Biology of DSDs: Ovotesticular DSD

Description

Ovotesticular disorder of sex development (known as OT-DSD) is a reproductive condition where the gonads develop elements of ovarian and testicular tissue in the same individual.

If you want to help improve medical research and psychological support for individuals with these conditions, you can donate to DSDFamilies (https://dsdfamilies.org/donate).

Sources

[1] Dayal, M. (2017). Ovotesticular disorder of sex development. Medscape.

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[3] ISNA. (2013). How common is intersex? Intersex Society of North America.

[4] Vilain, E. (2016). Ovotesticular disorder of sex development. Rare Diseases.

[5] Jones, R., Lopez, K. (2014). Chapter 5: Sexual differentiation. Human Reproductive Biology, 4th edition. Elsevier. 95.

[6] Witchel, S. (2017). Disorders of sex development. Best Practice and Research in Clinical Obstetrics and Gynaecology, 48, 90-102.

[7] Baetens, D., et al. (2017). NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular DSD.

[8] Ledig, S., et al. (2012). Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development.

[9] Matsui, F., et al. (2011). Long‐term outcome of ovotesticular disorder of sex development. International Journal of Urology.

[10] Scarpa, MG., et al. (2017). 46,XY ovotesticular disorders of sex development, a therapeutic challenge. Pediatric Reports, 9.

Transcript

Ovotesticular disorder of sex development (known as OT-DSD) is a reproductive condition where the gonads develop elements of ovarian and testicular tissue.

This can occur in three configurations: 1) an ovary on one side of the body and a testis on the other, 2) a mix of ovarian and testicular tissue on one side and a complete ovary or testis on the other, or 3) a mix of both tissues on both sides.

Molecular research has developed multiple causation theories, ranging from translocations of the SRY gene onto an X chromosome to duplications or inactivation of specific genes. Those with this condition do not have both sets of functioning reproductive anatomy, nor both sets of external genitalia, and therefore, cannot fulfill both reproductive roles.

Thus, affected patients develop one reproductive role, and are therefore male or female. Ovotesticular Disorder is one of the rarest DSDs, affecting approximately 1 and 83,000 newborns--a rate of around 0.001% of births. In fact, OT-DSD is so rare that only about 500 cases have been reported in the medical literature.

At conception, there are a variety of possible chromosome combinations. Of the 500 known cases of OT-DSD, 60% have a karyotype of 46,XX; 25% show various forms of mosaicism (a mix of karyotypes); 15% have a karyotype of 46,XY; and less than 1% have 46,XX/46,XY chimerism, which results from the fusion of two genetically unique embryos.

Let’s discuss the most common form: 46,XX OT-DSD.

Around the 8th week after conception, the 46,XX fetus undergoes gonadal differentiation. Because there is no Y chromosome with an active SRY gene, the bipotential gonads begin to develop into ovaries. And yet, despite the lack of an SRY gene to code for testicular development, the fetus begins to develop partial testicular tissue amidst the ovarian tissue. This testicular tissue results in the production of anti-Mullerian hormone, inhibiting the full development of the internal female anatomy. It is theorized that a rare mutation of the gene SOX9 is often a contributing factor to OT-DSD.

In typical circumstances, this gene helps encode the development of testicular cells after SRY gene activation. In 46,XX OT-DSD cases, SOX9 may be expressed without the SRY gene, leading to the growth of testicular tissue amidst the ovarian tissue.

The degree to which the XX fetus will develop the male reproductive, or Wolffian, structures versus the female reproductive, or Mullerian, structures depends on the amount of anti-Mullerian hormone released from developing testicular tissue. If there is no developing testicular tissue, no anti-Mullerian hormone is produced, and the female reproductive structures fully develop. Conversely, if there is any testicular tissue, anti-Mullerian hormone is produced from the developing testes, and female reproductive development is inhibited. The testosterone produced from the testicular tissue then stabilizes and develops the male reproductive structures.

Sex development in humans and other mammals is mutually antagonistic: if one reproductive system starts to develop, it inhibits the other. This is why individuals with Ovotesticular Disorder still develop towards one or the other reproductive role—the genetic and hormonal mechanisms do not allow both male and female systems to fully develop in the same individual. Thus, the inability for the complete development of both systems means that individuals with OT-DSD will have one main reproductive system and one secondary system with partial non-functioning elements. For example, an individual with 46,XY OT-DSD may have a male reproductive system with vestigial remnants of the Mullerian structure, such as a partial uterus. Or an individual with 46,XX OT-DSD may have a female reproductive system with vestigial remnants of the Wolffian structure, such as testicular tissue mixed with the ovarian tissue.

Although some cases of OT-DSD are diagnosed at birth, most cases are not diagnosed until puberty. The presence of both ovarian and testicular tissue in individuals with OT-DSD means that five factors of sex development must be considered to determine the individual’s sex: these include karyotype, gonadal tissue, hormone production / reception, internal reproductive structures, and external genitalia. Once analyzed, and the development path of the fetus is understood, a sex determination decision is made by specialists, which considers the best possible biological, psychological, and social outcome for the patient, including the chances of future fertility.

Fertility rates among individuals with OT-DSD are incredibly low. However, when such individuals are fertile, it is usually the ovarian tissue that is functional, not the underdeveloped testes. There is evidence that 50% of affected patients can ovulate, but the production of sperm is rare, with only three documented cases of males with OT-DSD fathering children.

There are important psychological issues to address if one is diagnosed. Like all other DSDs, it is critical that a diagnosis of Ovotesticular Disorder is not withheld from the patient. Doctors and parents of have a moral obligation to inform the patient of the diagnosis as soon as possible. The method and timing of providing information depends upon the patient’s age and cognitive development. If OT-DSD is diagnosed during adolescence, the parents and patient are usually told immediately. This allows the patient to be actively involved in the decision-making process for treatment. It is also critical that a patient with OT-DSD fully understands the details of their development path, what having the condition means, and how they can move forward. Understanding themselves and their bodies is critical for healthy psychological development and accurate medical treatment.

In conclusion, individuals with OT-DSD develop elements of ovarian and testicular tissue due to a variety of complex genetic and hormonal anomalies, many of which remain unknown. With loving support from parents and peers and medical professionals who care about the patient’s health and development, those with OT-DSD can live happy and healthy lives.

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