Context: The specific form of hypogonadism in Prader-Labhart-Willi syndrome (PWS) - central or peripheral - remains unexplained.

Objectives: To investigate the cause of hypogonadism in PWS and to determine whether hCG treatment can restore pubertal development.

Design: Clinical follow-up study, divided into 2 samples, over a duration of 1.5 and 4.5 yr.

Patients: 8 male infants and 6 peripubertal boys (age at start of observation 0.06-0.93 and 8.1-10.8 yr, respectively) with genetically confirmed PWS were studied.

Intervention: hCG 2x500-1500 U weekly from age 13.5 yr till present.

Main outcome measures: Serum FSH, LH, inhibin B and testosterone levels; pubertal development.

Results: Infants with PWS presented normal LH (2.3 ± 0.7 U/L) and testosterone (2.5 ± 0.9 nmol/L) levels (means ± SEM at 5 months) compared with the reference range. However, two thirds of boys displayed cryptorchidism. Inhibin B levels were at the lowest level of the normal range and decreased significantly between infancy and puberty (at 13 yr: 72 ± 17 pg/mL), while FSH secretion increased (9.9 ± 2.6 U/L). Pubertal maturation stopped at an average bone age of 13.9 yr. hCG therapy increased testosterone (11 ± 2 nmol/L) and reduced FSH levels (at 16 yr: 1.1 ± 0.9 U/L). Testicular volume (5.6 ± 1 mL) and inhibin B (26.5 ± 11.9 pg/mL) remained low.

Conclusion: Children with PWS display a specific form of combined hypothalamic (low LH) and peripheral (low inhibin B, high FSH) hypogonadism suggesting a primary defect in Sertoli and/or germ cell maturation or an early germ cell loss. hCG therapy stimulates testosterone production and virilization.