- Email: [email protected]
Miscellaneous hormones and prostaglandins
J.R. Peters
44
Miscellaneous hormones and prostaglandins
Editorial note In SEDA-17, Chapter 45 cons&ted of an extensive overview o f the literature covering far more than only references from 1992. In 1993, only a few articles were published with new information relevant to this chapter. It was therefore decided to include in this" chapter this year only those entries bearing new references of relevance.
Human growth hormone (hGH; somatotrophin) (SED-12, 1081; SEDA-14, 378; SEDA-15, 464; SEDA-16, 501; SEDA-17, 494) The usage, optimal timing, and dosage of growth hormone replacement therapy have been extensively studied (SEDA-14, 379; (1R)). New indications are chronic renal failure in children (2c), and Noonan's syndrome (3c). Long-term treatment is associated with a low incidence of adverse effects (4c). Adverse effects of growth hormone include irritation or lipodystrophy at the injection site. A slipped capitular femoral epiphysis has been reported (5~ but this may have been related to growth itself rather than the treatment (6R). Thyroid dysfunction has been repeatedly observed and may be due to the effect of growth hormone on the conversion of T4 to T3 (7c), or to the unmasking of prior TSH deficiency (8c). Even the administration of relatively high doses of growth hormone (0.3 U/kg/day) to children with short stature causes no impairment of glucose disposal as a consequence of predictable increased insulin secretion (9c). The incidence of insulin-dependent diabetes mellitus in a large cohort of children treated with growth
9 1995 Elsevier Science B.V. All rights reserved.
Side Eff'ects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
hormone is no larger than is to be expected by chance (10CR). Since 1986, 23 cases of benign intracranial hypertension (pseudotumor cerebri) have been reported in cases treated with recombinant hGH. All were symptomatic and with papilloedema. More than half presented within 8 weeks of begining treatment (11R).
Growth hormone-releasing hormone (GHRH) (SED-12, 1082; SEDA-14, 380; SEDA-15, 467, SEDA-16, 500; SEDA-17, 495) Evaluation of the clinical potential and adverse effects of a G H R H test using synthetic G H R H (91M4)-NH 2 in prepubertal children showed peak growth hormone concentrations at 120 min after injection of 2 r This correlated with the growth hormone area under the curve. Adverse effects were frequent, but mild transient facial skin flushing was reported during 81 of 574 tests, whereas a sensation of thoracic constriction, pallor, transient taste sensations, headache, nausea, transient hypotension or hypertension, and bradycardia or tachycardia occurred in less than 2% of cases. A single bolus injection of G H R H was therefore considered to be well tolerated and a potentially useful test for the evaluation of growth delay (12OR). Prolonged pulsatile G H R H administration (1/tg/kg every 3 h subcutaneously for 6 months followed by 2 r for another 6 months) was well tolerated. There were no changes in hematology, or in liver or kidney function. Worsening of pre-existing thyroid failure was observed in one child (13c). The acute growth hormone response to G H R H is in general a poor indicator of the growth response that may be expected to occur in response to long-term pulsatile G H R H infusion (14c), but a marked improvement in the mean growth rate can occur without seri421
422 ous adverse effects. However, the growth rate may be no better than with growth hormone therapy (13c, 15~, 16c).
Growth hormone-release inhibiting hormone (somatostatin) and analogs (SED-12, 1083; SEDA-14, 381; SEDA-15, 467, SEDA-16, 501; SEDA-17, 496) The use of somatostatin and its analogs is well established in the management of gastroentero-pancreatic tumors. The largest series (17 g) has shown most potential symptomatic benefit in cases of the carcinoid syndrome (80-90%), followed by VIPoma, glucagonoma, gastrinoma and insulinoma (50% improvement each). Experience with rarer peptide-secreting tumors is limited. Octreotide and related somatostatin analogs under development have been used as labeled probes for the identification of endocrine tumors (18 g, 19R).
