Presence of triiodothyronine, no detectable thyroxine and reverse triiodothyronine in human milk.

Thyroxine (T4), triiodothyronine (T3) and reverse triodothyronine (rT3) concentrations in human milk were measured by radioimmunoassay in 114 samples obtained from 1 week to 8 months postpartum. Several assay systems applied for the determination of serum thyroid hormone concentration were proved to be unsuitable for human milk, and the method of separating free and antibody-bound hormone by polyethylene glycol was also inappropriate for milk specimens, which tended to give a falsely high value. The binding of finity of T4 to milk was lower than that to serum protein, on which 8-anilino-1-naphthalene sulfonic acid showed no remarkable effect. In spite of the high sensitivity of 100 pg/tub in T4 assay system, no immunoassayable T4 was detected in all samples with or without ethanol extraction and trypsin hydrolysates of milk. In contrast, T3 was present in a measurable amount in most of the samples, the mean +/- SD value of which was 10 +/- 9 ng/100 ml, and those in colostrum were significantly higher than those in matured milk (P less than 0.01), whereas rT3 was not detectable in 76 samples tested. These results indicate that permeability of thyroid hormones through the mammary gland is different between T4 and T3 as well as in placental transport, and human milk can not be a source of thyroxine supply for the breast-fed infant.     

Characterization of canine triiodothyronine (T3) autoantibodies and their effect on total T3 in canine serum

A study of 3,5,3'-L-triiodothyronine autoantibody (T3 AA) in 18 dogs revealed an average apparent affinity constant for T3 of 2.24 +/- 1.78 X 10(10) M-1, an average T3 binding capacity of 639.3 +/- 666.5 ng/dl and a low thyroxine (T4) cross-reactivity (less than 1%) in all samples tested. A valid radioimmunoassay (RIA) procedure which involved heat treatment of samples for 1 hr at 70 degrees C and assay on Sephadex minicolumns was developed for measuring T3 in the presence of T3 AA. Total T3 was elevated (mean = 374.8 +/- 158.4 ng/dl) in samples in which T4 was in the normal canine range, but T3 was lower (mean = 96.1 +/- 63.3 ng/dl) in samples with T4 values in the hypothyroid range. For each sample the concentration of T3 not bound by T3 AA was calculated from the total T3 concentration, the affinity constant, and the binding capacity. In dogs with normal total T4 concentrations the average calculated T3 not bound by T3 AA was 147.2 +/- 144.4 ng/dl while in dogs with low total T4 the value was 15.7 +/- 26.3 ng/dl (normal canine range is 45-150 ng/dl). Canine samples containing T3 AA were compared to serum from three rabbits actively immunized against T3 to provide anti-T3 for commercial RIA. The rabbit T3-antisera had an average T3 affinity constant similar to those of the canine samples (1.57 X 10(10) M-1), but had average titer, T3 binding capacity, and total T3 values more than 10-fold higher. Our findings indicate that, in dogs with serum containing T3 AA and normal total T4 concentrations, a compensatory mechanism appears to exist to maintain non-T3 AA bound T3 within the range of normal total T3. This compensatory mechanism does not operate in those dogs with insufficient thyroid activity to maintain normal total T4 values.     

Congenital goiter sustaining normal level of serum triiodothyronine

We attempted to elucidate the deficient site of thyroid hormone biosynthesis in the thyroid gland and the mechanism of sustaining normal T3 level in sera of a patient with congenital goiter. TY, a 8-yr-old boy, first noted the onset of a diffuse goiter at the age of 2. There was no clinical evidence of hypothyroidism except for the slight impairment of intellectual development and the awkward physical activity. BMR, T3-RSU and T4 showed low values (-13%, 20.8% and 2.2 micrograms/dl), but serum T3 was normal (180 ng/dl). Serum TSH was 18 microU/ml. The intrathyroidal T3 and T4 were slightly low. Thyroidal 131I uptake was high, but KSCN discharge test was negative. Percent distribution of 131I labelled amino acids in the pancreatin digested thyroid homogenate was 17.4% in MIT, 33.4% in DIT and 11.3% in T3 and T4. Thyroid iodide peroxidase activities in mitochondrial and microsomal fractions were slightly low (19.6 and 26.8 (normal: 32 +/- 3.0 and 37.4 +/- 9.5) mumoles/mg protein). The activity was not increased by the addition of hematin. Thyroglobulin was found to be normal. A biological half life of 131I labelled T4 was shorter (3.5 days) than that of the normal. Electron microscopic examination exhibited the increment and expansion of endoplasmic reticulum in the follicular cell. Low iodide peroxidase activity of this patient may correlate to low T3 and T4 level in the thyroid cell. Moreover, shortened biological half life of T4 implies that normal T3 level in serum is sustained by the accelerated conversion of T4 to T3 in peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum T3 level in the patients with hyperthyroidism after therapy.

