Semin Reprod Med 2000; 18(3): 299-310
DOI: 10.1055/s-2000-12567
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Cytokines in Implantation

Lois A. Salamonsen1 , Evdokia Dimitriadis1 , Lorraine Robb2,3
  • 1Prince Henry's Institute of Medical Research, Clayton, Australia
  • 2The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
  • 3Cooperative Research Centre for Cellular Growth Factors, Parkville, Australia
Further Information

Publication History

Publication Date:
31 December 2000 (online)

ABSTRACT

The endometrium of most species is now recognized as an important site of production of cytokines and their receptors. The cellular origin of the cytokines varies but many predominate in the uterine glandular or luminal epithelium or in the decidualized stromal cells. From studies in genetically modified mice it is clear that implantation of the blastocyst can proceed in the absence of most individual cytokines, although leukemia inhibitory factor and interleukin-11 have indisputable roles in this process. In other cases, such as CSF-1, GM-CSF, IL-1, and IL-6, the numbers of implantation sites or litter sizes are reduced when the cytokine is absent. The same cytokines that are implicated in implantation in mice are generally maximally expressed in human endometrium with maximal production in the secretory phase, particularly during the ``window of implantation,'' but functional studies of their role in implantation in women and other primates are still required.

REFERENCES

  • 1 Wooding F BP, Flint A PF. Placentation. In: Lamming GE, ed. Marshall's Physiology of Reproduction London: Chapman & Hall 1994: 235-460
  • 2 Robertson S A. Cytokines. In: Encyclopedia of Reproduction San Diego: Academic Press 1999: 809-822
  • 3 Arceci R J, Shanahan F, Stanley E R, Pollard J W. Temporal expression and location of colony-stimulating factor 1 (CSF-1) and its receptor in the female reproductive tract are consistent with CSF-1 regulated placental development.  Proc Natl Acad Sci U S A . 1989;  86 8818-8822
  • 4 Robertson S A, Hudson S N. Cytokines: pivotal regulators of endometrial immunobiology. In: Glasser SR, Aplin JD, Giudice LC, Tabibzadeh S, eds. The Endometrium In press
  • 5 Hunt J S, Miller L, Roby K F, Huang J, Platt J S, DeBrot B L. Female steroid hormones regulate production of pro-inflammatory molecules in uterine leukocytes.  J Reprod Immunol . 1997;  35 87-99
  • 6 Zhang J, Lathbury L J, Salamonsen L A. Expression of the chemokine eotaxin and its receptor CCR3 in human endometrium.  Biol Reprod . 2000;  62 404-411
  • 7 Luetteke N C, Qui T H, Peiffer R I, Oliver P, Smithies O, Lee D C. TGF-α deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice.  Cell . 1993;  73 263-278
  • 8 Stanley E R, Guilbert L J, Tushinski R J, Bartelmez S H. CSF-1: a mononuclear phagocyte lineage-specific hemopoietic growth factor.  J Cell Biol . 1983;  21 151-159
  • 9 Bartocci A, Pollard J W, Stanley E R. Regulation of colony-stimulating factor 1 during pregnancy.  J Exp Med . 1986;  164 956-961
  • 10 Pollard J W, Bartocci A, Arceci R J, Orlofsky A, Ladner M B, Stanley E R. Apparent role of the macrophage growth factor CSF-1 in placental development.  Nature . 1987;  330 484-486
  • 11 Arceci R J, Pampfer S, Pollard J W. Expression of CSF-1/c-fms and SF/c-kit mRNA during preimplantation mouse development.  Dev Biol . 1992;  151 1-8
  • 12 Kauma S W, Aukerman S L, Eierman D, Turner T. Colony-stimulating factor-1 and c-fms expression in human endometrial and placenta during the menstrual cycle and early pregnancy.  J Clin Endocrinol Metab . 1991;  73 746-751
  • 13 Daiter E, Pampfer S, Yeung Y G, Barad D, Stanley E R, Pollard J W. Expression of colony-stimulating factor-1 in the human uterus and placenta.  J Clin Endocrinol Metab . 1992;  74 850-858
  • 14 Hamilton G S, Lysiak J J, Watson A J, Lala P K. Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion.  J Endocrinol . 1998;  159 69-77
