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INTERSEX and GENITAL AMBIGUITY Bltay fINVITED ARTICLE INTERSEX AND GENITAL AMBIGUITY BLTay ABSTRACT Normal sexual differentiation in males and females is described. Discussion of disorders of abnormal sexual development is confined to those producing genital ambiguity. Genital ambiguity is further subdivided into disorders of gonodal development and disorders of fetal endocrinology. Disorders of gonadal development with abnormal sex chromosome constitution include those with and without sexual ambiguity. Only those producing sexual ambiguity, true hermaphroditism and mixed gonadal dysgenesis are discussed further. Disorders of fetal endocrinology are divided into female and male pseudo hermaphroditism. The main features of each are highlighted. A practical method of management of patients with ambiguous genitalia then follows. Keywords: Sexual differentiation, Intersex, genital ambiguity. SINGAPORE MED J 1990; Vol 31: 255 - 258 INTRODUCTION development of the ipsilateral fallopian tube. To prevent The normal development, growth and function of the development of the uterus and vagina, both testes must genital organs make a fundamental contribution to the secrete adequate amounts of MIS. Thus, a patient with a and a balanced psychological and physical make-up of both testis contralateral streak, ovary, or ovotestis has males and females. A disturbance of the process of fetal generally a uterus and vagina and a single fallopian tube sexual differentiation may result in malformation or even on the side with the streak or ovary. ambiguity of the genitalia. Third, testosterone produced by the Leydig cells in the testis is required for the wolffian (mesonephric) duct to differentiate into epididymis, vas deferens and seminal EMBRYOLOGY OF SEXUAL DEVELOPMENT vesicle. Testosterone acts locally on the ipsilateral wolffian Human genetic sex is established at conception; the duct. In the absence of a testis, inability of a testis to homogametic state (XX) is considered female and the produce testosterone, or insensitivity of the wolffian duct heterogametic state (XY) is considered male. anlage to testosterone, differentiation of the wolffian duct First, the sex chromosomes determine whether the does not occur. indifferent gonad that develops in the urogenital ridge Fourth, development of male external genitalia and will differentiate into a testis or an ovary. Testicular differentiation of the prostate are dependent on the local differentiation is partly dependent on the presence of a conversion of testosterone (the prohormone) to threshold titre of H -Y antigen (H stands for histo- dihydrotestosterone (DHT), which is mediated by the compatibility) that is secreted by Sertoli cells. Two X enzyme 5-alpha-reductase. Dihydrotestosterone causes chromosomes are usually needed for normal ovarian (1) the genital tubercle to enlarge and form the glans development and maintenance. The testis is anatomically penis (2) the genital folds to enlarge and fuse to form distinct some weeks before ovarian differentiation. the penile shaft, with migration of the urethral orifice Second, Sertoli cells in the testis also produce a along the lower border of the shaft to the tip of the glans, mullerian-inhibiting substance (MIS), a polypeptide protein and (3) the genital swellings to fuse and form a scrotum. that causes the mullerian (paramesonephric) ducts to Fifth, female internal organs and external genitalia regress. In the absence of this substance, the mullerian develop in the absence of hormones secreted by the ducts develop passively to form the fallopian tubes, uterus fetal ovary and differentiate even when gonads are and upper vagina. MIS has a local action, which inhibits absent. Unless interrupted by the regressive influence of MIS, differentiation of the mullerian ducts results in formation of fallopian tubes, a uterus and a vagina. In Department of Maternal Fetal Medicine the absence of the masculinizing effect of DHT, the Kandang Kerbau Hospital undifferentiated external genital anlage develops into the Singapore 0821 vulva. The genital tubercle develops into the clitoris, the genital folds into the labia minora, and the genital B L Tay, MBBS, M MED (O & G), FRCOG, AM(S'pore) swellings into the labia majora. Thus, the infant with Senior Obstetrician & Gynaecologist and Head ovaries or streak gonads has female internal and external genitalia at birth. 