Background

Ovotestis refers to the histology of a gonad that contains both ovarian follicles and testicular tubular elements. Such gonads are found exclusively in people with ovotesticular disorder of sexual development (OT-DSD), formerly known as true hermaphroditism. Those diagnosed with this rare condition represent a small fraction of patients within the diagnostic category of the disorders of sexual development (DSD), formerly known as intersex. Within the spectrum of DSD, there are varying degrees of discordant genitalia to sex chromosomes. A diagnosis of OT-DSD is based solely on the presence of ovarian and testicular tissue in the gonad and not on the characteristics of the internal and external genitalia, even if ambiguous.

Pathophysiology

People with ovotesticular disorder of sexual development are individuals who have both ovarian and testicular tissue. This diagnostic nomenclature is applied regardless of the peripheral karyotype. The gonads may be ovotestis, or they may be a combination of an ovary on one side and a testis or ovotestis on the other. Ovotestes are usually compartmentalized, with connective tissue separating the ovarian components from the testicular components. However, on rare occasions, an intermixture of these elements may occur. Additionally, testicular and ovarian tissue may develop on the same side of the pelvis as a separate ovary and testis.

Ovotestes are the most frequent gonad present (60%), followed by the ovary and then the testis (9%). The ovotestis tends to be anatomically located in an ovarian position, in the labioscrotal fold, in the inguinal canal, or at the internal inguinal ring. Ovaries, when found, can occupy the normal abdominal position, although they may occasionally be found at the internal inguinal ring. Interestingly, ovaries occur more commonly on the left side than the right. The reason for this predilection is unknown. Testes are usually found in the scrotum, although they can be found at any level along the path of embryonic descent from abdomen to scrotum, frequently presenting as inguinal hernias.

Ovaries and ovarian portions of ovotestes appear normal and demonstrate follicular growth with estradiol production. Approximately 50% of ovotestes show evidence of ovulation. The presence of estradiol in developing ovarian follicles usually inhibits spermatogonia development in adjacent or contralateral seminiferous tubules. Degeneration and hyalinization of the seminiferous tubules with poor germ cell development is frequently observed. In all documented biopsied cases, there is a significant decline in germ cell development and an increase in tubular sclerosis by puberty. Leydig cell hyperplasia may also occur with aging. Spermatogenesis in testis and ovotestis is rare.

Internal duct development usually corresponds to the adjacent gonad. Many patients with ovotesticular disorder of sexual development have a uterus. Müllerian duct structures typically develop on the gonad side(s) not containing testicular tissue. Wolffian duct structures tend to be observed on the gonad side(s) containing functioning testicular tissue.

People with OT-DSD are born with ambiguous genitalia. Most affected individuals are reared as males due to the size of the phallus. Most have varying degrees of labioscrotal fusion and/or hypospadias. However, because of functioning normal ovarian tissue, most people experience breast development at puberty, and approximately two-thirds of those with a 46,XX peripheral karyotype menstruate.^[1]

Frequency

International

Ovotesticular disorder of sexual development is a rare condition. Most cases have a sporadic distribution, although there are a few documented cases of familial recurrence. Genital ambiguity occurs in 1 in 4,500 births, and ovotesticular disorder of sexual development occurs in fewer than 10% of all disorders of sexual development. More than 400 cases have been reported worldwide.^[2]

Mortality/Morbidity

Aside from the physical and emotional consequences associated with genital ambiguity, patients with true hermaphroditism usually do not possess other developmental malformations. These individuals usually possess average intelligence and in general have a normal life expectancy.

