Effect of Norethisterone on Coagulation and Fibrinolysis In

SINGAPORE MEDICAL JOURNAL

EFFECTS OF NORETHISTERONE ON COAGULATION AND FIBRINOLYSIS IN ASIAN WOMEN

F H M Tsakok SYNOPSIS S Koh in 70 Asian women treated for en- E Chua High doses of norethisterone S coagulation factors as S S Ratnam dometriosis were found to affect the blood level was C W Tyler well as the cellular components of the blood. Fibrinogen P Layde found to be decreased (p < 0.01). Prothrombin increased B L Evatt significantly (p.<0.001) at the initial three months' medication after which it gradually reverted to baseline values at nine months. Department of Obstetrics and Gynaecology Factor V and X were significantly increased throughout the National University of Singapore period of therapy (pc 0.001) whilst factor VIII showed no change. Kandang Kerbau Hospital This is evidence that coagulation factors from the liver are Singapore 0821 affected by norethisterone whilst that from the vascular en- is The changes in coagulation factors resulted in a Ph D dothelium not. F H M Tsakok, MRCOG, time and kaolin cephalin time in the initial Associate Professor shortened prothrombin period of treatment reflecting the initial increase in prothrombin prothrombin S Koh level. Jaundice occurred in three patients when their Senior Laboratory Technician levels were at their highest for the individual patient. The adjustment and return to baseline levels did not occur in jaundiced S E Chua patients although this was the trend in the other patients. Laboratory Technician Fibrinolytic activity as shown by the fibrin plate test was not changed, neither was the antithrombin III activity or the levels of ;S S Ratnam, FRCOG degradation product. Senior Professor and Head fibrinogen/fibrin The cellular components of blood in patients treated with Division norethisterone was affected. The packed cell volume and platelet Family Planning Evaluation effect of Bureau of Epidemiology numbers were increased. This may be an androgenic Department of Health, Education and Welfare norethisterone. Public Health Service Since the effect of norethisterone on coagulation factors is Center for Disease Control, Atlanta GA 30333 mainly via the effect of this progestogen in high doses on the USA liver, it would seem prudent to exclude liver dysfunction and previous liver disease before embarking on such form of treat- Tyler, MD C W ment, and to monitor its effect during treatment. would apply to all patients to be given norethisterone P Layde, MSc. This whether it be at low dose or especially at high doses. This is on liver Haemotology Division because of the unpredictable effect of the drug mg Bureau of Laboratories metabolism. Two patients who became jaundiced had 20 Department of Health and Human Services norethisterone per day for three months which was comparatively Public Health Service low dose in this study. Center for Disease Control, Atlanta, GA 30333 The results of this study should be considered when norethisterone is being contemplated for contraceptive use B L Evatt, MD especially in Asian women, since they are known to be more Correspondence to: F H M Tsakok prone to liver disease.

