Intravenous Administration Of Thyrotropin-releasing Hormone Research Articles

Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism

Primary hypothyroidism in dogs is associated with increased release of growth hormone (GH). In search for an explanation we investigated the effect of intravenous administration of thyrotropin-releasing hormone (TRH, 10 μg/kg body weight) on GH release in 10 dogs with primary hypothyroidism and 6 healthy control dogs. The hypothyroid dogs had a medical history and physical changes compatible with hypothyroidism and were included in the study on the basis of the following criteria: plasma thyroxine concentration <2 nmol/l and plasma thyrotropin (TSH) concentration >1 μg/l. In addition, 99mTcO 4 − uptake during thyroid scintigraphy was low or absent. TRH administration caused plasma TSH concentrations to rise significantly in the control dogs, but not in the hypothyroid dogs. In the dogs with primary hypothyroidism, the mean basal plasma GH concentration was relatively high (2.3 ± 0.5 μg/l) and increased significantly ( P = 0.001) 10 and 20 min after injection of TRH (to 11.9 ± 3.5 and 9.8 ± 2.7 μg/l, respectively). In the control dogs, the mean basal plasma GH concentration was 1.3 ± 0.1 μg/l and did not increase significantly after TRH administration. We conclude that, in contrast to healthy control dogs, primary hypothyroid dogs respond to TRH administration with a significant increase in the plasma GH concentration, possibly as a result of transdifferentiation of somatotropic pituitary cells to thyrosomatotropes.

Effect of Thyrotropin-Releasing Hormone and Its Synthetic Analogue Digipramine on Certain Indices of Hemostasis in vitro and in vivo

The effect of neuropeptide thyrotropin-releasing hormone (TRH) and its synthetic analogue digipramine on certain indices of blood coagulation and fibrinolysis were studied in vitro and in vivo. The peptides added to the pool of normal rat plasma at 10−10 to 10−3 M increased the procoagulant activity but had virtually no effect on fibrinolysis. Intravenous administration of TRH and digipramine increased the procoagulant activity of the blood and platelet aggregation but decreased fibrinolysis; digipramine had a more pronounced effect on the coagulation potential of the blood and a less pronounced effect on fibrinolytic indices as compared to TRH. Intranasal administration of the peptides did not change the pattern of their effect on indices of hemostasis although the effects became less pronounced.

Constitutionally Tall Stature with Morphological Abnormality of the Pituitary Gland

We describe two male pubertal cases of constitutionally tall stature (CTS) with an enlarged pituitary gland or pituitary microadenoma. Both patients' basal serum growth hormone (GH) levels were normal. Neither had oversecretion of any other pituitary hormones. However, their serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). A later GH response to an intravenous administration of luteinizing hormone-releasing hormone (LHRH) was also found in one patient. In addition, oral glucose loading (OGL) caused a late increase in serum GH at 180 min in both patients. Our present findings suggest that endocrinological and morphological abnormalities of the pituitary gland are found in some subjects with CTS during puberty. It is speculated that these paradoxical GH responses are associated with dysregulation of GH secretion. Finally, it is important to investigate whether tall children with morphological abnormalities of the pituitary gland such as our patients are preacromegalic, in which case, given that overproduction of GH secretion may occur in the future, further observation is necessary.