Vasopressln (SED-12, 1084; SEDA-14, 386; SEDA-15, 463; SEDA-16, 500; SEDA-17, 497) Vasopressin is a hypothalamic octopeptide, transported to and secreted from the neurohypophysis, with mixed antidiuretic and vasoconstrictor properties (20R). Because of its potential to causes generalized vasoconstriction, cutaneous pallor and increased blood pressure are dose-related adverse events. Angina pectoris with myocardial infarction may occur with overdosage, and has been reported with local infiltration of ornipressin, a synthetic analog (21c). 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 (22R). Hyponatremia and convulsions are increasingly reported, both with standard doses of DDAVP (23c-25~), and its use in combination with imipramine for nocturnal enuresis (26c, 27c). 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- to 4-fold. It can therefore replace cryoprecipitate as treatment in some patients with
Chapter 44 .I.R. Peters factor IX deficiency (28c). However, not all patients respond equally well (29c) and tachyphylaxis (30c), or thrombocytopenia (3 lC), may develop.
Gonadotrophin-releasing hormone (gonadorelin; GnRH) and analogs (SED-12, 1085; SEDA-14, 382; SEDA-15, 469; SEDA-16, 503; SEDA-17, 498) 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 (32c, 33R). The most frequent adverse effects are symptoms of hypoestrogenism (hot flushes in almost all patients), and less frequently, vaginal dryness, decreased libido and breast discomfort, initial headache and bleeding. Severe flushing, which occurs not uncommonly, may be treated effectively with either clonidine (34c), or the dopamine receptor antagonist veralipride (3Y). Ovarian hyperstimulation is less frequent than with gonadotrophin treatment in amenorrheic women (36~ 37CR). Osteoporosis, in the form of a reduction in trabecular bone density, has been regularly observed in men as well as women (38 c) with chronic gonadorelin agonist treatment, but is reversible within 6 months of withdrawal and is not considered to be a contraindication (39c, 40R). Reports of higher incidence of fatigue, depression and headache in patients taking intranasal compared with subcutaneous regimens (41c), have yet to be confirmed. Pl'ostaglandins E2, F2,~ 12 and analogs (SED-12, 1091; SEDA-14, 387; SEDA-1L 387) Prostacyclin infusions (using PGI2 or its synthetic analog iloprost) have been used during extracorporeal circulation to inhibit platelet aggregation in the dialysis coil (42c). Synthetic PGI: has also been used in ischemic arterial occlusive disease (43 cg, 44c), and ciprostene by continuous intravenous infusion can increase claudication time in non-critical peripheral vascular disease (45c). Fever, nausea, anorexia, diarrhea, and local pain at the infu-
Miscellaneous hormones and prostaglandins
Chapter 44
sion site are among the many reported adverse effects. A single study has suggested an increased risk of thromboembolism after the use of iloprost in peripheral vascular disease (46c). Prostaglandins of the E-type (misoprostol, enprostil) have antiulcer activity in the upper gastrointestinal tract (47CR). They inhibit gastric acid secretion and in lower dosages provide mucosal protection, particularly against nonsteroidal anti-inflammatory drugs. Diarrhea (4~38%), abdominal pain or cramps, flatulence, and nausea or vomiting account for most of the adverse effects, but these appear to be outweighed by the reduced risk of gastrointestinal
423
bleeding, when used in combination with N S A I D s (48c). Intracorporeal PGE1 induces artificial penile erection in cases of dysfunction; adverse effects are primarily local pain and burning (49c). PGEI may be more effective in combination with calcitonin gene-related peptide (50c). Massive diffuse hemorrhage in cystitis due to cyclophosphamide or radiation has been treated successfully with P G E 2 and (15S)-15methyl-PGF2~ intravesically. Febrile reactions and severe bladder spasm are dose-dependent (51c), and may be less with the newer F2~ prostaglandin analog carboprost tromethamine (52c).
