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ovotesticular DSD

Thursday 22 December 2005

Definition: Presence of both ovarian and testicular tissue in the same gonad (ovotesis) or in a contralateral gonad (ovary on one side, testis on another one). (Formerly: true hermaphroditism)

True hermaphroditism is defined as the presence of both testicular and ovarian tissue in a patient. Affected individuals may have either a female or a male phenotype with variable degrees of sexual ambiguity.

Because the wavy, cortical type stroma typically seen in the female gonad can be found in both female and male gonads and therefore is non-specific, follicular structures must be identified to classify gonadal tissue as ovarian and seminiferous tubules to classify the tissue as testicular.

In true hermaphrodites, the gonads may be ovary and testis separately or combined in an ovotestis.

True hermaphroditism is a rare condition both in North American and Europe, but one of the more common etiologies of male sexual ambiguity. It is, in contrast, common in Africa, especially in South Africa. Clusters in other geographic
locations are known.

Gonads in ovotesticular DSD

Ovotestis- The ovotestis is the most frequently encountered type of gonad in true hermaphroditism. In four-fifths of cases the ovarian and testicular tissues are arranged in an end-to-end fashion. The ovarian portion of an ovotestis has a convoluted surface while the testicular portion is smooth and glistening.

Frequently, a distinct line demarcates the two tissues. The firm nature of the palpable ovarian tissue and the soft texture of the testis are valuable clinical signs when evaluating the nature of a gonad in an infant with ambisexual external genitalia.

Ovary - An ovary, which preferentially develops on the left side, is the second most common gonad in true hermaphrodites. Every patient over 15 years of age in one series had either a corpus luteum or a corpus albicans. The testis, which is the gonad least often encountered, develops preferentially on the right.

The location of the gonad is influenced by the type and quantity of gonadal tissue present. Increasing amounts of ovarian tissue increase the probability that the gonad will be in an ovarian position. It is felt that this may be due to deficient
or absent MIS, which is needed for the initial descent of the testis to occur.

When a gonad with the macroscopic features of an ovary is situated in the inguinal canal or in the labioscrotal fold, the possibility of it being an ovotestis should be seriously considered.

Testis - The position of the testis is less constant. Most (63%) reside in the scrotum, 14% in the inguinal region, 1% in the internal inguinal ring, and 22% in a normal ovarian position.

The nature of the genital structure adjacent to a gonad in true hermaphroditism depends upon the nature of the gonad, which is in contrast to MGD in which a fallopian tube is often adjacent to the gonad, regardless of whether it is a testis or a streak.

In true hermaphroditism a fallopian tube is adjacent to an ovary and an epididymis or vas deferens is adjacent to a testis. Either a müllerian or wolffian structure, but not both, is adjacent to an ovotestis. MIS appears to be functional. Ninety five per cent of fallopian tubes adjacent to ovotestes have closed ostia.

Only 10% of uteri are normal; the other patients have absent uteri (13%), unicornuate uteri (10%), absent cervix (14%) or uterine hypoplasia (46%).

The most common karyotypes in true hermaphroditism are 46,XX (60%), 46,XY (12%), and mosaic (28%), usually 46,XX/46,XY, 46,XY/47,XXY, or least frequently 45,X/46,XY.

Patients with a ‘Y’ chromosome have a two- to three-fold increased frequency of having a testis as opposed to an ovotestis.

Nearly 75% of true hermaphrodites with an ovary and an ovotestis have a 46,XX karyotype.

As in other disorders of intersex, genetic aberrations appear to play a key role in the development of true hermaphroditism.

For example, chromosome Y-specifi c genes (e.g., SRY) have been detected in some 46,XX true hermaphrodites, suggesting one potential mechanism for the development of XX true hermaphroditism, similar to individuals with XX male syndrome.

In some series, SRY was undetected in the 46,XX patients, indicating that other mechanisms may also be important. But such data must be read with care as other case reports identify examples where the patient may be 46,XX and lack the SRY gene in usual cells examined (leukocytes).

Yet cells from the gonad itself demonstrate SRY. Mutations that mimic the SRY gene have been suggested as one possibility where the SRY gene was absent.

One explanation proposed for patients with an XY chromosome constitution is the possibility that the SRY gene, if present, may act at a time too late to stimulate the development of a testis, hence permitting ovarian tissue to develop.

