Disorders of sexual development

Contributors of Campbell-Walsh-Wein, 12th edition

Richard Nithiphaisal Yu, David Andrew Diamond, and Richard C. Rink

Normal sexual development

Normal sexual development can be categorized into three processes: establishment of genotypic (chromosomal) sex, establishment of phenotypic sex, and formation of gender identity. Disruption of any of these interactions is described as a disorder of sexual development (DSD).

During the first 6 weeks of development, the gonadal ridge, germ cells, internal ducts and external genitalia are bipotential in both 46,XY and 46,XX embryos . Multiple genes are thought to determine chromosomal sex. Specifically, the SRY (sex-determining region Y) gene on the Y chromosome is considered the testis-determining factor . Under this influence, the bipotential gonadal ridges differentiate into testes, and germ cells develop into spermatocytes ( Fig. 10.1 ). In the absence of SRY, ovarian organogenesis results ( Table 10.1 ).

Table 10.1

Common Embryologic Origins of Genital Structures.

MALE	EMBRYONIC STRUCTURE	FEMALE
Testis	Indifferent Gonad	Ovary
Seminiferous tubules	Gonadal cortex	Ovarian follicles
Rete testis	Gonadal medullar	Rete ovarii
Gubernaculum testis	Gubernaculum	Ovarian ligament Round ligament of uterus
Efferent ductules of testis Paradidymis	Mesonephric tubules	Epoöphroon Paraoöphoron
Appendix of epididymis Ductus deferens Ejaculatory duct and seminal vesicle Ureter, pelvis, calyces, collecting tubules	Wolffian duct (mesonephric duct)	Gartner duct Ureter, pelvis, calyces, and collecting tubules
Kidney Nephrons (glomerulus, proximal tubule, loop of Henle, distal tubule)	Intermediate mesoderm	Kidney Nephrons (glomerulus, proximal tubule, loop of Henle, distal tubule)
Appendix of testis	Müllerian duct (paramesonephric duct)	Paratubal cyst Fallopian tube Uterus Cervix
Bladder and trigone Urethra Prostate Verumontanum Prostatic utricle Periurethral glands (Littre) Bulbourethral glands (Cowper’s)	Urogenital sinus	Bladder and trigone Urethra Vagina, hymen Urethral glans (Skene’s) Greater vestibular glands (Bartholin’s)
Penis Glans penis Corpora cavernosa of penis Corpus spongiosum of penis	Genital tubercle	Clitoris Glans clitoris Corpora cavernosa of clitoris Bulb of vestibule
Ventral aspect of penis	Urethral folds/vestibular folds	Labia minora
Scrotum	Labioscrotal swellings	Labia majora

The Sertoli cells of the testis secrete anti-Müllerian hormone (AMH) at 7 to 8 weeks of gestation, which promotes Müllerian duct regression. Testosterone secretion by the fetal testis Leydig cells occurs at approximately 9 weeks of gestation. Androgens promote virilization of wolffian duct structures, the urogenital sinus, and the genital tubercle. Testosterone enters target tissues by passive diffusion, and wolffian duct virilization does not occur if local androgens are not present. In some cells, testosterone is converted to dihydrotestosterone (DHT) by intracellular 5α-reductase. Testosterone or DHT then binds to an intracellular androgen receptor. DHT binds to the receptor with greater affinity and stability than does testosterone. In tissues equipped with 5α-reductase at the time of sexual differentiation (e.g., prostate, urogenital sinus, external genitalia), DHT is the active androgen. Masculinization of the external genitalia is complete by 12–13 weeks of gestation ( Fig. 10.2 ). Penile growth and testicular descent occur over the third trimester. In the female fetus, the absence of testosterone maintains the appearance of external genitalia at the 6-week gestational stage ( Fig. 10.3 ).

The wolffian ducts adjacent to the testes form the epididymis, joining with the rete testes. Distally the wolffian ducts join the urogenital sinus to develop into the seminal vesicles. In the female fetus without testosterone, the wolffian ducts regress. Without AMH, the Müllerian ducts develop into the female internal reproductive tract, including the fallopian tubes and uterus. Contact of the ducts with the urogenital sinus ultimately forms the vagina. It is generally accepted that the proximal two thirds of the vagina is formed from the Müllerian ducts and the distal third from the urogenital sinus ( Fig. 10.4 ).

