Oxytocin and its Receptor in the Process of Parturition

Abstract

Objective: To review the potential roles of oxytocin (OT) and its receptor (OTR) in the regulation of parturition.

Methods: We reviewed the literature to describe thhe molecular aspects of the mechanisms of action and the regulation of OT and its receptor, particularly in relation to changes that occur at parturition.

Results: The literature provides strong support for a role for the OT/OTR system in teh regulation of human parturition. Paracrine rather than endocrine mechanisms might be more important, and the regulation of the receptor might be more important than the ligand. The system is regulated by a wide variety of chemical and physical factors, including sex steroids, orphan receptors, uterine stretch, and many others. There also might be important interactions with the immune system.

Conclusion: The OT/OTR system provides a potentially important therapeutic target for regulating the timing of human birth.

Keywords

Oxytocin oxytocin receptor regulation sex steroids parturition

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References

1. Dale HH . On some physiological actions of ergot. J Physiol 1906;34:163-206.

2. Blair Bell W . The pituitary body. Br Med J 1909;2:1609-1613.

3. Theobold GW , Robards MF , Suter T . Changes in myometrial sensitivity to oxytocin in man during the last six weeks of pregnancy. J Obstet Gynaecol Br Commonw 1969;76:385-390.

4. Du Vigneaud V , Ressler C , Trippet S . J Biol Chem 1953;205:949-957.

5. Land H , Grez M , Ruppert S , et al. Deduced amino acid sequence from the bovine oxytocin-neurophysin I precursor cDNA. Nature 1983;302:342-344.

6. Wathes DC , Swann RW . Is oxytocin an ovarian hormone? Nature 1982;297:225-227.

7. Chibbar R , Miller FD , Mitchell BF . Synthesis of oxytocin in amnion, chorion and decidua may influence the timing of human parturition. J Clin Invest 91;1993:185-192.

8. Lefebvre DL , Giaid A , Bennett H , Lariviere R , Zingg HH . Oxytocin gene expression in rat uterus. Science 1992;256:1553-1555.

9. Soloff MS , Alexandrova M , Fernstrom MJ . Oxytocin receptors: Triggers for parturition and lactation? Science 1979;204:1313-1315.

10.

10. Fuchs AR , Fuchs F , Husslein P , Soloff MS , Fernstrom M . Oxytocin receptors and human parturition: A dual role for oxytocin in the initiation of human labor. Science 1982;215:1396-1398.

11.

11. Goodman GT , Grosvenor CE . Neuroendocrine control of the milk ejection reflex. J Dairy Sci 1883;66:2226-2235.

12.

12. Kimura T , Tanizawa O , Mori K , Brownstein MK , Okayama H . Structure and expression of a human oxytocin receptor. Nature 1992;356:526-529.

13.

13. Ostrowski NL , Young WS , Lolait SJ , Knepper MA . Estrogen increases renal oxytocin gene expression. Endocrinology 1995;136:1801-1804.

14.

14. Gutkowska J , Jankowski M , Lambert C , Mukaddam-Daher S , Zingg HH , McCann SM . Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc Natl Acad Sci U S A 1997;94:11704-11709.

15.

15. Chard T . Fetal and maternal oxytocin in human parturition. Am J Perinatol 1989;2:145-152.

16.

16. Fuchs AR , Husslein P , Fuchs F . Oxytocin secretion and human parturition: Pulse frequency and duration increase during spontaneous labor in women. Am J Obstet Gynecol 1991;164:1515-1523.

17.

17. Hirst JJ , Haluska GJ , Cook MJ , Hess DL , Novy MJ . Comparison of plasma oxytocin and catecholamine concentrations with uterine activity in pregnant rhesus monkeys. J Clin Endocrinol Metab 1991;73:804-810.

18.

18. Fuchs AR , Periyasamy S , Alexandrova M , Soloff MS . Correlation between oxytocin receptor concentration and responsiveness to oxytocin in the pregnant rat myometrium. Endocrinology 1983;113:742-749.

