Thyrotropin-releasing Hormone In Patients Research Articles

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression

Background: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population.Methods: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 μU/mL.Results: There was no significant difference in mean CSF TRH between “blunters” (2.82 ± 1.36 pg/mL) and “nonblunters” (3.97 ± 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure.Conclusions: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus–hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem–dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.

Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness

Reactivation of Pituitary Hormone Release and Metabolic Improvement by Infusion of Growth Hormone-Releasing Peptide and Thyrotropin-Releasing Hormone in Patients with Protracted Critical Illness

Thyrotropin stimulating hormone response to thyrotropin releasing hormone in patients with panic disorder.

The aim of this study is to assess thyrotropin stimulating hormone (TSH) response to thyrotropin releasing hormone (TRH) in patients with panic disorder (PD). The effects of TRH administration on the release of TSH were examined in 15 patients who met DSM-III-R criteria for PD and compared their test results with those of 15 normal control subjects. Blood samples were taken before TRH administration (baseline values) and at 15, 30 and 60 min. delta max TSH values were lower in the panic disorder patients than in the control subjects. Using the criterion of delta max TSH < or = 7 mlU/l, nine of the 15 panic disorder patients and four of the 15 control subjects had a blunted TSH response to TRH. These results confirm the findings from earlier reports that patients with PD show blunted TSH response to TRH which is similar to that seen in depressed patients.

Low response of the thyroid gland to endogenous thyrotropin increased by thyrotropin-releasing hormone in patients with euthyroid Graves' disease.

Euthyroid Graves' disease is defined as Graves' ophthalmopathy without hyperthyroidism, and the thyroid-stimulating antibody (TSAb) has been known to be a good marker for diagnosis. However, the question of why TSAb does not cause hyperthyroidism arises. To settle this, we examined thyroid responsiveness to endogenous thyrotropin (TSH) increased by thyrotropin-releasing hormone (TRH) in 23 patients with euthyroid Graves' disease. Nineteen patients (83%) had positive TSAb and 21 (91%) had at least one of the autoantibodies to the thyroid gland. Only one patient (4%) had positive thyroid-stimulation blocking antibody (TSBAb). Basal levels of free thyroxine (FT4), free triiodothyronine (FT3), and thyrotropin (TSH) in patients were not different from those in age- and sex-matched normal controls (n = 25). Response of TSH to TRH was normal; however, an increase of FT3, either absolute or as a multiple of baseline, in the TRH test in these patients (0.46+/-0.23 pg/mL, P < 0.001; 1.14+/-0.09 fold, p < 0.001) was significantly lower than that in controls (0.86+/-0.19 pg/ml; 1.26+/-0.07 fold). There was no correlation between the deltaFT3/deltaTSH ratio and TSAb activity. It is concluded that thyroid responsiveness in euthyroid Graves' disease is lower than in normal controls and this explains the euthyroid function in the patients even in the presence of TSAb.

14-53 - Thyrotropin response to thyrotropin-releasing hormone in patients with panic disorder

14-53 - Thyrotropin response to thyrotropin-releasing hormone in patients with panic disorder

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.

The effect of repeated thyrotropin‐releasing hormone administration on regional cerebral blood flow in humans

Recently, regional cerebral blood flow (rCBF) was found to increase slightly in the thalamus after a single administration of thyrotropin‐releasing hormone (TRH) to healthy adults. Regarding the effect of prolonged TRH administration on rCBF, some scintigraphic improvements have been observed recently. However, no study has investigated the effect quantitatively, except for a preliminary study by positron emission tomography. Therefore, we examined the effect of repeated administration of TRH on rCBF in humans quantitatively. Eight patients with spinocerebellar degeneration (SCD) were given TRH intravenously at a daily dose of 2 mg for 14 days and rCBF was measured by the 133Xe intravenous injection method before and after repeated TRH administration. TRH caused a significant (p &lt; 0.01) increase of 12% in the gray matter flow (fast flow, F|), especially at the parietal and occipital lobes, and also caused a significant (p &lt; 0.05) increase of 8% in the initial slope index (ISI), especially at the parietal lobe. Among seven patients who improved clinically after TRH administration, F1 values were increased in all of them and ISI values were increased in six. We conclude that repeated TRH administration increases rCBF in humans. These results might warrant clinical investigation of a possible therapeutic role of TRH in patients with cerebral ischemia.

