Semin Reprod Med 2004; 22(3): 177-185
DOI: 10.1055/s-2004-831893
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Inhibins in Normal Male Physiology

Anne E. O’Connor1 , David M. de Kretser1
  • 1Centre for Molecular Reproduction and Endocrinology, Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria, Australia
Further Information

Publication History

Publication Date:
20 August 2004 (online)

Inhibin is a dimeric glycoprotein that suppresses follicle-stimulating hormone (FSH) secretion from the pituitary. Two bioactive forms of inhibin exist, inhibin A and B. The availability of specific immunoassays for each of the isoforms has enabled the study of the individual inhibins and their physiological roles. In the male, inhibin B is the circulating form in all species studied to date except the sheep. Inhibin B is produced in the testis, principally by the Sertoli cells. There are temporal changes in inhibin expression and secretion with the changing role of the Sertoli cell in immature and adult testes. Variations in inhibin B production between species reflect the different patterns of maturation. In the adult, inhibin B levels are positively correlated with Sertoli cell function, sperm number, and spermatogenic status and are negatively correlated with FSH. It appears that the regulation of inhibin B production is mediated by a complex interaction between FSH, Sertoli cells, Leydig cells, and germ cells. Inhibin may also play a role at an autocrine or paracrine level in modulating the actions of activin.