The clinical presentations of true hermaphrodites vary to some extent depending upon their ages at the time of diagnosis. Until recently, the condition often went undetected until adolescence when phenotypic male patients were evaluated for gynecomastia, or for cysts in the testis and treated surgically, and phenotypic female patients were evaluated for amenorrhea or failure to develop secondary sex changes.

Thus, in one series, three-fourths of patients were raised as males and one-fourth as females. Many patients, however, menstruated and a few became pregnant. Phenotypic males may experience monthly hematuria because of menstruation into a persistent urogenital sinus.

With an increased awareness of intersex states, the condition is recognized more
often in infants because of ambiguous genitalia, usually in the form of a small phallus (enlarged clitoris or micropenis).

Like MGD, the scrotum may be asymmetric, with the larger, more normal-appearing hemiscrotum containing a testis. Among 160 patients the external genitalia were asymmetric in three-fourths (labioscrotal folds in 63% and hemiscrota in 13%).

On microscopic examination, the gonadal tissue often appears normal if the patient is young. In infants, the ovarian tissue contains numerous follicles, whereas the testicular parenchyma discloses normal-appearing seminiferous tubules with spermatogonia.

Patients in the reproductive years may have ovarian tissue with structures indicative of ovulation, e.g., follicles, corpora lutea, and corpora albicantia, but spermatogenesis is rare in the testicular portion.

The testicular portion of an ovotestis is usually abnormal with incomplete development, loss of germ cells, and tubular sclerosis. Scrotal testes in these patients show less severe changes, sometimes showing faulty spermatogenesis.

At times, distinction between true hermaphroditism and MGD can be diffi cult, if not impossible. In the newborn, asymmetric ambiguous genitalia may be observed in both conditions.

If a streak gonad from a patient with MGD is serially sectioned, a rare primordial follicle may be encountered in what otherwise appears to be a testis with well-developed seminiferous tubules.

If the gonad is not removed, over time the gonad will progress to a streak gonad. If the term ‘true hermaphroditism’ is restricted to those patients in whom the ovarian and testicular tissue are both apparent grossly and the definition of an ovary requires development of at least the antral stage of follicular development, it should usually be possible to segregate more clearly those individuals in whom the ovarian tissue may be functional.

Gonadal tumors occur in less than 3% of affected individuals, and in one large series with long-term follow-up, not at all. Germinoma is the most common type of tumor, but gonadoblastomas and a variety of other tumors have been
reported.

One case has been reported where the primitive sex-cord cellular elements adjacent to seminiferous tubules in a testis gave rise to cancer in the form of a juvenile granulosa cell tumor.

Imaging

The characteristic imaging feature of true hermaphrodism is the presence of an ovotestis or of one testis and one ovary in the same patient.

An ovotestis may be seen as a structure with a combination of testicular echo-texture and follicles.

Gonads with a normal ovarian and testicular appearance at US may prove to be ovotestes at histologic analysis.

The uterus is almost always present in ovotesticular DSD.

Synopsis

- ovotesticular DSD
- true hermaphroditism
- ambiguous external genitalia
- normal uterus
- gonadal tissue in the inguinal canal or iliac fossa
- no follicles seen in gonads
- normal vagina
- urethral female type or severe hypospadias

Biopsy of gonads

- immature testicular tissue
- ovotestis

Cytogenetics analysis

- 46,XY in both gonads

Etiology (Exemple)

- translocation of the SRY gene to a cryptic site on the X chromosome described in a few cases
- SOX9 germline mutations (Cameron et al, 1996; Beaulieu-Bergeron M et al, 2009).

See also

- disorders of sexual differentiation (intersex disorders)
- hermaphrodisms
- pseudohermaphrodisms

  • male pseudohermaphrodism
  • female pseudohermaphrodism

- intersex

  • XY intersex
  • XX intersex

References

- A case of true hermaphroditism reveals an unusual mechanism of twinning. Souter VL, Parisi MA, Nyholt DR, Kapur RP, Henders AK, Opheim KE, Gunther DF, Mitchell ME, Glass IA, Montgomery GW. Hum Genet. 2007 Apr;121(2):179-85. PMID: #17165045#

Portfolio

  • Ovotestis (Left) and testis (Right)