Primary Testicular Dysfunction Is a Major Contributor to Abnormal Pubertal Development in Males with Prader-Willi Syndrome

Background: Recent studies challenge the assumption that hypogonadism in Prader-Willi syndrome (PWS) is due only to hypothalamic dysfunction. Objectives: The aims of the study were to characterize sexual development and reproductive hormones in PWS males and investigate the etiology of hypogonadism. Methods: Physical examination and blood sampling were performed on 37 PWS males, ages 4 months to 32 yr. 3Results: All had a history of undescended testes; age at orchiopexy ranged from 2 months to 6 yr. Pubertal signs were variable, but none achieved full genital development. Anti-Mullerian hormone (AMH) levels in PWS boys were near the lower limits of normal, decreasing from 44.4 +/- 17.8 ng/ml (mean +/- SD) in young children to 5.9 +/- 4.7 ng/ml in adolescents, similar to normal males. In contrast, inhibin B was consistently low (27.1 +/- 36.1 pg/ml) or undetectable in all age groups. In adult males, FSH levels were high (20.3 +/- 18.3 IU/liter), LH levels were normal (4.2 +/- 4.3 IU/liter), and testosterone levels were low (1.87 +/- 1.17 ng/ml). Only two adults had severe hypogonadotropic hypogonadism with undetectable levels of LH and FSH and high AMH levels (34.9 and 36.7 ng/ml), unlike the other nine adults with AMH levels 2.6 +/- 2.1 ng/ml. Androstenedione (1.06 +/- 0.30 ng/ml) and DHEAS (281.1 +/- 143.6 mu g/dl) in adult PWS were normal. Conclusions: Pubertal development in PWS is characterized by normal adrenarche, variable hypothalamic dysfunction, and hypogonadism due to a unique testicular defect. Primary testicular dysfunction is a major component of hypogonadism in PWS. (J Clin Endocrinol Metab 94: 2262-2268, 2009)