EFFECTS OF ANTAGONISTS OF GROWTH HORMONE-RELEASING HORMONE (GHRH) ON GH AND INSULIN-LIKE-GROWTH-FACTOR-I LEVELS IN TRANSGENIC MICE OVEREXPRESSING THE HUMAN GHRH GENE, AN ANIMAL-MODEL OF ACROMEGALY
M. Kovacs et al., EFFECTS OF ANTAGONISTS OF GROWTH HORMONE-RELEASING HORMONE (GHRH) ON GH AND INSULIN-LIKE-GROWTH-FACTOR-I LEVELS IN TRANSGENIC MICE OVEREXPRESSING THE HUMAN GHRH GENE, AN ANIMAL-MODEL OF ACROMEGALY, Endocrinology, 138(11), 1997, pp. 4536-4542
Transgenic mice overexpressing the human GH-releasing hormone (hGHRH)
gent, an animal model of acromegaly, were used to investigate the effe
cts of potent GHRH antagonists MZ-4-71 and MZ-5-156 on the excessive G
H and insulin-like growth factor I(IGF-I) secretion caused by overprod
uction of hGHRH. Because metallothionein (MT)-GHRH mice express the hG
HRH transgene in various tissues, including the pituitary and hypothal
amus, initial experi ments focused on the effectiveness of the GHRH an
tagonists in blocking basal and stimulated GH secretion from pituitary
cells in vitro. Both MZ-4-71 and MZ-5-166 suppressed basal release of
GH from superfused MT-GHRH pituitary cells, apparently by blocking th
e action of endogenously produced hGHRH. In addition, these antagonist
s effectively eliminated the response to stimulatory action of exogeno
us hGHRH(1-29)NH2(30 and 100 nM). To ascertain whether MZ-4-71 and MZ-
5-156 could antagonize the effect of hGHRH hyperstimulation in vivo, e
ach antagonist was administered to MT-GHRH transgenic mice in a single
iv dose of 10-200 mu g. Both compounds decreased serum GH levels in t
ransgenic mice by 39-72% at 1 h after injection. The inhibitory effect
of 50 mu g MZ-5-156 was maintained for 5 h. Twice daily ip administra
tion of 100 mu g MZ-5-156 for 3 days suppressed the highly elevated se
rum GH and IGF-I concentrations in transgenic mice by 56.8% and 39.0%,
respectively. This treatment also reduced IGF-I messenger RNA levels
in the liver by 21.8% but did not affect the level of GH messenger RNA
in the pituitary. Our results demonstrate that GHRH antagonists MZ-4-
11 and MZ-5-156 can inhibit elevated GH levels caused by over-producti
on of hGHRH. The suppression of circulating GH concentrations induced
by the antagonists seems to be physiologically relevant, because both
IGF-I secretion and synthesis also were reduced. Our findings, showing
the suppression of GH and IGF-I secretion with GHRH antagonists, sugg
est that this class of analogs could be used for the diagnosis and the
rapy of disorders characterized by excessive GHRH secretion.