A 15-year-old girl is brought to the office due to amenorrhea. She has never menstruated, but her mother underwent menarche at age 14. The patient has no chronic medical conditions and takes no medications. She does not use tobacco, alcohol, or illicit drugs. The patient plays violin for her high school orchestra and is the captain of her junior varsity tennis team. She is not sexually active. Height is 175.3 cm (5 ft 9 in) and weight is 65 kg (143.3 lb). BMI is 21.2 kg/m2. Examination shows fully developed secondary sexual characteristics. Pelvic ultrasound shows a shortened vaginal canal with a rudimentary uterus. Which of the following is the most likely diagnosis?
Müllerian agenesis vs androgen insensitivity syndrome | ||
Diagnosis | Müllerian agenesis | Androgen insensitivity syndrome |
Pathogenesis | Absent or hypoplastic müllerian ducts* | Androgen resistance due to X-linked androgen receptor mutation |
Hormone levels | Normal estrogen & testosterone | ↑ Testosterone & estrogen (aromatization) |
Reproductive | Absent or rudimentary uterus/upper vagina, normal ovaries | No uterus/upper vagina; cryptorchid testes |
Breasts | Normal | Normal |
Axillary & | Normal | Minimal to absent |
*Müllerian (paramesonephric) ducts give rise to the fallopian tubes, uterus, cervix & upper vagina. | ||
This patient is most likely a 46,XX female with müllerian agenesis. During sexual differentiation in females (XX), the müllerian (paramesonephric) ducts give rise to the fallopian tubes, uterus, cervix, and upper vagina; the urogenital sinus gives rise to the lower vagina; and the wolffian (mesonephric) ducts degenerate in females from lack of hormonal stimulation by testosterone.
Müllerian agenesis (ie, vaginal agenesis or Mayer-Rokitansky-Küster-Hauser syndrome) results in hypoplasia/aplasia of the müllerian structures (ie, uterus/cervix/upper vagina/fallopian tubes), leading to variable uterine development (eg, rudimentary uterus) with no upper vagina (eg, shortened vagina with blind vaginal pouch). Because the uterus is absent or hypoplastic, the patient cannot menstruate (ie, primary amenorrhea).
Patients with müllerian agenesis have normal ovaries, which arise embryologically from the genital ridge. Therefore, patients have normal, female-range levels of estrogen and testosterone and regular development of secondary sexual characteristics (eg, breast development, axillary/pubic hair). Patients with müllerian agenesis require renal ultrasound because up to 50% have a coexisting urologic anomaly (eg, renal agenesis).
(Choice A) Congenital adrenal hyperplasia (CAH), most commonly due to 21-Hydroxylase deficiency, has a variable presentation. Late-onset CAH usually presents with hirsutism, oligomenorrhea, and acne, which are not seen in this patient. Neonates typically have virilization and life-threatening hyponatremia (salt wasting).
(Choice B) Patients with androgen insensitivity syndrome (AIS) are 46,XY males with androgen receptor defects. Patients appear phenotypically female (ie, no external male genitalia but breast development due to peripheral aromatization of testosterone to estrogen); however, they have minimal axillary or pubic hair due to androgen resistance (unlike this patient with normal secondary sexual characteristics). In addition, patients with AIS have cryptorchid testes that actively secrete antimüllerian hormone, leading to complete regression of all müllerian structures with an absent (not rudimentary) uterus.
(Choice C) Kallmann syndrome occurs due to decreased synthesis of GnRH in the hypothalamus (hypogonadotropic hypogonadism). Although female patients are rarely affected, they can have primary amenorrhea but typically do not develop secondary sexual characteristics.
(Choice D) Klinefelter syndrome (47,XXY) affects males and is characterized by tall stature, poorly developed secondary sexual characteristics, atrophic testes, and infertility.
Educational objective:
Patients with müllerian agenesis (ie, Mayer-Rokitansky-Küster-Hauser syndrome) have variable uterine development and no upper vagina (eg, shortened vagina). These patients are 46,XX females with normal ovaries and secondary sexual characteristics.