Residency · Residency · Urology

Disorders of Sex Development: Urologic Considerations

Definition

Disorders of sex development (DSD) are congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomic sex. This terminology replaces older, now outdated terms such as intersex, hermaphrodite, and pseudohermaphrodite. The estimated incidence of genital ambiguity, a subset of DSD, is approximately 1 in 4,500 to 5,500 births, though the broader spectrum of DSD is more common.

Normal Sexual Differentiation

Sexual differentiation begins with genetic sex, determined at fertilization by the chromosomal complement, typically 46,XX for females and 46,XY for males. Gonadal sex is directed primarily by the presence or absence of the SRY gene on the Y chromosome. The SRY gene initiates testicular development by activating the SOX9 gene, which promotes differentiation of Sertoli cells. Sertoli cells produce anti-Mullerian hormone (AMH), which causes regression of the Mullerian ducts, the precursors to female internal reproductive structures. Leydig cells in the developing testes produce testosterone, which stimulates the development of the Wolffian ducts into male internal structures such as the epididymis, vas deferens, and seminal vesicles.

Phenotypic sex, or the external genitalia, is influenced by testosterone and its more potent derivative dihydrotestosterone (DHT), which is formed from testosterone by the enzyme 5-alpha reductase in target tissues. Testosterone promotes Wolffian duct development, while DHT masculinizes the external genitalia, leading to penile growth, scrotal fusion, and prostate development. In the absence of androgens, female external genitalia develop, and the Mullerian ducts persist to form the uterus, fallopian tubes, and upper vagina.

Key Hormones

AMH, secreted by Sertoli cells, is responsible for regression of the Mullerian ducts, preventing development of female internal structures in males. Testosterone, produced by Leydig cells, drives the development of Wolffian duct derivatives. DHT, converted from testosterone by 5-alpha reductase in target tissues, is crucial for masculinization of the external genitalia, including penile growth, scrotal fusion, and prostate formation. The enzyme 5-alpha reductase thus plays a critical role in sexual differentiation by converting testosterone to DHT.

<image>Flowchart of normal sexual differentiation from chromosomal sex through gonadal determination (SRY, SOX9) to hormonal pathways (AMH, testosterone, DHT) and phenotypic development</image>

DSD Classification (Chicago Consensus, 2006)

46,XX DSD

Individuals with 46,XX chromosomes typically have female genetic sex but may present with virilized external genitalia. The most common cause of DSD overall is congenital adrenal hyperplasia (CAH), primarily due to 21-hydroxylase deficiency, which accounts for over 90% of CAH cases. This enzyme deficiency leads to elevated 17-hydroxyprogesterone levels and variable degrees of virilization, classified by the Prader scale from I to V. The salt-wasting form of CAH can cause life-threatening adrenal crises in the neonatal period. Treatment involves glucocorticoid and mineralocorticoid replacement, with surgical feminization considered if desired. Other causes of 46,XX DSD include rare cases of SRY translocation, ovotesticular DSD (formerly termed true hermaphroditism), and maternal androgen exposure from exogenous sources or virilizing tumors.

46,XY DSD

Individuals with 46,XY chromosomes generally have male genetic sex but may present with undervirilized or female external genitalia. Disorders of androgen synthesis include 5-alpha reductase deficiency, which causes ambiguous genitalia at birth with virilization at puberty due to DHT deficiency, 17-beta-hydroxysteroid dehydrogenase deficiency, and Leydig cell hypoplasia. Disorders of androgen action encompass complete androgen insensitivity syndrome (CAIS), where individuals have female external genitalia, intra-abdominal or inguinal testes, absent uterus, and a blind vaginal pouch, and partial androgen insensitivity syndrome (PAIS), which presents with a variable phenotype ranging from predominantly female to predominantly male. Disorders of gonadal development include Swyer syndrome (complete gonadal dysgenesis) characterized by 46,XY karyotype with streak gonads, presence of Mullerian structures, and female phenotype; partial gonadal dysgenesis; and ovotesticular DSD. Disorders of AMH production or action result in persistent Mullerian duct syndrome (PMDS), where 46,XY males retain a uterus and fallopian tubes due to AMH deficiency or receptor defects, typically discovered incidentally during surgeries such as hernia repair or orchiopexy.