  • 15 Lewis M P, Clements M, Takeda S. Partial characterisation of an immortalised trophoblast cell-line.  Placenta . 1996;  17 137-146
  • 16 Pollard J W. Role of colony-stimulating factor-1 in reproduction and development.  Mol Reprod Dev . 1997;  46 54-61
  • 17 Pollard J W, Hunt J S, Wiktor-Jedrzejczak W, Stanley E R. A pregnancy defect in the osteopetrotic (op/op) mouse demonstrates the requirement for CSF-1 in female infertility.  Dev Biol . 1991;  148 273-283
  • 18 Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells.  Nature . 1989;  339 27-30
  • 19 Robertson S A, Mayrhofer G, Seamark R F. Uterine epithelial cells synthesize granulocyte-macrophage colony-stimulating factor and interleukin-6 in pregnant and non-pregnant mice.  Biol Reprod . 1992;  46 1069-1079
  • 20 Sharpe-Timms K L, Bruno P L, Penney L L, Bigsby R M. Immunohistochemical localization of granulocyte-macrophage colony-stimulating factor in matched endometriosis and endometrial tissues.  Am J Obstet Gynecol . 1994;  171 740-745
  • 21 Giacomini G, Tabibzadeh S S, Satyaswaroop P G. Epithelial cells are the major source of biologically active granulocyte macrophage colony-stimulating factor in human endometrium.  Hum Reprod . 1995;  10 3259-3263
  • 22 Zhao Y, Chegini N. The expression of granulocyte macrophage-colony stimulating factor (GM-CSF) and receptors in human endometrium.  Am J Reprod Immunol . 1999;  42 303-311
  • 23 Robertson S A, Mau V J, Tremellen K P, Seamark R F. Role of high molecular weight seminal vesicle proteins in eliciting the uterine inflammatory response to semen in mice.  J Reprod Fertil . 1996;  107 265-277
  • 24 Tremellen K P, Seamark R F, Robertson S A. Seminal transforming growth factor β1 stimulates granulocyte-macrophage colony-stimulating factor production and inflammatory cell recruitment in the murine uterus.  Biol Reprod . 1998;  58 1217-1225
  • 25 Robertson S A, Roberts C T, Farr K L, Dunn A R, Seamark R F. Fertility impairment in granulocyte-macrophage colony-stimulating factor-deficient mice.  Biol Reprod . 1999;  60 251-261
  • 26 Spandorfer S D, Barmat L I, Liu H C, Mele C, Veeck L L, Rosenwaks Z. Granulocyte macrophage-colony stimulating factor production by autologous endometrial co-culture is associated with outcome for in vitro fertilization patients with a history of multiple implantation failures.  Am J Reprod Immunol . 1998;  40 377-381
  • 27 Greenfeder S A, Nunes P, Kwee L, Labow M, Chizzonite R A, Ju G. Molecular cloning and characterisation of a second subunit of the interleukin 1 receptor complex.  J Biol Chem . 1995;  270 13757-13765
  • 28 Dinarello C A. The biology of interleukin-1.  Chem Immunol . 1992;  51 1-32
  • 29 Zheng H, Fletcher D, Kozak W. Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice.  Immunity . 1995;  3 9-19
  • 30 Li P, Allen H, Banerjee S. Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock.  Cell . 1995;  80 401-411
  • 31 Kuida K, Lippke J A, Ku G. Altered cytokine export and apoptosis in mice deficient in interleukin-1β converting enzyme.  Nature . 1995;  267 2000-2003
  • 32 Labow M, Shuster D, Zetterstrom M. Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice.  J Immunol . 1997;  159 2452-2461
  • 33 Abbondanzo S J, Cullinan E B, McIntyre K, Labow M A, Stewart C L. Reproduction in mice lacking a functional type 1 IL-1 receptor.  Endocrinology . 1996;  137 3598-3601
  • 34 Simon C, Frances A, Piquette G N. Embryonic implantation in mice is blocked by interleukin-1 receptor antagonist.  Endocrinology . 1994;  134 521-528
  • 35 Simon C, Valbuena D, Krussel J. Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium.  Fertil Steril . 1998;  70 896-906
  • 36 Murphy G. The cytoskeleton of uterine epithelial cells: a new player in uterine receptivity and the plasma membrane transformation.  Hum Reprod Update . 1995;  1 567-580
