Inhibins: A Historical Perspective

Inhibin research began in 1923 with the concept of gonadal feedback regulation of pituitary function. A nonsteroidal substance, capable of inhibiting pituitary cell activity was identified in aqueous testicular extracts and named inhibin in 1932. Another 50 years of research was required before inhibin was purified and cloned in 1985, and inhibin’s physiology was not revealed until advances in assay technology allowed analysis of circulating levels in animals and humans. Thus, after 80 years of research, a historical retrospective reveals that many advances were required to achieve our present understanding, and yet there is still a long way to go to reach the original objectives of using inhibin, or compounds based on its structure, to regulate fertility pharmaceutically. Nevertheless, this perspective points out important lessons learned during this journey that are applicable to other areas of endocrinology or are opportunities for future research.

KEYWORDS

Inhibin - hormone - endocrine - gonadotropin - follicle-stimulating hormone

REFERENCES

• 1 Mottram J C, Cramer W. On the general effects of exposure to radium on metabolism and tumour growth in the rat and the special effects on the testis and pituitary.  Q J Exp Physiol Cogn Med Sci. 1923;  13 209-229
• 2 McCullagh D R. Dual endocrine activity of testes.  Science. 1932;  76 19-20
• 3 Pierce J G, Parsons T F. Glycoprotein hormones: structure and function.  Annu Rev Biochem. 1981;  50 465-495
• 4 Phifer R F, Midgley A R, Spicer S S. Immunohistologic and histologic evidence that follicle-stimulating hormone and luteinizing hormone are present in the same cell type in the human pars distalis.  J Clin Endocrinol Metab. 1973;  36 125-141
• 5 Arimura A, Shino M, de la Cruz K G, Rennels E G, Schally A V. Effect of active and passive immunization with luteinizing hormone-releasing hormone on serum luteinizing hormone and follicle-stimulating hormone levels and the ultrastructure of the pituitary gonadotrophs in castrated male rats.  Endocrinology. 1976;  99 291-303
• 6 Setchell B P, Jacks F. Inhibin-like activity in rete testis fluid.  J Endocrinol. 1974;  62 675-676
• 7 de Jong F H. Inhibin.  Physiol Rev. 1988;  68 555-607
• 8 de Jong F H, Sharpe R M. Evidence for inhibin-like activity in bovine follicular fluid.  Nature. 1976;  263 71-72
• 9 Schwartz N, Channing C. Evidence for ovarian inhibin: suppression of the secondary rise in serum follicle-stimulating hormone levels in proestrus rats by injection of porcine follicular fluid.  Proc Natl Acad Sci USA. 1977;  74 5721-5724
• 10 Hudson B, Baker H W, Eddie L W et al.. Bioassays for inhibin: a critical review.  J Reprod Fertil Suppl. 1979;  26 17-29
• 11 Vale W, Grant G, Amoss M, Blackwell R, Guillemin R. Culture of enzymatically dispersed pituitary cells: functional validation of a method.  Endocrinology. 1972;  91 562-572
• 12 Robertson D M, Foulds L M, Leversha L et al.. Isolation of inhibin from bovine follicular fluid.  Biochem Biophys Res Commun. 1985;  126 220-226
• 13 Miyamoto K, Hasegawa Y, Fukuda M et al.. Isolation of porcine follicular fluid inhibin of 32K daltons.  Biochem Biophys Res Commun. 1985;  129 396-403
• 14 Rivier J, Spiess J, McClintock R, Vaughan J, Vale W. Purification and partial characterization of inhibin from porcine follicular fluid.  Biochem Biophys Res Commun. 1985;  133 120-127
• 15 Ling N, Ying S-Y, Ueno N, Esch F, Denoroy L, Guillemin R. Isolation and partial characterization of a Mr 32,000 protein with inhibin activity from porcine follicular fluid.  Proc Natl Acad Sci USA. 1985;  82 7217-7221
• 16 Mason A J, Hayflick J S, Ling N et al.. Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-beta.  Nature. 1985;  318 659-663
