Intersex disorders

There are three factors which determine an individual's sexual development. These are the effect of the sex chromosomes on the differentiation of the gonad, the proper functioning of the differentiated testis and the response of the end organ to this testicular function. The testes carry out their intrauterine function by producing two substances, testosterone and MIS.

Testosterone stimulates the development of the Wolffian duct, which differentiates into the internal male genitalia and also to the masculinization of the cloaca. MIS inhibits the development of the Mullerian structures which are always present and capable of development. MIS is a gly-coprotein produced by the Sertoli cells [15] and its action seems to be mediated by the release of hyalunidase by the Mullerian duct cells, and local destruction occurs. There may also be inhibition of growth factor stimulation, presumably through specific cell membrane-associated receptors, as the regression is quite specific. MIS may have unilateral action so that each testis appears to produce the hormone, which results in regression of the Mullerian structures on its own side. The sensitivity of Mullerian structures to MIF is present only during the first 8 weeks of gestation.

The manner in which testosterone, produced by developing testes, is utilized to bring about masculinization of the cloaca is through conversion of testosterone to dihydrotestosterone through the action of the enzyme 5a-reductase. Wolffian structures, however, are capable of utilizing testosterone directly and are therefore independent of 5a-reductase activity. Thus, in those patients with 5a-reductase deficiency abnormal development of the external genitalia will occur and an intersex state results. For effective utilization of both testosterone and 5a-reductase it is necessary for the testosterone to be bound to the receptors on the cell membranes and ineffective binding of testosterone leads to abnormal sexual differentiation in disorders known as androgen insensitivity.

It is therefore evident that sexual development may be abnormal in the following circumstances:

1 There may be sex chromosome abnormalities interfering with testicular differentiation; the only common one is 46X/46XY mosaicism, giving rise to one of the forms of gonadal dysgenesis.

2 Testes may be incapable of producing testosterone, either because of complete failure of testicular differentiation (anatomical testicular failure) or a biosynthetic defect of testosterone production (enzymatic testicular failure).

3 The end organs may be incapable of utilizing testosterone because of 5a-reductase deficiency or because the androgen receptor is abnormal and therefore testosterone cannot bind to the cell wall (androgen insensitivity).

4 The production of Mullerian inhibitor may be deficient, leading to the growth of Mullerian structures in an otherwise normal male.

5 In a genetic female masculinization of the external genitalia may result in cases of excessive androgen production in utero, for example, congenital adrenal hyperplasia.

6 Rarely, in a genetic female, genes capable of producing the H-Y antigen may be found on an autosome, leading to the condition known as the 46XX male.

7 True hermaphroditism, i.e. the presence of testicular and ovarian tissue in the same individual, may be present and such patients are commonly genetically female with mosaicism, though genetic male variants also exist.

Clinical presentation

The child with ambiguous genitalia may present in a number of ways:

1 a masculinized female due to congenital adrenal hyperplasia (CAH) or androgen stimulation from another source;

2 an undermasculinized male for one of the reasons discussed above; or

3 a true hermaphrodite.

The masculinized female is usually caused by CAH; she may be unable to retain salt and water and die within a few weeks of birth from salt loss and dehydration if the diagnosis is not made. An important generalization concerns the age of presentation. If, as is usually the case, the patient presents at birth with sexual ambiguity it is important that full investigations be undertaken at once to choose the appropriate sex of rearing. The reasons for this are first, if the child has CAH she may die if not correctly treated, and second, whatever the diagnosis, the orientation of the child in the chosen sex of rearing will be better if she or he is placed in that gender role as soon as possible after birth and is allowed to grow up in it without further doubts about gender being expressed. Parents in these circumstances are extremely anxious to know the sex of their child and the prognosis for the future, but it is wise not to assign a gender role until all the information is available as an attempt at a later stage to change the sex of rearing may cause considerable psychological trauma. It is important to understand that it is extremely difficult to establish the correct diagnosis through superficial examination of the external genitalia. It is important that thorough investigation be carried out with the swiftest possible means to establish the correct diagnosis.

