Semin Reprod Med 2007; 25(1): 014-020
DOI: 10.1055/s-2006-956772
Copyright © 2007 by Thieme Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Human Fetal Adrenal Gland, Corticotropin-Releasing Hormone, and Parturition

Victor E. Beshay2 , Bruce R. Carr1 , William E. Rainey2
  • 1Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
  • 2Department of Physiology, Medical College of Georgia, Augusta, Georgia
Further Information

Publication History

Publication Date:
05 January 2007 (online)


Labor initiation is a complex process that remains to be fully elucidated. An area of active research involves the study of the different mechanisms that may lead to successful signaling for parturition. This review focuses on the fetal-derived signals that lead to the initiation of labor. These signals may also play a role in preterm labor when activated prematurely. Studying these signals may prove important in the prediction, diagnosis, and possible intervention in preterm labor.


  • 1 Liggins G C, Fairclough R J, Grieves S A et al.. The mechanism of initiation of parturition in the ewe.  Recent Prog Horm Res. 1973;  29 111-159
  • 2 Liggins G C, Kennedy P C, Holm L W. Failure of initiation of parturition after electrocoagulation of the pituitary of the fetal lamb.  Am J Obstet Gynecol. 1967;  98(8) 1080-1086
  • 3 Challis J R, Sloboda D, Matthews S G et al.. The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health.  Mol Cell Endocrinol. 2001;  185(1-2) 135-144
  • 4 Challis J RG, Matthews S G, Gibb W et al.. Endocrine and paracrine regulation of birth at term and preterm.  Endocr Rev. 2000;  21(5) 514-550
  • 5 Siiteri P K, MacDonald P C. Placental estrogen biosynthesis during human pregnancy.  J Clin Endocrinol Metab. 1966;  26(7) 751-761
  • 6 Simmer H H, Easterling J, Pion R J et al.. Neutral C19-steroids and steroid sulfates in human pregnancy. I. Identification of dehydroepiandrosterone sulfate in fetal blood and quantification of this hormone in cord arterial, cord venous and maternal peripheral blood in normal pregnancies at term.  Steroids. 1964;  4(1) 125-135
  • 7 Lac G, Marquet P, Chassain A P et al.. Dexamethasone in resting and exercising men. II. Effects on adrenocortical hormones.  J Appl Physiol. 1999;  87(1) 183-188
  • 8 Spencer S J, Mesiano S, Lee J Y et al.. Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling.  J Clin Endocrinol Metab. 1999;  84(3) 1110-1115
  • 9 Rainey W E, Carr B R, Wang Z N et al.. Gene profiling of human fetal and adult adrenals.  J Endocrinol. 2001;  171(2) 209-215
  • 10 Bassett M H, Suzuki T, Sasano H et al.. The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase: implications for the control of adrenal functional zonation.  J Biol Chem. 2004;  279(36) 37622-37630
  • 11 Bassett M H, White P C, Rainey W E. A role for the NGFI-B family in adrenal zonation and adrenocortical disease.  Endocr Res. 2004;  30(4) 567-574
  • 12 Coulter C L, Goldsmith P C, Mesiano S et al.. Functional maturation of the primate fetal adrenal in vivo: I. Role of insulin-like growth factors (IGFs), IGF-I receptor, and IGF binding proteins in growth regulation.  Endocrinology. 1996;  137(10) 4487-4498
  • 13 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies.  Clin Endocrinol (Oxf). 2000;  53(6) 739-747
  • 14 Mesiano S, Coulter C L, Jaffe R B. Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17, 20-lyase, and 3 beta-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation.  J Clin Endocrinol Metab. 1993;  77(5) 1184-1189
  • 15 Shifren J L, Mesiano S, Taylor R N et al.. Corticotropin regulates vascular endothelial growth factor expression in human fetal adrenal cortical cells.  J Clin Endocrinol Metab. 1998;  83(4) 1342-1347
  • 16 Mesiano S, Jaffe R B. Role of growth factors in the developmental regulation of the human fetal adrenal cortex.  Steroids. 1997;  62(1) 62-72
  • 17 Parker Jr C R, Stankovic A M, Goland R S. Corticotropin-releasing hormone stimulates steroidogenesis in cultured human adrenal cells.  Mol Cell Endocrinol. 1999;  155(1-2) 19-25
  • 18 Smith R, Mesiano S, Chan E C et al.. Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells.  J Clin Endocrinol Metab. 1998;  83(8) 2916-2920
  • 19 Sirianni R, Rehman K S, Carr B R et al.. Corticotropin-releasing hormone directly stimulates cortisol and the cortisol biosynthetic pathway in human fetal adrenal cells.  J Clin Endocrinol Metab. 2005;  90(1) 279-285
  • 20 Sirianni R, Mayhew B A, Carr B R et al.. Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells.  J Clin Endocrinol Metab. 2005;  90(9) 5393-5400