442 VOLUME 25, NO. 6 DECEMBER 1984

INTRODUCTION medication and at three monthly intervals whilst on treatment. The medical regime consisted of a starting Since its synthesis in 1951 (1), norethisterone has dose of 15 mg norethisterone per day in divided doses. not only been the central element in the success of This dose was increased should there be breakthrough oral contraceptives, but has also played an important bleeding so that a period of at least role in hormonal treatment of gynaecological six months condi- amenorrhoea could be achieved. tions (2, 3, 4). Norethisterone, also known as norethin- Venous blood was collected into a plastic syringe drone, is as successful as combined oestrogen- with minimum stasis from patients after resting for progestogen preparations in producing amenorrhoea 30 minutes for the following assays. The overall screen- in the treatment of endometriosis (3). The combination ing tests included were the one -stage prothrombin oestrogen-progestogen preparations have been time (28) and kaolin cephalin clotting time (28). The reported to cause hypercoagulability in the blood (5-7) packed cell volume was also measured. In addition, and to increase the risk of thrombovascular disease the following coagulation factor assays were per- (8). A regime of progestogens-only was considered to formed: fibrinogen estimation (29), prothrombin assay be advantageous since it may not have these (30), Factor V assay (31), Factor VIII assay deleterious effects (9). The low dose of norethisterone (32), and Factor X (33). Antithrombin Ill activity was measured used in contraceptive pills have previously been by clotting test (34) and immunoelectrophoresis shown to be associated with very few coagulation (35). Test for fibrinolysis were plasminogen assay changes even after six months of continuous medica- (36), alpha-2-macroglobulin (37), and serum fibrinogen/ tion (10, 11). Similary, there were few effects on the fibrin degradation products (38). The fibrinolytic coagulation and fibrinolytic systems by other activi- pro- ty of plasma and resuspended euglobulin precipitate gestogen such as chlormadinone, medroxypro- on plasminogen enriched fibrin plates were performed gesterone acetate and retroprogesterone (12-16), as according to Nilsson and Olow (39). The plasma compared to the combined preparations. The occa- euglobulin clot lysis time (39) was also performed. sional finding of a prolonged bleeding time in- (14) Platelet count was performed using the Coulter creased fibrinolytic activity, decreased plasminogen, Counter Platelet aggregation was performed using a and decreased factor X by various studies indicated modification of the optical density technique of Born that hypocoagulability was more likely. No change in (40) while platelet adhesiveness was measured the prothrombin time or the level of by factor VII and Hellem's method (41). factor X could be detected after three months of high All investigations were subjected to internal and ex- doses of parenteral norethisterone oenanthate (17). In ternal quality control procedures. The results monkeys which were given ten times the dose for were analysed by self pairs. The results of each patient's human, only fibrinogen levels were found to be slightly coagulation tests at 3, 6 increased while all other coagulation and 9 months were compared proteins showed with their own values. no change (18). baseline The means of the differences was Norethisterone then analysed by the paired t -test. This undergoes various metabolic statistical evaluation was considered to be more transformations in the body and is known to have appropriate than using analysis of variance since it some oestrogenic properties. Of interest is the was more specific. metabolism of northisterone to 17-ethinyl oestradiol. Several investigators have reported increase urinary DEMOGRAPHIC RESULTS excretion of 17-ethinyl oestradiol after administration of norethisterone (19-21). It was calculated that from There were 70 women who were on norethisterone 12 mg of norethisterone administered, 1 mg of therapy for 3 months. Fifty-seven women continued to 17-ethinyl oestradiol could be formed (22). Under complete 6 months of treatment and 37 were treated physiological conditions, there is evidence to show for 9 months. The decreasing number of women in the that norethisterone is not aromatised to 17-ethinyl study is due to the following reasons. Some, especial- oestradio (23). In the treatment of endometriosis, high ly at 6 months, were taken off the study because they doses of norethisterone are often prescribed to had completed their treatment. Most of those who achieve amenorrhoea and pharmacological levels dropped gut after the third month from the coagula- prevail. It would be advantageous if norethisterone tions studies were because they found it inconvenient even at high doses should not cause changes in the to come for regular blood tests. Two women became coagulation system. Unlike Caucasion women. Asian jaundiced after three month's therapy and were taken women are less prone to thrombovascular disease off the treatment and the coagulations studies at the during their reproductive age (24, 25). However. Asian third month. None became sufficiently hypertensive women who were on estrogen -containing pill do during treatment to contraindicate continued therapy. develop hypercoagulable changes. These changes The group completing 9 months of treatment con- developing at a later time than in Caucasion women sisted of those women whose endometriosis had not comprise a decrease in antithrombin Ill levels (26) and resolved clinically. a marked increased in fibrinolytic activity. Asian In all, three women in the study developed jaundice. women are believed to have enhanced fibrinolysis One occurred at the completion of 9 months of therapy when they are on the combined pill. The present study and two after treatment for three months as men- seeks to evaluate whether women on long-term. con- tioned earlier. The dose of norethisterone used in the tinuous high dose of norethisterone have any change study varied from 15 mg/day to 40 mg/day for the first in their coagulation or fibrinolysis system. three months. In the second three months, the dose of norethisterone varied from 15 mg/day to 60 mg/day, and in the third three months from 15 mg/day to 80 mg/day. Even at the lowest dose, there is much more MATERIALS AND METHODS norethisterone than that present in contraceptive pills. The investigation was carried out in women COAGULATION STUDY RESULTS volunteers diagnosed to have endometriosis by laparoscopy or laparotomy. Blood was taken before The results of the coagulation tests have been

