- Email: [email protected]
Miscellaneous hormones and prostaglandins
J.R. Peters
43
Miscellaneous hormones and prostaglandins
Calcitonin and analogues (SED-12, 1080;
SED-16, 499; SEDA-17, 494) Recent studies suggest that both intranasal salmon (1 c) and intramuscular eel (2 c) calcitonin reverse bone loss in established osteoporosis, with concurrent reduction in fracture rates. The use of intermittent or discontinuous therapy has been reported to provide a saving of 15% in lumbar bone mass (3c). Side effects are as previously documented (SEDA-17, 494; 4R), but do not generally limit their use. Reversible gynecomastia has been reported in a single case (5c).
Parathyroid hormone (SED-12, 1081;
SEDA-14, 378; SEDA-17, 494) Parathyroid hormone is one of several agents currently being promoted to prevent the osteoporosis associated with gonadotrophin- releasing hormone (GnRH) analogue treatment in women. PTH(1--34) administered subcutaneously in a dose of 40/xg daily, completely inhibited the 3% decrease in lumbar bone density seen during 6 months treatment with Nafarelin 200 /xg intranasal twice daily (6c). No significant side effects were observed in keeping with previous experience of acute administration (7c).
Human growth hormone (hGH, somatotrophin) (SED-12, 1081; S EDA-16,
501; SEDA-17, 494; SEDA-18, 421) The putative indications for therapeutic use of growth hormone have increased with the general clinical availability of the recombinant form of hGH. In addition to childhood deficiency, Turner's (8 c) and Noonan's (9 c) syn9 1996 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 19 J.K. Aronson and C.J. van Boxtel, eds.
402
dromes, and chronic renal failure (10c), its use in adult G H deficiency is well established (llR). Other potential areas for use include critical illness, chronic hemodialysis, aging and chronic neuromuscular disease (SEDA17, 495; 12R). Long-term treatment is associated with a low incidence of side effects (13R). Adults appear to experience a higher frequency of carpal tunnel syndrome and acral dysesthesiae (114). Benign intracranial hypertension (pseudotumor cerebri), associated with papilledema, remains the most significant subacute onset side effect (14c). The recurrence of malignancy in children treated subsequently with h G H remains unsubstantiated (15r A possible reason for the apparent association between leukemia and h G H treatment (16 c) may be undiagnosed Fanconi's anemia in children with short stature (17c). The incidence of insulin-dependent diabetes in a large cohort of children treated With growth hormone is no greater than that to be expected by chance (18r A longer-term risk may be a greater susceptibility in GH-replaced individuals to osteoarthrosis (19 R, 20r
Insulin-like growth factor I (hlGF-1) Recombinant human IGF-1, although currently unlicensed, has been used in a variety of clinical settings (21R). It is the peptide through which G H exerts most of its growth promoting effects, and administration causes reduced endogenous G H and insulin secretion, with increased insulin sensitivity (22c). In normals and in non-insulin-dependent diabetes, it improves glucose tolerance, increases lipid oxidation and decreases L D L cholesterol and V L D L triglycerides (23 c, 24c). In combination with h G H its anabolic effects are synergistic (25c). Possible clinical uses have been described
Miscellaneous hormones and prostaglandins
Chapter43
in diabetes (26c) to overcome insulin resistance, in AIDS-associated cachexia (27 c) and in neuromuscular wasting (12R). Acute side effects include hypoglycemia, which is dose related, and fluid retention at days 3--4 (28a). Pseudotumor cerebri has been reported as with hGH (14 c, 29c). Bilateral parotid pain on eating (25 c) occurs frequently, as do tachycardia and flushing (26r The side effect frequency compelled the latter authors to suspend their study before completing the 8-week trial of subcutaneous treatment. Others suggest that the side effects are less limiting (30 cR)
Growth-hormone-release inhibiting hormone (somatostatin) and analogues (SED-12, 1083; SEDA-16, 500; SEDA-17, 496) The indications for, and use of somatostatin and its analogues, have been summarized elsewhere (SEDA-17, 496; 31R--33R). The combination of somatostatin with bromocriptine in the treatment of acromegaly may confer therapeutic advantage (34c). The use of intrathecal somatostatin to control pain in terminal disease continues (35R), but may be associated with dorsal root and column demyelination (36c). Adverse effects are those previously described, local gastrointestinal and cholelithiasis (SEDA-17, 496). The debate continues about the magnitude of effect on glucose tolerance and lipid metabolism in treated acromegaly (37 r 38r Withdrawal headache has been reported (39c). The requirement for multiple daily subcutaneous administration of octreotide appears to have been overcome with the development of the longer-acting octapeptide lanreotide (40R), allowing an injection frequency of 1--2 weeks. Studies using lanreotide in acromegaly (41 c) and carcinoid syndrome (42 c) indicate comparable efficacy and side effect profile compared with octreotide.