REFERENCES 1. Laron Z, Butenandt O (1991) Optimum use of growth hormone in children. Drugs, 42, 1-8. 2. Fine RN, Kohaut EC, Brown D, Perlman A (1994) Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized doubleblind placebo-controlled study. J. Pediat~, 124, 374-382. 3. Thomas BC, Stanhope R (1993) Long-term treatment with growth hormone in Noonan's syndrome. Acta Pediatr., 82, 853 855. 4. Price DA, Clayton PE, Crowne EH, Roberts CR (1993) Safety and efficacy of human growth hormone treatment in girls with Turner Syndrome. Horm. Res., 39 (Suppl. 2), 44 A8. 5. Schmid H, Hauffa BP (1993) Acceleration of epiphyseolysis capitis femoris lenta as a complication of growth hormone therapy in pituitary insufficiency. Klin. Padiatr., 205, 59-63. 6. Frasier SD (1983) Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocr. Rev., 4, 155 170. 7. Grunfeld C, Sherman BM, Cavalieri RR (1988) The acute effects of human growth hormone administation on thyroid function in normal men. J. Clin. Endocrinol. Metab., 67, 1111 1114. 8. Drayer NM (1988) Neveneffecten van groeihormoonbehandeling. Tijdschr. Kindergeneesk., 56 (Suppl. 1), 4041. 9. Walker J, Chaussain JL, Bougneres PF (1989) Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal. J. Clin. Endocrinol. Metab., 69, 253-258. 10. Czernichow P, Albertsson-Wikland K, Tuvemo T, Gunnarsson, R. (1991) Growth hormone treatment and diabetes: survey of the Kabi Pharmacia
International Growth Study. Acta Paediatr. Seand., 379 (Suppl.), 104-107. 11. Malozowksi S, Tanner LA, Wysowski D, Fleming GA (1993) Growth hormone, insulin-like growth factor 1, and benign intracranial hypertension. New Engl. Z Med., 329, 665 666 12. Chatelain P, Alamercery Y, Blanchard J, Boissel JP, Evain-Brion D, Morre M, Olivier M, Sizonenko P, van Vliet G (1987) Growth hormone (GH) response to a single intravenous injection of synthetic GH-releasing hormone in prepubertal children in growth failure. J. Clin. Endocrinol. Metab., 65, 387 394. 13. Low LCK, Wang C, Cheung PT, Ho P, Lam KS, Young RT, Yeung CY, Ling N (1988) Long term pulsatile growth hormone (GH)-releasing hormone therapy in children with GH deficiency. J. Clin. Endocrinol. Metab., 66, 611-617. 14. Hoffman DM, O'Sullivan AJ, Baxter RC, Ho KKY (1994) Diagnosis of growth-hormone deficiency in adults. Lancet, 343, 1064-1068. 15. Thorner MO, Rogol AD, Martha P, Chitwood JS, Klingensmith G J, Burr I, Najjar-Reichlin S, Smith P, et al (1987) The potential of GRF as a therapeutic agent in children with short stature. In: Laron Z, Butenandt D, Raita S (Eds.), Pediatric and Adolescent Endocrinology, Vol. 16, Clinieal Use of Growth Hormone." Present and Future Aspects, Karger, Basel, pp. 246-253. 16. Smith PJ, Brook CGD (1987) The place of intravenous GHRH 140 studies in the therapy of growth hormone deficient children with GHRH. Clin. Endocrinol., 27, 97 108. 17. Trautmann ME, Neuhaus Ch, Lenze H, Benning R, Benning M, Dennler H J, Bruns, Ch, Joseph K, Arnold R (1993) The role of somatostatin analogs in the treatment of endocrine gastrointesti-
424 nal tumors. Horm. Metab. Res, Suppl. 27, 24-27. 18. Lamberts SWJ, Holland LJ, De Herder WW, Kwekkeboom DJ, Reubi JC, Krenning EP (1993) Octreotide and related somatostatin analogs in the diagnosis and treatment of pituitary disease and somatostatin receptor scintigraphy. Front. Neuroendocrinol., 14, 27-55. 19. Fahlbusch R, Giovanelli M, Buchfelder M, Losa M (1993) Advances in the medical and surgical treatment of pituitary adenomas: the role of long-acting somatostatin analogs. J. Endocrinol. Invest., 16, 449~,60. 