443 SINGAPORE MEDICAL JOURNAL

proteins which showed consistent in groups. Some of the coagulation tests other coagulation tabulated or increase varying with the duration of the number of women studied at each increase an have less than therapy or no change. Factor II levels because certain tests were not available at norethisterone test period significantly after 3 months of therapy of treatment or there was insufficient blood increased the time The increase was 8.7% from the baseline The tables show the mean values of the test (p 0.001). collected. of 106.6%. The increase diminished with con- and the mean difference in values from values in question, 9 months, prothrombin levels I, II and Ill) tinued treatment and by the baseline at 3, 6 and 9 months. (Table of ranged had reverted back to normal. The changing amount The coefficient of variation of methods used prothrombin is reflected in the changes of coagulation from 0.8% to 9.2% except for fibrinolytic activity times. Both Factor V and Factor X levels were which was 19%. clotting significantly increased throughout therapy while there no in the level of Factor VIII. The inhibitory TEST (Table I) was change SCREENING - activity of antithrombin Ill was not changed although Ill molecules were significantly in- The screening tests consisted of the prothrombin antithrombin the treatment period (p 0.001). time, kaolin cephalin time and the packed cell volume. creased throughout was The mean prothrombin time before treatment SYSTEM (Table Ill) 15.35 sec. The prothrombin time was significantly FIBRINOLYTIC - by the third month. (p 0.01) shortened by 0.95 sec of plasminogen both by the prothrombin time diminished by the The measurement This decrease in the immunoetectrophoretic methods sec which is still a statistically caseinolytic and 6th month to 0.67 significant increases from baseline values change. By the 9th month, however, the revealed significant throughout the treatment period. The euglobulin clot had returned towards baseline values. The change lysis time was significantly shortened showing that kaolin cephalin clotting time showed the same trend the fibrinolytic activators were increased during the initial as the prothrombin time. At the third month 6 months of treatment. By 9 months, the activator level decrease from baseline values was highly statistically change of 55.95 had returned to baseline values. No significant significant (3.88 sec less than baseline value fibrin sec) in fibrinolytic activity could be shown by the sec). At 6 months the difference was less (2.93 to values plate test. There was also no evidence of any change and by the 9th month the test has reverted in level of fibrin/fibrinogen degradation products. before treatment. Fibrinolytic inhibitor, alpha-2-macroglobulin, did not cell volume increased significantly through- Packed show substantial change. out the period of therapy. There was a 0.05-0.06 unit The increase from the baseline value of 0.38 units. took a PLATELET TESTS (Table IV) screening tests consistently showed that blood - that this change was most shorter time to clot and The platelet count was significantly increased by marked at the third month of treatment. norethisterone treatment (pc0.001). The magnitude of the was substantial since the increase varied (Table II) change COAGULATION PROTEIN ASSAY S- from 62.47 to 76.17 x 103/mm3 as compared to the baseline value of 274.15 x 103/mm3. Norethisterone a high statistical difference in the There was therapy did not affect any of the platelet adhesiveness fibrinogen level before and after treatment. Fibrinogen few treatment or aggregation function tests, but there were too levels decreased consistently throughout to make any the baseline results in the platelet function studies with a decrease of 0,35-0.52 gIl from many useful comment. value of 3.34 g/l. This change is in contrast to

TABLE I VOLUME IN COAGULATION SCREENING TEST AND PACKED CELL PATIENTS ON NORETHISTERONE AFTER DIFFERENCES BETWEEN BASELINE VALUES AND VALUES NORETHISTERONE MEDICATION

Baseline Difference from Baseline after Norethisterone value treatment At At Assay Mean At 6 months 9 months (UNITS) Values 3 months No. No. No.

