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, 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, , 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, 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 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 , 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 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 patients with minimal labial fusion to complete Most of the fallopian tubes adjacent to ovotestes have from clitoromegaly fusion with the urethra opening at the tip of the closed ostia. A uterus is nearly always present, but it is scrotal the infant may usually hypoplastic, unicornuate or otherwise phallus. With the latter morphology, male with . maldeveloped. resemble a completely normal should examine every newborn Cryptorchidism is frequently present, together with Therefore, the obstetrician If no testes are palpable, some deficiency in labia -scrotal fusion. The external boy and palpate the scrotum. and appropriate diagnostic genitalia are generally more male than female, but at CAH should be suspected to establish the diagnosis puberty about three -fourths of true hermaphrodites tests performed. It is important 21-hydroxylase deficiency develop gynecomastia and more than half menstruate. soon after birth because the 3ß-o1 dehydrogenase deficiency The most common karyotypes in true hermaphrodites with salt wasting and the

256 may cause death. Once the diagnosis is suspected, it males, as they can ultimately have adequate sexual can be easily confirmed by testing for elevated levels of function. The appearance of virilization at puberty and serum 17-hydroxyprogesterone. the lack of breast development are in contrast to the Males with CAH have no evidence of genital ambiguity complete form of testicular feminization and defects of but may have an enlarged phallus and a hyperpigmented testosterone synthesis. rugated scrotum. The non -adrenal type of female GONADAL DEFECTS: pseudohermaphroditism is caused by excess exogenous or endogenous androgen stimulation of the fetus during These conditions are associated with regression pregnancy. Exogenous androgen can come from (destruction) of the gonads or their anlage during maternal ingestion of androgenic drugs, including oral intrauterine life, specific enzymatic defects in testosterone contraceptives. Fetal virilization is very likely if a pregnant synthesis or defects in elaboration or action of MIS. woman takes 19-nortestosterone derivatives between 14 Testicular Regression Syndrome. - Testicular and 18 weeks of gestation. Endogenous androgen can regression is a concept that unifies a variety of separate be produced by a virilizing ovarian tumour such as a conditions in which both testes have regressed during luteoma. The degree of virilization does not progress prenatal life. The various names given in the earlier with age. literature to aspects of the syndrome (rudimentary testis, complex bilateral anorchia, Swyer's syndrome, vanishing MALE PSEUDOHERMAPHRODITISM WITH PARTIAL testis) reflect the diverse findings in these patients. This FAILURE OF VIRILIZATION heterogenous group of disorders is a manifestation of the variable timing of gonadal regression resulting in a END -ORGAN DEFECTS: slightly different phenotypic expression and spectrum of The most common category is due to a defect in differentiation or atrophy of internal genital structures. At testosterone action. This most frequently is caused by a one end of the spectrum, the internal genitalia and gonads complete or partial defect of the androgen cellular are absent and the external genitalia are female. At the receptor in the target cells (androgen insensitivity or other end of the spectrum which is close to the endpoint testicular feminization syndrome.) As a result, neither of normal genital development, the patients are internal nor external genital organs respond normally. phenotypic males, but gonadal tissue is absent. Testicular feminization is inherited as an X -linked trait Intermediate in the spectrum are patients with genital and in the complete form, the external genitalia are ambiguity and various combinations of wolffian or phenotypically female. For this reason, the condition is mullerian duct development. rarely diagnosed before puberty unless an inguinal hernia Persistent Mullerian Duct Syndrome - In this syndrome, or labial mass is encountered or unless the disease is a defect in MIS synthesis leads to males with bilateral known to be familial. The patient usually presents after testes and normal male internal and external genitalia; puberty with primary amenorrhoea, scanty or absent body however, they also have a uterus and fallopian tubes. hair, absent internal genitalia and female external genitalia The latter are frequently present in an inguinal hernia with a short or absent vagina. These individuals have to (hernia uteri inguinalis). be differentiated from females with normal ovaries and Defects in Testosterone Synthesis - Patients with these congenital absence of the uterus. The latter have normal defects have a 46XY karyotype, male gonads and body hair. ambiguous external genitalia, and they may develop About 10% of patients have partial expression of the breasts at puberty. The fetal testes differentiate normally androgen insensitivity syndrome, inherited as an X -linked and produce normal amounts of MIS, so no mullerian recessive trait. In Type I patients, the clinical presentation structures remain. But the inadequate testosterone of this disorder ranges from almost complete failure of production causes incomplete differentiation of the virilization to essentially complete phenotypic external genitalia; ambiguity results. The degree of masculinization. All develop breasts at puberty, and ambiguity depends on the severity of the enzymatic varying -degrees of development of the male internal defect. There are five basic steps in the biosynthesis of genitalia also are seen. Since virilization may accompany testosterone from cholesterol. Deficencies of those breast development at puberty, gonadectomy should be enzymes that are also necessary for cortisol synthesis performed before puberty. constitute forms of the adrenogenital syndrome. The In Type II patients with incomplete androgen enzyme deficiencies occur in both the adrenal glands insensitivity syndrome (5 -alpha reductase deficiency), and the gonads, and inheritance is autosomal recessive. target organs in this familial form of male Only a few isolated patients have been reported with pseudohermaphroditism cannot reduce testosterone, the each of these genetic deficiencies. prohormone to DHT, the hormone that masculinizes the indifferent urogenital sinus. In this condition, the MANAGEMENT OF THE PATIENT WITH AMBIGUOUS abnormalities in the reproductive tract are confined to GENITALIA the external genitalia and prostate. The disorder is transmitted as an autosomal recessive. Affected males The management of the patient who presents with have ambiguous external genitalia at birth with bilateral ambiguous genitalia is in part dependent upon age. A undescended testes and a lack of a phallus (pseudo- newborn presenting with ambiguous genitalia represents vaginal perineoscrotal ). Puberty brings a medical emergency and requires immediate attention marked virilization, phallic growth and descent of the and investigation. Regardless of the complexity of the testes into the scrotum. The prostate, however, remains anomaly, appropriate and rapid gender assignment at impalpable. Gynecomastia does not occur. In certain delivery, or soon thereafter at referral hospitalization, often instances, individuals with this disorder can be raised as will determine the success of the final outcome for the

