Androgens—Molecular Basis and Related Disorders


The term androgen refers to any natural or synthetic compounds that stimulate or control development and maintenance of masculine characteristics. Most commonly, androgens refer to endogenous steroid sex hormones responsible for virilizing the accessory male sex organs and secondary sex characteristics. Androgens are mainly synthesized by the testes, although females also produce small amounts, which are important for positive protein balance, maintaining strong muscles and bones, and contribute to libido. There are two major androgens secreted by the testes: testosterone and 5α-dihydrotestosterone (5α–DHT). Two weaker androgens primarily synthesized in the adrenal cortex and in smaller amounts by the testes and ovaries are dehydroepiandrosterone (DHEA) and androstenedione, which are converted metabolically to testosterone and other androgens. There is one common androgen receptor (AR) that all androgens bind to, although their target genomic responses are distinctly different. Testosterone is the most abundant androgen with 4–10 mg secreted daily in adult men. 5α-DHT binds the AR with higher affinity than all other androgens, making 5α-DHT the most potent androgen. This chapter focuses on the fundamental molecular mechanisms of the effects of androgens, androgen metabolism in males and defects in the AR that is meant to communicate the complexity of intersex disorders.


Androgen Receptor External Genitalia Androgen Receptor Gene Urogenital Sinus Androgen Insensitivity Syndrome 
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18.8Glossary of Terms and Acronyms


17β-hydroxsteroid dehydrogenase


3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase




androgen-binding protein, a glycosylated dimeric protein secreted by the Sertoli cells homologous to steroid hormone-binding globulin

AF-1, -2 and -5:

activation function-1, -2 and -5.


androgen insensitivity syndrome


amyotrophic lateral sclerosis


absence of menstruation


anti-Müllerian hormone


androgen receptor

AR-A and AR-B:

androgen receptor isoforms


AR associated proteins


androgen response element


androgen sensitivity index


describe any bulb-shaped organ of the body


complete androgen insensitivity syndrome


computed topography


DNA-binding domain








follicle stimulating hormone


abnormal overdevelopment of the male breasts


heat shock protein


failure of the distal urethra to develop normally, resulting in a ventral urinary meatus


international units


ligand-binding domain


low density lipoproteins


luteinizing hormone


mild AIS


Müllerian-inhibiting substance


the presence of two populations of cells with different genotypes in one individual originated from a single fertilized egg


magnetic resonance imaging


cytochrome P450 aromatase


cytochrome P450 side chain cleavage


partial AIS


X-linked spinal and bulbar muscular atrophy or Kennedy Disease


steroid hormone-binding globulin, a glycosylated dimeric protein homologous to the androgen-binding protein secreted by the Sertoli cells of the testes


