Modulation of Gonadotropin Secretion by Proteins of the Inhibin Family: Studies in the Female Rat

  • Catherine Rivier
  • Wylie Vale
Part of the Serono Symposia USA book series (SERONOSYMP)


The secretion of FSH by anterior pituitary gonadotropes is controlled by both brain factors and those of peripheral origin. Gonadotropin releasing hormone (GnRH), a decapeptide originally characterized in mammalian hypothalamus (1, 2), stimulates FSH secretion in a variety of animal models; removal of GnRH, or blockade of its receptors, decreases basal FSH levels (reviewed in 3). However, several observations have suggested that existence of factors other than GnRH as major regulators of FSH secretion: Administration of GnRH antisera or antagonists to rats does not completely obliterate FSH release (4–10); LH can trigger a rise in FSH levels despite blockade of GnRH receptors (6) (a phenomenon that, as described below, is probably mediated through inhibin); and destruction of the dorsal anterior hypothalamus reduces LH, but not FSH, secretion by ovariectomized rats (11). At present, this GnRH-independent component of FSH release is believed to include sex steroids and gonadal proteins, such as inhibin, activin, and follistatin (reviewed in 12–114). The recent availability of recombinant human (rh) inhibin A has allowed us to reexamine the effect of this protein in a variety of animal models. Additionally, rh inhibin, combined with GnRH antagonists and inhibin antibodies, is proving to be a powerful tool with which to investigate the respective physiological role and pharmacological effects of GnRH and gonadal proteins in modulating reproductive functions.


Luteinizing Hormone Follicular Fluid GnRH Antagonist Gonadotropin Secretion Luteinizing Hormone Secretion 