Vasopressin (SED-12, 1084; SEDA-16, 500; SEDA-17, 497; SEDA-18, 422) Vasopressin is a hypothalamic octapeptide, transported to and secreted from the neurohypophysis, with mixed antidiuretic and vasoconstrictor properties (43R). Because of its potential to cause generalized
403
vasoconstriction, cutaneous pallor and increased blood pressure are dose-related adverse effects. Angina pectoris with myocardial infarction may occur with overdosage, and has been reported with local infiltration of vasopressin (44c), and of ornipressin, a synthetic analogue (45c). The difficulties of administration and adverse effects have favored the replacement of vasopressin by DDAVP (1-D-amino-8-D-arginine vasopressin or desmopressin), a synthetic analog with a prolonged duration of action and antidiuretic properties but little vasoconstrictor effect (46R). Hyponatremia and convulsions are increasingly reported, both with standard doses of DDAVP (47c, 48 c) and its use in combination with imipramine for nocturnal enuresis (50 c, 51c). The introduction of an oral formulation of desmopressin has coincided with renewed interest in the drug for nocturnal enuresis. Two studies in a total of 60 children and adolescents treated for between 6 and 12 weeks, suggest that two-thirds of individuals respond positively. There were no instances of water intoxication (52 c, 53c), and other adverse effects are rare. The drug also has hemostatic properties because of its ability to increase plasma concentrations of von Willebrand factor antigen 2--4-fold. It can therefore replace cryoprecipitate as treatment in some patients with factor IX deficiency (55c). However not all patients respond equally well (55 r 56c), and tachyphylaxis (57 c) or thrombocytopenia (58 c) may develop.
Gonadotrophin-releasing hormone (gonadorelin; GnRH) and analogues (SED-12, 1085; SEDA-16, 503; SEDA-17, 498; SEDA-18, 422) The hypothalamic releasing factor for both luteinizing hormone and follicle-stimulating hormone is a decapeptide, widely used in testing hypothalamic pituitary gonadal function. Several superagonist analogs with or without prolonged duration of action have been synthesized (59 R, 60R). The therapeutic indications for use of these agents have been summarized elsewhere (SEDA-17, 498). The most frequent adverse effects are symptoms of hypoestrogenism (hot flushes in almost all patients) and, less frequently, vaginal dryness, decreased libido and breast dis-
404 comfort, initial headache and bleeding. Severe flushing which appears not uncommonly may be treated with either clonidine (61 c) or the dopamine receptor antagonist, veralipride (62 c, 63c). Ovarian hyperstimulation is less frequent than with gonadotrophin treatment in amenorrheic w o m e n (64 c, 6 5 c a ) , and there appears to be no difference in the effect of different analogues to induce follicle cyst formation (66c). Osteoporosis in the form of a reduction of trabecular b o n e density, has b e e n regularly observed with chronic gonadorelin agonist treatment, but was initially reportedly reversible within 6 months of withdrawal, and was not considered a contraindication (67 c, 68R). Later reports however suggest m o r e rapid onset during t r e a t m e n t and less complete reversal of bone loss following discontinuation
Chapter 43
J.R. Peters
of G n R H (69 c, 70 R, 71r The prospect of routine 'add-back' concurrent treatment to prevent osteoporotic bone loss in this setting is increasing (72CR). Estrogens alone have been shown not to be effective (73c). Other more promising candidates include combinations of etidronate and norethindrone (74c), parathyroid h o r m o n e (6c), and the non-hormonal agent, ipriflavone (75c). O t h e r recently reported side effects to G n R H include thrombocytopenia in a patient with S L E (76c), and obstructive renal failure due to ureteric fibrosis in a patient treated for endometriosis (77c). In general, however, cumulative experience in large numbers of patients (78 R) suggests that in the treatment of benign gynecological conditions, apart from the incidence of predictable hypoestrogenic effects, gonadorelin agonists are associated with few acute adverse effects.
