Skip to main content
SpringerLink
Log in

Reversible Inhibition of Sexual Maturation in Male Rats: A Safety Evaluation for the Use of LHRH Analogues in Precocious Puberty

  • Chapter
GnRH Analogues in Cancer and Human Reproduction

Abstract

Treatment of precocious puberty is a therapeutic problem with few satisfactory options. In boys, temporary suppression of androgen secretion is achieved by cyproterone acetate, but the results are not fully satisfactory because of adrenal steroid suppression and associated side effects. In girls, cyproterone acetate [1], danazol or medroxyprogesterone acetate [2] also have problems of side effects [3]. All steroids used for suppression of pituitary function can have effects on spermatogenesis [4]. The reversible suppression of pituitary-gonadal function by LHRH agonists has been a major improvement [4–6]. However, concern has been expressed about the risk of irreversible damage to spermatogenesis and impaired fertility after long-term therapy.

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

  1. Kauli, R, Pertzelan, A, Prager-Lewin, R, Grüenbaum, M and Laron, Z (1976). Cyproterone acetate in treatment of precocious puberty. Arch Dis Child, 51, 202

    Article  PubMed  CAS  Google Scholar 

  2. Kaplan, SA and Irani Nayer, G (1968). Idiopathic isosexual precocity. Therapy with medroxyproxyprogesterone. Am J Dis Child, 116, 591

    PubMed  CAS  Google Scholar 

  3. Sadeghi-Nejad, A and Senior, B (1978). The effect of Provera on adrenocortical function in children with precocious puberty. J Pediatr, 78, 616

    Google Scholar 

  4. Camacho, R (1972). Alterations of testicular histology and chronsomes in patients with constitutional sexual precocity treated with medroxyprogesterone acetate. J Clin Endocrinol Metab, 34. 279

    Article  PubMed  CAS  Google Scholar 

  5. Luder AS, Holland, FJ, Costigan, DC, Jenner, MR, Wielgosz, G and Fazekas, ATA (1984). Intranasal and subcutaneous treatment of central preococious puberty in both sexes with a long acting analogue of luteinizing hormone-releasing hormone. J Clin Endocrinol Metab, 58, 966

    Article  PubMed  CAS  Google Scholar 

  6. Styne, DM, Harris DA, Egli, CA, Conte, FA, Kaplan, FA, Kaplan SL, Rivier, J, Vale, WW and Grumbach, MM (1985). Treatment of true precocious puberty with a potent luteinizing hormone-releasing factor agonist: effect on growth, sexual maturation, pelvic sonography and the hypothalamic-pituitary-gonadal axis. J Clin Endocrinol Metab, 61, 142

    Article  PubMed  CAS  Google Scholar 

  7. Sandow, J and Beier, B (1985). LHRH agonists — mechanism of action and effect on target tissues. In: Schröder, FH, Richards, B (eds.) “EORTC Genitourinary Group Monography 2, Part A: Therapeutic Principles in Metastatic Prostatic Cancer” pp.121. (New York: Alan Liss)

    Google Scholar 

  8. Sandow, J, Rechenberg, Wv, Jerzabek, G and Stoll, W (1978). Pituitary gonadotropin inhibition by a highly active analog of luteinizing hormone-releasing hormone. Fertil Steril, 30, 205

    PubMed  CAS  Google Scholar 

  9. Sandow, J, Rechenberg, Wv, Jerzabek, G, Engelbart, K, Kuhl, H and Fraser, H (1980). Hypothalamic-pituitary-testicular function in rats after supraphysiological doses of a highly active LHRH analogue (buserelin). Acta Endocrinol, 94. 489

    PubMed  CAS  Google Scholar 

  10. Sandow, J (1979). Toxicological evaluation of drugs affecting the hypothalamic-pituitary system. Pharmac Ther, 5, 297

    Article  CAS  Google Scholar 

  11. Sandow, J, Engelbart, K and Rechenberg, Wv (1985). The different mechanisms for suppression of pituitary and testicular function. Med Biol, 63. 192

    CAS  Google Scholar 

  12. Clegg, EJ (1966). Pubertal growth in the Leydig cells and accessory reproductive organs of the rat. J Anat, 100, 369

    PubMed  CAS  Google Scholar 

  13. Knorr, DW, Vanha-Perttula, T and Lipsett, MB (1970). Structure and function of rat testis through pubescence. Endocrinology, 86, 1298

    Article  PubMed  CAS  Google Scholar 

  14. Podesto, EJ and Rivarola, MA (1974). Concentration of androgens in whole seminiferous tubules and interstitial tissue of rats at different ages of development. Endocrinology, 95, 455

    Article  Google Scholar 

  15. Ketelslegers, J-M, Hetzel, WD, Sherins, RJ and Catt, KJ (1978). Developmental changes in testicular gonadotropin receptors: plasma gonadotropins and plasma testosterone in the rat. Endocrinology, 103, 212

