Semin Reprod Med 2004; 22(4): 327-336
DOI: 10.1055/s-2004-861549
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Human Fetal Adrenal: Making Adrenal Androgens for Placental Estrogens

William E. Rainey1 , Khurram S. Rehman1 , Bruce R. Carr1
  • 1Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
Further Information

Publication History

Publication Date:
05 January 2005 (online)

ABSTRACT

During most of gestation, the fetal adrenal gland is almost solely dedicated to the production of dehydroepiandrosterone sulfate (DHEA-S). This specialized ability of the fetal adrenal is unique to primates and occurs because of a specialized fetal zone that composes the bulk of the fetal adrenal gland. Morphologically and physiologically, the human fetal adrenal (HFA) glands are remarkable organs. The glands at term are almost the size of the fetal kidney due in large part to the presence of the fetal zone, which at term produces more steroid than is normally secreted by adrenal glands of the adult. Much of the steroid released by the fetal zone is DHEA-S, which is used by the placenta to produce estrogens. Herein, we review the features of the HFA gland, including its impressive ability to synthesize large amounts of adrenal androgens for use by the placenta to produce estrogens.

REFERENCES

  • 1 Carr B R, Simpson E R. Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland.  Endocr Rev. 1981;  2 306-326
  • 2 Elliott J R, Armour R G. The development of the cortex in the human suprarenal gland and its condition in hemicephaly.  J Pathol. 1911;  15 481-496
  • 3 Mesiano S, Jaffe R B. Developmental and functional biology of the primate fetal adrenal cortex.  Endocr Rev. 1997;  18 378-403
  • 4 Pepe G J, Albrecht E D. Regulation of the primate fetal adrenal cortex.  Endocr Rev. 1990;  11 151-176
  • 5 Narasaka T, Suzuki T, Moriya T, Sasano H. Temporal and spatial distribution of corticosteroidogenic enzymes immunoreactivity in developing human adrenal.  Mol Cell Endocrinol. 2001;  174 111-120
  • 6 Mesiano S, Coulter C L, Jaffe R B. Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17-α-hydroxylase/17,20-lyase, and 3-β-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation.  J Clin Endocrinol Metab. 1993;  77 1184-1189
  • 7 Coulter C L, Goldsmith P C, Mesiano S et al.. Functional maturation of the primate fetal adrenal in vivo. II. Ontogeny of corticosteroid synthesis is dependent upon specific zonal expression of 3β-hydroxysteroid dehydrogenase/isomerase.  Endocrinology. 1996;  137 4953-4959
  • 8 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies.  Clin Endocrinol (Oxf). 2000;  53 739-747
  • 9 Doody K M, Carr B R, Rainey W E et al.. β-hydroxysteroid dehydrogenase/isomerase in the fetal zone and neocortex of the human fetal adrenal gland.  Endocrinology. 1990;  126 2487-2492
  • 10 Rehman K S, Carr B R, Rainey W E. Profiling the steroidogenic pathway in human fetal and adult adrenals.  J Soc Gynecol Investig. 2003;  10 372-380
  • 11 Rainey W E, Carr B R, Wang Z N, Parker Jr C R. Gene profiling of human fetal and adult adrenals.  J Endocrinol. 2001;  171 209-215
  • 12 Rainey W E, Parker Jr C R, Rehman K, Carr B R. The adrenal genetic puzzle: how do the fetal and adult pieces differ?.  Endocr Res. 2002;  28 611-622
  • 13 Han V K, Lund P K, Lee D C, D'Ercole A J. Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization, and tissue distribution.  J Clin Endocrinol Metab. 1988;  66 422-429
  • 14 Mesiano S, Katz S L, Lee J Y, Jaffe R B. Insulin-like growth factors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation.  J Clin Endocrinol Metab. 1997;  82 1390-1396
