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Miscellaneous hormones and prostaglandins
R. Bouillon and F.A. van Assche
45
Miscellaneous hormones and prostaglandins
Calcitonin Calcitonin has been found to be markedly superior to diphosphonates in the treatment of Paget's disease of bone. In a recent study calcitonin produced a positive focal bone balance in nearly all patients without serious side effects, whereas even small doses of EHDP (disodium etidronate) aggravated osteolytic Paget's diseases (1C R). Salmon calcitonin also increased bone density and reduced the annual fracture rate in 48 children with osteogenesis imperfecta (2c); again no serious side effects were observed. A single case of deterioration o f diabetic control has been described. In a 71-year-old diabetic female treated with 1 g tolbutamide daily, porcine calcitonin (80 IU/day) was started because of increasing pagetic bone pain. Plasma glucose more than doubled and heavy glucosuria occurred. Her diabetes was again well controlled after withdrawal of calcitonin (3c). The diabetic deterioration in this case might, however, have been due to an indirect effect of calcitonin, since she also complained of nausea, cramps and headaches during calcitonin therapy; stress and altered food intake may therefore have been the real reason for the loss of control. Like many other hormonal peptides, calcitonin also seems to have potential behavioral effects: subcutaneous or intracerebral injections of calcitonin inhibit feeding in rats(4). Whether endogenous calcitonin is really involved in the regulation of feeding and appetite in man requires further study.
Somatostatin The impressive effects of somatostatin on the secretion of many hormones and gastrointestinal functions have stimulated
researchers to look for potential applications. Bleeding from esophagal (5 c) or gastrointestinal ulcers (11 c) can be successfully stopped by somatostatin infusions, probably due to a reduction in splanchnic blood flow and to the very strong inhibition of gastric acid output occurring during somatostatin infusion. Mild abdominal discomfort was the only side effect noted (6c). The inhibitory effect of somatostatin on gastrointestinal secretions has also been exploited in the Verner-Morrison syndrome. A dramatic improvement in stool volume was observed, but arrest of therapy was followed by a rebound phenomenon, which could have resulted in rapid dehydration and electrolyte imbalance if not immediately corrected (7 c).
Vasopressin and its analogues Vasopressin has generalized vasoconstrictor properties and coronary ischemia and even myocardial infarction are therefore potential side effects, especially in patients with pre-existent coronary insufficiency (SEDA-3, 355). Vasopressininduced ventricular fibrillation has now also been reported in a 48-year-old woman (8c). She had no demonstrable coronary insufficiency but occasional premature ventricular contractions occurred. Because of upper gastrointestinal bleeding she received a bolus injection of vasopressin (1.3 IU/min. for 15 min.), which was followed by slight hypertension, bradycardia and ventricular fibrillation, successfully treated with cardioversion. A vasopressin analogue, triglycylqysinevasopressin has a prolonged pharmacologic action due to the slow release of the active nonapeptide after enzymic release in vivo. Clinical improvements in patients with gastrointestinal bleedings have been documented in a few preliminary open stud-
R. Bouillon and F. A. van Assche
398 ies(9 C, 10 c , 11c). Only a slight pressor effect and modest bradycardia were observed, without serious cardiovascular side effects. Similar favorable effects of this drug were observed in patients with uterine bleeding (12 C, 13c). Vasopressin, and especially some of its analogues (desmopressin, DDAVP), enhance plasminogen activator release and, therefore, could become attractive drugs for thrombolytic therapy (14 c ). Gonadotropin-releasing hormones A synthetic long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH or LHRHa, has been tested in men and women (15 C, 16c). In comparison with the natural hormone, this compound was found to have a greater ability to release gonadotropins acutely and to sustain their release in normal and hypogonadotropic subjects. An increase in serum estradiol was observed after injection of LHRHa and not after the natural LHRH (15c). An improvement in sleep was observed after LHRH injection in depressed patients, followed by a sustained resolution of depressive symptoms in 8 patients with 'stress-associated depression' (17c). No such improvement was observed in unipolar or bipolar depression (17 c, 18c).