Serum T3 level in various thyroid diseases was determined in unextracted serum with the Dainabot kit for T3 RIA. The serum T3 level in 33 normal subjects was 0.8-1.6 ng/ml. It was 5.7 +/- 3.5 ng/ml (mean +/- S.D.) in 36 hyperthyroid patients, and undetectable to 0.8 ng/ml in 21 hypothyroid patients. Generally the serum T4 and serum T3 decreased in parallel after radioiodine therapy for hyperthyroidism. However, in some cases the serum T3 level remained high in spite of normalized serum T4 after radioiodine therapy. This state indicated "T3-toxicosis", and hyperthyroidism was apt to recur. When thyroid function was observed for 2 years following radioiodine treatment, the ratio of serum T3 (T3 level before treatment/T3 level after treatment) decreased more significantly as compared with the ratio of serum T4 in euthyroid cases. Serum T3 provides a more sensitive index of thyroid function than serum T4 in euthyroid states after radioiodine or anti-thyroid drug therapy. The present data indicate that the serum T3 level and the T4/T3 ratio are valuable aids in the estimation of prognosis of hyperthyroid patients after various treatments.     

Change in structure of the N-terminal region of transthyretin produces change in affinity of transthyretin to T4 and T3

The relationship between the structure of the N-terminal sequence of transthyretin (TTR) and the binding of thyroid hormone was studied. A recombinant human TTR and two derivatives of Crocodylus porosus TTRs, one with the N-terminal sequence replaced by that of human TTR (human/crocTTR), the other with the N-terminal segment removed (truncated crocTTR), were synthesized in Pichia pastoris. Subunit mass, native molecular weight, tetramer formation, cross-reactivity to TTR antibodies and binding to retinol-binding protein of these recombinant TTRs were similar to TTRs found in nature. Analysis of the binding affinity to thyroid hormones of recombinant human TTR showed a dissociation constant (Kd) for triiodothyronine (T3) of 53.26+/-3.97 nM and for thyroxine (T4) of 19.73+/-0.13 nM. These values are similar to those found for TTR purified from human serum, and gave a Kd T3/T4 ratio of 2.70. The affinity for T4 of human/crocTTR (Kd=22.75+/-1.89 nM) was higher than those of both human TTR and C. porosus TTR, but the affinity for T3 (Kd=5.40+/-0.25 nM) was similar to C. porosus TTR, giving a Kd T3/T4 ratio of 0.24. A similar affinity for both T3 (Kd=57.78+/-5.65 nM) and T4 (Kd=59.72+/-3.38 nM), with a Kd T3/T4 ratio of 0.97, was observed for truncated crocTTR. The obtained results strongly confirm the hypothesis that the unstructured N-terminal region of TTR critically influences the specificity and affinity of thyroid hormone binding to TTR.     

A case of hypothyroidism with simultaneous presence of stimulating type anti-thyrotropin (TSH) receptor antibodies and anti-thyroxine (T4) autoantibodies.

We have examined a hypothyroid patient with stimulating type anti-thyrotropin (TSH) receptor antibodies and without blocking type anti-TSH receptor antibodies. Although she had high serum TSH (240 microU/ml) and low free triiodothyronine (FT3, 0.49 pg/ml) concentrations, which agree with physical findings of hypothyroidism, she had an unusually high free thyroxine (FT4) concentration (3.56 ng/dl). Incubation of her serum with 125I-T4, followed by precipitation with 12.5% polyethylene glycol (PEG) disclosed a higher binding of 125I-T4 (34.4%) than in normal controls, being 5-7%. In addition, binding of 125I-T4 to her serum gamma-globulin was completely displaced by the addition of unlabelled T4. From these results it was concluded that her serum contained anti-T4 autoantibodies. Treatment with synthetic T4 was begun and her thyroid function was monitored by sensitive TSH radioimmunoassay (RIA) and RIA of FT4 after PEG treatment. Since both sensitive TSH RIA and FT4 RIA results after PEG treatment give results concordant with the physical findings, it was concluded that both of the RIA results are useful for the evaluation of thyroid function in patients with thyroid hormone autoantibodies.     

