BACKGROUND: CNS-irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to delayed puberty. The underlying mechanisms of these disorders are unknown. METHODS: A new animal model of experimentally induced pubertal disorders by cranial irradiation has been developed. In infantile or juvenile (12 - 23 days old) female rats precocious or delayed puberty have been induced by selective cranial Co60-irradiation (4 - 18 Gy). At age of 32 - 38 days or 3 months relevant hormone parameters have been studied basal and after stimulated conditions. RESULTS: Low radiation doses (5 or 6 Gy) led to accelerated onset of puberty as well as elevated LH- and estradiol levels. High radiation doses (9 - 18 Gy) caused retardation of sexual development, lower gonadotropin levels and growth retardation associated with growth hormone deficiency. After cranial irradiation with 5 Gy the release rates of the inhibitory neurotransmitter gamma-aminobutyric-acid (GABA) from hypothalamic explants were significantly lower (p < 0,05). The gonadotropin-releasing-hormone (GnRH) expression in the hypothalamic preoptic area of irradiated animals (5 Gy) was significantly higher than in controls (p < 0,05). CONCLUSION: The GnRH-pulse generator is very radiosensitive as low dose irradiation causes precocious puberty, whereas high dose irradiation is associated with delayed sexual maturation. Radiation induced 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 neurotransmitter disorders, molecular mechanisms and potential preventive intervention of radiation induced pubertal changes.
BACKGROUND: CNS-irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to delayed puberty. The underlying mechanisms of these disorders are unknown. METHODS: A new animal model of experimentally induced pubertal disorders by cranial irradiation has been developed. In infantile or juvenile (12 - 23 days old) female rats precocious or delayed puberty have been induced by selective cranial Co60-irradiation (4 - 18 Gy). At age of 32 - 38 days or 3 months relevant hormone parameters have been studied basal and after stimulated conditions. RESULTS: Low radiation doses (5 or 6 Gy) led to accelerated onset of puberty as well as elevated LH- and estradiol levels. High radiation doses (9 - 18 Gy) caused retardation of sexual development, lower gonadotropin levels and growth retardation associated with growth hormone deficiency. After cranial irradiation with 5 Gy the release rates of the inhibitory neurotransmitter gamma-aminobutyric-acid (GABA) from hypothalamic explants were significantly lower (p < 0,05). The gonadotropin-releasing-hormone (GnRH) expression in the hypothalamic preoptic area of irradiated animals (5 Gy) was significantly higher than in controls (p < 0,05). CONCLUSION: The GnRH-pulse generator is very radiosensitive as low dose irradiation causes precocious puberty, whereas high dose irradiation is associated with delayed sexual maturation. Radiation induced 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 neurotransmitter disorders, molecular mechanisms and potential preventive intervention of radiation induced pubertal changes.
Authors: Gregory T Armstrong; John A Whitton; Amar Gajjar; Larry E Kun; Eric J Chow; Marilyn Stovall; Wendy Leisenring; Leslie L Robison; Charles A Sklar Journal: Cancer Date: 2009-06-01 Impact factor: 6.860