REFERENCES

  • 1 McCullagh D R. Dual endocrine activity of the testes.  Science. 1932;  76 19-20
  • 2 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
  • 3 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
  • 4 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
  • 5 Phillips D J. The activin/inhibin family. In: Thomson AW, Lotze MT The Cytokine Handbook. London; Elsevier Science 2003: 1153-1177
  • 6 Robertson D M, Tsonis C G, McLachlan R I et al.. Comparison of inhibin immunological and in vitro biological activities in human serum.  J Clin Endocrinol Metab. 1988;  67 438-443
  • 7 Groome N P, Illingworth P J, O'Brien M et al.. Detection of dimeric inhibin throughout the human menstrual cycle by two-site enzyme immunoassay.  Clin Endocrinol (Oxf). 1994;  40 717-723
  • 8 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
  • 9 Illingworth P, Groome N, 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
  • 10 Plant T M, Padmanabhan V, Ramaswamy S et al.. Circulating concentrations of dimeric inhibin A and B in the male rhesus monkey (Macaca mulatta).  J Clin Endocrinol Metab. 1997;  82 2617-2621
  • 11 Sharpe R M, Turner K J, McKinnell C et al.. Inhibin B levels in plasma of the male rat from birth to adulthood: effect of experimental manipulation of Sertoli cell number.  J Androl. 1999;  20 94-101
  • 12 McNeilly A S, Souza C J, Baird D T et al.. Production of inhibin A not B in rams: changes in plasma inhibin A during testis growth, and expression of inhibin/activin subunit mRNA and protein in adult testis.  Reproduction. 2002;  123 827-835
  • 13 Ishida H, Tashiro H, Watanabe M et al.. Measurement of inhibin concentrations in men: study of changes after castration and comparison with androgen levels in testicular tissue, spermatic venous blood, and peripheral venous blood.  J Clin Endocrinol Metab. 1990;  70 1019-1022
  • 14 McFarlane J R, Foulds L M, Pisciotta A, Robertson D M, de Kretser D M. Measurement of activin in biological fluids by radioimmunoassay, utilizing dissociating agents to remove the interference of follistatin.  Eur J Endocrinol. 1996;  134 481-489
  • 15 Le Gac F, de Kretser D M. Inhibin production by Sertoli cell cultures.  Mol Cell Endocrinol. 1982;  28 487-498
  • 16 Grootenhuis A J, Timmerman M A, Hordijk P L, de Jong F H. Inhibin in immature rat Sertoli cell conditioned medium: a 32 kDa alpha beta-B dimer.  Mol Cell Endocrinol. 1990;  70 109-116
  • 17 Hancock A D, Robertson D M, de Kretser D M. Inhibin and inhibin alpha-chain precursors are produced by immature rat Sertoli cells in culture.  Biol Reprod. 1992;  46 155-161
  • 18 Ramaswamy S, Marshall G R, McNeilly A S, Plant T M. Evidence that in a physiological setting Sertoli cell number is the major determinant of circulating concentrations of inhibin B in the adult male rhesus monkey (Macaca mulatta).  J Androl. 1999;  20 430-434
  • 19 Pierik F H, Vreeburg J T, Stijnen T, De Jong F H, Weber R F. Serum inhibin B as a marker of spermatogenesis.  J Clin Endocrinol Metab. 1998;  83 3110-3114
  • 20 Roberts V J, Barth S L. Expression of messenger ribonucleic acids encoding the inhibin/activin system during mid- and late-gestation rat embryogenesis.  Endocrinology. 1994;  134 914-923
  • 21 Majdic G, McNeilly A S, Sharpe R M, Evans L R, Groome N P, Saunders P TK. Testicular expression of inhibin and activin subunits and follistatin in the rat and human fetus and neonate and during postnatal development in the rat.  Endocrinology. 1997;  138 2136-2147
  • 22 Roberts V J. Tissue-specific expression of inhibin/activin subunit and follistatin mRNAs in mid- to late-gestational age human fetal testis and epididymis.  Endocrine. 1997;  6 85-90
  • 23 Anderson R A, Cambray N, Hartley P S, McNeilly A S. Expression and localization of inhibin alpha, inhibin/activin betaA and betaB and the activin type II and inhibin beta-glycan receptors in the developing human testis.  Reproduction. 2002;  123 779-788
  • 24 Jarred R A, Cancilla B, Richards M, Groome N P, McNatty K P, Risbridger G P. Differential localization of inhibin subunit proteins in the ovine testis during fetal gonadal development.  Endocrinology. 1999;  140 979-986
  • 25 Meehan T, Schlatt S, O'Bryan M K, de Kretser D M, Loveland K L. Regulation of germ cell and Sertoli cell development by activin, follistatin, and FSH.  Dev Biol. 2000;  220 225-237
