No abstract

Thyroid hormones are essential for the normal growth and development of many tissues. In the rat, hypothyroidism is associated with growth impairment, and hyperthyroidism with the development of a hypercatabolic state and skeletal muscle wasting but, paradoxically, cardiac hypertrophy. The mechanism by which thyroid hormone produces cardiac hypertrophy and myosin isoenzyme changes remains unclear. The role of IGF-I, an anabolic hormone with both paracrine and endocrine actions, in producing cardiac hypertrophy was investigated during this study in hyperthyroid, 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 hyperthyroid (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 weight/body weight ratios were, however, significantly increased in the hyperthyroid (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 controls (2.26 +/- 0.03 x 10(-3). Serum IGF-I concentrations were similar in 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 serum, 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 mRNA levels were not statistically different in the control and hyperthyroid animals, but were significantly reduced in the hypothyroid animals (P < 0.05 vs control). Heart IGF-I mRNA levels were similar in the control and hypothyroid rats, but were significantly increased in the hyperthyroid and treated hypothyroid animals (increased by 32% in hyperthyroidism, 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 hypothyroid group (0.11 +/- 0.01 U/mg vs control, 0.13 +/- 0.01 U/mg). Low body mass during both hypothyroidism and hyperthyroidism is therefore associated with reduced systemic IGF bioactivity. In hypothyroidism there is a primary defect in the endocrine function of IGF-I, while in hyperthyroidism serum IGF bioactivity is reduced in the presence of normal endocrine production of this anabolic hormone.(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in thyroid status have a major effect on the GH/insulin-like growth factor (IGF) axis. The majority of IGF in the circulation is bound to specific IGF-binding proteins (IGFBPs) of which six have been cloned and sequenced. We have studied changes in hepatic gene expression of IGFBP-1, -2 and -3, in male Wistar rats rendered hyperthyroid (thyroxine, 200 micrograms/kg per day) or hypothyroid (propylthiouracil, 0.1% daily). Littermates of the same age were used as controls (n = 6 in each group). Thyroxine was measured by radioimmunoassay, and hepatic IGFBP-1, -2 and -3 mRNA levels by Northern blot analysis using specific rat cDNA probes with a 28S ribosomal probe as a loading control. Mean +/- S.E.M. thyroxine levels were 247.0 +/- 44.5 (hyperthyroid group), < 9.0 (hypothyroid group) and 76.0 +/- 4.5 nmol/l (control group). IGFBP-1 and -2 mRNA levels in the hypothyroid animals compared with the controls were significantly increased, but similar levels of expression were found in thyrotoxic and control rats. IGFBP-3 mRNA levels in hypothyroid animals were decreased, and increased in thyrotoxic animals. Thus, in the adult rat, hypothyroidism is associated with increased hepatic IGFBP-1 and -2 gene expression, but decreased IGFBP-3 gene expression, while in thyrotoxicosis there are normal IGFBP-1 and -2 mRNA levels but increased IGFBP-3 gene expression. These results suggest that there is specific and different transcriptional regulation for IGFBP-1, -2 and -3 in hypo- and hyperthyroid rats.

A partially purified fraction of human thyroid-stimulating hormone (DEAE-II) was further purified by ion-exchange chromatography on IRC\x=req-\ 50, gel-filtration on Sephadex G-100 and finally chromatography on DEAE-cellulose. Two fractions were obtained which were high in thyroi d\x=req-\ stimulating activity (8\ m=. \ 3 and 7\ m=. \ 3 units human Research Standard A/mg) and were comparable in potency to other preparations ofthe human hormone reported in the literature. They were also electrophoretically heterogeneous as were the preparations of other workers. Lipolytic activity toward cells obtained from human or rat adipose tissue was demonstrated for all fractions containing thyroid-stimulating activity, the two activities being roughly parallel. It is concluded that both thyroid-stimulating and lipolytic activities are probably present in the same protein molecule, but it is unlikely that the latter activity is of physiological significance. buffer (pH 7-5) containing 5 mM-sodium ion (Stockell Hartree, Butt & Kirkham, 1964). After elution of the unadsorbed fraction (IRC-1) the remaining protein (fraction IRC-2) was eluted from the column with 1 M-ammonium acetate. Each fraction was concentrated by rotary evaporation, the pH adjusted to 5-5 and protein precipitated by slow addition of five volumes of 96 % (v/v) ethanol with stirring. After 2 days the protein precipitate was recovered by centrifugation, washed once with cold 96 % ethanol, twice with ethyl ether and dried in vacuo. The mean weight yield and standard deviation of the fractions in seven experiments was 50-2 + 8-6 % for fraction IRC-1 and 32-5 + 5-5% for fraction IRC-2. Since previous studies had shown that the TSH activity would be concentrated in fraction IRC-2 (Stockell Tube no.