REFERENCES 1. Overgaard K, Hansen MA, Jensen SB et al. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. Br Med J 1992; 305:556--61. 2. Astengo F, Della Monica A, Fontana L, Fuliano P, Bigolari M. Efficacy and safety of two elcatonin regimens in the treatment of osteoporosis. Curr Ther Res 1994;55(12):1518-- 1526. 3. Overgaard K, Hansen MA, Hers Nielsen VA et al. Discontinuous calcitonin treatment of established osteoporosis: effect of withdrawal of treatment. Am J Med 1990;89:1--6. 4. Louis V, Avioli MD. Calcitonin therapy in osteoporotic syndromes. Rheum Dis Clin North Am 1994;20(3):777--785. 5. Vankrunkelsven PJ, Thijs MM. Salcatonin and gynaecomastia. Lancet 1994;344:482. 6. Finkelstein JS, Klibanski A, Schaefer EH, Hornstein MS, Schiff I, Neer RM. Parathyroid hormone for the prevention of bone loss induced by estrogen deficiency. New Engl J Med 1994;331(24):1618---1623. 7. Mallette LE. Synthetic human parathyroid hormone 1--34 fragment for diagnostic testing. Am Intern Med 1988;109:800--804. 8. Price DA, Clayton PE, Crowne EH, Roberts CR. Safety and efficacy of human growth hormone treatment in girls with Turner syndrome. Horm Res 1993;39(Suppl 2):44--48. 9. Thomas BC, Stanhope R. Long term treatment with growth hormone in Noonan's syndrome. Acta Pediatr 1993;82:853--855. 10. Fine RN, Kohaut EC, Brown D, Perlman A.
Growth after recombinant human growth hormone treatemnt in children with chronic renal failure: report of a multicentre randomised double-blind placebo-controlled study. J Pediatr 1994;124:374--382. 11. Jorgensen JOL, Muller J, Moller J, Wolthers T, Vahl N, Juul A, Skakkeboek NE, Christiansen JS. Adult growth hormone deficiency. Horm Res 1994;42:241. 12. Moxley RT. Potential for growth factor treatment of muscle disease. Curr Opin Neurol 1994;7:427--434. 13. Riedel M, Brabant G, Rieger K, von zur Muhlen A. Growth hormone therapy in adults: rationales, results, and perspectives. Exp Clin Endocrinol 1994;102:273--283. 14. Malozowksi S, Tanner LA, Wysowski D, Fleming GA. Growth hormone insulin-like factor 1 and benign intracranial hypertension. New Engl J Med 1993;329:665--666. 15. Ogilvy Stuart AI, Ryder WD, Gattamaneni HR, Clayton PE, Shalet SM. Growth hormone and tumour recurrence. Br Med J 1992; 304:1601 -- 1604 16. Fisher DA, Job JC, Preece M, Underwood LE. Leukaemia in patients treated with growth hormone. Lancet 1988fi:1159--1160. 17. Butturini A, Bernasconi S, Izzi G, Gertner JM, Gale RP. Short stature, Fanconi's anaemia, and risk of leukaemia after growth hormone therapy. Lancet 1994;343:1576. 18. Czernichow P, Albertsson-Wikland K, Tuvemo T, Gunnarsson R. Growth hormone treatment and diabetes: survey of the Kabi Pharmacia
Miscellaneous hormones and prostaglandins
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International Growth Study. Acta Paediatr Scand 1991 ;379(Suppl): 104-- 107. 19. Lamberts SWJ, Valk NK, Binnerts A. The use of growth hormone in adults: a changing scene. Clin Endocrinol 1992;37: I 11 -- 115. 20. Bagge E, Eden S, Rosen T, Bengtsson BA. The prevalence of radiographic osteoarthritis is low in elderly patients with growth hormone deficiency. Acta Endocrinol 1993;129:296--300. 21. Froesch ER, Zenobi PD, Hussain M. Metabolic and therapeutic effects of insulin-like growth factor I. Horm Res 1994;42:66--71. 22. Guler HP, Schmid Ch, Zapf J, Froesch ER. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci USA 1989;86:2868--2872. 