Müllerian, Genital & Sex-Development Anomalies

Müllerian development and agenesis

Paired ducts, one tract. When no anti-Müllerian hormone (AMH) is present, the paramesonephric (Müllerian) ducts become the fallopian tubes, uterus, cervix and upper vagina (classically the upper third). They grow alongside the mesonephric (Wolffian) ducts, which is why uterine and renal anomalies travel together. The lower vagina comes from the sinovaginal bulbs of the urogenital sinus and the ovaries from the gonadal ridge, so both develop independently of the Müllerian ducts.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Müllerian agenesis in a 46,XX female, roughly 1 in 5,000 female births. The uterus, cervix and upper vagina are absent or rudimentary, leaving a short blind vaginal pouch. The ovaries are normal, so estrogen, breast development, ovulation, female-range testosterone and pubic and axillary hair are normal. The classic patient is an adolescent with primary amenorrhea; MRKH is the second most common cause of primary amenorrhea after gonadal dysgenesis. Renal anomalies (unilateral agenesis, pelvic or horseshoe kidney) and vertebral anomalies are common, so the kidneys are imaged and the spine examined. Progressive vaginal dilation is first-line, and genetic children are possible through IVF with a gestational carrier because the oocytes are normal.

MRKH and complete androgen insensitivity (CAIS) both present with primary amenorrhea, breasts, a blind vaginal pouch and no uterus. CAIS is 46,XY with testes (often inguinal or abdominal), male-range testosterone and scant pubic and axillary hair; MRKH is 46,XX with ovaries, female-range testosterone and normal sexual hair.

Uterine fusion and resorption defects

Three steps. A normal uterus needs (1) both Müllerian ducts to form, (2) their lower portions to fuse in the midline and (3) the septum between them to be resorbed, producing one cavity. The step that fails predicts the anomaly.

Septate uterus. Fusion is normal but the midline septum persists. The poorly vascularized fibromuscular septum is a poor implantation site, making this the anomaly most associated with recurrent first-trimester loss; it is treated by hysteroscopic septum resection.

Imaging. Hysterosalpingography outlines only the cavity and cannot separate septate from bicornuate; MRI or 3D ultrasound shows the outer fundal contour.

Obstructed or rudimentary horns. In OHVIRA, menses flow from the open side, so a girl with regular periods can still have worsening cyclic pain from a blood-filled obstructed hemivagina. A noncommunicating rudimentary horn with functioning endometrium is usually excised.

Vaginal outflow obstruction

Imperforate hymen. The hymen, a thin membrane where the sinovaginal bulbs meet the urogenital sinus, normally perforates around birth. If it does not, secretions collect behind it: a bulging mucocolpos in a newborn, or hematocolpos (blood distending the vagina), sometimes with hematometra, at menarche. The adolescent has normal breasts and pubic hair, primary amenorrhea and cyclic lower abdominal or back pain; a bluish membrane bulges at the introitus, especially with Valsalva, and a large hematocolpos can cause urinary retention. Treatment is hymenotomy.

Transverse vaginal septum. Failure of the Müllerian upper vagina to join and canalize with the sinus-derived lower vagina leaves a horizontal membrane at any level. Symptoms mirror imperforate hymen, but the introitus looks normal and does not bulge; examination finds a short blind vagina with a mass above it. Treatment is surgical resection.

Primary amenorrhea with normal breasts: no uterus → MRKH (normal pubic hair) or CAIS (scant hair); a uterus that cannot drain → imperforate hymen (introital bulge) or transverse septum (no bulge).

Duct remnants and AMH defects

Wolffian remnants in females. Without testosterone the mesonephric ducts regress, but fragments can persist. A Gartner duct cyst sits on the anterolateral vaginal wall; the epoophoron and paroophoron lie in the broad ligament. Most are incidental.

Müllerian remnants in males. AMH removes almost all of the paramesonephric duct, leaving the appendix testis (hydatid of Morgagni) at the upper pole of the testis and the prostatic utricle, a small blind pouch in the prostatic urethra that is the male counterpart of the uterus and vagina. The appendix epididymis is a Wolffian remnant. Torsion of the appendix testis affects prepubertal boys: tenderness localizes to the upper pole, a "blue dot" may show through the scrotal skin, the cremasteric reflex is preserved, and management is conservative.