• 17 Mason A J, Niall H D, Seeburg P H. Structure of two human ovarian inhibins.  Biochem Biophys Res Commun. 1986;  135 957-964
• 18 Forage R G, Ring J M, Brown R W et al.. Cloning and sequence analysis of cDNA species coding for the two subunits from bovine follicular fluid.  Proc Natl Acad Sci USA. 1986;  83 3091-3095
• 19 Vale W, Rivier C, Hsueh A et al.. Chemical and biological characterization of the inhibin family of protein hormones.  Recent Prog Horm Res. 1988;  44 1-34
• 20 Mason A J. Structure and recombinant expression of human inhibin and activin. In: Hodgen GD, Rosenwaks Z, Spieler JM Non-Steroidal Gonadal Factors. Norfolk, VA; Jones Institute Press 1988: 15-21
• 21 McLachlan R I, Robertson D M, Burger H G, DeKretser D M. The radioimmunoassay of bovine and human follicular fluid and serum inhibin.  Mol Cell Endocrinol. 1986;  46 175-185
• 22 McLachlan R I, Robertson D M, Healy D L, Burger H G, DeKretser D M. Circulating immunoreactive inhibin levels during the normal human menstrual cycle.  J Clin Endocrinol Metab. 1987;  65 954-961
• 23 Schneyer A L, Mason A J, Burton L E, Ziegner J R, Crowley W F. Immunoreactive inhibin alpha subunit in human serum: implications for RIA.  J Clin Endocrinol Metab. 1990;  70 1208-1212
• 24 Sluss P M, Gentile D P, Ewing J F et al.. Multiple molecular weight forms of immunoreactive alpha inhibin in human seminal plasma.  J Clin Endocrinol Metab. 1993;  76 476-483
• 25 Lambert-Messerlian G M, Isaacson K, Crowley Jr W F, Sluss P, Schneyer A L. Human follicular fluid contains pro- and C-terminal immunoreactive alpha-inhibin precursor proteins.  J Clin Endocrinol Metab. 1994;  78 433-439
• 26 Knight P G, Beard A J, Wrathall J HM, Castillo R J. Evidence that the bovine ovary secretes large amounts of monomeric inhibin alpha subunit and its isolation from bovine follicular fluid.  J Mol Endocrinol. 1989;  2 189-200
• 27 Robertson D M, Giacometti M, Foulds L M et al.. Isolation of inhibin alpha-subunit precursor proteins from bovine follicular fluid.  Endocrinology. 1989;  125 2141-2149
• 28 Baly D L, Allison D E, Krummen L A et al.. Development of a specific and sensitive two-site enzyme-linked immunosorbent assay for measurement of inhibin-A in serum.  Endocrinology. 1993;  132 2099-2108
• 29 Groome N, O'Brien M. Immunoassays for inhibin and its subunits: further applications of the synthetic peptide approach.  J Immunol Methods. 1993;  165 167-176
• 30 Groome N, Illingworth P I, O'Brien M. Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay.  Clin Endocrinol (Oxf). 1994;  40 717-723
• 31 Lambert-Messerlian G M, Hall J E, Sluss P M et al.. Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site enzyme-linked immunosorbent assay.  J Clin Endocrinol Metab. 1994;  79 45-50
• 32 Illingworth P J, Groome N P, Byrd W et al.. Inhibin-B: a likely candidate for the physiologically important form of inhibin in men.  J Clin Endocrinol Metab. 1996;  81 1321-1325
• 33 Groome N P, Illingworth P J, O'Brien M et al.. Measurement of dimeric inhibin-B throughout the human menstrual cycle.  J Clin Endocrinol Metab. 1996;  81 1401-1405
• 34 Good T EM, Weber P SD, Ireland J LH et al.. Isolation of nine different biologically and immunologically active variants of bovine follicular inhibins.  Biol Reprod. 1995;  53 1478-1488
• 35 Robertson D M, Cahir N, Findlay J K, Burger H G, Groome N. The biological and immunological characterization of inhibin A and B forms in human follicular fluid and plasma.  J Clin Endocrinol Metab. 1997;  82 889-896
• 36 Mathews L S, Vale W W. Expression cloning of an activin receptor, a predicted transmembrane serine kinase.  Cell. 1991;  65 973-982
• 37 Lewis K A, Gray P C, Blount A L et al.. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling.  Nature. 2000;  404 411-414