Skip to main content
SpringerLink
Log in

LH-RH Antagonists: State of the Art and Future Perspectives

  • Chapter
Peptides in Oncology I

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 124))

Abstract

Luteinizing hormone-releasing hormone (LH-RH) is produced in hypothalamic nuclei, travels via the portal blood to the anterior pituitary, and acts on gonadotropic cells by inducing the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The gonadotropic hormones, in turn, regulate gonadal steroid production and gametogenesis. Reproductive functions, therefore, are critically dependent on LH-RH whose stimulatory effects are determined by its pulsatile release pattern (Knobil 1980) and by the availability of high-affinity binding sites at the pituitary site (Clayton and Catt 1981). Consequently, interference with the binding of native LH-RH to its pituitary receptors will provoke alterations of gonadal functions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adams LA, Bremner WJ, Nestor JJ Jr, Vickery BH, Steiner RA (1986) Suppression of plasma gonadotropins and testosterone in adult male monkeys (Macaca fascicularis) by a potent inhibitory analog of gonadotropin-releasing hormone. J Clin Endocrinol Metab 62:58–63

    Article  PubMed  CAS  Google Scholar 

  • Akhtar FB, Marshall GR, Wickings EJ, Nieschlag E (1983) Reversible induction of azoospermia in rhesus monkeys by constant infusion of a GnRH agonist using osmotic minipumps. J Clin Endocrinol Metab 56:534–540

    Article  PubMed  CAS  Google Scholar 

  • Akhtar FB, Weinbauer GF, Nieschlag E (1985) Acute and chronic effects of a gonadotrophin-releasing hormone antagonist on pituitary function in monkeys. J Endocrinol 104:345–354

    Article  CAS  Google Scholar 

  • Arslan M, Weinbauer GF, Khan SA, Nieschlag E (1989) Testosterone and dihydrotestos-terone, but not estradiol, selectively maintain pituitary and serum follicle-stimulating hormone in gonadotropin-releasing hormone antagonist treated male rats. Neuroen-docrinology 49:395–401

    CAS  Google Scholar 

  • Asch RH, van Sickle M, Rettori V, Balmaceda JP, Eddy CA, Coy DH, Scrially AV (1981) Absence of LH-RH binding sites in corpora lutea from rhesus monkeys (Macaca mulat-ta). J Clin Endocrinol Metab 53:215–217

    Article  PubMed  CAS  Google Scholar 

  • Bagatell CJ, McLachlan RI, de Kretser DM, Burger HG, Vale WW, Rivier J, Bremner WJ (1989) A comparison of the suppressive effects of testosterone and a potent new gonadotropin-releasing hormone antagonist on gonadotropin and inhibin levels in normal men. J Clin Endocrinol Metab 69:43–48

    Article  PubMed  CAS  Google Scholar 

  • Bajusz S, Scernus VJ, Janaky T, Bokser L, Fekete M, Schally AV (1988 a) New antagonists of LH-RH: II. Inhibition and potentiation of LH-RH by closely related analogues. Int J Pept Protein Res 32:425–435

    Article  PubMed  CAS  Google Scholar 

  • Bajusz S, Kovacs M, Gazdag M, Bokser L, Karashima T, Csernus VJ, Janaky T, Guoth J, Schally AV (1988 b) Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects. Proc Natl Acad Sci USA 85:1637–1641

    Article  PubMed  CAS  Google Scholar 

  • Behre HM, Klein B, Steinmeyer E, Nieschlag E (1991) Effective suppression of luteinizing hormone and testosterone by single doses of the new gonadotropin-releasing hormone antagonist SB-75 in normal men. 73rd annual meeting of the Endocrine Society, Washington, June 12-15 (abstract 1155)

    Google Scholar 

  • Behre HM, Nashan D, Hubert W, Nieschlag E (1992) Depot GnRH agonist blunts the androgen-induced suppression of spermatogenesis in a clinical trial for male contraception. J Clin Endocrinol Metab 74:84–90

    Article  PubMed  CAS  Google Scholar 

  • Bhasin S, Yuan QX, Steiner BS, Swerdloff RS (1987) Hormonal effects of gonadotropin-releasing hormone (GnRH) agonist in men: effects of long term treatment with GnRH agonist infusion and androgen. J Clin Endocrinol Metab 65:568–574

    Article  PubMed  CAS  Google Scholar 

  • Bhasin S, Fielder T, Peacock N, SodMoriah UA, Swerdloff RS (1988) Dissociating antifertility effects of GnRH antagonists from its adverse effects on mating behavior in male rats. Am J Physiol 32:E84–E91

    Google Scholar 

  • Boccon-Gibod L, Laudat MH, Dugue MA, Steg A (1986) Cyproterone acetate prevents initial rise of serum testosterone induced by luteinizing hormone-releasing hormone analogs in the treatment of metastatic carcinoma of the prostate. Eur Urol 12:400–402

    PubMed  CAS  Google Scholar 

  • Bokser L, Bajusz S, Groot K, Schally AV (1990) Prolonged inhibition of luteinizing hormone and testosterone levels in male rats with the luteinizing hormone-releasing hormone antagonist SB-75. Proc Natl Acad Sci USA 87:7100–7104

    Article  PubMed  CAS  Google Scholar 

  • Bokser L, Skralovic G, Szepeshazi K, Schally AV (1991) Recovery of pituitary-gonadal function in male and female rats after prolonged administration of a potent antagonist of luteinizing hormone-releasing hormone (SB-75). Neuroendocrinology 54:136–145

    Article  PubMed  CAS  Google Scholar 

  • Braden TD, Conn PM (1990) Altered rate of synthesis of gonadotropin-releasing hormone receptors: effects of homologous hormone appear independent of extracellular calcium. Endocrinology 126:2577–2582

    Article  PubMed  CAS  Google Scholar 

  • Bremner WJ, Bagatell CJ, Steiner RA (1991) Gonadotropin-releasing hormone antagonist plus testosterone: a potential male contraceptive. J Clin Endocrinol Metab 73:465–469