23. Zenobi PD, Jaeggi-Groisman SE, Riesen W, Roder M, Froesch ER. Insulin-like growth factor I improves glucose and lipid metabolism in type 2 diabetes mellitus. J Clin Invest 1992;90:2234-2241. 24. Zenobi PD, Graf S, Ursprung H, Froesch ER. Effects of insulin-like growth factor I on glucose tolerance, insulin levels, and insulin secretion. J Clin Invest 1992;89:1908--1913. 25. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest 1993;91:391--396. 26. Jabri N, Schalch DS, Schwartz SL, Fischer JS, Kipnes MS, Radnik B J, Turman N J, Marcsisin VS, Guler HP. Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. Diabetes 1994;43(3):369--374. 27. Lieberman SA, Butterfield GE, Harrison D, Hoffman AR. Anabolic effects of recombinant insulin-like growth factor-I in cachectic patients with the acquired immnnodeficiency syndrome. J Clin Endocrinol Metab 1994;78(2):404--410. 28. Froesch ER, Hussain M. Metabolic effects of insulin-like growth factor-I with special reference to diabetes. Acta Paediatr Suppl 1994;399:165-170. 29. Lordereau-Richard I, Roger M, Chaussain JL. Transient bilateral papilloedema in a 10 year old boy treated with recombinant insulin-like growth factor I for growth hormone receptor deficiency. Acta Paediatr Suppl 1994;399:152. 30. Ranke MB, Wilton P. Adverse events during treatment with recombinant insulin-like growth factor I in patients with growth hormone insensitivity. Acta Paediatr Suppl 1994;399(1):143--145. 31. Tauber MT, Harris AG, Rochiccioli P. Clinical use of the long acting somatostatin analogue octreotide in pediatrics. Cur J Pediatr 1994; 153:304--310. 32. Oberg K. Treatment of neuroendocrine tumors. Cancer Treatment Reviews 1994;20:331-355. 33. Acromegaly Therapy Consensus Development Panel. Consensus Statement: Benefits versus risks of medical therapy for acromegaly. Am J Med 1994;97:468--473.
405
34. Flogstad AK, Halse J, Grsss P, Abisch E, Djoseland O, Kutz K, Bodd E, Jervell J. A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. J Clin Endocrinol Metab 1994;97(2):461--465. 35. Yaksh TL. Spinal somatostatin for patients with cancer: Risk benefit assessment of an analgesic. Anesthesiology 1994;81(3):531--533. 36. Mollenholt P, Rawal N, Gordh T, Olsson Y. Intrathecal and epidural somatostatin for patients with cancer: Analgesic effects and postmortem neuropathologic investigations of spinal root and nerve roots. Anesthesiology 1994;81(3):534--542. 37. Koop BL, Harris AG, Ezzat S. Effect of octreotide on glucose tolerance in acromegaly. Cur J Endocrinol 1994;130(6):581--586. 38. Benito P, Calanas A, Galvez MA, Corpas MS. Effect of octreotide on plasma lipid metabolism on acromegaly. Ann Pharmaeother 1994;28:1198. 39. May A, Lederbogen S, Diener HC. Octreotide dependency and headache: a case report. Cephalalgia 1994;14:303--304. 40. Robinson C, Castaner J. Lanreotide Acetate. Drugs Future 1994;19(11):992--999. 41. Marek J, Hana V, Krsek M, Justova V, Catus F, Thomas F. Long term treatment of acromegaly with the slow-release somatostatin analogue lanreotide. Cur J Endocrinol 1994;131(1):20--26. 42. Scherubl H, Widenmann B, Riecken CO, Thomas F, Bohme E, Rath U. Treatment of carcinoid syndrome with a depot formulation of the somatostatin analogue lanreotide. Cur J Cancer 1994;30A(10):1591-- 1592. 43. Sandow J, Konig W. Chemistry of the hypothalamic hormones. In: Jeffcoate SL, Hutchinson JSM, eds. The Endocrine Hypothalamus. London: Academic Press, 1978;149. 