Presentation in the neonatal period

The first diagnosis to be confirmed or refuted is CAH. It must be admitted that, if a testis can be palpated with certainty, the likelihood of CAH is very small, but it should still be formerly excluded by the appropriate investigations.

CONGENITAL ADRENAL HYPERPLASIA

CAH is the most common cause of female intersex and is an autosomal recessive disorder resulting in enzyme deficiency related to the biosynthesis of cortisol and aldos-terone. The commonest enzyme defect is 21-hydroxylase deficiency which results in a failure of conversion of 17a-hydroxyprogesterone to desoxycortisol and also failure of conversion of progesterone to desoxycorticos-terone (Fig. 34.18). Two other enzyme deficiencies are recognized, although less common: -hydroxysteroid hydrogenase deficiency and 11^-hydroxylase deficiency. In 21-hydroxylase deficiency, which accounts for 90% of cases of CAH, the deficiency results in an increase in progesterone and 17a-hydroxyprogesterone, which is therefore converted to androstenedione and subsequently to testosterone.

21-hydroxylase deficiency is an autosomal recessive disorder. Its relationship to human leucocyte antigen (HLA) type was established by Dupont et al. [16], and this has allowed mapping of the gene, which is located on the short arm of chromosome 6 [17]. It is located between HLA-B and HLA-DR, and subgroups of HLA-B have been closely linked to salt-losing CAH and HLA-BW51 with the simple virilizing form. Studies by Donohoue et al. [18] have shown that there are two hydroxylase genes (21-OHA and 21-OHB). Only 21-OHB is active and they both lie between the fourth components of complements C4A and C4B. A variety of mutations have been reported, including gene deletions of 21-OHB [19], gene conversions [18] and point mutations [20]. The incidence of 21-hydroxylase deficiency is between 1 in 5000 and 1 in 15,000.

Affected females are born with enlargement of the clitoris and excessive fusion of the genital folds, which obscure the vagina and urethra (Fig. 34.19), forming in the process an artificial urogenital sinus which has a single opening at some point on the perineum, usually near the base of the clitoris, although sometimes along its ventral surface and rarely at the tip. Thickening and rugosity of the labia majora are evident and they bear some resemblance to a scrotum. There is much variation of the thickness of the fused labial folds and in extreme cases they are very thick, with narrowing of the lower part of the vagina (Fig. 34.20). The uterus, fallopian tubes and vagina are always present and the vagina opens at some point in the urogenital sinus; in more severe cases it may be very difficult to identify this opening precisely. These clinical changes of masculiniza-tion are secondary to the elevated levels of androgens as a result of the enzyme defect.

In some infants a dangerous salt-losing syndrome may arise because of associated aldosterone deficiency and the child may die of wasting and vomiting within a few weeks of life if the diagnosis is not appreciated.

17a-HYDROXY -PREGNENOLONE

DHEA

CHOLESTEROL

20, 22-Desmolase 1

PREGNENOLONE

3^-Dehydrogenase

ALDOSTERONE

ESTRONE

ESTRADIOL -

DEOXYCORTISOL ■

-CORTISOL

21-Hydroxylase 11-Hydroxylase

PROGESTERONE-----DOC-----CORTICOSTERONE

17-Hydroxylase

17«-HYDROXYPROGESTERONE -17, 20-Desmolase

a4-ANDROSTENEDIONE

17-Ketosteroid-reductase 5

TESTOSTERONE

Fig. 34.18 Diagram of the enzyme steps necessary to convert cholesterol through its various intermediate stages to aldosterone, cortisol and testosterone. Note that 3^-dehydrogenase (labelled 2) is active at two places, as are 17-hydroxylase (labelled 3) 17,20-desmolase (labelled 4), 21-hydroxylase (labelled 6) and 11-hydroxylase (labelled 7).