    Article  PubMed  CAS  Google Scholar 

  • Brensing KA, Schepke M, Enzweiler CH, Lademacher CH, Klingmüller D (1991) The new GnRH antagonist (“SB-75”) induced a safe and effective testosterone suppression in normal men: a phase I study. Acta Endocrinol (Copenh) 124:9 (abstr)

    Google Scholar 

  • Burgus R, Butcher M, Amoss M, Ling N, Monahan MW, Rivier J, Fellows T, Blackwell R, Vale W, Guillemin R (1972) Primary structure of the ovine hypothalamic luteinizing hormone-releasing hormone factor (LRF). Proc Natl Acad Sci USA 69:278–285

    Article  PubMed  CAS  Google Scholar 

  • Carone FA, Stetler-Stevenson MA, May V, LaBarbera A, Flouret G (1987) Differences between in vitro and in vivo degradation of LH-RH by rat brain and other organs. Am J Physiol 253:E317–E321

    PubMed  CAS  Google Scholar 

  • Cetel NS, Rivier J, Vale W, Yen SSC (1983) The dynamics of gonadotropin inhibition in women induced by an antagonistic analog of gonadotropin-releasing hormone. J Clin Endocrinol Metab 57:62–65

    Article  PubMed  CAS  Google Scholar 

  • Chan RL, Chaplin MD (1985) Plasma binding of LH-RH and nafarelin acetate, a highly potent LH-RH agonist. Biochem Biophys Res Commun 127:673–679

    Article  PubMed  CAS  Google Scholar 

  • Chan RL, Ho W, Webb AS, LaFargue JA, Nerenberg CA (1988) Disposition of Detirelix, a potent luteinizing hormone-releasing hormone antagonist, in rat and monkeys. Pharm Res 5:335–340

    Article  PubMed  CAS  Google Scholar 

  • Chillik CF, Itskovitz J, Hahn DW, McGuire JL, Danforth DR, Hodgen GD (1987) Characterizing pituitary response to a gonadotropin-releasing hormone (GnRH) antagonist in monkeys: tonic follicle-stimulating hormone/luteinizing hormone secretion versus acute GnRH challenge tests before, during and after treatment. Fertil Steril 48:480–485

    PubMed  CAS  Google Scholar 

  • Clayton RN, Catt KJ (1980) Receptor-binding affinity of gonadotropin-releasing hormone analogs: analysis by radioligand-receptor assay. Endocrinology 106:1154–1159

    Article  PubMed  CAS  Google Scholar 

  • Clayton RN, Catt KJ (1981) Gonadotropin-releasing hormone receptors: characterization, physiological regulation and relationship to reproductive function. Endocr Rev 2:186–209

    Article  PubMed  CAS  Google Scholar 

  • Clayton R, Huhtaniemi I (1982) Absence of gonadotropin-releasing hormone receptors in human gonadal tissue. Nature 299:56–59

    Article  PubMed  CAS  Google Scholar 

  • Clayton RN, Channabasavaiah K, Stewart JM, Catt KJ (1982) Hypothalamic regulation of pituitary gonadotropin-releasing hormone receptors: effects of hypothalamic lesions and a gonadotropin-releasing hormone antagonist. Endocrinology 110:1108–1115

    Article  PubMed  CAS  Google Scholar 

  • Clermont Y (1972) Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. Physiol Rev 52:198–236

    PubMed  CAS  Google Scholar 

  • Conn PM, Crowley WF Jr (1991) Gonadotropin-releasing hormone and its analogues. N Engl J Med 324:93–103

    Article  PubMed  CAS  Google Scholar 

  • Couzinet B, Lahlou N, Thomas G, Thalabard JC, Bouchard P, Roger M, Schaison G (1991) Effects of gonadotrophin releasing hormone antagonist and agonist on the pulsatile release of gonadotrophins and alpha-subunit in postmenopausal women. Clin Endocrinol (Oxf) 34:477–483

    Article  CAS  Google Scholar 

  • Coy DH, Horvath A, Nekola MV, Coy EJ, Erchegyi J, Schally AV (1982) Peptide antagonists of LH-RH: large increases in antiovulatory activities produced by basic D-amino acids in the six position. Endocrinology 110:1445–1449

    Article  PubMed  CAS  Google Scholar 

  • Crawford ED, Allen JA (1990) Treatment of newly diagnosed state D2 prostate cancer with leuprolide and flutamide or leuprolide alone, phase III, Intergroup study 0036. J Steroid Biochem Mol Biol 37:961–963

    Article  PubMed  CAS  Google Scholar 

  • Csernus VJ, Szende B, Groot K, Redding TW, Serially AV (1990) Development of a radioim-munoassay for a potent luteinizing hormone-releasing hormone antagonist. Drug Res 40:111–118

    CAS  Google Scholar 

  • Dahl KD, Pavlou SN, Kovacs WJ, Hsueh AJW (1986) The changing ratio of serum bioactive to immunoreactive follicle-stimulating hormone in normal men following treatment with gonadotropin releasing hormone antagonist. J Clin Endocrinol Metab 63:792–794

    Article  PubMed  CAS  Google Scholar 

  • Dahl KD, Bicsak TA, Hsueh AJW (1988) Naturally occurring antihormones: secretion of FSH antagonists by women treated with a GnRH analog. Science 239:72–74

    Article  PubMed  CAS  Google Scholar 

  • Daneshdoost L, Pavlou SN, Molitch ME, Gennarelli TA, Savino PJ, Sergott RC, Bosley TM, Rivier JE, Vale WV, Snyder PJ (1990) Inhibition of follicle-stimulating hormone secretion from gonadotroph adenomas by repetitive administration of a gonadotropin-releas-ing hormone antagonist. J Clin Endocrinol Metab 71:92–97

    Article  PubMed  CAS  Google Scholar 

  • Danforth DR, Gordon K, Leal JA, Williams RF, Hodgen GD (1990) Extended presence of antide (Nal-Lys GnRH antagonist) in circulation: prolonged duration of gonadotropin inhibition may derive from antide binding to serum proteins. J Clin Endocrinol Metab 70:554–556

