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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
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Publication History

Publication Date:
05 January 2005 (online)

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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.

KEYWORDS

Fetal adrenal - DHEA - CRH - ACTH - cortisol

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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 3 Mesiano S, Jaffe R B. Developmental and functional biology of the primate fetal adrenal cortex.  Endocr Rev. 1997;  18 378-403
    CrossrefPubMedSearch in Google Scholar
  • 4 Pepe G J, Albrecht E D. Regulation of the primate fetal adrenal cortex.  Endocr Rev. 1990;  11 151-176
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 17 Carr B R, Simpson E R. Cholesterol synthesis in human fetal tissues.  J Clin Endocrinol Metab. 1982;  55 447-452
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 21 Parker Jr C R. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging.  Steroids. 1999;  64 640-647
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 28 Hillhouse E W, Grammatopoulos D K. Role of stress peptides during human pregnancy and labour.  Reproduction. 2002;  124 323-329
    CrossrefPubMedSearch in Google Scholar
  • 29 McGrath S, Smith R. Corticotrophin-releasing hormone and parturition.  Clin Endocrinol (Oxf). 2001;  55 593-595
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 38 Stalla G K, Bost H, Stalla J et al.. Human corticotropin-releasing hormone during pregnancy.  Gynecol Endocrinol. 1989;  3 1-10
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 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
    PubMedSearch in Google Scholar
  • 52 Kirschner M A, Wiqvist N, Diczfalusy E. Studies on oestriol synthesis from dehydroepiandrosterone sulphate in human pregnancy.  Acta Endocrinol. 1966;  53 584-597
    PubMedSearch in Google Scholar
  • 53 Siiteri P K, MacDonald P C. Placental estrogen biosynthesis during human pregnancy.  J Clin Endocrinol Metab. 1966;  26 751-761
    PubMedSearch in Google Scholar
  • 54 Ryan K J. Metabolism of C-16-oxygenated steroids by human placenta: the formation of estriol.  J Biol Chem. 1959;  234 2006
    PubMedSearch in Google Scholar
  • 55 MacDonald P C, Siiteri P K. Origin of estrogen in women pregnant with an anencephalic fetus.  J Clin Invest. 1965;  44 465
    PubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar

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