  • 21 Jingami H, Matsukura S, Numa S et al.. Effects of adrenalectomy and dexamethasone administration on the level of prepro-corticotropin-releasing factor messenger ribonucleic acid (mRNA) in the hypothalamus and adrenocorticotropin/beta-lipotropin precursor mRNA in the pituitary in rats.  Endocrinology. 1985;  117(4) 1314-1320
  • 22 Goland R S, Wardlaw S L, Stark R I et al.. High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy.  J Clin Endocrinol Metab. 1986;  63(5) 1199-1203
  • 23 Lockwood C J, Radunovic N, Nastic D et al.. Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and maternal blood during the second half of pregnancy.  J Perinat Med. 1996;  24(3) 243-251
  • 24 Stalla G K, Bost H, Stalla J et al.. Human corticotropin-releasing hormone during pregnancy.  Gynecol Endocrinol. 1989;  3(1) 1-10
  • 25 Robinson B G, Emanuel R L, Frim D M et al.. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta.  Proc Natl Acad Sci USA. 1988;  85(14) 5244-5248
  • 26 Jones S A, Brooks A N, Challis J R. Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta.  J Clin Endocrinol Metab. 1989;  68(4) 825-830
  • 27 Karalis K, Majzoub J A. Regulation of placental corticotropin-releasing hormone by steroids. Possible implications in labor initiation.  Ann NY Acad Sci. 1995;  771 551-555
  • 28 Marinoni E, Korebrits C, Di Iorio R et al.. Effect of betamethasone in vivo on placental corticotropin-releasing hormone in human pregnancy.  Am J Obstet Gynecol. 1998;  178(4) 770-778
  • 29 Carr B R, Parker Jr C R, Madden J D et al.. Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy.  Am J Obstet Gynecol. 1981;  139(4) 416-422
  • 30 Casey M L, MacDonald P C, Mitchell M D. Despite a massive increase in cortisol secretion in women during parturition, there is an equally massive increase in prostaglandin synthesis. A paradox?.  J Clin Invest. 1985;  75(6) 1852-1857
  • 31 Dorr H G, Heller A, Versmold H T et al.. Longitudinal study of progestins, mineralocorticoids, and glucocorticoids throughout human pregnancy.  J Clin Endocrinol Metab. 1989;  68(5) 863-868
  • 32 Vale W, Spiess J, Rivier C et al.. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.  Science. 1981;  213(4514) 1394-1397
  • 33 Riley S C, Walton J C, Herlick J M et al.. The localization and distribution of corticotropin-releasing hormone in the human placenta and fetal membranes throughout gestation.  J Clin Endocrinol Metab. 1991;  72(5) 1001-1007
  • 34 Scatena C D, Adler S. Characterization of a human-specific regulator of placental corticotropin-releasing hormone.  Mol Endocrinol. 1998;  12(8) 1228-1240
  • 35 Sorem K A, Smikle C B, Spencer D K et al.. Circulating maternal corticotropin-releasing hormone and gonadotropin-releasing hormone in normal and abnormal pregnancies.  Am J Obstet Gynecol. 1996;  175(4 pt 1) 912-916
  • 36 Frim D M, Emanuel R L, Robinson B G et al.. Characterization and gestational regulation of corticotropin-releasing hormone messenger RNA in human placenta.  J Clin Invest. 1988;  82(1) 287-292
  • 37 Inder W J, Prickett T C, Ellis M J et al.. The utility of plasma CRH as a predictor of preterm delivery.  J Clin Endocrinol Metab. 2001;  86(12) 5706-5710
  • 38 Hobel C J, Arora C P, Korst L M. Corticotrophin-releasing hormone and CRH-binding protein. Differences between patients at risk for preterm birth and hypertension.  Ann NY Acad Sci. 1999;  897 54-65
  • 39 Korebrits C, Ramirez M M, Watson L et al.. Maternal corticotropin-releasing hormone is increased with impending preterm birth.  J Clin Endocrinol Metab. 1998;  83(5) 1585-1591
  • 40 Chan E C, Falconer J, Madsen G et al.. A corticotropin-releasing hormone type I receptor antagonist delays parturition in sheep.  Endocrinology. 1998;  139(7) 3357-3360
  • 41 Linton E A, Wolfe C D, Behan D P et al.. A specific carrier substance for human corticotrophin releasing factor in late gestational maternal plasma which could mask the ACTH-releasing activity.  Clin Endocrinol (Oxf). 1988;  28(3) 315-324
  • 42 Orth D N, Mount C D. Specific high-affinity binding protein for human corticotropin-releasing hormone in normal human plasma.  Biochem Biophys Res Commun. 1987;  143(2) 411-417
  • 43 Florio P, Woods R J, Genazzani A R et al.. Changes in amniotic fluid immunoreactive corticotropin-releasing factor (CRF) and CRF-binding protein levels in pregnant women at term and during labor.  J Clin Endocrinol Metab. 1997;  82(3) 835-838
  • 44 Petraglia F, Florio P, Simoncini T et al.. Cord plasma corticotropin-releasing factor-binding protein (CRF-BP) in term and preterm labour.  Placenta. 1997;  18(2-3) 115-119