    Article  PubMed  CAS  Google Scholar 

  • Danforth DR, Williams RF, Gordon K, Hodgen GD (1991 a) Inhibition of pituitary gonadotropin secretion by the gonadotropin-releasing hormone antagonist antide: I. In vitro studies on mechanism of action. Endocrinology 128:2036–2040

    Article  PubMed  CAS  Google Scholar 

  • Danforth DR, Williams RF, Gordon K, Leal JA, Hodgen GD (1991 b) Inhibition of pituitary gonadotropin secretion by the gonadotropin-releasing hormone antagonist antide: II. Development of an in vitro bioassay for characterization of pharmacokinetics and pharmacodynamics of antide in circulation. Endocrinology 128:2041–2044

    Article  PubMed  CAS  Google Scholar 

  • Davis MR, Veldhuis JD, Rogol AD, Dufau ML, Catt KJ (1987) Sustained inhibitory actions of a potent antagonist of gonadotropin-releasing hormone in postmenopausal women. J Clin Endocrinol Metab 64:1268–1274

    Article  PubMed  CAS  Google Scholar 

  • de Voogt HJ, Klijn JGM, Studer U, Schröder F, Sylvester R, de Pauw M (1990) Orchidecto-my versus buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843. J Steroid Biochem Mol Biol 37:965–969

    Article  PubMed  Google Scholar 

  • Duello TM, Nett TM, Farquhar MG (1983) Fate of a gonadotropin-releasing hormone agonist internalized by rat pituitary gonadotrophs. Endocrinology 112:1–10

    Article  PubMed  CAS  Google Scholar 

  • Flouret G, Stettler-Stevenson MA, Carone FA, Peterson DR (1984) Enzymatic degradation of LH-RH and analogs. In: Vickery BH, Nestor JJ Jr, Hafez ESE (eds) LH-RH and its analogs. MTP Press, Lancaster, pp 397–410

    Chapter  Google Scholar 

  • Franchimont P, Aimer SM, Charlet-Renard CJ, Daubresse CL, Kicovic PP (1991) Effects of a novel gonadotropin-releasing hormone antagonist (ORG 30850) on gonadotropin and prolactin secretion by rat pituitary cells in culture. Acta Endocrinol (Copenh) 124:98–106

    CAS  Google Scholar 

  • Fraser HM, Baird DT, McRae GI, Nestor JJ Jr, Vickery BH (1985) Suppression of luteal progesterone secretion in the stumptailed macaque by an antagonist analogue of luteinizing hormone-releasing hormone. J Endocrinol 104:R1–R4

    Article  PubMed  CAS  Google Scholar 

  • Fraser HM, Nestor JJ Jr, Vickery BH (1987) Suppression of the luteal function by a luteinizing hormone-releasing hormone antagonist during the early luteal phase in the stumptailed macaque monkey and the effects of subsequent administration of human chorionic gonadotropin. Endocrinology 121:612–618

    Article  PubMed  CAS  Google Scholar 

  • Frick J, Aulitzky W (1986) Effects of a potent LH-RH agonist on the pituitary gonadal axis with and without testosterone substitution. Urol Res 14:261–264

    Article  PubMed  CAS  Google Scholar 

  • Gaitan D, Lindner J, Farley MG, Monroe SE, Pavlou SN (1991) Antireproductive properties of a novel GnRH antagonist in men. 73rd annual meeting of the Endocrine Society, Washington, June 12-15 (Abstract 1156)

    Google Scholar 

  • Geisthövel F, Arana JB, Balmaceda JP, Tojas FJ, Asch RH (1988) Prolactin and go-nadotrophin dynamics in response to antagonists of LH-RH and dopamine in ovarec-tomized rhesus monkeys: a dissection of their common secretion. Hum Reprod 3:591–595

    Google Scholar 

  • Gonzalez-Barcena D, Ortiz HT, Gordon F, Kastin AJ, Coy D, Schally AV (1980) Influence of LH-RH agonists and antagonists on gonadotropin release in humans. Int J Fertil 25:185–189

    PubMed  CAS  Google Scholar 

  • Gordon K, Williams RF, Danforth DR, Hodgen GD (1991) Antide-induced suppression of pituitary gonadotropin and ovarian steroid secretion in cynomolgus monkeys. Premature luteolysis and prolonged inhibition of folliculogenesis following single treatment. Biol Reprod 44:701–706

    Article  PubMed  CAS  Google Scholar 

  • Habenicht UF, Schneider MR, El Etreby MF (1990) Effect of the new potent LH-RH antagonist antide. J Steroid Biochem Mol Biol 37:937–942

    Article  PubMed  CAS  Google Scholar 

  • Hahn DW, McGuire JL, Vale WV, Rivier J (1985) Reproductive/endocrine and anaphylac-toid properties of an LH-RH-antagonist, ORF 18260 [Ac-DNal1(2), 4FDPhe2, D-Trp3, D-Arg6]-GnRH. Life Sci 37:505–514

    Article  PubMed  CAS  Google Scholar 

  • Hall JE, Brodie TD, Badger TM, Rivier JE, Vale WV, Conn PM, Schoenfeld, Crowley WF Jr (1988) Evidence of differential control of FSH and LH secretion by gonadotropin-re-leasing hormone (GnRH) from the use of a GnRH antagonist. J Clin Endocrinol Metab 67:524–531

    Article  PubMed  CAS  Google Scholar 

  • Hall JE, Whitcomb RW, Rivier JE, Vale WV, Crowley WF Jr (1990) Differential regulation of luteinizing hormone, follicle-stimulating hormone, and free alpha-subunit secretion from the gonadotrope by gonadotropin-releasing hormone (GnRH): evidence from the use of two GnRH antagonists. J Clin Endocrinol Metab 70:328–335

    Article  PubMed  CAS  Google Scholar 

  • Harris ME, Bartke A, Weisz J, Watson D (1977) Effects of testosterone and dihydrotestos-terone on spermatogenesis, rete testis fluid, and peripheral androgen levels in hypo-physectomized rats. Fertil Steril 28:1113–1117

    PubMed  CAS  Google Scholar 

  • Heber D, Dodson R, Swerdloff RS, Channabasavaiah K, Stewart JM (1982) Pituitary receptor site blockade by a gonadotropin-releasing hormone antagonist in vivo: mechanism of action. Science 216:420–421

