Role of Inhibin in Normal and High-Risk Pregnancy

 

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Inhibins are glycoprotein hormones of which there are two molecular forms, inhibin A and inhibin B. Classically, inhibin is known to have a negative feedback effect on pituitary follicle-stimulating hormone secretion. The fetoplacental unit produces inhibin throughout pregnancy. Inhibin A is the predominant molecular form of inhibin in maternal circulation from 4 weeks of gestation. Although the precise biological function of inhibin A in pregnancy is unclear, it is evident from recent studies that inhibin A could be a better marker of placental function than human chorionic gonadotropin because of its shorter half-life. The possible clinical applications for the measurement of inhibin A in early pregnancy could be in predicting miscarriage, Down's syndrome, preeclampsia, and fetal growth restriction in the first and/or second trimester before the onset of the clinical symptoms. The source of inhibins, factors controlling inhibin production, the possible functions of inhibin, and the use of inhibin measurement in normal and high-risk pregnancy are reviewed.

REFERENCES

• 1 Ying S-Y. Inhibins, activins and follistatins: gonadal proteins modulating the secretion of follicle stimulating hormone.  Endocr Rev. 1988;  9 267-293
  PubMedGoogle Scholar
• 2 Mather J P, Moore A, Li R H. Activins, inhibins, and follistatins: further thoughts on a growing family of regulators.  Proc Soc Exp Biol Med. 1997;  215 209-222
  PubMedGoogle Scholar
• 3 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
  PubMedGoogle Scholar
• 4 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 1321-1325
  CrossrefPubMedGoogle Scholar
• 5 Muttukrishna S, Child T J, Groome N P, Ledger W L. Source of circulating levels of inhibin A, pro alpha C-containing inhibins and activin A in early pregnancy.  Hum Reprod. 1997;  12 1089-1093
  CrossrefPubMedGoogle Scholar
• 6 Lockwood G M, Ledger W L, Barlow D H, Groome N P, Muttukrishna S. Measurement of inhibin and activin in early human pregnancy: demonstration of feto-placental origin and role in prediction of early pregnancy outcome.  Biol Reprod. 1997;  57 1490-1494
  PubMedGoogle Scholar
• 7 Riley S C, Neville C W, Chard T, Groome N P, Wallace E. Inhibin in extra-embryonic coelomic and amniotic fluids and maternal serum in early pregnancy.  Hum Reprod. 1996;  11 2772-2776
  PubMedGoogle Scholar
• 8 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
  CrossrefPubMedGoogle Scholar
• 9 McLachlan R I, Healy D L, Robertson D M, Burger H G, de Kretser D M. Circulating immunoreactive inhibin in the luteal phase and early gestation in women undergoing ovulation induction.  Fertil Steril. 1987;  48 1001-1005
  PubMedGoogle Scholar
• 10 Abe Y, Hasegawa Y, Miyamoto K et al.. High concentrations of plasma immunoreactive inhibin during normal pregnancy in women.  J Clin Endocrinol Metab. 1990;  71 133-137
  PubMedGoogle Scholar
• 11 Tabie T, Ochiai K, Terashima Y, Takanashi N. Serum levels of inhibin in maternal and umbilical blood during pregnancy.  Am J Obstet Gynecol. 1991;  164 896-900
  PubMedGoogle Scholar
• 12 Yohkaichiya T, Polson D, O'Connor A et al.. Concentrations of immunoreactive inhibin in serum during human pregnancy: evidence for an ovarian contribution.  Reprod Fertil Dev. 1991;  3 671-678
  PubMedGoogle Scholar
• 13 Baird D T, Smith K B. Inhibin and related peptides in the regulation of reproduction.  Oxf Rev Reprod Biol. 1993;  15 191-232
  PubMedGoogle Scholar
• 14 McLachlan R I, Robertson D M, Burger H G, de Kretser D M. The radioimmunoassay of bovine and human follicular fluid and serum inhibin.  Mol Cell Endocrinol. 1986;  46 175-185
  CrossrefPubMedGoogle Scholar
