Cranial irradiation induces premature activation of the gonadotropin-releasing-hormone (GnRH)-pulse generator - a new animal model for radiation induced pubertal disorders

Background: CNS-irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to delayed puberty. The unde rlying mechanisms of these disorders are unknown. Methods: A new animal mod el of experimentally induced pubertal disorders by cranial irradiation has been developed. In infantile or juvenile (12-23 days old) female rats preco cious or delayed puberty have been induced by selective cranial Co60-irradi ation (4-18 Gy). At age of 32-38 days or 3 months relevant hormone paramete rs have been studied basal and after stimulated conditions. Results: Low ra diation doses (5 or 6 Gy) led to accelerated onset of puberty as well as el evated LH- and estradiol levels. High radiation doses (9-18 Gy) caused reta rdation of sexual development, lower gonadotropin levels and growth retarda tion associated with growth hormone deficiency. After cranial irradiation w ith 5 Gy the release rates of the inhibitory neurotransmitter gamma-aminobu tyric-acid (GABA) from hypothalamic explants were significantly lower (p < 0,05). The gonadotropin-releasing-hormone (GnRH) expression in the hypothal amic preoptic area of irradiated animals (5 Gy) was significantly higher th an in controls (p < 0,05). Conclusion: The GnRH-pulse generator is very rad iosensitive as low dose irradiation causes precocious puberty, whereas high dose irradiation is associated with delayed sexual maturation. Radiation i nduced precocious puberty might be caused by damage to inhibitory GABAergic neurons leading to desinhibition and premature activation of GnRH neurons. Our animal model of cranial irradiation seems to be suitable to study neur otransmitter disorders, molecular mechanisms and potential preventive inter vention of radiation induced pubertal changes.