19.

19. Fang X , Wong S , Mitchell BF . Relationships among sex steroids, oxytocin, and their receptors in the rat uterus during late gestation and at parturition. Endocrinology 1996;137:3213-3219.

20.

20. Fang X , Wong S , Mitchell BF . Effects of RU486 on estrogen, progestrone, oxytocin and their receptors in the rat uterus during late gestation. Endocrinology 1997;138:2763-2768.

21.

21. Nishimori K , Young LJ , Guo Q , Wang Z , Insel TR , Matzuk MM . Oxytocin is required for nursing but is not essential for parturition or reproductive behavior. Proc Natl Acad Sci U S A 1996;93:11699-11704.

22.

22. Young WS , Shepard E , Amico J , et al. Deficiency in mouse oxytocin prevents milk ejection, but not fertility or parturition. J Neuroendocrinol 1996;8:847-853.

23.

23. Baes M , Gulick T , Choi HS , Martinoli MG , Sihma D , Moore DD . A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol Cell Biol 1994;14:1544-1552.

24.

24. Brys R , Josson K , Castelli MP , et al. Reconstitution of the human 5-HT1D receptor-G-protein couplinc: Evidence for constitutive activity and multiple receptor conformations. Mol Pharmacol 2005;57:1132-1141.

25.

25. Dhanasekaran N , Heasley LE , Johnson GL . G protein-coupled receptor systems involved in cell grwoth and oncogenesis. Endocr Rev 1995;16:259-270.

26.

26. Toaff ME , Hextroni J , Toaff R . Induction of labour by pharmacological and physiological does of intravenous oxytocin. Br J Obstet Gynaecol 1978;85:101-108.

27.

27. Bossmar T , Akerlund M , Fantoni G , Szamatowicz J , Melin P , Maggi M . Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human pregnancy: Effects of the oxytocin antagonist atosiban. Am J Obstet Gynecol 1994;171:1634-1642.

28.

28. Manning M , Miteva K , Pancheva S , Stoev S , Wo NC , Chan WY . Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: Comparison with atosiban. Intl J Peptide Protein Res 1995;46:244-252.

29.

29. Akerlund M , Stromberg P , Hauksson A , et al. Inhibition of uterine contractions of premature labour with an oxytocin analogue. Results from a pilot study. Br J Obstet Gynaecol 1987;94:1040-1044.

30.

30. Goodwin TM , Paul RH , Millar L , et al. The Effects of the oxytocin antagonist atosiban on preterm uterine activity in humans. Am J Obstet Gynecol 1994;170:474-478.

31.

31. Romero R , Sibai BM , Sanchez-Ramos L , et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: A randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182:1173-1183.

32.

32. Nathanielsz PW , Honnebier MB , Mecenas C , Jenkins SL , Holland ML , Demarest K . Effect of the oxytocin antagonist atosiban (1-deamino-2-D-tyr(OET)-4-thr-8-orn-vasotocin/oxytocin) on nocturnal myometrial contractions, maternal cardiovascular function, transplacental passage, and fetal oxygenation in the pregnant baboon during the last third of gestation. Biol Reprod 1997;57:320-324.

33.

33. Fejgin MD , Pak SC , Warnell C , Flouret G , Parsons MT , Wilson L . Oxytocin antagonist inhibitory effect on the rat and baboon uterus may be overcome by prostglandins. Am J Obstet Gynecol 1994;171:1076-1080.

34.

34. Chan WY , Berezin I , Daniel EE , Russell KC , Hruby VJ . Effects of inactivation of oxytocin receptor and gap junction formation on labor in the rat. Can J Physiol Pharmacol 1991;69:1262-1267.

35.

35. Antonijevic IA , Douglas AJ , Dye S , Bicknell RJ , Leng G , Russell JA . Oxytocin antagonists delay the initiation of parturition and prolong its active phase in rats. J Endocrinol 1995;145:97-103.

