Schädelbestrahlung verursacht vorzeitige Aktivierung des Gonadotropin-Releasinghormon (GnRH)-Pulsgenerators bei Ratten - Ein neuesTiermodell für strahleninduzierte Störungen der Pubertät

Zusammenfassung.

Hintergrund: Die Bestrahlung des ZNS bei präpubertären Kindern im Rahmen der Behandlung einer Leukämie oder eines Hirntumors kann zu einer Pubertas praecox oder bei hohen Strahlendosen zu einer Pubertas tarda führen. Die zugrunde liegenden Mechanismen sind bisher unbekannt. Methode: Ein neues Tiermodell experimentell induzierter Pubertätsstörungen durch kraniale Radiatio wurde entwickelt. Durch selektive Kobalt(Co-60)-Schädelbestrahlung infantiler oder juveniler weiblicher Ratten (12 - 23 Tage alt) konnte dosisabhängig (4 - 18 Gy) eine Pubertas praecox oder Pubertas tarda induziert werden. Im Alter von 32 - 38 Tagen oder 3 Monaten wurden relevante Hormonparameter basal und zum Teil nach Stimulation untersucht. Ergebnisse: Nach Bestrahlung mit relativ niedriger Dosis (5 - 6 Gy) trat bei weiblichen Ratten als isolierte endokrine Störung eine vorzeitige Pubertätsentwicklung mit erhöhten LH- und Estradiol-Konzentrationen auf. Hohe Strahlendosen (9 - 18 Gy) verursachten dagegen eine verzögerte Pubertätsentwicklung, eine verminderte Gonadotropin-Sekretion und einen Minderwuchs bei Wachstumshormonmangel. In Superfusionsexperimenten mit explantiertem Hypothalamusgewebe war nach niedriger Strahlendosis (5 Gy) eine verringerte Sekretion des inhibitorischen Neurotransmittters GABA nachzuweisen (p < 0,05). Die Expression von Gonadotropin-Releasinghormon (GnRH) in der präoptischen Region des Hypothalamus bei bestrahlten Tieren (5 Gy) war signifikant höher als bei Kontrolltieren (p < 0,05). Schlussfolgerung: Der GnRH-Pulsgenerator ist sehr strahlensensibel - niedrige Strahlendosen können eine vorzeitige und hohe Dosen eine verzögerte Pubertät verursachen. Die Ergebnisse sprechen für eine strahleninduzierte Schädigung inhibitorischer GABAerger-Neurone, wodurch es zu einer Desinhibition und Aktivierung von GnRH-Neuronen kommen kann. Unser Tiermodell ist zur Untersuchung von Neurotransmitterstörungen, molekularen Mechanismen und potenziellen präventiven Maßnahmen der strahleninduzierten Pubertätsstörungen geeignet.

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.

Schlüsselwörter

Kraniale Radiatio - Pubertas praecox - Pubertas tarda - Gonadotropin-Releasinghormon mRNA - GABA (γ-Aminobuttersäure)

Key words

Cranial irradiation - precocious puberty - delayed puberty - gonadotropin-releasing-hormone - GABA (gamma-aminobutyric-acid)

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