Gonadal Dominance and Internal Genitalia Phenotypes of Patients with Ovotesticular Disorders of Sex Development: Report of 22 Cases and Literature Review.

This study aimed to delineate internal genitalia phenotypes in patients with ovotesticular disorders of sex development (OT-DSD). Therefore, a cohort of 22 OT-DSD patients admitted to the Peking Union Medical College Hospital from March 1977 to August 2019 was analyzed retrospectively. The characteristics of karyotype, gonad type and location, and internal genital organs were reviewed and compared to 242 pooled cases from the Chinese literature. As a result, the most common karyotype was 46,XX (68.2% in 22 cases of our hospital, 60.8% in the domestic literature). The combination of gonads was separated (ovary-testis, 45.1%), unilateral (ovotestis-ovary, 17.4%; ovotestis-testis, 13.0%), and bilateral (ovotestis-ovotestis, 24.5%). All the cases in our hospital had a uterus on the side of the ovary or ovotestis. Among the 19 female patients, 5 had a hysterectomy due to genital tract obstruction, 9 had vaginal dysplasia, 3 had premature ovarian failure, and only 2 women gave birth to a child. In conclusion, OT-DSD is a typical model of unilateral gonadal determinism: the uterus is present on the side of the ovotestis and ovary and the internal genital organs predominantly exhibit female characteristics. However, combined reproductive tract malformation and ovarian function of premature failure are not uncommon.

XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: additional evidence for a common origin.

CONTEXT: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(-), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family. OBJECTIVE: We report on a case of SRY(-) 46,XX monozygotic twins with genital ambiguity. METHODS: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained. RESULTS: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified. CONCLUSIONS: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.

Multiparameter Investigation of a 46,XX/46,XY Tetragametic Chimeric Phenotypical Male Patient with Bilateral Scrotal Ovotestes and Ovulatory Activity.

We report on an adult male initially presenting with gynecomastia and a painless scrotal mass without additional genital anomalies. Hyperpigmentation of the skin following the Blaschko's lines was identified. He underwent gonadectomy because of suspected cancer. Histological analyses revealed an ovotestis with ovulatory activity confirmed by immunohistochemistry with multiple markers. Karyotyping of cultured peripheral blood lymphocytes and a buccal smear revealed a 46,XX/46,XY chimeric constitution with different percentages. Multiple molecular analyses as well as blood typing implied a tetragametic origin. After the unilateral gonadectomy, the patient developed recurrent painful cystic swellings of the remaining gonad. Because of the wish to preserve hormonal activity as well as future fertility, the patient underwent surgical resection of a cystic gonadal area. The removed tissue showed ovulation-related features in addition to both testicular and ovarian tissue, diagnosed as an ovotestis. Testosterone therapy was initiated to suppress the persistently elevated gonadotropins and thereby suppress ovarian activity. During treatment, the recurrent pain complaints and cystic swellings ceased, although gonadotropin levels were not fully suppressed. Based on these observations, the importance of a detailed genetic and pathological diagnosis and the clinical dilemmas including the pros and cons of personalized treatment with gonadal preservative surgery are discussed.

The Effect of the Testis on the Ovary: Structure-Function Relationships in a Neonate with a Unilateral Ovotestis (Ovotesticular Disorder of Sex Development)
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AIMS: To evaluate gonadal function in a newborn with suspected ovotesticular disorder of sex development (DSD). METHODS: Gonadal function was evaluated at baseline and after gonadotropin-releasing hormone agonist (GnRHag) stimulation testing. RESULTS: A full-term 46,XX neonate with genital ambiguity produced serum testosterone and anti-Müllerian hormone (AMH) levels appropriate for males within days, while serum estradiol remained prepubertal, both spontaneously and in response to GnRHag stimulation testing. Ovotesticular DSD was diagnosed at laparoscopy: the left gonad was an ovotestis and the right gonad an ovary arrested at the primordial follicle stage of development. Mosaicism for an isochromosome of the Y short arm in 6-18% of gonadal cells was demonstrated. After ovotestis removal at 3 weeks of age, serum AMH became low within a month, but the elevated testosterone was slow to resolve, apparently from ovarian androgenic hyperfunction coincident with ovarian estrogenic hyperfunction and an adult degree of ovarian development. Ovarian morphology and function gradually normalized as neonatal minipuberty waned. CONCLUSIONS: In a neonate with genital ambiguity due to ovotesticular DSD, testicular AMH and testosterone production respectively appear to account for the initial arrest of ovarian development and subsequent rapid hyperfunction of the contralateral ovary after ovotestis removal.
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46,XX/SRY-negative true hermaphrodite.

OBJECTIVE: To describe genetic evaluation and response to surgery and letrozole therapy of a 46,XX/SRY-negative true hermaphrodite. DESIGN: Case report. SETTING: University Medical Center. PATIENT(S): Nineteen-year-old male with penile hypospadias, micropenis, and crytorchidism at the time of birth. INTERVENTION(S): Unilateral gonadectomy, and contralateral conservative gonadal surgery, followed by therapy with letrozole. MAIN OUTCOME MEASURE(S): Histopathologic, genetic and hormonal studies. RESULT(S): Genetic analysis showed that the subject was 46,XX/SRY-negative. Gonadectomy of the left gonad was performed at 16 years. The gonad resected was an ovotestes. The patient's estradiol was high (492±25 pmol/L), whereas the testosterone was low (4.2±0.5 nmol/L). Nineteen months later, conservative gonadal surgery of the contralateral gonad was performed to resect ovarian tissue, and treatment with letrozole was started. During letrozole treatment, testosterone was significantly increased (8±0.7 nmol/L), but estradiol was not changed (323±118 pmol/L). After letrozole withdrawal, testosterone did not decreased significantly (6.9±0.4 nmol/L), estradiol showed an oscillating pattern and a gonadal ultrasound showed an ovoid structure, which appeared to correspond to a follicle. At that time, estradiol was elevated (393 pmol/L). CONCLUSION(S): We present the case of a 46,XX/SRY-negative phenotypic male with bilateral ovotestes. Conservative gonadal surgery should be performed only when all ovarian tissue can be resected. Our results suggest that letrozole is not an adequate treatment for 46,XX true hermaphrodite males with ovotestes.