    Article  PubMed  CAS  Google Scholar 

  • Huhtaniemi IT, Stewart JM, Channabasavaiah K, Fraser HM, Clayton RN (1984) Effect of treatment with GnRH antagonist, GnRH antiserum and bromocriptine on pituitary-tes-ticular function of adult rats. Mol Cell Endocrinol 34:127–135

    Article  PubMed  CAS  Google Scholar 

  • Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJ (1988) Serum bioactive and immunoreac-tive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy. J Clin Endocrinol Metab 66:308–313

    Article  PubMed  CAS  Google Scholar 

  • Jockenhövel F, Bhasin S, Steiner B, Rivier JE, Vale WV, Swerdloff RS (1988) Hormonal effects of single gonadotropin-releasing hormone antagonist doses in men. J Clin Endocrinol Metab 66:1065–1070

    Article  PubMed  Google Scholar 

  • Jockenhövel F, Khan SA, Niechlag E (1990) Varying dose-response characteristics of different immunoassays and an in vitro bioassay for FSH are responsible for changing ratios of biologically active to immunologically active FSH. J Endocrinol 127:523–532

    Article  PubMed  Google Scholar 

  • Karten MJ, Rivier J (1986) Gonadotrophin-releasing hormone analog design. Structure-function towards the development of agonists and antagonists: rationale and perspective. Endocr Rev 7:44–66

    Article  PubMed  CAS  Google Scholar 

  • Karten MJ, Hoeger CA, Hook WA, Lindberg MC, Naqvi RH (1990) The development of safer GnRH antagonists: strategy and status. In: Bouchard P, Haour F, Franchimont P, Schatz B (eds) Recent progress on GnRH and gonadal peptides. Elsevier, Paris, pp 147–158

    Google Scholar 

  • Kenigsberg D, Hodgen GD (1986) Ovulation inhibition by administration of weekly gonadotropin-releasing hormone antagonist. J Clin Endocrinol Metab 62:734–738

    Article  PubMed  CAS  Google Scholar 

  • Kenigsberg D, Littman BA, Hodgen GD (1984) Medical hypophysectomy: I. Dose-response using a gonadotropin-releasing hormone antagonist. Fertil Steril 42:112–115

    PubMed  CAS  Google Scholar 

  • Kessel B, Dahl KD, Kazer RR, Liu CH, Rivier J, Vale W, Hsueh AJW, Yen SSC (1988) The dependency of bioactive follicle-stimulating hormone secretion on gonadotropin-releasing hormone in hypogonadal and cycling women. J Clin Endocrinol Metab 66:361–366

    Article  PubMed  CAS  Google Scholar 

  • Khurshid S, Weinbauer GF, Nieschlag E (1991) Effects of testosterone and gonadotropin-re-leasing hormone (GnRH) antagonist on basal and GnRH-stimulated gonadotrophin-se-cretion in orchidectomized monkeys. J Endocrinol 129:363–370

    Article  PubMed  CAS  Google Scholar 

  • Klibanski A, Jameson JL, Killer BMK, Crowley WF Jr, Zervas NT, Rivier J, Vale WV, Bikkal H (1989) Gonadotropin and alpha-subunit responses to chronic gonadotropin-releasing hormone analog administration in patients with glycoprotein hormone-secreting tumors. J Clin Endocrinol Metab 68:81–86

    Article  PubMed  CAS  Google Scholar 

  • Knobil E (1980) The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53–88

    PubMed  CAS  Google Scholar 

  • Lahlou N, Delivet S, Bardin CW, Roger M, Spitz IM, Bouchard P (1990) Changes in gonadotropin and alpha-subunit after a single administration of gonadotropin-releasing hormone antagonist in adult males. Fertil Steril 53:898–905

    PubMed  CAS  Google Scholar 

  • Leal JA, Williams RF, Danforth DR, Gordon K, Hodgen GD (1988) Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist. J Clin Endocrinol Metab 67:1325–1327

    Article  PubMed  CAS  Google Scholar 

  • Leal JA, Gordon K, Williams RF, Danforth DR, Roh SI, Hodgen GD (1989 a) Probing studies on multiple dose effects of antide (Nal-Lys) GnRH antagonist in ovariectomized monkeys. Contraception 40:623–633

    Article  PubMed  CAS  Google Scholar 

  • Leal JA, Williams RF, Danforth DR, Gordon K, Hodgen GD (1989 b) Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist. J Clin Endocrinol Metab 67:1325–1327

    Article  Google Scholar 

  • Lee CH, Van Antwerp D, Hedley L, Nestor JJ Jr, Vickery BH (1989) Comparative studies on the hypotensive effect of LH-RH antagonists in anesthetized rats. Life Sci 45:697–702

    Article  PubMed  CAS  Google Scholar 

  • Limonta P, Bardin CW, Ladishenskaya A, Pavlou S, Sundaram K, Thau RB (1985) Species differences in the sensitivity to a GnRH antagonist. Contraception 32:75–85

    Article  PubMed  CAS  Google Scholar 

  • Lindner J, Rivier JE, Vale WV, Pavlou SN (1990) Regulation of pituitary glycoprotein alpha-subunit secretion after administration of a luteinizing hormone-releasing hormone antagonist in normal men. J Clin Endocrinol Metab 70:1216–1224

    Article  Google Scholar 

  • Ljungqvist A, Feng DM, Tang PFL, Kubota M, Okamoto Y, Zhang Y, Bowers CY, Hool WA, Folkers K (1987) Design, synthesis and bioassays of antagonists of LH-RH which have high antiovulatory activity and release negligible histamine. Biochem Biophys Res Comm 148:849–856

    Article  PubMed  CAS  Google Scholar 

  • Loumaye E, Catt KJ (1983) Agonist-induced regulation of pituitary receptors for gonadotropin-releasing hormone. J Biol Chem 258:12002–12009

    PubMed  CAS  Google Scholar 

  • Loumaye E, Wynn PC, Coy D, Catt KJ (1984) Receptor-binding properties of gonadotropin-releasing hormone derivatives. J Biol Chem 259:12663–12671