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  1. 1.
    Burgus R, Butcher M, Amoss M, et al. Primary structure of the ovine hypothalamic luteinizing hormone-releasing factor (LRF). Proc Natl Acad Sci USA 1972; 69: 278–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsuo H, Baba Y, Nair R, et al. Structure of the porcine LH- and FSH-releasing hormone, I. Proposed amino acid sequence. Biochem Biophys Res Commun 1971; 43: 1334–9.PubMedCrossRefGoogle Scholar
  3. 3.
    McNeilly AS. The control of FSH secretion. Acta Endocrinol (Copenh) 1988; 288: 31–40.Google Scholar
  4. 4.
    Charlesworth C, Grady RR, Shin L, et al. Differential suppression of FSH and LH secretion by follicular fluid in the presence or absence of GnRH. Neuroendocrinology 1984; 38: 199–205.PubMedCrossRefGoogle Scholar
  5. 5.
    Grady RR, Shin L, Charlesworth MC, et al. Differential suppression of follicle-stimulating hormone and luteinizing hormone secretion in vivo by a gonadotropinreleasing hormone antagonist. Neuroendocrinology 1985; 40: 246–52.PubMedCrossRefGoogle Scholar
  6. 6.
    Schwartz NB, Rivier C, Rivier J, et al. Effect of gonadotropin releasing hormone antagonists on serum follicle-stimulating hormone and luteinizing hormone under conditions of singular FSH secretion. Biol Reprod 1985; 32: 391–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Karton K, Schwartz NB. Effects of a potent antagonist to gonadotropin-releasing hormone on male rats: luteinizing hormone is suppressed more than follicle-stimulating hormone. Biol Reprod 1987; 36: 103–8.CrossRefGoogle Scholar
  8. 8.
    Rivier C, Meunier H, Roberts V, et al. Inhibin: role and secretion in the rat. In: Clark JH, ed. Recent progress in hormone research. Laurentian horm conf. Newport Beach, CA, August 26–30, 1989. Orlando, FL: Academic Press, 1990; 46.Google Scholar
  9. 9.
    Culler MD, Negro-Vilar A. Pulsatile follicle-stimulating hormone secretion is independent of luteinizing hormone-releasing hormone (LHRH): pulsatile replacement of LHRH bioactivity in LHRH-immunoneutralized rats. Endocrinology 1987; 120: 2011–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Culler MD, Negro-Vilar A. Evidence that pulsatile follicle-stimulating hormone secretion is independent of endogenous luteinizing hormone-releasing hormone. Endocrinology 1986; 118: 609–12.PubMedCrossRefGoogle Scholar
  11. 11.
    Lumpkin MD, McCann SM. Effect of destruction of the dorsal anterior hypothalamus on follicle-stimulating hormone secretion in the rat. Endocrinology 1984; 115: 2473–80.PubMedCrossRefGoogle Scholar
  12. 12.
    Vale W, Rivier C, Hsueh A, et al. Chemical and biological characterization of the inhibin family of protein hormones. In: Clark JH, ed. Recent progress in hormone research. Proc Laurentian horm conf. San Diego: Academic Press, 1988; 44: 1–34.Google Scholar
  13. 13.
    Vale W, Hsueh A, Rivier C, et al. The inhibin/activin family of hormones and growth factor. In: Sporn MA, Roberts AB, eds. Peptide growth factors and their receptors. Handbook of experimental pharmacology. Heidelberg: Springer-Verlag, 1990: 211–48.CrossRefGoogle Scholar
  14. 14.
    DeKretser DM, Robertson DM. The isolation and physiology of inhibin and related proteins. Biol Reprod 1989; 40: 33–47.CrossRefGoogle Scholar
  15. 15.
    Vale W, Rivier C, Brown M. Physiology and pharmacology of hypothalamic regulatory peptides. In: Morgane PJ, Panksepp J, eds. Physiology of the hypothalamus. New York: Marcel Dekker, 1980: 165–251.Google Scholar
  16. 16.
    Karten MJ, Rivier JE. GnRH analog design structure-function studies toward the development of agonists and antagonists: rationale and perspective. Endocr Rev 1986; 7: 44–66.PubMedCrossRefGoogle Scholar
  17. 17.
    Levine JE, Duffy T. Simultaneous measurement of luteinizing hormone (LH)-releasing hormone, LH, and follicle-stimulating hormone release in intact and short-term castrate rats. Endocrinology 1988; 122: 2211–21.PubMedCrossRefGoogle Scholar
  18. 18.
    Urbanski HF, Pickle RL, Ramirez VD. Simultaneous measurement of gonadotropinreleasing hormone, luteinizing hormone, and follicle-stimulating hormone in the orchidectomized rat. Endocrinology 1988; 123: 413–9.PubMedCrossRefGoogle Scholar
  19. 19.
    DePaolo LV. Differential regulation of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone secretion in ovariectomized rats disclosed by treatment with a LH-releasing hormone antagonist and phenobarbital. Endocrinology 1985; 117: 1826–33.CrossRefGoogle Scholar
  20. 20.
    Mason AJ, Hayflick JS, Ling N, et al. Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-ß. Nature 1985; 318: 659–63.PubMedCrossRefGoogle Scholar
  21. 21.
    Mayo KE, Cerelli GM, Spiess J, et al. Inhibin a-subunit cDNAs from porcine ovary and human placenta. Proc Natl Acad Sci USA 1986; 83: 5849–53.PubMedCrossRefGoogle Scholar
  22. 22.
    Rivier C, Vale W. Inhibin: measurement and role in the immature female rat. Endocrinology 1987; 120: 1688–90.PubMedCrossRefGoogle Scholar
