Original Article

Journal of Investigative Dermatology (1974) 63, 75–84; doi:10.1111/1523-1747.ep12678097

TESTICULAR FEMINIZATION: STUDIES OF THE MOLECULAR BASIS OF A GENETIC DEFECT

C Wayne Bardin and Leslie P Bullock

Top

Abstract

Testicular feminization is an inherited disorder which is transmitted by some women to half their male offspring. The affected individuals are genetic males with end organ insensitivity to endogenous and exogenous androgens. As a consequence, they lack androgen-dependent differentiation and present clinically as phenotypic females with primary amenorrhea. Testicular feminization has also been described in the rat and the mouse. Studies on these rodents indicate that a major tissue abnormality in testicular feminization is decreased cytosol androgen receptor activity. Deficiency of this cytosol binder could account for the lowered nuclear binding of testosterone and dihydrotestosterone in these animals. If androgen uptake and binding in the nucleus is required to initiate RNA and DNA synthesis, the inability to concentrate androgens at the active site in the nucleus of the cell could account for the androgen insensitivity in testicular feminization. Since a detect in the androgen receptor was present in rodents with testicular feminization, a similar abnormality will probably be found in man.

Top

References

  1. Morris, JM: The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol 1953 65: 1192–1211,  | PubMed | ChemPort |
  2. Simmer, HH, Pion, RJ, Dignam, WJ: Testicular Feminization 1965 Edited by WA Selle. Springfield, Ill, Charles C Thomas,
  3. Naftolin, F, Judd, HL: Testicular feminization, Obstetrics and Gynecology Annual 1973 Edited by RW Wynn. New York, Appleton-Century-Crofts, pp 25–53,
  4. Mauvais-Jarvis, P, Bercovici, JP, Crepy, O, Gauthier, F: Studies on testosterone metabolism in subjects with testicular feminization syndrome. J Clin Invest 1970 49: 31–40,  | PubMed | ChemPort |
  5. Stanley, AJ, Gumbreck, LG: Male pseudohermaphroditism with feminizing testis in the male rat—a sex-linked recessive character. Program of the 46th Meeting of the Endocrine Society 1964 p 40,
  6. Bardin, CW, Bullock, L, Schneider, G, Allison, JE, Stanley, AJ: Pseudohermaphrodite rat: end organ insensitivity to testosterone. Science 1970 167: 1136–1137,  | PubMed | ChemPort |
  7. Lyon, MF, Hawkes, SG: X-linked gene for testicular feminization in the mouse. Nature (Lond) 1970 227: 1217–1219,  | ChemPort |
  8. Ohno, A, Lyon, MF: X-linked testicular feminization in the mouse as a non-inducible regulatory mutation of the Jacob-Monod type. Clinical Genetics 1970 1: 121–127,
  9. D'Amour, FE, Funk, D: Spontaneous intersexuality in the rat. Endocrinology 1941 28: 727–728,
  10. Matthews, LH: On an intersexual wild brown rat Rattus norwegicus (Erxleben). Proc Zool Soc 1947 117: 44–48,
  11. Jost, A: Problems of fetal endocrinology: the gonadal and hypophyseal hormones. Recent Progr Horm Res 1953 8: 379–418,
  12. Stanley, AJ, Gumbreck, LG, Allison, JE, Easley, RB: Part I. Male pseudohermaphroditism in the laboratory Norway rat. Recent Progr Horm Res 1973 29: 43–64,  | PubMed | ChemPort |
  13. Bullock, LP, Bardin, CW, Gram, TE, Schroeder, DH, Gillette, JR: Hepatic ethylmorphine demethylase and Delta4-steroid reductase in the androgen-insensitive pseudohermaphroditic rat. Endocrinology 1971 88: 1521–1523,  | PubMed | ChemPort |
  14. Grossman, SH, Axelrod, B, Bardin, CW: Effect of testosterone on renal and hepatic L-gulonolactonase activities in male, female and pseudohermaphroditic rats. Life Sci [II] 1971 10: 175–180,
  15. Sherins, RJ, Bardin, CW: Preputial gland growth and protein synthesis in the androgen-insensitive male pseudohermaphroditic rat. Endocrinology 1971 89: 835–841,  | PubMed | ChemPort |
  16. Goldman, AS: Animal models of inborn errors of steroidgenesis and steroid action. Sonderdruck aus 21. Colloquim der Gesellschaft für Biologische Chemie, Mosbach/Baden 1970 Berlin, Heidelberg, Springer-Verlag, pp 389–436,