    PubMed  CAS  Google Scholar 

  • Lunglmayr G (1989) “Zoladex” versus “Zoladex” plus flutarnide in the treatment of ad-vanced prostate cancer: first interim analysis of an international trial. In: Murphy GP, Khoury S (eds) Therapeutic progress in urological cancers. Liss, New York, pp 145–152 (Progress in clinical and biological research, Vol 303)

    Google Scholar 

  • Mann DR, Adams SR, Gould KG, Orr TE, Collins DC (1989) Evaluation of the possible direct effects of gonadotrophin-releasing hormone analogues on the monkey (Macaca mulatta) testis. J Reprod Fertil 85:89–95

    Article  PubMed  CAS  Google Scholar 

  • Marshall GR, Nieschlag E (1987) The role of FSH in male reproduction. In: Sheth AR (ed) Inhibins: isolation, estimation and physiology, vol 1. CRC Press, Boca Raton, Florida, pp 3–15

    Google Scholar 

  • Marshall GR, Akhtar FB, Weinbauer GF, Nieschlag E (1986 a) Gonadotrophin-releasing hormone (GnRH) overcomes GnRH antagonist-induced suppression of LH secretion in primates. J Endocrinol 110:145–150

    Article  PubMed  CAS  Google Scholar 

  • Marshall GR, Jockenhövel F, Lüdecke D, Nieschlag E (1986 b) Maintenance of complete but quantitatively reduced spermatogenesis in hypophysectomized monkeys by testosterone alone. Acta Endocrinol (Copenh) 113:424–431

    CAS  Google Scholar 

  • Marshall LA, Fluker MR, Jaffe RB, Monroe SE (1991) Inhibition of follicular development by a potent antagonistic analog of gonadotropin-releasing hormone (detirelix). J Clin Endocrinol Metab 72:927–933

    Article  PubMed  CAS  Google Scholar 

  • Matsumoto AM (1989) Hormonal control of spennatogenesis. In: Burger H, de Kretser DM (eds) The testis, 2nd edn. Raven, New York, pp 181–196

    Google Scholar 

  • Matsuo H, Baba Y, Nair RM, Arimura A, Schally AV (1971) Structure of the porcine LH-and FSH-releasing hormone: I. The proposed amino acid sequence. Biochem Biophys Res Comm 43:1334–1339

    Article  PubMed  CAS  Google Scholar 

  • McNeilly JR, Brown P, Clark AJ, McNeilly AS (1991) Gonadotrophin-releasing hormone modulation of gonadotrophins in the ewe: evidence for differential effects on gene expression and hormone secretion. J Mol Endocrinol 7:35–43

    Article  PubMed  CAS  Google Scholar 

  • Meldrum DR, Tsao Z, Monroe SE, Braunstein GD, Sladek J, Lu JKH, Vale W; Rivier J, Judd HL, Chang RJ (1984) Stimulation of LH fragments with reduced bioactrvity following GnRH agonist administration in women. J Clin Endocrinol Metab 58:755–757

    Article  PubMed  CAS  Google Scholar 

  • Morel G, Dihl F, Aubert ML, Dubois PM (1987) Binding and internalization of native gonadoliberin (GnRH) by anterior pituitary gonadotrophs of the rat. A quantitative autoradiographic study after cryo-ultramicrotomy. Cell Tissue Res 248:541–550

    Article  PubMed  CAS  Google Scholar 

  • Morgan JE, O’Neil CE, Coy DH, Hocart SJ, Nekola MV (1986) Antagonistic analogs of luteinizing hormone-releasing hormone are mast cell secretagogues. Int Arch Allergy Appl Immunol 80:70–75

    Article  PubMed  CAS  Google Scholar 

  • Mortola JF, Sathanandam M, Pavlou SN, Dahl KD, Hsueh AJW, Rivier JE, Vale WV, Yen SSC (1989) Suppression of bioactive and immunoreactive folhcle-stimulating hormone and luteinizing hormone levels by a potent gonadotropin-releasing hormone antagonist: pharmacodynamic studies. Fertil Steril 51:957–963

    PubMed  CAS  Google Scholar 

  • Namiki M, Sonoada T, Nonomura N, Nishimune Y, Nakamura M, Matsumoto K, Okuya-ma (1987) Effects of a gonadotropin-releasing hormone agonist analog (ICI 118630) on endocrine functions of human testis in vivo and in vitro. Fertil Steril 48:1012–1017

    PubMed  CAS  Google Scholar 

  • Nekola M, Coy DH (1984) LH-RH antagonists in females. In: Vickery BH, Nestor JJ Jr, Hafez ESE (eds) LH-RH and its analogs. MTP Press, Lancaster, pp 125–136

    Chapter  Google Scholar 

  • Nestor JJ Jr, Ho TL, Tahilramani R, McRae GI, Vickery BH (1984) Long-acting LH-RH agonists and antagonists. In: Vickery BH, Nestor JJ Jr, Hafez ESE (eds) LH-RH and its analogs. MTP Press, Lancester, pp 24–35

    Google Scholar 

  • Nestor JJ Jr, Tahilramani R, Ho TL, Goodpasture JC, Vickery BH, Ferrandon P (1988) Design of luteinizing hormone-releasing hormone antagonists with reduced potential for side effects. In: Jung G (ed) Peptides 1988: proceedings of the 20th European Peptide Symposium. De Gruyter, Berlin, pp 592–594

    Google Scholar 

  • Nieschlag E, Behre HM, Weinbauer GF (1989) Hormonal methods for the regulation of male fertility. In: Serio M (ed) Perspectives in andrology. Raven, New York, pp 517–529 (Serono symposia, vol 53)

    Google Scholar 

  • Olive DL, Sabella V, Riehl RM, Schenken RS, Moreno A (1989) Gonadotropin-releasing hormone antagonists attenuate estrogen/progesterone-induced hyperprolactinemia in monkeys. Fertil Steril 51:1040–1045