  23. 23.
    Rivier C, Roberts V, Vale W. Possible role of LH and FSH in modulating inhibin secretion and expression during the estrous cycle of the rat. Endocrinology 1989; 125: 876–82.PubMedCrossRefGoogle Scholar
  24. 24.
    Hasegawa Y, Miyamoto K, Igarashi M. Changes in serum concentrations of immunoreactive inhibin during the oestrous cycle of the rat. J Endocrinol 1989; 121: 91–100.PubMedCrossRefGoogle Scholar
  25. 25.
    Rivier C, Rivier J, Vale W. Inhibin-mediated feedback control of follicle-stimulating hormone secretion in the female rat. Science 1986; 234: 205–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Rivier C, Vale W. Immunoneutralization of endogenous inhibin modifies hormone secretion and ovulation rate in the rat. Endocrinology 1989; 125: 152–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Culler MD, Negro-Vilar A. Endogenous inhibin suppresses only basal follicle-stimulating hormone secretion but suppresses all parameters of pulsatile luteinizing hormone secretion in the diestrous female rat. Endocrinology 1989; 124: 2944–53.PubMedCrossRefGoogle Scholar
  28. 28.
    Culler MD, Negro-Villar A. Passive immunoneutralization of endogenous inhibin: sex-related differences in the role of inhibin during development. Mol Cell Endocrinol 1988; 58: 263–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Hasegawa Y, Miyamoto K, Yazaki C, et al. Regulation of the second surge of follicle-stimulating hormone; effects of antiluteinizing hormone-releasing hormone serum and pentobarbital. Endocrinology 1981; 109: 130–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Blake CA, Kelch RP. Administration of antiluteinizing hormone-releasing hormone serum to rats: effects on periovulatory secretion of luteinizing hormone and follicle-stimulating hormone. Endocrinology 1981; 109: 2175–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Condon TP, Heber D, Stewart JM, et al. Differential gonadotropin secretion: blockade of periovulatory LH but not FSH secretion by a potent LHRH antagonist. Neuroendocrinology 1984; 38: 357–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Ashiru OA, Blake CA. Stimulation of endogenous follicle-stimulating hormone release during estrus by exogenous follicle-stimulating hormone of luteinizing hormone at proestrus in the phenobarbital-blocked rat. Endocrinology 1979; 105: 1162–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Shander D, Anderson LD, Barraclough CA. Follicle-stimulating hormone and luteinizing hormone affect the endogenous release of pituitary follicle-stimulating hormone and the ovarian secretion of inhibin in rats. Endocrinology 1980; 106: 1047–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Ashiru OA, Blake CA. Variations in the effectiveness with which rat follicle-stimulating hormone can stimulate its own secretion during the rat estrous cycle. Endocrinology 1980; 106: 476–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Schwartz NB, Talley WL. Effects of exogenous LH of FSH on endogenous FSH, progesterone and estradiol secretion. Biol Reprod 1978; 17: 820–8.CrossRefGoogle Scholar
  36. 36.
    Schwartz NB, Channing CP. Evidence for ovarian “inhibin”: suppression of the secondary rise in serum follicle stimulating hormone levels in proestrous rats by injection of porcine follicular fluid. Proc Natl Acad Sci USA 1977; 74: 5721–4.PubMedCrossRefGoogle Scholar
  37. 37.
    DePaolo LV, Wise PM, Anderson LD, et al. Suppression of the pituitary folliclestimulating hormone secretion during proestrus and estrus in rats by porcine follicular fluid: possible site of action. Endocrinology 1979; 104: 402–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Rush ME, Ashiru OA, Lipner H, et al. The actions of porcine follicular fluid and estradiol on periovulatory secretion of gonadotropic hormones in rats. Endocrinology 1981; 108: 2316–23.PubMedCrossRefGoogle Scholar
  39. 39.
    Channing CP, Gordon WL, Liu WK, et al. Physiology and biochemistry of ovarian inhibin. Proc Soc Exp Biol Med 1985; 178: 339–61.PubMedGoogle Scholar
  40. 40.
    DeJong FH. Inhibin. Physiol Rev 1988; 68: 555–607.Google Scholar
  41. 41.
    Vale W, Rivier J, Vaughan J, et al. Purification and characterization of an FSHreleasing protein from porcine ovarian follicular fluid. Nature 1986; 321: 776–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Ling N, Ying SY, Ueno N, et al. Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature 1986; 321: 779–82.PubMedCrossRefGoogle Scholar
  43. 43.
    Esch FS, Shimasaki S, Mercado M, et al. Structural characterization of follistatin: a novel follicle-stimulating hormone release inhibiting polypeptide from the gonad. Mol Cell Endocrinol 1987; 1: 849–54.CrossRefGoogle Scholar
  44. 44.
