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S Refetoff

Publications and source records attributed to S Refetoff.

At least 199 records · Page 11Linked to original sources
PubMed1981

Growth hormone responses to thyroid hormone in the neonatal rat: resistance and anamnestic response.

Differences in the growth hormone (GH) responses to primary and to secondary stimulation with triiodothyronine (T3) were studied in rats deprived of thyroid hormone from birth. Neonatal hypothyroidism was induced in pups by feeding pregnant rats an iodine-deficient, propylthiouracil-containing diet. T3 stimulation was carried out in pups by subcutaneous injection of a single dose of 50 mug T3/100 g body wt. Pituitary GH content, rate of GH synthesis in vitro, and GH messenger (m)RNA activity in a cellfree translation system were measured.No significant differences in body weight and in pituitary GH content were observed between hypothyroid and normal pups at ages 1, 3, and 6 d. 10- and 28-d-old hypothyroid pups showed a significant arrest of growth, decreased pituitary GH content, and development of GH responsiveness to T3. In contrast, serum thyroxine concentration in hypothyroid pups was <0.15 mug/dl, significantly lower than normal at all ages.GH synthesis and GH mRNA activity studied in pituitaries of 28-d-old rats were expressed as percent total protein synthesis and percent mRNA activity, respectively. GH synthesis and mRNA activity were 3.0 and 2.6% in hypothyroid rats, 3.3 and 2.9% in hypothyroid rats given a single T3 injection 14 d earlier (T3-withdrawn rats), and 26.8 and 27.1% in normal rats. Administration of T3 to hypothyroid rats induced an increase in GH synthesis and GH mRNA activity, reaching 5.8 and 5.6% 12 h after primary stimulation and 12.2 and 16.1% 12 h after secondary stimulation. The response rates were linear but 2.5-fold more rapid after secondary stimulation. The latter response was similar to that observed after T3 stimulation of rats rendered hypothyroid during adulthood. The responses of GH synthesis and mRNA activity were concordant after both primary and secondary T3 stimulation. A twofold increase in both parameters was observed as early as 2 h after T3 injection. Four conclusions can be drawn from these experiments. First, during neonatal life, GH accumulation in rat pituitaries is independent of thyroid hormone and is insensitive to T3. Second, GH dependence on and sensitivity to thyroid hormone is acquired between the 6th and 10th d of neonatal life. Third, secondary T3 stimulation produces an anamnestic response manifested by an increased rate of GH synthesis and mRNA activity. Fourth, primary T3 stimulation is not associated with a lag in the endogenous translation of the newly accumulated GH mRNA.

Animals↗
PubMed1981

The effect of thyroid hormone on glycosaminoglycan accumulation in human skin fibroblasts.

Because the dermis of myxedematous humans is known to accumulate increased amounts of glycosaminoglycan (GAG), we were prompted to study the effects of thyroid hormone depletion in vitro. Human skin fibroblasts were grown to confluence in medium containing 10% fetal calf serum (FCS). Some cultures were shifted to a medium containing FCS depleted of thyroid hormone (D-FCS) or to a D-FCS medium to which 10(-7) M triiodothyronine (T3) was added (D-FCS + T3). Cultures were then labeled for 16 h with [3H]-acetate, harvested and combined with the media. After pronase digestion, the non-trichloroacetic acid precipitable, non-dialysable material was digested with streptomyces hyaluronidase followed by chondroitinase ABC. Digestable material was separated by G-50 Sephadex column chromatography. The cultures incubated in media containing D-FCS accumulated 2.8-fold more hyaluronic acid and 2.1-fold more chondroitin sulfate than did sister cultures incubated in the presence of D-FCS + T3. The addition of T3 to the D-FCS reduced the amounts of GAG accumulated nearly to the levels observed in cultures grown in FCS. The data indicate that thyroid hormone exerts an inhibitory effect on GAG accumulation in human skin fibroblasts. This model offers the opportunity to study thyroid hormone action in vitro using an easily accessible human tissue.

Cells, Cultured↗
PubMed1980

Ontogenetic patterns of thyrotropin-releasing hormone-like material in rat hypothalamus, pancreas, and retina: selective effect of light deprivation.

Recent observations have shown the presence of thyrotropin-releasing hormone-like material (TRH-LM) in rat pancreatic islets and in retina. Its immunological and biological properties are identical to those of synthetic thyrotropin-releasing hormone (thyroliberin). This communication deals with the ontogenesis of TRH-LM in rat pancreas and retina as compared to that of rat hypothalamus. Effects of sex and exposure to constant dark were also studied. Results show that asynchronous changes in the concentration of TRH-LM occur during the postnatal maturation of these tissues, presumably mediated by organ-specific control mechanisms--e.g., light affects only the accumulation of TRH-LM in the retina. TRH-LM may act as neurotransmitter in the regulation of pancreatic islet cell function and in the development of photo-reception in the retina. Increases in hypothalamic TRH-LM seem to parallel the development of the pituitary-thyroid secretory activity, but the function of extrahypothalamic TRH-LM remains speculative.

Animals↗
PubMed1980

Thyroid function in a uremic rat model. Evidence suggesting tissue hypothyroidism.