36.

36. Kobayashi M , Akahane M , Minami K , et al. Role of oxytocin in the initiation of term and preterm labor in rats: Changes in oxytocin receptor density and plasma oxytocin concentration and the effect of an oxytocin antagonist, L-366,509. Am J Obstet Gynecol 1999;180:621-627.

37.

37. Schellenberg JC . The effect of oxytocin receptor blockade on parturition in guinea pigs. J Clin Invest 1995;95:13-19.

38.

38. Pettibone DJ , Clineschmidt BV , Anderson PS , et al. A structurally unique, potent and selective oxytocin antagonist derived from Streptomyces silvensis. Endocrinology 1989;125:217-222.

39.

39. Guillon G , Balestre MN , Roberts JM , Bottari SP , Oxytocin and vasopressin: Distinct receptors in myometrium. J Clin Endocrinol Metab 1987;64:1129-1135.

40.

40. Ivanisevic M , Behrens O , Helmer H , Demarest K , Fuchs AR . Vasopressin receptors in human pregnant myometrium and decidua: Interactions with oxytocin and vasopressin agonists and antagonists. Am J Obstet Gynecol 1989;161:1637-1643.

41.

41. Helmer H , Hackl T , Schneeberger C , et al. Oxytocin and vasopressin la receptor gene expression in the cycling or pregnant human uterus. Am J Obstet Gynecol 1998;179:1572-1578.

42.

42. Chan WY , Ng CW , Manning M . The role of oxytocin receptors and V1a receptors in uterine contractions in rats: Implications for tocolytic therapy with oxytocin antagonists. Am J Obstet Gynecol 1996;175:1331-1335.

43.

43. Valenzuela GJ , Craig J , Bernhardt MD , Holland ML . Placental passage of the oxytocin antagonist atosiban. Am J Obstet Gynecol 1995;172:1304-1306.

44.

44. Greig PC , Massmann GA , Demarest KT , Weglein RC , Holland ML , Figueroa JP . Maternal and fetal cardiovascular effects and placental transfer of the oxytocin antagonist atosiban in late-gestation pregnant sheep. Am J Obstet Gynecol 1993;169:897-902.

45.

45. Bossmar T , Brouard R , Doberl A , Akerlund A . Effects of SR 49059, an orally active V1a vasopressin receptor antagonist, on vasopressin-induced uterine contractions. Br J Obstet Gynaecol 1997;104:471-477.

46.

46. Summar ML , Phillips JA , Battey J , et al. Linkage relationships of human arginine vasopressin-neurophysin II and oxytocin-neurophysin I to prodynorphin and other loci on chromosome 20. Mol Endocrinol 1990;4:947-950.

47.

47. Walther N , Wehrenberg U , Brackmann B , Ivell R . Mapping of the bovine oxytocin gene control region: Identification of binding sites for luteal nuclear proteins in the 5′ non-coding region of the gene. J Neuroendocrinol 1991;3:539-550.

48.

48. Inoue T , Kimura T , Azuma C , et al. Structural organization of te human oxytocin receptor gene. J Biol Chem 1994;269:32451-32456.

49.

49. Rozen F , Russo C , Banville D , Zingg HH . Structure, characterization, and expression of the rat oxytocin receptor gene. Proc Natl Acad Sci U S A 1995;92:200-204.

50.

50. Hoare S , Copland JA , Wood TG , Jeng YJ , Izban MG , Soloff MS . Identification of a GAPBα/β binding site involved in the induction of oxytocin receptor gene expression in human breast cells. Potentiaiton by c-Fos/c-Jun. Endocrinology 1999;140:2268-2279.

51.

51. Tora L , Gaub MP , Mader S , Dierich A , Bellard M , Chambon P . Cell-specific activity of a GGTCA half-palindromic estrogen-responsive element in the chicken ovalbumin gene promotor. EMBO J 1988;7:3771-3778.