57 -0.67` 36 -0.18Ns Prothrombin 15.36 64 -0.95" time (secs) 57 -2.93" 36 -0.87Ns Kaolin 55.95 65 -3.88t" cephalin clotting time (secs) 53 +0.06"t 34 + O.Ost" Packed cell 0.38 67 +005't' volume (units)

NS = not significant = p<0.05 = p<0.01 *tt _ P<0.001

Paired t -test

444 VOLUME 25, NO. 6 DECEMBER 1984

TABLE II COAGULATION FACTORS AND INHIBITORS IN PATIENTS ON NORETHISTERONE

DIFFERENCES BETWEEN BASELINE VALUES AND VALUES AFTER NORETHISTERONE MEDICATION

Baseline Difference from Baseline after Norethisterone value treatment` Assay Mean At At At (UNITS) Values 3 months 6 months 9 months

No. No. No. Fibrinogen gil 3.34 70 -0.45"' 57 - 0.52"" 37 - 0.35" Factor 11 % 106.60 70 +8.70"' 57 +7.46" 37 +3.62N5 Factor V % 101.37 70 +24.09"' 56 +33.39"' 35 +24.49"' Factor VIII 1.11 71 +0.06 57Ns + 0.04NS 37 + 0.04Ns. ulml Factor X % 101.56 71 + 16.72*** 57 + 17.40"' 36 + 17.53*** Activity 96.02 49 +0.27 32 - 6.09* 19 --4.32N5 Antithrombin III civ Immuno- 0.23 68 +0.02"' 53 +0.02*** 36 +0.03"' electrophoresis Anti III gil Anti XA % 92.83 68 +4.15' 54 +4.96' 37 +0.38Ns

NS = not significant = p<0.05 = p<0.01 p<0.001

Paired t -test

TABLE III FIBRINOLYTIC INHIBITORS FIBRINOLYTIC TEST IN PATIENTS ON NORETHISTERONE

DIFFERENCES BETWEEN BASELINE VALUES AND VALUES AFTER NORETHISTERONE MEDICATION

Baseline Difference from Baseline after Norethisterone Value treatment Assay Mean AT AT At (UNITS) Values 3 months 6 months 9 months No. No. No. Plasminogen 2.58 62 +0.26" 46 +0.27* 32 +0.51" (casein) ulml Plasminogen 5.21 67 + 1.32*** 54 + 1.37"' 37 + 1.56"' (Immuno) cu/ml ECLT hrs 5.08 56 - 2.35"' 44 -2.24*** 31 + 0.45Ns Fibrin Plate 197.96 45 +22.02 39 +3849Ns 22 +51.95Ns mm2 FDP ugiml 2.88 69 +0.12Ns 36 -0.01 NS Alpha 2 2.07 65 - 0.15* 49 +0.02Ns 33 -0.08Ns macro gil

NS = not significant = p<0.05 ** = p<0.01 "" = p<0.001

Paired t -test

445 SINGAPORE MEDICAL JOURNAL

TABLE IV NORETHISTERONE FUNCTION TESTS IN PATIENTS ON PLATELET COUNT & PLATELET MEDICATION VALUES AND VALUES AFTER NORETHISTERONE DIFFERENCES BETWEEN BASELINE Difference from Baseline after Norethisterone Baseline treatment Value At At AT Assay Mean 9 months 3 months 6 months (UNITS) Values No. No. No. +76.17"" +62.47' n 54 +62.76"' 35 Platelet count 274.15 68 103/mm3 18 +167N5 + 4.00N5 25 + 2.12Ns Platelet 35.14 38 adhesiveness +6.33Ns +4.73* 6 -5.83Ns 3 Platelet 63.91 11 aggregation Max. transmission with Collagen % -1p13Ns -11.59` 16 -5.81Ns 8 Platelet 55.56 17 aggregation Max. transmission ADP % with + 11.44Ns 5 - 54.00' 22 - 18.77Ns 9 Platelet 243.41 aggregation velocity with Collagen mm/min -62.53' -32.94* 23 - 15.61Ns 15 Platelet 232.39 31 aggregation velocity with ADP mm/min