Sex Chromosome DSD

Sex chromosome DSD includes Turner syndrome (45,X), characterized by a female phenotype with streak gonads, short stature, and absent puberty; Klinefelter syndrome (47,XXY), presenting with a male phenotype, small testes, gynecomastia, and infertility; mixed gonadal dysgenesis (45,X/46,XY), which shows a variable phenotype with a streak gonad and dysgenetic testis; and ovotesticular DSD, where both ovarian and testicular tissue are present, with variable karyotypes.

Evaluation of Ambiguous Genitalia

Neonatal Emergency Considerations

Congenital adrenal hyperplasia with salt-wasting is a potentially fatal adrenal crisis that can occur within the first two weeks of life. Any neonate presenting with ambiguous genitalia requires urgent evaluation, and sex should not be assigned based solely on external appearance.

Physical Examination

The physical examination should assess phallus size, with micropenis defined as a stretched penile length less than 2.5 cm in a term neonate. The position of the urethral meatus should be noted, particularly for hypospadias. The labioscrotal folds are evaluated for fusion and the presence of rugae. Palpation for gonads is critical; palpable gonads are almost always testes or ovotestes, as ovaries do not descend. Bilateral non-palpable gonads in the presence of ambiguous genitalia necessitate urgent evaluation for CAH. Genital skin pigmentation may suggest excess adrenocorticotropic hormone (ACTH) stimulation, as seen in CAH. The degree of virilization can be graded using the Prader scale, which ranges from mild clitoromegaly to complete male-appearing genitalia.

Laboratory Workup

Laboratory evaluation includes karyotyping, with fluorescence in situ hybridization (FISH) for the SRY gene available within 24 to 48 hours and full karyotype results in 5 to 7 days. Measurement of 17-hydroxyprogesterone is essential to detect 21-hydroxylase deficiency in CAH. Serum electrolytes should be monitored for signs of salt-wasting crisis, such as hyponatremia and hyperkalemia. Androgen levels, including testosterone, DHT, and androstenedione, help assess androgen synthesis. AMH and inhibin B serve as markers of testicular function, reflecting Sertoli cell activity. The human chorionic gonadotropin (hCG) stimulation test evaluates testosterone production to confirm functional testicular tissue. Gonadotropins (LH and FSH) provide information on hypothalamic-pituitary-gonadal axis status. The ACTH stimulation test is used to diagnose enzyme deficiencies, and urine steroid profiling offers a comprehensive assessment of adrenal and gonadal steroid biosynthesis.

Imaging

Pelvic ultrasound is used to identify the presence of a uterus and gonads, although its sensitivity may be limited in neonates. A genitogram, a contrast study performed via the urogenital sinus, delineates vaginal and urethral anatomy and the level of confluence. Magnetic resonance imaging (MRI) of the pelvis can provide better localization of gonads in selected cases. Diagnostic laparoscopy may be necessary for gonadal identification and biopsy.

<image>Prader classification scale (I-V) showing progressive virilization of female external genitalia in CAH, from mild clitoromegaly (I) to complete male appearance with penile urethra (V)</image>

Multidisciplinary Team Approach

Management of DSD requires a multidisciplinary team including pediatric urology, pediatric endocrinology, genetics and genetic counseling, psychology or psychiatry, neonatology, social work, and ethics consultation when needed. Sex assignment should be a collaborative decision involving both the medical team and the family. Factors to consider include the specific diagnosis, surgical options, potential for fertility, hormone replacement needs, and family and cultural considerations.

Sex Assignment

Sex assignment is based on the underlying diagnosis and etiology, gonadal function and fertility potential, anatomical possibilities for surgical reconstruction, expected pubertal development and hormone replacement therapy requirements, as well as family preferences and cultural context. For example, individuals with 46,XX CAH are typically raised female due to functional ovaries and potential fertility with treatment. Those with complete androgen insensitivity syndrome (CAIS) are raised female, as they have a female phenotype and consistently identify as female. In 5-alpha reductase deficiency, sex assignment is variable; traditionally, affected individuals have been raised female in some cultures, but virilization at puberty and male gender identity are common. Current guidelines recommend delaying irreversible surgery when possible to allow the individual to participate in decision-making.