• 15 Muttukrishna S, George L, Fowler P A, Groome N P, Knight P G. Measurement of serum concentrations of inhibin A (α-βA dimer) during human pregnancy.  Clin Endocrinol (Oxf). 1995;  42 391-397
  PubMedGoogle Scholar
• 16 Illingworth P J, Groome N P, Duncan W C et al.. Measurement of circulating inhibin forms during the establishment of pregnancy.  J Clin Endocrinol Metab. 1996;  81 1471-1475
  CrossrefPubMedGoogle Scholar
• 17 Fowler P A, Evans L W, Groome N P, Templeton A, Knight P G. A longitudinal study of maternal serum inhibin-A, inhibin-B, activin-A, activin-AB, pro-alphaC and follistatin during pregnancy.  Hum Reprod. 1998;  13 3530-3536
  CrossrefPubMedGoogle Scholar
• 18 Petraglia F, Garuti G C, Calza L et al.. Inhibin subunits in human placenta: localization and messenger ribonucleic acid levels during pregnancy.  Am J Obstet Gynecol. 1991;  165 750-758
  PubMedGoogle Scholar
• 19 Petraglia F, Gallinelli A, Grande A et al.. Local production and action of follistatin in human placenta.  J Clin Endocrinol Metab. 1994;  78 205-210
  CrossrefPubMedGoogle Scholar
• 20 Petraglia F, Calza L, Garuti G C et al.. Presence and synthesis of inhibin subunits in human decidua.  J Clin Endocrinol Metab. 1990;  71 487-492
  PubMedGoogle Scholar
• 21 Petraglia F, Lim A TW, Rivier J, Vale W. Localisation, secretion and action of inhibin in human placenta.  Science. 1987;  237 187-189
  PubMedGoogle Scholar
• 22 Minami S, Yamoto M, Nakano R. Immunohistochemical localization of inhibin/activin subunits in human placenta.  Obstet Gynecol. 1992;  80 410-414
  PubMedGoogle Scholar
• 23 McCluggage W G, Ashe P, McBride H, Maxwell P, Sloan J M. Localization of the cellular expression of inhibin in trophoblastic tissue.  Histopathology. 1998;  32 252-256
  CrossrefPubMedGoogle Scholar
• 24 Yamoto M, Minami S, Nakano R. Immunohistochemical localization of inhibin subunits in human corpora lutea during menstrual cycle and pregnancy.  J Clin Endocrinol Metab. 1991;  73 470-477
  PubMedGoogle Scholar
• 25 Birdsall M, Ledger W L, Groome N P, Abdalla H, Muttukrishna S. Inhibin A and activin A in the first trimester of human pregnancy.  J Clin Endocrinol Metab. 1997;  82 1557-1560
  CrossrefPubMedGoogle Scholar
• 26 Riley S C, Leask R, Balfour C, Brennand J E, Groome N. Production of inhibin forms by the fetal membranes, decidua, placenta and fetus at parturition.  Hum Reprod. 2000;  15 578-583
  CrossrefPubMedGoogle Scholar
• 27 Riley S C, Balfour C, Wathen N C et al.. Follistatin and activin A in extra embryonic coelomic and amniotic fluids and maternal serum in early pregnancy.  Hum Reprod. 1998;  13 2624-2628
  CrossrefPubMedGoogle Scholar
• 28 Luisi S, Battaglia C, Florio P et al.. Activin A and inhibin B in extra -embryonic coelomic and amniotic fluids and maternal serum in early pregnancy.  Placenta. 1998;  19 435-438
  CrossrefPubMedGoogle Scholar
• 29 Muttukrishna S, Chamberlain P, Evans L W, Asselin J, Groome N P, Ledger W L. Amniotic fluid concentrations of dimeric inhibins, activin A and follistatin in pregnancy.  Eur J Endocrinol. 1999;  140 420-424
  CrossrefPubMedGoogle Scholar
• 30 Muttukrishna S, Jauniaux E, Pahal G, Groome N P, Rodeck C H. In vivo distribution of inhibin A, activin A and follistatin in early pregnancy. Presented at the European Congress in Obstetrics and Gynaecology Ceska Gynekol; 2002 2(suppl): 76
  Google Scholar
• 31 Debieve F, Beerlandt S, Hubinont C, Thomas K. Gonadotropins, prolactin, inhibin A, inhibin B and activin A in human fetal serum from midpregnancy and term pregnancy.  J Clin Endocrinol Metab. 2000;  85 270-274
  CrossrefPubMedGoogle Scholar
• 32 Florio P, Severi F M, Luisi S et al.. Abnormal umbilical artery Doppler waveforms and cord blood inhibin A and inhibin B levels.  Biol Neonate. 2003;  84 281-286
  CrossrefPubMedGoogle Scholar
• 33 Jenkin G, McFarlane J R, de Kretser D M. Implication of inhibin and related proteins in fetal development.  Reprod Fertil Dev. 1995;  7 323-331
