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.

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

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

Literatur

• 01 Ayala  M-E, Monroy  J, Morales  L, Castro  M-E, Dominguez  R. Effects of a lesion in the dorsal raphe nuclei performed during the juvenile period of the female rat, on puberty.  Brain Res Bull. 1998;  47 211-221
• 02 Birkebaek  N-H, Fisker  S, Clausen  N, Tuovinen  V, Pedersen  Sindet, Christiansen  J-S. Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood.  Med Pediatr Oncol. 1998;  30 351-356
• 03 Bourguignon  J-P, Gérard  A, Alvarez Gonzalez  M-L, Franchimont  P. Neuroendocrine mechanisms of onset of puberty.  J Clin Invest. 1992;  90 1736-1744
• 04 Canfi  A, Chayoth  R, Weill  S, Bedrak  E. The reproductive system of male rats exposed to very low doses of ionizing radiation, hormonal profile of animals exposed after sexual maturity.  Andrologia. 1990;  22 129-136
• 05 Clayton  P-E, Shalet  S-M. Dose dependency of time of onset of radiation-induced growth hormone deficiency.  J Pediatr. 1991;  118 226-228
• 06 Feleder  C, Jarry  H, Leonhardt  S, Wuttke  W, Moguilevsky  J-A. The GABAergic control of gonadotropin-releasing hormone secretion in male rats during sexual maturation involves effects on hypothalamic excitatory and inhibitory amino acid systems.  Neuroendocrinology. 1996;  64 305-312
• 07 Floran  B, Silva  I, Nava  C, Aceves  J. Presynaptic modulation of the release of GABA by GABA A receptors in pars compacta and by GABA B receptors in pars reticulata of the rat substantia nigra.  Eur J Pharmacol. 1988;  150 277-286
• 08 Freud  A, Canfi  A, Sod-Moriah  U-A, Chayoth  R. Neonatal low-dose gamma irradiation-induced impaired fertility in mature rats.  Isr J Med Sci. 1990;  26 611-615
• 09 Genazzani  A-R, Bernardi  F, Monteleone  P, Luisi  S, Luisi  M. Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty.  Ann NY Acad Sci. 2000;  900 1-9
• 10 Jarry  H, Leonhardt  S, Schwarze  T, Wuttke  W. Preoptic rather than mediobasal hypothalamic amino acid neurotransmitter release regulates GnRH secretion during the estrogen-induced LH surge in the ovariectomized rat.  Neuroendocrinology. 1995;  62 479-486
• 11 Junier  M-P, Hill  D-F, Costa  M-E, Felder  S, Ojeda  S-R. Hypothalamic lesions that induce female precocious puberty activate glial expression of the epidermal growth factor receptor gene: differential regulation of alternatively spliced transcripts.  J Neurosci. 1993;  13 703-713
• 12 Lannering  B, Jansson  C, Rosberg  S, Albertsson-Wikland  K. Increased LH and FSH secretion after cranial irradiation in boys.  Med Ped Oncol. 1997;  29 280-287
• 13 Leiper  A-D, Stanhope  R, Kitching  P, Chessells  J-M. Precocious and premature puberty associated with treatment of acute lymphoblastic leukaemia.  Arch Dis Child. 1987;  62 1107-1112
• 14 Martinez-Flores  I, Egozcue  J, Garcia  M. Effects on female fertility and germinal cells in prepubertal and adult rats (Rattus norvegicus) after X-ray irradiation.  Adv Exp Med Biol. 1998;  444 215-219
• 15 Matsumoto  M, Shinohara  O, Ishiguro  H, Shimizu  T, Hattori  K, Ichikawa  M, Yabe  H, Kubota  C, Yabe  M, Kato  S. Ovarian function after bone marrow transplantation performed before menarche.  Arch Dis Child. 1999;  80 452-454
• 16 Melin  A-E, Adan  L, Leverger  G, Souberbielle  J-C, Schaison  G, Brauner  R. Growth hormone secretion, puberty and adult height after cranial irradiation with 18 Gy for leukaemia.  Eur J Pediatr. 1998;  157 703-707
• 17 Mitsushima  D, Hei  D-L, Terasawa  E. γ-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty.  Proc Natl Acad Sci USA. 1994;  91 395-399
• 18 Moguilevsky  J-A, Carbone  S, Szwarcfarb  B, Rondina  D. Sexual maturation modifies the GABAergic control of gonadotrophin secretion in female rats.  Brain Res. 1991;  563 12-16