  • 37 Bazan J F, Timans J C, Kastelein R A. A newly defined interleukin-1.  Nature . 1996;  379 591
  • 38 Kauma S W, Matt D, Strom S, Eierman D, Turner T T. Interleukin-1β, human leukocyte antigen HLA-DRa, and transforming growth factor-β expression in endometrium, placenta and placental membranes.  Am J Obstet Gynecol . 1990;  163 130-137
  • 39 Takacs L, Kovacs E J, Smith M R, Young H A, Durum S K. Detection of IL-1 alpha and IL-1 beta gene expression by in situ hybridization. Tissue localization of IL-1 mRNA in the normal C57BL/6 mouse.  J Immunol . 1988;  141 3081-3095
  • 40 Simon C, Piquette G N, Frances A, Polan M L. Localization of interleukin-1 type I receptor and interleukin-1 beta in human endometrium throughout the menstrual cycle.  J Clin Endocrinol Metab . 1993;  77 549-555
  • 41 Tabibzadeh S, Sun X Z. Cytokine expression in human endometrium throughout the menstrual cycle.  Hum Reprod . 1992;  7 1214-1221
  • 42 Simon C, Piquette G N, Frances A, Westphal L M, Heinrichs W L, Polan M L. Interleukin-1 type I receptor messenger ribonucleic acid expression in human endometrium throughout the menstrual cycle.  Fertil Steril . 1993;  59 791-796
  • 43 Zolti M, Ben-Rafael Z, Meirom R. Cytokine involvement in oocytes and early embryos.  Fertil Steril . 1991;  56 265-272
  • 44 Sheth K V, Roca G L, al-Sediary S T, Parhar R S, Hamilton C J, al-Abdul Jabbar F. Prediction of successful embryo implantation by measuring interleukin-1 and immunosuppressive factor(s) in preimplantation embryo culture fluid.  Fertil Steril . 1991;  55 952-957
  • 45 Baranao R I, Piazza A, Rumi L S, Polak de Fried E. Determination of IL-1 and IL-6 levels in human embryo culture-conditioned media.  Am J Reprod Immunol . 1997;  37 191-194
  • 46 Austgulen R, Arntzen K J, Vatten L J, Kahn J, Sunde A. Detection of cytokines (interleukin-1, interleukin-6, transforming growth factor-beta) and soluble tumour necrosis factor receptors in embryo culture during in-vitro fertilization.  Hum Reprod . 1995;  10 171-176
  • 47 Seifer D B, Romero R, Berlinsky D, Haning Jr V R. Absence of immunoreactive cytokines in supernatants of individual preimplantation human embryos.  Am J Reprod Immunol . 1993;  30 105-107
  • 48 Karagouni E E, Chryssikopoulos A, Mantzavinos T, Kanakas N, Dotsika E N. Interleukin-1beta and interleukin-1alpha may affect the implantation rate of patients undergoing in vitro fertilization-embryo transfer.  Fertil Steril . 1998;  70 553-559
  • 49 Simon C, Mercader A, Gimeno M J, Pellicer A. The interleukin-1 system and human implantation.  Am J Reprod Immunol . 1997;  37 64-72
  • 50 Heaney M L, Golde D W. Soluble cytokine receptors.  Blood . 1996;  87 847-857
  • 51 Robb L, Hilton D J, Brook-Carter P T, Begley C G. Identification of a second murine interleukin-11 receptor alpha chain gene (IL11Ra2) with a restricted pattern of expression.  Genomics . 1997;  40 387-394
  • 52 Robb L, Li R, Hartley L, Nandurkar H H, Koentgen F, Begley C G. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation.  Nat Med . 1998;  4 303-308
  • 53 Dimitriadis E, Salamonsen L A, Robb L. Expression of interleuken-11 during the human menstrual cycle: coincidence with stromal cell decidualization and relationship to leukaemia inhibitory factor and prolactin.  Mol Hum Reprod . 2000;  6 907
  • 54 Tabibzadeh S, Kong Q F, Babaknia A, May L T. Progressive rise in the expression of interleukin-6 in human endometrium during menstrual cycle is initiated during the implantation window.  Hum Reprod . 1995;  10 2793-2799
  • 55 Cullinan E B, Abbondanzo S J, Anderson P S, Pollard J W, Lessey B A, Stewart C L. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation.  Proc Natl Acad Sci U S A . 1996;  93 3115-3210
  • 56 Sharkey A M, Dellow K, Blayney M, Macnamee M, Charnock-Jones D S, Smith S K. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos.  Biol Reprod . 1995;  53 974-981