Neoplasia
- Gonadal tumors with malignant potential occur in 2.6% of all cases of ovotesticular disorder of sexual development. The testis or testicular component of an ovotestis is likely to be dysgenetic; dysgerminomas, seminomas, gonadoblastomas, and yolk sac carcinomas have all been reported.
- Those with the 46,XY karyotype are at the greatest risk of developing a gonadal malignancy. Benign tumors, including mucinous cystadenomas, benign teratomas, and Brenner tumors, have also been reported.
- If a testis is located in the scrotum, maintaining rigorous follow-up with sonography and/or pelvic MRI is prudent, and a biopsy after puberty is indicated to detect early premalignant or malignant transformation.
- One case report of a 47-year-old 46,XX/46,XY woman with a malignant phyllodes tumor in the right breast and an invasive lobular carcinoma in the left breast suggests a modified breast cancer risk similar to that observed in Klinefelter syndrome.^[3]
- Another case reported an invasive squamous cell carcinoma of the vagina, serving as a reminder that malignant changes can occur in residual müllerian tissue.^[4]
Obstructed genital tract: Cryptomenorrhea, hematometra, and lower abdominal pain associated with endometriosis may occur in individuals with cervical atresia or other forms of müllerian duct anomalies.
Hernias and cryptorchism: Because of malposition of the gonads, gonadal torsion, and associated duct structures, a variety of organs have been encountered within the inguinal canal, and inguinal hernias are a common occurrence. Complications associated with undescended or partial testicular descent also may be encountered.

Race

Geographic variation has been noted, with the highest incidence occurring in the black population of southern Africa.

Age

Despite the fact that most people with true hermaphroditism present with genital ambiguity, less than 20% are diagnosed before age 5 years. Seventy-five percent are diagnosed by age 20 years.