Formation of gender identity is a complex and poorly understood phenomenon. Research suggests that gender identity may be affected not only by chromosomal sex and prenatal hormones but also postnatal environmental factors.

Terminology and definitions

The most widely used terminology for the myriad conditions of abnormal sexual differentiation is disorders of sexual development (DSD) , or disorders of sexual differentiation. Although there is no clear consensus, individuals affected by DSD may prefer the term difference of sex development, intersex, or more specific terminology to the diagnosis, such as androgen insensitivity syndrome ( Table 10.2 ).

Table 10.2

Overview of Nomenclature and Classification for Disorders of Sexual Development

CLASSIFICATION	INCIDENCE	EXAMPLES	PATHOPHYSIOLOGY	PRESENCE OF GONADS
1. Disorders of Gonadal Differentiation and Development
*Klinefelter Syndrome*	1/600 (classic)		Classic 47,XXY: meiotic nondisjunction	Bilateral testes
*46,XX Male*	1/20,000		Translocation of Y chromosome material to X chromosome	Bilateral testes
*Gonadal Dysgenesis*
Turner syndrome	1/2500		Classic 45,X; presence of one normal X chromosome and absent/abnormal other chromosome/mosaicisim	Bilateral streak (dysgenetic) gonads (primary follicles described in some)
46,XX “pure” gonadal dysgenesis				Bilateral streak (dysgenetic) gonads
Mixed gonadal dysgenesis	Second most common cause of ambiguous genitalia in neonates		Most 45,XO/46,XY	Unilateral testis, contralateral streak gonad
Partial gonadal dysgenesis			45,X/46,XY or 46,XY	Bilateral dysgenetic testes
46,XY “pure” gonadal dysgenesis (Swyer syndrome)			Complete absence of testis-determining factor; mutations in SRY gene in some	Bilateral dysgenetic testes
*Embryonic Testicular Regression/Bilateral Vanishing Testes Syndrome*			46,XY; loss of testicular tissue during embryogenesis	Bilateral hemosiderin deposition

2. Ovotesticular DSD
(True hermaphroditism)			46,XX, 46,XY or mosaicism	Two ovotestes or one ovary/one testis

3. 46,XX DSD
(Female pseudohermaphroditism)
*Congenital Adrenal Hyperplasia*	1/5000–15,000 (21-hydroxylase)	21-Hydroxylase, 11β-hydroxylase deficiencies	Inborn error of metabolism in one of enzymes involved in cortisol production; increased testosterone production	Bilateral ovaries
*Maternal Androgen Excesst*			Exogenous androgen effects on fetal development	Bilateral ovaries
4. 46,XY DSD (Male pseudohermaphroditism)
*Leydig Cell Agenesis/Unresponsiveness*			Leydig cell aplasia or abnormal LH receptor	Bilateral testes
*Disorders of Testosterone Biosynthesis (CAH variants)*		StAR deficiency, 3β-hydroxysteroid dehydrogenase deficiency	Defect of enzymes converting cholesterol to testosterone	Bilateral testes
*Disorders of Androgen-Dependent Target Tissue*
Syndrome of complete androgen insensitivity	1/20,000–1/60,000		X-linked; androgen resistance secondary to abnormality of androgen receptor	Bilateral testes
Syndrome of partial androgen insensitivity			X-linked; androgen resistance secondary to abnormality of androgen receptor	Bilateral testes
Mild androgen insensitivity syndrome			Androgen resistance secondary to abnormality of androgen receptor	Bilateral testes
5α-Reductase deficiency			Abnormality in type II isoenzyme that converts testosterone to DHT	Bilateral testes
Persistent Müllerian duct syndrome			Abnormality of AMH gene or receptor	Bilateral testes
5. Unclassified DSD
*Mayer-Rokitansky-Küster-Hauser Syndrome*	1/4000–5000		46,XX, genetic basis unknown	Bilateral ovaries