Molecular Genetics, Structure-Function Relationships, and Tissue-Specific Expression and Regulation of the 3βHSD Gene Family

  • Fernand Labrie
  • Jacques Simard
  • Van Luu-The
  • Georges Pelletier
Conference paper
Part of the Serono Symposia, USA book series (SERONOSYMP)


Despite its essential role in the biosynthesis of all classes of hormonal steroids, structure of the 3β-hydroxysteroid dehydrogenase/ Δ 5 - Δ 4 -isomerase (3βHSD) gene family was only recently elucidated (1). This enzyme, as illustrated in Figure 7.1, is required for the biosynthesis of progesterone, glucocorticoids, and mineralocorticoids, as well as androgens and estrogens. 3βHSD is found not only in classical steroidogenic tissues—namely, the placenta, adrenal cortex, ovary, and testis—but also in several peripheral tissues, including the skin, adipose tissue, breast, lung, endometrium, prostate, liver, kidney, epididymis, and brain (1). The widespread distribution of 3βHSD expression indicates that this enzyme is likely to play an important role in the intracrine (2) formation of sex steroids in peripheral target tissues. Such a high level of extragonadal formation of sex steroids is especially important in the human and some other primates whose adrenals secrete large amounts of the precursor sex steroids dehydroepiandrosterone (DHEA) and especially DHEA sulfate (2–5).


