True Hermaphroditism

True hermaphroditism, or ovotesticular disorder of sexual development (ODSD), is characterized by the presence of an ovotesticular gonad that contains both ovarian and testicular elements. Individuals are usually born with ambiguous genitalia, but the diagnosis is rarely confirmed before puberty. The most common karyotype is 46,XX, and less often, 46,XY can be identified. Gonadal biopsy with histologic examination confirms the diagnosis. Management needs to consider the individual’s preferences wherever possible. Treatment options range from hormone replacement to surgical removal of part of the ovotestis gonad to improve fertility and to decrease the risk of malignancies.

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Overview

Epidemiology

  • Incidence of true hermaphroditism, or ovotesticular disorder of sexual development (ODSD): rare 
  • More common in Southern Africa than anywhere else in the world
  • Estimated frequency of the presence of ovotestis is 1 in 83,000 births.
  • Responsible for approximately 10% of cases of ambiguous genitalia
  • Only 20% of cases are diagnosed by 5 years of age.
  • Only 75% of cases are diagnosed by 20 years of age.

Genetics

  • Karyotype: typically normal
    • 46,XX (80% of cases)
    • 46,XY (approximately 10%)
    • 46,XX and XY mosaicism (< 1%)
  • Possible etiologies include:
    • Translocation of SRY (sex determining the region on the Y chromosome) to the X chromosome or any other non-sex chromosome → SRY needed for gonadal development and testis differentiation
    • NR5A1 gene mutation, which is important for gonadal development and testicular differentiation

Pathophysiology

Ovotesticular disorder of sexual development (ODSD) is characterized by the presence of gonads that contain ovarian tissue with primordial follicles and testicular tissue with seminiferous tubules in the same individual.

An affected person may have:

  • An ovotestis gonad:
    • Gonad in which testicular and ovarian elements are combined
    • Present in approximately 60% of patients with ODSD
    • May be bilateral (50%) or unilateral (20%) 
    • 50% intra-abdominal, 25% inguinal, and 25% labioscrotal 
    • Ovarian part of the ovotestis usually functional and responds to estrogens → resulting in excess estrogen → inhibiting spermatozoa development → rendering the testicular part of the ovotestis non-functional
  • A normal ovary on 1 side (typically the left side) and an ovotestis gonad on the other
  • A normal testis on 1 side (typically the right side) and an ovotestis gonad on the other
  • A normal testis on 1 side and a normal ovary on the other (30%)

The type of internal genitalia present depends on the adjacent gonad:

  • Fallopian tubes develop beside an ovary.
  • Vas deferens and epididymis develop beside a testicle.
  • In the presence of ovotestis, fallopian tubes develop in 60%–70% of cases.
  • A uterus can develop in the case of an ovotestis with a contralateral ovary.

Ovotestis gonads

A: Gross appearance of a bilobed ovotestis with a fallopian tube: The tan-yellow tissue in the center of the ovotestis revealed ovarian tissue and the white tissue at each pole showed testicular tissue on histologic examination.
B: Microscopic examination of the tan-yellow tissue showed typical ovarian stroma with primordial and primary follicles (arrow), and examination of the white tissue.
C: Image shows unremarkable testicular tissue with well-developed seminiferous tubules (arrow), with no definite spermatids.

Image: “Pathological analysis” by the Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, PR China. License: CC BY 2.0.

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Clinical Presentation

Female individuals (46,XX)

  • Infancy:
    • May have normal external genitalia
    • Labial fusion
    • Urogenital sinus (only 1 opening/exit for both tracts)
  • Adulthood:
    • Cervical atresia producing an obstructed genital tract:
      • Cryptomenorrhea (menstruation occurs but not visible due to obstruction of the outflow tract)
      • Hematometra (blood collects or retains in the uterus)
      • Endometriosis (tissue that normally lines the inside of the uterus is outside of the uterus)
    • Amenorrhea secondary to outflow obstruction or uterus did not form
    • Lower abdominal pain due to menstrual flow obstruction
    • Uterus may be abnormally structured.
    • Fertility possible but may have infertility as well

Male individuals (46,XY)

  • Infancy: 
    • May have normal external genitalia
    • Hypospadias (congenital defect in which the urethra opening is on the underside of the penis instead of the tip)
    • Cryptorchidism (undescended testes)
  • Adulthood:
    • Gynecomastia
    • Recurrent groin or scrotal pain
    • Testicular enlargement
    • Infertility (defective spermatogenesis)

Associated conditions

  • Emotional insecurities and social stigma
  • Malignant tumors of the gonads develop in approximately 6% of cases (typically gonadoblastoma or dysgerminoma)
  • Inguinal hernias 
  • Gonadal torsion

External genitalia in hermaphroditism
An individual with hermaphroditism with a well-developed phallus and right scrotal ovotestis gonad (a), and penoscrotal hypospadias (b)

Image: “Case of True Hermaphrodite” by Shilpa Sharma and Devendra K. Gupta. License: CC BY 4.0.