44. Martin JD, Shenk LG. Intraoperative myocardial infarction after paracervical vasopressin infiltration. Anesth Analg 1994;79:1201-- 1202. 45. Veit S, Muser HG, Bottcher E, Bruckner JB. Myocardial ischaemia following peritonsillar infiltration of ornipressin. Anaesthesist 1993; 42:320--323. 46. Richardson DW, Robinson AG. Desmopressin. Ann Intern Med 1985;103:228--239. 47. Beach PS, Beach RE, Smith LR. Hyponatremic seizures in a child treated with desmopressin to control enuresis. A rational approach to fluid intake. Clin Paediatr 1992;31:566--569. 48. Humphries JE, Siragy H. Significant hyponatremia following DDAVP administration in a healthy adult. Am J Hematol 1993;4412--4415. 49. Kallio J, Rautava P, Huupponen R, Korvenranta H. Severe hyponatremia caused by intranasal desmopressin for nocturnal enuresis. Acta Paediatr Intern J Paediatr 1993;82:881-882. 50. Hamed M, Mitchell H, Clow DJ. Hyponatremic convulsion associated with desmopressin and imipramine treatment. Br Med J 1993; 306:1169. 51. Hourihane J, Salisbury AJ. Use caution in prescribing desmopressin for nocturnal enuresis. Br Med J 1993;306:1545. 52. Stenberg A, Lackgren G. Desmopressin tab-
406 lets in the treatment of severe nocturnal enuresis in adolescents. Pediatrics 1994;94(6):841--846. 53. Matthiesen TB, Rittig S, Djurhuus JC, Norgaard JP. A dose titration, and an open 6-week efficacy and safety study of desmopressin tablets in the management of nocturnal enuresis. J Urol 1994;151(2):460--463. 54. Nieuwenhuis HK, Sixma JJ. 1-Desamino-8-Darginine vasopressin (desmopressin) shortens the bleeding time in storage pool deficiency. Ann Intern Med 1988;108:65--67. 55. Kyrle PA, Niessner H, Dent J, Panzer S, Brenner B, Zimmerman TS, Lechner K. IIB yon Willebrand's disease: pathogenetic and therapeutic studies. Br J Haematol 1988;69:55--59. 56. Casonato A, Pontara E, Dannhaeuser D, Bertomoro A, Sartori MT, Zerbinati P, Girolami A. Re-evaluation of the therapeutic efficacy of DDAVP in type IIB yon Willebrand's disease. Blood Coagul Fibrinolysis 1994;5(6):959--964. 57. Mannucci PM, Bettega D, Cattaneo M. Patterns of development of tachyphylaxis in patients with haemophilia and yon Willebrand disease after repeated doses of desmopressin (DDAVP). Br J Haematol 1992;82:87--93. 58. Castaman G, Rodeghiero F, Lattuada A, Mannucci PM. Desmopressin-induced thrombocytopenia in type 1 platelet discordant yon Willebrand disease. Am J Hematol 1993;43:5--9. 59. Barbieri RL. Clinical applications of GnRH and its analogues. Trends Endocrinol Metab 1992;3:30--34. 60. Crowley WF Jr, Beitins IZ, Vale W, Kliman B, Rivier J, Rivier C, McArthur JW. The biologic activity of a potent analogue of gonadotropinreleasing hormone in normal and hypogonadotropic men. New Engl J Med 1980;302:1052-1057. 61. Bressler LR, Murphy CM, Shevrin DH, Warren RF. Use of clonidine to treat hot flushes secondary to leuprolide or goserelin. Ann Pharmacother 1993;27:182--185. 62. Vercellini P, Vendola N, Colombo A, Passadore C, Trespidi L, Crosignani PG. Veralipride for hot flushes during gonadotropin releasing hormone agonist treatment. Gynaecol Obstet Invest 1992;34:102-- 104. 63. Vercellini P, Sacerdote P, Trespidi L, Manfredi B, Panerai AE, Crosignani PG. Veralipride for hot flushes induced by a gonadotropin-releasing hormone agonist: A controlled study. Fertil Steril 1994;62(5):938--942. 64. Geisthovel F, Peters F, Breckwoldt M. Ovarian hyperstimulation due to long term pulsatile intravenous G n R H treatment. Arch Gynaecol 1985 ;236:255 -- 259. 65. Rizk B, Smitz J. Ovarian hyperstimulation syndrome after superovulation using GnRH agon-