Thyr o tropin-releasing hormone Thyrotropin-releasing hormone (TRF) was originally isolated from hypothalami and stimulates thyrotropin release from the pituitary. This tripeptide, however, is distributed throughout the nervous system, the retina, pancreas, gastrointestinal tract, adrenals and placenta. It might well represent a ubiquitous neurotransmitter that rather by coincidence also functions as a pituitary-releasing factor (19R). The influence of TRF on behavior has been studied before and some analogues even have selective and powerful effects on the central nervous system (20 c).
Human growth hormone tropin)
(GH,
Somato-
A detailed report on the extensive experience with the clinical use of human growth hormone in GH-deficient children
has been published by the MRC Working Party in Britain (21CR). Three injections per week (3 x 5 IU) seem to be better than 2, even if the total dose per week is lower. Antibody formation is markedly more frequent with the Raben-type GH (66%) as opposed to the Wilheimi-type of GH extraction (18%). These antibodies do not decrease the growth response unless they have an association constant higher than 107 M-a and a binding capacity higher than 1 mg/l. The overall prevalence of growth-inhibiting antibodies is about 2 - 3 % . A decrease in thyroid function occurred only once in 241 patients, contradicting previous experience (SEDA-1, 325). As pointed out in an Editorial (22 R), the general results with GH therapy in idiopathic GH deficiency are satisfactory when treatment starts early in life. The mean age at the beginning of therapy is, however, still 2 - 3 years behind the optimal age. The second problem remains the marginal supply of hGH at least until the present extraction from human pituitaries can be replaced by means of production (e.g. bacterial synthesis after genetic engineering).
Relaxin Relaxin is a polypeptide hormone structually related to insulin and somatomedins. Purified porcine rr given on the evening before induction of labor induced labor in one-third of the patients and improved the cervical scores in the other 75%. Since uterine activity was not markedly enhanced a direct effect of relaxin on cervical ripening and subsequent parturition is suggested (23c). No side effects were experienced by the patients and no neonatal complications were observed. PROSTAGLANDINS AND OXYTOCIN
Prostaeycline Prostacyclin is an unstable prostaglandin, produced enzymatically by intact endothelial ceils, which inhibits platelet aggregation. In cases of endothelial lesions, however, another prostaglandin, called thromboxane A2, is produced by thrombocytes using the same or similar endoperoxidases. Thromboxane A2 then enhances throm-
Miscellaneous hormones and prostaglandins b o c y t e aggregation and subsequent b l o o d coagulation. Platelet aggregation thus seems to be regulated b y a balanced equilibrium b e t w e e n 2 prostaglandins, prostacyclin and t h r o m b o x a n e A2, secreted and p r o d u c e d by interactions of endothelial cells with t h r o m b o c y t e s (24 R, 25). The potential use o f these new prostaglandins in various diseases are n o w under study. Prostacyclin seems to have favorable effects in h y p e r tension with (26 c) or w i t h o u t pregnancy (27c). It is t o o early to draw conclusions as to possible adverse reactions.
