The effect of high-dose cranial-and craniospinal irradiation and chemotherapy on the gonadotropin-sex steroid axis was studied during different stages of puberty by measuring pulsatile secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone. The patients were thirteen boys who had been treated for malignant brain tumor residing well away from the hypothalamo-pituitary region. The median time to follow-up was 9 (1-16) years. The onset of puberty was early in the patients, median 10.5 years, compared to the average age for Swedish boys, which is at median 12.4 years. There was, before puberty, no significant difference in LH and FSH secretion between patients and a control group of normal boys. In early, mid-and late stages of puberty, however, LH and FSH secretion was increased in the patients overall, whereas testosterone secretion was maintained within the normal range in spite of signs of gonadotoxocity with small testicular volumes. These results indicate that the vulnerable parts of the gonadotropin releasing hormone (GnRH)-gonadotropin (LH, FSH)-gonadal axis are the regulatory system that determines the timing of pubertal induction and the gonads. The GnRH-LH, FSH-releasing neurons appear relatively resistant to cranial irradiation as they are able to respond with supranormal LH and FSH levels for long periods of time after treatment.