A 26-year-old man comes to the office with his wife due to inability to conceive after a year of regular unprotected intercourse. His wife has a child from a previous marriage. The patient reports decreased libido but has no trouble achieving or maintaining erection. Temperature is 37 C (98.6 F), blood pressure is 116/70 mm Hg, and pulse is 60/min. His height is 185 cm (6 ft 1 in), weight is 70 kg (154 lb), and BMI is 20 kg/m². Physical examination shows intact sense of smell and visual fields. He has bilateral gynecomastia and sparse facial and body hair. Genital examination shows normal penis morphology, but the testes are firm and about 6 mL in volume (normal: 18-25 mL). Which of the following is the most likely cause of this patient's infertility?

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11ec25c8_d478_8d83_bc81_61a61efd8e4a_MD0003_00 This patient has infertility associated with tall stature, gynecomastia, small testes, and signs of decreased virilization (eg, decreased body hair), consistent with Klinefelter syndrome (47,XXY). This condition can be due to nondisjunction in either parent and is the most common cause of inherited primary hypogonadism. Other than the characteristic eunuchoid body habitus, patients may be phenotypically normal. However, they may also develop a small phallus, hypospadias, and cryptorchidism. Late complications include increased risk of male breast cancer. body habitus Klinefelter syndrome is most commonly detected during evaluation for gynecomastia or infertility. In Klinefelter syndrome, infertility is due to testicular fibrosis with seminiferous tubule dysgenesis, azoospermia, hypogonadism, and elevated FSH and LH levels. As gonadal failure progresses, testosterone levels gradually decline. Patients may also be brought for evaluation due to intellectual disability, psychiatric disorders, or autism spectrum disorders. Diagnosis can be confirmed on karyotype analysis of peripheral leukocytes. (Choice A) Congenital androgen insensitivity syndrome (CAIS) is due to mutations in the androgen receptor. Patients with the complete syndrome are genetically male but phenotypically female and most often present with primary amenorrhea. (Choice B) Congenital idiopathic hypogonadotropic hypogonadism can cause infertility but is often associated with anosmia (Kallmann syndrome) and other congenital abnormalities (eg, cleft palate, skeletal abnormalities) not seen in this patient. Newborn boys with this condition often have microphallus. Klinefelter syndrome is more common than congenital idiopathic hypogonadotropic hypogonadism and more consistent with this patient's presentation. (Choice D) Cushing syndrome can be associated with hyperandrogenism due to co-secretion of adrenal androgens with cortisol. Women may develop menstrual irregularities, acne, and hirsutism, but males are usually asymptomatic. In addition, this patient has no notable cushingoid features (eg, central obesity, hypertension, proximal muscle weakness). (Choice E) Optimal spermatogenesis occurs at temperatures slightly below core body temperature. Conditions (eg, cryptorchidism, varicocele) or behaviors (eg, hot tub use, laptop computing) that raise testicular temperatures can decrease fertility. Distance running is not associated with a significant abnormality in testicular temperatures. (Choice F) Anabolic steroid use can lead to impaired testicular function, with decreased gonadal size and lowered sperm counts. It can also cause gynecomastia, but typically increases libido and does not lead to sparse facial and body hair. Educational objective: Klinefelter syndrome (47,XXY) is characterized by a eunuchoid habitus, gynecomastia, small testes, and decreased virilization. It can lead to infertility due to testicular fibrosis with seminiferous tubule dysgenesis, azoospermia, hypogonadism, and elevated FSH and LH levels. References: Klinefelter syndrome and medical treatment: hypogonadism and beyond. (http://www.ncbi.nlm.nih.gov/pubmed/26732150)

A 26-Year-Old Man Comes to the Office with His Wife