Diagnosis

  • History and physical examination
  • Measurement of baseline electrolytes and adrenal steroids → exclude congenital adrenal hyperplasia (potentially life threatening!)
  • Labs: follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH), testosterone levels:
    • Assessment of testicular function: Administration of a human chorionic gonadotropin (hCG) stimulation test is accompanied by a rise in the baseline testosterone levels.
    • Assessment of ovarian function: 
      • Measurement of inhibin A level
      • Administration of a human menopausal gonadotropins (hMG) stimulation test is accompanied by a rise in estrogen levels.
  • Imaging: ultrasound or magnetic resonance imaging (MRI) of the abdomen and pelvis to assess the presence and structure of gonads, uterus, and/or vagina
  • Karyotyping: should be done as soon as possible:
    • If 46,XX karyotype: Conditions that lead to the virilization of female newborns should be excluded.
    • If 46,XY karyotype: Causes of ambiguous genitalia should be excluded.
  • Gonadal biopsy: the gold standard to confirm the diagnosis of ODSD via histologic examination

Management

Medical management

  • Gender assignment typically still recommended during the neonatal period
  • Hormone replacement therapy to initiate puberty if delayed
  • Counseling services with expertise in disorders of sexual development

Surgical management

  • Removal of the abnormal gonad (testis, ovary, or ovotestis) is often indicated once the diagnosis is confirmed:
    • Removal of testicular tissue improves fertility for 46,XX individuals with functional ovarian tissue.
    • Removal of ovotestis gonad in individuals with a Y chromosome due to the risk of malignant transformation
  • If not removed, gonads with Y chromosomal material positioned intra-abdominally should be brought down to the scrotum and/or placed in a fixed position that can be easily monitored.
  • Surgical reconstruction of genitalia often delayed beyond infancy:
    • Chromosomal, behavioral, and hormonal factors are considered.
    • The child should be involved in the decision-making process!

Differential Diagnosis

  • Aromatase deficiency: a rare genetic condition with autosomal recessive inheritance that is characterized by congenital estrogen deprivation with increased levels of testosterone due to decreased levels of the aromatase enzyme. Aromatase deficiency is characterized by ambiguous genitalia in girls, virilization, changes in stature, and other clinical manifestations. Girls have female reproductive organs internally and boys have normal gonadal and external genitalia development. Treatment involves hormone replacement therapy.  
  • Congenital adrenal hyperplasia (CAH): consists of a group of autosomal recessive disorders that cause a deficiency of an enzyme used in cortisol and/or aldosterone synthesis, resulting in increased formation of androgens with virilization of the external female genitals. Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in 46,XX genotypic females. All forms of CAH are characterized by low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH), and adrenal hyperplasia. Surgical correction of ambiguous genitalia and lifelong glucocorticoid replacement therapy are needed. 
  • Mixed gonadal dysgenesis: a condition in which there is asymmetric gonadal development, with typically the right gonad developing into a testis and the left gonad being an ovary or streak gonad and corresponding ipsilateral development of respective internal and external reproductive anatomy. External genitalia may appear asymmetric. Mixed gonadal dysgenesis is associated with Turner syndrome mosaicism with an 45,X0/46,XY karyotype. Additional features of Turner syndrome may be present. Karyotyping and biopsy of gonadal tissue help make the diagnosis.

References

  1. Chan, Y., & Levitsky, L. L. (2020). Causes of differences of sex development. UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/causes-of-differences-of-sex-development
  2. Chan, Y., & Levitsky, L. L. (2020). Evaluation of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/evaluation-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
  3. Houk, C.P., Baskin, L.S., & Levitsky, L.L. (2020). Management of the infant with atypical genitalia (disorder of sex development). UpToDate. Retrieved January 4, 2021, from https://www.uptodate.com/contents/management-of-the-infant-with-atypical-genitalia-disorder-of-sex-development
  4. Mao, Y., Chen, S., Wang, R., Wang, X., Qin, D., & Tang, Y. (2017). Evaluation and treatment for ovotesticular disorder of sex development (OT-DSD) – Experience based on a Chinese series. BMC urology, 17(1), 21. https://doi.org/10.1186/s12894-017-0212-8

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