Effects Of Carbamazepine On The Hypothalamic-Pituitary-Thyroid Axis

To evaluate the effects of treatment with carbamazepine on the hypothalamic-pituitary-thyroid axis and thyroid hormone concentrations in patients with epilepsy. We undertook a prospective study in seven subjects in whom the diagnosis of epilepsy had been established and a regimen of carbamazepine (200 mg three times a day) was initiated. All participants underwent 24-hour 123 I thyroid uptake studies, as well as assessment of the basal thyrotropin concentration and the thyrotropin response to intravenous administration of thyrotropin-releasing hormone. In addition, thyroxine (T(4)), free T(4) index, triiodothyronine (T(3)), free T(3) index, reverse T(3), and T(3) resin uptake were determined before initiation of carbamazepine treatment and again after 3 to 4 months of carbamazepine therapy. Serum T(4), T(3), and free T(4) index decreased significantly (P<0.05) after therapy with carbamazepine, whereas no significant alterations were noted in T(3) resin uptake, free T(3) index, and reverse T(3) concentrations. A significant increase occurred in basal serum thyrotropin level (P<0.05). Moreover, the peak thyrotropin concentration, the absolute change from the basal thyrotropin level, and an integrated thyrotropin response expressed as cumulative response to thyrotropin-releasing hormone stimulation were all significantly increased after carbamazepine therapy in comparison with values documented before initiation of therapy (P<0.05 for all comparisons). Finally, 24-hour 123 I uptake by the thyroid gland increased slightly after carbamazepine therapy, but the change was not statistically significant. All values determined both before and after carbamazepine therapy remained within normal ranges. Carbamazepine therapy induces significant alterations in serum thyroid hormone concentrations as well as in the hypothalamic-pituitary-thyroid axis. Nevertheless, patients receiving carbamazepine treatment continue to remain euthyroid despite these significant changes.

Inhibited Hypothalamic-Pituitary-Thyroid Axis in Type I Pseudohypoparathyroidism

To assess the hypothalamic-pituitary-thyroid axis in two patients with the diagnosis of type I pseudohypoparathyroidism established previously by characteristic clinical features and laboratory findings, including low serum Ca++, high parathyroid hormone concentration, and subnormal urinary cyclic adenosine monophosphate (cAMP) responses to exogenous administration of parathyroid hormone. We determined serum thyroxine, triiodothyronine (T(3)), T(3) resin uptake, and 24-hour thyroidal uptake of 123 I before and after subcutaneous administration of thyroid-stimulating hormone (TSH), 10 U daily for 3 days. Serum TSH levels were determined before and again at 15, 30, 45, and 60 minutes after intravenous administration of thyrotropin-releasing hormone (TRH) (400 microg) after an overnight fast. Values noted in the two patients with type I pseudohypoparathyroidism were compared with those obtained in 10 normal volunteer control subjects. Serum thyroxine (T(4)), triiodothyronine (T(3)), T(3) resin uptake, and 24-hour 123 I uptake values for both patients with type I pseudohypoparathyroidism were within the normal ranges (5.5 to 11.5 microg/dL for T(4), 90 to 190 ng/dL for T(3), 35 to 45% for T(3) resin uptake, and 10 to 35% for 24-hour 123I uptake). Their responses to administration of TSH, however, were all significantly lower in comparison with the mean values for the 10 healthy control subjects. Basal TSH was higher in both patients with type I pseudohypoparathyroidism than in normal subjects, but TSH responses after administration of TRH, although not significantly different from normal, were blunted in relationship to the basal concentrations, as expressed as a percentage increase in TSH as well as a cumulative TSH response. The responses of pituitary thyrotrophs to TRH and the thyroid gland to TSH were both considerably inhibited in the patients with type I pseudohypoparathyroidism in comparison with normal control subjects. This finding may be yet another evidence of the lack of adequate generation of cAMP, an important second messenger needed for normal functioning of most polypeptide hormones, including TRH and TSH, in this syndrome.

Local cerebral blood flow in motor neuron disease: correlation with clinical findings

Local cerebral blood flow (CBF) measured by xenon-enhanced CT was correlated with the clinical findings in 21 patients with motor neuron disease (mean ± SD age, 60 ± 10 years). In 11 patients, CBF was also measured after intravenous injection of 2 mg thyrotropin releasing hormone (TRH). There were no significant differences in CBF of the cerebral cortex, basal ganglia, thalamus, and subcortical white matter with respect to age, duration of illness, or presence (n = 9) or absence (n = 12) of bulbar palsy. In patients with upper motor neuron disturbance (n = 10), however, local CBF in the frontal cortex was significantly lower (p < 0.05) than in those without it (n = 11). Within the frontal cortex, CBF reduction was marked in the upper posterolateral part (p < 0.05) that included the motor and premotor areas. Intravenous administration of TRH did not significantly alter the local CBF in any of the brain regions examined. An additional patient with motor neuron disease and severe dementia showed marked CBF reduction in the frontal lobe, which was in common with but much greater than the reduction in those exhibiting subcortical dementia (e.g., progressive supranuclear palsy). We conclude that in motor neuron disease patients with upper motor neuron involvement, the selective reduction of CBF in brain regions that include primary motor and premotor areas may reflect functional disturbance or neuronal degeneration in these regions. The ameliorating effect of TRH in patients with motor neuron disease, if any, appears not to be related to increases in local CBF or activation of brain function.

