Molecular Endocrinology of Sex Differentiation

Garry L. Warne; Shankar Kanumakala

doi:10.1055/s-2002-35381

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2002; 20(3): 169-180
DOI: 10.1055/s-2002-35381

Molecular Endocrinology of Sex Differentiation

Garry L. Warne, Shankar Kanumakala

Centre for Hormone Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia

Abstract

ABSTRACT

Differentiation of a testis or an ovary from a bipotential gonad is a complex developmental process involving various genes and hormones. Similarly, internal and external genital organs develop from an indeterminate stage from the complex differentiation of Wolffian and Müllerian ducts. Differentiation of the Wolffian ducts, urogenital sinus, and external genitalia is androgen dependent. Female sex differentiation appears to be a more passive process that is independent of estrogen. This article reviews the process of differentiation of the gonads and the genitalia and the factors affecting it. In addition, a clinical approach to patients with sexual ambiguity or sex reversal is discussed.

KEYWORDS

Sex differentiation - Wolffian duct - Müllerian duct - ambiguous genitalia - sex reversal

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References

REFERENCES

1 Segaloff D L, Ascoli M. The lutropin/chorionic gonadotropin receptor: 4 years later. Endocr Rev . 1993; 14 324-347
2 de Roux N, Milgrom E. Inherited disorders of GnRH and gonadotropin receptors. Mol Cell Endocrinol . 2001; 179 83-87
3 Aittomaki K, Hreva R, Stenman U-H. Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. J Clin Endocrinol Metab . 1996; 81 3722-3726
4 Boehmer A L, Brinkmann A O, Sandkuijl L A. 17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab . 1999; 84 4713-4721
5 Shaw G, Renfree M B, Leihy M W. Prostate formation in a marsupial is mediated by the testicular androgen 5α-androstane-3α,17β-diol. Proc Natl Acad Sci U S A . 2000; 97 12256-12259
6 Chetyrkin S V, Hu J, Gough W H, Dumaual N, Kedishvili N Y. Further characterization of human microsomal 3alpha-hydroxysteroid dehydrogenase. Arch Biochem Biophys . 2001; 386 1-10
7 Shozu M, Akasofu K, Harada T, Kubota Y. A new cause of female pseudohermaphroditism: placental aromatase deficiency. J Clin Endocrinol Metab . 1991; 72 560-566
8 Grumbach M M, Auchus R J. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab . 1999; 84 4677-4694
9 Chamberlain N L, Driver E D, Miesfeld R L. The length and location of the CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res . 1994; 22 3181-3186
10 Bratt O, Borg A, Kristoffersson U. CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer . 1999; 81 672-676
11 Ishii T, Sato S, Kosaki K. Micropenis and the AR gene: mutation and CAG repeat-length analysis. J Clin Endocrinol Metab . 2001; 86 5372-5378
12 Lobaccaro J M, Lumbroso S, Poujol N, Belon C, Sultan C. Molecular genetics of androgen insensitivity syndromes. Cell Mol Biol . 1994; 40 301-308
13 Boehmer A L, Bruggenwirth H, van Assendelft C. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab . 2001; 86 4151-4160
14 Josso N, di Clemente N, Gouédard L. Anti-Müllerian hormone and its receptors. Mol Cell Endocrinol . 2001; 179 25-32
15 Arango N A, Lovell-Badge R, Behringer R R. Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development. Cell . 1999; 99 409-419
16 Tremblay J J, Viger R S. Transcription factor GATA-4 enhances Müllerian inhibitory substance gene transcription through a direct interaction with the nuclear receptor SF-1. Mol Endocrinol . 1999; 13 1388-1401
17 Allard S, Adin P, Gouédard L. Molecular mechanisms of hormone-related Mullerian duct regression: involvement of β-catenin. Development . 2000; 127 3349-3360
18 Imbéaud S, Belville C, Messika-Zeitoun L. A 27 base-pair deletion of the anti-Müllerian type II receptor gene is the most common cause of the persistent Müllerian duct syndrome. Hum Mol Genet . 1996; 5 1269-1277
19 Heyns C F, Hutson J M. Historical review of theories on testicular descent. J Urol . 1995; 153 754-767
20 O'Connell H E, Hutson J M, Anderson C R, Plenter R J. Anatomical relationship between urethra and clitoris. J Urol . 1998; 159 1892-1897
21 Folch M, Pigem I, Konje J C. Mullerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv . 2000; 55 644-649
22 Hamerton J L, Canning N, Ray M, Smith S. A cytogenetic survey of 14,069 newborn infants: I. Incidence of chromosome abnormalities. Clin Genet . 1975; 8 223-243
23 Creighton S M, Minto C L, Steele S J. Objective cosmetic and anatomical outcomes at adolescence of feminising surgery for ambiguous genitalia done in childhood. Lancet . 2001; 358 124-125
24 May B, Boyle M, Grant D B. A comparative study of sexual experiences: women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Health Psychol . 1996; 1 479-492
25 Woodhouse C R. The sexual and reproductive consequences of congenital urinary abnormalities. J Urol . 1994; 152 645-651
26 Diamond M, Sigmundson H K. Management of intersexuality: guidelines for dealing with persons with ambiguous genitalia. Arch Pediatr Adolesc Med . 1997; 151 1046-1050
27 Gourlay W A, Johnson H W, Pantzar J TM. Gonadal tumors in disorders of sexual differentiation. Urology . 1994; 43 537-540
28 Slowikowska-Hilczer J, Szarras-Czapnik M, Kula K. Testicular pathology in 46,XY dysgenetic male pseudohermaphroditism: an approach to pathogenesis of testis cancer. J Androl . 2001; 22 781-792