  PubMedGoogle Scholar
• 34 Qu J, Thomas K. Regulation of inhibin secretion in human placental cell culture by epidermal growth factor, transforming growth factors and activin.  J Clin Endocrinol Metab. 1993;  77 925-931
  CrossrefPubMedGoogle Scholar
• 35 Qu J, Thomas K. Prostaglandins stimulate the secretion of inhibin from human placental cells.  J Clin Endocrinol Metab. 1993;  77 556-564
  CrossrefPubMedGoogle Scholar
• 36 Keelan J, Song Y, France J T. Comparative regulation of inhibin, activin and human chorionic gonadotrophin production by placental trophoblast cells in culture.  Placenta. 1994;  15 803-818
  PubMedGoogle Scholar
• 37 Bandivdekar A H, Varadkar A M, Sheth A R. Endocrine control of inhibin biosynthesis by human placenta.  Biol Res Pregnancy Perinatol. 1985;  6 128-132
  PubMedGoogle Scholar
• 38 Mohan A, Asselin J, Sargent I L, Groome N P, Muttukrishna S. Effect of cytokines and growth factors on the secretion of inhibin A, activin A and follistatin by term placental villous trophoblasts in culture.  Eur J Endocrinol. 2001;  145 505-511
  CrossrefPubMedGoogle Scholar
• 39 Manuelpillai U, Schneider-Kolsky M, Thirunavukarasu P, Dole A, Waldron K, Wallace E M. Effect of hypoxia on placental activin A, inhibin A and follistatin synthesis.  Placenta. 2003;  24 77-83
  CrossrefPubMedGoogle Scholar
• 40 Blumenstein M, Mitchell M D, Groome N P, Keelan J A. Hypoxia inhibits activin A production by term villous trophoblast in vitro.  Placenta. 2002;  23 735-741
  PubMedGoogle Scholar
• 41 Petraglia F, Vaughan J, Vale W. Inhibin and activin modulate the release of gonadotropin-releasing hormone, human chorionic gonadotropin, and progesterone from cultured human placental cells.  Proc Natl Acad Sci USA. 1989;  86 5114-5117
  PubMedGoogle Scholar
• 42 Mersol-Barg M S, Miller K F, Choi C M, Lee A C, Kim M I. Inhibin suppresses chorionic gonadotrophin secretion in term but not first trimester placenta.  J Clin Endocrinol Metab. 1990;  71 1294-1298
  PubMedGoogle Scholar
• 43 Steele G L, Currie W D, Yuen B H, Jia X C, Perlas E, Leung P CK. Acute stimulation of chorionic gonadotrophin secretion by recombinant human activin A in first trimester human trophoblast.  Endocrinology. 1993;  133 297-303
  CrossrefPubMedGoogle Scholar
• 44 Leung P H, Salamonsen L-A, Findlay J K. Immunolocalization of inhibin and activin subunits in human endometrium across the menstrual cycle.  Hum Reprod. 1998;  13 3469-3477
  CrossrefPubMedGoogle Scholar
• 45 Ethier J F, Findlay J K. Roles of activin and its signal transduction mechanisms in reproductive tissue.  Reproduction. 2001;  121 667-675
  CrossrefPubMedGoogle Scholar
• 46 Otani T, Minami S, Yamoto M, Umesaki N. Production of activin A in hyperplasia and adenocarcinoma of the human endometrium.  Gynecol Oncol. 2001;  83 31-38
  CrossrefPubMedGoogle Scholar
• 47 Jones R L, Salamonsen L A, Critchley H O, Rogers P A, Affandi B, Findlay J K. Inhibin and activin subunits are differentially expressed in endometrial cells and leukocytes during the menstrual cycle, in early pregnancy and in women using progestin-only contraception.  Mol Hum Reprod. 2000;  6 1107-1117
  CrossrefPubMedGoogle Scholar
• 48 Healy D L, Mamers P, Bangah M, Burger H G. Clinical and pathophysiological aspects of inhibin.  Hum Reprod. 1993;  8 138-140
  PubMedGoogle Scholar
• 49 Yohkaichiya T, Fudaya T, Hoshiai H, Yajima A, de Kretser D M. Inhibin, a new circulating marker in hydatidiform mole.  BMJ. 1989;  298 1684-1686
  PubMedGoogle Scholar
• 50 Minami S, Yamoto M, Nakano R. Immunohistochemical localisation of inhibin-activin subunits in hydatidiform mole and invasive mole.  Obstet Gynecol. 1993;  82 414-418
  PubMedGoogle Scholar
• 51 Kato T, Seki K, Matsui H, Sekiya S. Circulating inhibin forms in patients with hydatidiform mole.  Gynecol Obstet Invest. 2002;  54 114-117