• 19 Mohnike  K, Dörffel  W, Timme  J, Kluba  U, Aumann  V, Vorwerk  P, Mittler  U. Final height and puberty in 40 patients after antileukaemic treatment during childhood.  Eur J Pediatr. 1997;  156 272-276
• 20 Müller  H-L, Klinkhammer-Schalke  M, Kühl  J. Final height and weight of long-term survivors of childhood malignancies.  Exp Clin Endocrinol Diab. 1998;  106 135-139
• 21 Ogilvy-Stuart  A-L, Clayton  P-E, Shalet  S-M. Cranial irradiation and early puberty.  J Clin Endocrinol Metab. 1994;  78 1282-1286
• 22 Pinkel  D, Woo  S. Prevention and treatment of meningeal leukemia in children.  Blood. 1994;  84 355-366
• 23 Plant  T-M, Gay  V-L, Marshall  G-R, Arslan  M. Puberty in monkeys is triggered by chemical stimulation of the hypothalamus.  Proc Natl Acad Sci USA. 1989;  86 2506-2510
• 24 Quigley  C, Cowell  C, Jiminez  M, Burger  H, Kirk  J, Bergin  M, Stevens  M, Simpson  J, Silink  M. Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia.  N Engl J Med. 1989;  321 143-151
• 25 Rage  F, Hill  D-F, Sena-Esteves  M, Breakefield  X-O, Coffey  R-J, Costa  M-E, McCann  S-M, Ojeda  S-R. Targeting transforming growth factor alpha expression to discrete loci of the neuroendocrine brain induces female sexual precocity.  Proc Natl Acad Sci USA. 1997;  94 2735-2740
• 26 Rappaport  R, Brauner  R, Czernichow  P, Thibaud  E, Renier  D, Zucker  J-M, Lemerle  J. Effect of hypothalamic and pituitary irradiation on pubertal development in children with cranial tumors.  J Clin Endocrinol Metab. 1982;  54 1164-1168
• 27 Roth  C, Jung  H, Kim  K, Arias  P, Moguilevsky  J, Jarry  H, Leonhardt  S, Wuttke  W. Involvement of gamma amino butyric acid (GABA) in the postnatal function of the GnRH pulse generator as determined on the basis of GnRH and GnRH-receptor gene expression in the hypothalamus and the pituitary.  Exp Clin Endocrinol Diabetes. 1997;  105 353-358
• 28 Roth  C, Schmidberger  H, Schaper  O, Leonhardt  S, Lakomek  M, Wuttke  W, Jarry  H. Cranial irradiation of female rats causes dose- and age-dependent activation or inhibition of pubertal development.  Pediatr Res. 2000;  47 586-591
• 29 Roth  C, Schmidberger  H, Lakomek  M, Witt  O, Wuttke  W, Jarry  H. Reduction of gamma-aminobutyric acid-ergic neurotransmission as a putative mechanism of radiation induced activation of the gonadotropin releasing-hormone-pulse generator leading to precocious puberty in female rats.  Neurosci Lett. 2001;  297 45-48
• 30 Schrappe  M, Reiter  A, Sauter  S, Ludwig  W-D, Wörmann  B, Harbott  J, Bender-Götze  C, Dörffel  W, Dopfer  R, Frey  E, Havers  W, Henze  G, Kühl  J, Richter  R, Ritter  J, Treuner  J, Zintl  F, Odenwald  E, Welte  K, Riehm  H. Konzeption und Zwischenergebnis der Therapiestudie ALL-BFM 90 zur Behandlung der akuten lymphoblastischen Leukämie bei Kindern und Jugendlichen: Die Bedeutung des initialen Therapieansprechens im Blut und Knochenmark.  Klin Pädiatr. 1994;  206 208-209
• 31 Shetty  G, Wilson  G, Huhtaniemi  I, Shuttlesworth  G-A, Reissmann  T, Meistrich  M-L. Gonadotropin-releasing hormone analogs stimulate and testosterone inhibits the recovery of spermatogenesis in irradiated rats.  Endocrinology. 2000;  141 1735-1745
• 32 Terasawa  E, Noonan  J-J, Nass  T-E, Loose  M-D. Posterior hypothalamic lesions advance the onset of puberty in the female rhesus monkey.  Endocrinology. 1984;  115 2241-2250
• 33 Thind  K-K, Goldsmith  P-C. Glutamate and Gabaergic neurointeractions in the monkey hypothalamus: a quantitative immunomorphological study.  Neuroendocrinology. 1995;  61 471-485
• 34 Wildt  L, Marshall  G, Knobil  E. Experimental induction of puberty in the infantile female rhesus monkey.  Science. 1980;  207 1373-1375
• 35 Winterer  J, Barnes  K-M, Lichter  A-S, Deluca  A-M, Loriaux  D-L, Cutler  G-B Jr. Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph.  Endocrinology. 1988;  122 884-890