  • 45 Perkins A V, Wolfe C D, Eben F et al.. Corticotrophin-releasing hormone-binding protein in human fetal plasma.  J Endocrinol. 1995;  146(3) 395-401
  • 46 Dautzenberg F M, Hauger R L. The CRF peptide family and their receptors: yet more partners discovered.  Trends Pharmacol Sci. 2002;  23(2) 71-77
  • 47 Grammatopoulos D, Dai Y, Chen J et al.. Human corticotropin-releasing hormone receptor: differences in subtype expression between pregnant and nonpregnant myometria.  J Clin Endocrinol Metab. 1998;  83(7) 2539-2544
  • 48 Karteris E, Randeva H S, Grammatopoulos D K et al.. Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals.  J Clin Endocrinol Metab. 2001;  86(9) 4512-4519
  • 49 Winters A J, Oliver C, Colston C et al.. Plasma ACTH levels in the human fetus and neonate as related to age and parturition.  J Clin Endocrinol Metab. 1974;  39(2) 269-273
  • 50 Klimaviciute A, Calciolari J, Bertucci E et al.. Corticotropin-releasing hormone, its binding protein and receptors in human cervical tissue at preterm and term labor in comparison to non-pregnant state.  Reprod Biol Endocrinol. 2006;  4(1) 29
  • 51 Hillhouse E W, Grammatopoulos D K. Role of stress peptides during human pregnancy and labour.  Reproduction. 2002;  124(3) 323-329
  • 52 McGrath S, Smith R. Corticotrophin-releasing hormone and parturition.  Clin Endocrinol (Oxf). 2001;  55(5) 593-595
  • 53 Petraglia F, Florio P, Benedetto C et al.. Urocortin stimulates placental adrenocorticotropin and prostaglandin release and myometrial contractility in vitro.  J Clin Endocrinol Metab. 1999;  84(4) 1420-1423
  • 54 Benedetto C, Petraglia F, Marozio L et al.. Corticotropin-releasing hormone increases prostaglandin F2 alpha activity on human myometrium in vitro.  Am J Obstet Gynecol. 1994;  171(1) 126-131
  • 55 Florio P, Lombardo M, Gallo R, Activin A et al.. corticotropin-releasing factor and prostaglandin F2 alpha increase immunoreactive oxytocin release from cultured human placental cells.  Placenta. 1996;  17(5-6) 307-311
  • 56 Li W, Challis J R. Corticotropin-releasing hormone and urocortin induce secretion of matrix metalloproteinase-9 (MMP-9) without change in tissue inhibitors of MMP-1 by cultured cells from human placenta and fetal membranes.  J Clin Endocrinol Metab. 2005;  90(12) 6569-6574
  • 57 Challis J R. CRH, a placental clock and preterm labour.  Nat Med. 1995;  1(5) 416
  • 58 McLean M, Bisits A, Davies J et al.. A placental clock controlling the length of human pregnancy.  Nat Med. 1995;  1(5) 460-463
  • 59 McLean M, Bisits A, Davies J et al.. Predicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations.  Am J Obstet Gynecol. 1999;  181(1) 207-215
  • 60 Coleman M A, France J T, Schellenberg J C et al.. Corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A in maternal serum: prediction of preterm delivery and response to glucocorticoids in women with symptoms of preterm labor.  Am J Obstet Gynecol. 2000;  183(3) 643-648
  • 61 Campbell M K, Challis J R, DaSilva O et al.. A cohort study found that white blood cell count and endocrine markers predicted preterm birth in symptomatic women.  J Clin Epidemiol. 2005;  58(3) 304-310
  • 62 Sibai B, Meis P J, Klebanoff M et al.. Plasma CRH measurement at 16 to 20 weeks' gestation does not predict preterm delivery in women at high-risk for preterm delivery.  Am J Obstet Gynecol. 2005;  193(3 Pt 2) 1181-1186
  • 63 Vogel I, Thorsen P, Curry A et al.. Biomarkers for the prediction of preterm delivery.  Acta Obstet Gynecol Scand. 2005;  84(6) 516-525
  • 64 McGregor J A, Jackson G M, Lachelin G C et al.. Salivary estriol as risk assessment for preterm labor: a prospective trial.  Am J Obstet Gynecol. 1995;  173(4) 1337-1342
  • 65 Ellis M J, Livesey J H, Inder W J et al.. Plasma corticotropin-releasing hormone and unconjugated estriol in human pregnancy: gestational patterns and ability to predict preterm delivery.  Am J Obstet Gynecol. 2002;  186(1) 94-99
  • 66 Shams M, Kilby M D, Somerset D A et al.. 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction.  Hum Reprod. 1998;  13(4) 799-804
  • 67 Murphy V E, Clifton V L. Alterations in human placental 11beta-hydroxysteroid dehydrogenase type 1 and 2 with gestational age and labour.  Placenta. 2003;  24(7) 739-744
  • 68 Alfaidy N, Li W, MacIntosh T et al.. Late gestation increase in 11beta-hydroxysteroid dehydrogenase 1 expression in human fetal membranes: a novel intrauterine source of cortisol.  J Clin Endocrinol Metab. 2003;  88(10) 5033-5038

William E Rainey

Department of Physiology, Medical College of Georgia

1120 15th Street, CA3094, Augusta, GA 30912