  • 57 van Eijk J M, Mandelbaum J, Salat-Baroux J. Expression of leukaemia inhibitory factor receptor subunits LIFR beta and gp130 in human oocytes and preimplantation embryos.  Mol Hum Reprod . 1996;  2 355-360
  • 58 Tomida M, Yamamoto-Yamaguchi Y, Hozumi M. Purification of a factor inducing differentiation of mouse myeloid leukaemic M1 cells from conditional medium of mouse fibroblast L929 cells.  J Biol Chem . 1984;  259 10978-10982
  • 59 Hilton D J, Nicola N A, Gough N M, Metcalf D. Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-inducing activity on murine myeloid leukaemia cell lines.  J Biol Chem . 1988;  263 9238-9243
  • 60 Hilton D J, Nicola N A, Metcalf D. Purification of a murine leukaemia inhibitory factor from Krebs ascites conditioned cells.  Anal Biochem . 1988;  173 359-367
  • 61 Hilton D J. LIF: lots of interesting functions.  Trends Biochem Sci . 1992;  17 72-76
  • 62 Metcalf D. Leukemia inhibitory factor: a puzzling polyfunctional regulator.  Growth Factors . 1992;  7 169-173
  • 63 Smith A G, Heath J K, Donaldson D D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides.  Nature . 1988;  336 688-690
  • 64 Williams R L, Hilton D J, Pease S. Myeloid leukaemia inhibitory factor maintains the developmental potential for embryonic stem cells.  Nature . 1988;  336 684-687
  • 65 Stewart C L, Kaspar P, Brunet L J. Blastocyst implantation depends on maternal expression of leukemia inhibitory factor.  Nature . 1992;  359 76-79
  • 66 Bhatt H, Brunet L J, Stewart C J. Uterine expression of leukemia inhibitory factor coincides with the onset of blastocyst implantation.  Proc Natl Acad Sci U S A . 1991;  88 11408-11412
  • 67 Shen M M, Leder P. Leukemia inhibitory factor is expressed by the preimplantation uterus and selectively blocks primitive ectoderm formation in vitro.  Proc Natl Acad Sci U S A . 1992;  89 8240-8244
  • 68 Escary J-L, Perreau J, Dumenil D, Ezine S, Brulet P. Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation.  Nature . 1993;  363 361-364
  • 69 Stewart C L. Leukaemia inhibitory factor and the regulation of pre-implantation development of the mammalian embryo.  Mol Reprod Dev . 1994;  39 233-238
  • 70 Ware C B, Horowitz M C, Renshaw B R. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.  Development . 1995;  121 1283-1299
  • 71 Yoshida K, Taga T, Saito M. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and haematological disorders.  Proc Natl Acad Sci U S A . 1996;  93 407-411
  • 72 Poirier F, Chan C-TJ, Timmons P M, Robertson E J, Evans M J, Rigby P W. The murine H19 gene is activated during embryonic stem cell differentiation in vitro and at the time of implantation in the developing embryo.  Development . 1991;  113 1105-1114
  • 73 Charnock-Jones D S, Sharkey A M, Fenwick P, Smith S K. Leukaemia inhibitory factor mRNA concentration peaks in human endometrium at the time of implantation and the blastocyst contains mRNA for the receptor at this time.  J Reprod Fertil . 1994;  101 421-426
  • 74 Kojima K, Kanzaki H, Iwai M. Expression of leukemia inhibitory factor in human endometrium and placenta.  Biol Reprod . 1994;  50 882-887
  • 75 Arici A, Engin O, Attar E, Olive D L. Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium.  J Clin Endocrinol Metab . 1995;  80 1908-1914
  • 76 Vogiagis D, Marsh M M, Fry R C, Salamonsen L A. Leukemia inhibitory factor in human endometrium throughout the menstrual cycle.  J Endocrinol . 1996;  148 95-102
  • 77 Baird D T, Cameron S T, Critchley H OD. Prostaglandins and menstruation.  Eur J Obstet Gynecol Reprod Biol . 1996;  70 15-17
  • 78 Gemzell-Danielsson K, Swahn M-L. The effects of various doses of mifepristone on endometrial leukaemia inhibitory factor in the midluteal phase: an immunohistochemical study.  Hum Reprod . 1997;  12 1293-1297