5α-reductase-1 gene


5α-reductase-2 gene


sex determining region of the Y chromosome


steroidogenic acute regulatory protein


  1. 1.
    Gwynne JT, Strauss JF III. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endoc Rev 1982; 3:299–329.CrossRefGoogle Scholar
  2. 2.
    Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1966; 17: 221–44.Google Scholar
  3. 3.
    Braunstein GD. Testes. In: Greenspan FS, Gardner DG, editors. Basic & Clinical Endocrinology, sixth edition. New York: McGraw-Hill, 2001:422–52.Google Scholar
  4. 4.
    Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev 1987; 8:1–28.PubMedCrossRefGoogle Scholar
  5. 5.
    Davison Sl, Bell R. Androgen physiology. Semin Reprod Med 2006; 24:71–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Sinisi AA, Pasquali D, Notaro A, et al. Sexual differentiation. Endocrinol Invest 2003; 26:23–8.Google Scholar
  7. 7.
    Trapman J, Klaassen P, Kuiper GG. Cloning, structure and expression of a cDNA encoding the human androgen receptor. Biochem Biophys Res Commun 1988; 153:241–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Wilson CM. McPhaul MJ. A and B forms of the androgen receptor are present in human genital skin fibroblasts. Proc Natl Acad Sci USA 1994; 91:1234–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Jenster G, Van der Korput HA, Trapman J. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem 1995; 270: 7341–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Klokk TI, Kurys P, Elbi C. Ligand-specific dynamics of the androgen receptor at its response element in living cells. Mol Cell Biol 2007; 27:1823–43.PubMedCrossRefGoogle Scholar
  11. 11.
    Schaufele F, Carbonell X, Guerbadot M. The structural basis of androgen receptor activation: intramolecular and intermolecular amino-carboxy interactions. Proc Natl Acad Sci U S A 2005; 102:9802–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Berrevoets CA, Doesburg P, Steketee K. Functional interactions of the AF-2 activation domain core region of the human androgen receptor with the amino-terminal domain and with the transcriptional coactivator TIF2 (transcriptional intermediary factor2). Mol Endocrinol 1998; 12:1172–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Dubbink HJ, Hersmus R, Verma CS. Distinct recognition modes of FXXLF and LXXLL motifs by the androgen receptor. Mol Endocrinol 2004; 18:2132–50.PubMedCrossRefGoogle Scholar
  14. 14.
    Gottlieb B, Beitel LK, Wu JH, et al. The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 2004; 23:527–33.Google Scholar
  15. 15.
    Evans BAJ, Ismail RA, France T, et al. Analysis of the androgen receptor gene structure in a patient with complete androgen insensitivity syndrome. J Endocrinology 1991; 129:Abstr 65.Google Scholar
  16. 16.
    Yong EL, Chua KL, Yang M, et al. Complete androgen insensitivity due to a splice-site mutation in the androgen receptor gene and genetic screening with single-stranded conformation polymorphism. Fertil Steril 1994; 61:856–62.PubMedGoogle Scholar
  17. 17.
    Ris-Stalpers C, Kuiper GG, Faber PW, et al. Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity. Proc Natl Acad Sci U S A 1990; 87:7866–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Kohler B, Lumbroso S, Leger J, et al. Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counselling. J Clin Endocrinol Metab 2005; 90:106–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Kuiper GG, Faber PW, van Rooij HC, et al. Structural organization of the human androgen receptor gene. J Mol Endocrinol 1989; 2:R1–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Lubahn DB, Brown TR, Simental JA, et al. Sequence of the intron/exon junctions of the coding region of the human androgen receptor gene and identification of a point mutation in a family with complete androgen insensitivity [published erratum appears in Proc Natl Acad Sci U S A 1990; 87:4411]. Proc Natl Acad Sci U S A 1989; 86:9534–8.Google Scholar
  21. 21.
    Holterhus PM, Brüggenwirth HT, Hiort O, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab 1997; 82:3584–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Adachi M, Takayanagi R, Tomura A, et al. Androgen-insensitivity syndrome as a possible coactivator disease. New Eng J Med 2000; 343:856–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Yanase T, Adachi M, Goto K, et al. Coregulator-related diseases. Intern Med 2004; 43:368–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 1968; 18:671–80.PubMedGoogle Scholar
  25. 25.
    Fischbeck KH, Ionasescu V, Ritter A, et al. Localization of the gene for X-linked spinal muscular atrophy. Neurology 1986; 36:1595–8.PubMedGoogle Scholar
  26. 26.
    Dejager S, Bry-Gauillard H, Bruckert E. A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab 2002; 87:3893–901.PubMedCrossRefGoogle Scholar
  27. 27.
    Imperato-McGinley J, Miller M, Wilson JD, et al. A cluster of male pseudohermaphroditer with 5α-reductase deficiency in Papua New Guinea. Clin Endocrinol 1991; 34:293–8.CrossRefGoogle Scholar
  28. 28.
    Katz MD, Cai L-Q, Zhu Y-S, et al. The biochemical and phenotypic characterization of female homozygous for 5α-reductase 2 deficiency. J Clin Endocrinol Metab 1995; 80:3160–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Hiort, Olaf, Schütt, et al. A novel homozygous disruptive mutation in the SRD5A2-gene in a partially virilized patient with 5α-reductase deficiency. Int J Androl 2002; 25:55.PubMedCrossRefGoogle Scholar
  30. 30.
    Brinkmann AO. Androgen physiology: Receptor and metabolic disorders. In: McLachlan R, editor. Endocrinology of Male Reproduction, [Internet], 2006, Chapter 3.Google Scholar
  31. 31.
    Imperato-McGinley J, Guerrero L, Gautier T, et al. Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphrodism. Science 1974; 186:1213–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Saenger P, Goldman AS, Levine LS, et al. Prepubertal diagnosis of steroid 5α-reductase deficiency. J Clin Endocrinol Metab 1978; 46:627–34.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of BiologyUniversity of Saskatchewan College of Art and SciencesSaskatoonCanada

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