    PubMed  CAS  Google Scholar 

  • Parmar H, Phillips RH, Lightman SL, Edwards L, Allen L, Schally AV (1985) Randomised controlled study of orchidectomy vs long-acting D-Trp6-LH-RH microcapsules in advanced prostatic carcinoma. Lancet ii: 1201–1205

    Article  Google Scholar 

  • Pavlou SN (1991) GnRH antagonists in men: development of a male contraceptive. Tianjin international symposium on LH-RH analogues, Tianjng, China, September 24-26 (Abstract 33)

    Google Scholar 

  • Pavlou SN, Devoid CR, Island DP, Wakefield G, Rivier J, Vale W, Rabin D (1986) Single subcutaneous doses of a luteinizing hormone-releasing hormone antagonist suppress serum gonadotropin and testosterone levels in normal men. J Clin Endocrinol Metab 63:303–308

    Article  PubMed  CAS  Google Scholar 

  • Pavlou SN, Interlandi JW, Wakefield G, Island DP, Rivier J, Vale W, Kovacs WJ (1987 a) Gonadotropins and testosterone escape from suppression during prolonged luteinizing hormone-releasing hormone antagonist administration in normal men. J Clin En-docrinol Metab 64:1070–1074

    Article  CAS  Google Scholar 

  • Pavlou SN, Wakefield GB, Island DP, Hoffman PG, LePage ME, Chan RL, Nerenberg CA, Kovacs WJ (1987b) Suppression of pituitary-gonadal function by a potent new luteiniz-ing hormone-releasing hormone antagonist in normal men. J Clin Endocrinol Metab 64:931–936

    Article  PubMed  CAS  Google Scholar 

  • Pavlou SN, Dahl KD, Wakefield G, Rivier J, Vale W, Hsueh AJW, Lindner J (1988) Maintenance of the ratio of bioactive to immunoreactive follicle-stimulating hormone in normal men during chronic luteinizing-hormone agonist administration. J Clin Endocrinol Metab 66:1005–1009

    Article  PubMed  CAS  Google Scholar 

  • Pavlou SN, Wakefield G, Schlechter NL, Lindner J, Souza KH, Kamilaris TC, Kondidaris S, Rivier JE, Vale WW, Toglia M (1989) Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing hormone antagonist in normal men. J Clin Endocrinol Metab 68:446–454

    Article  PubMed  CAS  Google Scholar 

  • Pavlou SN, DeBold CR, Orth DN (1990 a) LH-RH antagonists: clinical studies in man. In: Bouchard P, Haour F, Franchimont P, Schatz B (eds) Recent progress on GnRH and gonadal peptides. Elsevier, Paris, pp 195–208

    Google Scholar 

  • Pavlou SN, Veldhuis JD, Lindner J, Souza KH, Urban RJ, Rivier JE, Vale WW, Stallard DJ (1990 b) Persistence of concordant luteinizing hormone (LH), testosterone, and alpha-subunit pulses after LH-releasing hormone antagonist administration in normal men. J Clin Endocrinol Metab 70:1472–1478

    Article  PubMed  CAS  Google Scholar 

  • Phillips A, Hahn DW, McGuire JL, Ritchie D, Capetola RJ, Bowers C, Folkers K (1988) Evaluation of the anaphylactoid activity of a new LH-RH antagonist. Life Sci 43:883–888

    Article  PubMed  CAS  Google Scholar 

  • Puente M, Catt KJ (1986) Inhibition of pituitary-gonadal function in male rats by a potent GnRH antagonist. J Steroid Biochem 25:917–925

    Article  PubMed  CAS  Google Scholar 

  • Rajfer J, Sikka SC, Swerdloff RS (1987) Lack of a direct effect of gonadotropin hormone-releasing hormone agonist on human testicular steroidogenesis. J Clin Endocrinol Metab 64:62–67

    Article  PubMed  CAS  Google Scholar 

  • Rea MA, Marshall GR, Weinbauer GF, Nieschlag E (1986) Testosterone maintains pituitary and serum FSH and spermatogenesis in gonadotrophin-releasing hormone antagonist-suppressed rats. J Endocrinol 108:101–107

    Article  PubMed  CAS  Google Scholar 

  • Redding TW, Schally AV (1990) Inhibition of the pituitary-gonadal axis in nude male mice by continuous administration of LH-RH agonists and antagonists. J Endocrinol 126:309–315

    Article  PubMed  CAS  Google Scholar 

  • Reissmann T, Hilgard P, Harleman JH, Engel J, Comaru-Schally AM, Schally AV (1992) Treatment of experimental DMBA induced mammary carcinoma with Cetrorelix (SB-75): a potent antagonist of luteinizing hormone-releasing hormone. J Cancer Res Clin Oncol 118:44–49

    Article  PubMed  CAS  Google Scholar 

  • Rivier C, Vale W (1981) Temporal relationship between the abortifacient effects of GnRH antagonists and hormonal secretion. Biol Reprod 24:1061–1067

    Article  PubMed  CAS  Google Scholar 

  • Rivier C, Rivier J, Vale W (1980) Antireproductive effects of a potent gonadotropin-releasing hormone antagonist in the male rat. Science 210:93–95

    Article  PubMed  CAS  Google Scholar 

  • Rivier C, Rivier J, Vale W (1981) Effect of a potent GnRH antagonist and testosterone propionate on mating behaviour and fertility in the male rat. Endocrinology 108:1998–2001

    Article  PubMed  CAS  Google Scholar 

  • Rivier JE, Rivier C, Perrin M, Porter J, Vale WW (1984) LH-RH analogs as antiovulatory agents. In: Vickery BH, Nestor JJ Jr, Hafez ESE (eds) LH-RH and its analogs. MTP Press, Lancaster, pp 11–22

    Chapter  Google Scholar 

  • Rivier JE, Porter J, Rivier CL, Perrin M, Corrigan A, Hook WA, Siraganian RP, Vale WW (1986) New effective gonadotropin-releasing hormone antagonists with minimal potency for histamine release in vitro. J Med Chem 29:1846–1851