Clinical Presentation

Dutta D, Shivaprasad KS, Das RN, Ghosh S, Chatterjee U, Chowdhury S, et al. Ovotesticular disorder of sexual development due to 47,XYY/46,XY/45,X mixed gonadal dysgenesis in a phenotypic male presenting as cyclical haematuria: clinical presentation and assessment of long-term outcomes. Andrologia. 2014 Mar. 46(2):191-3. [Medline].
Josso N, Audi L, Shaw G. Regional variations in the management of testicular or ovotesticular disorders of sex development. Sex Dev. 2011. 5(5):225-34. [Medline].
Kasami M, Yoshida M, Isogaki J, et al. Bilateral breast tumors, malignant phyllodes tumor and invasive lobular carcinoma in a 46,XX/46,XY mosaic female with family history of breast cancer. Pathol Int. 1997 Feb-Mar. 47(2-3):147-54. [Medline].
Chaudhury P, Majmudar B, Moller KA. Invasive squamous cell carcinoma of the vagina in the setting of true hermaphroditism. Gynecol Oncol. 2006 Jan. 100(1):210-2. [Medline].
Selver Eklioglu B, Atabek ME, Akyurek N, Ari Yuca S, Piskin M. The 46XX Ovotesticular Disorders of Sexual Development with Dismorphic Features. J Pediatr Adolesc Gynecol. 2015 Dec. 28 (6):e157-9. [Medline].
Ouhilal S, Turco J, Nangia A, et al. True hermaphroditism presenting as bilateral gynecomastia in an adolescent phenotypic male. Fertil Steril. 2005 Apr. 83(4):1041. [Medline].
Sanlaville D, Vialard F, Thepot F, et al. Functional disomy of Xp including duplication of DAX1 gene with sex reversal due to t(X;Y)(p21.2;p11.3). Am J Med Genet A. 2004 Jul 30. 128(3):325-30. [Medline].
Chen CP, Chern SR, Sheu JC, et al. Prenatal diagnosis, sonographic findings and molecular genetic analysis of a 46,XX/46,XY true hermaphrodite chimera. Prenat Diagn. 2005 Jun. 25(6):502-6. [Medline].
Verkauskas G, Jaubert F, Lortat-Jacob S, Malan V, Thibaud E, Nihoul-Fékété C. The long-term followup of 33 cases of true hermaphroditism: a 40-year experience with conservative gonadal surgery. J Urol. 2007 Feb. 177(2):726-31; discussion 731. [Medline].
Sugawara N, Tokunaga Y, Maeda M, et al. A successful pregnancy outcome using frozen testicular sperm from a chimeric infertile male with a 46, XX/46, XY karyotype: case report. Hum Reprod. 2005 Jan. 20(1):147-8. [Medline].
Schultz BA, Roberts S, Rodgers A, Ataya K. Pregnancy in true hermaphrodites and all male offspring to date. Obstet Gynecol. 2009 Feb. 113(2 Pt 2):534-6. [Medline].
Kousta E, Papathanasiou A, Skordis N. Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals. Hormones (Athens). 2010 Jul-Sep. 9(3):218-131. [Medline].
Sircili MH, Denes FT, Costa EM, Machado MG, Inacio M, Silva RB, et al. Long-term followup of a large cohort of patients with ovotesticular disorder of sex development. J Urol. 2014 May. 191(5 Suppl):1532-6. [Medline].
Matsui F, Shimada K, Matsumoto F, Itesako T, Nara K, Ida S, et al. Long-term outcome of ovotesticular disorder of sex development: a single center experience. Int J Urol. 2011 Mar. 18(3):231-6. [Medline].
Abbas NE, Toublanc JE, Boucekkine C, et al. A possible common origin of "Y-negative" human XX males and XX true hermaphrodites. Hum Genet. 1990 Mar. 84(4):356-60. [Medline].
Ablett MJ, Masters J, Elliott ST. Case report: A rapidly expanding testicular mass due to a ruptured ovarian follicle. Br J Radiol. 1996 Apr. 69(820):366-7. [Medline].
al Jurayyan NA, Patel PJ, al Herbish AS, et al. Ambiguous genitalia: comparative role of pelvic ultrasonography and genitography. Ann Trop Paediatr. 1995 Sep. 15(3):203-7. [Medline].
Almaguer MC, Saenger P, Linder BL. Phallic growth after hCG. A clinical index of androgen responsiveness. Clin Pediatr (Phila). 1993 Jun. 32(6):329-33. [Medline].
Bercovici JP, Nahoul K, Maudelonde T, et al. Plasma androgens during the luteal phase in a case of true hermaphroditism with bilateral ovotestis. J Steroid Biochem. 1985 May. 22(5):631-4. [Medline].
