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Biomedical subjects

R Docter

Publications and source records attributed to R Docter.

At least 37 records · Page 2Linked to original sources
PubMed1993

The importance of thyroid microsomal antibodies in the development of elevated serum TSH in middle-aged women: associations with serum lipids.

OBJECTIVE: We assessed the relative risk of both serum TSH and antithyroid antibody concentrations with regard to progression of thyroid failure and studied the lipid profiles of individuals with elevated TSH levels. DESIGN, PATIENTS AND MEASUREMENTS: In a randomly selected group of 427 women aged 40-60 (mean 55) years volunteering in an epidemiological survey in Zoetermeer, TSH and thyroid microsomal antibodies (TMA) were determined. Ten years after the initial survey only TSH was measured and the lipid profiles of the individuals with elevated serum TSH levels were studied and compared with a reference group. RESULTS: During follow-up, four of 427 women were treated with thyroxine. Seventeen of 423 women initially had elevated serum concentrations of TSH (> 4.2 mU/l), 11 of whom were TMA positive. In the group of 406 women with initially a normal TSH, nine out of 37 (24%) TMA-positive women developed elevated serum levels of TSH over 10 years. In contrast only 10 of 369 (3%) TMA-negative women had elevated serum TSH levels 10 years after the initial survey (P < 0.001). Altogether, at the end of the observation period, 40% of TMA-positive subjects had elevated serum TSH concentrations, compared to 3% in the TMA-negative group (P < 0.01). TSH levels in the upper part of the normal range also appeared to have a predictive value: if those both with TSH levels between 2.0 and 4.2 and with a positive TMA status were contrasted with those without antibodies and low TSH, the crude relative risk was 71.5 (31.0-164.3), whereas the crude relative risk of presence versus absence of TMA was only 36.3 (18.8-70.3). Women with elevated TSH levels did not show changes in serum concentrations of total cholesterol (7.4 +/- 1.1 mmol/l), apo-A, (4.7 +/- 1.0 mmol/l) and apo-B (3.1 +/- 0.7 mmol/l) lipoproteins, compared with control individuals (7.2 +/- 1.3, 4.7 +/- 0.8 and 3.0 +/- 0.7 mmol/l, respectively). CONCLUSIONS: The determination of serum TMA in middle-aged women can identify an important group of women at risk of developing an elevated serum TSH. TMA measurement is of potential use in the prevention of cardiovascular disease. An elevated serum TSH, however, in our study-group does not seem to be accompanied by an abnormal lipid profile, as reported by others.

Adult↗
PubMed1993

Evidence for carrier-mediated uptake of triiodothyronine in cultured anterior pituitary cells of euthyroid rats.

T3 uptake and TSH secretion were investigated in anterior pituitary cells isolated from adult fed Wistar rats and cultured for 3 days in medium containing 10% fetal calf serum. TSH release during culture increased linearly with the number of cells in the range of 80,000-800,000 cells/well. Uptake and incubation experiments were performed at 37 C in medium containing 0.5% BSA. Incubation with TRH (0.1 microM) for 2 h stimulated TSH release 2.6-fold, and this effect was partly (approximately 45%) suppressed by preexposure for 2 h to T3 (0.01-1 microM) or T4 (1 microM). Similar concentrations of T3 and T4 reduced the cellular uptake of [125I]T3 (50 pM) during 1 h of incubation by 55%. After 15 min of incubation, [125I]T3 uptake (percent dose) amounted to 1.26 +/- 0.05% (mean +/- SE; n = 9)/500,000 cells. The major part (75%) of the [125I]T3 was found in the extranuclear fraction. Simultaneous incubation with unlabeled T3 (1 or 10 microM) reduced [125I]T3 uptake by 43% (n = 3; P < 0.001) and 52% (n = 6; P < 0.001), respectively. Reduction of the temperature to 20 C diminished the T3-suppressible fraction of [125I]T3 uptake approximately 3-fold. After preincubation (30 min) and incubation (15 min) with monodansylcadaverine (100 microM), the uptake of [125I]T3 was reduced by 32% (n = 3; P < 0.01). When the Na+ gradient was reduced by preincubation and incubation with ouabain (0.5 mM) or monensin (10 or 100 microM), T3 uptake was inhibited by 25% (n = 5; P < 0.01), 37% (n = 6; P < 0.001), and 61% (n = 3; P < 0.001), respectively. It is concluded that 1) T3 is taken up by the pituitary by a carrier-mediated mechanism, and 2) this uptake is at least partly dependent on the Na+ gradient.

Animals↗
PubMed1993

High neonatal triiodothyronine levels reduce the period of Sertoli cell proliferation and accelerate tubular lumen formation in the rat testis, and increase serum inhibin levels.

T3 was injected daily in newborn rats from birth to 16 days of age. Control rats received daily injections of vehicle during the same period. The proliferative activity of the Sertoli cells was studied by means of bromodeoxyuridine incorporation, and tubular lumen formation and nuclear size were taken as markers of Sertoli cell differentiation. T3 treatment strongly reduced the proliferative activity of Sertoli cells from day 7 on, and on day 12, proliferation of Sertoli cells had ceased, while in control rats proliferating Sertoli cells were observed up to day 16. As a result of the reduced Sertoli cell proliferation, the final Sertoli cell number per testis at 23 days of age was reduced by 50% from 38 +/- 1 x 10(6) in control rats to 19 +/- 1 x 10(6) in T3-treated rats. Lumen formation in seminiferous tubules of T3-treated rats began at 12 days of age, while in controls lumen formation was first observed at 16 days. The area of the Sertoli cell nuclei was somewhat larger in T3-treated rats on day 16, but not at any other age examined. Body and testis weights in adult rats at 100 days of age were reduced by 46% and 48% of control values, respectively. The high neonatal T3 levels reduced serum levels of TSH on days 7 and 9, but not at any other age examined. FSH levels were reduced in T3-injected rats on days 5 and 7 and increased on day 23, after cessation of treatment. Immunoreactive inhibin-alpha levels were increased on days 5-9 and reduced on days 16 and 23. These findings indicate that T3 stimulates the production of immunoreactive inhibin by Sertoli cells, but also of bioactive inhibin, as indicated by the reduced FSH levels. It is concluded that the levels of thyroid hormones early in life are important for the terminal differentiation of Sertoli cells and, therefore, for determining adult testis size. The data indicate that this might be a direct effect of T3 on Sertoli cells.

Aging↗
PubMed1993

A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia.

We studied the effects of 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate, and hippuric acid on iodide production by rat hepatocytes in primary cultures. We questioned whether these substances could explain the alteration of serum thyroid hormone parameters observed in renal failure. Iodide production from [125I]T4 by rat hepatocytes was significantly inhibited in the presence of serum from uremic patients. Serum concentrations of CMPF, indoxyl sulfate, and hippuric acid were markedly elevated in uremic patients. The minimum concentration that inhibited iodide production, when expressed as a molar ratio of the inhibitor to BSA, was 0.13 for CMPF, 0.53 for indoxyl sulfate, and 1.33 for hippuric acid. This molar ratio was lower than the corresponding mean molar ratio in uremic sera for CMPF (0.38) and indoxyl sulfate (0.63), while it was higher than that found for hippuric acid (0.85). The inhibition was reproduced when the inhibitors were added to normal human serum. The decreased iodide production was not due to the inhibition of deiodinase activity. The deiodination of rT3 by rat liver microsomes was unaffected by these inhibitors. Charcoal adsorption of uremic serum normalized the iodide production by hepatocytes. This normalization coincided with almost complete removal of CMPF and indoxyl sulfate, with a concomitant reduction of the free T4 fraction. Dialysis of uremic serum only partially restored iodide production. Even though indoxyl sulfate and hippuric acid were no longer detectable, a high concentration of CMPF remained in the serum. The serum free T4 fraction remained elevated in uremic patients after dialysis. Our studies indicate that CMPF and indoxyl sulfate in concentrations normally present in the serum of uremic patients inhibit cellular transport and subsequent deiodination of T4. These substances may account for the low total T3 level in uremic patients.

Adsorption↗
PubMed1993

Inhibition of thyroxine transport into cultured rat hepatocytes by serum of nonuremic critically ill patients: effects of bilirubin and nonesterified fatty acids.

We investigated bilirubin and oleic acid as causes of low plasma T3 in nonuremic critically ill patients with gross changes in serum thyroid hormone levels (T4, < or = 60; T3, < or = 1.1; rT3, > or = 0.45 nmol/L) and elevated bilirubin concentrations (> or = 33 mumol/L). Iodide production from [125I]T4 was inhibited by 42% when rat hepatocytes in primary cultures were incubated with 10% serum from these patients. The mean serum concentration of albumin was reduced by 41%, while the concentrations of bilirubin and nonesterified fatty acids (NEFA) were increased by 2022% and 115%, respectively, in the patients. The molar ratios of bilirubin/albumin and NEFA/albumin in the patients were 0.42 and 3.18, respectively. Addition of oleic acid (50-400 mumol/L) and bilirubin (3-130 mumol/L) to 10% normal human serum (albumin, 70 mumol/L; NEFA, 54 mumol/L; bilirubin, 1.1 mumol/L) progressively inhibited the production of iodide by rat hepatocytes. The decreased iodide production was presumed to be caused by inhibition of T4 transport into hepatocytes. The deiodination of rT3 by rat liver microsomes was unaltered by free bilirubin and free oleic acid concentrations up to 0.1 mumol/L. These free concentrations are at least 1 order of magnitude higher than that attained in nonthyroidal illness. The inhibition of iodide production by the sera of critically ill patients (n = 12) was significantly correlated with the molar ratios of bilirubin/albumin (r = 0.72; P < 0.01) and NEFA/albumin (r = 0.58; P < 0.05). Extensive dialysis or treatment of the sera with charcoal did not completely remove the inhibitory activity on iodide production. Serum concentrations of indoxyl sulfate, 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid, and hippuric acid in the critically ill patients (other known T4 transport inhibitors into hepatocytes) were similar to those in the normal subjects. This study together with the well known effects of carbohydrate on T3 neogenesis suggest that elevated bilirubin and NEFA and the low albumin level in non-uremic critical illness may be at least partly responsible for the T4 transport inhibition in T3-producing tissues (e.g. the liver) and, thus, the low plasma T3 levels in these critically ill patients. The question of whether inhibitors of T4 transport into the hepatocytes are also present in other patients with nonthyroidal illness who show only mild changes in thyroid hormone levels and have low concentrations of bilirubin and NEFA remains to be determined.

Adsorption↗
PubMed1993

Transport and metabolism of iodothyronines in cultured human hepatocytes.

Thyroid hormone uptake into cultured human hepatocytes was studied using measurement of cell-associated radioactivity of radioiodinated thyroid hormones after 10-min incubation in culture medium with 0.5% BSA. Furthermore, 20-h incubations were performed to study transport and further intracellular metabolism. The results indicate the presence of saturable active uptake systems for T4, T3, and rT3, as addition of the unlabeled hormone (1, 5, and 2 mumol/L, respectively) to the medium resulted in a decrease in cell-associated radioactivity of 20-30%. Inhibition was also achieved after 30-min preincubation with fructose (10 mmol/L), which induces a decrease in intracellular ATP or ouabain (0.5 mmol/L), indicating energy dependence and the necessity for a sodium gradient for at least part of the transport process, respectively. After 20-h incubation, iodide production was inhibited in the presence of ouabain (0.5 mmol/L), propylthiouracil (100 mumol/L), or a monoclonal antibody (81-1A1-10; ascites dilution, 1:200) directed against thyroid hormone transport systems in rat hepatocytes. These data indicate that there is a high degree of similarity between the properties of the uptake process and subsequent conversion of thyroid hormones in human and rat hepatocytes, although the rates of uptake and conversion are lower in human hepatocytes. Furthermore, regulation of thyroid hormone uptake at the level of the plasma membrane may also be operative in human hepatocytes.

Adenosine Triphosphate↗
PubMed1993

Decreased peripheral 3,5,3'-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues.

T4, rT3, and T3 kinetic studies have been performed in a T4-substituted female who showed an increased serum T4/T3 ratio and substantially increased rT3 serum levels in the presence of normal serum thyroid hormone binding properties. The kinetic studies were performed to discriminate between T4 transport inhibition into plasma T3-producing tissues and inhibition of extrathyroidal T4 to T3 conversion. The principal findings were that both T4 and rT3 transport were inhibited into the rapid equilibrating pool (REP), which mainly consists of the liver. The plasma T3 production rate was decreased. Despite an elevated serum free T4 level, serum TSH was elevated, pointing to T4 transport inhibition at the level of the thyrotroph as well. Transport of T4 and rT3 was normal to the slowly equilibrating pool, whereas no transport inhibition of T3 was found to either pool. Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.

Aged↗
PubMed1993

Hepatobiliary handling of iodine-125-Tyr3-octreotide and indium-111-DTPA-D-Phe1-octreotide by isolated perfused rat liver.