Leydig Cell Seminiferous Tubule Congenital Adrenal Hyperplasia Plasma Testosterone Level Hydroxysteroid Dehydrogenase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Labrie F, Simard J, Luu-The V, Bélanger A, Pelletier G. Structure, function and tissue-specific gene expression of 3β-hydroxysteroid dehydrogenase/-5-ene-4-ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues. J Steroid Biochem Mol Biol 1992;43:805–26.CrossRefGoogle Scholar
  2. 2.
    Labrie F. Intracrinology. Mol Cell Endocrinol 1991;78:C113–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Cutler GB, Glenn M, Bush M, Hodgen GD, Graham CE, Loriaux DL. Adrenarche: a survey of rodents, domestic animals and primates. Endocrinology 1978;103:2112–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Labrie F, Dupont A, Bélanger A. Complete androgen blockade for the treatment of prostate cancer. In: De Vita V, Hellman S, Rosenberg SA, eds. Important advances in oncology. Philadelphia: J.B. Lippincott, 1985:193–217.Google Scholar
  5. 5.
    Bélanger B, Bélanger A, Labrie F, Dupont A, Cusan L, Monfette G. Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men. J Steroid Biochem 1989;32:695–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Luu-The V, Lachance Y, Labrie C, et al. Full length cDNA structure and deduced amino acid sequence of human 3β-hydroxy-5-ene steroid dehydrogenase. Mol Endocrinol 1989;3:1310–2.PubMedCrossRefGoogle Scholar
  7. 7.
    Lorence MC, Murry BA, Trant JM, Mason JL. Human 3β-hydroxysteroid dehydrogenase/Δ54 isomerase from placenta: expression in nonsteroido-genic cells of a protein that catalyses the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 1990;126:2493–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Rhéaume E, Lachance Y, Zhao HF, et al. Structure and expression of a new cDNA encoding the almost exclusive 3β-hydroxysteroid dehydrogenase/Δ54 isomerase in human adrenals and gonads. Mol Endocrinol 1991;5:1147–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Zhao HF, Rhéaume E, Trudel C, Couet J, Labrie F, Simard J. Structure and sexual dimorphic expression of a liver-specific rat 3β-hydroxysteroid dehydrogenase/isomerase. Endocrinology 1990;127:3237–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhao HF, Labrie C, Simard J, et al. Characterization of 3β-hydroxysteroid dehydrogenase/Δ54 isomerase cDNA and differential tissue-specific expression of the corresponding mRNAs in steroidogenic and peripheral tissues. J Biol Chem 1991;266:583–93.PubMedGoogle Scholar
  11. 11.
    Lorence MC, Naville D, Graham-Lorence SE, et al. 3β-hydroxysteroid dehydrogenase/Δ54 isomerase expression in rat and characterization of the testis isoform. Mol Cell Endocrinol 1991;80:21–31.PubMedCrossRefGoogle Scholar
  12. 12.
    Naville D, Keeney DS, Jenkin G, Murry BA, Head JR, Mason JI. Regulation of expression of male-specific rat liver microsomal 3β-hydroxy steroid dehydrogenase. Mol Endocrinol 1991;5:1090–100.PubMedCrossRefGoogle Scholar
  13. 13.
    Simard J, Zhao HF, Labrie C, et al. Molecular cloning of rat 3β-HSD: structure of two types of cDNAs and differential expression of corresponding mRNAs in the ovary. In: Gibori G, ed. Signaling mechanisms and gene expression in the ovary. New York: Springer-Verlag, 1991:274–9.Google Scholar
  14. 14.
    Simard J, Meiner MH, Breton N, et al. Characterization of macaque 3β-hydroxy-5-ene steroid dehydrogenase/Δ54 isomerase: structure and expression in steroidogenic and peripheral tissues in primates. Mol Cell Endocrinol 1991;75:101–10.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhao HF, Simard J, Labrie C, et al. Molecular cloning, cDNA structure and predicted amino acid sequence of bovine 3β-hydroxy-5-ene steroid dehydro-genase/Δ54 isomerase. FEBS Lett 1989;259:153–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Bain PA, Yoo M, Clarke T, Hammond SH, Payne AH. Multiple forms of mouse 3β-hydroxysteroid dehydrogenase/Δ54 isomerase and differential expression in gonads, adrenal glands, liver, and kidneys of both sexes. Proc Natl Acad Sci USA 1991;88:8870–4.PubMedCrossRefGoogle Scholar
  17. 17.
    Lachance Y, Luu-The V, Labrie C, et al. Characterization of human 3β-hydroxysteroid dehydrogenase/Δ54 isomerase gene and its expression in mammalian cells. J Biol Chem 1990;265:20469–75.PubMedGoogle Scholar
  18. 18.
    Lachance Y, Luu-The V, Verreault H, et al. Structure of the human type II 3β-hydroxysteroid dehydrogenase/Δ54 isomerase (3β-HSD) gene: adrenal and gonadal specificity. DNA Cell Biol 1991;10:701–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Lorence MC, Jo Corbin C, Kamimura N, Mahendroo MS, Mason JI. Structural analysis of the gene encoding human 3β-hydroxy steroid dehydrogenase/Δ54-isomerase. Mol Endocrinol 1990;4:1850–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Dupont E, Luu-The V, Labrie F, Pelletier G. Ontogeny of 3β-hydroxysteroid dehydrogenase/Δ54 isomerase (3β-HSD) in human adrenal gland performed by immunocytochemistry. Mol Cell Endocrinol 1990;74:R7–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Dupont E, Zhao HF, Rhéaume E, et al. Localization of 3β-hydroxy-5-ene steroid dehydrogenase/Δ54 isomerase in the rat gonads and adrenal glands by immunocytochemistry and in situ hybridization. Endocrinology 1990;127: 1394–403.PubMedCrossRefGoogle Scholar