Bergmann M, Schleicher G, Bocker R, Nieschlag E. True hermaphroditism with bilateral ovotestis: a case report. Int J Androl. 1989 Apr. 12(2):139-47. [Medline].
Berkovitz GD, Fechner PY, Marcantonio SM, et al. The role of the sex determining region of the X chromosome (SRY) in the etiology of 46XX true hermaphroditism. Hum Genet. 1992. 88:411.
Berkovitz GD, Fechner PY, Zacur HW, et al. Clinical and pathologic spectrum of 46,XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine (Baltimore). 1991 Nov. 70(6):375-83. [Medline].
Bernard-Gallon DJ, Dechelotte P, Vissac C, et al. BRCA1 and BRCA2 protein expressions in an ovotestis of a 46, XX true hermaphrodite. Breast Cancer Res. 2001. 3(1):61-5. [Medline].
Burgner DP, Kinmond S, Wallace AM, et al. Male pseudohermaphroditism secondary to panhypopituitarism. Arch Dis Child. - Kinmond S. 75(2):153-5. [Medline].
Damario MA, Rock JA. Diagnostic Approach to Ambiguous Genitalia. Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive Endocrinology, Surgery, and Technology. Philadelphia, Pa: Lippincott Williams & Wilkins; 1996. 890-914.
Damiani D, Fellous M, McElreavey K, et al. True hermaphroditism: clinical aspects and molecular studies in 16 cases. Eur J Endocrinol. 1997 Feb. 136(2):201-4. [Medline].
Decker JP, Lerner HJ, Schwartz I. Breast carcinoma in a 46, XX true hermaphrodite. Cancer. 1982 Apr 1. 49(7):1481-4. [Medline].
Diamond M, Sigmundson HK. Management of intersexuality. Guidelines for dealing with persons with ambiguous genitalia. Arch Pediatr Adolesc Med. 1997 Oct. 151(10):1046-50. [Medline].
Eberenz W, Rosenberg HK, Moshang T, et al. True hermaphroditism: sonographic demonstration of ovotestes. Radiology. 1991 May. 179(2):429-31. [Medline].
Farag TI, Al-Awadi SA, Tippett P, et al. Al-Awadi SA. J Med Genet. 1987 Dec. 24(12):784-6. [Medline].
Fechner PY. The role of SRY in mammalian sex determination. Acta Paediatr Jpn. 1996 Aug. 38(4):380-9. [Medline].
Giltay JC, Brunt T, Beemer FA, et al. Polymorphic detection of a parthenogenetic maternal and double paternal contribution to a 46,XX/46,XY hermaphrodite. Am J Hum Genet. 1998 Apr. 62(4):937-40. [Medline].
Guaschino S, Stola E, Spinillo A, et al. True hermaphroditism: diagnosis and surgical treatment. Clin Exp Obstet Gynecol. 1988. 15(3):74-9. [Medline].
Hadjiathanasiou CG, Brauner R, Lortat-Jacob S, et al. True hermaphroditism: genetic variants and clinical management. J Pediatr. 1994 Nov. 125(5 Pt 1):738-44. [Medline].
Harbison MD, Magid ML, Josso N, et al. Anti-Mullerian hormone in three intersex conditions. Ann Genet. 1991. 34(3-4):226-32. [Medline].
Hasty LA, Rock JA. True hermaphroditism. Adashi EY, Rock JA, Rosenwaks Z, eds. Reproductive Endocrinology, Surgery, and Technology. Philadelphia, Pa: Lippincott Williams & Wilkins; 1996. 978-988.
Hayashi T, Kageyama Y, Ishizaka K, et al. True hermaphroditism associated with microphthalmia. Eur J Endocrinol. 1999 Jan. 140(1):62-5. [Medline].
Heyns CF, de Kock ML, Deale CJ. A true hermaphrodite with some unusual features. Urology. 1990 Mar. 35(3):247-9. [Medline].
Inoue H, Nomura M, Yanase T, et al. A rare case of 46,XX true hermaphroditism with hidden mosaicism with sex-determining region Y chromosome-bearing cells in the gonads. Intern Med. 1998 May. 37(5):467-71. [Medline].
Iyer AK, McCabe ER. Molecular mechanisms of DAX1 action. Mol Genet Metab. 2004 Sep-Oct. 83(1-2):60-73. [Medline].
Jakubowski L, Jeziorowska A, Constantinou M, et al. Xp;Yp translocation inherited from the father in an SRY, RBM, and TSPY positive true hermaphrodite with oligozoospermia. J Med Genet. 2000 Oct. 37(10):E28. [Medline].
Jarrah N, El-Shanti H, Khier A, et al. Familial disorder of sex determination in seven individuals from three related sibships. Eur J Pediatr. 2000 Dec. 159(12):912-8. [Medline].