Obstetric use of prostaglandins and oxytocin The indications and c o m p l i c a t i o n s of the therapeutic use o f prostaglandins and o x y tocin in obstetrics and g y n e c o l o g y are alm o s t the same as previously r e p o r t e d (SED 9, 719). The main indications for prostaglandins are mid-trimester a b o r t i o n and i n d u c t i o n of labor. F o r the i n d u c t i o n of labor oral prostaglandin E2 is m o s t l y used (28 C, 29 C). The most c o m m o n side effects are gastrointestinal complaints and uterine hypertonus. The c o m b i n e d use of prostaglandins and o x y t o c i n for the i n d u c t i o n o f labor m a y result in an increased incidence o f neonatal hyperbilirubinemia (30 c , 31 c ). F o r t e r m i n a t i o n of pregnancy the intramuscular and intra-amniotic ways of administration have been replaced by the use o f prostaglandin E2 in vaginal suppositories (32 C) or in gels for extra-amniotic use (33C). Sudden collapse, death and uterine rupture c o n t i n u e to be very rarely r e p o r t e d (32 c , 33 c , 34c). New analogues with supposedly less side effects have been in-
399 t r o d u c e d for t e r m i n a t i o n of pregnancy 35 c, 36c). Callen et al. (37 C) studied the incidence of intrapartum and postpartum pyrexia and infection after i n d u c t i o n with extra-amniotic prostaglandin E2 in tylose. 124 women, bearing 127 children, in whom labor was induced with extra-amniotic prostaglandin E2 in tylose were studied. High vaginal swabs taken from 11 patients immediately before insertion of prostaglandin E2 were examined, specific identification of microbes being restricted to those present in the amniotic fluid, to fred hemolytic streptococci, and to other specific microbes. Lancefield group B streptococci were isolated from 9 patients, and in 8 of these the microbes were isolated from the amniotic fluid. Amniotic fluid was examined from 86 patients and was shown to be contaminated with microbes potentially pathogenic for mother or baby in 11 out of 86 (13%) of the patients examined; in 8 patients, the contaminating pathogen was the group B streptococcus. All 127 blood cultures taken during or just after delivery were negative. Six out of 9 patients with a group B streptococcus in the vagina developed fever and proven streptococcal endometritis; one child developed fever and another streptococcal septicemia. Pyrexia and i n f e c t i o n cannot, of course, be regarded as true adverse effects o f prostaglandin E2, but t h e y are a c o n s e q u e n c e of the t e c h n i q u e in which this substance is e m p l o y e d , and the facts r e c o r d e d in this series, where o f the 124 w o m e n induced 12 developed intrapartum fever and 6 fever during the puerperium, underline the fact that the t e c h n i q u e has its risks, including the p e n e t r a t i o n o f pathogens from the vaginal fault.
REFERENCES i. Nagant de Deuxchaines, C., Rombouts-Lindemans, C., Huaux, J.P., Devogelaer, J.P., Malghem, J. and Maldague, B. (1979): Roentgenologic evaluation of the action of the diphosphonate EHDP and of combined therapy (EHDP and calcitonin) in Paget's disease of bone. In: Molecular Endocrinology, p. 405. Editors: I. Maclntyre and M. Szelke. Elsevier North-Holland Biomedical Press, Amsterdam. 2. Castells, S., Colbert, Ch., Chakrabarti, Ch., Bachtell, R.S., Kassner, G.E. and Yasumura, S. (1979): Therapy of osteogenesis imperfecta with synthetic salmon calcitonin. J. Pediat., 95, 807. 3. Thomas, D.W., Frewin, D.B. and Jolley, P.T.
(1979): Deterioration in diabetic control during calcitonin therapy. Med. J. Aust., 2, 699. 4. Freed, W.J., Perlow, M.J. and Wyatt, R.J. (1979): Calcitonin: inhibitory effect on eating in rats. Science, 206,850. 5. Limberg, B. and KommereU, B. (1979): Somatostatin after failure of cimetidine for acute bleeding ulcers. Lancet, H, 1361. 6. Tyd6n, G., Samnegard, H., Thulin, L. and Efendic, S. (1979): Somatostatin and bleeding esophageal varice~ New Engl. J. Med., 301, 46. 7. Bonfils, S., Ren6, E., Pignal, F. and Ramhaud, J.C. (1979): Rebound effect after somatostatin treatment in Verner-Morrison syndrome. Lancet, H, 476.
