The metabolic effects of short-term administration of physiological versus high doses of GH therapy in GH deficient adults.
OBJECTIVE
GH treatment has demonstrated favourable effects on most features of GH deficiency in hypopituitary adults. However, most studies employed supraphysiological GH doses, resulting in deterioration in insulin sensitivity (SI). The short-term metabolic effects of physiological doses of GH therapy in GH deficient (GHD) adults are largely unknown. We therefore compared the effects of short-term administration of two 'physiological' ('lowest' dose: 0.0017 mg/kg/day; 'low' dose: 0.0033 mg/kg/day) with two 'supraphy-siological' ('high' dose: 0.010 mg/kg/day; 'highest' dose: 0.025 mg/kg/day) GH doses on SI, beta-cell function, IGF-1 and IGFBPs -1 and -3 in a group of GHD adults.


METHODS
Thirteen GHD adults were recruited (seven men, aged 23-63 years). For each of the four doses, six patients (three men) were allocated randomly to undergo a 7-day treatment phase. Fasting blood samples were collected daily (days 1-8), and SI and beta-cell function were calculated using the homeostasis model assessment (HOMA).


RESULTS
All four GH doses increased IGF-1, IGFBP-3 and IGF-1/IGFBP-3 ratio, and decreased IGFBP-1 from day 3 onwards (P < 0.05). The highest dose increased fasting glucose (P < 0.001), insulin (P < 0.001) and beta-cell function (P < 0.001), but decreased SI (P < 0.001). The high and low doses did not modify fasting glucose and insulin, SI or beta-cell function, whereas the lowest dose enhanced beta-cell function (P < 0.05). The overall increase in the GH dose increased IGF-1, IGFBP-3, fasting glucose and insulin (P < 0.001), demonstrated a positive correlation with the final change in fasting glucose (r = 0.5, P < 0.05) and insulin (r = 0.8, P < 0.001) and a negative correlation with final SI (r = -0.5, P < 0.05).


CONCLUSIONS
Our results suggest that short-term administration of the highest GH dose induced insulin resistance, whereas the lowest dose (0.0017 mg/kg/day) could represent the optimal starting dose in GHD adults due to its beneficial effects on beta-cell function without compromising SI. It is, however, yet to be determined whether the positive effects of the lowest GH dose on beta-cell function can be demonstrated over a longer period of time.
University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, UK.
K
K
Yuen
D
D
Cook
K
K
Ong
P
P
Chatelain
L
L
Fryklund
P
P
Gluckman
M B
MB
Ranke
R
R
Rosenfeld
D
D
Dunger
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019382:Human Growth Hormone / Q000008:administration & dosage* / Q000172:deficiency* / Q000627:therapeutic use; D006801:Humans; D007018:Hypopituitarism / Q000097:blood / Q000188:drug therapy*; D007328:Insulin / Q000097:blood; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D001786:Blood Glucose; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I