Enlarged Clitoris
Fig. 34.19 The external genitalia of a child with CAH. Note the clitoral enlargement and the excessive fusion of labial folds which have resulted in only a single opening on the perineum.

When an infant is born with ambiguous genitalia, management also includes counselling the parents. It is helpful to reassure them that the child is healthy but there is a developmental anomaly of the genitalia. If the initial examination of the child fails to identify palpable gonads it is most likely that the child is female and the parents should be informed as such and the likelihood of CAH may be raised. The diagnosis must then be made with as much haste as possible to alleviate parental anxiety.

Investigation of a suspected case of CAH should include:

1 karyotyping, which may be performed on cord blood and results rapidly obtained;

2 measurement of 17a-hydroxyprogesterone in blood, which will be elevated in 21-hydroxylase deficiency;

3 examination of electrolytes to check the possibility of a salt-losing syndrome, and if the salt-losing state is present, sodium and chloride may be low and potassium raised; and

4 pelvic ultrasound to discover the presence of a uterus and vagina. This is not only reassuring to the parents, but highly indicative of the correct diagnosis.

The immediate management of such a child should always be undertaken by or in cooperation with the paediatrician. Cortisol or one of its related synthetic compounds must be given to suppress adrenocorticotrophic hormone secretion. If the child is a salt loser then salt loss must be very carefully controlled. For further management of the endocrine disorder the reader is referred to standard paediatric texts.

The surgical attention required for congenital adrenal hyperplasia patients has become extremely complex in recent years. In the past it has been standard practice to carry out two corrective procedures. First, the reduction

Androgen Insensitivity SyndromeAndrogen Insensitivity Syndrome

Fig. 34.20 Diagrammatic representation of clitoral enlargement and excessive fusion of labial folds to show (a) the different thickness of the folds, (b) the narrowing of the vagina in the most marked cases, and (c) variations in the point at which the urogenital sinus opens.

Androgen Insensitivity Syndrome
Fig. 34.21 Identification of the corpora cavernosa which are excised following preservation of the nerve and blood supply to the glans.

in the size of the clitoris if it is enlarged and, second, the division of the fused labial folds to expose the urethra and vagina beneath. Clitoral reduction which involves the removal of the shaft of the clitoris with preservation of the neurovascular bundle and the glands has been a standard procedure carried out by paediatric urologists for the last 30 years and has usually been carried out soon after birth or within the first few months of birth (Fig. 34.21). In collaboration with surgery to the labial folds, the fused labial folds may be divided and exposed (Fig. 34.22). However, these procedures have been carried out from a cosmetic point of view and also for the intention of deciding the gender of rearing and the physical reinforcement of that gender selection. A number of ethical issues have arisen in recent years challenging the practice of clitoral reduction. Minto et al. [21] reported that sexual function can be compromised following clitoral surgery suggesting all had sexual difficulty. While this study failed to address other reasons for sexual satisfaction other than the physical ability, it raises the question as to whether or not a surgical approach in early life is wise. Certainly, further research is needed to ensure that the outcome for these individuals is optimized and individualized.

The division of the fused labial folds is simple if they are thin, when it may be performed at almost any age. However, in more complex cases, division at this early stage may give an indifferent result and the operation may need to be repeated later when the patient is beyond puberty, but surgery at this stage can be rather difficult. If the folds are very thick and especially if the vagina is narrowed more elaborate procedures will be required to open the introital ring and achieve a functional vaginal result.

Careful supervision by the paediatrician will be required throughout childhood such that normal menstrual and fertility patterns can be established. Grant et al. [22], in a review of menstrual and fertility patterns, indicated that menarche is often delayed by up to 2 years. The age of menarche is directly related to the hormonal control of the disease, although menstrual irregularity, including oligomenorrhoea and even amenorrhoea, may occur in spite of good control [23]. Fertility is reduced to some extent, although this seems to be a greater problem for salt losers [24].

OTHER CAUSES OF MASCULINIZATION IN GENETIC FEMALES

These cases of masculinized genetic females are now rare. There are cases of androgen-secreting tumours that have occurred in pregnancy, which have resulted in virilization of the fetus, especially luteomy [25], polycystic ovaries [26] and Krukenberg tumours [27]. The association between the use of progestogens and masculinization of the fetus is extremely rare.

It should be mentioned that the features of the genetic female masculinized from other androgen sources are not likely to be significantly different from those seen in CAH as far as the degree of masculinization is concerned (Fig. 34.23). There will, however, be no other metabolic defect and no salt-losing syndrome will be recognized but the management of such a case is to exclude CAH as the

Severe Masculinization

Fig. 34.23 Considerable masculinization of the external genitalia of a female child whose mother was treated with methyltestosterone in early pregnancy.

cause of the ambiguity and, having done this, the infant may be reared in her correct female role and surgical treatment carried out as for CAH. If no source of androgen can be identified, consideration must be given to the possibility of the child being a 46XX true hermaphrodite and if the degree of external masculinization is considerable it would be wise to consider gonadal biopsy. Rarely, no obvious androgenic source can be detected to explain the masculinization of the genitalia.

Male intersex and true hermaphrodites

If masculinization of a genetic female from CAH exogenous androgens has been excluded, which is done within the 1st week of life, distinction must be made between an undermasculinized male and a true hermaphrodite with ovarian and testicular tissue. The distinction can be made for certain only by laparotomy and gonadal biopsy. Laparoscopic biopsy is not adequate for establishing the nature of a gonad in an intersex child. The organ may be an ovotestis and, unless a representative biopsy is taken along the length of the gonad, it must be stressed that the biopsy of the gonad is not undertaken to determine what the sex of rearing should be. This decision is principally made on the suitability of external genitalia for sexual life in one or other gender role. It is necessary to know the nature of the gonad, however, so that if gonadal tissue is present which is inappropriate to the chosen gender role, as it always will be in a true hermaphrodite and in a male intersex being brought up as a female, gonadal tissue can be removed. Various conditions present under the general heading of male intersex and true hermaphroditism and these will now be considered.

XY FEMALES

Faults in androgen production

In this group of patients androgen production may fail from either anatomical or enzymatic testicular failure.

Anatomical testicular failure. Failure of normal testicular differentiation and development may be the result of a chromosome mosaicism affecting the sex chromosomes or possibly associated with an abnormal isochromosome [28], but usually the sex chromosomes appear to be normal

Fig. 34.23 Considerable masculinization of the external genitalia of a female child whose mother was treated with methyltestosterone in early pregnancy.

and the condition is referred to as pure gonadal dysgenesis. Clinically such cases show variable features depending on how much testicular differentiation is present. Since differentiation is often poor, most patients have mild mas-culinization or none at all, and the uterus, tubes and vagina are generally present [29]. The presence of the uterus in this condition contrasts with the other forms of XY female described below.

Management of this group of patients is concerned with the reconstruction of the external genitalia in the manner described in previously and removal of the streak or rudimentary gonad in view of their raised potential for cancer. The degree of masculinization of such patients is often minimal and, if it is limited to a minor degree of clitoral enlargement with little or no fusion of the genital folds, surgery need not be undertaken. The risk of malignancy in the rudimentary testes is probably in the order of 30% and gonadal removal during childhood would be wise. Around the age of puberty replacement oestrogen-progestogen therapy must be started to produce secondary sexual development and menstruation.

Enzymatic testicular failure Several metabolic steps are necessary for the complete formation of testosterone from cholesterol (Fig. 34.18). A number of biosynthetic defects have been reported at each stage of the process. As a result, clinical features are somewhat varied but since such enzyme defects are generally incomplete there is external genital ambiguity of varying degrees, the uterus, tubes and upper vagina being absent since the production of MIS by the testes is normal.

The decision on the sex of rearing will depend upon the degree of masculinization of the external genitalia but the female role is often the chosen one (Fig. 34.24). Surgical management is as already described. The identification of the precise enzyme defect can be difficult, but may be approached through human chorionic gonadotrophin stimulation of the gonads and measurement of various androgens to determine where the enzyme block occurs.

END-ORGAN INSENSITIVITY

In this group of conditions the end organ may be insensitive to androgen production because of 5a-reductase deficiency or from partial androgen insensitivity.

5a-Reductase deficiency

As described above, normal masculinization of the external genitalia requires the conversion of testosterone to dihydrotestosterone by 5a-reductase. Although the Wolf-fian structures respond directly to testosterone, in the presence of 5a-reductase deficiency a male infant will

Labia Elongation
Fig. 34.24 A patient with enzymatic testicular failure believed to be due to 17-ketosteroid-reductase deficiency. Reproduced from [35] with permission.

have poor masculinization of external genitalia but the uterus, tubes and upper vagina will always be absent since MIS production will be normal. As a rule, the degree of genital masculinization is small or at worst moderate and most children are initially placed in the female role (Fig. 34.25). At puberty, however, the testes produce increased amounts of testosterone and there is greater vir-ilization, perhaps to an extent that the patient may wish to change the gender role from female to male. Penis size tends to remain barely adequate, however, and the female gender role will often be a better one for such patients. 5a-Reductase deficiency is a familial disorder due to an autosomal recessive gene, so that the evidence of other similar affected members in the family often assists the diagnosis. If there is no such history, precise diagnosis may be attempted by human chorionic gonadotrophin stimulation of the gonad for 3 days with measurement of testosterone at the beginning and end of each test.

Child Genitalia
Fig. 34.25 The external genitalia of a 10-year-old 46XY child with 5a-reductase deficiency. Reproduced from [35] with permission.

Androgen insensitivity. This syndrome is seen only in the newborn if the enzyme defect giving rise to it is partial. Presentation in later life is described in p. 344 When patients in the partial form present at birth as of ambiguous sex, the principles of management are those outlined in p. 342 for 5a-reductase deficiency.

True hermaphrodites

True hermaphrodites are rare in Europe and the USA, but in some countries, notably South Africa, they appear to be much more common. They present with varying degrees of sexual ambiguity (Fig. 34.26) - maleness predominates in some patients, femaleness in others. In the majority the uterus and vagina are present. The karyotype in most true hermaphrodites is that of an apparently normal female (46XX); this occurred in 58% of the 172 cases reviewed by VanNiekerk [30] and VanNiekerkand Retief [31]. The next most frequent karyotype was 46XX/XY which appeared in 13%, followed by 46XY (11%) and 46XY/47XXY (6%) with other mosaics accounting for 10%.

Distribution of the gonads is interesting in that the commonest combination is for an ovotestis to be present on one side and an ovary on the other, with a testis on

True Hermaphrodite Genitalia

Fig. 34.26 External genitalia in two true hermaphrodites. (a) Behind a considerable degree of clitoral enlargement it is possible to identify the urethra (not shown in the figure) and the vagina, which is illustrated. (b) An equivalent amount of clitoral enlargement, but the excessive fusion of labial folds has led to only a single perineal opening and it is not possible to identify the urethra and vagina separately.

Fig. 34.26 External genitalia in two true hermaphrodites. (a) Behind a considerable degree of clitoral enlargement it is possible to identify the urethra (not shown in the figure) and the vagina, which is illustrated. (b) An equivalent amount of clitoral enlargement, but the excessive fusion of labial folds has led to only a single perineal opening and it is not possible to identify the urethra and vagina separately.

one side and an ovary on the other being almost as frequent. Ovotestis maybe bilateral or combined with a testis. Diagnosis of true hermaphroditism can only be made by gonadal biopsy to demonstrate that ovarian and testicular tissue are both present. Sex of rearing is determined on the functional capability of the external genitalia, after which inappropriate organs are removed. In some cases it maybe possible to identify the ovarian and testicular portions of an ovotestis for certain and to remove only that part which is unwanted. If this is not possible both must be removed. If the patient then requires to be brought up in the gender role for which there is no appropriate gonadal tissue replacement hormone therapy at puberty will be required.

Patients presenting after infancy

Doubt about an individual's sex may arise for the first time some years after birth, generally around puberty, when some heterosexual feature may become evident or a pre-existing minor feature becomes more profound. Sometimes an older patient is seen whose intersexual state had been recognized at birth but not investigated. The investigation of such patients follows the general pattern outlined above and is different in only minor respects. If, for example, a patient is seen with late-onset CAH about the time of puberty, the likelihood of a salt-losing syndrome is minimal and investigation of this aspect need not be intensive. Management is different in one particular and very important respect. The patient, of necessity, will have lived in one or other sex role for some time and may have become so well adjusted that no attempts should be made to change this gender role. This aspect of the matter is best illustrated by 46XY patients with androgen insensitivity discussed next. Such patients have no masculinization of external genitalia at all and in most instances are well-developed, phenotypic females. To suggest that they should change to the male role because they have male karyotypes and intra-abdominal testes would be the height of folly.

Androgen insensitivity

The intersexual condition most likely to be evident for the first time at or after puberty, but which may sometimes be encountered earlier in childhood, is the condition of androgen insensitivity. This was formerly known as testic-ular feminization. It will be evident from the discussion in p. 337 that there are several mechanisms by which a patient who has testes may be feminized, so this term is no longer appropriate. Since the basis of the condition is insensitiv-ity to androgen, this term is a much more satisfactory one. The clinical picture of complete androgen insensitivity is remarkably uniform, although it now seems probable that two distinct mechanisms of insensitivity are present.

Intersex Genitalia Images
Fig. 34.27 The external genitalia of a patient with androgen insensitivity.

Most patients with androgen insensitivity present for the first time after puberty when, despite normal breast development, there is primary amenorrhoea. Further clinical examination will reveal absent or scanty pubic and axillary hair, a normal vulva (Fig. 34.27) but a short blind vagina with no cervix palpable. If a laparoscopy or laparotomy is performed, the uterus will be found to be absent and the testes are generally to be found within the abdomen in the inguinal canal or occasionally in the labia. Examination of the karyotype will disclose a normal 46XY male pattern.

Endocrine investigation reveals testosterone levels within the normal male range. Oestrogen levels are generally within the range where normal male and normal female values overlap. Luteinizing hormone values are generally elevated due, it is believed, to the insensitivity of the hypothalamus and the pituitary gland to testosterone. Follicle-stimulating hormone levels are more variable but are usually within the normal male range or slightly raised.

The aetiology of this condition may be due to complete absence of the gene for the androgen receptor or due to mutations or defects in the gene itself, leading to a receptor that cannot function. Thus the condition may be complete in those patients who have an absent androgen receptor whereby no interpretation of testosterone can occur at the cell membrane or in some cases, where the androgen receptor mutation is not complete, some receptivity may persist and, as a result of that, partial androgenization may occur. In these cases it is known as partial androgen insen-sitivity syndrome. Although most patients present some time after puberty because of primary amenorrhoea, the condition is occasionally seen in the child when a testis is found to occupy a hernial sac or when the presence of the

Androgen Insensitivity Syndrome

Fig. 34.28 The external appearance of a 46XY individual with androgen insensitivity. Note the excellent breast development and complete absence of pubic hair.

an appropriate explanation is given at the correct time. The clinician should take great care to ensure that the explanation given is correct and in appropriate language, so that the patient can understand the nature of her condition. It is important to emphasize that they are entirely female in spite of their chromosomal make up. Counselling of these women is often required and they should be referred to appropriate centres for management. None of these women should be left following gonadectomy without long-term follow-up and access to a specialist with an interest in this area.

Following gonadectomy, hormone replacement therapy with oestrogen should be given and this need not be cyclical since the uterus is absent. If the patient is seen for the first time in childhood and a diagnosis of complete androgen insensitivity is made, it can confidently be stated that feminization will occur at puberty and nothing need be done until that time. If, however, there are heterosexual features present it is very likely that masculinization will occur to some extent at puberty. This will have a profound psychological effect on the patient when she has been brought up in the female role. In these circumstances gonadectomy in childhood is wise, followed by induction of puberty with hormone replacement therapy at the appropriate time (Fig. 34.29). Surgery is seldom necessary in these women to elongate the vagina as it is usually functional, but should elongation be required graduated dilatation using Frank's procedure is the treatment of choice.

Fig. 34.28 The external appearance of a 46XY individual with androgen insensitivity. Note the excellent breast development and complete absence of pubic hair.

full blown syndrome in another sister leads to examination of a younger one and the male karyotype is revealed.

Management of the patient with androgen insensitivity depends upon the age at which the patient is seen. If seen after puberty when breast development is complete (Fig. 34.28), whether or not to remove the testes is considered. It seems likely that such patients have a raised potential for cancer, which is probably of the order of 5% during their lives [32]. Most would agree that this risk is sufficiently high to warrant gonadectomy and, therefore, this is advised. Discussion with the patient about the nature of her gonads will depend on the individual case. All patients should be informed of the nature of their condition when it is felt appropriate, but this depends on the maturity of the patient at the time of presentation. These women whose gonads are removed will question this procedure in the future. It is extremely important that

Other disorders encountered in the older patient

When the disorders discussed in pp. 337-334 as presenting at birth are seen in later life, certain differences in clinical features of management must be emphasized. The patient with CAH who has been reared as a female is unlikely to have sufficient masculinization of the external genitalia (Fig. 34.30) so reconstructive surgery is less commonly necessary. Secondary sexual development is apt to be poor or absent, but once the diagnosis has been made and the condition controlled by cortisol, spontaneous secondary sexual development should follow. If, however, a serious error has been made at birth because of an extreme degree of masculinization, the child being placed in the male role, management depends entirely upon the orientation of the patient to the male sex. If this is good and the phallus of a size judged suitable for intercourse, it may be wiser to allow the patient to continue in that gender role. It should be remembered, however, that if cortisol is used to inhibit the excess adrenocorticotrophic hormone activity, the apparent male will probably begin to menstruate so total hysterectomy and oophorectomy will be needed,

Intersex Genitalia Pictures
Fig. 34.29 External genitalia of a 7-year-old 46XY child with a degree of masculinization. Reproduced from [35] with permission.
Intersexuelles Genitale
Fig. 34.30 External genital appearance of a 46XX individual with CAH seen for the first time at the age of 16 years.

testosterone should be administered and, if appropriate, a testicular prosthesis inserted.

Patients with 5a-reductase deficiency placed in the female role but otherwise untreated are likely to have male type puberty and may wish to change sex. An extremely difficult decision must then be made since, as already indicated, the phallic size is seldom sufficient for coitus. Many patients wish to change their gender role nonetheless, and this important psychological aspect of management must be fully assessed in deciding what to do for the best.

Menstruation and/or breast development may occur at puberty in a true hermaphrodite who has been thought to be male. In such a case, the adjustment to masculinity is likely to be good so mastectomy and hysterectomy with the removal of the ovary will be indicated.

Two other conditions require brief mention, although they are unlikely to be seen by the gynaecologist. Pheno-typic males are rarely found to have a 46XX karyotype. Wachtel and Bard [33] refer to more than 80 cases reported in the literature. Those who have been appropriately examined have been shown to be H-Y antigen-positive and there is little clinical ambiguity in this group, the external genitalia being generally normal, although underdeveloped, and hypospadias has been mentioned several times.

Isolated deficiency of Müllerian inhibition has also been reported but such cases do not present clinically as examples of doubtful sex unless some unrelated surgical procedure reveals the surprising presence of Müllerian structures in an otherwise normal or near normal male.

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  • almaz negassi
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