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Intersex.Pdf Blackwell Science, LtdOxford, UK BJUBJU International1464-4096BJU International 90 2920 INTERSEX I.A. HUGHES 10.1046/j.1464-4096.2002.02920.x Update Article769776BEES SGML BJU International (2002), 90, 769–776 doi:10.1046/j.1464-4096.2002.02920.x Intersex I.A. HUGHES Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK terminology ‘pseudohermaphrodite’ with male or female Introduction prefixes currently has no place in an enlightened era of The term intersex conventionally refers to the appearance intersex management involving closer collaboration with of the external genitalia being at variance with normal the patient and family. Geneticists, particularly those development for either sex and to present a problem of sex working on identifying sex-determining genes, prefer the assignment. Generally the problem is evident at birth, terms ‘complete’ and ‘partial’ sex reversal, prefixed by the manifesting as ambiguous genitalia of the newborn. sex chromosomes (XY or XX). Puberty is another stage when an intersex disorder may arise by the masculinizing effects on the external genitalia Embryology of prenatal sex development of a child hitherto raised as a female. How to establish a cause for intersex and thereby formulate a management There is compelling evidence that internal and external plan is probably one of the most challenging clinical con- prenatal sex development is constitutively female. The ditions for the practising paediatric endocrinologist and studies by Jost [1] in rabbit embryos showed female phe- appropriate surgical colleague. Management in the longer notypic development when the ovary or testis was excised, term needs the skills of counsellors trained and experi- whereas a male phenotype could be restored with testis enced in psychosexual issues affecting children and engrafting. The imprint of his seminal work on the under- adolescents. Genetic issues dominate the pathophysiology standing mammalian sex development is summarized in of intersex and genetic counselling should be available to Fig. 1. The dual formation of internal genital ducts in both families needing advice about recurrence risks, carrier sexes is described in standard texts [2–4]; they comprise detection and options for prenatal diagnosis, and perhaps the Wolffian and Müllerian ducts. The former develop prenatal treatment. Clearly, the management of intersex is from the mesonephric tubules and differentiate into the complex and a multidisciplinary team network of appro- vas deferens, epididymis and seminal vesicles under the priate professionals is mandatory. influence of high concentrations of androgens (testoster- The approach to investigating and managing intersex one) acting locally. The Müllerian ducts stabilize in the requires an understanding of normal prenatal sexual absence of anti-Müllerian hormone (AMH, secreted by development. The complexity of intersex management has Sertoli cells) and form the uterus, Fallopian tubes and been compounded by the use of confusing terminology upper part of the vagina. While not generally regarded as and lack of clarity in the use of definitions. For the purpose a problem of intersex, the persistent Müllerian duct syn- of this review, sex determination refers to the formation drome in otherwise normally developed males is caused by of the gonad (testis or ovary) and sex differentiation refers mutation of either the AMH or the AMH receptor gene [5]. to the formation of the genital phenotype (internal and External genital development is also common to both external) consequent upon hormonal effects. The com- sexes initially, the genital tubercle only enlarging from posite of these two processes defines sex development; fur- 10 weeks of gestation onwards in the male as a result of ther hormone-induced amplification of genital phenotype androgen action. The genital swellings later develop either occurs at puberty, followed by the acquisition of reproduc- into the scrotum or labia majora, depending on exposure tive potential. Sex outcome at birth is the result of a co- to androgens. In the developing male, the urethral folds ordinated and sequential series of developmental events fuse ventrally to form the urethra, with the urogenital controlled by a network of temporally expressed genes and orifice finally sited at the tip of the glans penis. Failure in hormones. How an intersex disorder may occur can be this developmental pathway results in hypospadias, the ascertained logically when normal sex determination and commonest congenital anomaly in males. differentiation is understood. When the classification and Formation of the gonad precedes the events of internal causes of intersex are considered in this review, the termi- and external genital development by several weeks. A