Jimenez AL, Kofman-Alfaro S, Berumen J, et al. Partially deleted SRY gene confined to testicular tissue in a 46,XX true hermaphrodite without SRY in leukocytic DNA. Am J Med Genet. 2000 Aug 28. 93(5):417-20. [Medline].
Kojima Y, Hayashi Y, Asai N, et al. Detection of the sex-determining region of the Y chromosome in 46,XX true hermaphroditism. Urol Int. 1998 Aug. 60(4):235-8. [Medline].
Koopman P. The molecular biology of SRY and its role in sex determination in mammals. Reprod Fertil Dev. 1995. 7(4):713-22. [Medline].
Krob G, Braun A, Kuhnle U. True hermaphroditism: geographical distribution, clinical findings, chromosomes and gonadal histology. Eur J Pediatr. 1994 Jan. 153(1):2-10. [Medline].
Krstic Z, Perovic S, Radmanovic S, et al. Surgical treatment of intersex disorders. J Pediatr Surg. 1995 Sep. 30(9):1273-81. [Medline].
Kucheria K, Mohapatra I, Taneja N, et al. Genetic heterogeneity in true hermaphrodites. A report of two cases. J Reprod Med. 1994 Jul. 39(7):550-2. [Medline].
Kutteh WH, Santos-Ramos R, Ermel LD. Accuracy of ultrasonic detection of the uterus in normal newborn infants: implications for infants with ambiguous genitalia. Ultrasound Obstet Gynecol. 1995 Feb. 5(2):109-13. [Medline].
Letterie GS, Page DC. Dysgerminoma and gonadal dysgenesis in a 46,XX female with no evidence of Y chromosomal DNA. Gynecol Oncol. 1995 Jun. 57(3):423-5. [Medline].
Lim DJ, Mullins DL, Stevens PS. Crossed ectopia of ovotestis in a case of true hermaphroditism. J Pediatr Surg. 1996 Oct. 31(10):1440-2. [Medline].
Lobaccaro JM, Lumbroso S, Belon C, et al. [Genes of the Y chromosome and Turner syndrome]. Ann Endocrinol (Paris). 1994. 54(5):323-9. [Medline].
Lobe TE, Woodall DL, Richards GE, et al. The complications of surgery for intersex: changing patterns over two decades. J Pediatr Surg. 1987 Jul. 22(7):651-2. [Medline].
Luks FI, Hansbrough F, Klotz DH Jr, et al. Early gender assignment in true hermaphroditism. J Pediatr Surg. 1988 Dec. 23(12):1122-6. [Medline].
Maciel-Guerra AT, de Mello MP, Coeli FB, Ribeiro ML, Miranda ML, Marques-de-Faria AP, et al. XX Maleness and XX true hermaphroditism in SRY-negative monozygotic twins: additional evidence for a common origin. J Clin Endocrinol Metab. 2008 Feb. 93(2):339-43. [Medline].
MacLean HE, Warne GL, Zajac JD. Intersex disorders: shedding light on male sexual differentiation beyond SRY. Clin Endocrinol (Oxf). 1997 Jan. 46(1):101-8. [Medline].
Malavaud B, Mazerolles C, Bieth E, et al. Pure seminoma in a male phenotype 46,XX true hermaphrodite. J Urol. 2000 Jul. 164(1):125-6. [Medline].
Margarit E, Coll MD, Oliva R, et al. SRY gene transferred to the long arm of the X chromosome in a Y-positive XX true hermaphrodite. Am J Med Genet. 2000 Jan 3. 90(1):25-8. [Medline].
McGillivray BC. The newborn with ambiguous genitalia. Semin Perinatol. 1992 Dec. 16(6):365-8. [Medline].
Minowada S, Hara M, Shinohara M, et al. Investigation of genetic markers in a true hermaphrodite with chi 46,XX/46,XY. Hum Genet. 1982. 60(4):376-8. [Medline].
Morohashi K. The ontogenesis of the steroidogenic tissues. Genes Cells. 1997 Feb. 2(2):95-106. [Medline].
Mulhall JP, Reijo R, Alagappan R, et al. Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis: fertilization, normal embryonic development and pregnancy occur when retrieved testicular spermatozoa are used for intracytoplasmic sperm injection. Hum Reprod. 1997 Mar. 12(3):503-8. [Medline].
Nihoul-Fékété C, Thibaud E, Lortat-Jacob S, Josso N. Long-term surgical results and patient satisfaction with male pseudohermaphroditism or true hermaphroditism: a cohort of 63 patients. J Urol. 2006 May. 175(5):1878-84. [Medline].
Page J. The newborn with ambiguous genitalia. Neonatal Netw. 1994 Aug. 13(5):15-21. [Medline].