Chapter 43
J.R. Peters
ists for IVF and related procedures. Hum Reprod 1992;7:320--327. 66. Tarlatzis BC, Bili H, Bontis J, Lagos S, Vatev 1, Mantalenakis S. Follicle cyst formation after administration of different gonadotrophin releasing hormone analogues for assisted reproduction. Hum Reprod 1994;9(11):1983--1986. 67. Matta WH, Shaw RH, Hesp R, Evans R. Reversible trabecular bone density loss following induced hypo-oestrogenism with the GnRH analogue buserelin in premenopausal women. Clin Endocrinol 1988;29:45--51. 68. Fogelman I. Gonadotropin-releasing hormone agonists and the skeleton. Fertil Steril 1992; 57:715--724. 69. Orwoll ES, Yuzpe AA, Burry KA, Heinrichs L, Buttram VC Jr, Hornstein MD. Nafarelin therapy in endometriosis: Long-term effects on bone mineral density. Am J Obstet Gynecol 1994; 171(5): 1221-- 1225. 70. Dawood MY. Hormonal therapies for endometriosis: Implications for bone metabolism. Acta Obstet Gynecol Scand Suppl 1994;73(159):22-34. 71. Maillefert JF, Sibilia J, Kuntz JL, Tavernier C. Gonadotrophin-releasing hormone agonists induce osteoporosis. Br J Rheumatol 1994;33:12. 72. Adashi EY. Long term gonadotrophin releasing hormone agonist therapy: The evolving issue of steroidal 'add back' paradigms. Hum Reprod 1994;9(7):1380-- 1397. 73. Leather AT, Studd JWW, Watson NR, Holland EFN. The prevention of bone loss in young women treated with GnRH analogues with 'addback' estrogen therapy. Obstet Gynecol 1993; 81:104-- 107. 74. Surrey ES, Fournet N, Voigt B, Judd HL. Effects of sodium etidronate in combination with low-dose norethindrone in patients administered a long-acting G n R H agonist: a preliminary report. Obstet Gynecol 1993;81:581--586. 75. Gambacciani M, Spinetti A, Piaggesi L, Cappagli B, Taponeco F, Manetti P, Weiss C, Teti GC, La-Commare P, Facchini V. Ipriflavone prevents the bone mass reduction in premenopausal women treated with gonadotropin hormone-releasing hormone agonists. Bone Miner 1994; 26(1):19--26. 76. Miyagawa S, Shirai T, Shimamoto I, Ichijo M. Worsening of systemic lupus erythematousassociated thrombocytopenia after administration of gonadotropin-releasing hormone analog. Arthr Rheum 1994;37(11):1708--1709. 77. Barrington, JW, Roberts A. Acute renal failure precipitated by luteinizing hormone releasing hormone analogue for the treatment of endometriosis. Br J Urol 1994;74:672. 78. Miller RM, Frank RA. Zoladex (goserelin) in the treatment of benign gynaecological disorders: an overview of safety and efficacy. Br J Obstet Gynaecol 1992;99(Suppl 7):37--41.
43
Miscellaneous hormones and prostaglandins
Calcitonin and analogues (SED-12, 1080;
SED-16, 499; SEDA-17, 494) Recent studies suggest that both intranasal salmon (1 c) and intramuscular eel (2 c) calcitonin reverse bone loss in established osteoporosis, with concurrent reduction in fracture rates. The use of intermittent or discontinuous therapy has been reported to provide a saving of 15% in lumbar bone mass (3c). Side effects are as previously documented (SEDA-17, 494; 4R), but do not generally limit their use. Reversible gynecomastia has been reported in a single case (5c).