52.

52. Altstein M , Gainer H . Differential biosynthesis and posttranslational processing of vasopressin and oxytocin in rat brain during embryonic and postnatal development. J Neurosci 1988;8:3967-3977.

53.

53. Hawtin SR , Howard HC , Wheatley M . Identification of an extracellular segment of the oxytocin receptor producing agonist-specific binding epitopes. Biochem J 2001;354:465-472.

54.

54. Postina R , Kojro E , Fahrenholz F . Identification of neurohypophysial hormone receptor domains involved in ligand binding and G-protein coupling. Adv Exp Med Biol 1999;449:371-385.

55.

55. Oh K , Grazzini E , Zingg HH . Determination of interaction sites between steroid hormones and the oxytocin receptor. Proceedings of the 1999 World Congress on Neurohypophysial Horm ones, Edinburgh, UK. p 59-59.

56.

56. Simon MI , Strathman MP , Gautam N . Diversity of G-proteins in signal transduction. Science 1991;252:802-808.

57.

57. Ku CY , Quian A , Wen Y , Anwer K , Sanborn BM . Oxytocin stimulates myometrial guanosine triphosphate and phospholipase-C activities via coupling to Gαq/11. Endocrinology 1995;136:1509-1515.

58.

58. Smrka A , Stermweis PC . Regulation of purified subtypes of phosphatidylinositol-specific phospholipase Cβ by G protein α and βγ subunits. J Biol Chem 1993;268:9667-9674.

59.

59. Berrdige MJ . Inositol trisphosphate and calcium signaling. Ann N Y Acad Sci 1995;766:31-43.

60.

60. Phaneuf S , Europe-Finner N , Varney M , Mackenzie IZ , Watson FP , Lopez-Bernal A . Oxytocin-stimulated phosphoinositide hydrolysis in human myometrial cells: Involvement of pertussi-sensitive and -insensitive G-proteins. J Endocrinol 1993;136:497-509.

61.

61. Luckas MJM , Taggart MJ , Wray S . Intracellular calcium stores and agonist-induced contractions in isolated human myometrium. Am J Obstet Gynecol 1999;181:468-476.

62.

62. Monga M , Campbell DF , Sanborn BM . Oxytocin-stimulated capacitative calcium entry in human myometrial cells. Am J Obstet Gynecol 1999;181:424-429.

63.

63. Ohmichi M , Koike K , Nohara A , et al. Oxytocin stimulates mitogen-activated protein kinase activity in cultural human puerperal myometrial cells. Endocrinology 1995;136:2082-2087.

64.

64. Molnar M , Rigo J , Romero R , Hertelendy F . Oxytocin cyvates mitogen-activated protein kinase and up-regulates cyclooxygense-2 and prostaglandin production in human myometrial cells. Am J Obstet Gynecol 1999;181:42-49.

65.

65. Hoare S , Copland JA , Strakova Z , et al. The proximal portion of the COOH terminus of the oxytocin receptor is required for coupling to Gq, but not Gi. J Biol Chem 1999;274:28682-28689.

66.

66. Soloff MS , Jeng YJ , Copland JA , Strakova Z , Hoare S . Signal pathways mediating oxytocin stimulation of prostaglandin synthesis. Exp Physiol 2000;85(suppl):51S-58S.

67.

67. Soloff MS , Alexandrova M , Fernstrom MJ . Oxytocin receptors: Triggers for parturition and blactation? Science 1979;204:1313-1315.

68.

68. Amico JA , Crowley RS , Insel TR , Thomas A , O'Keefe JA . Effect of gonadal steroids upon hypothalamic oxytocin expression. Adv Exp Med Biol 1995;395:23-36.

69.

69. Chibbar R , Wong S , Miller FD , Mitchell BF , Estrogen stimulates oxytocin gene expression in human fetal membranes and decidua. J Clin Endocrinol Metab 1995;80:567-572.