NS = not signi scant = p<0.05 = p<0.01 = p<0.001

Paired ttest

(rhesus monkeys), high doses of animals, no changes RESULTS OF JAUNDICED PATIENTS norethisterone oenanthate (18) produced for an increase in Chinese in protein analyses except were two Indian women and one There two, jaundice fibrinogen. woman who developed jaundice. In decreased. In the Only fibrinogen levels were substantially after the third month of treatment. proteins occurred months This is in contrast to all other coagulation jaundice occurred after completion of 9 three months which third, the remain- produced by the liver at the initial treatment. Two were nulliparous whilst in contrast to previous of normotensive increased. The results are also had 3 pregnancies. They were levels in rhesus ing had from of increased fibrinogen and weights did not vary much reports (18) on all records not monkeys given similar doses of norethisterone All their coagulation tests were doses (10, 43, baseline reading. no change in human female on low mean of the whole study group ex- and in 20 different from the Decrease in fibrinogen levels was found levels. The patient who com- 17, 11). cept for prothrombin with familial type Ill, IV and V hyperlipopro-. of treatment started with the lowest patients pleted 9 months given norethisterone acetate (43). These of the study group and ended with teinemia levels other- prothrombin level to patients also had increased prothrombin prothrombin level. Jaundice seems These patients the highest to be at wise, other factors were unchanged. prothrombin levels were found at 20 mg/day. occur when had been given norethisterone acetate their highest. levels in the present study showed a Prothrombin the initial transient effect. The increase is more in period after which the difference from baseline The changes in other coagulation proteins DISCUSSION diminished. from the not alter with time. Coagulation proteins in this study have few do Factor X The results presented showed increases such as Factor V, human. This is because liver vascular previous comparison in the VIII which is synthesised by the on women who whilst Factor these studies have been performed is not affected. norethisterone. The endothelium have been on therapeutic doses of seems not to affect fibrinolytic given in a three- Norethisterone minimum amount of norethisterone in contrast to other types of progestogens three monthly dose of activity The month period was 1680 mg. The medroxyprogesterone acetate (16, 44). for contraception is 200 such as in- norethisterone oenanthate activator level in the blood is however this is at least 8 times plasminogen mg. Therefore, in these patients, (45) found no change in fibrinolytic contraception. In creased. Greig the dose of norethisterone used for