Bioactivity of Plasma Prolactin in Ovariectomized, Diethylstilbestrol-Treated Long-Evans and Holtzman Rats after Thyrotropin-Releasing Hormone or Bromocriptine Administration

The objective of this study was to determine the effects of thyrotropin-releasing hormone (TRH) and bromocriptine on plasma levels of biologically active prolactin in ovariectomized, diethylstilbestrol (DES)-treated rats. Female Long-Evans and Holtzman rats were ovariectomized and each was given a subcutaneous implant of diethylstilbestrol (DES). One week later, groups of DES-treated rats were fitted with indwelling intra-atrial catheters, and 2 days later blood samples were withdrawn before and at 1, 2, 5, 10, and 20 min after intravenous administration of TRH (250, 500, or 1000 ng/rat). Blood samples were obtained from other groups at 4 weeks of DES treatment by orbital sinus puncture under ether anesthesia before and at 30, 60, and 120 min after bromocriptine administration (2.5 mg/rat sc). Plasma was assayed for prolactin by conventional radioimmunoassay (RIA) and by Nb2 lymphoma bioassay (BA). Holtzman rats released significantly more prolactin following TRH than did Long-Evans rats when the RIA was used to measure prolactin. However, when the BA was used to assay prolactin in the same samples, the Long-Evans rats released more prolactin than did the Holtzman rats. In addition, the ratio of the BA to RIA values was significantly increased in both strains following TRH, but the greatest increase was observed in the Long-Evans rats, in which the ratio was 4.5 at the peak of the TRH-induced rise in plasma prolactin. Gel filtration chromatography of plasma obtained at 5 min after TRH treatment in Long-Evans rats revealed large molecular forms of prolactin with BA to RIA ratios of 4-5. In addition, monomeric prolactin had a BA to RIA ratio of 2. Bromocriptine treatment reduced prolactin levels in both strains, but the effect was more rapid in Holtzman than in Long-Evans rats. In addition, bromocriptine treatment of Holtzman, but not Long-Evans, rats significantly reduced the BA to RIA ratio of plasma prolactin. The results indicate that TRH and bromocriptine affect the release of biologically active prolactin to a greater extent than prolactin detected by antibody in the RIA, and that Long-Evans and Holtzman rats respond to these secretagogues differently with regard to BA to RIA comparisons.

TRH-induced vagal stimulation of duodenal HCO-3 mediated by VIP and muscarinic pathways

The central nervous system effects of thyrotropin-releasing hormone (TRH) on proximal duodenal bicarbonate secretion were studied in freely moving rats. Cerebroventricular administration of TRH (0.5-5.0 nmol) significantly stimulated basal duodenal bicarbonate secretion, whereas intravenous administration of TRH did not. Ganglionic blockade with chlorisondamine and truncal vagotomy abolished TRH-induced bicarbonate secretion, whereas atropine significantly attenuated the response. The vasoactive intestinal peptide (VIP) receptor antagonist, (4Cl-D-Phe6, Leu17) VIP given intravenously completely prevented the stimulatory effect of central TRH on duodenal bicarbonate secretion. In contrast, hypophysectomy, adrenalectomy, opiate and noradrenergic blockade, or indomethacin did not affect the TRH-induced bicarbonate response. Intravenous administration of VIP and carbachol significantly stimulated bicarbonate outputs, and these responses were blocked by the VIP antagonist and atropine, respectively. These results indicate that TRH may serve as a central nervous system mediator that stimulates duodenal bicarbonate secretion in rats by increasing vagal outflow. Vagal stimulation induced by TRH increases duodenal bicarbonate secretion by the release of VIP and, in part, by activation of a muscarinic pathway but not by pituitary, adrenal, and noradrenergic pathways or endogenous opiates and prostaglandins. The actions of peripheral VIP and carbachol appear to be mediated by specific VIP and muscarinic receptors, respectively.