70.

70. Lefebvre DL , Farookhi R , Giaid A , Neculcea J , Zingg HH . Uterine oxytocin gene expression. II. Induction by exogenous steroid administration. Endocrinology 1994;134:2562-2566.

71.

71. Soloff MS , Uterine receptors for oxytocin: Effects of estrogen. Biochem Biophys Res Commun 1975;65:205-212.

72.

72. Adachi S , Masataka O . The regulation of oxytocin receptor expression in human myometrial monolayer culture. J Smooth Muscle Res 1995;31:175-197.

73.

73. Soloff MS , Fernstrom MJ , Periyasamy S , Soloff S , Baldwin S , Wider M . Regulation of oxytocin receptor concentration in rat uterine explants by estrogen and progesterone. Can J Biochem Cell Biol 1983;61:625-630.

74.

74. Ivell R , Walther N . The role of sex steroids in the oxytocin hormone system. Mol Cell Endocrinol 1999;151:95-101.

75.

75. Adan RA , Cox JJ , Beischlag TV , Burbach JP , A composite hormone response element mediated the transactivation of the rat oxytocin gene by different classes of nuclear hormone receptors. Mol Endocrinol 1993;7:47-57.

76.

76. Chu K , Zingg HH . Activation of the mouse oxytocin promoter by the orphan receptor RORα. J Mol Endorcinol 1999;23:337-346.

77.

77. Wehrenberg U , Ivell R , Jansen M , Van Goedecke S , Walther N . Two orphan receptors binding to a common site are involved in the regulation of the oxytocin gene in the bovine ovary. Proc Natl Acad Sci U S A 1994;91:1440-1444.

78.

78. Lala DS , Syka PM , Lazarchik SB , Mangelsdorf DJ , Parker KL , Heyman RA . Activation of the orphan nuclear receptor steroidogenic factor 1 by oxyteroids. Proc Natl Acad Sci U S A 1997;94:4895-4900.

79.

79. Kascheike B , Ivell R , Walther N . Alteration in the chromatin structure of the distal promoter region of the bovine oxytocin gene correlate with ovarian expression. DNA Cell Biol 1997;16:1237-1248.

80.

80. Kimura T , Mizumoto Y , Ivell R . Differential protein-DNA binding analysis identifies a novel enhancer element, US-1, involved in the upregulation of the oxytocin receptor gene in human myometrium at term. Mol Cell Endocrinol 1999;148:137-149.

81.

81. Ou CW , Chen ZQ , Qi S , Lye SJ . Increased expression of the rat myometrial oxytocin receptor messenger ribonucleic acid during labor requires both mechanical and hormonal signals. Biol Reprod 1998;59:1055-1061.

82.

82. Wu WX , Ma XH , Yoshizato T , Shinozuka N , Nathanielsz PW . Differential expression of myometrial oxytocin receptor and prostaglandin H synthase 2, but not estrogen receptor α and heat shock protein 90 messenger ribonucleic acid in the gravid horn and non-gravid horn in sheep during betamewthasone-induced labor. Endocrinology 1999;140:5712-5718.

83.

83. Ferguson JWK . A study of the motility of the intact uterus at term. Surg Gynecol Obstet 1941;73:359-366.

84.

84. Goodfellow CF , Hull MGR , Swaab DF , Dogteroin J , Buijs RM . Oxytocin deficiency at delivery with epidural analgesia. Br J Obstet Gynaecol 1983;90:214-219.

85.

85. Stern JE , Armstrong WE . Changes in the electrical properties of supraoptic nucleus oxytocin and vasopressin neurons during lactation. J Neurosci 1996;16:4861-4871.

86.

86. Phaneuf S , Asboth G , MacKenzie IZ , Melin P , Lopez Bernal A . Effects of oxytocin antagonists on the activation of human myometrium in vitro: Atosiban prevents oxytocin-induced desensitisation. Am J Obstet Gynecol 1994;171:1627-1634.