Quigley MM, Vaughn TC, Hammond CB, Haney AF. Production of testosterone and estrogen in vitro by gonadal tissue from a 46,XY true hermaphrodite with gonadal failure and gonadoblastoma. Obstet Gynecol. 1981 Aug. 58(2):253-9. [Medline].
Ramkissoon Y, Goodfellow P. Early steps in mammalian sex determination. Curr Opin Genet Dev. 1996 Jun. 6(3):316-21. [Medline].
Reijo R, Alagappan RK, Patrizio P, Page DC. Severe oligozoospermia resulting from deletions of azoospermia factor gene on Y chromosome. Lancet. 1996 May 11. 347(9011):1290-3. [Medline].
Roth LM, Cleary RE, Hokum WL. Ultrastructure of an ovotestis in a case of true hermaphroditism. Obstet Gynecol. 1976 Nov. 48(5):619-24. [Medline].
Schiebel K, Winkelmann M, Mertz A, et al. Abnormal XY interchange between a novel isolated protein kinase gene, PRKY, and its homologue, PRKX, accounts for one third of all (Y+)XX males and (Y-)XY females. Hum Mol Genet. 1997 Oct. 6(11):1985-9. [Medline].
Schwartz S, Depinet TW, Leana-Cox J, et al. Sex chromosome markers: characterization using fluorescence in situ hybridization and review of the literature. Am J Med Genet. 1997 Jul 11. 71(1):1-7. [Medline].
Secaf E, Hricak H, Gooding CA, Ho VW, Gorczyca DP, Ringertz H, et al. Role of MRI in the evaluation of ambiguous genitalia. Pediatr Radiol. 1994. 24(4):231-5. [Medline].
Sloan MS, Rosenberg SM, Brown JA. Primary amenorrhea and virilization in a true hermaphrodite with a rare dicentric Y chromosome. Obstet Gynecol. 1984 Sep. 64(3 Suppl):64S-67S. [Medline].
Sugimoto S, Igarashi T, Tada M, et al. [Two cases of true hermaphrodite: the usefulness of laparoscopic gonadectomy in childhood. A case report]. Nippon Hinyokika Gakkai Zasshi. 1998 Dec. 89(12):971-4. [Medline].
Talerman A, Verp MS, Senekjian E, et al. True hermaphrodite with bilateral ovotestes, bilateral gonadoblastomas and dysgerminomas, 46,XX/46,XY karyotype, and a successful pregnancy. Cancer. 1990 Dec 15. 66(12):2668-72. [Medline].
Tanaka Y, Fujiwara K, Yamauchi H, et al. Pregnancy in a woman with a Y chromosome after removal of an ovarian dysgerminoma. Gynecol Oncol. 2000 Dec. 79(3):519-21. [Medline].
Teele RL, Share JC. Ultrasonography of the female pelvis in childhood and adolescence. Radiol Clin North Am. 1992 Jul. 30(4):743-58. [Medline].
Toublanc JE, Boucekkine C, Abbas N, et al. Hormonal and molecular genetic findings in 46,XX subjects with sexual ambiguity and testicular differentiation. Eur J Pediatr. 1993. 152 Suppl 2:S70-5. [Medline].
Tsuchiya K, Reijo R, Page DC, Disteche CM. Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet. 1995 Dec. 57(6):1400-7. [Medline].
van Niekerk WA, Retief AE. The gonads of human true hermaphrodites. Hum Genet. 1981. 58(1):117-22. [Medline].
Verp MS, Harrison HH, Ober C, et al. Chimerism as the etiology of a 46,XX/46,XY fertile true hermaphrodite. Fertil Steril. 1992 Feb. 57(2):346-9. [Medline].
Viger RS, Silversides DW, Tremblay JJ. New insights into the regulation of mammalian sex determination and male sex differentiation. Vitam Horm. 2005. 70:387-413. [Medline].
Vojnovic M, Martinov-Cvejin M, Grujic V. [Biosocial aspects of physician-patient communication in general medicine]. Med Pregl. 1997 Sep-Oct. 50(9-10):395-8. [Medline].
Walker AM, Walker JL, Adams S, et al. True hermaphroditism. J Paediatr Child Health. 2000 Feb. 36(1):69-73. [Medline].
Wiersma R. True hermaphroditism in southern Africa: the clinical picture. Pediatr Surg Int. 2004 May. 20(5):363-8. [Medline].
Williams C, Hughes IA. Unusual dual genital duct remnants in true hermaphroditism. J Med Genet. 1988 Mar. 25(3):206-8. [Medline].
Wright NP, Wales JK. An unusal case of hermaphroditism--a 46,XX/69,XXY chimera. J Pediatr Endocrinol Metab. 2004 Jun. 17(6):905-8. [Medline].
Yu Q, Huang S, Ye L, et al. The role of sexual related Y gene detection in the diagnosis of patients with gonadal dysgenesis. Chin Med J (Engl). 2001 Feb. 114(2):128-31. [Medline].