A 27-year-old man comes to the office for an infertility evaluation. He and his wife have been trying to conceive for the last 16 months. A previous evaluation of his wife showed no abnormalities. The patient has no prior medical conditions and takes no medications. Height is 188 cm (6' 2") and weight is 75 kg (165.3 lb). BMI is 21 kg/m2. On physical examination, heart and lung sounds are normal. There is bilateral gynecomastia, and genital examination shows small, firm testes. The lower extremities appear abnormally long. Further evaluation will most likely show which of the following sets of findings in this patient?
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This patient has infertility, gynecomastia, and long lower extremities, findings which together are highly suggestive of Klinefelter syndrome. Klinefelter syndrome is a chromosomal disorder (47,XXY) that can lead to azoospermia and infertility, although individuals with mosaic variants may have variable degrees of spermatogenesis. Common nonreproductive manifestations include intellectual and language impairment.
Klinefelter syndrome is the most common cause of male hypogonadism and is characterized by progressive destruction and hyalinization of the seminiferous tubules, leading to small, firm testes. Serum inhibin levels are decreased as a result of the Sertoli cell damage; Leydig cells are usually dysfunctional as well, resulting in reduced testosterone levels. The loss of feedback inhibition leads to increased FSH and LH secretion. Gynecomastia is caused by an increased ratio of estrogens to androgens (high gonadotropin levels increase aromatase activity, which increases conversion of testosterone to estradiol).
(Choice A) Hypogonadotropic (central) hypogonadism is caused by injury or dysfunction of the hypothalamus (eg, Kallmann syndrome) or pituitary gland (eg, adenomas). LH, FSH, and testosterone levels are all low, and spermatogenesis is impaired. Unlike in this patient, testes in central hypogonadism are atrophic and soft (not hyalinized and firm), and gynecomastia is uncommon because the decrease in gonadotropins reduces aromatase activity.
(Choice B) Azoospermia associated with a normal hormonal profile suggests an obstruction along the path from the testes to the seminal fluid (eg, congenital absence of the vas deferens in cystic fibrosis). In these patients, the testes and breasts are grossly normal.
(Choice C) Decreased LH, normal FSH, and elevated testosterone in the setting of a low sperm count suggest exogenous testosterone use. High androgen levels suppress LH secretion, decreasing endogenous testosterone production. Despite the high circulating levels of exogenous androgen, these patients have a low sperm count because local androgen concentrations in the seminiferous tubule are suboptimal for spermatogenesis. Over time, this leads to atrophy of the seminiferous tubules and soft, small testes.
(Choice E) Normal LH and testosterone, elevated FSH, and a low sperm count can be seen in patients with cryptorchidism. In this condition, the seminiferous tubules are damaged (resulting in elevated FSH levels), and the interstitial Leydig cells are preserved (maintaining normal LH and testosterone levels).
Educational objective:
Klinefelter syndrome (47,XXY) causes infertility characterized by primary hypogonadism (elevated FSH and LH, low testosterone) and azoospermia. Other findings include long lower extremities; small, firm testes; and gynecomastia.