In 4 patients with hypothalamic amenorrhea, the pituitary responsiveness to an intravenous challenge of 20 micrograms synthetic gonadotropin-releasing hormone (GnRH) was evaluated before and following a 3-days treatment course with GnRH (100 micrograms/per day i.m.) or ethinyl estradiol, (100 micrograms/day orally). The amenorrheic patients all had normal or reduced levels of serum gonadotropins, no evidence of galactorrhea and no other endocrine abnormality. Following GnRH treatment basal luteinizing hormone levels as well as the luteinizing hormone and follicle-stimulating hormone responses to GnRH were markedly reduced when compared with responses to GnRH before the treatment. Responses to GnRH were significantly augmented after treatment with estrogens. In patients with previous treatment with GnRH the augmented estrogen-induced LH response to GnRH was abolished. These preliminary results support the pathophysiological concept that in amenorrheic patients with hypothalamic dysfunction long-term administration of GnRH does not result in an improvement but rather in a deterioration of pituitary gonadotropic function.