    Article  PubMed  CAS  Google Scholar 

  16. Huhtaniemi, I, Bolton, N, Leinonen, P Et al (1982). Testicular luteinizing hormone receptor content and in vitro stimulation of cyclic adenosine 3′,5′-monophosphate and steroid production: a comparison between man and rat. J Clin Endocrinol Metab, 55, 882

    Article  PubMed  CAS  Google Scholar 

  17. Pahnke, VG, Leidenberger, FA and Kunzig, HJ (1975). Correlation between hCG (LH)-binding capacity Leydig cell number and secretory activity of rat testis throughout pubescence. Acta Endocrinol (Copenh) 79, 610

    CAS  Google Scholar 

  18. Paz, GF, Winter, JSD, Reyes, FI and Faiman, C (1980). Developmental pattern of testosterone production by the rat testis. Steroids, 36, 675

    Article  PubMed  CAS  Google Scholar 

  19. Hodgson, YM and de Kretser, DM (1984b). The temporal response of rat testes to hCG stimulation during sexual maturation. Int J Androl, 7, 203

    Article  PubMed  CAS  Google Scholar 

  20. Huhtaniemi, IT, Nozu, K, Warren, DW, Dufau, ML and Catt, KJ (1982). Acquisition of regulatory mechanisms for gonadotropin receptors and steroidogenesis in the maturing rat testis. Endocrinology, 111, 1711

    Article  PubMed  CAS  Google Scholar 

  21. Corpichot, C, Baullieu, E-E and Robel, P (1981). Testosterone, dihydrotestosterone and androstanendiols in plasma, testes and prostates of rats during development. Acta Endocrinol (Copenh), 96, 127

    Google Scholar 

  22. Akhtar, BF, Marshall, GR, Wickings, EJ and Nieschlag, E (1983). Reversible induction of azoospermia in rhesus monkeys by constant infusion of gonadotropin-releasing hormone agonist using osmotic minipumps. J Clin Endocrinol Metab, 56, 534

    Article  PubMed  CAS  Google Scholar 

  23. Schürmeyer, T, Knuth, UA, Freischem, CW, Sandow, J, Akhtar, BF and Nieschlag, E (1984). Suppression of pituitary and testicular function in normal agonist infusion. J Clin Endocrinol Metab, 50, 19

    Article  Google Scholar 

  24. Comite, F, Cutler, GB, Rivier, J, Vale, WW, Loriaux, DL and Crowley, WF (1981). Short-term treatment of idiopathic precocious puberty with a long-acting analogue of luteinizing hormone releasing hormone. N Engl J Med, 305, 1546

    Article  PubMed  CAS  Google Scholar 

  25. Christensen, AK and Peacock, KC (1980). Increase in Leydig cell number in testes of adult rats treated chronically with an excess of human chorionic gonadotropin. Biol Reprod, 22, 383

    PubMed  CAS  Google Scholar 

  26. Catt, KJ, Harwood, JP, Clayton, RN, Davies, TF, Chan, V, Katikineni, M, Nozu, K and Dufau, ML (1980). Regulation of peptide hormone receptors and gonadal steroidogenesis. Rec Prog Horm Res, 36, 557

    PubMed  CAS  Google Scholar 

  27. Chasalow, F, Marr, H, Haour, F and Saez, JM (1979). Testicular steroidogenesis after hCG desensitization in rats. J Biol Chem, 254, 5613

    PubMed  CAS  Google Scholar 

  28. Dufau, ML, Cogorraga, S, Baukal, AO, Sorrell, S, Bator, JM, Neubauer, JF and Catt, KJ (1979). Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin. Endocrinology, 105, 1314

    Article  PubMed  CAS  Google Scholar 

  29. Damber, JE, Bergh, A and Daehlin, L (1984). Stimulatory effect of an LHRH-agonist on testicular blood flow in hypophysectomized rats. Int J Androl, 7, 236

    Article  PubMed  CAS  Google Scholar 

  30. Sandow, J, Fraser, HM, Seidel, H, Krauss, B, Jerabek-Sandow, Gand Rechenberg, Wv (1987). Buserelin: pharmacokinetics, metabolism and mechanisms of action. Brit J Clin Pract, 41 (Suppl 48), 6

    Google Scholar 

  31. Schaison, G, Brailly, S, Vuagnat, P, Bouchard, P and Milgrom, E (1984). Absence of a direct inhibitory effect of the gonadotropin-releasing hormone (GnRH) agonist D-Ser(TBU)6, des-Gly-NH 102 GnRH ethylamide (buserelin) on testicular steroidogenesis in men. J Clin Endocrinol Metab, 59, 885