20. Sandow J, Konig W (1978) Chemistry of the hypothalamic hormones. In: Jeffcoate SL, Hutchinson JSM (Eds)., The Endocrine Hypothalamus, Academic Press, London, p. 149. 21. Veit S, Muser HG, Bottcher E, Bruckner JB (1993) Myocardial ischaemia following peritonsillar infiltration of ornipressin. Anaesthesist, 42, 320323. 22. Richardson DW, Robinson AG (1985) Desmopressin. Ann. Intern. Med., 103, 228-239. 23. Beach PS, Beach RE, Smith LR (1992) Hyponatremic seizures in a child treated with desmopressin to control enuresis. A rational approach to fluid intake. Clin. Paediatr., 31, 566--569. 24. Humphries JE, Siragy H (1993) Significant hyponatremia following DDAVP administration in a healthy adult. Am. J. Hematol., 4412~1415. 25. Kallio J, Rautava P, Huupponen R, I(orvenranta H (1993) Severe hyponatremia caused by intransal desmopressin for nocturnal enuresis. Acta Paediatr. Intern. ,L Paediatr, 82, 881-882. 26. Hamed M, Mitchell H, Clow DJ (1993) Hyponatraemic convulsion associated with desmopressin and imipramine treatment. Br. Med. J. 306, 1169. 27. Hourihane J, Salisbury AJ (1993) Use caution in prescribing desmopressin for nocturnal enuresis. Br. Med. J. 306, 1545. 28. Nieuwenhuis HK, Sixma JJ (1988) 1-Desamino-8-D-arginine vasopressin (desmopressin) shortens the bleeding time in storage pool deficiency. Ann. lntern. Meal, 108, 65-67 29. Kyrle PA, Niessner H, Dent J, Panzer S, Brenner B, Zimmerman TS, Lechner K (1988) liB von Willebrand's disease: pathogenetic and therapeutic studies. Br. J. Haematol., 69, 55-59. 30. Mannucci PM, Bettega D, Cattaneo M (1992) Patterns of development of tachyphylaxis in patients with haemophilia and von Willebrand disease after repeated doses of desmopressin (DDAVP). B~ J. Haematol., 82, 87 93. 31. Castaman G, Rodeghiero F, Lattuada A, Mannucci PM (1993) Desmopressin-induced thrombocytopenia in type I platelet discordant von Willebrand disease. Am. J. Hematol., 43, 5-9. 32. Barbieri RL (1992) Clinical applications of GnRH and its analogues. Trends Endocrinol. Metab., 3, 30 34.
Chapter 44 J.R. Peters 33. Crowley WF Jr, Beitins IZ, Vale W, Kliman B, Rivier J, Rivier C, McArthur JW (1980) The biologic activity of a potent analogue of gonadotropin-releasing hormone in normal and hypogonadotropic men. New EngL Z Med., 302, 1052 1057. 34. Bressler LR, Murphy CM, Shevrin DH, Warren RF (1993) Use of clonidine to treat hot flushes secondary to leuprolide or goserelin. Ann. Pharmacother, 27, 182-185. 35. Vercellini P, Vendola N, Colombo A, Passadore C, Trespidi L, Crosignani PG (1992) Veralipride for hot flushes during gonadotropin releasing hormone agonist treatment. Gynaecol. Obstet. Invest., 34, 102-104. 36. Geisthovel F, Peters F, Breckwoldt M (1985) Ovarian hyperstimulation due to long term pulsatile intravenous GnRH treatment. Arch. Gynaecol., 236, 255-259. 37, Rizk B, Smitz J (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum. Reprod., 7, 320 327. 38, Goldray D, Weisman Y, Jaccard N, Merdler C (1993) Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6-GnRH). Z Clin. Endocrinol. Metab., 76, 288-290. 39. Matta WH, Shaw RW, Hesp R, Evans R (1988) Reversible trabecular bone density loss following induced hypo-oestrogenism with the GnRH analogue buserelin in premenopausal women. Clin. Endocrinol., 29, 45-51. 40. Fogelman 1 (1992) Gonadotropin releasing hormone agonists and the skeleton. Fertil. Steril., 57, 715-724 41. Tapanainen J, Hovatta O, Juntunen K (1993) Subcutaneous goserelin versus intranasal buserelin for pituitary down-regulation in patients undergoing IVF: A randomized comparative study. Hum. Reprod., 8, 2052 2055. 