400 8. Kelly, K., Stang, J.M. and Mekhjian, H.S. (1980): Vasopressin provocation of ventricular dysrhythmia. Ann. intern. Med., 92, 205. 9. Aronsen, K.F., Wetterlin, S., Emas, S., Vojtisek, V., Mulder, J.L. and Cort, J.H. (1975): Die Wirkung von Triglycyl-Lysin-Vasopressin auf Kontrollpersonen und Patienten mit Blutungen des oberen Gastrointestinaltraktes. Klin. ICschr., 53, 747. 10. Rabol, A., Juhl, E., Schmidt, A. and Winkler, K. (1976): The effect of vasopressin and triglycyl lysine vasopressin (glypressin) on the splanchnie circulation in cirrhotic patients with portal hypertension. Digestion, 14, 285. 11. Vosmik, J., Jedlicka, K., Mulder, J.L. and Cort, J.H. (1977): Action of the triglycyl hormonogen of vasopressin (glypressin) in patients with liver cirrhosis and bleeding esophageal varices. Gastroenterology, 72,605. 12. Akerlund, M. and Andersson, K.-E. (1976): Vasopressin response and terbutaline inhibition of the uterus. Obstet. Gynec., 48, 528. 13. Pavlin, V., Flynn, M.J., Mulder, J.L. and Cort, J.H. (1978): The treatment of uterine bleeding with vasopressin hormonogen (glypressin). A pilot study. Brit. J. Obstet. Gynaec., 85,801. 14. Cash, J.D., Gader, A. M. A., Mulder, J.L. and Cort, J.H. (1978): Structure-activity relations of the fibrinolytic response to vasopressins in man. Clin. Sci. molec. Med., 54,403. 15. Crowley, W.F., Beitins, I.Z., Vale, W., Kliman, B., Rivier, J., Rivier, C. and McArthur, J.W. (1980): The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men. New Engl. J. Med., 302, 1052. 16. Casper, R.F., Sheehan, K.L. and Yen, S. S. C. (1980): Gonadotropin-estradiol responses to a superactive luteinizing hormone-releasing hormone agonist in women. J. clin. Endrocr., 50, 179. 17. German, G.A. and Stampfer, H. G. (1979): Hypothalamic releasing factor for reactive depression. Lancet, II, 789. 18. Gambrell, R. D. and Greenblatt, R. B. (1979): Effect of gonadotropin-releasing hormone on depressed mood. Lancet, H, 1138. 19. Morley, J.E. (1979): Extrahypothalamic thyrotropin releasing hormone (TRH). Its distribution and its functions. Life Sciences, 25, 1539. 20. Veber, D. F,, Holly, F.W., Paleveda, W. J., Nutt, R.F., Bergstrand, S.J., Torchiana, M., Glitzer, M.S., Saperstein, R. and Hirschmann, R. (1978): Conformational restricted bicyclic analogs of somatostatin. Proc. nat. Acad. ScL USA, 75, 2636. 21. Milner, R . D . G . , Russell-Fraser, T., Brook, C. G, D., Cotes, P.M., Farquhar, J.W., Parkin, J.M., Preece, M.A., Snodgrass, G . J . A . I . , Mason, S.A., Tanner, J.M. and Vince, F.P. (1979): Experience with human growth-hormone
R. Bouillon and F. A. van Assche in Great Britain: the report of the MRC working party. Clin. Endocrinol., 11, 15. 22. Editorial (1980): Experience with growth hormone treatment in Great Britain. Brit. med. J., 1,270. 23. MacLennan, A.H., Green, R.C., BryantGreenwood, G.D., Greenwood, F.C. and Seamark, R.F. (1980): Ripening of the human cervix and induction of labour with purified porcine relaxin. Lancet, 1,220. 24. Editorial (1978): Circulating prostacyclin. Lancet, I1, 21. 25. Woods, H.F., Ash, G., Weston, M. J., Bunting, S., Moncade, S. and Vane, J.R. (1978): Prostacyclin can replace heparin in haemodialysis in dogs. Lancet, 11, 1075. i 26. Fidler, J., Bennett, M., De Swiet, M., Ellis, C. and Lewis, P. (1980): Treatment of pregnancy hypertension with prostaeyelin. Lancet, H, 31. 27. Fitzgerald, G.A., Friedman, L.A., Miyamori, J., O'Grady, J. and Lewis, P.J. (1979): A double blind placebo controlled crossover study of prostacyclin in man. Life Sciences, 25, 665. 28. Campos, G. and Liggins, G.C. (1979): Oral prostaglandin E2 for induction of labour at term. N. Z. med. J., 89,326. 29. Squires, D. J. P. and Masson, E.L. (1980): Induction of labour with oral prostaglandin E2: A Canadian multicentre study. J. int. reed. Res., 8, 175. 30. Bardos, A., Pohlova, G. and Bohacikova, A. (1980): Can oxytocin cause hyperbilirubinaemia in the newborn? Bratisl. Lek. Listy, 73, 161. 31. Imperale, F. and Mazzanti, A. (1979): Prostaglandins and ocytocin in labour and hyperbilirubinaemia in the newborn. Minerva Ginec., 31,531. , 32. Sander, R.Z., Knutzen, U.K., Milano, C.M. and Gleicher, N. (1979): Uterine rupture with the use of vaginal prostaglandin E2 suppositories. Amer. J. Obstet. Gynec., 134, 348. 33. Craft, J.L., Evans, D.V. and Richfield, L. B. (1979): Facilitation of suction termination using extra-amniotic prostaglandins in gel. Prostaglandins, 18, 143. 34. Cates Jr., W. and Jordaan, H. V. F. (1979): Sudden collapse and death of women obtaining abortions induced with prostaglandin F 2 ~. Amer. J. Obstet. Gynec., 133, 398. 35. Bygdeman, M. and Green, K. (1979): New prostaglandin E2 analogue for pregnancy termination. Lancet, I, 1136. 36. Wagatsuma, T., Tabuchi, T., Tabei, T. and Kaku, R. (1979): Interruption of pregnancy with vaginal suppositories containing 16,16Dimethyl-Trans-/\ 2 -prostaglandin E1 methyl ester. Contraception, 30, 383. 37. Callen, P. J., De Louvois, J., Hurley, R. and Trudinger, B.J. (1980): Intrapartum and postpartum pyrexia and infection after induction with extra-amniotic prostaglandin E2 in tylose. Brit. J. Obstet. Gynec., 87, 513.