  22. 22.
    Dupont E, Luu-The V, Labrie F, Pelletier G. Ontogeny of 3β-hydroxy steroid dehydrogenase/Δ54 isomerase (3β-HSD) in human testis as studied by immunochemistry. J Androl 1991;12:161–4.PubMedGoogle Scholar
  23. 23.
    Dupont E, Labrie F, Luu-The V, Pelletier G. Immunochemical localization of 3β-hydroxysteroid dehydrogenase/Δ54 isomerase (3β-HSD) in human ovary. J Clin Endocrinol Metab 1992;74:994–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Riley SC, Dupont E, Walton JC, et al. Immunohistochemical localization of 3β-hydroxy-5-ene-steroid dehydrogenase/Δ54 isomerase in human placenta and fetal membranes. J Clin Endocrinol Metab 1992;96:127–34.Google Scholar
  25. 25.
    Luu-The V, Côté J, Labrie F. Purification and characterization of human placental 3β-hydroxysteroid dehydrogenase/Δ54 isomerase. Clin Invest Med 1988;11:C200.Google Scholar
  26. 26.
    Luu-The V, Takahashi M, Labrie F. Purification of mitochondrial 3β-hydroxysteroid dehydrogenase/Δ54 isomerase from human placenta. Ann NY Acad Sci 1990;595:386–8.CrossRefGoogle Scholar
  27. 27.
    Bongiovanni AM, Kellenbenz G. The adrenogenital syndrome with deficiency of 3β-hydroxysteroid dehydrogenase. J Clin Invest 1962;41:2086–92.PubMedCrossRefGoogle Scholar
  28. 28.
    New M, White P, Pang S, Dupont B, Speiser PW. The adrenal hyperplasias. In: Scriver CR, Beaudet A, Sly WS, Valle D, eds. The metabolic basis of inherited diseases. 6th ed. New York: McGraw-Hill, 1989:1881–917.Google Scholar
  29. 29.
    Bérubé D, Luu-The V, Lachance Y, Gagné R, Labrie F. Assignment of the human 3β-hydroxy steroid dehydrogenase gene to the p13 band of chromosome 1. Cytogen Cell Genet 1989;52:199–200.CrossRefGoogle Scholar
  30. 30.
    Luu-The V, Lachance Y, Leblanc G, Labrie F. Human 3β-hydroxysteroid dehydrogenase/Δ54 isomerase: characterization of three additional related genes [#1499]. Proc 74th meet Endocr Soc, 1992:426.Google Scholar
  31. 31.
    de Launoit Y, Zhao HF, Bélanger A, Labrie F, Simard J. Expression of liver-specific member of the 3β-hydroxysteroid dehydrogenase family, an isoform possessing an almost exclusive 3-keto steroid reductase activity. J Biol Chem 1992;267:4513–7.PubMedGoogle Scholar
  32. 32.
    Luu-The V, Takahashi M, de Launoit Y, Dumont M, Lachance Y, Labrie F. Evidence for distinct dehydrogenase and isomerase sites within a single 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase protein. Biochemistry 1991;30:8861–5.PubMedCrossRefGoogle Scholar
  33. 33.
    Griffin JE, Wilson JD. The testis. In: Browdy PK, Rosenberg LE, eds. Metabolic control and disease. 8th ed. Philadelphia: W.B. Saunders, 1980: 1535–78.Google Scholar
  34. 34.
    Forest MG, Cathiard AM. Pattern of plasma testosterone and Δ4-andro-stenedione in normal newborns: evidence for testicular activity at birth. J Clin Endocrinol Metab 1975;41:977–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Bidlingmainer F, Dorr HG, Eisenmenger W, Kuhnle U, Knorr D. Testosterone and androstenedione concentrations in human testis and epididymis during first two years of life. J Clin Endocrinol Metab 1983;57:311–5.CrossRefGoogle Scholar
  36. 36.
    Winter JSD, Hughes IA, Reyes FI. Pituitary-gonadal relations in infancy, 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endocrinol Metab 1976;42:679–86.PubMedCrossRefGoogle Scholar
  37. 37.
    Frasier SD, Gafford F, Horton R. Plasma androgens in childhood and adolescence. J Clin Endocrinol Metab 1969;29:1404–8.PubMedCrossRefGoogle Scholar
  38. 38.
    August GP, Grumbach MM, Kaplan SL. Hormonal changes in puberty, III. Correlation of plasma testosterone, LH, FSH, testicular size, and bone age with male pubertal development. J Clin Endocrinol Metab 1972;34: 319–26.PubMedCrossRefGoogle Scholar
  39. 39.
    Baillie AH, Niemi M, Ikanen M. 3β-hydroxysteroid dehydrogenase activity in the human fetal testis. Acta Endocrinol (Copenh) 1965;48:429–38.Google Scholar
  40. 40.
    Morel Y, Miller WL. Clinical and molecular genetics of congenital hyperplasia due to 21-hydroxylase deficiency. Adv Hum Genet 1991;20:1–68.PubMedGoogle Scholar
  41. 41.
    Bongiovanni AM. Acquired adrenal hyperplasia with special reference to 3β-HSD. Fertil Steril 1981;35:599–608.PubMedGoogle Scholar
  42. 42.
    de Peretti E, Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in human from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab 1978;47:572–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Zachmann M, Völlmin JA, Mürset G, Curtius HCH, Prade A. Unusual type of congenital adrenal hyperplasia probably due to deficiency 3β-hydroxy-steroid dehydrogenase: case report of a surviving girl and steroid studies. J Clin Endocrinol 1970;30:719–26.CrossRefGoogle Scholar
  44. 44.
    Zachmann M, Forest MG, de Peretti E. 3β-hydroxysteroid dehydrogenase deficiency follow-up study in a girl with pubertal bone age. Horm Res 1979;11:292–302.PubMedCrossRefGoogle Scholar
  45. 45.