Radiolabeled bioactive peptides may show receptor-mediated binding to tumors, making them suitable for scintigraphic imaging. The liver is an important organ for peptide clearance. To gain insight into the uptake and intracellular processing of somatostatin analogs, we compared the hepatobiliary handling of 125I-Tyr3-octreotide and 111In-DTPA-D-Phe1-octreotide, which are successfully used to image somatostatin receptor-positive tumors in vivo in isolated recirculating perfused rat livers. Sixty minutes following administration of the radiolabeled peptides, perfusion medium and biliary radioactivity were analyzed. Radioiodinated Tyr3-octreotide was rapidly cleared by the liver and 60% of the dose was excreted intact into the bile after 60 min. In contrast, 111In-DTPA-D-Phe1-octreotide was not cleared by the liver; medium radioactivity levels remained about constant and only 2% of the dose was found in the bile. These results are in agreement with in vivo findings in rats and humans. We concluded that isolated rat liver perfusion is a good system to rapidly gain insight into the hepatic handling of radiopharmaceuticals.

Animals↗
PubMed1993

Free thyroxine assessed with three assays in sera of patients with nonthyroidal illness and of subjects with abnormal concentrations of thyroxine-binding proteins.

Three methods for estimating free thyroxine (FT4) in serum were studied: equilibrium dialysis, the SPAC-ET FT4 radioimmunoassay kit, and the Amerlite MAB FT4 luminometric assay. Serum samples from 10 subjects with above-normal thyroxine-binding globulin (TBG), 6 with low TBG, 30 with familial dysalbuminemic hyperthyroxinemia (FDH), 13 with nonesterified fatty acids (NEFA) concentrations in serum > 1.0 mmol/L, and 178 patients with various degrees of nonthyroidal illness (NTI) were measured and compared with samples from 42 euthyroid blood donors. The Amerlite MAB FT4 assay compared well with equilibrium dialysis, whereas the SPAC-ET assay averaged 40% lower. All three assays were not influenced by changes in TBG and showed no or only little changes in the presence of NEFA. Mean FT4 values in the FDH samples were somewhat higher than in controls when measured with the SPAC-ET assay, about equal with equilibrium dialysis, and somewhat below the mean control value with the Amerlite MAB FT4 assay, although individual results were within the control reference range. In NTI patients, no FT4 values were below the control reference range by the Amerlite MAB FT4 assay, 4 of 178 were below this range by equilibrium dialysis, and 1 of 178 was below this range by the SPAC-ET assay. In all assays a large proportion of the NTI samples showed FT4 values above the control reference range, a result that will interfere with the efficacy of these assays for assessing thyroid function in NTI patients.

Dialysis↗
PubMed1992

Transport of 3,5,3'-triiodothyronine into the perfused rat liver and subsequent metabolism are inhibited by fasting.

The effects of 48-h fasting on transport of T3 and subsequent metabolism in the isolated perfused rat liver were investigated. Tracer T3 disappearance curves from the recirculating medium consisted of a fast component (FC) and a slow component (SC). Using a two-compartment model, both transport [expressed as the fractional transport rate constant from medium to liver (k21)] and disposal of T3 were calculated. After fasting, k21, total metabolism, and metabolism corrected for differences in mass transfer were diminished, pointing to both decreased transport and metabolism, presumably caused by depletion of liver ATP. Concerning transport, it was shown that only transport into the intracellular liver compartment and not transport to the extracellular liver compartment was decreased after fasting. As for metabolism, T3 glucuronidation was diminished; T3 sulfation and subsequent deiodination were not affected. All mentioned decreased parameters normalized after the addition of a combination of insulin, cortisol, and/or glucose to the medium, possibly by (partially) restoration of cellular energy stores.

Adenosine Triphosphate↗
PubMed1992

The effect of hypothyroidism on Sertoli cell proliferation and differentiation and hormone levels during testicular development in the rat.

In this study we show that 6-propyl-2-thiouracil (PTU) treatment of Wistar rats from birth up to day 26 p.p. retards the morphological differentiation of Sertoli cells, and prolongs the proliferation of these cells up to day 30. Sertoli cell numbers per testis, determined at day 36, were increased by 84% compared to controls. PTU treatment increased serum thyroid-stimulating hormone (TSH) levels and reduced serum levels of thyroxine (T4) from 5 days onwards, indicative of severe hypothyroidism. Follicle-stimulating hormone (FSH) levels were reduced from day 5 to 9, normal at day 12 and 16, and reduced again from day 20 to 36. Inhibin levels were decreased from day 9 to 20 and increased at 36 days of age. The increase in the number of Sertoli cells per testis in PTU treated rats, as has been reported in the present study, is likely to be responsible for the increased testis size observed by other groups (1) in these animals, when adult.

Aging↗
PubMed1991

Thyroxine and 3,3',5-triiodothyronine are glucuronidated in rat liver by different uridine diphosphate-glucuronyltransferases.

Male Wistar rats were treated with 50 mg 3,3',4,4'-tetrachlorobiphenyl (TCB)/kg BW or vehicle. After 4 days, the livers were isolated and perfused for 90 min with 2 nM [125I]T3 or 10 nM [125I]T4 in Krebs-Ringer medium containing 1% albumin. Deiodination and conjugation products and remaining substrates were determined in bile and medium samples by Sephadex LH-20 chromatography and HPLC. TCB treatment did not affect hepatic uptake and metabolism of T3. However, biliary excretion of T4 glucuronide was strongly increased by TCB, resulting in an augmented T4 disappearance from the medium, although initial hepatic uptake of T4 was not altered. Measurement of the microsomal UDP-glucuronyltransferase (UDPGT) activities confirmed that T4 UDPGT was induced by TCB, whereas T3 glucuronidation was unaffected. T3 UDPGT activity showed a discontinuous variation, which completely matched the genetic heterogeneity in androsterone glucuronidation in Wistar rats. These results indicate that different isozymes catalyze the glucuronidation of T3 and T4.

Animals↗
PubMed1990

Development and use of a mathematical two-pool model of distribution and metabolism of 3,3',5-triiodothyronine in a recirculating rat liver perfusion system: albumin does not play a role in cellular transport.

To describe the T3 kinetics in a recirculating rat liver perfusion system, we have developed a mathematical two-pool model consisting of medium and liver. It appeared that all parameters of the model could be fully resolved by using the time-dependent disappearance of radioactive T3 (2 nM) from the medium only. The model calculates the T3 medium pool, the T3 liver pool, and the amount of hormone metabolized at different times after the start of the perfusion. To check the validity of the model, metabolism was also estimated from the appearance of labeled metabolites (glucuronides, sulfates, and I-) in the medium and the cumulative excretion of T3 and metabolites into the bile. The medium pool was also estimated by the product of medium volume and remaining T3 concentration, and the liver pool as the amount of T3 at time zero minus medium pool minus T3 metabolized). These results were in excellent agreement with the predicted values from the model. Taking the metabolites appearing in medium and bile together, about 38% of the total amount of T3 metabolized during 60 min was converted into T3 glucuronide, 12% into T3 sulfate, and 48% into I-, respectively, while about 3% was excreted in the bile unaltered. The results show that not all T3 transported to the liver is being metabolized, but part is bound outside the cellular compartment. This latter pool of T3 is dependent on the albumin concentration in the medium. The amount of T3 metabolized is solely determined by the free T3 concentration and is independent of total T3 or albumin concentration in the medium.

Animals↗
PubMed1990

Receptor scintigraphy with a radioiodinated somatostatin analogue: radiolabeling, purification, biologic activity, and in vivo application in animals.

Radioiodinated Tyr-3-octreotide, a somatostatin analogue, is a useful ligand for the in vitro detection of somatostatin receptors. In this study, we have investigated the possible in vivo application of this radioligand in the detection of somatostatin receptor-bearing tumors by scintigraphy. The specific somatostatin-like biologic activity of radioiodinated Tyr-3-octreotide was confirmed in vitro: (a) radioiodinated Tyr-3-octreotide competes in the nanomolar range with specific receptor binding of somatostatin to suspended human meningioma membranes and (b) the secretion of growth hormone by cultured rat pituitary cells was similarly inhibited by iodinated Tyr-3-octreotide and somatostatin. In rats, intravenously injected 123I-Tyr-3-octreotide is rapidly cleared from the circulation mainly by the liver. Although this rapid clearance limits the amount of tracer available for somatostatin receptor-bearing tumors, the advantage of this rapid clearance is that the background level is rapidly reduced in favor of scintigraphic imaging of these tumors. Pancreatic tumors in rats were localized by scintigraphy after intravenous injection of 123I-Tyr-3-octreotide.

Animals↗
PubMed1989

[The effect of immunoscintigraphy with monoclonal antibodies on assays of hormones and tumor markers. This is not the end of the matter!].

The use of monoclonal antibodies in medicine for in-vivo diagnostic methods and for therapeutic purposes will increase in the future. Although monoclonal antibodies possess a high specificity, the animal origin of these antibodies remains a problem. Repeated administration of animal monoclonal antibodies (in vivo) may induce the formation of human antibodies against these monoclonal antibodies. Because animal monoclonal antibodies are also used in laboratory assays (in vitro), the presence of human antibodies against these animal monoclonal antibodies may cause spuriously elevated or depressed results of these assays. The clinician should be alert to this possibility. A case history is presented to demonstrate the problem.

Aged↗