    Article  PubMed  CAS  Google Scholar 

  • Robinson DM, Mahler C, Smith PH, Keuppens F, De Moura JLC, Bono E, Newling D, Sylvester R, De Pauw R, Vermeylen K, Ongena P, members of the EORTC-GU Group (1990) Orchidectomy versus Zoladex plus Eulexin in patients with metastatic prostate cancer (EORTC 30853). J Steroid Biochem Mol Biol 37:951–959

    Article  PubMed  Google Scholar 

  • Roman SH, Goldstein M, Kourides IA, Comité F, Bardin CW, Krieger DT (1984) The luteinizing hormone-releasing hormone (LH-RH) agonist D-Trp6-Pro9-NEt LH-RH increased rather than lowered LH and alpha-subunit levels in a patient with an LH-secret-ing tumor. J Clin Endocrinol Metab 58:313

    Article  PubMed  CAS  Google Scholar 

  • Salameh W, Bhasin S, Steiner B, McAdams LA, Peterson M, Swerdloff RS (1991) Marked suppression of gonadotropins and testosterone by an antagonist analog of gonadotropin-releasing hormone in men. Fertil Steril 55:156–164

    PubMed  CAS  Google Scholar 

  • Sandow J, König W (1979) Studies with fragments of highly active analogue of luteinizing hormone releasing hormone. J Endocrinol 8:175–182

    Article  Google Scholar 

  • Sandow J, Stöckemann K, Jerabek-Sandow G (1990 a) Pharmacokinetics and endocrine effects of slow release formulations of LH-RH analogues. J Steroid Biochem Mol Biol 37:925–931

    Article  PubMed  CAS  Google Scholar 

  • Sandow J, Stöckemann K, Kibet PG, Lill NM, Neubauer H, Jerabek-Sandow G, Hahn M, Kille S (1990 b) Effect of a new LH-RH antagonist on DMBA-induced mammary tumours. 2nd international symposium on “Hormonal manipulation of cancer: peptides, growth factors and new (anti)steroidal agents”, Rotterdam, 9-11 April (Abstract 116). Eur J Cancer 26:175

    Google Scholar 

  • Santen RJ, Demers LM, Max DT, Smith J, Stein BS, Glode LM (1984) Long term effects of administration of a gonadotropin-releasing hormone superagonist analog in men with prostatic carcinoma. J Clin Endocrinol Metab 58:397–400

    Article  PubMed  CAS  Google Scholar 

  • Schally AV, Coy DH (1983) Stimulatory and inhibitory analogs of LH-releasing hormone. In: McCann SM, Dhindsa DS (eds) Role of peptides and proteins in control of reproduction. Elsevier, New York, pp 89–110

    Google Scholar 

  • Schmidt F, Sundaram K, Thau RB, Bardin CW (1984) (Ac-D-Nal(2), 4FD-Phe2,D-Trp3,D-Arg6)-LH-RH, a potent antagonist of LH-RH, produces transient edema and behavioral changes in rats. Contraception 29:283–289

    Article  PubMed  CAS  Google Scholar 

  • Sharma OP, Weinbauer GF, Behre HM, Nieschlag E (1992) The gonadotropin-releasing hormone (GnRH) agonist-induced initial rise of bioactive LH and testosterone secretion can be blocked in a dose-dependent manner by GnRH antagonist in the nonhuman primate. Urol Res (in press)

    Google Scholar 

  • Sharpe KL, Bertero MC, Lyon BP, Muse KN, Vernon MW (1990) Follicular atresia and infertility in rats treated with gonadotropin-releasing hormone antagonist. Endocrinology 127:25–31

    Article  PubMed  CAS  Google Scholar 

  • Srkalovic G, Bokser L, Radulovic S, Korkut E, Schally AV (1990) Receptors for luteinizing hormone-releasing hormone (LH-RH) in dunning R 3327 prostate cancers and rat anterior pituitaries after treatment with a sustained delivery system of LH-RH antagonist SB-75. Endocrinology 127:3052–3060

    Article  PubMed  CAS  Google Scholar 

  • Spicer DV, Shoupe D, Pike MC (1991) GnRH agonists as contraceptive agents: predicted significantly reduced risk of breast cancer. Contraception 44:289–310

    Article  PubMed  CAS  Google Scholar 

  • Struthers RS, Tanaka G, Koerber SC, Solmajer T, Baniak EL, Gierasch LM, Vale W, Rivier J, Halger AT (1990) Design of biologically active, conformationally constrained GnRH antagonists. Proteins 8:295–304

    Article  PubMed  CAS  Google Scholar 

  • Szende B, Skralovic G, Groot K, Lapis K, Schally AV (1990 a) Growth inhibition of mouse MIXT mammary tumor by the luteinizing hormone-releasing hormone antagonist SB-75. JNCI 82:513–517

    PubMed  CAS  Google Scholar 

  • Szende B, Srkalovic G, Groot K, Lapis K, Schally AV (1990 b) Regression of nitrosamide-in-duced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists. Cancer Res 50:3716–3721

    PubMed  CAS  Google Scholar 

  • Szepeshazi K, Korkut E, Szende B, Lapis K, Schally AV (1991) Histological changes in dunning prostate tumors and testes of rats treated with LH-RH antagonist SB-75. Prostate 18:255–270

    Article  PubMed  CAS  Google Scholar 

  • Tenover JS, Dahl KD, Vale WV, Rivier JE (1990) Hormonal responses to a potent gonadotropin-releasing hormone antagonist in normal elderly men. J Clin Endocrinol Metab 71:881–888

    Article  PubMed  CAS  Google Scholar 

  • Tom L, Salameh W, Bhasin S, Steiner B, Peterson M, Swerdloff RS (1991) Male contraception: achievement of reversible azoospermia by combined gonadotropin releasing hormone antagonist and testosterone treatment. 73rd annual meeting of the Endocrine Society, Washington, June 12-15 (Abstract 1154)

    Google Scholar 

  • Urban RJ, Pavlou SN, Rivier JE, Vale W, Daufau ML, Veldhuis JD (1988) Suppressive actions of a gonadotropin-releasing hormone antagonist on luteinizing hormone, folli-cle-stimulating hormone, and prolactin release in estrogen-deficient postmenopausal women. Am J Obstet Gynecol 162:1255–1260