  • 15 L'Allemand D, Penhoat A, Lebrethon M C et al.. Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells.  J Clin Endocrinol Metab. 1996;  81 3892-3897
  • 16 Latinkic B V, Mo F E, Greenspan J A et al.. Promoter function of the angiogenic inducer Cyr61gene in transgenic mice: tissue specificity, inducibility during wound healing, and role of the serum response element.  Endocrinology. 2001;  142 2549-2557
  • 17 Carr B R, Simpson E R. Cholesterol synthesis in human fetal tissues.  J Clin Endocrinol Metab. 1982;  55 447-452
  • 18 Waterham H R, Koster J, Romeijn G J et al.. Mutations in the 3β-hydroxysterol delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis.  Am J Hum Genet. 2001;  69 685-694
  • 19 Parker Jr C R, Carr B R, Winkel C A et al.. Hypercholesterolemia due to elevated low density lipoprotein-cholesterol in newborns with anencephaly and adrenal atrophy.  J Clin Endocrinol Metab. 1983;  57 37-43
  • 20 Parker Jr C R, MacDonald P C, Carr B R, Morrison J C. The effects of dexamethasone and anencephaly on newborn serum levels of apolipoprotein A-1.  J Clin Endocrinol Metab. 1987;  65 1098-1101
  • 21 Parker Jr C R. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging.  Steroids. 1999;  64 640-647
  • 22 Voutilainen R, Ilvesmaki V, Miettinen P J. Low expression of 3β-hydroxy-5-ene steroid dehydrogenase gene in human fetal adrenals in vivo; adrenocorticotropin and protein kinase C-dependent regulation in adrenocortical cultures.  J Clin Endocrinol Metab. 1991;  72 761-767
  • 23 Ebert S N, Balt S L, Hunter J P et al.. Egr-1 activation of rat adrenal phenylethanolamine N-methyltransferase gene.  J Biol Chem. 1994;  269 20885-20898
  • 24 Wilson T E, Mouw A R, Weaver C A, Milbrandt J, Parker K L. The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase.  Mol Cell Biol. 1993;  13 861-868
  • 25 Davis I J, Lau L F. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands.  Mol Cell Biol. 1994;  14 3469-3483
  • 26 Bassett M H, Suzuki T, Sasano H et al.. The orphan nuclear receptor NGFIB regulates transcription of 3β-hydroxysteroid dehydrogenase: implications for the control of adrenal functional zonation.  J Biol Chem. 2004;  279 37622-37630
  • 27 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 19-25
  • 28 Hillhouse E W, Grammatopoulos D K. Role of stress peptides during human pregnancy and labour.  Reproduction. 2002;  124 323-329
  • 29 McGrath S, Smith R. Corticotrophin-releasing hormone and parturition.  Clin Endocrinol (Oxf). 2001;  55 593-595
  • 30 Rehman K S, Sirianni R, Carr B, Rainey W E, Parker C R. Endocrine controls of human parturition: corticotropin-releasing hormone (CRH) directly stimulates cortisol and the cortisol biosynthetic pathway in the human fetal adrenal.  J Soc Gynecol Investig. 2004;  11 80A
  • 31 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;  181 207-215
  • 32 Campbell E A, Linton E A, Wolfe C D et al.. Plasma corticotropin-releasing hormone concentrations during pregnancy and parturition.  J Clin Endocrinol Metab. 1987;  64 1054-1059
  • 33 Petraglia F, Sawchenko P, Rivier J, Vale W. Evidence for local stimulation of ACTH by corticotropin-releasing hormone in human placenta.  Nature. 1987;  328 717-719
  • 34 Robinson B G, Emanuel R L, Frim D M, Majzoub J A. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta.  Proc Natl Acad Sci USA. 1988;  85 5244-5248
  • 35 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;  68 825-830
  • 36 Karalis K, Majzoub J A. Regulation of placental corticotropin-releasing hormone by steroids. Possible implications in labor initiation.  Ann N Y Acad Sci. 1995;  771 551-555