The main objective of this study was to determine whether the principal abnormality of thyroid function observed in patients with chronic renal failure, low serum triiodothyronine (T(3)) concentration, causes hypothyroidism at the tissue level. A partially nephrectomized (Nx) uremic rat model was developed and the following parameters of thyroid function were assessed: serum total thyroxine (TT(4)), total T(3) (TT(3)), and thyrotropin and liver T(3) content, and activity of two thyroid hormone-dependent enzymes, mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosol malate dehydrogenase (MDH). The results were compared to those of intact control (C), thyroidectomized (Tx), and nephrectomized-thyroidectomized (NxTx) littermates.Results expressed as mean+/-SEM showed that Nx rats had a fivefold increase in blood urea nitrogen, (112+/-20 mg/dl in Nx, and 22+/-1 mg/dl in C) and manifested all the changes of of thyroid function observed in uremic men, including a low serum TT(3) level (30+/-7 ng/dl in Nx and 50+/-6 ng/dl in C). In the liver, T(3) was significantly reduced (18+/-2 ng/total liver in Nx and 35+/-3 ng/total liver in C) as well as the activities of alphaGPD (8.8+/-1.0 and 16.1+/-1.5 DeltaOD/min per total liver in Nx and C, respectively) and MDH (6.3+/-1.6 and 12.6+/-2.2 U/total liver in Nx and C, respectively). The reduction in liver enzyme activities correlated significantly with the decrease in T(3) content. The changes in Tx rats were as expected, showing a profound reduction in serum hormone levels, liver T(3) content, and liver enzyme activities. Serum thyrotropin was markedly elevated to 2,390+/-212 ng/ml as compared to 703+/-61 in C and 441+/-87 ng/ml in Nx rats. The NxTx rats showed the combined effects of nephrectomy and thyroidectomy; blood urea nitrogen was elevated to 203, and serum levels of TT(4), TT(3), and thyrotropin were 0.4, <10, and 2,525, respectively. Total liver T(3) and alphaGPD and MDH were strikingly low; the corresponding values were 3.5, 2.4, and 2.5.l-triiodothyronine replacement (0.4 mug/100 g body wt/d) for 4 wk in the Nx rats resulted in significant increases in liver enzyme activities, alphaGPD and MDH rose by 70 and 60% over their respective basal values without alteration in the severity of azotemia. From these data, we conclude that the reduction of liver T(3) content in the uremic rats, accompanied by a decrease in alphaGPD and MDH activity, indicates the presence of hypothyroidism at the tissue level. Restoration of enzyme activities toward normal levels after T(3) administration provided further supporting evidence that the diminution in liver enzyme activity was causally related to tissue T(3) deficiency.

Animals↗
PubMed1980

Transient elevation of serum thyroid hormone concentration after initiation of replacement therapy in myxedema.

Measurements of thyroid hormone concentrations in serum are commonly used to determine the proper dose of hormone replacement. We have noted that early in the course of thyroxine (T4) replacement in myxedema, serum T4 concentrations may be transiently elevated before reaching a lower "steady-state" level. This observation is illustrated in a study of six patients. Serum T4, free thyroxine index, and triiodothyronine (T3) rose to peak concentrations at 2 to 6 weeks, 35% to 120% above the values achieved 4 to 8 months later. Values were transiently in the thyrotoxic range in five of the six patients. This phenomenon is most likely due to a decrease in the metabolic clearance rate of the absorbed hormone associated with hypometabolism. Thus, serum T4 and T3 concentrations during the first 6 months of therapy do not reflect the optimal dose of T4 replacement on a long-term basis.

Adolescent↗
PubMed1979

Comparison of primary and secondary stimulation of male rats by estradiol in terms of prolactin synthesis and mRNA accumulation in the pituitary.

Male rats received acute or chronic primary or acute secondary stimulation with estradiol, and the effects on pituitary prolactin synthesis and its mRNA accumulation were examined. Prolactin synthesis was determined by the in vitro incorporation of [(3)H]leucine into prolactin over a period of 1 hr. Prolactin mRNA was measured both by cell-free translation in a nuclease-treated rabbit reticulocyte lysate and by hybridization to the complementary DNA. The latter two methods gave similar results under all experimental conditions. Acute primary stimulation with estradiol produced a significant increase in pituitary prolactin mRNA accumulation at 12 hr, which further increased by 2- to 3-fold over the next 48 hr. In contrast, no increase in prolactin synthesis was observed during the first 24 hr. Chronic stimulation with estradiol induced increases of both prolactin synthesis and prolactin mRNA that were quantitatively indistinguishable over the period of 1-4 weeks, reaching a plateau at 5-fold the basal values. By the 13th day after withdrawal of therapy both prolactin synthesis and mRNA had returned to the prestimulation levels. When the effects of estradiol on previously unexposed and estrogen withdrawn animals were compared, it was found that secondary stimulation not only produced a more rapid accumulation of the prolactin mRNA but also abolished the lag period of prolactin synthesis observed during the primary estrogen stimulation. These data demonstrate a lag in the endogenous translation of newly accumulated pituitary prolactin mRNA translatable in vitro after primary estrogen stimulation of male rats. The mechanism for the abolition of this lag during the secondary stimulation is now known.

Animals↗
PubMed1978

High concentration of thyrotropin-releasing hormone in pancreatic islets.

The concentration of thyrotropin-releasing hormone (TRH, thyroliberin) in rat islets of Langerhans is 30-fold higher than in whole rat pancreas, indicating that the islets are the main source of pancreatic TRH. The TRH extracted from islets is indistinguishable from synthetic TRH in its immunological and biological properties and in its inactivation by human serum. The physiologic function of islet TRH is unknown. However, because TRH is antagonistic to somatostatin in other systems, and somatostatin also is concentrated in islets in high concentrations, it is possible that islet TRH may serve a similar antagonistic function in the regulation of islet cell secretory activity.

Animals↗