  17. Sherins, RJ, Bullock, L, Gay, VL, Vanha-Perttula, T, Bardin, CW: Plasma LH and FSH levels in the androgen insensitive pseudohermaphroditic rat: responses to steroid administration. Endocrinology 1971 88: 763–770,  | PubMed | ChemPort |
  18. Allison, JE, Chan, F, Stanley, AJ, Gumbreck, LG: Androgen insensitivity in male pseudohermaphrodite rats. Endocrinology 1971 89: 615–617,  | PubMed | ChemPort |
  19. Neuhaus, OW, Irwin, JF: Non-inducibility of the sex-dependent urinary protein in male pseudohermaphroditic rats. Life Sci [II] 1972 11: 631–636,
  20. Huggins, C, Parsons, FM, Jensen, EV: Promotion of growth of preputial glands by steroids and the pituitary growth hormone. Endocrinology 1955 57: 25–32,  | PubMed | ChemPort |
  21. Wilson, JD, Gloyna, RE: The intranuclear metabolism of testosterone in the accessory organs of reproduction. Recent Progr Horm Res 1970 26: 309–336,  | PubMed | ChemPort |
  22. Bullock, LP, Bardin, CW: In vivo and in vitro testos-sterone metabolism by the androgen insensitive rat. Journal of Steroid Biochemistry 1973 4: 139–151,  | Article | PubMed | ChemPort |
  23. Richardson, GS, Axelrod, LR: Metabolism of labeled testosterone by minces and nuclei of preputial glands of male rats. Endocrinology 1971 88: 890–894,  | PubMed | ChemPort |
  24. Bullock, L, Bardin, CW: Decreased dihydrotestosterone retention by preputial gland nuclei from the androgen insensitive pseudohermaphrodite rat. J Clin Endocrinol Metab 1970 31: 113–115,  | PubMed | ChemPort |
  25. Bardin, CW, Bullock, L, Blackburn, WR, Sherins, RJ, Vanha-Perttula, T: Testosterone metabolism in the androgen-insensitive rat: a model for testicular feminization, The Clinical Delineation of Birth Defects 1971 VII: Edited by D Bergsma. Baltimore, Williams & Wilkins, pp 185–192,
  26. Liao, S, Fang, S: Receptor-proteins for androgens and the model of action of androgens on gene transcription in ventral prostate. Vitam Horm 1969 27: 17–91,  | PubMed | ChemPort |
  27. Mauvais-Jarvis, P, Floch, HH, Bercovici, JP: Studies on testosterone metabolism in human subjects with normal and pathological sexual differentiation. J Clin Endocrinol Metab 1968 28: 460–471,  | PubMed | ChemPort |
  28. Northcutt, RC, Island, DP, Liddle, GW: An explanation for the target organ unresponsiveness to testosterone in the testicular feminization syndrome. J Clin Endocrinol Metab 1969 29: 422–425,  | PubMed | ChemPort |
  29. Wilson, JD, Walker, JD: The conversion of testosterone to 5alpha-androstan-17beta-ol-3-one (dihydrotestosterone) by skin slices of man. J Clin Invest 1969 48: 371–379,  | PubMed | ISI | ChemPort |
  30. Bullock, L, Schneider, G, Bardin, CW: 5alpha-steroid reductase activity in tissues from rats with end organ insensitivity to testosterone. Life Sci [I] 1970 9: 701–705,
  31. Williams-Ashman, HG, Reddi, AH: Actions of vertebrate sex hormones. Annu Rev Physiol 1971 33: 31–82,  | Article | PubMed | ChemPort |
  32. Stern, JM, Eisenfeld, AJ: Androgen accumulation and binding to macromolecules in seminal vesicles: inhibition by cyproterone. Science 1969 166: 233–235,  | PubMed | ChemPort |
  33. Fang, S, Liao, S: Antagonistic action of anti-androgens on the formation of a specific dihydrotestosterone-receptor protein complex in rat ventral prostate. Mol Pharmacol 1969 5: 428–431,  | PubMed | ChemPort |
  34. Baulieu, EE, Jung, I: A prostatic cytosol receptor. Biochem Biophys Res Commun 1970 38: 599–606,  | Article | PubMed | ChemPort |
  35. Kochakian, CD: The role of hydrolytic enzymes in some of the metabolic activities of steroid hormones. Recent Progr Horm Res 1946 1: 177–216,
  36. Kochakian, CD: Intracellular regulation of nucleic acids of mouse kidney by androgens. Gen Comp Endocrinol 1969 13: 146–150,  | Article | PubMed | ChemPort |
  37. Yamanaka, H, Furuya, N, Shimazaki, J, Shida, K: Effects of testosterone administration on RNA synthesis in kidneys of castrated rats. Endocrinol Jap 1969 16: 29–36,  | ChemPort |