  • 26 Wallace E M, Riley S C, Crossley J A et al.. Dimeric inhibins in amniotic fluid, maternal serum, and fetal serum in human pregnancy.  J Clin Endocrinol Metab. 1997;  82 218-222
  • 27 Tena-Sempere M, Kero J, Rannikko A, Yan W, Huhtaniemi I. The pattern of inhibin/activin alpha- and betaB-subunit messenger ribonucleic acid expression in rat testis after selective Leydig cell destruction by ethylene dimethane sulfonate.  Endocrinology. 1999;  140 5761-5770
  • 28 Buzzard J J, Loveland K L, O'Bryan M K et al.. Changes in circulating and testicular levels of inhibin A and B and activin A during post-natal development in the rat.  Endocrinology. 2004;  145 3532-3541
  • 29 Okuma Y, O'Connor A E, de Kretser D M, Hedger M P. Reciprocal regulation of activin A by interleukin (IL)-1 and follicle-stimulating hormone (FSH) in immature rat Sertoli cell in vitro. Abstract P214. Proceedings of the 11th International Congress of Endocrinology Sydney, Australia; October 2000
  • 30 Buzzard J J, Farnworth P G, De Kretser D M, O'Connor A E, Wreford N G, Morrison J R. Proliferative phase Sertoli cells display a developmentally regulated response to activin in vitro.  Endocrinology. 2003;  144 474-483
  • 31 Feng Z M, Wu A Z, Chen C L. Characterization and regulation of two testicular inhibin/activin beta B-subunit messenger ribonucleic acids that are transcribed from alternate initiation sites.  Endocrinology. 1995;  136 947-955
  • 32 Andersson A M, Toppari J, Haavisto A M et al.. Longitudinal reproductive hormone profiles in infants: peak of inhibin B levels in infant boys exceeds levels in adult men.  J Clin Endocrinol Metab. 1998;  83 675-681
  • 33 Byrd W, Bennett M J, Carr B R, Dong Y, Wians F, Rainey W. Regulation of biologically active dimeric inhibin A and B from infancy to adulthood in the male.  J Clin Endocrinol Metab. 1998;  83 2849-2854
  • 34 Chada M, Prusa R, Bronsky J et al.. Inhibin B, follicle stimulating hormone, luteinizing hormone and testosterone during childhood and puberty in males: changes in serum concentrations in relation to age and stage of puberty.  Physiol Res. 2003;  52 45-51
  • 35 Crofton P M, Illingworth P J, Groome N P et al.. Changes in dimeric inhibin A and B during normal early puberty in boys and girls.  Clin Endocrinol (Oxf). 1997;  46 109-114
  • 36 Andersson A M, Muller J, Skakkebaek N E. Different roles of prepubertal and postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B levels.  J Clin Endocrinol Metab. 1998;  83 4451-4458
  • 37 Andersson A M, Juul A, Petersen J H, Muller J, Groome N P, Skakkebaek N E. Serum inhibin B in healthy pubertal and adolescent boys: relation to age, stage of puberty, and follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol levels.  J Clin Endocrinol Metab. 1997;  82 3976-3981
  • 38 Bohring C, Krause W. Serum levels of inhibin B in men of different age groups.  Aging Male. 2003;  6 73-78
  • 39 Bergh A, Cajander S. Immunohistochemical localization of inhibin-alpha in the testes of normal men and in men with testicular disorders.  Int J Androl. 1990;  13 463-469
  • 40 Anderson R A, Irvine D S, Balfour C, Groome N P, Riley S C. Inhibin B in seminal plasma: testicular origin and relationship to spermatogenesis.  Hum Reprod. 1998;  13 920-926
  • 41 Marchetti C, Hamdane M, Mitchell V et al.. Immunolocalization of inhibin and activin alpha and betaB subunits and expression of corresponding messenger RNAs in the human adult testis.  Biol Reprod. 2003;  68 230-235
  • 42 Kinniburgh D, Anderson R A. Differential patterns of inhibin secretion in response to gonadotrophin stimulation in normal men.  Int J Androl. 2001;  24 95-101
  • 43 Adamopoulos D, Kapolla N, Nicopoulou S, Pappa A, Koukkou E, Gregoriou A. Assessment of Sertoli cell functional reserve and its relationship to sperm parameters.  Int J Androl. 2003;  26 215-225
  • 44 McLachlan R I, O'Donnell L, Meachem S J et al.. Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man.  Recent Prog Horm Res. 2002;  57 149-179
  • 45 Rulli S B, Ahtiainen P, Makela S, Toppari J, Poutanen M, Huhtaniemi I. Elevated steroidogenesis, defective reproductive organs, and infertility in transgenic male mice overexpressing human chorionic gonadotropin.  Endocrinology. 2003;  144 4980-4990
