Development of Antagonists and Agonists of Follicle Stimulating Hormone

  • Marjolein Hage-van Noort
  • Wooter C. Puijk
  • Wim M. M. Schaaper
  • Douwe Kuperus
  • Nico J. C. M. Beekman
  • Henk H. Plasman
  • J. Anton Grootegoed
  • Robert H. Meloen
Conference paper
Part of the Schering Foundation Workshop book series (SCHERING FOUND, volume 4)


The initiation and maintenance of spermatogenesis are under the control of follicle stimulating hormone (FSH) and testosterone. For different mammalian species, it is clear that FSH is an important regulator, in particular during the first wave of spermatogenesis, and that testosterone is the major stimulator of spermatogenesis in adult males. FSH exerts multiple effects on its target cell, the Sertoli cell, and its action is most evident in testis from immature or hypophysectomized animals (Fritz 1978). However, at all stages of development, the actions of FSH and testosterone seem to be highly integrated. Although the importance of FSH in adult males is not clear, in either the human or in animal species, it appears that FSH is necessary for quantitative maintenance and repair of spermatogenesis. It has been shown that the FSH receptor is carefully regulated in adult rats and, presumably, has an important function in spermatogenesis (Heckert and Griswold 1992). A marked quantitative stimulation of spermatogenesis occurs when FSH is administered to intact adult cynomolgous monkeys (Van Alphen et al. 1988). Administration of anti-FSH antibodies to rats leads to a decrease in spermatogonia (Vaishnav and Moudgal 1992). It cannot be excluded that male fertility will be impaired upon inhibition of FSH action. The possibility of inducing male infertility by blocking FSH action is very attractive for two reasons. First, according to current knowledge, testicular Sertoli cells are the exclusive target cells for FSH in the male, which guarantees specificity. Second, lutropin (LH) action and testicular androgen production would not be affected. Different approaches have been considered to interfere with FSH stimulation of the testis, without acting upon LH stimulation of testicular androgen production. In our laboratory, we are trying to develop FSH antagonistic peptides and peptide vaccines directed against FSH. Synthetic peptides and especially synthetic peptide vaccines instead of “native” protein hormone (vaccines) have been predicted to be especially well suited for mass application in developing countries because peptides are relatively cheap, easy to produce, to store, to transport and to modify. However, a major obstacle to the development of anti-FSH vaccines or FSH antagonistic peptides has been the absence of detailed knowledge about the antigenic determinants and receptor sites on the hormone.


