Hal Landy

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

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 of the agents.

Sleep Modulation of Neuroendocrine Function: Developmental Changes in Gonadotropin-Releasing Hormone Secretion during Sexual Maturation

ABSTRACT: To assess sleep-associated changes in gonadotropin-releasing hormone secretion during sexual maturation, we studied nighttime and daytime patterns of LH and FSH secretion in two groups with qualitatively similar sex steroid levels: girls with central precocious puberty and young adult women in the early follicular phase of an ovulatory menstrual cycle. In the girls with central precocious puberty, all indices of LH secretion were significantly higher at night than during the day (mean LH levels, 12 ± 2 versus 5 ± 1 IU/L, p ≤ 0.01; LH pulse amplitude 16 ± 2 versus 7 ± 1 IU/L, p ≤ 0.01; and LH pulse frequency 0.70 ± 0.05 versus 0.35 ± 0.08 pulse/patient-h, p ≤ 0.01). Girls with a history of menses, who were presumably the most mature, lacked this diurnal variability. Mean nocturnal FSH levels were only slightly higher than daytime levels (7.6 ± 0.5 versus 7.2 ± 0.5 IU/L, p ≤ 0.05) resulting in alternating periods of LH (nighttime) and FSH (daytime) predominance in this pubertal population. In contrast, the adult women had lower mean gonadotropin levels and LH pulse frequencies at night than during the day (mean LH 7 ± 1 versus 10 + 1 IU/L, p ≤ 0.05; mean FSH 9 ± 1 versus 10 ± 1 IU/L, p ≤ 0.05; LH pulse frequency 0.40 ± 0.08 versus 0.70 ± 0.10 pulse/patient-h, p ≤ 0.05) and often (six of eight) demonstrated striking suspension of gonadotropin-releasing hormone secretion during sleep. The smaller changes in FSH again resulted in periods of relative LH (daytime) and FSH (nighttime) predominance. When between-group comparisons were made, the girls with central precocious puberty differed significantly from the women in the early follicular phase with respect to each index of gonadotropin secretion except for daytime LH pulse amplitude. Thus, neuroendocrine maturation in the human female appears to be characterized by changes in both the pattern of gonadotropin-releasing hormone secretion and the daily alternating periods of relative LH and FSH predominance in response to sleep.

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency.

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen®) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.

GRF 1-29(Geref®) Therapy Accelerates Growth in Growth Hormone - Deficient(GHD)Children Beyond the First Year of Therapy † 463

GRF 1-29(Geref®) Therapy Accelerates Growth in Growth Hormone - Deficient(GHD)Children Beyond the First Year of Therapy † 463

Prolonged Growth Response to GH (Saizen®) in Pediatric Subjects with GHD Who Responded Poorly to GHRH (Geref®) Therapy

Prolonged Growth Response to GH (Saizen®) in Pediatric Subjects with GHD Who Responded Poorly to GHRH (Geref®) Therapy

Clinical Studies with Growth Hormone Releasing Hormone

Growth hormone secretion is regulated by the interaction of two hypothalamic hormones, growth hormone releasing hormone (GHRH) and somatostatin (SRIH) (1,2). The interaction of these two hypothalamic hormones regulates the pulsatile secretion of growth hormone, which mediates its biological actions. (Fig. 14.1)