257 child and the family. The goal in the management of For infants without a cervix and uterus their gender such patients is to establish a diagnosis and to assign a assignment often will depend on the adequacy of the sex of rearing that is most compatible with a well -adjusted phallic structure. Infants with an inadequate phallus and/ life arid sexual adequacy. The sex chromosome pattern or severe hypospadias are best assigned the female and gonadal histology are entirely immaterial regarding gender. Errors in testosterone action tend topreclude gender assignment. Once the sex for rearing is assigned, adequate virilization, and infants born with these disorders the gender role is reinforced by the use of appropriate usually should be assigned the female gender. The same surgical, hormonal or psychological measures. holds true for the most infants with 5-alpha-reductase It is imperative that the parents be informed deficiency. immediately in a non -traumatic manner. They should be When an infant does have palpable gonads, distinction told that the baby's sex organs are developed should be made between an infant with unilaterally and incompletely and that this birth defect precludes one with bilaterally palpable gonads. A unilaterally immediate gender assignment. However, diagnostic palpable gonad may indicate asymmetric development studies will commence at once to determine the gender of the internal genitalia and be consistent with either of the baby. Until then, the sex of the child should not be mixed gonadal dysgenesis or true hermaphroditism. A announced and a birth certificate cannot be completed. genito-urogram may show unilateral or complete mullerian The newborn patient is considered to be at risk for duct development. Such infants are best assigned the the development of an adrenal crisis until the diagnosis female gender. Infants with ambiguous genitalia and of one of the forms of adrenal hyperplasia, associated symmetric labioscrotal or inguinal gonads usually with the impairment of glucocorticoid and represent cases of incomplete androgen insensitivity of mineralocorticoid production and ambiguous genitalia, is Type 1 or Type 2 or defects in testosterone biosynthesis. ruled out. Prompt diagnosis and institution of appropriate No infant with bilateral palpable gonads will have a cervix therapy are therefore essential. With early treatment, or uterus. Again such infants are assigned the female normal external genitalia and fertility can be achieved. gender. When examining the newborn with ambiguous It is unnecessary to obtain a karyotype before gender genitalia, it is usually not possible to distinguish between can be assigned. The karyotype is helpful only when it male and female pseudohermaphroditism on the basis confirms the clinical and anatomical findings. of appearance of the external genitalia. However, gonads All intra -abdominal gonads or gonadal streaks in that have descended to labial, scrotal or inguinal regions patient with intersex disorders and a Y chromosome have are almost always testes. Thus, the presence of one or a relatively high potential for becoming malignant. The two palpable gonads rules out virilization of an otherwise two most common tumours are dysgerminoma and normal female, the most common form of ambiguous gonadoblastoma. Tumour incidence markedly increases genitalia. Conversely, the infant born with ambiguous at about the time of puberty in all intersex disorders with genitalia without palpable gonads most often represents a Y chromosome other than testicular feminization. virilization of a genetic female, usually as the result of Therefore, the gonads should be removed before puberty CAH. Thus, determining the presence or absence of from individuals with these disorders and a Y palpable gonads is the key in the initial evaluation. chromosome. Tumours are uncommon before the age The initial anatomical evaluation of the infant without of 25 in individuals with testicular feminization. Because palpable gonads is designed to establish whether a cervix the gonadal secretion of these individuals induces normal and uterus are present. This is accomplished by pubertal feminization, including breast development, ultrasonography and/or genitography. The presence of removal of their gonads may be delayed until after age mullerian derivatives in an infant with ambiguous genitalia 20 with relative safety. Intersex patients without a Y excludes male pseudohermaphroditism except for the chromosome rarely develop gonadal tumours, so their cytogenetic forms resulting in gonadal dysgenesis. Infants gonads or streaks should not be removed. with a cervix and uterus almost always -will be assigned Patients with ambiguous genitalia presenting after the female gender irrespective of phallus size, because early infancy, or those who present in adolescence with they äl? either virilized genetic females with full pubertal failure, also require prompt medical attention reproductive potential (CAH, exogenous androgens, and evaluation in a manner similar to that outlined for maternal virilizing disorders), individuals with mixed the neonate. A severe form of adrenal insufficiency, (asymmetric) gonadal dysgenesis, or true however, is essentially ruled out by later presentation, hermaphrodites. A careful search for the presence of although milder forms must still be considered and other somatic anomalies is of great importance in the investigation of adrenal function, along with gonadal examination of the neonate. function, is warranted.

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