  38. Frieden, EH, Ku, C: Acute effects of testosterone propionate upon RNA synthesis in mouse kidney. Proc Soc Exp Biol Med 1971 137: 1110–1120,  | PubMed | ChemPort |
  39. Fishman, WH, Farmelant, MH: Effects of androgens and estrogens on beta-glucuronidase in inbred mice. Endocrinology 1953 52: 536–545,  | PubMed | ChemPort |
  40. Bardin, CW, Bullock, LP, Sherins, RJ, Mowszowicz, I, Blackburn, WR: Part II. Androgen metabolism and mechanism of action in male pseudohermaphroditism: a study of testicular feminization. Recent Progr Horm Res 1973 29: 65–109,  | PubMed | ChemPort |
  41. Tettenborn, U, Dofuku, R, Ohno, S: Noninducible phenotype exhibited by a proportion of female mice heterozygous for the x-linked testicular feminization mutation. Nature [New Biol] 1971 234: 37–40,
  42. Ohno, S, Dofuku, R, Tettenborn, U: More about x-linked testicular feminization of the mouse as a noninducible (ia) mutation of a regulatory locus: 5a-androstan-3alpha-17beta-diol as the true inducer of kidney alcohol dehydrogenase and beta-glucuronidase. Clin Genet 1971 2: 128–140,  | PubMed | ChemPort |
  43. Robel, P, Lasnitski, I, Baulieu, E: Hormone metabolism and action: testosterone and metabolites in prostate organ culture. Biochim Biophys Acta 1971 53: 81–96,  | ChemPort |
  44. Bullock, LP, Bardin, CW, Ohno, S: The androgen insensitive mouse: absence of intranuclear androgen retention in the kidney. Biochem Biophys Res Commun 1971 44: 1537–1543,  | Article | PubMed | ChemPort |
  45. Gloyna, RE, Wilson, JD: A comparative study of the conversion of testosterone to 17beta-hydroxy-5alphaandrostan-3-one (dihydrotestosterone) by prostate and epididymis. J Clin Endocrinol Metab 1969 29: 970–977,  | PubMed | ChemPort |
  46. Bullock, LP, Bardin, CW: Androgen receptors in mouse kidney: a study of male, female and androgen insensitive (tfm/y) mice. Endocrinology 1974 94: 120,
  47. Goldstein, JL, Wilson, JD: Studies on the pathogenesis of the pseudohermaphroditism in the mouse with testicular feminization. J Clin Invest 1972 51: 1647–1658,  | PubMed | ISI | ChemPort |
  48. Gehring, U, Tomkins, GM, Ohno, S: Effect of the androgen-insensitivity mutation on a cytoplasmic receptor for dihydrotestosterone. Nature [New Biol] 1971 232: 106–107,
  49. Bullock, LP, Bardin, CW: Androgen receptors in testicular feminization. J Clin Endocrinol Metab 1972 35: 935–937,  | PubMed | ChemPort |
  50. Jensen, EV, deSombre, ER, Jungblut, PW: Estrogen receptors and breast cancer response to adrenalectomy, Endogenous Factors Influencing Host-Tumor Balance 1967 Edited by RW Wissler, TL Dao, S Wood, Jr. Chicago, University of Chicago Press, pp 15–30,
  51. McGuire, WL, Julian, JA: Comparison of macromolecular binding of estradiol in hormonedependent and hormone-independent rat mammary carcinoma. Cancer Res 1971 31: 1440–1445,  | PubMed | ChemPort |
  52. McGuire, WL, Julian, JA, Chamness, GC: A dissociation between ovarian dependent growth and estrogen sensitivity in mammary carcinoma. Endocrinology 1971 89: 969–973,  | PubMed | ChemPort |
  53. McGuire, WL, Huff, K, Jennings, A, Chamness, GC: Mammary carcinoma: a specific biochemical defect in autonomous tumors. Science 1972 175: 335–336,  | PubMed | ChemPort |
  54. Chamness, GC, McGuire, WL: Estrogen receptor in the rat uterus, physiological forms and artifacts. Biochemistry 1972 11: 2466–2472,  | Article | PubMed | ChemPort |
  55. Baxter, JD, Harris, AW, Tomkins, GM, Cohn, M: Glucocorticoid receptors in lymphoma cells in culture: relationship to glucocorticoid killing activity. Science 1971 171: 189–191,  | PubMed | ChemPort |
  56. Rosenau, W, Baxter, JD, Rousseau, GG, Tomkins, GM: Mechanism of resistance to steroids: glucocorticoid receptor defect in lymphoma cells. Nature [New Biol] 1972 237: 20–24,
  57. Boczkowski, K: Testicular feminization syndrome without and with sexual hair. Obstet Gynecol 1971 38: 719–723,  | PubMed | ChemPort |

Extra navigation

.
ADVERTISEMENT