87.

87. Phaneuf S , Asboth G , Carrasco MP , et al. The desensitisation of oxytocin receptors in human myometrial cells in accompanied by down-regulation of oxytoxin receptor messenger RNA. Endocrinology 1997;154:7-18.

88.

88. Brenninkmeijer CBAP , Price SA , Lopez Bernal A , Phaneuf S . Expression of G-protein-coupled receptor kinases in pregnant term and non-pregnant human myometrium. J Endocrinol 1999;162:401-408.

89.

89. Chan WY . The separate uterotonic and prostaglandin-releasing actions of oxytocin. Evidence and comparison with angiotensin and methacholine in the isolated rat uterus. J Pharmacol Exp Ther 1980;213:575-579.

90.

90. Wilson T , Liggins GC , Whittaker DJ . Oxytocin stimulates the release of arachidonic acid and prostaglandin F2α from human decidual cells. Prostaglandins 1988;35:771-780.

91.

91. Pasetto N , Zicari A , Piccione E , Lenti L , Pontieri G , Ticconi. Influence of labor and oxytocin on in vitro leukotriene release by human fetal membranes and uterine decidua at term gestation. Am J Obstet Gynecol 1992;166:1500-1506.

92.

92. Chen DL , Chan WY , Manning M . Agonist and antagonist specificities of decidual prostaglandin-releasing oxytocin receptors and myometrial uterotonic oxytocin receptors in pregnant rats. J Reprod Fertil 1994;102:337-343.

93.

93. Chan WY , Berezin I , Daniel EE . Effects of inhibition of prostaglandin synthesis on uterine oxytocin receptor concentration and myometrial gap junction density in parturient rats. Biol Reprod 1988;39:1117-1128.

94.

94. Chan WY , Chen DL . Myometrial oxytocin receptors and prostaglandins in the parturition process in the rat. Biol Reprod 1992;46:58-64.

95.

95. Vince GS , Starkey PM , Jackson MC , Sargent IL, Redman CWG. Flow cytometric characterization of cell populations in human pregnancy decidua and isolation of decidual macrophages. J Immunol Methods 1990;132:181-189.

96.

96. Hunt JS . Immunologically relevant cells in the uterus. Biol Reprod 1994;50:461-466.

97.

97. Romero R , Brody DT , Oyarzun E . Infection and labor. III. Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol 1989;16: 1117-1123.

98.

98. Romero R , Manogue KR , Mitchell MD . Infection and labor. IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol 1989;161:336-341.

99.

99. Romero R , Avila C , Santhanam U , Sehgal PB . Amniotic interleukin-6 in preterm labor. J Clin Invest 1990;85:1392-1400.

100.

100. Opsjon SL , Wathen NC , Tingulstad S , et al. Tumor necrosis factor, interleukin-1, and interleukin-6 in normal human pregnancy. Am J Obstet Gynecol 1993;169:397-404.

101.

101. Casey ML , Cox SM , Beutler B , Milewich L , MacDonald PC . Cachetin/tumor necrosis factor-α formation in human decidua. J Clin Invest 1989;83:430-436.

102.

102. Romero R , WU YK , Brody DT , Oyarzun E , Duff GW , Durum SK . Human decidua: A source of interleukin-1. Obstet Gynecol 1989;73:31-34.

103.

103. Dudley DJ , Trautman MS , Araneo BA , Edwin SS , Mitchell MD . Decidual cell biosynthesis of interleukin-6: Regulation by inflammatory cytokines. J Clin Endocrinol Metab 1992;74:884-889.

104.

104. Romero R , Durum SK , Dinarello CA , Oyarzun E , Hobbins JC , Mitchell MD . Interleukin stimulates prostaglandin biosynthesis by human amnion. Prostaglandins 1989;37:13-22.

105.

