The assessment of fetal cardiac output in maternal hypothyroidism under levothyroxine treatment
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In this study, we investigated whether maternal hypothyroidism has a role in the cardiac output (CO) of the fetus or not.Pregnant women between 33 and 37 gestational weeks known to have hypothyroidism and using levothyroxine were accepted as the case group. Gestational age-matched healthy euthyroid pregnant women constituted the control group. Fetal echocardiography was performed. Diameters and the velocity waveform of the pulmonary artery (PA) and aortic valves were measured. Velocity time integral (VTI) was also measured from the ventricular outflow tract. CO was calculated using VTI × π (Aortic Valve or Pulmonary Valve diameter/2) 2 × heart rate formula.The aortic and PA annulus were measured larger in the control group. (p = .003, p = .005, respectively). Furthermore, the right and left CO of the case group were lower than the control group. Whereas the mean combined CO (ml/min) of the case group was 674.8 ± 146.2, it was 827.8 ± 167.9 in the control group (p < .001). Additionally, a negative correlation was observed between thyroid-stimulating hormone and aortic VTI (r:-.480; p:.006).The findings of our study suggest that the CO of the fetus may be affected by maternal hypothyroidism.Keywords:
Levothyroxine
Abstract. Previous works from this laboratory have demonstrated that oestradiol benzoate (EB) in euthyroid male and female rats induced a significant decrease in the pituitary content of TSH while serum levels of this hormone remained normal. The present work studied the effects of EB (25 μg/100 g body weight, during 9 days) on the peripheral metabolism of [ 125 I]rTSH and on the pituitary and plasma concentration of TSH in euthyroid and hypothyroid rats. No significant variations were observed in [ 125 I]rTSH kinetics of EB-treated euthyroid rats vs untreated controls: fractional turnover rate 2.8 ± 0.2 vs 3.0 ± 0.3%/min, distribution space 6.5 ± 0.4 vs 6.8 ± 0.5 ml/100 g body weight, disposal rate 18.4 ± 2.4 vs 18.1 ± 1.9 μU/100 g/min and extrapituitary pool 645 ± 42 vs 614 ± 43 μU/100 g body weight. Similarly, in hypothyroid rats oestrogens induced no changes in TSH kinetics except for an increase in distribution space ( P < 0.025). However, oestrogens decreased the pituitary pool of TSH ( P < 0.001) in both euthyroid and hypothyroid rats and increased the plasma TSH in hypothyroid animals ( P <0.01), all vs their respective controls. Neither hypothyroid group had detectable plasma levels of T 4 and T 3 . In summary: 1) the marked decrease of pituitary TSH with normal plasma TSH induced by EB appears unrelated to the peripheral metabolism of TSH, 2) the results from hypothyroid rats suggest that EB stimulates the release of TSH from the pituitary gland.
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The role of somatostatin (SRIF) in the regulation of thyroid homeostasis was studied by measuring hypothalamic SRIF-like immunoreactivity (SRIF-LI) content and in vitro release in hypothyroid (T3-treated and untreated), euthyroid, and T3-treated normal rats. Hypothalamic SRIF-LI content was decreased in hypothyroid rats and was restored to euthyroid levels by T3 treatment. SRIF-LI release from hypothalami of hypothyroid rats was decreased compared to that in euthyroid controls under basal and stimulated (60 mM K+ or 10-6 M dopamine) in vitro conditions. The release of SRIF-LI from hypothalami of hypothyroid rats treated with T3 was restored to euthyroid levels. The release of SRIF-LI from normal rat hypothalami was unaffected by TRH or TSH but was stimulated by T3. These results suggest that T3 exerts its negative feedback effect on pituitary TSH release via stimulation of hypothalamic SRIF release as well as by a direct pituitary effect, and that the elevated TSH levels seen in primary hypothyroidism may result in part from a decrease in the tonic inhibitory effect of hypothalamic SRIF. Pancreatic, but not antral or colonic, SRIF-LI was increased in hypothyroid rats, and the levels were reduced by T3 treatment. The changes cannot be explained by alterations in food intake and may represent primary effects of the hypothyroid state.