Dietary Iodine Sufficiency and Moderate Insufficiency in the Lactating Mother and Nursing Infant: A Computational Perspective

The Institute of Medicine recommends that lactating women ingest 290 μg iodide/d and a nursing infant, less than two years of age, 110 μg/d. The World Health Organization, United Nations Children’s Fund, and International Council for the Control of Iodine Deficiency Disorders recommend population maternal and infant urinary iodide concentrations ≥ 100 μg/L to ensure iodide sufficiency. For breast milk, researchers have proposed an iodide concentration range of 150–180 μg/L indicates iodide sufficiency for the mother and infant, however no national or international guidelines exist for breast milk iodine concentration. For the first time, a lactating woman and nursing infant biologically based model, from delivery to 90 days postpartum, was constructed to predict maternal and infant urinary iodide concentration, breast milk iodide concentration, the amount of iodide transferred in breast milk to the nursing infant each day and maternal and infant serum thyroid hormone kinetics. The maternal and infant models each consisted of three sub-models, iodide, thyroxine (T4), and triiodothyronine (T3). Using our model to simulate a maternal intake of 290 μg iodide/d, the average daily amount of iodide ingested by the nursing infant, after 4 days of life, gradually increased from 50 to 101 μg/day over 90 days postpartum. The predicted average lactating mother and infant urinary iodide concentrations were both in excess of 100 μg/L and the predicted average breast milk iodide concentration, 157 μg/L. The predicted serum thyroid hormones (T4, free T4 (fT4), and T3) in both the nursing infant and lactating mother were indicative of euthyroidism. The model was calibrated using serum thyroid hormone concentrations for lactating women from the United States and was successful in predicting serum T4 and fT4 levels (within a factor of two) for lactating women in other countries. T3 levels were adequately predicted. Infant serum thyroid hormone levels were adequately predicted for most data. For moderate iodide deficient conditions, where dietary iodide intake may range from 50 to 150 μg/d for the lactating mother, the model satisfactorily described the iodide measurements, although with some variation, in urine and breast milk. Predictions of serum thyroid hormones in moderately iodide deficient lactating women (50 μg/d) and nursing infants did not closely agree with mean reported serum thyroid hormone levels, however, predictions were usually within a factor of two. Excellent agreement between prediction and observation was obtained for a recent moderate iodide deficiency study in lactating women. Measurements included iodide levels in urine of infant and mother, iodide in breast milk, and serum thyroid hormone levels in infant and mother. A maternal iodide intake of 50 μg/d resulted in a predicted 29–32% reduction in serum T4 and fT4 in nursing infants, however the reduced serum levels of T4 and fT4 were within most of the published reference intervals for infant. This biologically based model is an important first step at integrating the rapid changes that occur in the thyroid system of the nursing newborn in order to predict adverse outcomes from exposure to thyroid acting chemicals, drugs, radioactive materials or iodine deficiency.     

Subcellular localization and binding of 125I-triiodothyronine in calf thyroid

The subcellular distribution of 125I-T3 was studied in calf thyroid slices, under the same experimental conditions where T3 inhibits protein and RNA synthesis, labelled hormone was found mainly in the 20,000 X g supernatant. The specificity of each subcellular localization was determined by incubating the slices with 10(-5)M T3. Only in the purified nuclei a significant decrease was found, indicating a specific localization of the labelled hormone. When slices were incubated with 125I both labelled T3 and T4 were found in purified nuclei, indicating that endogenously synthesized hormones can reach thyroid nuclei. Purified thyroid nuclei were incubated with labelled T3 and increasing amounts of cold hormone. Specific binding reached a plateau after 90 min of incubation at 20 degrees C. When the displacement curves were analysed by a Scatchard plot a binding site with a Ka of 5.2 X 10(7) M-1 and a capacity of 3.0 X 10(-15) moles/microgram DNA was observed. Digestion of nuclei with trypsin and protease abolished completely the binding of 125I-T3 thus indicating the protein nature of the receptor. The hormone-receptor complex could be extracted with 0.4M KCI and eluted in the void volume after Sephadex G-25 column chromatography, similar to peripheral tissues nuclear T3 receptors. The present studies provide the first evidence for the existence of nuclear receptors for T3 in the thyroid, an event probably related to the autoregulatory mechanism.     