Optimal Daily Levothyroxine Dose in Primary Hypothyroidism

Several studies have described the mean optimal replacement daily dose of levothyroxine sodium in subjects with primary hypothyroidism. Furthermore, a cautious approach in replacement therapy of the elderly population is well established. However, the initial dose of levothyroxine has remained variable, especially in young subjects, since the guidelines for the prediction of the final replacement dose are scarce. This study assessed the efficacy of pretreatment thyroid hormone indexes in determination of the final maintenance levothyroxine dose in 156 subjects with primary hypothyroidism. The optimal daily levothyroxine dose as defined by normalization of serum thyroxine and basal thyroid-stimulating hormone levels, as well as thyroid-stimulating hormone response to the intravenous administration of thyrotropin-releasing hormone, varied between 50 micrograms and 200 micrograms and, hence, the subjects were grouped according to the final levothyroxine dose. Significant correlations were noted between the levothyroxine dose for individual groups and pretreatment serum triiodothyronine, thyroxine, and thyroid-stimulating hormone concentrations. However, the serum thyroid-stimulating hormone concentration demonstrated a markedly closer relationship with the levothyroxine dose than did either triiodothyronine or thyroxine for both comparisons. Furthermore, when assessed for all subjects, the correlation between levothyroxine dose and thyroid-stimulating hormone level, alone, remained significant. This study demonstrates that obtaining routine thyroid hormone indexes prior to initiation of replacement levothyroxine therapy may be reliable predictors of the final levothyroxine dose; serum thyroid-stimulating hormone concentration being the best index. Thus, the levothyroxine dose may be reliably predicted depending on a specific range of thyroid-stimulating hormone levels. Therefore, in an individual subject, aiming for the predicted dose rather than the mean dose, a procedure described in the medical literature, may be more helpful in arriving at an optimal levothyroxine dose.

Contribution of cholinergic vasodilators on the increase in cerebral cortical blood flow responses to the intravenous administration of thyrotropin releasing hormone in anesthetized rats

The effect of an intravenous administration of thyrotropin-releasing hormone (TRH) on the regional cerebral blood flow in the sensory cortex was studied in halothane-anesthetized adult Wistar rats. The regional cerebral blood flow was continuously monitored with the laser Doppler flowmetry. The cerebral blood flow increased dose-dependently following the administration of 3 × 10 2 and 3 × 10 3 μg/kg TRH. The systemic blood pressure also increased simultaneously. After maintaining the systemic blood pressure at a constant level via a pressure reservoir system, the TRH-induced increases in the cerebral blood flow continued to be observed. In atropinized animals, the blood pressure increased as high as that indicated in non-atropinized animals following TRH administration, but the responses of the cerebral blood flow in the latter were much attenuated. It was suggested that the cholinergic vasodilative system contributed to the TRH-induced increase in cerebral blood flow.

Effects of repetitive intravenous administration of thyrotropin-releasing hormone in normal subjects

Continuous infusion of thyrotropin-releasing hormone (TRH) into normal subjects leads to divergent TSH and PRL responses. Whereas TSH values remain elevated up to the end of infusion, PRL levels decline progressively. In this study we investigated the pattern of TSH, PRL, GH, and peripheral thyroid hormone secretion in response to repetitive administration of TRH at 90-min intervals, which resembles more closely the physiological pattern of TRH release.

The involvement of central cholinergic mechanisms in cardiovascular responses to intracerebroventricular and intravenous administration of thyrotropin-releasing hormone

Intracerebroventricular (i.c.v.) administration of thyrotropin-releasing hormone (TRH) in a range from 0.1 to 100 μg induced a dose-related increase in blood pressure in conscious rats, whereas TRH-free acid (TRH-OH) and histidyl-proline diketopiperazine (His-Pro-DKP), metabolites of TRH, did not. The blood pressure responses to intravenous (i.v.) injection of 5mg/Kg TRH were similar to those induced by TRH (i.c.v.). Pretreatment with atropine (50 μg, i.c.v.) significantly reduced the pressor effect of TRH administered through either route. Hemicholinium-3 (50 μg, i.c.v.), an inhibitor of choline uptake, also prevented the increase in blood pressure induced by TRH (10 μg, i.c.v.). These results indicate that both centrally and peripherally administered TRH have pressor effects that are mediated by central cholinergic mechanisms, probably by activating cholinergic neurons.

Inhibition of gastric acid secretion by immunoneutralization of endogenous brain thyrotropin-releasing hormone

Previous studies have shown that intracisternal (i.c.), but not intravenous administration of thyrotropin-releasing hormone (TRH), an endogenous tripeptide ( pGlu-His-Pro-NH 2), produces a time-, dose-dependent and vagus-mediated stimulation of acid secretion in rats. This study was designed to test the hypothesis that endogenous brain TRH plays a role in regulation of acid secretion in the pylorus-ligation model. In confirmation of previous reports, i.c. TRH (1 μg) significantly ( P < 0.01) stimulated gastric acid output, gastric secretory volume and decreased gastric intraluminal pH. Intracerebroventricular (i.c.v.) infusion of TRH antiserum (anti-TRH) 30 min prior to pyloric occlusion significantly reduced acid output, secretory volume and raised gastric pH. This inhibitory gastric acid secretory response to i.c.v. anti-TRH appears to be specific since i.c.v. infusion of normal rabbit serum or antisera raised against neurotensin (NT), Leu-enkephalin (L-enk), gonadotropin-releasing hormone (GnRH), somatostatin (SRIF) and α-melanocyte stimulating hormone (α-MSH) were without measurable effect. The findings of this study indicate that endogenous brain TRH, but not NT, L-enk, GnRH, SRIF or α-MSH plays a physiological role in regulation of acid secretion.

Effects of thyrotropin-releasing hormone in the fetal lamb

Thyrotropin-releasing hormone causes neurobehavioral arousal and stimulates breathing in adult, newborn, and preterm experimental animals. Its effects on behavioral state, breathing, blood pressure, and heart rate were studied in the chronically instrumented late term fetal lamb. Fetal intravenous administration of thyrotropin-releasing hormone resulted in behavioral arousal with electrocortical desynchronization, increased body and eye movements, rapid and deep breathing movements, and a transient bradycardia followed by prolonged tachycardia, associated with an increase in both systolic and diastolic blood pressure. The effects were similar following intracisternal administration of thyrotropin-releasing hormone. The effects of thyrotropin-releasing hormone on behavior, but not breathing, was abolished in the presence of muscarinic blockade. Thyrotropin-releasing hormone may play a role in the modulation of central regulation of cardiovascular, respiratory, and behavioral activity in the fetus.

Age-related differences in the pituitary prolactin response to thyrotropin-releasing hormone

We have previously reported that human subjects undergoing surgery for inguinal hernias exhibit an age-related attenuation in the plasma prolactin response, with no differences during resting conditions. We suggested that these differences were due to age-related neuroendocrine changes, but that peripheral factors may play a role as well. In the present study, we have assessed the pituitary response to 500 μg of thyrotropin-releasing hormone (TRH) in the very same subjects previously studied during surgery. Blood samples were drawn immediately prior to, as well as 10, 20, 40 and 60 minutes following the intravenous administration of TRH. There was a clear-cut age-related attenuation in the pituitary prolactin response with no difference in the thyrotropin (TSH) response. Maximum prolactin response in the young subjects was 31.7 μg/l and 19.2 μg/l in old subjects (F(4) = 3.5, p < .01, two-way ANOVA). These results indicate that the age-related differences in the prolactin response to stress are mainly due to pituitary changes. However, prolactin-secreting cells are under the control of the hypothalamus. Therefore, the possibility must be considered that aging or other concurrent factors could be exerting their influence via the hypothalamus and not necessarily directly at the pituitary level.

Thyrotropin-releasing hormone tests in an outpatient clinic.

Measurement of thyroid-stimulating hormone (TSH) levels in various timed blood samples after administration of thyrotropin-releasing hormone (TRH) has become a standard part of the diagnostic armamentarium for suspected thyroid disease. We reviewed the records of 165 patients who received TRH tests in an endocrinology outpatient clinic to assess the diagnostic utility of the test based upon other clinical parameters, and to assess concordance of the 30-minute TSH value after intravenous administration of TRH. Standard (control) values for TRH testing were obtained in 41 normal subjects. Patients were divided into groups of hyperresponders, hyporesponders, and normal responders. The overall concordance rate of the ultimate thyroid diagnosis and the 30-minute TSH value was 97%. With close adherence to clinical indications, the TRH test is of considerable benefit as an outpatient tool in the diagnostic assessment of thyroid disease. Basal and 30-minute TSH values are satisfactory for diagnosis in the majority of patients, thereby rendering unnecessary the discomfort and expense of multiple samples for TSH measurements.

Serum calcium decline after intravenous administration of thyrotropin-releasing hormone in man.

The influence of iv administration of 0.2 mg thyrotropin-releasing hormone (TRH) on serum calcium was examined in 20 subjects divided into three different groups: one, comprising patients with primary hypothyroidism (A), another, containing euthyroid patients with various diseases (B), and a third, including healthy volunteers (C). Ninety min after the TRH injection total serum calcium (T-Ca) had fallen by 0.19 +/- 0.03 mmol/l in group A (p less than 0.01), by 0.10 +/- 0.02 mmol/l in group B (p less than 0.01), and by 0.08 +/- 0.02 mmol/l in group C (p less than 0.02). Ionized serum calcium (I-Ca) fell in parallel with T-Ca in group A and B. In contrast, serum magnesium was unaffected in all groups. Neither the renal excretion of calcium nor the serum concentration of parathyroid hormone, glucagon or calcitonin changed significantly in response to TRH. These results indicate that TRH has a slight hypocalcemic effect in man which is not caused by plasma dilution, direct influence on the kidneys, or TRH effects on the major calcium regulating hormones. Whether TRH per se, or an increased serum TSH level, induces calcium to leave the vascular space remains to be elucidated.

Clinical Response to CB-154 and the Pituitary Response to Thyrotropin-Releasing Hormone-Gonadotropin-Releasing Hormone in Patients with Galactorrhea-Amenorrhea

Ten patients with galactorrhea and amenorrhea were treated with 2-bromo-alpha-ergocryptine (CB-154). All patients had normal anteroposterior and lateral x-rays of the sella turcica and normal or low gonadotropin levels. Before treatment, serum prolactin (PRL) levels were between 80 and 1575 ng/ml. Prior to initiating therapy, six patients were further evaluated by the intravenous administration of thyrotropin-releasing of a pituitary etiology in all patients. During treatment, PRL levels were measured at monthly intervals. After 1 month, serum PRL concentrations were reduced between 13% and 99%. In eight subjects there was complete cessation of galactorrhea. During treatment, nine patients resumed ovulatory menstrual cycles and three patients conceived. After discontinuing therapy, five of seven subjects had a recurrence of galactorrhea, amenorrhea, and hyperprolactinemia.

The clinical utility of a heterologous radioimmunoassay for human prolactin

A specific and sensitive double antibody radioimmunoassay for human prolactin has been developed utilizing anti-human prolactin and purified ovine prolactin for radioiodination. Employing this radioimmunoassay, as little as 1.5 ng of prolactin can be quantified in a ml of human serum. The prolactin in serum detected by the radioimmunoassay behaved in a similar manner to purified human 125 I-labeled prolactin on polyacrylamide gel electrophoresis. Exogenous prolactin could be completely recovered when varying amounts were added to a constant volume of serum. In normal control and primary hypothyroid subjects, intravenous administration of thyrotropin-releasing hormone elicited a peak prolactin response 30 min post-injection. Hyperthyroid and hypopituitary subjects did not manifest a significant increase in serum prolactin concentration after the injection. Subjects with functional galactorrhea had high resting prolactin levels and exhibited peak increase in serum prolactin concentration at 60 min following the administration of thyrotropin-releasing hormone.