17 ± 0.82
' Key to headings: I = prior treatment (3rd day of cycle); II = after 10 x 0.08 mg of mestranol (15th day of cycle); and III after 20 x 0.08 mg of mestranol and 10 x 1 mg of norethisterone acetate (25th day of cycle). ' Aspartate aminotransferase. : Alanine aminotransferase.
administration of chlormadinone acetate as a gestagen in addition to the estrogen caused this value to drop to 5.43 U/liter. No statistically secured changes were noted at the different examination times for the other biochemical parameters, including the Ujoviridin ICG half-life. T a b l e II shows the mean values and standard deviations observed during the sequential therapy involving mestranol and norethisterone acetate administration. Statistically significant changes in the values during the first phase of treatment were found only in connection with rises in the aj-globulin content a n d the G P T activity. T h e changes in all other parameters were insignificant and remained within the normal range. This applies also to the Ujoviridin ICG half-life. Comparison of the two sequential therapies by means of simple factorial analysis and the comparison of the mean values of the biochemical parameters at the different examination times produced no statistically secured differences between the two gestagen phases involving the use of chlormadinone acetate a n d norethisterone acetate, respectively.
DISCUSSION O u r studies have shown that the sequential therapies involving the use of mestranol as an estrogen
IntJ Gynaecol Obstet 16
and chlormadinone acetate and norethisterone acetate, respectively, as gestagens led to no significant changes in the biochemical parameters, including the Ujoviridin ICG half-life, during the acute adaptation phase in the course of the first cycle of clinical treatment. Similar results were obtained during the application of ethynyl estradiol as an estrogen and chlormadinone acetate or norethisterone acetate as a gestagen (2). This can probably be attributed to the ten-day estrogen phase and the estrogen-gestagen phase of identical length. Plotz (22) came to the conclusion that pathologic aminotransferase values occur in women virtually only after the menopause upon application of estrogen and rarely in younger women of fertile age. In the course of continuous treatment, these elevated aminotransferase activity values return to the normal range. Oldershausen observed a swelling of the liver but no inflammatory reaction upon lynostrenol and mestranol application (18). Eisenstadt (13) and Larsson-Cohn (16) have reported similar findings. O u r studies naturally permit no conclusions to be drawn regarding the reactions of the enzymes to the same therapies during long courses of treatment. Piel and his co-workers (21) observed a rise in the numbers of mitochondria and lysosomes during electron microscopic investigation of liver samples taken by biopsy during the application of contraceptive steroids. Forker (14) was able to show that bile secretion in rats can be reduced by more than 50%
Oral contraceptives and liver function
upon application of ethynyl estradiol, with the result that estrogen production is reduced. This might also explain why cholostasia occurs in man, although it must be stressed that the estrogen-gestagen concentrations used in man are substantially lower than those used in animal experiments. It can thus be suspected that genetic factors play some role in the occurence of this jaundice form (8).
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after liver disease. Br M e d J 5:561, 1971. 12. Eisalon A, Tárvinen PA, Luuhkainen T : Hepatic impairment during the intake of contraceptive pills: clinical trial with postmenopausal women. Br Med J 2:426, 1964. 13. Eisenstadt H B : Abnormal liver function and synthetic estrogens. J A M A 194:933, 1965. 14. Forker EL: T h e effect of estrogen in bile formation in the rat. J Clin Invest 48:645, 1968. 15. Larsson-Cohn U: Oral contraception a n d liver-function tests. Br Med J /.1414, 1965. 16. Larsson-Cohn U: Transaminase activity during oral contraceptive therapy. Acta Obstet Gynecol Scand 45:196, 1966. 17. Linthorst G: Liver function after long-term progestational treatment with and without oestrogen. Br Med J 2:920, 1964. 18. Oldershausen H F v: Arzneimittel und Leberschaden. Therapiewoche 2/:2339, 1971. 19. Oral contraceptives and the liver. Br Med J /:430, 1974. 20. Palva IP, Mustala O D : Oral contraceptives a n d liver damage. Br Med J 2:688, 1964. 21. Piel E, Rais O , Zeuchner E: Functional a n d morphological liver changes in women taking oral contraceptives. Acta C h i r Scand 134:639, 1968. 22. Plotz EJ: Nebenwirkungen antikonzeptioneller Steroide. Geburtshilfe Frauenheilkd 30:193, 1970. 23. Royal College of General Practitioners: Oral Contraceptives a n d Health: An Interim Report from the O r a l Contraception Study of the Royal College of General Practitioners. Pilmann Publishing Corporation, New York, 1974. 24. Tyler E T : Oral contraception and liver d a m a g e . Br Med J 2:1264, 1964. 25. Westerholm B: Oral contraceptives and jaundice. In Sensitization to Drugs, Proceedings of the European Society for the Study of Drug Toxicity, Oxford, April 1968 (ed GB de C Baker, J T r i p o d ) , Vol 10, p 158. Excerpta Medica, Amsterdam, 1969.
Address for reprints: E. Brugmann Internal Medicine Clinic Wilhelm Pieck University Ernst-Heydemann Strasse 6 25 Rostock German Democratic Republic
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