Effects of Cranial Radiation on Hypothalamic- Adenohypophyseal Function: Abnormal Growth Hormone Secretory Dynamics

Chrousos, George P.; Poplack, David G.; Brown, Teri J.; O'Neill, Dondra; Schwade, James G.; Bercu, Barry B.

doi:10.1210/jcem-54-6-1135

Cited by 89 publications

(34 citation statements)

References 24 publications

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“…GH response to insulininduced hypoglycaemia was, however, subnormal (Blatt et al 1984, Romshe et al 1984, Ahmed et al 1986). This combination of GH axis responses was also demonstrated in two monkeys cranially irradiated with 40 Gy that showed impaired spontaneous GH secretion and a reduced GH peak to insulin-induced hypoglycaemia but an adequate GH peak response with arginine (Chrousos et al 1982).…”

Section: The Impact Of Cranial Irradiation On the Gh Axismentioning

confidence: 59%

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Murray¹,

Higham²,

Clayton³

2015

Journal of Endocrinology

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At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis.

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Section: The Impact Of Cranial Irradiation On the Gh Axismentioning

confidence: 59%

60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years

Murray¹,

Higham²,

Clayton³

2015

Journal of Endocrinology

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“…The growth hormone requirements of children treated for ALL are still controversial (12). Studies of growth hormone responses in both monkeys (35) and humans (36) have indicated that the hypothalamus is more sensitive than the pituitary to cranial irradiation. Therefore, hypothalamic GRF might be important to children with radiation-induced growth hormone deficiency, as has been suggested by some investigators (12,34).…”

Section: Discussionmentioning

confidence: 99%

Radiation Effects on Growth Are Altered in Rats by Prednisolone and Methotrexate

Schunior¹,

Mullenix

Zengel³

et al. 1994

Pediatr Res

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ABSTRACT. CNS therapy for childhood leukemia has adverse effects upon growth and cognition. The cause of these deficits is unknown. In a rat model, we determined which agent, or combination of agents, in CNS therapy affected growth. Young Sprague-Dawley rats were exposed to cranial irradiation (1000 cGy), methotrexate (2 or 4 mg[ kg, intraperitoneally), or prednisolone (18 or 36 mg[kg, intraperitoneally) alone or in two-or three-agent combinations. Matched control groups received appropriate sham radiation, intraperitoneal saline, or both. Body weight was recorded from 14 through 150 d of age. After the rats were killed at 150 d, body length was recorded and the head and left femur were removed to determine body and craniofacial proportions. Cranial irradiation alone, but not methotrexate or prednisolone alone, stunted growth permanently and altered craniofacial proportions. When these agents were combined, methotrexate and prednisolone modified the growth response to cranial irradiation. Methotrexate given before cranial irradiation prevented radiation stunting in males. This protection was lost when the dose of methotrexate was increased, when prednisolone was added to the combination, or when females were studied. The protection in males was effective against both growth and behavioral deficits. These results indicate that the physical and behavioral side effects of CNS therapy are better understood in the context of dose, sex, and interactions ofthe agents. (Pediatr Res 35: 416-423,1994) The cause of these adverse effects has been reported to be cranial irradiation alone (9-11), or cranial irradiation interacting with chemotherapy ( I, 4, 12).Cranial irradiation or methotrexate has been manipulated in CNS therapy in an attempt to prevent neurotoxic interactions (13-15). Yet, the impact of these manipulations is uncertain, considering that some cranial irradiation and methotrexate interactions may be protective rather than neurotoxic. Balsom et al. (16) found that preirradiation methotrexate protected against decreased intellectual function in ALL survivors, illustrating the importance of agent interactions and sequence of administration to long-term outcome.We developed an animal model to study growth and behavioral deficits associated with exposures to cranial irradiation, methotrexate, and prednisolone, either as single agents or as combinations (17,18). Cranial irradiation alone stunted growth without significantly altering behavior, whereas cranial irradiation combined with methotrexate and prednisolone disrupted behavior in addition to stunting growth. Further study of behavior (19) demonstrated how different agent interactions affected outcome: 1) behavioral "signatures" varied with the components of the agent combinations; 2) behavioral outcome was influenced by steroids as welI as by cranial irradiation and methotrexate; 3) behavioral outcome was sex dependent; and 4) behavioral outcome varied with dose, which determined whether agents interacted antagonistically or synergisticalIy. Therefore, not...

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“…Another approach to diagnosis of GH deficiency is the 24 hour spontaneous plasma GHSP on the assumption that such a diurnal pattern provides a better diagnostic tool of GH deficiency (28). A low GHSP has been observed in leukemic patients given prophylactic cranial radiation treatment (29) and in experimental studies on irradiated monkeys (30). However, the relative diagnostic value of an abnormal GHSP as compared with stimulated levels of GH remains controversial according to a recent study in normal short prepubertal children (31).…”

Section: Growth Hormone Deficiencymentioning

confidence: 99%

“…These data provide evidence for both pituitary and hypothalamic damage. Other evidence for hypothalamic damage includes the observations that 1 ) plasma prolactin levels may be elevated (43), 2) the rise in TSH after thyrotropin-releasing hormone stimulation is elevated and delayed, 3) adrenocortical function is subnormal although the corticotropin response to corticotropin releasing factor is normal (44), 4) there is a discrepancy between GH secretion responses to insulin and arginine (see above), and 5) physiologic G H secretion is severely blunted despite a normal GH response to arginine and L-dopa in irradiated monkeys (30) and in some patients (29). The positive growth response to longterm GHRH 1-29 therapy also is consistent with a predominant hypothalamic lesion (45).…”

Section: Growth Hormone Deficiencymentioning

confidence: 99%