Surgical Considerations

Feminizing Genitoplasty

Feminizing genitoplasty includes clitoroplasty, vaginoplasty, and labioplasty. Clitoroplasty involves reduction of the clitoris while preserving the neurovascular bundle to maintain future sexual function; clitorectomy is avoided. Vaginoplasty entails creating or exteriorizing a vaginal opening. For low confluence urogenital sinus, a pull-through vaginoplasty is performed. Higher confluence requires total urogenital mobilization (TUM), and very high confluence may be addressed via a posterior sagittal approach (Pena technique). Labioplasty reconstructs the labia from labioscrotal folds. Historically, these surgeries were performed in infancy, but the timing is increasingly debated.

Masculinizing Genitoplasty

Masculinizing genitoplasty includes standard hypospadias repair, correction of chordee, orchiopexy for undescended testes, and rarely phalloplasty, which is complex and typically deferred until adolescence or adulthood.

Gonadectomy

Indications for gonadectomy include dysgenetic gonads containing Y chromosome material due to a high risk (15-30%) of gonadoblastoma or dysgerminoma, non-functional gonads discordant with the sex of rearing, and in CAIS, where gonadectomy has historically been recommended due to a 3-5% risk of gonadoblastoma. The timing of gonadectomy in CAIS is debated, with some advocating for deferral until after puberty to allow natural estrogenization. Gonadectomy is contraindicated in functional gonads concordant with the sex of rearing.

Evolving Perspectives on Timing

Historically, early surgery in infancy was performed for psychosocial reasons. However, there is growing advocacy for deferring elective, irreversible genital surgery until the individual can participate in decision-making. Emphasis on patient autonomy and informed consent has increased. The American Urological Association (AUA) and Endocrine Society recommend shared decision-making with families and do not mandate early surgery universally. Certain conditions with high malignancy risk may still warrant early intervention.

<image>Surgical anatomy of the urogenital sinus in virilized 46,XX DSD showing low versus high confluence and corresponding vaginoplasty approaches (flap vaginoplasty, total urogenital mobilization)</image>

Long-Term Follow-Up

Long-term follow-up includes hormone replacement therapy at puberty if gonadectomy has been performed, monitoring of sexual function, psychological well-being, and gender identity, as well as fertility counseling and assisted reproduction options. Transition of care from pediatric to adult providers is essential, along with patient support groups and peer support.

Clinical Pearls

In neonates with ambiguous genitalia and bilateral non-palpable gonads, congenital adrenal hyperplasia with salt-wasting should be presumed until proven otherwise, necessitating urgent evaluation of electrolytes and 17-hydroxyprogesterone levels. A palpable gonad in a phenotypic female is almost always a testis or ovotestis, as ovaries do not descend through the inguinal canal. CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia and can be life-threatening because of adrenal crisis, making it a neonatal emergency. Persistent Mullerian duct syndrome is typically discovered incidentally during inguinal hernia repair or orchiopexy in an otherwise normal-appearing male. Patients with complete androgen insensitivity syndrome are phenotypically female, identify as female, and should be raised female; the key surgical consideration is the timing of gonadectomy, whether pre- or post-pubertal. The ethical landscape surrounding early genital surgery in DSD is rapidly evolving, with increasing emphasis on informed consent, patient autonomy, and deferral of irreversible procedures.

References

• Lee PA, et al. "Consensus statement on management of intersex disorders." Pediatrics. 2006;118(2):e488-e500 (Chicago Consensus).
• Lee PA, et al. "Global DSD update consortium: an update." Horm Res Paediatr. 2016;85(3):158-180.
• AUA Guidelines on DSD (clinical principles)
• EAU/ESPU Guidelines on Pediatric Urology (DSD), 2024 Update
• Speiser PW, et al. "Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical practice guideline." J Clin Endocrinol Metab. 2018.
• Campbell-Walsh-Wein Urology, 12th Edition, Chapter on Disorders of Sex Development

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