255 Thus, the sex of an individual can be identified by are 46XX, 46XY and mosaic, usually 46XX/46XY. four anatomical characteristics: (1) sex chromosomes, (2) gonads, (3) internal genitalia, and (4) external MIXED GONADAL DYSGENESIS genitalia. The psychological characteristics are usually Mixed gonadal dysgenesis (MGD) or asymmetric gonadal related to the morphology of the external genitalia. is syndrome characterized in most patients Intersexuality results when there is a discrepancy in the dysgenesis a mosaic 45X/46XY karyotype, persistent mullerian genetic, gonadal or genital make-up of an individual. by a structures, an abnormal testis, and a contralateral Disorders of sexual differentiation have traditionally been duct gonad. In contrast to true hermaphroditism, in classified into three categories according to gonadal streak a fallopian tube is often adjacent to the gonad morphology. Female pseudohermaphroditism describes MGD regardless of whether it is a testis or streak, confirming genital ambiguity resulting from abnormal virilization of nature of the testis. the female fetus with normal ovaries. The male the dysgenetic MGD is detected in the neonate principally because counterpart - male pseudohermaphroditism - is the result of ambiguity of the external genitalia. Frequently, a of incomplete virilization of the male fetus with normally indirect inguinal hernia differentiated testes. A third category consisting of palpable testis bulges through an into the labio -scrotal fold, subjects with abnormal gonadal differentiation includes or descends completely resulting in asymmetry of the genital swellings. the true hermaphrodite, who has both male and female gonadal tissue, and other syndromes of dysgenetic gonadal development. DISORDERS OF FETAL ENDOCRINOLOGY can be further divided Disorders of sexual ambiguity The second major category, disorders of fetal major categories based on their aetiology: (1) into two endocrinology, can be subdivided into female pseudo - disorders of gonadal development, in which the basic hermaphroditism with partial virilization and male pseudo - major chromosomal lesion which defect is usually a hermaphroditism with partial failure of virilization. occurs by chance and is not hereditary, and (2) disorders of fetal endocrinology, in which the individual has normal WITH chromosomes but usually has a genetic defect that in FEMALE PSEUDOHERMAPHRODITISM many instances is hereditary. PARTIAL VIRILIZATION Female pseudohermaphroditism usually is due to DISORDERS OF GONADAL DEVELOPMENT congenital adrenal hyperplasia (CAH), although some forms have non -adrenal aetiology. CAH is the most or mosaicism of the sex Additions, deletions, frequent cause of ambiguous genitalia in the newborn. It chromosomes characterize individuals in this category. is important to recognise this condition as the lack of The of the gonads is variable and ranges appearance specific adrenal steroids may threaten the life of the from the appearance of a streak gonad to a nearly female patient. or male gonad. It is also the only type of intersex condition with the The most common disorders of gonadal development, possibility of entirely normal sexual function, including Klinefelter's Syndrome (47XXY) and gonadal dysgenesis fertility, as virilization involves only the external genitalia. and its variants) do not cause genital (Turner's Syndrome Although six different enzyme defects have thus far ambiguity. been reported as variants of CAR, only three - 21- Other disorders of gonadal development resulting hydroxylase deficiency, with or without salt wasting, 11- in true hermaphroditism frequently sexual ambiguity are hydroxylase deficiency, and 3ß-ol dehydrogenase and mixed gonadal dysgeriesis. deficiency - are associated with virilization of the external female genitalia. Deficiency of 11-hydroxylase is TRUE HERMAPHRODITISM associated with hypertension. Deficiency of 3ß-ol is associated with True hermaphroditism is defined as the presence of both dehydrogenase, the least common it is fatal because it testicular and ovarian tissue in a patient. The gonads the mildest virilization, but usually results in severe adrenal insufficiency. These autosomal may Ize ovary and testis separately or combined in an lack of cortisol synthesis ovotestis. recessive disorders in turn cause hormone The ovotestis is the most frequently encountered with a resultant increase in adreno-corticotrophic The increased ACTH causes gonad in true hermaphroditism, followed by an ovary. (ACTH) production. of androgens, which The testis is least often encountered. The nature of the increased production adrenal external genitalia only. This is because genital organ adjacent to a gonad in true hermaphroditism masculinizes the stimulus arrives too late to switch on the is dependent on the nature of the gonad. Thus, a fallopian the androgenic production can tube is adjacent to an ovary and an epididymis or vas wolffian ducts. Because the androgen the enzymatic defect, the degree of deferens is adjacent to a testis. Either a mullerian or a vary according to is variable and can range wolffian structure, but not both, is adjacent to an ovotestis. virilization in these
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