446 VOLUME 25, NO. 6 DECEMBER 1984

activity in African women on norethisterone but the nor were they known to have hyperlipidaemia. This dose was only 0.36 mg daily. This could be the result of unusual effect of norethisterone may be the balance 'between increased levels of peculiar to plasminogen Asian women. Asian people are known to develop and increased levels of plasminogen activators found jaundice in the study. frequently, have a higher incidence of Fibrinolytic inhibitors were not substan- hepatomas and in tially increased. whom neonatal jaundice is the rule rather that the exception. Although the women's The inhibitor of thrombin, antithrombin Ill, was significantly routine liver function tests when on norethisterone increased as measured by the im- were within normal limits, munoelectrophoretic method. perhaps additional liver Although antithrombin function tests in this group may explain Ill molecules were increased, has the unex- as been observed by pected decrease in fibrinogen level. others (43, 45, 46), no increase in antithrombin Ill activity could be demonstrated. Fibrinogen/fibrin degradation products remained unchanged. The increase in coagulation proteins, the REFERENCES shortening of the clotting time of blood, and the increase of platelet 1. Djerassi C. Miramontes L, Rosen -Kranz G. Sonaheimer count would contribute to a hyper - F: Synthesis of 19 17 coagulatory state. The hypercoagulatory nor ethinyl testosterone and 19 nor state seems 17 methyl testosterone. J Am Chem to be most accentuated at the third month, Soc 1954; 76:4092-9. after which 2. Bishop PMF, Cabral de Almeida JC: Treatment of func- there is an adjustment towards pretreatment levels. tional menstrual disorders with norethisterone. Br Med J Coagulation factors produced by the liver become 1960; 1:1103-5. to adjusted the effects of norethisterone. If adjust- 3. Kistner RW: Newer progestins in the treatment of en- ment by the liver does not occur, it seems, then there dometriosis. Int J Fertil 1961; 6:1-6. is decompensation with the development of jaundice. 4. Koetsavang A. perpakkham S: The effects of norethis- In the 3 patients who became jaundiced prothrombin terone on metropathic bleeding. J Med Assoc Thai 1972; 55:406. levels were at their highest when jaundice developed. Other 5. Poller L, Thomson JM: Clotting factors during oral con- coagulation proteins and fibrinolytic com- traception: ponents changed Further report 1966; 2:23-5. with the same trend as the whole 6. Nilsson group. IM, Kullander S: Coagulation and fibrinolytic studies during use of gestagens. Acta Obstet Gynecol The cellular changes are not the result of altered Scand 1967; 46:286-92. liver function. The highly significant increase in 7. Tsakok FHM. Koh S, Ratnam SS: Coagulation studies in platelet count and the packed cell volume could be Asian women on the 50 ug combined oral contraceptive pill. due to the androgenic effect of norethisterone and the Thromb and Haemostasis 1977; 38(1):290-1. 8. Vessey M: Mortality among latter change also from the amenorrhoea. The an- women participating in the drogenic effect of norethisterone is Oxford/Family Planning Association contraceptive quite well study. Lancet 6:1977; 731-3. recognised in animal experiments (47, 48, 49), causing 9. Poller L: The effects of progestogens on blood clotting vrrilising signs in female fetuses (50, 51). However, and platelet function. J Clin Pathol 1972; their effects on platelets and 25:1007-8. erythrocytes are less 10. Poller L, Thomson JM, Thomas PW: Effects of pro- well known in human. In patients with hypoplastic gestogens oral contraceptives with NE on blood clotting anaemia, androgenic steroids are given to raise and platelets. Br Med J 1972; 4:391-3. platelet count and haematocrit levels (52, 54, 27). 11. Korsan Bengtsen K, Larsson B: Effect on blood coagulation and Thus, norethisterone seems to have two types of fibrìolysis in women using norethisterone or a combination of E effects on blood coagulation components. The oestradiol and quingestranol. an- Gynaecol Obst Inv drogenic effect causes increase in cellular component 1978; 6:312-8. red blood 12. Poller L, Thomson JM, Tabiowo A et al: Progesterone cells and platelets. It is possible that oral leucocytes contraception and blood coagulation. Br Med J may also be increased. The second effect 1969; 1:554-6. on coagulation components is via the effects on liver 13. Monk AB, Courey NG, Moore RH, Ambrus CM, Ambrus function. The increase in coagulation and fibrinolytic JL: Progestational agents and blood coagulation IV components is thought to be due to increased changes induced by progeston only. AM J Obstet synthesis by the liver caused by a stimulating effect of Gynecol 1972; 113:739-43. norethisterone on the liver. From animal experiments 14. Wodzicki AM, Coopland AT: Chlormadinone acetate and it is its effect on the known that norethisterone levels build up in a haemostatic mechanism. Med Assoc J 1972; staircase fashion when given orally and the 107:38.41. drug is 15. Baele G, Vermylen slowly excreted (55). In animals it affects the A, Thiery M: Blood coagulation and liver by platelet function parameters before stimulating its growth and also affects its and during parental drug and administration of medroxyprogesterone acetate as con- protein metabolising activity (56) often by reducing traceptive agent. Thrombos Diathos Haemorrh 1977; this enzyme activity. The effect is dose dependent, 31:346-53. also species and even sex dependent (57). It is known 16. Tsakok FHM. Koh S, Ratnam SS: Effects of the pill on that norethisterone has cholestatic effects (58, 61). In blood coagulation in non-caucasian women. Singapore particular it has more pronounced retention effects on J Obstet Gynaecol 1978; 9:39-45. 17. Howard G, Myatt L. Eider bromsulphthalein (59, 60, 42, 43). Jaundice is a well MG: The effects of IM known complication of androgen therapy. norethisterone oenantnate used as a contraceptive on Some of the IV glucose tolerance test coagulation changes found in this and on blood coagulation fac- study may be due to tors VII X.Br J Obst and the decrease in Gynaecol 1977; 84:618-21. metabolism of the coagulation pro- 18. PF, Wadsworth Heywood R, Allen DG, Hossack DJ, Sort - teins causing a up in build blood levels. well RJ. Walton RM: Treatment of rhesus In contrast, monkeys fibrinogen levels are significantly (Macaca mulatta) with intravaginal rings impregnated decreased throughout norethisterone therapy. In with either progesterone or norethisterone. Contracep- normal women, norethisterone has been found either tion 1979: 20:339-51. to 19. Breuer H. cause to change in fibrinogen levels (9. 14, 17) or an Dardenns V, Noche W: Auscheidung von 17 increase (46). Only ìn hyperlipoproteinemic ketosteroiden 17 ketogen steroiden und ostrogenen women beim menchen nach was fibrinogen decreased with norethisterone treat- gaben von 17 aethynyl 19 nortesto- steronestern. Acta Endocinol ment. The Asian women studied here were KBH 1960:33:10-2. clinìcaly 21. Langecker H: Die metabolite in normal. Their lipid levels. however. were not measured menschilichen haro nach verabreichung von 17 aethynyl 19 nortestosteron

