Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

A 34-year-old man is evaluated for a 2-year history of fatigue, low libido, and infertility. His family history is notable for a brother with infertility. His medical history is unremarkable, and he takes no medications.

On physical examination, vital signs are normal. His height is 195.6 cm (77 in), and his weight is 86.2 kg (190 lb). Genital examination reveals small, firm testes bilaterally.

Laboratory studies reveal a morning serum total testosterone level of 140 ng/dL (4.9 nmol/L) (which was confirmed on repeat testing), a serum follicle-stimulating hormone level of 24 mU/mL (24 U/L), and a serum luteinizing hormone level of 18 mU/mL (18 U/L). Repeated semen analyses reveal azoospermia.

Which of the following is the most appropriate diagnostic test to perform next?

A: Karyotype
B: MRI of the pituitary
C: Scrotal ultrasound
D: Serum prolactin measurement

MKSAP Answer and Critique

The correct answer is A: Karyotype.

The most appropriate diagnostic test to perform next is a karyotype. This patient has evidence of hypergonadotropic hypogonadism based on elevated gonadotropin levels and low testosterone level. Klinefelter syndrome is a common cause of hypergonadotropic hypogonadism and azoospermia, resulting in infertility. A 47,XXY karyotype is diagnostic of Klinefelter syndrome. Mosaic variants of this condition exist but typically present with oligoasthenospermia, testicular failure, or hypogonadism. Concomitant symptoms often include sexual dysfunction and generalized fatigue. Tall stature is a common finding. Patients with Klinefelter syndrome may fail to achieve puberty or may present after sexual maturation with azoospermia. Fertility may be achieved from ejaculated sperm, if present, or extracted testicular sperm; however, advanced reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are necessary to achieve pregnancy. Some couples may opt to include genetic testing by preimplantation genetic diagnosis and embryo biopsy to avoid transmission of the disorder to subsequent generations. Typically, gonadotropin levels are high in patients with Klinefelter syndrome, representing testicular hypofunction. After plans for conception are completed, supplementation with exogenous androgens may be considered to prevent osteoporosis.

Conception with donor sperm is an alternative fertility treatment option.

MRI of the pituitary would be needed only to rule out a pituitary mass in the setting of hypogonadotropic hypogonadism. Because this patient’s gonadotropin levels are high, a pituitary mass is unlikely.

Scrotal ultrasound would identify small testicles in a patient with suspected Klinefelter syndrome, but it would not identify the cause of this patient’s elevated gonadotropin levels.

Serum prolactin level would likely be normal, as Klinefelter syndrome is characterized by primary hypogonadism with normal prolactin levels. Therefore, measurement of serum prolactin is not the most useful test for this patient.

Key Point

• Klinefelter syndrome is a common cause of hypergonadotropic hypogonadism and azoospermia.

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