  • 37 Goland R S, Wardlaw S L, Stark R I, Brown Jr L S, Frantz A G. High levels of corticotropin-releasing hormone immunoactivity in maternal and fetal plasma during pregnancy.  J Clin Endocrinol Metab. 1986;  63 1199-1203
  • 38 Stalla G K, Bost H, Stalla J et al.. Human corticotropin-releasing hormone during pregnancy.  Gynecol Endocrinol. 1989;  3 1-10
  • 39 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;  24 243-251
  • 40 Perkins A V, Wolfe C D, Eben F, Soothill P, Linton E A. Corticotrophin-releasing hormone-binding protein in human fetal plasma.  J Endocrinol. 1995;  146 395-401
  • 41 Florio P, Woods R J, Genazzani A R, Lowry P J, Petraglia F. 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;  82 835-838
  • 42 Goland R S, Jozak S, Warren W B et al.. Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses.  J Clin Endocrinol Metab. 1993;  77 1174-1179
  • 43 Goland R S, Tropper P J, Warren W B et al.. Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia.  Reprod Fertil Dev. 1995;  7 1227-1230
  • 44 Petraglia F, Aguzzoli L, Florio P et al.. Maternal plasma and placental immunoreactive corticotrophin-releasing factor concentrations in infection-associated term and pre-term delivery.  Placenta. 1995;  16 157-164
  • 45 Ruth V, Hallman M, Laatikainen T. Corticotropin-releasing hormone and cortisol in cord plasma in relation to gestational age, labor, and fetal distress.  Am J Perinatol. 1993;  10 115-118
  • 46 Petraglia F, Florio P, Benedetto C et al.. High levels of corticotropin-releasing factor (CRF) are inversely correlated with low levels of maternal CRF-binding protein in pregnant women with pregnancy-induced hypertension.  J Clin Endocrinol Metab. 1996;  81 852-856
  • 47 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 N Y Acad Sci. 1999;  897 54-65
  • 48 Murphy B E. Human fetal serum cortisol levels related to gestational age: evidence of a midgestational fall and a steep late gestational rise, independent of sex or mode of delivery.  Am J Obstet Gynecol. 1982;  144 276-282
  • 49 Goland R S, Jozak S, Conwell I. Placental corticotropin-releasing hormone and the hypercortisolism of pregnancy.  Am J Obstet Gynecol. 1994;  171 1287-1291
  • 50 Falkenberg E R, Davis R O, DuBard M, Parker Jr C R. Effects of maternal infections on fetal adrenal steroid production.  Endocr Res. 1999;  25 239-249
  • 51 Bolte E, Wiqvist N, Diczfalusy E. Metabolism of dehydroepiandrosterone and dehydroepiandrosterone sulphate by the human foetus at midpregnancy.  Acta Endocrinol. 1966;  52 583-597
  • 52 Kirschner M A, Wiqvist N, Diczfalusy E. Studies on oestriol synthesis from dehydroepiandrosterone sulphate in human pregnancy.  Acta Endocrinol. 1966;  53 584-597
  • 53 Siiteri P K, MacDonald P C. Placental estrogen biosynthesis during human pregnancy.  J Clin Endocrinol Metab. 1966;  26 751-761
  • 54 Ryan K J. Metabolism of C-16-oxygenated steroids by human placenta: the formation of estriol.  J Biol Chem. 1959;  234 2006
  • 55 MacDonald P C, Siiteri P K. Origin of estrogen in women pregnant with an anencephalic fetus.  J Clin Invest. 1965;  44 465
  • 56 Cantineau R, Kremers P, De Graeve J, Gielen J E, Lambotle R. 15- and 16-hydroxylations of androgens and estrogens in the human fetal liver: a critical step in estetrol biosynthesis.  J Steroid Biochem. 1985;  22 195-201

William E RaineyPh.D. 

Department of OB/GYN, UT Southwestern Medical Center

5323 Harry Hines Blvd., Dallas

TX 75390-9032

Email: william.rainey@utsouthwestern.edu

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