ENDOCRINE AND CARDIAC PARACRINE ACTIONS OF INSULIN-LIKE GROWTH FACTOR-I (IGF-I) DURING THYROID-DYSFUNCTION IN THE RAT - IS IGF-I IMPLICATEDIN THE MECHANISM OF HEART-WEIGHT BODY-WEIGHT CHANGE DURING ABNORMAL THYROID-FUNCTION

Thyroid hormones are essential for the normal growth and development o f many tissues. In the rat, hypothyroidism is associated with growth i mpairment, and hyperthyroidism with the development of a hypercataboli c state and skeletal muscle wasting but, paradoxically, cardiac hypert rophy. The mechanism by which thyroid hormone produces cardiac hypertr ophy and myosin isoenzyme changes remains unclear. The role of IGF-I, an anabolic hormone with both paracrine and endocrine actions, in prod ucing cardiac hypertrophy was investigated during this study in hypert hyroid, hypothyroid and control rats. A treated hypothyroid group was also included in order to assess the effect of acute normalization of thyroid function. Body weight was significantly lower in the hyperthyr oid (mean +/- S.E.M.; 535.5 +/- 24.9 g, P < 0.05), hypothyroid (245.3 +/- 9.8 g, P < 0.001) and treated hypothyroid (265.3 +/- 9.8 g, P < 0. 001) animals when compared with controls (618.5 +/- 28.6 g). Heart wei ght/body weight ratios were, however, significantly increased in the h yperthyroid (2.74 +/- 0.11 x 10(-3), P < 0.01) and treated hypothyroid (2.87 +/- 0.07 x 10(-3), P < 0.001) animals when compared with contro ls (2.26 +/- 0.03 x 10(-3)). Serum IGF-I concentrations were similar i n the control and hyperthyroid rats (0.91 +/- 0.07 vs 0.78 +/- 0.04 U/ ml, P = 0.26), but bioactivity was reduced by 70% in hyperthyroid seru m, suggesting a circulating inhibitor of IGF. Serum IGF-I levels (0.12 +/- 0.03 U/ml, P < 0.001) and bioactivity (0.12 +/- 0.04 U/ml, P < 0. 001) were significantly lower in the hypothyroid group. Liver IGF-I mR NA levels were not statistically different in the control and hyperthy roid animals, but were significantly reduced in the hypothyroid animal s (P < 0.05 vs control). Heart IGF-I mRNA levels were similar in the c ontrol and hypothyroid rats, but were significantly increased in the h yperthyroid and treated hypothyroid animals (increased by 32% in hyper thyroidism, P < 0.05; increased by 57% in treated hypothyroidism, P < 0.01). Cardiac IGF-I was significantly elevated in hyperthyroidism (0. 16 +/- 0.01 U/mg heart tissue, P < 0.01), was low in hypothyroidism (0 .08 +/- 0.01 U/mg, P < 0.01) and was normalized in the treated hypothy roid group (0.11 +/- 0.01 U/mg vs control, 0.13 +/- 0.01 U/mg). Low bo dy mass during both hypothyroidism and hyperthyroidism is therefore as sociated with reduced systemic IGF bioactivity. In hypothyroidism ther e is a primary defect in the endocrine function of IGF-I, while in hyp erthyroidism serum IGF bioactivity is reduced in the presence of norma l endocrine production of this anabolic hormone. In contrast, the para crine actions of IGF-I are increased in the heart during hyperthyroidi sm, and this hormone appears to play a part in the development of hype rthyroid cardiac hypertrophy.