  • 79 Laird S M, Tuckerman E M, Dalton C F, Dunphy B C, Li T C, Zhang X. The production of leukaemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture.  Hum Reprod . 1997;  12 569-574
  • 80 Salamonsen L A, Young R J, Garcia S, Findlay J K. Mitogenic actions of endothelin and other growth factors in ovine endometrium.  J Endocrinol . 1997;  152 283-290
  • 81 Giess R, Tanasescu I, Steck T, Sendtner M. Leukaemia inhibitory factor gene mutates in infertile women.  Mol Hum Reprod . 1999;  5 581-586
  • 82 Delage G, Moreau J F, Taupin J L. In vivo endometrial secretion of human interleukin for DA cells/leukaemia inhibitory factor by explant culture from fertile and infertile women.  Hum Reprod . 1995;  10 2483-2488
  • 83 Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation.  J Reprod Fertil . 1998;  39 137-143
  • 84 Dunglison G F, Barlow D H, Sargent I L. Leukaemia inhibitory factor significantly enhances the blastocyst formation rates of human embryos cultured in serum-free medium.  Hum Reprod . 1996;  11 191-196
  • 85 Du X X, Williams D A. Interleukin-11: a multifactorial growth factor derived from the hematopoietic microenvironment.  Blood . 1994;  83 2023-2030
  • 86 Sands B E, Bank S, Sninsky C A. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.  Gastroenterology . 1999;  117 58-64
  • 87 Billinski P, Roopenian D, Gossler A. Maternal IL-11R function is required for normal decidua and fetoplacental development in mice.  Genes Dev . 1998;  12 2234-2243
  • 88 Bryant-Greenwood G D, Rutanen E-M, Partanen S, Coelho T K, Yamamoto S Y. Sequential appearance of relaxin, prolactin and IGFBP-1 during growth and differentiation of the human endometrium.  Mol Cell Endocrinol . 1993;  95 23-29
  • 89 Schwertschlag U S, Trepicchio W L, Dykstra K H, Keith J C, Turner K J, Dorner A J. Hematopoietic, immunomodulatory and epithelial effects of interleukin-11.  Leukemia . 1999;  13 1307-1315
  • 90 Wegmann T G, Lin H, Guilbert L J, Mosmann T R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?.  Immunol Today . 1993;  14 353-356
  • 91 Kopf M, Baumann H, Freer G. Impaired immune and acute-phase responses in interleukin-6-deficient mice.  Nature . 1994;  368 339-340
  • 92 Robertson S A, O'Connell A, Ramsey A. The effect of interleukin-6 deficiency on implantation, fetal development and parturition in mice.  Proc Aust Soc Reprod Biol . 2000;  31 97
  • 93 Kingsley D M. The TGF-β superfamily: new members, new receptors and new genetic tests of function in different organisms.  Genes Dev . 1994;  8 133-146
  • 94 Piek E, Heldin C H, Ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.  FASEB J . 1999;  13 2105-2124
  • 95 Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis.  Genes Dev . 2000;  14 163-176
  • 96 Sinha S, Nevett C, Shuttleworth C A, Kielty C M. Cellular and extracellular biology of the latent transforming growth factor-β binding proteins.  Matrix Biol . 1998;  17 529-545
  • 97 Litterio J J, Roberts A B. TGF-β: a critical modulator of immune cell function.  Clin Immunol Immunopathol . 1997;  84 244-250
  • 98 Tamada H, McMaster M T, Flanders K C, Andrews G K, Dey S K. Cell type-specific expression of transforming growth factor-beta 1 in the mouse uterus during the periimplantation period.  Mol Endocrinol . 1990;  4 965-972
  • 99 Das S K, Flanders K C, Andrews G K, Dey S K. Expression of transforming growth factor-beta isoforms (beta 2 and beta 3) in the mouse uterus: analysis of the periimplantation period and effects of ovarian steroids.  Endocrinology . 1992;  130 3459-3466
  • 100 Takahashi T, Eitzman B, Bossert N L. Transforming growth factors beta 1, beta 2, and beta 3 messenger RNA and protein expression in mouse uterus and vagina during estrogen-induced growth: a comparison to other estrogen-regulated genes.  Cell Growth Differ . 1994;  5 919-935