    Article  Google Scholar 

  32. Schirren, C (1971). Praktische Andrologie, Verlag Brüder Hartmann, Berlin, 38

    Google Scholar 

  33. Bell, JBG, Vinson, GP, Hopkin, DJ and Lacy, D (1968). Pathways for androgen biosyntehsis from /7-alpha-3H-/ pregnenolone and /4-14C/progesterone by rat testis interstitium in vitro. Biochim Biophys Acta, 164, 412

    PubMed  CAS  Google Scholar 

  34. Brophy, PJ and Gower, DB (1974). Studies on the inhibition by 5-alpha-pregnane-3,20-dione of the biosynthesis of 16-androstenes and dehydroepiandrosterone in boar testis preparations. Biochem Biophys Acta, 360, 252

    PubMed  CAS  Google Scholar 

  35. Mahajan, DK and Samuels, LT (1975). Inhibition of 17,20(17)-Hydroxyprogesteron-lyase by progesterone. Steroids, 25, 217

    Article  PubMed  CAS  Google Scholar 

  36. Aoki, A and Fawcett, DW (1978). Is there a local feedback from the seminiferous tubules affecting the activity of the Leydig cells? Biol Reprod, 19, 144

    Article  PubMed  CAS  Google Scholar 

  37. Bergh, A (1982). Local differences in Leydig cell morphology in the adult rat testis: evidence of a local control of Leydig cells by adjacent seminiferous tubules. Int J Androl, 5, 325

    Article  PubMed  CAS  Google Scholar 

  38. Bergh, A and Damber, JE (1984). Paracrine regulation of Leydig cells by the seminiferous tubules — effect of short-term cryptorchidism. Int J Androl, 7, 409

    Article  PubMed  CAS  Google Scholar 

  39. de Kretser, DM (1982). Sertoli cell — Leydig cell interaction in regulation of testicular function. Int J Androl. Suppl, 5, 11

    Article  Google Scholar 

  40. Parvinen, M (1982). Regulation of the seminiferous epithelium. Endocr Rev, 3, 404

    Article  PubMed  CAS  Google Scholar 

  41. Parvinen, M, Nikula, H and Huhtaniemi, I (1984). Influence of rat seminiferous tubules on Leydig cell testosterone production in vitro. Mol Cell Endocrinol, 37, 331

    Article  PubMed  CAS  Google Scholar 

  42. Seguin, C, Belanger A, Labrie, F and Hansel, W (1982). Study of the direct action of luteinizing hormone-releasing hormone agonists at the testicular level in intact rats treated with an antiluteinizing hormone serum. Endocrinology, 110, 524

    Article  PubMed  CAS  Google Scholar 

  43. Sharpe, RM (1983). Local control of testicular function. Quart J Exp Physiol, 68. 265

    CAS  Google Scholar 

  44. Sandow, J, Engelbart, K, Rechenberg, Wv and Krauss, B (1983a). Reversible inhibition of sexual maturation in male rats. Acta Endocrinol, 102, Suppl. 253, 154

    Google Scholar 

  45. Sandow, J, Hahn, M, Krauss, B and Rechenberg, Wv (1983). Reproductive function male and female rats treated with luteinizing hormone releasing hormone agonist (buserelin) before puberty. In: Endocrine Society, 65th. Annual Meeting, June 8–10, 1983, Abstract 1262, 396

    Google Scholar 

  46. Belanger, A, Tremblay, Y, Lacoste, D, Giasson, M, Dupont, A and Labrie, F (1984). The dog, a good model for the study of LHRH agonists as blockers of androgen secretion and potential contraceptives. In: Labrie, F, Belanger, A and Dupont, A (eds.) “LHRH and its Analogues”, pp.141. (Elsevier Science Publishers BV)

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hoechst AG, D-6230, Frankfurt/Main 80, Germany

    J. Sandow, K. Engelbart, W. von Rechenberg, M. Hahn & S. Kille

Authors
  1. J. Sandow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Engelbart
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. von Rechenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Hahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Kille
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Syntex Research, Institute of Biological Science, Palo Alto, CA, 94304, USA

    B. H. Vickery

  2. Institute of Endocrinology, Sheba Medical Center and Bar Ilan University, Remat Gan, 52621, Israel

    B. Lunenfeld

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Kluwer Academic Publishers

About this chapter

Cite this chapter

Sandow, J., Engelbart, K., von Rechenberg, W., Hahn, M., Kille, S. (1990). Reversible Inhibition of Sexual Maturation in Male Rats: A Safety Evaluation for the Use of LHRH Analogues in Precocious Puberty. In: Vickery, B.H., Lunenfeld, B. (eds) GnRH Analogues in Cancer and Human Reproduction. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-0725-6_2

Download citation

  • DOI: https://doi.org/10.1007/978-94-009-0725-6_2

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-6811-6

  • Online ISBN: 978-94-009-0725-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation