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Biomedical subjects

S Refetoff

Publications and source records attributed to S Refetoff.

At least 19 recordsLinked to original sources
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 When the effects of estradiol on previously unexposed and estrogen withdrawn animals were compared, it was found that secondary stimulation not only produced a more rapid accumulation of the prolactin mRNA but also abolished the lag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↗
PubMed1978

Early in vitro induction of rat pituitary GH mRNA by T31.

Previous work has shown that thyroid hormone stimulates rat pituitary GH synthesis and GH mRNA activity and concentration. However, the earliest demonstration of increase in GH mRNA activity was 24 hours following T3 addition whereas stimulation of GH synthesis has been observed 2 hours after treatment with T3. Thus, it is unknown whether increase in pituitary GH mRNA is a prerequisite for the stimulation of GH synthesis. In the present investigation in vitro addition of 1.5 x 10(-10) M T3 to pituitaries isolated from hypothyroid rats resulted in a slight but significant increase of GH mRNA activity within 2 hours. Further stimulation of GH mRNA activity was observed over the period of 12 hours. No increase of GH mRNA activity occurred in the absence of T3, and T3 had no effect on the PRL mRNA activity. These findings suggest that increase in GH mRNA may be responsible for the observed induction of GH synthesis, and that at least one of the primary actions of thyroid hormone is at the nuclear level.

Animals↗
PubMed1978

Heterogeneous human prolactin from a giant pituitary tumor in a patient with panhypopituitarism.

A patient with hypopituitarism and an unusually large chromophobe adenoma which secreted an enormous amount of human PRL (hPRL) provided us with a unique opportunity to study the heterogeneity of hPRL. Serum samples obtained before and after surgery as well as pituitary extract were studied. Each sample contained three distinct hPRL peaks on gel filtration designated as big medium, and small. The hPRL moiety of each peak fraction was stable in size, immunoreactivity, and bioreactivity, indicating that the polymorphic hPRL components, once formed, were not interconvertible. As the relative proportion of medium and small hPRL components in all blood samples obtained before surgery and in the pituitary tumor extracts were similar, it seems that these two forms of hPRL originate from the tumor. However, there was a lack of correlation between big, medium, and small hPRL in samples obtained before and 1 yr after surgery. Also, increasing amounts of radioactive substance similar to increasing amounts of radioactive substance similar to big PRL were formed by exposure of 125I-labeled small PRL to progressively larger concentrations of serum. Thus, only small and possibly medium PRL are secretory products.

Adenoma, Chromophobe↗
PubMed1978

Abnormalities of triiodothyronine binding to lymphocyte and fibroblast nuclei from a patient with peripheral tissue resistance to thyroid hormone action.

T3 binding to lymphocyte nuclei has been studied in normal individuals and in a patient (MaG) with peripheral resistance to thyroid hormone action. This syndrome is defined by the presence of hypothyroidism or euthyroidism with high plasma levels of thyroid hormone. T3 bound to a single set of binding sites in normal adult lymphocyte nuclei with a mean Ka of 8.9 +/- 7.1 x 109 M-1, and a capacity of 4.4 +/- 2.9 fmol/100 micrograms DNA. A single binding site was also disclosed in MaG's lymphocytes with a Ka of 0.43 x 109 M-1 and a capacity of 10.5 fmol/100 micrograms DNA. This low affinity was not due to the presence of high plasma T3 level in the patient, since administration of 100 micrograms T3 to normal adult volunteers induced the presence of two different binding sites. The mechanism responsible for this phenomenon is unknown. To binding was also studied using cultured fibroblasts which were incubated in serum-less medium before the binding experiments. One single binding site (Ka, 1.9 x 10(10) M-1, capacity, 12.9 fmol/100 micrograms DNA) was detected in normal fibroblast nuclei. In contrast, a curvilinear Scatchard plot was obtained when MaG's fibroblasts were used. This result could be compatible with the presence of either two different binding sites or negative cooperativity. In support of the latter possibility, Hill plots gave a number lower than unity. The results suggest that the syndrome of peripheral tissue resistance to thyroid hormone action due to a defect at the level of the nuclear receptor. The possible existence of similar syndromes due to an alteration at the level of a post-T3-binding mechanism is not eliminated.

Adolescent↗
PubMed1977

Iodination-deiodination. A radiochemical method for detection of structure and changes in structure in RNA.

Bound iodine is released from radioiodinated nucleotides in polymers exposed to sodium bisulfite. The rate of bisulfite-catalyzed deiodination of pyrimidines can be controlled both by change of temperature of pH and is also dependent on the molecular association of the nucleotide. The rate of release of iodine from iodocytidine in polycytidylate is greater than the rate of elimination from RNA. Experiments testing the influence of base-pairing of the iodopyrimidines in synthetic polynucleotides showed that pairing of the substituted nucleotide protected the iodine bond. The rates of bisulfite-catalyzed deiodination of several radioiodinated RNAs were measured. The action of bisulfite on all single stranded RNAs tested was multiphasic consisting of a rapid early deiodination reaction supplanted by a slower phase which was followed by reacceleration of release. The release of iodine from double stranded RNA and DNA-RNA duplexes was retarded in comparison with the release from ribosomal and messenger RNA fractions. The deiodination profiles of single and double stranded RNA suggested that the intermediate stage iodine release is governed by melting of paired zones of low stability. Late release may result from destablization of the molecule through the addition of bisulfite to the pyrimidine ring or deamination. The effect of several substances expected to complex with polynucleotides was tested. Acridine orange and ethidium bromide increased loss of iodine from ribosomal RNA but slightly decreased elimination from double stranded viral RNA. A basic protein fraction isolated from ribosomal particles accelerated the deiodination of ribosomal RNA. While the destabilization caused by this protein fraction was greater than that caused by an equal amount of albumin, as tested the effect was non-specific. The results show that a change in sensitivity to chemical deiodination may folow the interaction of small amounts of protein with polynucleotides.

Animals↗
PubMed1977

Triiodothyronine stimulates specifically growth hormone mRNA in rat pituitary tumor cells.

In a cell-free protein-synthesizing system from a rabbit reticulocyte lysate, total RNA extracted from cultured rat pituitary tumor (GH3) cells directed, in a dose-related manner, the synthesis of proteins that were precipitated by antisera specific to rat growth hormone (somatotropin) and rat prolactin. A marked decrease in growth hormone secretion and growth hormone mRNA activity was observed when cells were grown in a medium deficient in thyroid hormone. Addition of triiodothyronine in physiologic amounts both prevented and completely reversed this effect within 48 hr. Thyroid hormone had no effect on prolactin secretion or prolactin mRNA activity. These data suggest that thyroid hormone may stimulate synthesis of growth hormone through induction of transcriptional activity. The possibility of an additional effect at the posttranscriptional level has not been excluded. Although thyroid hormone is believed to have a general effect on a variety of metabolic processes, some effects, at the molecular level, may be quite selective, as indicated by the observed changes in growth hormone but not prolactin mRNA activity. The GH3 cell model is useful in the study of triiodothyronine action because of independence from secondary hormonal effects caused by hypothyroidism and because simultaneous measurement of prolactin mRNA activity serves as a unique internal control.

Cell Line↗
PubMed1977

The action of thyroid hormone.

Thyroid hormone affects both developmental and metabolic processes. It has a relatively specific effect on the synthesis of a number of enzymes and other proteins. The fundamental cellular mechanism of action seems to be at the level of genetic regulation. It involves interaction with nuclear receptors, leading to an activation of the protein synthesizing machinery. How binding to receptors is coupled to genetic activation is completely unknown. At least part of the metabolic effects of thyroid hormone could be mediated through an interaction with mitochondria and cell membrane, and with some enzymatic systems such as adenylcyclase.

Animals↗
PubMed1977

Thyroid dysfunction in chronic renal failure. A study of the pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine.

Thyroid function was evaluated in 46 patients with end-stage kidney disease and 42 normal subjects. Patients were studied before and after the institution of maintenance hemodialysis (HD) and after renal transplantation (RT). Serum total triiodothyronine concentrations (TT(3), ng/100 ml, mean+/-SD) were 63+/-17 and 83+/-22 in the non-HD and HD groups, respectively. Values from normal subjects were 128+/-25 and from RT patients 134+/-20. The TT(3) was in the hypothyroid range (<78 ng/100 ml; 2 SD below normal mean) in 80% of non-HD and 43% of HD patients. Mean serum total thyroxine concentration (TT(4)), although within the normal range, was lower than the control value. T(4)-binding globulin capacity was also slightly lower but the difference was not statistically significant. Among patients whose TT(4) was 1 SD below the normal mean, the free T(4) index was equally depressed, suggesting that factors other than decreased binding capacity might be responsible for the low TT(4). In addition, there was a 37% incidence of goiter. Mean serum thyroid-stimulating hormone (TSH) was not elevated and the TSH response to thyrotropin-releasing hormone (TRH) was distinctly blunted, suggesting the possibility of pituitary dysfunction as well. In vivo (125)I-l-T(4) and (131)I-l-T(3) kinetics during 0.2 mg/day of l-T(4) replacement showed marked reduction in T(3) turnover rate in the uremic patients, both before and during HD; the values (mug T(3)/day, mean+/-SD) for the different groups were as follows: normal, 33.8+/-6.1; non-HD, 13.5+/-2.6; HD, 12.9+/-3.1; and RT, 30.3+/-7.1. The low T(3) turnover rate was due to impaired extrathyroidal conversion of T(4) to T(3). The mean percent+/-SD of metabolized T(4) converted to T(3) was 37.2+/-5.8 in normal subjects, 15.7+/-3.1 in non-HD, 12.8+/-1.7 in HD, and 34.0+/-14.7 in RT patients. In contrast, thyroidal T(3) secretion rate was not different between the control and the three patient groups. Thus, it appears that uremia affects thyroid function at several levels: (a) subnormal pituitary TSH response to TRH; (b) possible intrathyroidal abnormalities as suggested by slightly decreased TT(4) and high incidence of goiter; and (c) abnormal peripheral generation of T(3) from T(4). Restoration of renal function with RT resulted in normalization of all parameters of thyroid function with the exception of blunted or absent TSH response to TRH. The latter may be a direct consequence of glucocorticoid administration.

Adult↗
PubMed1977

Induction of hypothyroidism and hypoprolactinemia by growth hormone producing rat pituitary tumors.

The GH3 rat pituitary tumor cell line which secretes both growth hormone (GH) and prolactin (PRL) stopped releasing PRL when transplanted to animals; furthermore, it suppressed PRL production by the hosts' pituitary glands. When the same tumor was transferred back to cell culture, PRL production resumed. The PRL to GH ratio in cell culture medium and cells ranged from 5 to 1 while in the tumor and serum of the host animals it averaged 0.09 and 0.001, respectively. To investigate further this phenomenon, female rats were transplanted with GH3 tumors (T) and compared to intact normal (N) and to thyroidectomized (Tx) rats. T animals were larger and had splanchnomegaly but smaller pituitaries and thyroids. Serum PRL concentrations in the basal state were decreased, as were levels of triiodothyronine (T3), thyroxine (T4), and free T4 index. Despite reduced serum thyroid hormone concentrations, and in contrast to Tx animals, the serum thyrotropin (TSH) level in T rats was not elevated and they did not show a supranormal TSH response to thyrotropin-releasing hormone (TRH) administration. The PRL response to TRH in T animals was completely abolished while all N and Tx animals responded by a significant increase in serum PRL. Serum corticosteroids and estrogens were normal in T rats. Pituitary content of PRL was decreased and that of TSH increased in T rats. Tx animals, however, had a reduced pituitary content of PRL, TSH, and GH. When GH3 cells were grown in cell culture media containing serum from T animals, there was a reduction of PRL content in cells and released in the medium. Addition of T3 to the T serum did not alter its suppressive effect on PRL nor did rat GH added to N serum alter PRL production and release in vitro. In a preliminary experiment, rats injected ip with 50 mug hGH in two divided doses for eighteen days, suppressed serum T4 and T3 concentrations; pituitary content of TSH was significantly increased and that of PRL slightly decreased. Injection with 250 mug oPRL or saline, on the same schedule and for the same length of time, had no significant effect on the levels of serum thyroid hormones. Thus, GH, but also possibly other substance(s) secreted by GH3 tumors in vivo a) suppress the production of tumor and pituitary PRL; b) suppress the release of TSH, causing mild hypothyroidism; c) inhibit the PRL and TSH responses to TRH; and d) decrease the production of PRL in tissue culture. Although no simple and unifying theory could explain these findings, an hypothesis implicating somatomedin is presented.

Adrenal Cortex Hormones↗
PubMed1977

Graves' disease associated with familial deficiency of thyroxine-binding globulin.

Five patients presented with symptoms of Graves' disease and a marked decrease in their thyroxine-binding globulin (TBG) capacity. While thyrotoxic, mean values +/- SD for the 5 patients were: total thyroxine (TT4) 8.8+/-2.0 mug/100 ml (normal range 4.4-9.3); TBG capacity 6.1+/-1.1 mug T4/100 ml (normal range 16-24); free thyroxine index (FTI) 25.3+/-8.9 (normal range 3.6-9.3); and total triiodo-thyronine (TT3) 244+/-56 ng/100 ml (normal range 80-160). When euthyroid, both TT4 (2.8+/-0.8 mug/100 ml) and TT3 (68+/-12 ng/100 ml) were below the normal range and FTI (5.8+/-0.6) was normal. All patients were male, and family studies revealed decreased TBG capacity in blood relatives consistent with X-chromosome linked inheritance. All examined relatives relatives of the propositi, whether hemizygous or heterozygous, were euthyroid. Over the same period of time 7 additional patients (excluding family members of propositi) were found to be euthyroid but had decreased TBG capacity. The occurrence of thyrotoxicosis in 5 out of 12 patients with inherited TBG deficiency suggests an association rather than a coincidental finding, although initial tests were performed because of suspected thyroid dysfunction. The incidence of thyrotoxicosis in patients with inherited TBG deficiency is also high on the basis of the reported prevalence of the latter genetic abnormality. This study stresses the importance of determining TT3 and FTI on patients who are clinically thyrotoxic but have normal TT4.

Adult↗
PubMed1977

Serum albumin and antibodies in the diagnosis of thyroid cancer.

Anti-thyroglobulin antibodies, anti-thyroid microsomal antibodies, serum thyroglobulin, and carcinoembryonic antigen were assayed in sera of patients with a history of thyroid irradiation and in patients with thyroid cancer. In irradiated patients, the frequency of positive results for each test was increased above the frequency found in a control population, with a significant increase at P less than .05 for TGHA and TG levels. However, the tests (with the exception of serum thyroglobulin) did not clearly segregate irradiated patients with benign or malignant lesions from those with no clinically detectable abnormalities. Elevations of serum thyroglobulin above 300 ng/ml were found only in patients with thyroid cancer, but in these patients the diagnosis was usually clinically obvious.

Adult↗