  • 46 Risbridger G P, Clements J, Robertson D M et al.. Immuno- and bioactive inhibin and inhibin alpha-subunit expression in rat Leydig cell cultures.  Mol Cell Endocrinol. 1989;  66 119-122
  • 47 Roberts V, Meunier H, Sawchenko P E, Vale W. Differential production and regulation of inhibin subunits in rat testicular cell types.  Endocrinology. 1989;  125 2350-2359
  • 48 Klaij I A, van Pelt A M, Timmerman M A, Blok L J, de Rooij D G, de Jong F H. Expression of inhibin subunit mRNAs and inhibin levels in the testes of rats with stage-synchronized spermatogenesis.  J Endocrinol. 1994;  141 131-141
  • 49 Gonzales G F, Risbridger G P, Hodgson Y H, Pollanen P, de Kretser D M. Stage-specific inhibin secretion by rat seminiferous tubules.  Reprod Fertil Dev. 1989;  1 275-279
  • 50 Risbridger G P, Thomas T, Gurusinghe C J, McFarlane J R. Inhibin-related proteins in rat prostate.  J Endocrinol. 1996;  149 93-99
  • 51 Thomas T Z, Chapman S M, Hong W et al.. Inhibins, activins, and follistatins: expression of mRNAs and cellular localization in tissues from men with benign prostatic hyperplasia.  Prostate. 1998;  34 34-43
  • 52 Thomas T Z, Wang H, Niclasen P et al.. Expression and localization of activin subunits and follistatins in tissues from men with high grade prostate cancer.  J Clin Endocrinol Metab. 1997;  82 3851-3858
  • 53 Matzuk M M, Finegold M J, Su J G, Hsueh A J, Bradley A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.  Nature. 1992;  360 313-319
  • 54 Risbridger G P, Shibata A, Ferguson K L, Stamey T A, McNeal J E, Peehl D M. Elevated expression of inhibin alpha in prostate cancer.  J Urol. 2004;  171 192-196
  • 55 Garem Y F, Arini A F, Beheiry A H, Zeid S A, Comhaire F H. Possible relationship between seminal plasma inhibin B and spermatogenesis in patients with azoospermia.  J Androl. 2002;  23 825-829
  • 56 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
  • 57 Vanttinen T, Kuulasmaa T, Liu J, Voutilainen R. Expression of activin/nhibin receptor and binding protein genes and regulation of activin/inhibin peptide secretion in human adrenocortical cells.  J Clin Endocrinol Metab. 2002;  87 4257-4263
  • 58 Wreford N G, O'Connor A E, de Kretser D M. Gonadotropin-suppressing activity of human recombinant inhibin in the male rat is age dependent.  Biol Reprod. 1994;  50 1066-1067
  • 59 Tilbrook A J, De Kretser D M, Clarke I J. Human recombinant inhibin A suppresses plasma follicle-stimulating hormone to intact levels but has no effect on luteinizing hormone in castrated rams.  Biol Reprod. 1993;  49 779-788
  • 60 Ramaswamy S, Pohl C R, McNeilly A S, Winters S J, Plant T M. The time course of follicle-stimulating hormone suppression by recombinant human inhibin A in the adult male rhesus monkey (Macaca mulatta).  Endocrinology. 1998;  139 3409-3415
  • 61 Plant T M, Marshall G R. The functional significance of FSH in spermatogenesis and the control of its secretion in male primates.  Endocr Rev. 2001;  22 764-786
  • 62 Wallace E M, Groome N P, Riley S C, Parker A C, Wu F CW. Effects of chemotherapy-induced testicular damage on inhibin, gonadotropin, and testosterone secretion: a prospective longitudinal study.  J Clin Endocrinol Metab. 1997;  82 3111-3115
  • 63 Anderson R A, Wallace E M, Groome N P, Bellis A J, Wu F C. Physiological relationships between inhibin B, follicle stimulating hormone secretion and spermatogenesis in normal men and response to gonadotrophin suppression by exogenous testosterone.  Hum Reprod. 1997;  12 746-751
  • 64 Anawalt B D, Bebb R A, Matsumoto A M et al.. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction.  J Clin Endocrinol Metab. 1996;  81 3341-3345
  • 65 Sheckter C B, McLachlan R I, Tenover J S et al.. Stimulation of serum inhibin concentrations by gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism.  J Clin Endocrinol Metab. 1988;  67 1221-1224
  • 66 Nachtigall L B, Boepple P A, Seminara S B et al.. Inhibin B secretion in males with gonadotropin-releasing hormone (GnRH) deficiency before and during long-term GnRH replacement: relationship to spontaneous puberty, testicular volume, and prior treatment-a clinical research center study.  J Clin Endocrinol Metab. 1996;  81 3520-3525