447 SINGAPORE MEDICAL JOURNAL

of Obstet and Gynaecol 1979; 86:806-9. Acta Endocrinologica KBH 1961; J Ill and (noraethisteron). 45. Grieg HB: Oral contraceptives, antithrombin 37:14-9. in Africans. Acta Haematol (Basel) AI: Metabolism of (4 fibrinolytic activity 21, Kamyab S, Fotherby K, Klopper 1968: 1977; 58:138-44. in women. J Endocrinol U: Concentra- 14C) norethisterone Larsson Cohn U, Fagerbol MK, Abilgaard 46. only oral 41:263-70. tion of At Ill during combined and progestogen HAF: Urinary oestrogen metabolites of Scand 22. Brown JB, Blair contraceptive treatment. Acta Obst Gynecol and its esters. Proc Roy Soc Med 10 norethisterone 1972; 51:315-7. 53:433. Meyer RK: Myotrophic 1960; Lancet 47. Hershberger LG. Shipley EG. H: Metabolism of progestogens. deter- 23. Breuer activity of 19 norethisterone and other steriods (Sept 19) 615-6. Vol II. Proc Sci Exp Biol 1970;7673 Thai mined by modified levator ani method. T: Postoperative thrombosis in 24. Chumnijarakij Med 1953; 83:175, Lancet 1975 (June 21) Vol 1:1357-8. of the anabolic and women. An- 48. Edgren RA: A comparative study Thromboembolic disease in women. Acta En- 25. Tsakok FHM: anarogenic effects of various steriods Academy of Medicine Singaproe. 1974; 3:399-04. nals of of docrinological 1963: Supp 187:3-21. Koh S, Yuen R, Ratnam SS: The effect Asselin J 26. Tsakok FHM, F. Ferland L. Lagace L. Drouin J. contraception on coagulation in Asian 49. Labrie inhibitory long-term steroid Azadian-Boulanger G. Raynaud JP: High Medical Journal 1980: 21:612-9. women. Singaproe of R5020 a pure progestin, at the hypothalamic- Nattran DG: The mortality of acquired activity 27. Li FP, Alter BP, adenohypophysial level of gonadotrophin secretion. in children's. Blood. 1972; 40:153-8. aplastic anemia Fertil Steril 1977: 28:1104-12. blood coagulation. Haemostasis and RS: 28. Biggs R: Human Wilkins L. Jones HM. Holman GH. Stempfel Oxford Blackwell 1972. 50. with Thrombosis p 609, Mascutinisation of the female fetus associated C: A new method for the determina- progestins 29. Ratnoff OD, Menzie administration of oral and intramuscular in small samples of plasma. J Lab Clin pseudoher- tion of fibrinogen during gestation - non adrenal female 1951; 37:316-20. Metab 1958: 18:559-85. Med of maphrodism. J Clin Endocinol Bonet( R, Biggs R: The specific assay therapy during 30. Denson KWE, Jacobson BD: Hazards of norethindrone using the Taipan Snake Venom. Brit J 51. Prothrombin pregnancy. Am J Obstet Gynecol 1962: 84:962-8. Haematol 1971; 21:219-26. R: Effect of androgens on the method for 52. McCullagh EP. Jones JN, Matsuoka T, Fukui H: A simple Metab 1942: 31. Shanberg V blood count of men. J Clin Endocrinol of a substrate for a one -stage Factor the preparation 2:243-51. 1967; 47:4:533-7. I. assay. Am J Clin Pathol FH. Pringle JC: Androgens and erythropoeisis for antihaemophìlic globulin. Brit J 53. Gardner 1961: 32. Biggs R: The assay preliminary clinical observations. Arch Intern Med Haematol 1955; 1:20-34. of Prower Stuart factor 107-846-62. 