Follicle Stimulate Hormone Sertoli Cell Synthetic Peptide cAMP Production Receptor Binding Site 
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  1. Boniface JJ, Reichert Jr LE (1990) Evidence for a novel thioredoxin-like catalytic property of gonadotropic hormones. Science 247: 61–64PubMedCrossRefGoogle Scholar
  2. Calvo FO, Ryan RJ (1985) Inhibition of adenylyl cyclase activity in rat corpora luteal tissue by glycopeptides of human chorionic gonadotropin and the a-subunit of human chorionic gonadotropin. Biochemistry 24: 1953–1959PubMedCrossRefGoogle Scholar
  3. Charlesworth MC, McCormick DJ, Madden B, Ryan RI (1987) Inhibition of human choriotropin binding to receptor by human choriotropin a-peptides. J Biol Chem 262: 13409–13416PubMedGoogle Scholar
  4. Combarnous Y, Hennen G (1974) The disulphide bridges of porcine luteinizing hormone a-subunit. Biochem Sci Trans 2: 915–917Google Scholar
  5. Dahl KD, Bicsak TA, Hsueh AJW (1988) Naturally occurring antihormones: secretion of FSH antagonists by women treated with a GNRH analog. Science 239: 72–74PubMedCrossRefGoogle Scholar
  6. Erickson LD, Rizza SA, Bergert ER, Charlesworth MC, McCormick DJ, Ryan RJ (1990) Synthetic a-subunit peptides stimulate testosterone production in vitro by rat Leydig cells. Endocrinol 126: 2555–2560CrossRefGoogle Scholar
  7. Fournier A, Wang C-T, Felix AM (1988) Applications of BOP reagent in solid phase synthesis. Int J Peptide and Protein Res 31: 86–97CrossRefGoogle Scholar
  8. Fritz lB (1978) Sites of actions of androgens and follicle stimulating hormone on cells of the seminiferous tubule. In: Litwack G (ed) Biochemical actions of hormones. Vol V, Academic Press, New York Academic Press, pp 249–281CrossRefGoogle Scholar
  9. Geysen HM, Meloen RH, Barteling SJ (1984) Peptide synthesis used to probe viral antigens for epitopes to a resolution of single aminoacid. Proc Natl Acad Sci USA 81: 3998–4002PubMedCrossRefGoogle Scholar
  10. Gordon WL, Ward DN (1985) Structural aspects of luteinizing hormone actions In: Ascoli M (ed) Luteinizing hormone action and receptors, CRC Press, Boca Raton, Florida, pp 174–197Google Scholar
  11. Hage-van Noort M, Puijk WC, Plasman HH, Kuperus D, Schaaper WMM, Beekman NJCM, Grootegoed JA, Meloen RH (1992) Synthetic peptides based upon a three dimensional model for the receptor recognition site of follicle stimulating hormone exhibit antagonistic or agonistic activity at low concentrations. Proc Natl Acad Sci USA (in press)Google Scholar
  12. Harris DC, Machin KJ, Evin GM, Morgan FJ, Isaacs NW (1989) Preliminary X-ray diffraction analysis of human chorionic gonadotropin. J Biol Chem 264: 6705–6706PubMedGoogle Scholar
  13. Heckert L, Griswold MD (1992) The changing functions of follicle stimulating hormone in the testes of prenatal, newborn, immature and adult rats. In: Hunzicker-Dunn M, Schwartz NB (eds) Follicle stimulating hormone: Regulation of secretion and molecular mechanisms of action. Springer Verlag, New York, Berlin, Heidelberg pp 237–245Google Scholar
  14. Holmgren A (1989) Thioredoxin and glutaredoxin systems. J Biol Chem 264: 13963–13966PubMedGoogle Scholar
  15. Jameson JL, Becker CB, Lindell CM, Habener JF(1988) Human follicle-stimulating hormone (3-subunit gene encodes multiple messenger ribonucleic acids. Molec Endocrinol 2: 806–815Google Scholar
  16. Ji I, Ji TH (1990) Differential interactions of human choriogonadotropin and its antagonistic aglycosylated analog with their receptor. Proc Natl Acad Sci USA 87: 4396–4400PubMedCrossRefGoogle Scholar
  17. Keutmann HT, Johnson L, Ryan RJ (1985) Evidence for a conformational change in deglycosylated glycoprotein hormones. FEBS Letters 185: 333–338PubMedCrossRefGoogle Scholar
  18. Keutmann HT, Charlesworth MC, Mason KA, Ostrea T, Johnson L, Ryan RJ (1987) A receptor-binding region in human choriogonadotropin/ lutropin 3-subunit. Proc Natl Acad Sci USA 84: 2038–2042PubMedCrossRefGoogle Scholar
  19. Keutmann HT,Charlesworth MC, Kitzmann K, Mason KA, Johnson L, Ryan RJ (1988) Primary and secondary structural determinants in the receptor binding sequence 13-(38–57) from human luteinizing hormone. Biochem 27: 8939–8944CrossRefGoogle Scholar
  20. Keutmann HT, Mason KA, Kitzmann K, Ryan RJ (1989) Role of the 1393–100 determinant loop sequence in receptor binding and biological activity of human luteinizing hormone and chorionic gonadotropin. Molec Endocrinol 3: 526–531CrossRefGoogle Scholar
  21. Matzuk MM, Boime I (1989) Mutagenesis and gene transfer define site spe- cific roles of the gonadotropin oligosaccharides. Biol Reprod 40: 48–53PubMedCrossRefGoogle Scholar