45
Miscellaneous hormones and prostaglandins
Calcitonin Calcitonin has been found to be markedly superior to diphosphonates in the treatment of Paget's disease of bone. In a recent study calcitonin produced a positive focal bone balance in nearly all patients without serious side effects, whereas even small doses of EHDP (disodium etidronate) aggravated osteolytic Paget's diseases (1C R). Salmon calcitonin also increased bone density and reduced the annual fracture rate in 48 children with osteogenesis imperfecta (2c); again no serious side effects were observed. A single case of deterioration o f diabetic control has been described. In a 71-year-old diabetic female treated with 1 g tolbutamide daily, porcine calcitonin (80 IU/day) was started because of increasing pagetic bone pain. Plasma glucose more than doubled and heavy glucosuria occurred. Her diabetes was again well controlled after withdrawal of calcitonin (3c). The diabetic deterioration in this case might, however, have been due to an indirect effect of calcitonin, since she also complained of nausea, cramps and headaches during calcitonin therapy; stress and altered food intake may therefore have been the real reason for the loss of control. Like many other hormonal peptides, calcitonin also seems to have potential behavioral effects: subcutaneous or intracerebral injections of calcitonin inhibit feeding in rats(4). Whether endogenous calcitonin is really involved in the regulation of feeding and appetite in man requires further study.
Somatostatin The impressive effects of somatostatin on the secretion of many hormones and gastrointestinal functions have stimulated
researchers to look for potential applications. Bleeding from esophagal (5 c) or gastrointestinal ulcers (11 c) can be successfully stopped by somatostatin infusions, probably due to a reduction in splanchnic blood flow and to the very strong inhibition of gastric acid output occurring during somatostatin infusion. Mild abdominal discomfort was the only side effect noted (6c). The inhibitory effect of somatostatin on gastrointestinal secretions has also been exploited in the Verner-Morrison syndrome. A dramatic improvement in stool volume was observed, but arrest of therapy was followed by a rebound phenomenon, which could have resulted in rapid dehydration and electrolyte imbalance if not immediately corrected (7 c).
Vasopressin and its analogues Vasopressin has generalized vasoconstrictor properties and coronary ischemia and even myocardial infarction are therefore potential side effects, especially in patients with pre-existent coronary insufficiency (SEDA-3, 355). Vasopressininduced ventricular fibrillation has now also been reported in a 48-year-old woman (8c). She had no demonstrable coronary insufficiency but occasional premature ventricular contractions occurred. Because of upper gastrointestinal bleeding she received a bolus injection of vasopressin (1.3 IU/min. for 15 min.), which was followed by slight hypertension, bradycardia and ventricular fibrillation, successfully treated with cardioversion. A vasopressin analogue, triglycylqysinevasopressin has a prolonged pharmacologic action due to the slow release of the active nonapeptide after enzymic release in vivo. Clinical improvements in patients with gastrointestinal bleedings have been documented in a few preliminary open stud-
R. Bouillon and F. A. van Assche
398 ies(9 C, 10 c , 11c). Only a slight pressor effect and modest bradycardia were observed, without serious cardiovascular side effects. Similar favorable effects of this drug were observed in patients with uterine bleeding (12 C, 13c). Vasopressin, and especially some of its analogues (desmopressin, DDAVP), enhance plasminogen activator release and, therefore, could become attractive drugs for thrombolytic therapy (14 c ). Gonadotropin-releasing hormones A synthetic long-acting analogue of luteinizing hormone-releasing hormone, D-Trp6-Pro9-NEt-LHRH or LHRHa, has been tested in men and women (15 C, 16c). In comparison with the natural hormone, this compound was found to have a greater ability to release gonadotropins acutely and to sustain their release in normal and hypogonadotropic subjects. An increase in serum estradiol was observed after injection of LHRHa and not after the natural LHRH (15c). An improvement in sleep was observed after LHRH injection in depressed patients, followed by a sustained resolution of depressive symptoms in 8 patients with 'stress-associated depression' (17c). No such improvement was observed in unipolar or bipolar depression (17 c, 18c).
Thyr o tropin-releasing hormone Thyrotropin-releasing hormone (TRF) was originally isolated from hypothalami and stimulates thyrotropin release from the pituitary. This tripeptide, however, is distributed throughout the nervous system, the retina, pancreas, gastrointestinal tract, adrenals and placenta. It might well represent a ubiquitous neurotransmitter that rather by coincidence also functions as a pituitary-releasing factor (19R). The influence of TRF on behavior has been studied before and some analogues even have selective and powerful effects on the central nervous system (20 c).
Human growth hormone tropin)
(GH,
Somato-
A detailed report on the extensive experience with the clinical use of human growth hormone in GH-deficient children
has been published by the MRC Working Party in Britain (21CR). Three injections per week (3 x 5 IU) seem to be better than 2, even if the total dose per week is lower. Antibody formation is markedly more frequent with the Raben-type GH (66%) as opposed to the Wilheimi-type of GH extraction (18%). These antibodies do not decrease the growth response unless they have an association constant higher than 107 M-a and a binding capacity higher than 1 mg/l. The overall prevalence of growth-inhibiting antibodies is about 2 - 3 % . A decrease in thyroid function occurred only once in 241 patients, contradicting previous experience (SEDA-1, 325). As pointed out in an Editorial (22 R), the general results with GH therapy in idiopathic GH deficiency are satisfactory when treatment starts early in life. The mean age at the beginning of therapy is, however, still 2 - 3 years behind the optimal age. The second problem remains the marginal supply of hGH at least until the present extraction from human pituitaries can be replaced by means of production (e.g. bacterial synthesis after genetic engineering).
Relaxin Relaxin is a polypeptide hormone structually related to insulin and somatomedins. Purified porcine rr given on the evening before induction of labor induced labor in one-third of the patients and improved the cervical scores in the other 75%. Since uterine activity was not markedly enhanced a direct effect of relaxin on cervical ripening and subsequent parturition is suggested (23c). No side effects were experienced by the patients and no neonatal complications were observed. PROSTAGLANDINS AND OXYTOCIN
Prostaeycline Prostacyclin is an unstable prostaglandin, produced enzymatically by intact endothelial ceils, which inhibits platelet aggregation. In cases of endothelial lesions, however, another prostaglandin, called thromboxane A2, is produced by thrombocytes using the same or similar endoperoxidases. Thromboxane A2 then enhances throm-
Miscellaneous hormones and prostaglandins b o c y t e aggregation and subsequent b l o o d coagulation. Platelet aggregation thus seems to be regulated b y a balanced equilibrium b e t w e e n 2 prostaglandins, prostacyclin and t h r o m b o x a n e A2, secreted and p r o d u c e d by interactions of endothelial cells with t h r o m b o c y t e s (24 R, 25). The potential use o f these new prostaglandins in various diseases are n o w under study. Prostacyclin seems to have favorable effects in h y p e r tension with (26 c) or w i t h o u t pregnancy (27c). It is t o o early to draw conclusions as to possible adverse reactions.