Parathyroid hormone (SED-12, 1081;
SEDA-14, 378; SEDA-17, 494) Parathyroid hormone is one of several agents currently being promoted to prevent the osteoporosis associated with gonadotrophin- releasing hormone (GnRH) analogue treatment in women. PTH(1--34) administered subcutaneously in a dose of 40/xg daily, completely inhibited the 3% decrease in lumbar bone density seen during 6 months treatment with Nafarelin 200 /xg intranasal twice daily (6c). No significant side effects were observed in keeping with previous experience of acute administration (7c).
Human growth hormone (hGH, somatotrophin) (SED-12, 1081; S EDA-16,
501; SEDA-17, 494; SEDA-18, 421) The putative indications for therapeutic use of growth hormone have increased with the general clinical availability of the recombinant form of hGH. In addition to childhood deficiency, Turner's (8 c) and Noonan's (9 c) syn9 1996 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 19 J.K. Aronson and C.J. van Boxtel, eds.
402
dromes, and chronic renal failure (10c), its use in adult G H deficiency is well established (llR). Other potential areas for use include critical illness, chronic hemodialysis, aging and chronic neuromuscular disease (SEDA17, 495; 12R). Long-term treatment is associated with a low incidence of side effects (13R). Adults appear to experience a higher frequency of carpal tunnel syndrome and acral dysesthesiae (114). Benign intracranial hypertension (pseudotumor cerebri), associated with papilledema, remains the most significant subacute onset side effect (14c). The recurrence of malignancy in children treated subsequently with h G H remains unsubstantiated (15r A possible reason for the apparent association between leukemia and h G H treatment (16 c) may be undiagnosed Fanconi's anemia in children with short stature (17c). The incidence of insulin-dependent diabetes in a large cohort of children treated With growth hormone is no greater than that to be expected by chance (18r A longer-term risk may be a greater susceptibility in GH-replaced individuals to osteoarthrosis (19 R, 20r
Insulin-like growth factor I (hlGF-1) Recombinant human IGF-1, although currently unlicensed, has been used in a variety of clinical settings (21R). It is the peptide through which G H exerts most of its growth promoting effects, and administration causes reduced endogenous G H and insulin secretion, with increased insulin sensitivity (22c). In normals and in non-insulin-dependent diabetes, it improves glucose tolerance, increases lipid oxidation and decreases L D L cholesterol and V L D L triglycerides (23 c, 24c). In combination with h G H its anabolic effects are synergistic (25c). Possible clinical uses have been described
Miscellaneous hormones and prostaglandins
Chapter43
in diabetes (26c) to overcome insulin resistance, in AIDS-associated cachexia (27 c) and in neuromuscular wasting (12R). Acute side effects include hypoglycemia, which is dose related, and fluid retention at days 3--4 (28a). Pseudotumor cerebri has been reported as with hGH (14 c, 29c). Bilateral parotid pain on eating (25 c) occurs frequently, as do tachycardia and flushing (26r The side effect frequency compelled the latter authors to suspend their study before completing the 8-week trial of subcutaneous treatment. Others suggest that the side effects are less limiting (30 cR)
Growth-hormone-release inhibiting hormone (somatostatin) and analogues (SED-12, 1083; SEDA-16, 500; SEDA-17, 496) The indications for, and use of somatostatin and its analogues, have been summarized elsewhere (SEDA-17, 496; 31R--33R). The combination of somatostatin with bromocriptine in the treatment of acromegaly may confer therapeutic advantage (34c). The use of intrathecal somatostatin to control pain in terminal disease continues (35R), but may be associated with dorsal root and column demyelination (36c). Adverse effects are those previously described, local gastrointestinal and cholelithiasis (SEDA-17, 496). The debate continues about the magnitude of effect on glucose tolerance and lipid metabolism in treated acromegaly (37 r 38r Withdrawal headache has been reported (39c). The requirement for multiple daily subcutaneous administration of octreotide appears to have been overcome with the development of the longer-acting octapeptide lanreotide (40R), allowing an injection frequency of 1--2 weeks. Studies using lanreotide in acromegaly (41 c) and carcinoid syndrome (42 c) indicate comparable efficacy and side effect profile compared with octreotide.
