What is the underlying cause of a phenotypic female with primary amenorrhea, absent male external genitalia, and a 46,XY karyotype—is it due to absent androgen‑receptor activity rather than low testosterone?

Complete Androgen Insensitivity Syndrome (CAIS)

The underlying cause is absent androgen receptor activity, not low testosterone levels. In this patient with 46,XY karyotype, phenotypically female appearance, primary amenorrhea, and absent male external genitalia, the diagnosis is Complete Androgen Insensitivity Syndrome (CAIS), caused by mutations in the androgen receptor gene that render target tissues completely insensitive to androgens despite normal or elevated testosterone production. 1, 2

Pathophysiology and Mechanism

CAIS results from severe defects in androgen receptors, causing developing XY male fetuses to ignore the masculinizing effect of androgens and show an unambiguous female exterior. 1 The key distinction is that testosterone levels are typically normal to elevated (male-range), but the androgen receptor cannot respond to the hormone. 2, 3, 4

The molecular basis involves:

• Mutations throughout the AR gene on the X chromosome, with preponderance in the ligand-binding domain 5, 6
• Complete loss of androgen receptor function, preventing testosterone and dihydrotestosterone from exerting masculinizing effects 5
• Novel mutations continue to be identified, such as the Q65X mutation causing truncated nonfunctional protein 4

Clinical Presentation Confirming CAIS

Your patient demonstrates the classic triad:

• Female external genitalia with normal breast development (from increased conversion of testosterone to estrogen at puberty) 1, 2, 4
• Characteristically sparse or absent pubic/axillary hair (pathognomonic feature distinguishing CAIS from Müllerian agenesis) 2, 3, 4
• Absent uterus and fallopian tubes with blind-ending vagina 2, 4

Diagnostic Confirmation Algorithm

Measure serum testosterone first—it will be in the male range (not low), definitively excluding testosterone deficiency as the cause. 2, 3 The diagnostic sequence:

1. Hormonal assessment: Testosterone elevated (male-range), LH often elevated, FSH normal 2
2. Karyotype analysis: 46,XY (definitive test per American College of Medical Genetics) 2, 3
3. Imaging: Pelvic ultrasound or MRI confirms absent Müllerian structures and identifies testicular location (intra-abdominal or inguinal) 2, 4
4. AR gene sequencing: Identifies specific mutation in most cases 4, 7, 5

Critical Diagnostic Pitfall

Do not confuse CAIS with Müllerian agenesis—both present with primary amenorrhea and absent uterus, but the Endocrine Society emphasizes that karyotype (46,XY vs 46,XX), testosterone levels (male-range vs female-range), and presence/absence of pubic hair definitively distinguish them. 2 Müllerian agenesis patients have 46,XX karyotype, normal female testosterone levels, and normal pubic/axillary hair. 2, 3

Why Not the Other Options

• Absolute hormone lack: Incorrect—testosterone is normal to elevated in CAIS 2, 4, 5
• Absent Müllerian inhibiting factor (AMF): Incorrect—AMF is produced normally by functioning testes in CAIS, which is why Müllerian structures (uterus, fallopian tubes) are absent 2
• Low testosterone: Incorrect—this describes androgen deficiency states, not CAIS where testosterone production is intact 2, 5

Management Implications

Gonadectomy is required due to 3.6-50% malignancy risk, with timing debated but typically performed after spontaneous puberty completion. 6 Post-gonadectomy, lifelong estrogen replacement therapy maintains bone health and prevents menopausal symptoms. 8, 6 These patients develop feminine gender identity and sexual orientation due to brain insensitivity to androgens combined with unambiguous female upbringing. 1