    Google Scholar 

  • Waxman J (1989) Short-term anti-androgen therapy and very long-acting depot gonadotropin-releasing hormone agonist for prostatic cancer. In: Murphy GP, Khoury S (eds) Therapeutic progress in urological cancers. Liss, New York, pp 61–68 (Progress in clinical and biological research, vol 303)

    Google Scholar 

  • Weinbauer GF, Nieschlag E (1985) Regulation of primate testicular function by GnRH analogues. Med Biol 63:210–217

    CAS  Google Scholar 

  • Weinbauer GF, Nieschlag E (1990 a) Evaluation of the antigonadotropic activity of different GnRH antagonists in the nonhuman primate. Gynecol Endocrinol 4:21 (abstr)

    Google Scholar 

  • Weinbauer GF, Nieschlag E (1990 b) The role of testosterone in spermatogenesis. In: Nieschlag E, Behre HM (eds) Testosterone. Action, deficiency, substitution. Springer, Berlin Heidelberg New York, pp 23–50

    Google Scholar 

  • Weinbauer GF, Nieschlag E (1990 c) Preclinical studies with GnRH antagonists. In: Maggi M, Geenen V (eds) Horizons in endocrinology. Raven, New York, pp 287–296

    Google Scholar 

  • Weinbauer GF, Surmann FJ, Akhtar FB, Shah GV, Vickery BH, Nieschlag E (1984) Reversible inhibition of testicular function by a gonadotropin-releasing hormone antagonist in monkeys (Macaca fascicularis). Fertil Steril 42:906–914

    PubMed  CAS  Google Scholar 

  • Weinbauer GF, Marshall GR, Nieschlag E (1986) New injectable testosterone ester maintains serum testosterone of castrated monkeys in the normal range for four months. Acta Endocrinol (Copenh) 113:128–132

    CAS  Google Scholar 

  • Weinbauer GF, Respondek M, Themann H, Nieschlag E (1987 a) Hypogonadotropic status and testicular morphology in nonhuman primates (Macaca mulatta and M fascicularis). In: Spera G, de Kretser DM (eds) Morphological basis of human reproductive function. Plenum, New York, pp 45–48

    Chapter  Google Scholar 

  • Weinbauer GF, Respondek M, Themann H, Nieschlag E (1987 b) Reversibility of long-term effects of GnRH agonist administration on testicular histology and sperm production in the nonhuman primate. J Androl 8:319–329

    PubMed  CAS  Google Scholar 

  • Weinbauer GF, Surmann FJ, Nieschlag E (1987 c) Suppression of spermatogenesis in a nonhuman primate (Macaca fascicularis) by concomitant gonadotropin-releasing hormone antagonist and testosterone treatment. Acta Endocrinol (Copenh) 114:138–146

    CAS  Google Scholar 

  • Weinbauer GF, Göckeler E, Nieschlag E (1988) Testosterone prevents complete suppression of spermatogenesis in the gonadotropin-releasing hormone (GnRH) antagonist-treated nonhuman primate (Macaca fascicularis). J Clin Endocrinol Metab 67:284–290

    Article  PubMed  CAS  Google Scholar 

  • Weinbauer GF, Khurshid S, Fingscheidt U, Nieschlag E (1989) Sustained inhibition of sperm production and inhibin secretion induced by a gonadotrophin-releasing hormone antagonist and delayed testosterone substitution in nonhuman primates (Macaca fascicularis). J Endocrinol 123:303–310

    Article  PubMed  CAS  Google Scholar 

  • Weinbauer GF, Behre HM, Nieschlag E (1990) Contraceptive studies with GnRH analogs in men and nonhuman primates. In: Bouchard P, Haour F, Franchimont P, Schatz B (eds) Recent progress on GnRH and gonadal peptides. Elsevier, Paris, pp 181–194

    Google Scholar 

  • Weinbauer GF, Behre HM, Fingscheidt U, Nieschlag E (1991 a) Human follicle-stimulating hormone exerts a stimulatory effect on spermatogenesis, testicular size, and serum inhibin levels in the gonadotropin-releasing hormone antagonist-treated nonhuman primate (Macaca fascicularis). Endocrinology 129:1831–1839

    Article  PubMed  CAS  Google Scholar 

  • Weinbauer GF, Fingscheidt U, Khurshid S, Nieschlag E (1991 b) Endocrine regulation of primate testicular function. In: Moudgal NR, Yoshinaga K, Rao AJ, Adiga PR (eds) Perspectives in primate reproductive biology. Wiley, New Delhi, pp 165–172

    Google Scholar 

  • WHO: World Health Organization Task Force on Methods for the Regulation of Male Fertility (1990) Contraceptive efficacy of testosterone-induced azoospermia in normal men. Lancet 336:955–959

    Article  Google Scholar 

  • Wynn PC, Suarez-Quian CA, Childs GV, Catt KJ (1986) Pituitary binding and interaaliza-tion of radioiodinated gonadotropin-releasing hormone agonist and antagonist ligands in vitro and in vivo. Endocrinology 119:1852–1863

    Article  PubMed  CAS  Google Scholar 

  • Zarate A, Canales ES, Sthory I, Coy DH, Comaru-Schally AM, Schally AV (1981) Anovu-latory effect of a LH-RH antagonist in women. Contraception 24:315–320

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Reproduktionsmedizin der Universität, WHO Kollaborationszentrum zur Erforschung der männlichen Fertilität, Steinfurterstraße 107, W-4400, Münster, Germany

    G. F. Weinbauer & E. Nieschlag

Authors
  1. G. F. Weinbauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Nieschlag
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Hufelandstraße 55, W-4300, Essen, Germany

    K. Höffken

Rights and permissions

Reprints and permissions

Copyright information

© 1992 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Weinbauer, G.F., Nieschlag, E. (1992). LH-RH Antagonists: State of the Art and Future Perspectives. In: Höffken, K. (eds) Peptides in Oncology I. Recent Results in Cancer Research, vol 124. Springer, Milano. https://doi.org/10.1007/978-88-470-2186-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-2186-0_11

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-2188-4

  • Online ISBN: 978-88-470-2186-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation