INTRODUCTION	Section 2 of 10
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Background: Ovotestis refers to the histology of a gonad that contains both ovarian follicles and testicular tubular elements. Such gonads are found exclusively in people with true hermaphroditism. Ovotestes are usually compartmentalized, with connective tissue separating the ovarian components from the testicular components. However, on rare occasions, an intermixture of these elements may occur.

Pathophysiology: People with true hermaphroditism are individuals who have both ovarian and testicular tissue. This diagnostic nomenclature is applied regardless of the peripheral karyotype. The gonads may be ovotestis, or they may be separate, with an ovary on one side and a testis or ovotestis on the other. Additionally, testicular and ovarian tissue may develop on the same side of the pelvis as a separate ovary and testis.

Ovotestes are the most frequent gonad present in true hermaphroditism. This gonad may be anatomically located in an ovarian position, in the labioscrotal fold, in the inguinal canal, or at the internal inguinal ring.

Ovaries are the second most common gonad found in true hermaphroditism. They usually occupy the normal abdominal position, although they may occasionally be found at the internal inguinal ring. Interestingly, ovaries occur more commonly on the left side than the right. The reason for this predilection is unknown.

Testes are the least common gonad found in true hermaphroditism. Testes are usually found in the scrotum, although they may be found at any level along the path of embryonic descent from abdomen to scrotum and frequently present as inguinal hernias.

Internal duct development usually corresponds to the adjacent gonad so that wolffian duct structures are observed on the gonad side(s) containing functioning testicular tissue. Müllerian duct structures are observed on the gonad side not containing testicular tissue.

Ovaries and ovarian portions of ovotestes appear normal and demonstrate follicular growth with estradiol production. Approximately 50% of ovotestes show evidence of ovulation. The presence of estradiol in developing ovarian follicles usually inhibits spermatogonia development in adjacent or contralateral seminiferous tubules. Degeneration and hyalinization of the seminiferous tubules with poor germ cell development is frequently observed. Leydig cell hyperplasia may also occur. Spermatogenesis in testis and ovotestis is rare.

People with true hermaphroditism have ambiguous genitalia at birth. The majority of affected individuals have been reared as males. However, because of functioning normal ovarian tissue, most people with true hermaphroditism experience breast development at puberty, and 40% with a 46,XX peripheral karyotype menstruate.

Frequency:

• Internationally: True hermaphroditism is a rare condition and makes up less than 10% of all intersex cases. More than 400 cases have been reported worldwide.

Mortality/Morbidity: Aside from the physical and emotional consequences associated with genital ambiguity, patients with true hermaphroditism usually do not possess other developmental malformations. These individuals usually possess average intelligence and in general have a normal life expectancy.

• Neoplasia: Gonadal tumors with malignant potential occur in 2.6% of all cases of true hermaphroditism. Dysgerminomas, seminomas, gonadoblastomas, and yolk sac carcinomas have been reported. Benign tumors, including mucinous cystadenomas, benign teratomas, and Brenner tumors, also have been reported. One case report of a 47-year-old 46,XX/46,XY woman with a malignant phyllodes tumor in the right breast and an invasive lobular carcinoma in the left breast suggests a modified breast cancer risk similar to that observed in Klinefelter syndrome.

• Obstructed genital tract: Cryptomenorrhea, hematometra, and lower abdominal pain associated with endometriosis may occur in individuals with cervical atresia or other forms of müllerian duct anomalies.

• Hernias and cryptorchism: Because of malposition of the gonads, gonadal torsion, and associated duct structures, a variety of organs have been encountered within the inguinal canal, and inguinal hernias are a common occurrence. Complications associated with undescended or partial testicular descent also may be encountered.

Race: Geographic variation has been noted, with the highest incidence occurring in the black population of southern Africa.

Age: Despite the fact that most people with true hermaphroditism present with genital ambiguity, less than 20% are diagnosed before age 5 years. Seventy-five percent are diagnosed by age 20 years.

	CLINICAL	Section 3 of 10
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History: The presence of both testicular and ovarian tissue within one individual gives rise to varying degrees of ambisexual development.

• The most common presenting symptom is abnormal appearing external genitalia.

• Although some cases of true hermaphroditism are diagnosed in the newborn period, only 20% are diagnosed prior to age 5 years.

• Most people with true hermaphroditism are given a male sex assignment at birth but develop breasts at puberty or later.

• Approximately 40% of those individuals with a 46,XX peripheral karyotype menstruate or present signs of obstructed genital outflow tract at puberty.

Physical: A thorough physical examination is mandatory.

• Newborn period: When faced with the delivery of an infant with genital ambiguity, the physician must determine if the newborn is a virilized female, an undermasculinized male, or a rare person with true hermaphroditism. Physical examination should focus on the following considerations:

• Genetic stigmata: A general assessment of the infant's body habitus should be made, giving special attention to the presence of any genetic stigmata.

• Skin pigmentation: Skin pigmentation pattern should be noted as areolar, and scrotal hyperpigmentation may be a manifestation of high serum adrenocorticotropic hormone (ACTH) levels associated with congenital adrenal hyperplasia (CAH). Skin mottling and heterochromia of the iris may be present in the rare person with chimeric hermaphroditism.

• Genital examination: Determine the penile length and the location of the urethral opening, inspect the frenulum, determine the labioscrotal condition, document the number and location of perineal orifices, and identify the position of the gonads. One important clinical finding that may be present is a palpable gonad in one of the labioscrotal folds. If the newborn has true hermaphroditism, the palpated gonad is most likely an ovotestis or testis and usually is located on the right side. Discerning a difference between the ovarian (firmer) and testicular (softer) components of an ovotestis by palpation may be possible.

• Pubertal period: Most cases of true hermaphroditism are diagnosed in the pubertal period when the young male begins to experience feminization. Cyclic hematuria from an occult müllerian tract and late breast development are not uncommon. By puberty, most of the life-threatening conditions associated with genital ambiguity have been diagnosed previously, such as salt wasting adrenogenital syndrome in virilized females and pituitary insufficiency in undermasculinized males. Aside from the physical examination findings discussed in the newborn section, pay special attention to the following:

• Sexual hair distribution: Adrenarche is a normal part of both male and female puberty. The absence of pubic and axillary hair suggests androgen insensitivity. Alternatively, a feminine sexual hair pattern in a pubescent male should trigger further investigation.

• Uterus: In true hermaphroditism, the presence or absence of a uterus is variable. Anomalies are common when the uterus is present. Uterine hypoplasia and cervical atresia are the most frequent uterine anomalies noted.

• Vagina: The vagina, when present, is normal in only 9% of cases of true hermaphroditism. The vagina generally shares the urogenital sinus with the urethra as the common external orifice.

• Phallus: The phallus, if present, is almost always in chordee. Phallic length varies greatly. The urethra most commonly opens as a urogenital sinus. Hypospadias, often associated with bifid scrotal folds, is the most common anomaly of the external genitalia encountered in true hermaphroditism.

• Labia/scrotum: The presence or absence of labioscrotal fusion is variable. In one review, 7% of people with true hermaphroditism had normal labia majora, 13% had hemiscrotum, 17% had a normal scrotum, and 63% had labioscrotal folds. Gonads were found frequently on the right side of the labioscrotal folds.

• Breast development: Thelarche occurs in over 90% of people with true hermaphroditism.

Causes: Normal sexual differentiation is based on genetic sex (XX or XY), which is established at conception. Determinants controlled by the established genetic sex promote development of the undifferentiated gonad to move toward becoming either a testis or an ovary. Once differentiated, the testis directs internal and external male genital development. Female internal and external genital development occurs in the absence of a normal embryonic testis.

Testicular differentiation requires a highly regulated expression of a series of genes. To better define the role of specific genes in testicular development, investigators have used several techniques, including gene cloning, mutation analysis, transgenic mice experiments, and gene deletion studies.

Differentiation of the indifferent gonad into a testis is dependent on a 35-kilobase (kb) gene determinant located on the distal short arm of the Y chromosome. This region is known as SRY (sex determining region of the Y chromosome) and is highly conserved in a wide range of mammals. SRY codes for a transcription factor that acts in the somatic cells of the genital ridge. The transient expression of this gene triggers a cascade of events that leads to the development of testicular Sertoli and Leydig cells. SRY expression directs testicular morphogenesis, characterized by the production of MIS (müllerian inhibiting substance), and testosterone.

Surprisingly, most people with XX true hermaphroditism lack SRY despite the presence of testicular differentiation. This suggests that this gene codes for a product that reacts with other genes on Y, X, and/or autosomes to complete testicular differentiation. Recently, an inactivating mutation in an autosomal gene, SRY-related high mobility box 9 gene (SOX9), was shown to be associated with autosomal sex reversal and camptomelic dysplasia.

The DAZ (deleted in azoospermia) gene family consists of a cluster of genes on the Y chromosome, which give rise to proteins that influence male germ cell differentiation. In humans, deletion of any 1 of 3 DAZ regions (ie, AZFa, AZFb, AZFc) disrupts spermatogenesis. Today, deletion of the AZFc region of the Y chromosome is the most frequent molecularly defined cause of spermatogenic failure.

Ovarian differentiation appears to rely on a mechanism that is triggered in the absence of the testicular determinant. In humans, a complete 46,XX chromosomal complement is necessary for normal ovarian differentiation. Autosomal genes appear to be involved in ovarian maintenance. Properties of the X-linked gene DAX1 (DSS-AHC critical region on X chromosome, gene 1) suggest that this gene is important in ovarian determination. Investigators have postulated that the DAX1 gene product may actually be antagonistic to the action of SRY.

In humans, genetic sex has traditionally been evaluated through establishing the karyotype of peripheral lymphocytes. However, the peripheral karyotypes of true hermaphroditism show marked variation. Approximately 60% of people with true hermaphroditism are 46,XX; 15% are 46,XY; and 25% show various forms of mosaicism. Less than 1% show 46,XX/46,XY chimerism or the existence of 2 or more cell lines, each of which has a different genetic origin. True hermaphroditism, therefore, is a genetically heterogeneous condition. Phenotypic, gonadal, and molecular studies have led to several causation theories:

• Genetic chimerism: Less than 1% of people with true hermaphroditism have 46,XX/46,XY chimerism or the existence of 2 or more cell lines, each of which has a different genetic origin. Chimerism can result from several events. Dispermic chimerism (double fertilization) can arise from fertilization of the secondary oocyte and first polar body, fertilization of the ovum and the first polar body, or fertilization of the ovum and the second polar body. Chimerism also can arise as an exchange of cells between dizygous twins of different sex (ie, fusion of 2 embryos).

• Nondisjunction: Postzygotic mitotic errors arising from anaphase lag may occur in 45,X/46,XY or 45,X/46,XY/47,XYY mosaicism. Note, however, that most 45,X/46,XY individuals have mixed gonadal dysgenesis as opposed to true hermaphroditism.

• X-Y translocation: Paternal meiotic exchange between the pseudoautosomal regions of chromosomes X and Y could provide a mechanism for the translocation Y-chromosomal sequences, including SRY onto an X chromosome in some forms of 46,XX testicular differentiation.

• Mutation: A mutation of a gene on the X chromosome or alternatively on an autosome that allows testis determination without the SRY gene could explain some forms of 46,XX testicular differentiation.

• Occult mosaicism: Although most people with true hermaphroditism have a 46,XX peripheral karyotype, recent case reports have documented the detection of occult mosaicism in the gonads of some of these individuals through molecular techniques. Polymerase chain reaction (PCR) has identified SRY-positive tissue in gonads from several, but not all, people with 46,XX true hermaphroditism.

	DIFFERENTIALS	Section 4 of 10
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Other Problems to be Considered:

Adrenogenital syndrome
Androgen insensitivity
Enzymatic defects in testosterone synthesis
Gonadotropin deficiency
Maternal exposure to high levels of androgen
Multiple congenital anomalies
Structural testicular abnormalities