Gonadotropin releasing hormone 500 mcg was administered twice daily to four patients (two male, two female) with hypogonadotrophic hypogonadism due to LHRH deficiency, for a minimum of 1 year. Despite initially encouraging biochemical responses and physical changes in all four patients, gonadotrophin responsiveness waned, sex steroid levels were not maintained and pubertal development has not occurred. This diminishing responsiveness appears to be a severe limitation on the use of LHRH as a therapeutic agent.