Persistent Müllerian duct syndrome (PMDS). An autosomal recessive defect in the AMH gene or the AMH type II receptor in a 46,XY male. Testes, testosterone and DHT are normal, so Wolffian structures and external genitalia are fully male, but a uterus and fallopian tubes persist. It is usually discovered during orchiopexy or inguinal hernia repair; the undescended testes add infertility and malignancy risk.

External genitalia: homologs, hypospadias and epispadias

DHT decides. 5α-reductase type 2 converts testosterone to dihydrotestosterone (DHT) in genital tissue. DHT makes the external primordia fuse and elongate; without it they stay open and form female structures. Because fusion is androgen-dependent, labioscrotal fusion or clitoromegaly in a 46,XX infant means androgen excess, most often from 21-hydroxylase deficiency.

Hypospadias. Failure of the urethral folds to fuse leaves the meatus on the ventral (under) surface, anywhere from the glans to the perineum, often with chordee (ventral curvature) and a dorsal hooded foreskin. At about 1 in 250 male births it is the most common penile anomaly, and it is associated with cryptorchidism and inguinal hernia. Circumcision is avoided because the foreskin is used in the repair. Proximal hypospadias with an undescended testis calls for a karyotype and DSD evaluation (virilized 46,XX CAH, partial androgen insensitivity, 5α-reductase deficiency).

Epispadias. Faulty positioning of the genital tubercle places the meatus on the dorsal (upper) surface. It is part of the exstrophy-epispadias complex, in which the bladder mucosa lies open on the lower abdominal wall and the pubic symphysis is widened.

Other disorders of sex development

Framework. DSDs are grouped by karyotype: sex-chromosome (45,X/46,XY, Turner, Klinefelter), 46,XY and 46,XX. Congenital adrenal hyperplasia is the most common cause of ambiguous genitalia in a newborn.

Swyer syndrome (46,XY complete gonadal dysgenesis). SRY mutation or another testis-determining defect leaves fibrous streak gonads. With no Sertoli cells there is no AMH, so uterus and tubes form; with no Leydig cells there is no testosterone, so Wolffian ducts regress and external genitalia are female. At puberty there is no estrogen: primary amenorrhea, absent breasts, high FSH and LH. Y-containing streaks develop gonadoblastoma (a precursor of dysgerminoma) and are removed. Pregnancy is possible with donor oocytes because the uterus is normal.

Mixed gonadal dysgenesis. 45,X/46,XY mosaicism usually produces a dysgenetic testis on one side and a streak gonad on the other, with asymmetric ambiguous genitalia. AMH and testosterone act mainly on the ducts next to the gonad that makes them, so a tube and hemiuterus form on the streak side. Turner features such as short stature can occur, and gonadoblastoma risk leads to gonadectomy.

Ovotesticular DSD. Formerly true hermaphroditism: ovarian tissue with follicles and testicular tissue with seminiferous tubules coexist, as an ovotestis or a separate ovary and testis. Most patients are 46,XX and usually SRY-negative. Genitalia are ambiguous, and each duct system follows the gonad beside it.

46,XX testicular DSD (XX male). An abnormal X–Y exchange during paternal meiosis moves SRY onto an X chromosome. Testes develop, AMH and testosterone produce a male phenotype, and no Müllerian structures remain. The Yq spermatogenesis genes are missing, so men have small testes and azoospermia, sometimes gynecomastia. The picture resembles Klinefelter syndrome, but the karyotype is 46,XX (not 47,XXY from nondisjunction) and stature is shorter.

Aromatase deficiency. Autosomal recessive loss of CYP19A1 blocks conversion of androgens to estrogens. Placental aromatase normally converts fetal adrenal androgen precursors to estrogen; without it androgens reach mother and fetus. The mother virilizes during pregnancy (hirsutism, acne, deepened voice), regressing after delivery, and a 46,XX infant has ambiguous genitalia with a normal uterus and ovaries. At puberty: no breasts, multicystic ovaries, high gonadotropins and delayed epiphyseal closure (tall stature, osteoporosis).

Localizing a defect with testosterone and LH