  • 101 Gold L I, Saxena B N, Mittal K R. Increased expression of transforming growth factor beta isoforms and basic fibroblast growth factor in complex hyperplasia and adenocarcinoma of the endometrium: evidence for paracrine and autocrine action.  Cancer Res . 1994;  54 2347-2358
  • 102 Tabibzadeh S, Lessey B, Satyaswaroop P G. Temporal and site-specific expression of transforming growth factor-beta4 in human endometrium.  Mol Hum Reprod . 1998;  4 595-602
  • 103 Casslen B, Sandberg T, Gustavsson B, Willen R, Nilbert M. Transforming growth factor beta1 in the human endometrium: cyclic variation, increased expression by estradiol and progesterone, and regulation of plasminogen activators and plasminogen activator inhibitor-1.  Biol Reprod . 1998;  58 1343-1350
  • 104 Kulkarni A B, Karlsson S. Transforming growth factor-β1 knockout mice: a mutation in one cytokine gene causes a dramatic inflammatory disease.  Am J Pathol . 1993;  143 3-9
  • 105 Shull M M, Ormsby I, Kier A B. Targeted disruption of the mouse transforming growth factor-beta 1 gene in multifocal inflammatory disease.  Nature . 1992;  359 693-699
  • 106 Bonyadi M, Rusholme S A, Cousins F M. Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice.  Nat Genet . 1997;  15 207-211
  • 107 Letterio J J, Geiser A G, Kukarni A B, Roche N S, Sporn M B, Roberts A B. Maternal rescue of transforming growth factor-β 1 null mice.  Science . 1994;  264 1936-1938
  • 108 Ling N, Ying S Y, Ueno N. Pituitary FSH is released by a heterodimer of the beta-subunits from the three forms of inhibin.  Nature . 1986;  321 779-782
  • 109 Vale W, Rivier C, Hsueh A. Chemical and biological characterization of the inhibin family of protein hormones.  Recent Prog Horm Res . 1988;  44 1-34
  • 110 Mather J P, Woodruff T K, Krummen L A. Paracrine regulation of reproductive function by inhibin and activin.  Proc Soc Exp Biol Med . 1992;  201 1-15
  • 111 Knight P G. Roles of inhibins, activins, and follistatin in the female reproductive system.  Front Neuroendocrinol . 1996;  17 476-509
  • 112 Lockwood G M, Muttukrishna S, Ledger W L. Inhibins and activins in human ovulation, conception and pregnancy.  Hum Reprod Update . 1998;  4 284-295
  • 113 Findlay J K. An update on the role of inhibin, activin, and follistatin as local regulators of folliculogenesis.  Biol Reprod . 1993;  48 15-23
  • 114 Woodruff T K. Regulation of cellular and system function by activin.  Biochem Pharmacol . 1998;  55 953-963
  • 115 Jones R L, Salamonsen L A, Critchley H OD, Rogers P AW, 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
  • 116 Oliver C, Montes M J, Galindo J A, Ruiz C, Olivares E G. Human decidual stromal cells express α-smooth muscle actin and show ultrastructural similarities with myofibroblasts.  Hum Reprod . 1999;  14 1599-1605
  • 117 Li Q, Karam S M, Coerver K A, Matzuk M M, Gordon J I. Stimulation of activin receptor II signalling pathways inhibits differentiation of multiple gastric epithelial lineages.  Mol Endocrinol . 1998;  12 181-192
  • 118 Robinson G, Hennighausen L. Inhibins and activins regulate mammary epithelial cell differentiation through mesenchymal-epithelial interactions.  Development . 1997;  124 2701-2708
  • 119 Gu Y, Srivastava R K, Ou J, Krett N L, Mayo K E, Gibori G. Cell-specific expression of activin and its two binding proteins in the rat decidua: role of α2-macroglobulin and follistatin.  Endocrinology . 1995;  136 3815-3822
  • 120 Manova K, Paynton B V, Bachvarova R F. Expression of activins and TGF beta 1 and beta 2 RNAs in early postimplantation mouse embryos and uterine decidua.  Mech Dev . 1992;  36 141-152
  • 121 Matzuk M M, Rajendra Kumar T, Shou W. Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development.  Recent Prog Horm Res . 1996;  51 123-157
  • 122 Barker D J, Clark P M. Fetal undernutrition and disease in later life.  Rev Reprod . 1997;  2 105-112
    >