    Zachmann M, Kempken B, Anner I, Pezzoli V. Age-related differences in the excretion of delta 5 steroids (D5S) in two related girls with 3β-hydroxysteroid dehydrogenase deficiency. Pediatr Res 1988;24:543.CrossRefGoogle Scholar
  46. 46.
    Parks GA, Bermudez JA, Anast CS, Bongiovanni AM, New MI. Pubertal boy with the 3β-hydroxysteroid dehydrogenase defect. J Clin Endocrinol 1971;33:269–78.CrossRefGoogle Scholar
  47. 47.
    Cara JF, Moshang T, Bongiovanni AM, Marx BS. Elevateci 17-hydroxyprogesterone and testosterone in a newborn with 3β-hydroxysteroid dehydroepiandrosterone sulfate levels in human from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab 1985;47:572–7.Google Scholar
  48. 48.
    Rhéaume E, Simard J, Morel Y, et al. Congenital adrenal hyperplasia due to point mutations in the type II 3β-hydroxysteroid dehydrogenase gene. Nature Genet 1992;1:239–45.PubMedCrossRefGoogle Scholar
  49. 49.
    Simard J, Rhéaume E, Sanchez R, et al. Molecular basis of congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency. Mol Endocrinol 1993.Google Scholar
  50. 50.
    Baker ME, Blasco R. Expansion of the mammalian 3β-hydroxysteroid dehydrogenase/plant dihydroflavonol reductase superfamily to include a bacterial cholesterol dehydrogenase, a bacterial UDP-galactose-4-epimerase and open reading frames in vaccinia virus and fish lymphocystis disease virus. FEBS Lett 1992;301:89–93.PubMedCrossRefGoogle Scholar
  51. 51.
    Goldman AS, Yakovac WC, Bongiovanni AM. Development of activity of 3β-hydroxysteroid dehydrogenase in human fetal tissues and in two anencephalic newborns. J Clin Endocrinol Metab 1966;26:14–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Milewich L, Shaw CE, Doody KM, Rainey WE, Mason JI, Carr BR. 3β-hydroxysteroid dehydrogenase activity in glandular and extraglandular human fetal tissues. J Clin Endocrinol Metab 1991;73:1134–40.PubMedCrossRefGoogle Scholar
  53. 53.
    Simard J, de Launoit Y, Labrie F. Characterization of the structure-activity of rat type I and type II 3β-hydroxysteroid dehydrogenase/Δ54 isomerase by site-directed mutagenesis and expression in HeLa cells. J Biol Chem 1991; 266:14842–5.PubMedGoogle Scholar
  54. 54.
    de Launoit Y, Simard J, Durocher F, Labrie F. Androgenic 17β-hydroxy-steroid dehydrogenase activity of expressed rat type I 3β-hydroxysteroid dehydrogenase/Δ54 isomerase. Endocrinology 1992;130:553–5.PubMedCrossRefGoogle Scholar
  55. 55.
    Bogovich K, Payne AH. Purification of rat testicular 17-ketosteroid reductase, evidence that 17-ketosteroid reductase and 17β-hydroxysteroid dehydrogenase are distinct enzymes. J Biol Chem 1980;255:5552–9.PubMedGoogle Scholar
  56. 56.
    Inano H, Tamaoki BI. Purification and properties of NADP+-dependent 17β-hydroxysteroid dehydrogenase solubilized from porcine testicular microsomal fraction. Eur J Biochem 1974;44:13–23.PubMedCrossRefGoogle Scholar
  57. 57.
    Goslar HG, Passia D, Hilscher W, Hilscher B. Enzymhistochemische Untersuchungen zur kinetik des inter-und peritubulären Leydig-zellsystem der ratte. Acta Histochem Suppl (Jena) 1980;Band XXI:243–6.Google Scholar
  58. 58.
    Haider SG, Passia D, Overmeyer G. Studies on the fetal and postnatal development of rat Leydig cells employing 3β-hydroxy steroid dehydrogenase activity. Acta Histochem Suppl (Jena) 1986;Band XXXII: 197–202.Google Scholar
  59. 59.
    Kerr JB, Knell CM. The fate of fetal Leydig cells during the development of the fetal and postnatal rat testis. Development 1988;103:535–44.PubMedGoogle Scholar
  60. 60.
    Weisz J, Ward I. Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses and neonatal offspring. Endocrinology 1980;106:306–16.PubMedCrossRefGoogle Scholar
  61. 61.
    Passia D, Hahner J, Hilscher B, Hilscher W. Enzymhistochemische Untersuchungen an dem inter-und peritubularen Leydig-zellsystem der ratte. Verh Dtsch Ges Anat 1978;73:699–700.Google Scholar
  62. 62.
    Ziegler HG, Haider SG, Passia D, Hilscher W. Enzymohistochemical and morphometrical studies on Δ5-3β-hydroxysteroid dehydrogenase during the fetal and neonatal development of rat Leydig cells. Andrologia 1983; 15: 392–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Wilson JD. Sexual differentiation. Annu Rev Physiol 1978;40:279–306.PubMedCrossRefGoogle Scholar
  64. 64.
    Chowdhury M, Steinberger E. Pituitary and plasma levels of gonadotrophins in foetal and newborn male and female rats. J Endocrinol 1976;69:381–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Huhtaniemi I, Warren DW, Catt KJ. Regulation of infant and developing rat testicular gonadotropin and prolactin receptors and steroidogenesis by treatments with human chorionic gonadotropin, gonadotropin-releasing hormone analogs, bromocriptine, prolactin and estrogens. Biol Reprod 1985;32:721–32.PubMedCrossRefGoogle Scholar
  66. 66.
    Huhtaniemi IT, Warren DW, Catt KJ. Functional maturation of rat testis Leydig cells. Ann New York Acad Sci 1984;438:283–303.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York, Inc. 1994

Authors and Affiliations

  • Fernand Labrie
  • Jacques Simard
  • Van Luu-The
  • Georges Pelletier

There are no affiliations available

Personalised recommendations