  CrossrefPubMedGoogle Scholar
• 52 Florio P, Severi F M, Cobellis L et al.. Serum activin A and inhibin A: new clinical markers for hydatidiform mole.  Cancer. 2002;  94 2618-2622
  CrossrefPubMedGoogle Scholar
• 53 Yohkaichiya T, Polson D W, Hughes E G et al.. Serum immunoreactive inhibin levels in early pregnancy after in vitro fertilisation and embryo transfer.  Fertil Steril. 1993;  59 1081-1089
  PubMedGoogle Scholar
• 54 Seifer D B, Labertmesserlian G M, Canick J A, Frishman G N, Schneyer A L. Serum inhibin levels are lower in ectopic than intrauterine spontaneously conceived pregnancies.  Fertil Steril. 1996;  65 667-669
  PubMedGoogle Scholar
• 55 Lockwood G M, Ledger W L, Barlow D H, Groome N P, Muttukrishna S. Identification of the source of inhibins at the time of conception provides a diagnostic role for them in very early pregnancy.  Am J Reprod Immunol. 1998;  40 303-308
  PubMedGoogle Scholar
• 56 Muttukrishna S, Jauniaux E, Greenwold N et al.. Levels of inhibin A, activin A and follistatin in missed and recurrent miscarriages.  Hum Reprod. 2002;  17 3072-3078
  CrossrefPubMedGoogle Scholar
• 57 Luisi S, Florio P, D'Antona D et al.. Maternal serum inhibin A levels are a marker of a viable trophoblast in incomplete and complete miscarriage.  Eur J Endocrinol. 2003;  148 233-236
  CrossrefPubMedGoogle Scholar
• 58 Van Lith J M, Pratt J J, Beekhuis J R, Mantingh A. Second trimester maternal serum immunoreactive inhibin as a marker for fetal Down's syndrome.  Prenat Diagn. 1992;  12 801-806
  CrossrefPubMedGoogle Scholar
• 59 Spencer K, Wood P J, Antony F W. Elevated levels of maternal serum inhibin immunoreactivity in second trimester pregnancies affected by Down's syndrome.  Ann Clin Biochem. 1993;  30 219-220
  PubMedGoogle Scholar
• 60 Cuckle H S, Holding S, Jones R. Maternal serum inhibin levels in second trimester Down's syndrome pregnancies.  Prenat Diagn. 1994;  14 387-390
  PubMedGoogle Scholar
• 61 Cuckle H S, Holding S, Jones R, Wallace E M, Groome N P. Maternal serum dimeric inhibin A in second trimester Down's syndrome pregnancies.  Prenat Diagn. 1995;  15 385-392
  PubMedGoogle Scholar
• 62 Canick J A, Lambert-Messerlian G M, Palomaki G E et al.. Maternal serum dimeric inhibin is elevated in Down's syndrome pregnancy.  Am J Hum Genet. 1994;  55 A37
  PubMedGoogle Scholar
• 63 Aitken D A, Wallace E M, Crossley J A et al.. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy.  N Engl J Med. 1996;  334 1231-1236
  CrossrefPubMedGoogle Scholar
• 64 Wallace E M, Healy D L. Inhibins and activins: roles in clinical practice.  Br J Obstet Gynaecol. 1996;  103 945-956
  PubMedGoogle Scholar
• 65 Tul N, Pusenjak S, Osredkar J, Spencer K, Novak-Antolic Z. Predicting complications of pregnancy with first trimester maternal serum free-beta hCG, PAPP A and inhibin A.  Prenat Diagn. 2003;  23 990-996
  CrossrefPubMedGoogle Scholar
• 66 Benn P A, Fang M, Egan J F, Horne D, Collins R. Incorporation of inhibin A in second trimester screening for Down syndrome.  Obstet Gynecol. 2003;  101 451-454
  CrossrefPubMedGoogle Scholar
• 67 Dalgliesh G L, Aitken D A, Lyall F, Howatson A G, Connor J M. Placental and maternal serum inhibin-A and activin-A levels in Down's syndrome pregnancies.  Placenta. 2001;  22 227-234
  CrossrefPubMedGoogle Scholar
• 68 Wallace E M, Crossley J A, Groome N P, Aitken D A. Amniotic fluid inhibin-A in chromosomally normal and Down's syndrome pregnancies.  J Endocrinol. 1997;  152 109-112
  CrossrefPubMedGoogle Scholar
• 69 Muttukrishna S, Knght G, Groome N P, Redman C WG, Ledger W L. Inhibin A and activin A: new endocrine markers for pre-eclampsia?.  Lancet. 1997;  349 1285-1288
  CrossrefPubMedGoogle Scholar
• 70 Cuckle H, Sehmi I, Jones R. Maternal serum inhibin A can predict pre-eclampsia.  Br J Obstet Gynaecol. 1998;  105 1101-1103
