Summary
Male and female embryos develop in an identical fashion during the initial portion of gestation. If the indifferent gonad differentiates into an ovary (or if no gonad is present), a female phenotype is formed. Male phenotypic differentiation, however, requires the presence of an endocrinologically active testis. Two secretion of the fetal testis, Müllerian inhibiting substance and testosterone, are responsible for male development. Studies of single gene mutations that interfere with androgen action indicate that testosterone itself is responsible for virilization of the Wolffian duct system into the epididymis, vas deferens, and seminal vesicle, whereas the testosterone metabolite dihydrotestosterone induces development of the prostate and male external genitalia. Thus, impairment of dihydrotestosterone formation results in a characteristic phenotype consisting of predominantly female external genitalia but normally virilized Wolffian ducts. The molecular mechanisms by which testosterone and dihydrotestosterone act during fetal development appear to involve the same high affinity receptor, a protein that transports both testosterone and dihydrotestosterone to the nucleus of target cells. When this receptor is either absent, deficient, or structurally abnormal, the actions of both testosterone and dihydrotestosterone are impaired, and the resulting developmental anomalies involve both internal and external genital structures.
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References
Amrhein JA, Meyer WJ, Jones HW, Migeon CJ (1976) Androgen insensitivity in man: Evidence for genetic heterogeneity. Proc Natl Acad Sci USA 73:891–894
Bongiovanni AM (1978) Congenital adrenal hyperplasia and related conditions. In: Stanbury JB, Wyngaarden JB, Fredericksen DS (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 868–893
Catt KJ, Dufau ML, Neaves WB, Walsh PC, Wilson JD (1975) LH-hCG receptors and testosterone content during differentiation of the testis in the rabbit embryo. Endocrinology 97:1157–1165
Gehring U, Tomkins GM, Ohno S (1971) Effect of the androgeninsensitivity mutation on a cytoplasmic receptor for dihydrotestosterone. Nature (New Biol) 232:106–107
George FW, Milewich L, Wilson JD (1978) Oestrogen content of the embryonic rabbit ovary. Nature 274:172–173
George FW, Wilson JD (1978) Conversion of androgen to estrogen by the human fetal ovary. J Clin Endocrinol Metab 47:550–555
George FW, Wilson JD (1980) Endocrine differentiation of the foetal rabbit ovary in culture. Nature 283:861–863
George FW, Simpson ER, Milewich L, Wilson JD (1979) Studies on the regulation of the onset of steroid hormone biosynthesis in fetal rabbit gonads. Endocrinology 105:1100–1106
Goldstein JL, Wilson JD (1972) Studies on the pathogenesis of the pseudohermaphroditism in the mouse with testicular feminization. J Clin Invest 51:1647–1658
Griffin JE (1979) Testicular feminization associated with a thermolabile androgen receptor in cultured human fibroblasts. J Clin Invest 64:1624–1631
Griffin JE, Durrant JL (1980) Qualitative defects in the human androgen receptor also occur in androgen resistance with a male phenotype. Clin Res 28:883A
Griffin JE, Wilson JD (1980) The syndromes of androgen resistance. N Engl J Med 302:198–209
Imerato-McGinley J, Guerrero L, Gautier T, Peterson RE (1974) Steroid 5α-reductase deficiency in man: An inherited form of pseudohermaphroditism. Science 186:1213–1215
Imperato-McGinley J, Peterson RE, Leshin M, Grinffin JE, Cooper G, Draghi S, Berenyi M, Wilson JD (1980) Steroid 5α-reductase deficiency in a 65-year-old male pseudohermaphrodite: The natural history, ultrastructure of the testis and evidence for inherited enzyme heterogeneity. J Clin Endocrinol Metab 50:15–22
Jost A (1972) A new look at the mechanisms controlling sex differentiation in mammals. Johns Hopkins Med J 130:38–53
Keenan BS, Meyer WJ, Hadjian AJ, Jones HW, Migeon CG (1974) Syndrome of androgen insensitivity in man: Absence of 5α-dihydrotestosterone binding protein in skin fibroblasts. J Clin Endocrinol Metab 38:1143–1146
Leshin M, Griffin JE, Wilson JD (1978) Hereditary male pseudohermaphroditism associated with an unstable form of 5α-reductase. J Clin Invest 62:685–691
Lyon MF, Hawkes SG (1970) X-linked gene for testicular feminization in the mouse. Nature 227:1217–1219
Milewich L, George FW, Wilson JD (1977) Estrogen formation by the ovary of the rabbit embryo. Endocrinology 100:187–196
New MI, Dupont B, Pollack MS, Levine LS (1981) The biochemical basis for genotyping 21-hydroxylase deficiency. Hum Genet 58: 123–127
Siiteri PK, Wilson JD (1974) Testosterone formation and metabolism during male sexual differentiation in the human embryo. J Clin Endocrinol Metab 38:113–125
Sloan WR, Walsh PC (1976) Familial persistent Müllerian duct syndrome. J Urol 115:459–461
Vigier B, Picard J-Y, Bezard, J, Josso N (1981) Anti-Müllerian hormone: a local or long-distance morphogenetic factor? Hum Genet 58:85–90
Walsh PC, Madden JD, Harrod MJ, Goldstein JL, MacDonald PC, Wilson JD (1974) Familial incomplete male pseudohermaphroditism, Type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 291:944–949
Wilson JD, Siiteri PK (1973) Developmental pattern of testosterone synthesis in the fetal gonad of the rabbit. Endocrinology 92:1182–1191
Wilson JD, Harrod MJ, Goldstein JL, Hemsell DL, MacDonald PC (1974) Familial incomplete male pseudohermaphroditism, Type I. Evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome. N Engl J Med 290: 1097–1103
Wilson JD, Goldstein JL (1975) Classification of hereditary disorders of sexual development. In: Bergsma D (ed) Genetic forms of hypogonadism. Birth Defects: Orig Art Ser, vol 11 Stratton Corp, New York, pp 894–913
Wilson JD (1978) Sexual differentiation. Ann Rev Physiol 40:279–306
Wilson JD, MacDonald PC (1978) Male pseudohermaphroditism due to androgen resistance: testicular feminization and related syndromes. In: Stanbury JB, Wyngaarden JB, Fredericksen DS (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 894–913
Wilson JD, Lasnitzki I (1971) Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology 89:659–668
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The original work described in this review was supported by grant AM 03892 from the National Institutes of Health
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Wilson, J.D., Griffin, J.E., Leshin, M. et al. Role of gonadal hormones in development of the sexual phenotypes. Hum Genet 58, 78–84 (1981). https://doi.org/10.1007/BF00284153
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DOI: https://doi.org/10.1007/BF00284153