Hypothalamic–pituitary–thyroid axis
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ABSTRACT In order to investigate whether the impaired GH secretion associated with hypothyroidism and hyperthyroidism is due to a hypothalamic or a pituitary disorder, we have studied plasma GH responses to GH-releasing factor (1–29) (GRF) in euthyroid, hypothyroid and hyperthyroid rats. Hypothyroid rats showed a significant ( P < 0·001) reduction in GH responses to GRF (5 μg/kg) at 5 min (350 ± 35 vs 1950 ±260 μg/l), 10 min (366±66 vs 2320 ± 270 μg/l) and 15 min after GRF injection (395 ± 72 vs 1420 ± 183 μg/l; means ± s.e.m. ) compared with euthyroid rats. Hyperthyroid rats showed a significant ( P <0·05) decrease in GH responses to 5 μg GRF/kg after 30 min (200±14 vs 325 ± 35 μg/l) but not at other time-points, or after the administration of 1 μg GRF/kg. These data indicate that in hypothyroidism and perhaps hyperthyroidism there is an alteration in the responsiveness of the somatotroph to GRF administration. J. Endocr (1986) 109, 53–56
Microgram
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Neuromedin B (NB) is a recently discovered neuropeptide related to bombesin. It is localized to thyrotropes and we have previously shown that it directly inhibits thyrotropin (TSH) release from the anterior pituitary gland of euthyroid rats. In the current studies, we further evaluated the action of NB and antiserum directed against it in euthyroid rats and compared the actions with those in hypo- and hyperthyroid rats. Rats were rendered hypothyroid by treatment with propylthiouracil and hyperthyroid by treatment with thyroxine. In euthyroid rats, NB suppressed TSH release from hemipituitaries in vitro. Incubation of these pituitaries with highly specific antiserum against NB produced a stimulation of TSH release, whereas normal rabbit serum had no effect on the output of TSH. Thus, in euthyroid animals NB is a physiologically significant inhibitor of TSH release from the pituitary. In hypothyroid as in euthyroid animals, NB inhibited TSH release when microinjected into the third ventricle (3V) in the same dose (0.5 micrograms; 0.44 nmol) as in euthyroid rats. TSH release from hemipituitaries of hypothyroid animals was also suppressed by NB as in euthyroid animals. In hypothyroid animals, anti-NB antiserum was ineffective both in vivo after its microinjection into the 3V and in vitro on hemipituitaries, which suggests that the peptide has little physiologic significance in this condition, presumably because of its reduced release from the thyrotropes associated with diminished NB content in the pituitary of the hypothyroid rat. Intraventricular injection of NB failed to lower plasma TSH in hyperthyroid rats, which suggests that the action of the peptide is already maximal in hyperthyroidism. When antiserum to NB was microinjected twice into the 3V, there was a delayed increase in plasma TSH manifest 24 hr after the initial injection. TSH release from pituitaries of these animals was markedly increased in the presence of NB antiserum. Thus, NB has a physiologically significant TSH release-inhibiting action at the pituitary in the hyperthyroid as well as in the euthyroid rat. We conclude that in the euthyroid animal NB acts in an autocrine fashion to suppress TSH release from the thyrotropes directly. In hypothyroidism, NB synthesis and presumably release from the pituitary is decreased, such that there is no physiologic significance to the residual NB release, although the responsiveness to the inhibitory action of the peptide is increased, possibly via upregulation of its postulated receptors on the thyrotrope. In hyperthyroidism, the concentration of NB in thyrotropes and presumably its release is increased so that it has a physiologically significant TSH release-inhibiting action.