Vasopressin (SED-12, 1084; SEDA-16, 500; SEDA-17, 497; SEDA-18, 422) Vasopressin is a hypothalamic octapeptide, transported to and secreted from the neurohypophysis, with mixed antidiuretic and vasoconstrictor properties (43R). Because of its potential to cause generalized
403
vasoconstriction, cutaneous pallor and increased blood pressure are dose-related adverse effects. Angina pectoris with myocardial infarction may occur with overdosage, and has been reported with local infiltration of vasopressin (44c), and of ornipressin, a synthetic analogue (45c). The difficulties of administration and adverse effects have favored the replacement of vasopressin by DDAVP (1-D-amino-8-D-arginine vasopressin or desmopressin), a synthetic analog with a prolonged duration of action and antidiuretic properties but little vasoconstrictor effect (46R). Hyponatremia and convulsions are increasingly reported, both with standard doses of DDAVP (47c, 48 c) and its use in combination with imipramine for nocturnal enuresis (50 c, 51c). The introduction of an oral formulation of desmopressin has coincided with renewed interest in the drug for nocturnal enuresis. Two studies in a total of 60 children and adolescents treated for between 6 and 12 weeks, suggest that two-thirds of individuals respond positively. There were no instances of water intoxication (52 c, 53c), and other adverse effects are rare. The drug also has hemostatic properties because of its ability to increase plasma concentrations of von Willebrand factor antigen 2--4-fold. It can therefore replace cryoprecipitate as treatment in some patients with factor IX deficiency (55c). However not all patients respond equally well (55 r 56c), and tachyphylaxis (57 c) or thrombocytopenia (58 c) may develop.
Gonadotrophin-releasing hormone (gonadorelin; GnRH) and analogues (SED-12, 1085; SEDA-16, 503; SEDA-17, 498; SEDA-18, 422) The hypothalamic releasing factor for both luteinizing hormone and follicle-stimulating hormone is a decapeptide, widely used in testing hypothalamic pituitary gonadal function. Several superagonist analogs with or without prolonged duration of action have been synthesized (59 R, 60R). The therapeutic indications for use of these agents have been summarized elsewhere (SEDA-17, 498). The most frequent adverse effects are symptoms of hypoestrogenism (hot flushes in almost all patients) and, less frequently, vaginal dryness, decreased libido and breast dis-
404 comfort, initial headache and bleeding. Severe flushing which appears not uncommonly may be treated with either clonidine (61 c) or the dopamine receptor antagonist, veralipride (62 c, 63c). Ovarian hyperstimulation is less frequent than with gonadotrophin treatment in amenorrheic w o m e n (64 c, 6 5 c a ) , and there appears to be no difference in the effect of different analogues to induce follicle cyst formation (66c). Osteoporosis in the form of a reduction of trabecular b o n e density, has b e e n regularly observed with chronic gonadorelin agonist treatment, but was initially reportedly reversible within 6 months of withdrawal, and was not considered a contraindication (67 c, 68R). Later reports however suggest m o r e rapid onset during t r e a t m e n t and less complete reversal of bone loss following discontinuation
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of G n R H (69 c, 70 R, 71r The prospect of routine 'add-back' concurrent treatment to prevent osteoporotic bone loss in this setting is increasing (72CR). Estrogens alone have been shown not to be effective (73c). Other more promising candidates include combinations of etidronate and norethindrone (74c), parathyroid h o r m o n e (6c), and the non-hormonal agent, ipriflavone (75c). O t h e r recently reported side effects to G n R H include thrombocytopenia in a patient with S L E (76c), and obstructive renal failure due to ureteric fibrosis in a patient treated for endometriosis (77c). In general, however, cumulative experience in large numbers of patients (78 R) suggests that in the treatment of benign gynecological conditions, apart from the incidence of predictable hypoestrogenic effects, gonadorelin agonists are associated with few acute adverse effects.
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