    Ueno N, Ling N, Ying S-Y, et al. Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci USA 1987; 84: 8282–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Vaughan JM, Rivier J, Corrigan AZ, et al. Detection and purification of inhibin using antisera generated against synthetic peptide fragments. In: Conn PM, ed. Methods in enzymology. Orlando, FL: Academic Press, 1989: 588–617.Google Scholar
  46. 46.
    Mason AJ, Schwall R, Renzy M, et al. Human inhibin and activin: structure and recombinant expression in mammalian cells. In: Burger HG, DeKretser DM, Findlay JK, et al., eds. Inhibin-non-steroidal regulation of follicle-stimulating hormone secretion. New York: Raven Press, 1987: 77–88.Google Scholar
  47. 47.
    Rivier C, Schwall R, Mason A, et al. Effect of recombinant inhibin on LH and FSH secretion in the rat. Endocrinology 1990.Google Scholar
  48. 48.
    Grady RR, Charlesworth MC, Schwartz NB. Characterization of the FSHsuppressing activity in follicular fluid. Recent Prog Horm Res 1982; 38: 409–56.PubMedGoogle Scholar
  49. 49.
    Campbell CS, Schwartz NB. Time course of serum FSH suppression in ovariectomized rats injected with porcine follicular fluid (folliculostatin): effect of estradiol treatment. Biol Reprod 1979; 20: 1093–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Marder ML, Channing CP, Schwartz NB. Suppression of serum follicle stimulating hormone in intact and acutely ovariectomized rats by porcine follicular fluid. Endocrinology 1977; 101: 1639–42.CrossRefGoogle Scholar
  51. 51.
    Williams AT, Lipner H. Negative feedback control of gonadotropin secretion by chronically administered estradiol and porcine follicular fluid (gonadostatin) in ovariectomized rats. Endocrinology 1981; 109: 1496–501.PubMedCrossRefGoogle Scholar
  52. 52.
    Koiter TR, VanDerSchaaf-Verdonk GCJ, Kuiper H, et al. Control of follicle-stimulating hormone secretion by steroid-free bovine follicular fluid in the ovariectomized rat. J Endocrinol 1983; 99: 1–8.PubMedCrossRefGoogle Scholar
  53. 53.
    DeGreef WJ, Eilers GAM, DeKonnig J, et al. Effects of ovarian inhibin on pulsatile release of gonadotrophins and secretion of LHRH in ovariectomized rats: evidence against a central action of inhibin. J Endocrinol 1987; 113: 449–55.CrossRefGoogle Scholar
  54. 54.
    Lumpkin MD, DePaolo LV, Negro-Vilar A. Pulsatile release of follicle-stimulating hormone in ovariectomized rats is inhibited by porcine follicular fluid (inhibin). Endocrinology 1984; 114: 201–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Fukuda M, Miyamoto K, Hasegawa Y, et al. Action mechanism of inhibin in vitro—cycloheximide mimics inhibin actions on pituitary cells. Mol Cell Endocrinol 1987; 51: 41–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Farnworth PG, Robertson DM, DeKretser DM, et al. Effects of 31 kDa bovine inhibin on FSH and LH in rat pituitary cells in vitro antagonism of gonadotrophinreleasing hormone agonists. J Endocrinol 1988; 119: 233–41.PubMedCrossRefGoogle Scholar
  57. 57.
    Campen CA, Vale W. Interaction between purified ovine inhibin and steroids on the release of gonadotropins from cultured rat pituitary cells. Endocrinology 1988; 123: 1320–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Robertson DM, Giacometti MS, DeKretser DM. The effects of inhibin purified from bovine follicular fluid in several in vitro pituitary cell culture systems. Mol Cell Endocrinol 1986; 46: 29–36.PubMedCrossRefGoogle Scholar
  59. 59.
    Wang QF, Farnworth PG, Findlay JK, et al. Effect of purified 31K bovine inhibin on the specific binding of gonadotropin-releasing hormone to rat anterior pituitary cells in culture. Endocrinology 1988; 123: 2161–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Jakubowiak A, Janecki A, Steinberger A. Similar effects of inhibin and cycloheximide on gonadotropin release in superfused pituitary cell cultures. Biol Reprod 1989; 41: 454–63.PubMedCrossRefGoogle Scholar
  61. 61.
    Mercer JE, Clements JA, Funder JW, et al. Rapid and specific lowering of pituitary FSH mRNA levels by inhibin. Mol Cell Endocrinol 1987; 53: 251–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Carroll RS, Corrigan AZ, Gharib SD, et al. Inhibin, activin and follistatin: regulation of follicle-stimulating hormone messenger ribonucleic acid levels. Mol Cell Endocrinol 1989; 3: 1969–76.CrossRefGoogle Scholar
  63. 63.
    Attardi B, Keeping HS, Winters SJ, et al. Rapid and profound suppression of messenger ribonucleic acid encoding follicle-stimulating hormone fi by inhibin from primate Sertoli cells. Mol Cell Endocrinol 1989; 3: 280–7.CrossRefGoogle Scholar
  64. 64.
    Wang QF, Famworth PB, Findlay JK, et al. Inhibitory effect of pure 31-kilodalton bovine inhibin in gonadotropin-releasing hormone (GnRH)-induced up-regulation of GnRH binding sites in cultured rat anterior pituitary cells. Endocrinology 1989; 124: 363–8.PubMedCrossRefGoogle Scholar

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© Springer-Verlag New York, Inc. 1992

Authors and Affiliations

  • Catherine Rivier
  • Wylie Vale

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