True Hermaphroditism

Gonad is the generic term used to identify the organs responsible for the production of sperm and egg cells, i.e., the testicles and the ovaries, respectively. These organs also produce sex hormones (testosterone, estrogen, progesterone). The ovaries or testicles develop in the embryo based on whether the person’s genetic make-up has a precise series of genes located on the X chromosome or on the Y chromosome. In other words, where the “pro-ovary” genes prevail, the ovary will develop; where the “pro-testis” genes prevail, the testis will develop. This is why, in most cases, the ovaries develop in the presence of a typically female 46,XX karyotype, and in the presence of a typically male 46,XY karyotype the testicles develop. Ovotesticular Variation of Sex Characteristic (VSC)/Difference of Sex Development (DSD) –once called True Hermaphroditism– is characterized by the presence, in a single individual, of both an ovary and a testicle, or gonads made up of both a functioning testicular component and a functioning ovarian component (ovotestis). While functioning egg cells can be found in the ovary, it is very rare for the testis to contain sperm, which in any case will not survive into adulthood. In some cases, the ovotestis can be associated with malformations of other organs in a syndromic condition (i.e., a condition in which there are alterations of several organs or systems). The expression of this alteration of gonadal development is extremely variable, and may be associated with atypical genitalia, i.e., which look neither typically male nor female. During puberty, the ovary and testis often produce sex steroids, resulting in the simultaneous development of varying degrees of typically male and female body characteristics. It is not uncommon for the menstrual cycle to start as well. In these cases, the gender identity of people with ovotestis is also extremely variable. It is a rare condition, with an incidence of less than 1/20,000.

Genetic traits
This atypical development of the gonads usually occurs in individuals with karyotype 46,XX, rarely in individuals with chimerism (i.e., the presence of partly male and partly female sex chromosomes in the different cells of the body) 46,XX/46,XY or 46,XX/47,XXY. In any case, there is a root “imbalance” between the genes that regulate ovary rather than testis development. Many of these genes have been identified, while there could be others which are still unknown.

Identification
Most cases of ovotestis are diagnosed at birth because of genital atypia. Hormone assays and a genetic investigation can be used to identify the presence, absence, or excess of genes involved in the development of the ovary and testicle.

Despite an accurate clinical overview, at birth and in the first years of life it is difficult to quantify the proportion of the two components –testicular and ovarian– even using invasive methods (such as tissue sampling of the gonad). It is equally difficult to predict the degree of feminization and/or masculinization of the body at puberty. In this form of VSC, the risk of gonadal tumours is not higher than average, except in those individuals who have the Y chromosome in their karyotype, in whom the risk is significant and calls for closer medical attention.

Medical options
Compared with other forms of VSCS/DSDs, in newborns with ovotestis the assignment of sex at birth is particularly complex, and must be done after careful evaluation by a multidisciplinary team. Some of the parameters that need to be taken into consideration are the estimated amount of testicular or ovarian tissue, the presence or absence of well-developed internal reproductive organs, and the appearance of the external genitalia. Of course, only the individual will be able to express their gender identity, which may or may not be congruent with the sex assigned at birth. Therefore, the most recent recommendations support the need to postpone partially reversible or irreversible interventions (including any surgery to remove all or part of the gonads) to a time when the person can express their informed consent on the issue.  Later on, it will be possible to opt for further treatments, in line with the person’s wishes and gender identity. Where possible, the removal of only the testicular or ovarian component can be considered an option, to guarantee the hormone production that induces and maintains the desired body characteristics. However, the production of male hormones by the testicular component is generally insufficient, and requires replacement therapy in most cases; in fact, no cases of effective sperm production are known. On the other hand, the ovaries can often support the production of female hormones and the menstrual cycle. Although cases of spontaneous pregnancies have been described in people with ovotestis, it is advisable to offer the person fertility preservation techniques (specifically oocyte cryopreservation). With so few existent cases, the possibility of deterioration of this function over time is hard to predict.

Bibliography 
Domenice S et al. 46,XY Differences of Sexual Development. Last Update: 2022 Aug 21. In: Endotext [Internet]
Lee PA et al. Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care. Hormone research in paediatrics. 2016;85:158–180
Syryn H, Van De Vijver K, Cools M. Ovotesticular Difference of Sex Development: Genetic Background, Histological Features, and Clinical Management. Hormone research in paediatrics. 2023;96(2):180-189 

Further links 
Orphanet. 46,XX ovotesticular difference of sex development