35. Denson KWE: The specific assay and erythropoeisis. New Eng J 1961; 25:105-120. 54. Shahidi NT: Androgens and Factor VII. Acta Haematological and heparin. Med 1973; 28:82. R: Antithrombin Ill, antifactor Xa, JO. Braselton 34. Biggs 55. Mahesh VB. Mills TM, Lin TJ. Ellegood Brit J Haematol 1970; 19:283-05. metabolic clearance rate blood Ill in a Clinical WE: Metabolism. 35. Redner U, Nilson IM: Antithrombin blood half life of norethindrone and 1973; 3:631-41. metabolites and Material Thrombosis Research & WH Berendes. Pharm of SOL: The mestranol, Edt S Grattini N, Anthony P Fletcher, Sherry Press NY 117, 1977. 36. Alkjaersig J Clin Inv Steroid Contra Drug. Raven of clot dissolution by plasmin. FE: Hormonal control of mechanism 56, Brown RJ. Bardin CW. Green 1959; 38:1086-95. P-450 dependent ethyl morphine n. of alpha-2-mascroglobulin as cytochrome of Steroid 37. Ganrot PO: Determination demethylase activity of the mouse. Pharma protein esterase. Clin Chin Acta 1966: Press NY 327. trypsin Contra Drugs Grattini Benendes, Raven 14:493-501. AJ: estima- 1977. C, Kleiner GJ. Johnson Quantitative L. G: Effect of con- 38. Merskey rela- 57. Joni A, Salmona M, Cantoni Guiso products of fibrinogen in human serum in severál tion of split traceptive drugs on liver meno oxygenase and treatment. Blood 1966:28:1-18. Drugs Eld tion to diagnosis animal species. Pharm of Steroid Contra Olow: Fibrinolysis induced by streptokinase 1977. 39. Nilsson and Grattini & Berendes. Raven Press NY 313. Chir Scand 123:247-66. R. Peters in man. Acta Kory RC. Bradley MH. Watson RN. Callahan Aggregation of blood platelets. J Physiol 58. norethan- 40. Born GVR: BJ: A six month evaluation of an anabolic. II bromosulphtalein 1963; 168:178-95. blood drolone in underweight person The adhesiveness of human J Med 1959: 41. Hellem's AJ: (BSP) retention and liver function test. Amer vitro. Scand J Clin Lab Invest 1960: 12-Sup- platelets in 26;243.8. plem 51. Endocrinologic and metabolic function tests after the 59. Feldman EB, Carter AC: 42. FM, Abd -El -Hay MM: Liver 19 nortestosterone in women. J Clin Saleh contraceptives. Con- effects of 17 methyl use of long actingprogestrational Endocrinol Metab 1960: 20.842.56. 1977; 16:409-16. Jaundice associated with traception in patients 60. Perez Mera RA, Shield CE: CJ: Clotting mechanisms J Med 1962. 43. Glueck HI, Glueck or norethindrone acetate therapy. New Eng hyperlipidaemia during therapy with anabolic with 1973: 267:1137-8. drug. Thrombos Diathes Haemorrh I: Effect of progestational 61. Vermylen J Verstraete M. Brosens on haemostasis and liver 29:499. progestogen dydrogesterone (duphaston) KAE: The effect of an injectable Cwlth 1973: 80(1):75-82. 44. Whigham fibrinolysis. Brit function. J Obstet Gvnecol Br contraceptive on blood coagulation and

448