  22. Mertz WE (1984) Structure-function relationships of gonadotropins: Human choriogonadotropin as a model. In: Runnebaum B, Rabe T, Kiesel L, Mertz WE (eds) Secretion and action of gonadotropins. Physiology and clinic. Springer Verlag, Berlin, Heidelberg, New York, pp 59–82Google Scholar
  23. Oonk RB, Grootegoed JA (1985) Comparison of the effects of insulin and follitropin on glucose metabolism by Sertoli cells from immature rats. Mol Cell Endocrinol 42: 39–48PubMedCrossRefGoogle Scholar
  24. Pierce JG, Parsons TF (1981) Glycoprotein hormones: structure and function. Ann Rev Biochem 50: 465–495PubMedCrossRefGoogle Scholar
  25. Pierce JG (1988) Gonadotropins: Chemistry and Biosynthesis. In: Knobil E, Neill J (eds) The physiology of reproduction, Raven Press, New York, pp 1335–1349Google Scholar
  26. Rebois RV, Liss MT (1987) Antibody binding to the (3-subunit of deglycosylated chorionic gonadotropin converts the antagonist to an agonist. J Biol Chem 262: 3891–3896PubMedGoogle Scholar
  27. Reichert Jr LE, Dattatreyamurty B (1989) The follicle-stimulating hormone (FSH) receptor in testis: Interaction with FSH, mechanism of signal transduction, and properties of the purified receptor. Biol Reprod 40: 13–26PubMedCrossRefGoogle Scholar
  28. Ryan RJ, Charlesworth MC, McCormick, DJ, Milius, RP, Keutman, HT (1988) The glycoprotein hormones: recent studies of structure function relationships. Faseb J 2: 2661–2669PubMedGoogle Scholar
  29. Ryan RJ, Keutmann HT, Charlesworth MC, McCormick DJ, Milius RP, Calvo FO, Vutyavanich T (1987) Structure-function relationships of gonadotropins. Recent Progress Hormone Res 43, 383–422Google Scholar
  30. Santa Coloma TA, Reichert Jr LE (1990) Identification of a follicle-stimulating hormone receptor-binding region in hFSH ß981–95) using synthetic peptides. J Biol Chem 265: 5037–5042Google Scholar
  31. Santa Coloma TA, Dattatreyamurty B, Reichert Jr LE (1990) A synthetic peptide corresponding to human FSH 3-subunit 33–53 binds to FSH receptor, simulates basal estradiol biosynthesis, and is a partial antagonist of FSH. Biochem 29: 1194–1200CrossRefGoogle Scholar
  32. Schaaper WMM, Beekman NJCM, Hage M, Briel P, Kuperus D, Meloen RH (1992) Synthesis of large numbers of peptides for rapid screening of bioactive sequences. In: Smith JA (ed) Proceedings of the 12th American peptide symposium, ESCOM, Leiden (in press)Google Scholar
  33. Schneyer AL, Sluss PM, Huston JS, Ridge RJ, Reichert Jr LE (1988) Identification of a receptor binding region on the ßsubunit of human follicle-stimulating hormone. Biochem 27: 666–671CrossRefGoogle Scholar
  34. Sluss PM, Krystek Jr SR, Andersen TT, Melson BE, Huston JS, Ridge R, Reichert Jr LE (1986) Inhibition of iodine-125-labeled human follitropin binding to testicular receptor by epidermal growth factor and synthetic peptides. Biochem 25: 2644–2649CrossRefGoogle Scholar
  35. Sprengel R, Braun T (1992) Glycoprotein hormone receptors: A particular class of G-protein-coupled receptors. In: Hunzicker-Dunn M, Schwartz NB (eds) Follicle stimulating hormone: Regulation of secretion and molecular mechanisms of action, Springer Verlag, New York Berlin Heidelberg, pp 129–141CrossRefGoogle Scholar
  36. Van Alphen MMA, Van de Kant HJG, de Rooij DG (1988) Follicle stimulating hormone stimulates spermatogenesis in the adult monkey. Endocrinol 123: 1449–1455CrossRefGoogle Scholar
  37. Van der Zee R, Van Eden W, Meloen RH, Noordzij A, Van Embden JDA (1988) Efficient mapping and characterization of a T Cell epitope by the simultaneous synthesis of multiple peptides. Eur J Immunol 191: 43–48Google Scholar
  38. Vaishnav MY, Moudgal NR (1992) Effects of specific FSH deprivation on testicular germ cell transformations and on LDH-X and hyaluronidase activity of immature and adult rats. In:Follicle stimulating hormone: Regulation of secretion and molecular mechanisms of action, Hunzicker-Dunn M and Schwartz NB (Eds) Springer-Verlag, New York, Berlin, Heidelberg, pp 364–368CrossRefGoogle Scholar
  39. Willey KP, Leidenberger F (1989) Functionally distinct agonist and receptor-binding regions in human chorionic gonadotropin. Development of a tertiary structure model. J Biol Chem 264: 19716–19729PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • Marjolein Hage-van Noort
  • Wooter C. Puijk
  • Wim M. M. Schaaper
  • Douwe Kuperus
  • Nico J. C. M. Beekman
  • Henk H. Plasman
  • J. Anton Grootegoed
  • Robert H. Meloen

There are no affiliations available

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