42. Zusman RM, Rubin RH, Cato AE, Cocchetto DM, Crow JW, Tolkoff-Rubin N (1981) Hemodialysis using prostacyclin instead of heparin as the sole antithrombotic agent. New Engl. J. Med., 304, 934-939. 43. Gruss JD, Vargas-Mantano H, Barrels D, et al. (1984) Use of prostaglandins in arterial occlusion diseases. Int. Angiol., 3 (Suppl.), 7-17. 44. Nizankowksi R, Krolikowski W, Bielatowicz J, Szczeklik A (1985) Prostacyclin for ischemic ulcers in peripheral arterial disease. A random assignment, placebo controlled study. Thromb. Res., 37, 2128. 45. Wolf DL, Metzler CM, Froeschke MO, Luderer J (1993) Continuous intravenous dosing with ciprostene using a portable pump in ambulatory patients. J. Clin. Pharmacol. 33, 150-153. 46. Kovacs IB, Mayou SC, Kirby JD (1991) Infu-
Miscellaneous hormones and prostaglandins
Chapter 44
sion of a stable prostacyclin analogue, iloprost, to patients with peripheral vascular disease: lack of antiplatelet effect but risk of thromboembolism. Am. ,L Med, 90, 41-46. 47. O'Keefe SJD, Spitaels JM, Mannion G, Naiker N (1985) Misoprostol, a synthetic prostaglandin Et analogue, in the treatment of duodenal ulcers. A double blind, cimetidine-controlled trial. South Afr. Med J., 67, 321 324. 48. Gagnier P (1993) Review of the safety of diclofenac/misoprostol. Drugs, 45 (SuppL 1), 3135. 49. Waldhauser M, Schramek P (1988) Efficiency and side effects of prostaglandin E t in the treatment of erectile dysfunction..L UroZ, 140, 525 527.
425
50. Djamilian M, Stief CG, Kuczyk M, Jonas U (1993) Follow up results of a combination of calcitonin gene-related peptide and prostaglandin El in the treatment of erectile dysfunction. J. Urol. 149 (Suppl. 5), 1296-1298. 51. Hemal AK, Vaidyanathan S, Sankaranarayanan A, Ayyagari, S, Sharma PL (I988) Control of massive vesical hemorrhage due to radiation cystitis with intravesical instillation of (15s)-I 5-methyl-prostaglandin Fz~. Int. J. Clin. Pharmacol. Ther. Toxicol., 26, 477-478. 52. Levine LA, Jarrard DF (1993) Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine. J. UroZ, 149, 719-723.
44
Miscellaneous hormones and prostaglandins
Editorial note In SEDA-17, Chapter 45 cons&ted of an extensive overview o f the literature covering far more than only references from 1992. In 1993, only a few articles were published with new information relevant to this chapter. It was therefore decided to include in this" chapter this year only those entries bearing new references of relevance.
Human growth hormone (hGH; somatotrophin) (SED-12, 1081; SEDA-14, 378; SEDA-15, 464; SEDA-16, 501; SEDA-17, 494) The usage, optimal timing, and dosage of growth hormone replacement therapy have been extensively studied (SEDA-14, 379; (1R)). New indications are chronic renal failure in children (2c), and Noonan's syndrome (3c). Long-term treatment is associated with a low incidence of adverse effects (4c). Adverse effects of growth hormone include irritation or lipodystrophy at the injection site. A slipped capitular femoral epiphysis has been reported (5~ but this may have been related to growth itself rather than the treatment (6R). Thyroid dysfunction has been repeatedly observed and may be due to the effect of growth hormone on the conversion of T4 to T3 (7c), or to the unmasking of prior TSH deficiency (8c). Even the administration of relatively high doses of growth hormone (0.3 U/kg/day) to children with short stature causes no impairment of glucose disposal as a consequence of predictable increased insulin secretion (9c). The incidence of insulin-dependent diabetes mellitus in a large cohort of children treated with growth
9 1995 Elsevier Science B.V. All rights reserved.