Effect of physical conditioning on measures of thyroid hormone action

Serum thyroid function tests (T4, T3, rT3 and TSH levels) and measures of peripheral thyroid hormone action (serum dopamine-beta-hydroxylase activity (DBH) and sex hormone binding globulin (SHBG] were determined in 6 women before and one month after initiating an aerobic physical conditioning program. The same measurements were made in a control group of 6 women who did not increase their activity during this time. In physically conditioned subjects, the resting heart rate decreased from 65.1 +/- 3.9 (mean +/- SE) at baseline to 58.0 +/- 2.9 beats per minute after one month (P less than 0.025), indicating an appreciable state of physical conditioning was achieved. However, there were no statistically significant changes in thyroid function test, serum DBH or SHBG levels in either the physically conditioned or the control group. These data indicate that being physically conditioned has a negligible effect on thyroid status.     

Decrease of TSH levels and epithelium/colloid ratio in rat thyroid glands following administration of proadrenomedullin N-terminal peptide (12-20).

Adrenomedullin (AM) exerts a potent and long-lasting hypotensive effect and is considered to be an important hormone in blood pressure control. AM is a 52-amino-acid peptide synthesized as part of a 185-amino-acid preprohormone that also contains 20-amino-acid residues in the N-terminus, which has similar biological activity. This sequence is named a proadrenomedullin N-terminal 20 peptide (PAMP). Also, proadrenomedullin N-terminal peptide (PAMP)(12-20) exerts vasodepressor response, however this response is 3-fold less potent than the effect evoked by full-sequence peptide. Both AM and PAMP controls secretory activity of the pituitary gland and adrenal cortex, however, their action on the other endocrine glands is not recognized. Therefore, the aim of the study was to examine whether PAMP(12-20) is able to affect the structure and function of the rat thyroid gland. In adult female rats, subcutaneous PAMP(12-20) administration (1 or 4 nmol/rat/day for 6 days, autopsy 60 min after the last injection) had no effect on the weight of the thyroid gland. Peptide administration however, resulted in a dose-dependent increase in the volume of thyroid colloid, and lowered epithelium/colloid ratio in the gland (3.76 +/- 0.49, 2.66 +/- 0.27, 2.38 +/- 0.26, means +/- SE, n = 6, control, 1 and 4nmol PAMP/rat, respectively). PAMP administration changed neither the length of thyroid capillaries per unit area of surface nor their diameter. Lower dose of PAMP(12-20) significantly lowered blood TSH concentration (p < 0.01) while total and free T3 and T4 concentrations remained unchanged. Collectively, these findings suggest that PAMP(12-20) exerts a mild inhibitory effect on secretory activity of the rat thyroid gland.     

Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal illnesses.

In order to clarify the role of free fatty acid (FFA) in thyroid hormone abnormalities in patients with nonthyroidal illness, thyroid function, FFA, inhibitor of extrathyroidal conversion of T4 to T3 (IEC) and thyroid hormone binding inhibitor (THBI) were studied in 99 patients with various nonthyroidal illnesses including diabetes mellitus (DM) (n = 35), liver cirrhosis (LC) (n = 33), chronic obstructive pulmonary disease (COPD) (n = 17) and chronic heart failure (CHF) (n = 14). Patients were divided into three groups based on the level of serum T3: Group I (T3 < 50 ng/dl), Group II (50 < or = T3 < 80) and Group III (80 < or = T3). Serum T4, FT3 and the T3/T4 ratio decreased significantly in the order Group III, Group II and Group I (Group III > II > I). The plasma FFA level was 0.91 +/- 0.12 mmol/l in Group I (P < 0.05, vs. Group III), 0.65 +/- 0.06 in Group II and 0.54 +/- 0.04 in Group III, respectively. The incidence of positive IEC was 80.0% in Group I (P < 0.05, vs. Group III), 53.7% in Group II (P < 0.05, vs. Group III) and 34.2% in Group III. However, IEC was not correlated with the serum T3 concentration. The incidence of positive THBI was 80% in Group I (P < 0.05, vs. Group III), 68.3% in Group II and 47.4% in Group III, but THBI was not correlated with the serum T4 level. Positive correlations were observed among FFA, IEC and THBI (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Low serum reverse T3 levels in patients with primary hyperparathyroidism

Although patients with primary hyperparathyroidism (1 degree HPT) were euthyroid, we measured serum thyroid hormone levels in 16 patients with 1 degree HPT together with 17 patients with hypercalcemia due to malignant diseases (HCM). In patients with 1 degree HPT, serum levels of T3, T4 and T3U were within normal range, but serum rT3 (reverse T3) levels (205 +/- 37 pg/ml, mean +/- SD) were significantly decreased as compared with those in normal controls (276 +/- 44 pg/ml, P less than 0.01). A significant inverse correlation was observed between the serum levels of rT3 and parathyroid hormone (PTH) (r = 0.54, P less than 0.05). After parathyroidectomy, serum rT3 levels were significantly elevated (240 +/- 56 pg/ml) compared to preoperative levels (P less than 0.01). Low levels of serum rT3 seemed to be attributed to the high levels of serum PTH. On the other hand, serum levels of T3 and T4 were low and serum rT3 levels were high in patients with HCM. Low serum rT3 allows for the differentiation of patients with 1 degree HPT from those with HCM.     

n-acetyl-beta-hexosaminidase activity in human breast milk

1. The lysosomal enzyme, N-acetyl-beta-hexosaminidase (HEX) is present in human breast milk. It is composed predominantly of "A" (heat-labile) and "B" (heat-stable) isozymes which coelute with the corresponding major serum isozymes on DE-52 ion-exchange chromatography. 2. Total HEX activity in "early" milk obtained at 2.8 +/- 1.4 weeks post partum, is approx. 2.5-fold higher (87 +/- 29 nmol/60'/mg protein. n = 10) than that of pregnancy serum (35.7 nmol/60'/mg protein) prior to delivery. 3. These levels increase to greater than 3-fold (110 +/- 20 nmol/60'/mg protein, n = 13) as the milk matures (10.3 +/- 4.2 weeks). 4. The specific activity of HEX A in the milk changes little with time post partum, because absolute 5. In contrast, HEX B specific activity is increased, as absolute levels (per volume) remain constant in the face of decreasing milk protein content, 5. These changes result in a high degree of correlation (r = 0.81) between time of lactation and % HEX A observed.     

Analysis of nuclear 3,3',5-triiodothyronine receptor in the brown adipose tissue (BAT) of the postnatal lamb.

Postnatal thermogenesis in sheep is associated with increased sympathoadrenal activities, a T3 surge and an enhanced brown adipose tissue (BAT) type II 5'-monodeiodinating (5'-MDI) activity. The latter peaks 3-4 days after birth and is known to be important in generating intracellular T3 for nuclear receptor binding. In order to further investigate the mechanism(s) responsible for neonatal thermogenesis, thyroid hormone nuclear receptor (T3NR) binding characteristics were quantified in lamb BAT from newborn (NB) to 30d of postnatal age. Maximal binding capacities (MBC, mean +/- SEM fmoles T3/mg DNA) in BAT showed a decrease as studied by ANOVA during the first 11 days (NB to 1d, 148 +/- 24 [N = 5, p < 0.01, cf. 3-5d group]; 3-5 d, 61 +/- 5.5 [N = 5]; 10-11d, 72 +/- 9.1 [N = 4]). Afterwards, MBC increased at 30d (196 +/- 32, N = 4, p less than 0.01, cf. 3-5d group). BAT T3NR binding affinities (10(9) M-1) were comparable in all age groups studied (NB-1d, 2.8 +/- 0.3; 3-5d, 3.4 +/- 0.3; 10-11d, 4.0 +/- 1.1; 30d, 2.4 +/- 0.4). The data suggest that the postnatal surge in T3 and type II 5'-MDI is accompanied with a concurrent decrease in MBC of BAT T3NR. The latter may represent a down-regulation of T3NR presumably in an attempt to regulate the overall effect of thyroid hormone in neonatal thermogenesis.     

The partial replacement of the serum growth factor requirement of SV3T3 cells by lactalbumin hydrolyzate.

Lactalbumin hydrolyzate (LH), a commercially prepared, enzymatic digest of a milk protein fraction, can partially replace the serum requirement of SV3T3 cells. In a low, but obligatory, background of calf serum (0.15% v/v), LH carses a large increase in the final cell density (5-10 x over the control) while modestly steimulating the actual growth rate. Lactalbumin hydrolyzate does not contain survival activity for SV3T3 cells and does not affect the growth of 3T3 cells. Since even prolonged exposure to pH 4 or 2 results in complete abolishment of the growth-rate stimulatory capability without affecting the capacity to increase the final cell density, it is possible that the LH growth activity may consist of two dissociable components. All of LH growth activity is water soluble, autoclavable, and resists proteolytic treatment. On Sephadex G15 growth activity appears as a single peak at the void volume but on G25 it is retained beyond the void volume as a broad, skewed peak. The relevant molecular weight range lies between 1,500 and 4,000. The putative low pH resistant material is strongly adsorbed to Dowex 1 x 2 and can be displaced from the column by a reduction in the pH. A comparison of the properties of the LH factors with those of known growth promoting agents isolated from serum and various enzymatic digests indicates that these new factors do not correspond to any of these agents.     

Serum T(4) and serum T(3) concentrations in immature captive whitetip reef sharks, Triaenodon obesus.

Serum T(3) (3,5,3' triiodothyronine) and serum T(4) (thyroxine) concentrations were repetitively assayed by radioimmunoassay over a three-year period in two male and two female immature captive whitetip reef sharks, Triaenodon obesus. These sharks were maintained at the Waikiki Aquarium, Honolulu, Hawaii, in an open system holding pool receiving 568 liters per minute of water from a saltwater well with an iodide concentration of 0.076 mg/liter. No significant male-female difference was observed for either serum T(3) or serum T(4). No seasonal pattern of serum T(3) was detected (P = 0.07). Serum T(3) concentrations ranged (mean +/- SEM) from 0. 52 to 0.83 ng/mL (0.67 +/- 0.01; n = 64). A significant seasonal difference was observed for serum T(4) (P < 0.001). Serum T(4) concentration was higher in winter (October-January) with a mean (range +/- SEM) of 6.58 ng/mL (1.48-8.77 +/- 0.35; n = 24) and lower in summer (May-August) with a mean of 3.62 ng/mL (1.34-5.71 +/- 0. 22; n = 24). The thyroid hormone T(4) has a seasonal rhythm even in immature sharks and may have an important role in physiology. J. Exp. Zool. 284:500-504, 1999.     

Helodermin, but not cholecystokinin, somatostatin, or thyrotropin releasing hormone, acutely increases thyroid blood flow in the rat

In the present study, we investigated whether peptides located within the thyroid gland, but not directly found in nerve fibers associated with blood vessels, might influence thyroid blood flow. Specifically, we evaluated the effects of helodermin, cholecystokinin (CCK), somatostatin (SRIF) and thyrotropin releasing hormone (TRH) given systemically on thyroid blood flow and circulating thyroid hormone levels. Blood flows in the thyroid and six other organs were measured in male rats using 141Ce-labeled microspheres. Circulating thyrotropin (TSH) and thyroid hormone levels were monitored by RIA. Helodermin (10(-10) mol/100 g BW, i.v. over 4 min) markedly elevated thyroid blood flow (52 +/- 6 vs. 10 +/- 2 ml/min.g in vehicle-infused rats; n = 5). Blood flows to the salivary gland, pancreas, lacrimal gland and stomach (but not adrenal and kidney) were also increased during helodermin infusions. CCK, SRIF, and TRH were without effect on blood flows to the thyroid and other organs even though these peptides were tested at higher molar doses than helodermin. Helodermin, CCK, or SRIF did not affect thyroid hormone or plasma calcium levels. As expected however, plasma TSH and T3 levels were increased at 20 min and 2 h, respectively, following TRH infusions. Since helodermin shares sequence homology with VIP, we next compared the relative effects of these two peptides on thyroid and other organ blood flows. VIP (10(-11) mol/100 g BW, i.v.) was more potent in increasing blood flows to the thyroid, salivary gland, and pancreas than an equimolar dose of helodermin. This study shows that while helodermin, like VIP, has the ability to increase thyroid and other organ blood flows, it appears to be a less potent vasodilator.     

Effect of thyroid hormone therapy on plasma insulin-like growth factor I levels in normal subjects, hypothyroid patients and endemic cretins

The effect of thyroid hormone therapy (L-T4 or L-T3) on plasma immunoreactive insulin-like growth factor I (somatomedin C, Sm-C) concentrations was studied in 8 normal controls, 14 primary hypothyroid subjects and in 7 patients with endemic cretinism. In normals basal levels of Sm-C (1.56 +/- 0.77 U/ml) increased to (2.46 +/- 1.0 U/ml; L-T4) and to (2.9 +/- 0.95 U/ml; L-T3). Plasma Sm-C basal levels were significantly lower in primary hypothyroid subjects (0.81 +/- 0.48 U/ml) and increased to 2.54 +/- 1.43 U/ml (L-T4) and to 2.16 +/- 0.83 U/ml (L-T3). A significant and positive correlation (r = 0.56) was found between Sm-C and serum T4 and T3 concentrations. Plasma Sm-C concentrations in endemic cretinism were initially normal in 4 patients, but low in the remaining 3 (mean +/- SD: 1.18 +/- 0.63 U/ml) and did not increase after 12 months (1.34 +/- 0.61 U/ml) or 18 months (1.01 +/- 0.43 U/ml) of L-T4 and L-T3 therapy. Plasma T4 levels and free T4 increased considerably in EC after therapy with a significant decrease in the previously elevated plasma TSH concentrations. The subnormal response of plasma Sm-C during effective thyroid thyroid hormone therapy could be an additional factor involved in growth failure of endemic cretins.     

Thyroid hormones and the reactivities of genetic variants of human erythrocytic glucose-6-phosphate dehydrogenase

Thyroid hormones, throxine (T4) and triiodothyronine (T3) which are known to activate glucose-6-phosphate dehydrogenase (G6PD) activity in vivo act as substrate inhibitors of G6PD in vitro. T4 competitively inhibits NADP in human erythrocyte G6PD variants G6PDA, G6PDB and G6PDA- with inhibition constants of 2.40 +/- 0.90 X 10(-6), 3.44 +/- 0.63 X 10(-6) and 6.53 +/- 0.60 X 10(-6) mol/l, respectively. The inhibition is, however, noncompetitive with respect to G6P in the three variants. T3 also has similar inhibition pattern to T4 with inhibition constants for NADP of 1.9 +/- 0.08 X 10(-5) and 1.28 +/- 0.17 X 10(-5) mol/l for G6PDB and G6PDA-, respectively. cAMP on the other hand inhibits G6P competitively with inhibition constants 1.50 +/- 0.22 X 10(-4), 1.06 +/- 0.24 X 10(-4) and 1.76 +/- 0.14 X 10(-4) mol/l for G6PDB, G6PDA and G6PDA-, respectively. There are significant differences in the inhibition effects of T4 and cAMP with respect to NADP as substrates for the normal enzyme G6PDA or G6PDB and the deficient enzyme G6PDA- when NADP is the substrate, the latter being much more inhibited. The activation effect of thyroid hormones in vivo may therefore not be a direct result of thyroid hormone binding to the G6PD enzyme nor mediated through the action of cAMP but plausibly be through complexation of inhibitory trace metal ions by the thyroid hormones T4 and T3.     

Effects of T3R alpha 1 and T3R alpha 2 gene deletion on T and B lymphocyte development

Thyroid hormones bind to several nuclear receptors encoded by T3R alpha and T3R beta genes. There is now accumulating evidence that thyroid hormones act on the immune system. Indeed, mice deficient for thyroid hormones show a reduction in lymphocyte production. However, the mechanisms involved and, in particular, the role of the different thyroid hormone receptors in lymphocyte development have not been investigated. To address that question, we have studied lymphocyte development in mice deficient for the T3R alpha 1 and T3R alpha 2 gene products. A strong decrease in spleen cell numbers was found compared with wild-type littermates, B lymphocytes being more severely affected than T lymphocytes. A significant decrease in splenic macrophage and granulocyte numbers was also found. In bone marrow, a reduction in CD45+/IgM- pro/pre-B cell numbers was found in these mice compared with wild-type littermates. This decrease seems to result from a proliferation defect, as CD45+/IgM- cells incorporate less 5-bromo-2'-deoxyuridine in vivo. To define the origin of the bone marrow development defect, chimeric animals between T3R alpha-/- and Rag1-/- mice were generated. Results indicate that for B cells the control of the population size by T3R alpha 1 and T3R alpha 2 is intrinsic. Altogether, these results show that T3R alpha 1 or T3R alpha 2 gene products are implicated in the control of the B cell pool size.