Obstetric use of prostaglandins and oxytocin The indications and c o m p l i c a t i o n s of the therapeutic use o f prostaglandins and o x y tocin in obstetrics and g y n e c o l o g y are alm o s t the same as previously r e p o r t e d (SED 9, 719). The main indications for prostaglandins are mid-trimester a b o r t i o n and i n d u c t i o n of labor. F o r the i n d u c t i o n of labor oral prostaglandin E2 is m o s t l y used (28 C, 29 C). The most c o m m o n side effects are gastrointestinal complaints and uterine hypertonus. The c o m b i n e d use of prostaglandins and o x y t o c i n for the i n d u c t i o n o f labor m a y result in an increased incidence o f neonatal hyperbilirubinemia (30 c , 31 c ). F o r t e r m i n a t i o n of pregnancy the intramuscular and intra-amniotic ways of administration have been replaced by the use o f prostaglandin E2 in vaginal suppositories (32 C) or in gels for extra-amniotic use (33C). Sudden collapse, death and uterine rupture c o n t i n u e to be very rarely r e p o r t e d (32 c , 33 c , 34c). New analogues with supposedly less side effects have been in-
399 t r o d u c e d for t e r m i n a t i o n of pregnancy 35 c, 36c). Callen et al. (37 C) studied the incidence of intrapartum and postpartum pyrexia and infection after i n d u c t i o n with extra-amniotic prostaglandin E2 in tylose. 124 women, bearing 127 children, in whom labor was induced with extra-amniotic prostaglandin E2 in tylose were studied. High vaginal swabs taken from 11 patients immediately before insertion of prostaglandin E2 were examined, specific identification of microbes being restricted to those present in the amniotic fluid, to fred hemolytic streptococci, and to other specific microbes. Lancefield group B streptococci were isolated from 9 patients, and in 8 of these the microbes were isolated from the amniotic fluid. Amniotic fluid was examined from 86 patients and was shown to be contaminated with microbes potentially pathogenic for mother or baby in 11 out of 86 (13%) of the patients examined; in 8 patients, the contaminating pathogen was the group B streptococcus. All 127 blood cultures taken during or just after delivery were negative. Six out of 9 patients with a group B streptococcus in the vagina developed fever and proven streptococcal endometritis; one child developed fever and another streptococcal septicemia. Pyrexia and i n f e c t i o n cannot, of course, be regarded as true adverse effects o f prostaglandin E2, but t h e y are a c o n s e q u e n c e of the t e c h n i q u e in which this substance is e m p l o y e d , and the facts r e c o r d e d in this series, where o f the 124 w o m e n induced 12 developed intrapartum fever and 6 fever during the puerperium, underline the fact that the t e c h n i q u e has its risks, including the p e n e t r a t i o n o f pathogens from the vaginal fault.
REFERENCES i. Nagant de Deuxchaines, C., Rombouts-Lindemans, C., Huaux, J.P., Devogelaer, J.P., Malghem, J. and Maldague, B. (1979): Roentgenologic evaluation of the action of the diphosphonate EHDP and of combined therapy (EHDP and calcitonin) in Paget's disease of bone. In: Molecular Endocrinology, p. 405. Editors: I. Maclntyre and M. Szelke. Elsevier North-Holland Biomedical Press, Amsterdam. 2. Castells, S., Colbert, Ch., Chakrabarti, Ch., Bachtell, R.S., Kassner, G.E. and Yasumura, S. (1979): Therapy of osteogenesis imperfecta with synthetic salmon calcitonin. J. Pediat., 95, 807. 3. Thomas, D.W., Frewin, D.B. and Jolley, P.T.
(1979): Deterioration in diabetic control during calcitonin therapy. Med. J. Aust., 2, 699. 4. Freed, W.J., Perlow, M.J. and Wyatt, R.J. (1979): Calcitonin: inhibitory effect on eating in rats. Science, 206,850. 5. Limberg, B. and KommereU, B. (1979): Somatostatin after failure of cimetidine for acute bleeding ulcers. Lancet, H, 1361. 6. Tyd6n, G., Samnegard, H., Thulin, L. and Efendic, S. (1979): Somatostatin and bleeding esophageal varice~ New Engl. J. Med., 301, 46. 7. Bonfils, S., Ren6, E., Pignal, F. and Ramhaud, J.C. (1979): Rebound effect after somatostatin treatment in Verner-Morrison syndrome. Lancet, H, 476.
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