  PubMedGoogle Scholar
• 71 Lambert-Messerlian G M, Silver H M, Petraglia F et al.. Second-trimester levels of maternal serum human chorionic gonadotropin and inhibin A as predictors of preeclampsia in the third trimester of pregnancy.  J Soc Gynecol Investig. 2000;  7 170-174
  PubMedGoogle Scholar
• 72 Muttukrishna S, North R A, Morris J et al.. Serum inhibin A and activin A are elevated prior to the onset of pre-eclampsia.  Hum Reprod. 2000;  15 1640-1645
  CrossrefPubMedGoogle Scholar
• 73 Grobman W A, Wang E Y. Serum levels of activin A and inhibin A and the subsequent development of preeclampsia.  Obstet Gynecol. 2000;  96 390-394
  CrossrefPubMedGoogle Scholar
• 74 Davidson E J, Riley S C, Roberts S A, Shearing C H, Groome N P, Martin C W. Maternal serum activin, inhibin, human chorionic gonadotrophin and alpha-fetoprotein as second trimester predictors of pre-eclampsia.  BJOG. 2003;  110 46-52
  PubMedGoogle Scholar
• 75 Keelan J A, Taylor R, Schellenberg J-C, Groome N P, Mitchell M D, North R A. Serum activin A, inhibin A and follistatin concentrations in pre-eclampsia or small for gestational age pregnancies.  Obstet Gynecol. 2002;  99 267-274
  CrossrefPubMedGoogle Scholar
• 76 Florio P, Cobellis L, Luisi S et al.. Changes in inhibins and activin secretion in healthy and pathological pregnancies.  Mol Cell Endocrinol. 2001;  180 123-130
  CrossrefPubMedGoogle Scholar
• 77 Florio P, Ciarmela P, Luisi S et al.. Pre-eclampsia with fetal growth restriction: placental and serum activin A and inhibin A levels.  Gynecol Endocrinol. 2002;  16 365-372
  PubMedGoogle Scholar
• 78 Silver H M, Lambert-Messerlian G M, Reis F M, Diblasio A M, Petraglia F, Canick J A. Mechanism of increased maternal serum total activin A and inhibin A in pre eclampsia.  J Soc Gynecol Investig. 2002;  9 308-312
  PubMedGoogle Scholar
• 79 Bersinger N A, Groome N P, Muttukrishna S. Pregnancy-associated and placental proteins in the placental tissue of normal and pre-eclamptic women at delivery.  Eur J Endocrinol. 2002;  147 785-793
  CrossrefPubMedGoogle Scholar
• 80 Casagrandi D, Bearfield C, Geary J, Redman C W, Muttukrishna S. Inhibin, activin, follistatin, activin receptors and betaglycan gene expression in the placental tissue of pre eclampsia patients.  Mol Hum Reprod. 2003;  9 199-203
  CrossrefPubMedGoogle Scholar
• 81 Bobrow C S, Holmes R P, Muttukrishna S et al.. Maternal serum activin A, inhibin A and follistatin in pregnancies with appropriately grown and small for gestational age fetuses classified by umbilical artery Doppler.  Am J Obstet Gynecol. 2002;  186 283-287
  CrossrefPubMedGoogle Scholar
• 82 D'Antona D, Reis F M, Benedetto C et al.. Increased maternal serum activin A but not follistatin levels in pregnant women with hypertensive disorders.  J Endocrinol. 2000;  165 157-162
  CrossrefPubMedGoogle Scholar
• 83 Jauniaux E, Watson A L, Hempstock J, Bao Y P, Skepper J N, Burton G J. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure.  Am J Pathol. 2000;  157 2111-2122
  Google Scholar
• 84 Hustin J, Jauniaux E, Schaaps J P. Histological study of the materno-embryonic interface in spontaneous abortion.  Placenta. 1990;  11 477-486
  CrossrefPubMedGoogle Scholar
• 85 Jauniaux E, Hempstock J, Greenwold N, Burton G J. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.  Am J Pathol. 2003;  162 115-125
  CrossrefPubMedGoogle Scholar
• 86 Hung T H, Skepper J N, Burton G J. In vitro ischemia-reperfusion injury in term human placenta as a model for oxidative stress in pathological pregnancies.  Am J Pathol. 2001;  159 1031-1043
  CrossrefPubMedGoogle Scholar

Shanthi MuttukrishnaB.Sc. Ph.D. 

Department of Obstetrics and Gynaecology, Royal Free University College Medical School

86-96 Chenies Mews, London WC1E 6HX, United Kingdom