Side Eff'ects of Drugs Annual 18 J.K. Aronson and C.J. van Boxtel, eds.
hormone is no larger than is to be expected by chance (10CR). Since 1986, 23 cases of benign intracranial hypertension (pseudotumor cerebri) have been reported in cases treated with recombinant hGH. All were symptomatic and with papilloedema. More than half presented within 8 weeks of begining treatment (11R).
Growth hormone-releasing hormone (GHRH) (SED-12, 1082; SEDA-14, 380; SEDA-15, 467, SEDA-16, 500; SEDA-17, 495) Evaluation of the clinical potential and adverse effects of a G H R H test using synthetic G H R H (91M4)-NH 2 in prepubertal children showed peak growth hormone concentrations at 120 min after injection of 2 r This correlated with the growth hormone area under the curve. Adverse effects were frequent, but mild transient facial skin flushing was reported during 81 of 574 tests, whereas a sensation of thoracic constriction, pallor, transient taste sensations, headache, nausea, transient hypotension or hypertension, and bradycardia or tachycardia occurred in less than 2% of cases. A single bolus injection of G H R H was therefore considered to be well tolerated and a potentially useful test for the evaluation of growth delay (12OR). Prolonged pulsatile G H R H administration (1/tg/kg every 3 h subcutaneously for 6 months followed by 2 r for another 6 months) was well tolerated. There were no changes in hematology, or in liver or kidney function. Worsening of pre-existing thyroid failure was observed in one child (13c). The acute growth hormone response to G H R H is in general a poor indicator of the growth response that may be expected to occur in response to long-term pulsatile G H R H infusion (14c), but a marked improvement in the mean growth rate can occur without seri421
422 ous adverse effects. However, the growth rate may be no better than with growth hormone therapy (13c, 15~, 16c).
Growth hormone-release inhibiting hormone (somatostatin) and analogs (SED-12, 1083; SEDA-14, 381; SEDA-15, 467, SEDA-16, 501; SEDA-17, 496) The use of somatostatin and its analogs is well established in the management of gastroentero-pancreatic tumors. The largest series (17 g) has shown most potential symptomatic benefit in cases of the carcinoid syndrome (80-90%), followed by VIPoma, glucagonoma, gastrinoma and insulinoma (50% improvement each). Experience with rarer peptide-secreting tumors is limited. Octreotide and related somatostatin analogs under development have been used as labeled probes for the identification of endocrine tumors (18 g, 19R).
Vasopressln (SED-12, 1084; SEDA-14, 386; SEDA-15, 463; SEDA-16, 500; SEDA-17, 497) Vasopressin is a hypothalamic octopeptide, transported to and secreted from the neurohypophysis, with mixed antidiuretic and vasoconstrictor properties (20R). Because of its potential to causes generalized vasoconstriction, cutaneous pallor and increased blood pressure are dose-related adverse events. Angina pectoris with myocardial infarction may occur with overdosage, and has been reported with local infiltration of ornipressin, a synthetic analog (21c). 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 (22R). Hyponatremia and convulsions are increasingly reported, both with standard doses of DDAVP (23c-25~), and its use in combination with imipramine for nocturnal enuresis (26c, 27c). 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- to 4-fold. It can therefore replace cryoprecipitate as treatment in some patients with
Chapter 44 .I.R. Peters factor IX deficiency (28c). However, not all patients respond equally well (29c) and tachyphylaxis (30c), or thrombocytopenia (3 lC), may develop.
