Postnatal overexpression of insulin-like growth factor II in transgenic mice is associated with adrenocortical hyperplasia and enhanced steroidogenesis

The influence of postnatal insulin-like growth factor II (IGF-II) overexpre ssion on adrenal growth and function was investigated in 3-month-old male p hosphoenolpyruvate carboxykinase (PEPCK) promoter human IGF-II transgenic m ice, which are characterized by 4- to 6-fold elevated postnatal IGF-II seru m levels. Plasma corticosterone levels of PEPCK-IGF-II transgenic mice were 2-fold higher than in age- and sex-matched controls, both in the morning ( 7.4 +/- 1.5 vs. 17.8 +/- 3.9 ng/ml, P < 0.01) and in the evening (33.3 +/- 6.5 vs. 65.3 +/- 12 ng/ml, P < 0.01). When PEPCK-IGF-II transgenic mice wer e subjected to an ACTH challenge, corticosterone levels were stimulated g-f old, to 396 +/- 17 ng/ml after 60 min, compared with 230 +/- 24 ng/ml in th e control group. In contrast to corticosterone, plasma ACTH levels were sim ilar in transgenic and control mice, excluding an indirect effect of IGF-II at the hypothalamic or pituitary level. In vitro, the basal and ACTH-induc ed corticosterone production of adrenal glands from transgenic mice was hig her (2-fold and 1.8-fold, respectively) than that of control organs. Howeve r, when normalized for adrenal weight, the in vitro corticosterone secretio n was similar in both groups. At autopsy, adrenal weights of transgenic mic e were significantly greater than those of control adrenal glands (3.3 +/- 0.2 vs. 2.0 +/- 0.2 mg, P < 0.01, n = 10). Furthermore, a local expression of human IGF-II could be demonstrated in transgenic adrenal glands by RT-PC R, whereas in normal adult mice, no adrenal expression of IGF-II was detect ed. Stereological investigation of adrenal glands from another set of PEPCK -IGF-II transgenic mice and controls (6-month-old males) demonstrated that the increase in adrenal weight in transgenic mice is mainly caused by a 50% increase in the number of zona fasciculata cells, whereas cell Volume and zonation of transgenic adrenal glands remained unchanged. In conclusion, ou r data indicate that postnatal overexpression of IGF-II induces an increase d adrenal weight and elevated corticosterone serum levels, presumably by a direct mitogenic effect of IGF-II on adrenocortical fasciculata cells.