  • 67 Burger H G, Tiu S C, Bangah M L, de Kretser D M. Human chorionic gonadotrophin raises serum immunoreactive inhibin levels in men with hypogonadotrophic hypogonadism.  Reprod Fertil Dev. 1990;  2 137-144
  • 68 Feng Z M, Li Y P, Chen C L. Analysis of the 5′-flanking regions of rat inhibin alpha- and beta-B-subunit genes suggests two different regulatory mechanisms.  Mol Endocrinol. 1989;  3 1914-1925
  • 69 Kaipia A, Penttila T L, Toppari J. Follicle-stimulating hormone regulation of inhibin alpha-subunit mRNA in staged rat seminiferous tubules.  Eur J Endocrinol. 1994;  131 323-329
  • 70 Pineau C, Sharpe R M, Saunders P T, Gerard N, Jegou B. Regulation of Sertoli cell inhibin production and of inhibin alpha-subunit mRNA levels by specific germ cell types.  Mol Cell Endocrinol. 1990;  72 13-22
  • 71 Cortes D, Muller J, Skakkebaek N E. Proliferation of Sertoli cells during development of the human testis assessed by stereological methods.  Int J Androl. 1987;  10 589-596
  • 72 Foresta C, Bettella A, Petraglia F, Pistorello M, Luisi S, Rossato M. Inhibin B levels in azoospermic subjects with cytologically characterized testicular pathology.  Clin Endocrinol (Oxf). 1999;  50 695-701
  • 73 von Eckardstein S, Simoni M, Bergmann M et al.. Serum inhibin B in combination with serum follicle-stimulating hormone (FSH) is a more sensitive marker than serum FSH alone for impaired spermatogenesis in men, but cannot predict the presence of sperm in testicular tissue samples.  J Clin Endocrinol Metab. 1999;  84 2496-2501
  • 74 de Kretser D M, McLachlan R I, Robertson D M, Burger H G. Serum inhibin levels in normal men and men with testicular disorders.  J Endocrinol. 1989;  120 517-523
  • 75 Lambert-Messerlian G M, Crowley Jr W F, Schneyer A L. Extragonadal alpha-inhibin precursor proteins circulate in human male serum.  J Clin Endocrinol Metab. 1995;  80 3043-3049
  • 76 Jensen T K, Andersson A M, Hjollund N H et al.. Inhibin B as a serum marker of spermatogenesis: correlation to differences in sperm concentration and follicle-stimulating hormone levels. A study of 349 Danish men.  J Clin Endocrinol Metab. 1997;  82 4059-4063
  • 77 Zhang Z, Short R V, Meehan T, De Kretser D M, Renfree M B, Loveland K L. Functional analysis of the cooled rat testis.  J Androl. 2004;  25 57-68
  • 78 Allenby G, Foster P M, Sharpe R M. Evidence that secretion of immunoactive inhibin by seminiferous tubules from the adult rat testis is regulated by specific germ cell types: correlation between in vivo and in vitro studies.  Endocrinology. 1991;  128 467-476
  • 79 Foresta C, Bettella A, Moro E, Roverato A, Merico M, Ferlin A. Sertoli cell function in infertile patients with and without microdeletions of the azoospermia factors on the Y chromosome long arm.  J Clin Endocrinol Metab. 2001;  86 2414-2419
  • 80 Clifton R J, O'Donnell L, Robertson D M. Pachytene spermatocytes in co-culture inhibit rat Sertoli cell synthesis of inhibin beta B-subunit and inhibin B but not the inhibin alpha-subunit.  J Endocrinol. 2002;  172 565-574
  • 81 Frydelund-Larsen L, Krausz C, Leffers H et al.. Inhibin B: a marker for the functional state of the seminiferous epithelium in patients with azoospermia factor C microdeletions.  J Clin Endocrinol Metab. 2002;  87 5618-5624
  • 82 Massague J. TGF-beta signal transduction.  Annu Rev Biochem. 1998;  67 753-791
  • 83 Roberts V, Meunier H, Vaughan J et al.. Production and regulation of inhibin subunits in pituitary gonadotropes.  Endocrinology. 1989;  124 552-554
  • 84 Corrigan A Z, Bilezikjian L M, Carroll R S et al.. Evidence for an autocrine role of activin B within rat anterior pituitary cultures.  Endocrinology. 1991;  128 1682-1684
  • 85 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
  • 86 Chong H, Pangas S A, Bernard D J et al.. Structure and expression of a membrane component of the inhibin receptor system.  Endocrinology. 2000;  141 2600-2607
  • 87 MacConell L A, Leal A M, Vale W W. The distribution of betaglycan protein and mRNA in rat brain, pituitary, and gonads: implications for a role for betaglycan in inhibin-mediated reproductive functions.  Endocrinology. 2002;  143 1066-1075

 Professor
David M de KretserM.D.  Director

Monash Institute of Reproduction and Development, Monash University

27-31 Wright Street, Clayton

Victoria 3168, Australia

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