nology will refer to the masculinized female, the under- thickening of the coelomic mesoderm on the medial aspect masculinized male and the true hermaphrodite as three of the urogenital ridge at around 5–6 weeks of gestation principal classes of disorders. It is recommended that the is the first indication of a gonad which, at this stage, is © 2002 BJU International 769 770 I.A. HUGHES Fig. 1. Embryology of internal genital development, as based on experiments of Jost [1]. Sertoli Cell Leydig Cell Fig. 2. Schematic of male fetal sex Activity Activity development. The solid line represents the rise Testosterone in fetal serum testosterone concentrations; maximum levels ≈ 10 nmol/L. Testis Descent Male External External Genital Differentiation Genital Growth Wolffian Duct Differentiation .. Germ Cell Mullerian Duct Migration Regression 45678 91011 12 13 14 15 40 Gestation, weeks histologically indifferent. The development is juxtaposed Prenatal male sex development is completed by the with mesonephric cells of the primitive kidney. The migration of the testis into the scrotum; this is a two-stage close interdependence between gonad and kidney develop- process of transabdominal migration and inguinoscrotal ment is illustrated by the absence of gonads and kidneys descent [11]. The first phase of descent, at least in the in mice with targeted disruption of the wt-1 gene which mouse, is controlled by an insulin-like peptide relaxin pro- prevents thickening of the mesoderm in the urogenital duced by the testis; when the gene encoding this protein ridge [6]. The human Denys-Drash and Frasier syndromes is disrupted, bilateral cryptorchidism occurs [12]. How- resulting from mutations in WT-1 are characterized by ever, studies of the human homologue of this gene in boys renal disorders and varying degrees of gonadal dysgenesis with undescended testes have only rarely reported muta- [7,8]. tions [13,14]. Inguinoscrotal descent is androgen- The first histological evidence for testis development dependent, as exemplified by abnormal gonadal positions is the appearance of seminiferous cords from the con- in hypogonadotrophic hypogonadism and syndromes of densation of primary sex cords together with Sertoli cells. androgen insensitivity [15,16]. Sex determination and sex This occurs at ≈ 7 weeks’ gestation; by contrast, the ovary differentiation is dependent in the male on a coordinated is not defined for about another 4 weeks. Interstitial cells interplay of temporally related genetic and hormonal con- derived from the mesenchyme are present by 9 weeks trol events. The embryological events are schematically and differentiate as the steroid-secreting Leydig cells. summarized in Fig. 2; the following section briefly Primordial germ cells migrate to the site of gonad forma- describes the key genes and hormones involved in prenatal tion from the wall of the yolk sac, via the mesentery of the male sex development. hindgut. The migratory pathway is dependent on chemo- attractants and cell adhesion molecules, a process still to Genetic and hormonal control of fetal be fully explained [9,10]. While gonad determination will sex development take place even if germ cells fail to migrate, there may be some sex-dependence to the pattern of germ cell Sex development is constitutively female so that the active migration. imposition of male development requires factors to deter- © 2002 BJU International 90, 769–776 INTERSEX 771 mine the testis, regress the Müllerian ducts and differen- tiate the internal and external genitalia as male. There is a panoply of genes involved in testis determination, many yet to be identified. Syndromes of sex reversal and studies on mouse embryos have been critical in identifying key genes (see [17–19] for detailed reviews). The SRY gene (sex-related gene on the Y chromosome) is central to testis formation, as exemplified by the presence of testes in XX Fig. 3. Main genetic factors controlling testis or ovary determination males and the male outcome after transgenic insertion of from a bipotential gonad. the sry gene into XX mouse embryos. Pairing of X and Y chromosomes at their pseudoautosomal regions occurs during paternal meiosis. As SRY is located close to the pseudoautosomal boundary, the gene can become trans- gens during a critical period (Fig. 2). Furthermore, the located to the X chromosome if X-Y interchange of genetic principal androgens, testosterone and DHT, mediate their material extends beyond the pseudoautosomal boundary. developmental effects through binding to a specific andro- SRY encodes a protein which contains a central region of gen receptor (AR) in target tissues. Androgens are synthe- 80 amino acids and is homologous with a large family of sized by the Leydig cells, initially autonomously,
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