105. Mitchell MD , Dudley DJ , Edwin SS , Lundin-Schiller S . Interleukin-6 stimulates prostaglandin production by human amnion and decidual cells. Eur J Pharmacol 1991;192:189-191.

106.

106. Lundin-Schiller S , Mitchell MD . Prostglandin production by chorion laeve cells in response to inflammatory mediators. Placenta 1991;12:3253-3263.

107.

107. Mitchell MD , Romero RJ , Edwin SS , Trautman MS . Prostaglandins and parturition. Reprod Fertil Dev 1995;7:469-477.

108.

108. Strakova Z , Copland JA , Lolait SJ , Soloff MS . ERK2 mediates oxytocin-stimulated PGE2 synthesis. Am J Physiol 1998;274:E634-E641.

109.

109. Schmid B , Wong S , Mitchell BF . Transcriptional regulation of oxytocin receptor by interleukin-1β and interleukin-6. Endocrinology 2001;142:1380-1385.

110.

110. Helmer H , Knofler M , Hackl T , Husslein P . Cytokine induced responses of primary and transformed human myometrial cells. J Soc Gynecol Investig 1998;5:179-179.

111.

111. Rauk PN , Friebe-Hoffmann U . Interleukin-1β down-regulates the oxytocin receptor in cultured uterine smooth muscle cells. Am J Reprod Immunol 2000,43:85-91.

112.

112. Rauk PN , Chiao JP . Oxytocin signaling in human myometrium is impaired by prolonged exposure to interleukin-1β. J Soc Gynecol Invest 1999;6(Suppl):50-50.

113.

113. Fang X , Wong S , Mitchell BF . Effects of LPS and IL-6 on oxytocin receptor in non-pregnant and pregnant rat uterus. Am J Reprod Immunol 2000;44:65-72.

114.

114. Duff P , Sanders R , Gibbs RS . The course of labor in term patients with chorioamnionitis. Am J Obstet Gynecol 1983;147:391-395.

115.

115. Mark SP , Croughan-Minihane MS , Kilpatrick SJ . Chorioamnionitis and uterine function. Obstet Gynecol 2000;95:909-912.

116.

116. Hooper KC , Jessup JC . The distribution of enzymes destroying oxytocin and vasopressin in human placentae. J Physiol 1959;146:539-549.

117.

117. Glass JD , Dubois BM , Schwartz IL , Walter R . Inactivation of neurohypophysical peptides by a uterine enzyme. Characterization of the hydrolytic cleavage. Endocrinology 1970;87:730-737.

118.

118. Page EW , Titus MA , Mohun G , Glendening MB . The origin and distribution of oxytocinase. Am J Obstet Gynecol 1961;82:1090-1095.

119.

119. Thornton S , Davison J , Baylis PH . Effect of human pregnancy on metabolic clearance rate of oxytocin. Am J Physiol 1989;259:21-24.

120.

120. Mizutani S , Tomoda Y . Oxytocinase: Placental cystine aminopeptidase or placental leucine aminopeptidase (PLAP). Semin Reprod Endocrinol 1992;10:146-153.

121.

121. Mitchell BF , Wong S . Metabolism of oxytocin in human decidua, chorion and placenta. J Clin Endocrinol Metab 1996;80:2729-2734.

122.

122. Mitchell BF , Fang X , Wong S . Metabolism of oxytocin in rat uterus and placenta in late gestation. Biol Reprod 1997;57:807-012.

123.

123. Amico J , Hempel J . An oxytocin precursor intermediate circulates in the plasma of humans and rhesus monkeys administered estrogen. Neuroendocrinology 1990;51:437-443.

124.

124. Mitchell BF , Fang X , Wong S . The role of carboxy-extended forms of oxytocin in the rat uterus in the process of parturition. Biol Reprod 1998;59:1321-1327.

125.

125. Grazzini E , Guillon G , Mouillac B , Zingg HH . Inhibition of oxytocin receptor function by direct binding of progesterone. Nature 1998;392:509-512.