Thyrotropic cell
Propylthiouracil
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Propylthiouracil (PTU) in maximally inhibitory doses for liver and kidney iodothyronine 5'-deiodinase activity (5'D-I), reduces extrathyroidal T4 to T3 conversion by only 60-70% in euthyroid rats. A second pathway of T4 to T3 conversion (5'D-II) has been found in pituitary, central nervous system, and brown adipose tissue. 5'D-II is insensitive to PTU and increases in hypothyroidism, whereas 5'D-I decreases in hypothyroid rats. Thyroxine (T4) and triiodothyronine (T3) kinetics were assessed in euthyroid and thyroidectomized rats by noncompartmental analysis after injecting [125I]T4 and [131I]T3. Neither the volume of distribution nor the rate of fractional removal of plasma T4 was affected by the thyroid status, but the fractional removal rate of T3 was approximately 50% reduced in hypothyroid rats (P less than 0.001). Fractional T4 to T3 conversion was 22% in euthyroid and 26% in hypothyroid rats. In euthyroid rats, sufficient PTU to inhibit liver and kidney 5'D-I greater than 90% reduced serum [125I]T3 after [125I]T4 (results given as percent dose per milliliter X 10(-3) +/- SEM): 4 h, control 16 +/- 2 vs. PTU 4 +/- 1, P less than 0.005, and 22 h, control 6.4 +/- 0.4 vs. PTU 3.6 +/- 0.7, P less than 0.025. In thyroidectomized rats, the same dose of PTU also inhibited 5'D-I in liver and kidney, but had no effect on the generation of serum [125I]T3 from [125I]T4. Similarly, after 1 microgram T4/100 g bw was given to thyroidectomized rats, serum T3 (radioimmunoassay) increased by 0.30 +/- 0.6 ng/ml in controls and 0.31 +/- 0.09 ng/ml in PTU-treated rats. However, when the dose of T4 was increased to 2-10 micrograms/100 g bw, PTU pretreatment significantly reduced the increment in serum T3. T3 clearance was not affected by PTU in hypothyroid rats. The 5'D-II in brain, pituitary, and brown adipose tissue was reduced to less than or equal to 60% of control by 30 micrograms/100 g bw reverse T3 (rT3), an effect that lasted for at least 3 h after rT3 had been cleared. In rT3-pretreated thyroidectomized rats, the generation of [125I]T3 from tracer [125I]T4 was reduced in the serum: 6 +/- 1 vs. 12 +/- 1 X 10(-3)% dose/ml, P less than 0.01, during this 3-h period. We conclude that virtually all the T3 produced from low doses of exogenous T4 given to hypothyroid rats is generated via a PTU-insensitive pathway, presumably catalyzed by the 5'D-II. This is a consequence of the enhanced activity of this low Km enzyme together with the concomitant decrease in the hepatic and renal 5'D-I characteristic of the hypothyroid state. The results indicate that in some circumstances, 5D-II activity may contribute to the extracellular, as well as intracellular, T3 pool.
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The interrelationships in the regulation of thyroid-stimulating hormone (TSH) and prolactin (PRL) secretion in man were studied by following their response to drugs and hormones known to affect the serum concentration of either TSH or PRL. Administration of a single 0.5 oral dose of l-dopa to 12 patients with primary hypothyroidism produced a consistent suppression of the elevated TSH level in all patients. In contrast, l-dopa given to patient with known primary hypothyroidism, in whom thyroid hormone replacement therapy was discontinued for 3–4 weeks, produced suppression of TSH in only 2 out of patients, and there was no correlation between the basal TSH level and the responsiveness to l-dopa. The TSH response to l-dopa in a group of 13 euthyroid patients could not be interpreted due changes in TSH within the limits of the assay sensitivity. The TSH but not the PRL response to synthetic thyrotropin releasing hormone (TRH) was blunted early in the course of thyroid hormone replacement. After 2½ to 5 months, however, both TSH and PRL responses to TRH were virtually abolished. Administration of l-dopa 1 and 2 hr but not 3 hr prior to TRH abolished or diminished the PRL rise in response to TRH in patients with hypothyroidism of long duration. The TSH response to TRS, however, was unaltered by l-dopa given 1, 2, or 3 hr prior to TRH. The time course of both stimulatory and inhibitory responses of TSH paralleled those of PRL. These results suggest that TSH and PRL secretion in man is controlled by an interrelated pathway. If a common regulatory mechanism is involved, the pituitary thyrotrophs and lactotrophs have shown differential sensitivity to the common stimulatory and inhibitory substances.
TRH stimulation test
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Thyroid-stimulating hormone
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Glucose metabolism was investigated in humans before and 14 days after 300 micrograms L-thyroxine (T4)/day using a sequential clamp protocol during short-term somatostatin infusion (500 micrograms/h, 0-6 h) at euglycemia (0-2.5 h), at 165 mg/dl (2.5-6 h), and during insulin infusion (1.0 mU.kg-1.min-1, 4.5-6 h). T4 treatment increased plasma T4 (+96%) and 3,5,3'-triiodothyronine (T3, +50%), energy expenditure (+8%), glucose turnover (+32%), and glucose oxidation (Glucox +87%) but decreased thyroid-stimulating hormone (-96%) and nonoxidative glucose metabolism (Glucnonox, -30%) at unchanged lipid oxidation (Lipox). During somatostatin and euglycemia glucose production (Ra, -67%) and disposal (Rd, -28%) both decreased in euthyroid subjects but remained at -22% and -5%, respectively, after T4 treatment. Glucox (control, -20%; +T4, -25%) fell and Lipox increased (control, +42%; +T4, +45%) in both groups, whereas Glucnonox decreased before (-36%) but increased after T4 (+57%). During somatostatin infusion and hyperglycemia Rd (control, +144%; +T4, +84%) and Glucnonox (control, +326%; +T4, +233%) increased, whereas Glucox and Lipox remained unchanged. Insulin further increased Rd (+76%), Glucox (+155%), and Glucnonox (+50%) but decreased Ra (-43%) and Lipox (-43%). All these effects were enhanced by T4 (Rd, +38%; Glucox, +45%; Glucnonox, +35%; Ra, +40%; Lipox, +11%). Our data provide evidence that, in humans, T3 stimulates Ra and Rd, which is in part independent of pancreatic hormones.