Gonadotrophin-releasing hormone (gonadorelin; GnRH) and analogs (SED-12, 1085; SEDA-14, 382; SEDA-15, 469; SEDA-16, 503; SEDA-17, 498) 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 (32c, 33R). The most frequent adverse effects are symptoms of hypoestrogenism (hot flushes in almost all patients), and less frequently, vaginal dryness, decreased libido and breast discomfort, initial headache and bleeding. Severe flushing, which occurs not uncommonly, may be treated effectively with either clonidine (34c), or the dopamine receptor antagonist veralipride (3Y). Ovarian hyperstimulation is less frequent than with gonadotrophin treatment in amenorrheic women (36~ 37CR). Osteoporosis, in the form of a reduction in trabecular bone density, has been regularly observed in men as well as women (38 c) with chronic gonadorelin agonist treatment, but is reversible within 6 months of withdrawal and is not considered to be a contraindication (39c, 40R). Reports of higher incidence of fatigue, depression and headache in patients taking intranasal compared with subcutaneous regimens (41c), have yet to be confirmed. Pl'ostaglandins E2, F2,~ 12 and analogs (SED-12, 1091; SEDA-14, 387; SEDA-1L 387) Prostacyclin infusions (using PGI2 or its synthetic analog iloprost) have been used during extracorporeal circulation to inhibit platelet aggregation in the dialysis coil (42c). Synthetic PGI: has also been used in ischemic arterial occlusive disease (43 cg, 44c), and ciprostene by continuous intravenous infusion can increase claudication time in non-critical peripheral vascular disease (45c). Fever, nausea, anorexia, diarrhea, and local pain at the infu-
Miscellaneous hormones and prostaglandins
Chapter 44
sion site are among the many reported adverse effects. A single study has suggested an increased risk of thromboembolism after the use of iloprost in peripheral vascular disease (46c). Prostaglandins of the E-type (misoprostol, enprostil) have antiulcer activity in the upper gastrointestinal tract (47CR). They inhibit gastric acid secretion and in lower dosages provide mucosal protection, particularly against nonsteroidal anti-inflammatory drugs. Diarrhea (4~38%), abdominal pain or cramps, flatulence, and nausea or vomiting account for most of the adverse effects, but these appear to be outweighed by the reduced risk of gastrointestinal
423
bleeding, when used in combination with N S A I D s (48c). Intracorporeal PGE1 induces artificial penile erection in cases of dysfunction; adverse effects are primarily local pain and burning (49c). PGEI may be more effective in combination with calcitonin gene-related peptide (50c). Massive diffuse hemorrhage in cystitis due to cyclophosphamide or radiation has been treated successfully with P G E 2 and (15S)-15methyl-PGF2~ intravesically. Febrile reactions and severe bladder spasm are dose-dependent (51c), and may be less with the newer F2~ prostaglandin analog carboprost tromethamine (52c).
REFERENCES 1. Laron Z, Butenandt O (1991) Optimum use of growth hormone in children. Drugs, 42, 1-8. 2. Fine RN, Kohaut EC, Brown D, Perlman A (1994) Growth after recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter randomized doubleblind placebo-controlled study. J. Pediat~, 124, 374-382. 3. Thomas BC, Stanhope R (1993) Long-term treatment with growth hormone in Noonan's syndrome. Acta Pediatr., 82, 853 855. 4. Price DA, Clayton PE, Crowne EH, Roberts CR (1993) Safety and efficacy of human growth hormone treatment in girls with Turner Syndrome. Horm. Res., 39 (Suppl. 2), 44 A8. 5. Schmid H, Hauffa BP (1993) Acceleration of epiphyseolysis capitis femoris lenta as a complication of growth hormone therapy in pituitary insufficiency. Klin. Padiatr., 205, 59-63. 6. Frasier SD (1983) Human pituitary growth hormone (hGH) therapy in growth hormone deficiency. Endocr. Rev., 4, 155 170. 7. Grunfeld C, Sherman BM, Cavalieri RR (1988) The acute effects of human growth hormone administation on thyroid function in normal men. J. Clin. Endocrinol. Metab., 67, 1111 1114. 8. Drayer NM (1988) Neveneffecten van groeihormoonbehandeling. Tijdschr. Kindergeneesk., 56 (Suppl. 1), 4041. 9. Walker J, Chaussain JL, Bougneres PF (1989) Growth hormone treatment of children with short stature increases insulin secretion but does not impair glucose disposal. J. Clin. Endocrinol. Metab., 69, 253-258. 10. Czernichow P, Albertsson-Wikland K, Tuvemo T, Gunnarsson, R. (1991) Growth hormone treatment and diabetes: survey of the Kabi Pharmacia
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Miscellaneous hormones and prostaglandins
Chapter 44
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425
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