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Atriopeptin (AP) is a polypeptide produced by atrial myocytes that is capable of inducing diuresis, natriuresis, and vasodilatation. Because thyroid dysfunction is known to be associated with alterations in both renal function and vasomotor control, we investigate the possible effects of varying thyroid function on AP in humans and rats. Plasma AP concentrations were determined in hyperthyroid and hypothyroid patients and normal subjects. Plasma AP was also measured in some patients after the iv infusion of 1 L 150 mmol/L NaCl and after treatment of hyperthyroidism or hypothyroidism. Plasma and atrial AP concentrations were measured in hyperthyroid, euthyroid, and hypothyroid rats. Plasma AP concentrations did not differ in the hyperthyroid (n = 22), euthyroid (n = 45), and hypothyroid (n = 16) subjects [47.1 ± 18.2 (mean ± sd), 45.1 ± 28.9, and 42.4 ± 20.0 pg/mL, respectively]. After NaCl infusion, mean plasma AP concentrations did not increase significantly in any of the three groups. Treatment of hyperthyroidism and hypothyroidism did not result in a significant change in plasma AP levels. In contrast, plasma AP concentrations were significantly higher in T4-treated (hyperthyroid) rats than in either euthyroid or propylthiouracil-treated (hypothyroid) rats [621 ± 17 vs. 266 ± 41 (P < 0.01) and 210 ± 28 pg/mL (P < 0.001), respectively], whereas atrial AP contents were similar in the three groups of rats. We conclude that hyperthyroidism and hypothyroidism in man are not associated with significantly altered plasma AP concentrations. The higher plasma AP levels in T4-treated rats may reflect the relatively shorter duration or greater severity of thyroid dysfunction or thyroid hormone-induced myocardial hypertrophy in the animals.
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Leptin, the product of the ob gene, is secreted by adipocytes and has been shown to decrease appetite and increase energy expenditure. Leptin mRNA in adipocytes correlates with body wt, and serum leptin levels correlate with body fat. Alterations in thyroid status are frequently associated with changes in body wt. To evaluate the possible influence of thyroid status on the leptin system, we have measured serum leptin concentrations in thyroidectomized rats infused either with placebo, or with different doses of T4 (0.8 to 8.0 microg/100 g body wt per day) or T3 (0.25 to 2.0 microg/100 g body wt per day), covering a wide range of thyroid hormone concentrations, from overt hypothyroidism to hyperthyroidism. Intact animals infused with placebo were used as euthyroid controls. Infusion of T4 or T3 into thyroidectomized rats resulted in a decrease in serum leptin levels with respect to the thyroidectomized animals infused with placebo. When compared to the control group, serum leptin levels were decreased in the groups infused with the higher T4 and T3 doses, and tended to be elevated in the thyroidectomized animals infused with placebo. The leptin/body wt ratio was markedly increased in thyroidectomized rats infused with placebo, and decreased in the animals infused with the higher thyroid hormone doses. In conclusion, thyroid hormones exert a negative influence on serum leptin concentrations, which is greater than expected by the changes in body wt The precise mechanism of this influence remains to be elucidated.
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SUMMARY The serum triiodothyronine concentration was evaluated before and after thyrotrophin releasing hormone in fifty‐six patients with hypothalamic‐pituitary disorders (thirty‐four had secondary hypothyroidism, twenty‐two were euthyroid) and in twenty‐four normal controls. Basal serum T3 was low in fifteen hypothyroid subjects and normal in the remainders. After TRH, serum T3 did not increase normally in twenty‐five hypothyroid and in ten euthyroid patients; even the patients with normal or supranormal plasma TSH increase had significantly lower T3 responses than normal controls ( P <0.0001 for hypothyroid, P <0.01 for euthyroid subjects). The finding of low T3 response to TRH in some euthyroid patients with hypothalamic‐pituitary disorders can perhaps identify cases of preclinical secondary hypothyroidism, probably due to low biological activity of released TSH.
Basal (medicine)
Pituitary disorder
Hypothalamic disease
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