Thyroid antoantibodies and the response to thyrotropin releasing hormone in patients with subclinical hypothyroidism.

To evaluate the clinical usefulness of the thyrotropin releasing hormone (TRH) test and estimation of thyroid autoantibody concentrations in patients with borderline raised thyroid stimulating hormone (TSH). The records of 34 consecutive patients with persistent borderline increased TSH (4.4-9.9 mU/l) referred to the Medical Investigation Unit were reviewed. The response of patients with thyroid autoantibodies to the TRH test was compared with that of patients with a negative antibody screen. Eleven (44%) of 25 patients with positive anti-thyroid microsomal and/or thyroglobulin antibody tests and three (33%) of nine patients with a negative antibody screen had hypothyroid responses to TRH. Neither age nor sex affected the response to TRH. Basal TSH alone was poorly correlated with these indices. Twelve (35%) patients who had elevated basal TSH had a normal response to the TRH test. Patients with positive or negative thyroid autoantibodies and an exaggerated response to the TRH test should be regarded as hypothyroid and treated with thyroxine. Patients with positive thyroid autoantibodies and normal TSH response may subsequently develop hypothyroidism and should be given long term follow up.

Effect of glucocorticoids on the paradoxical growth hormone response to thyrotropin-releasing hormone in patients with acromegaly

It has been hypothesized that in acromegalic patients, as well as in normal subjects, acute increases in serum cortisol levels may cause an enhancement of hypothalamic somatostatin secretion, which in turn may be responsible for the glucocorticoid-mediated growth hormone (GH) inhibition. The aim of this study was to investigate short-term effects of an intravenous (IV) infusion of hydrocortisone on the GH response to thyrotropin-releasing hormone (TRH) in acromegaly. We studied six adult patients with active acromegaly. The group was composed of four women and two men with a mean age of 55.8 ± 6.4 years (range, 27 to 68) and a mean body mass index of 26.7 ± 1 kg/m 2 (range, 23.3 to 30). All patients underwent the following treatments: (1) hydrocortisone alone: a bolus IV injection of hydrocortisone succinate 100 mg in 2 mL saline at time −60 minutes, followed by a 120-minute IV infusion of hydrocortisone succinate 250 mg in 250 mL saline from −60 to 60 minutes; (2) TRH + hydrocortisone: a bolus IV injection of TRH 200 μg 60 minutes after initiation of a 2-hour hydrocortisone infusion; (3) TRH alone: a bolus IV injection of TRH at time 0, 60 minutes after initiation of a 2-hour saline infusion. In all six patients, TRH induced large GH increases (absolute peak GH level, 58.1 ± 23.2 μg/L; maximum % GH change with respect to baseline, 1,397.8% ± 807.8%; range, 205% to 5,219%). In the whole group of acromegalic patients, hydrocortisone infusion did not significantly affect the mean GH response to TRH (absolute peak GH level, 45.4 ± 19.5 μg/L; maximum % GH change with respect to 0-minute level, 894.8% ± 320%; range, 106% to 1,988%). After hydrocortisone + TRH administration, all six patients showed significantly higher absolute GH values as compared with values obtained with hydrocortisone alone from time 15 to 45 minutes. Our data show that the paradoxical GH response to TRH in acromegaly is resistant to the inhibitory action of an acute and sustained elevation of serum cortisol level.

The evaluation of hypothalamic somatostatin tone using pyridostigmine and thyrotropin releasing hormone in patients with acromegaly

To indirectly evaluate the hypothalamic somatostatin (SS) tone in patients with acromegaly, the effects of pyridostigmine (PD), a cholinesterase inhibitor which can inhibit hypothalamic SS secretion, on TRH-induced TSH secretion and the effects of SMS 201-995 on TSH or GH secretion were studied in acromegalic patients (31-69 yr, n = 10), normal young (21-24 yr, n = 7) and normal old male subjects (62-71 yr, n = 7). After pretreatment with PD (60 mg po, -30 min), normal young subjects showed significantly enhanced TSH responses to TRH (500 micrograms i.v., 0 min) compared to single administration of TRH, whereas normal old and acromegalic patients did not show such enhancement. Plasma TSH response to a single administration of TRH in acromegalic patients was significantly lower than that of normal young and old subjects. Although normal young and old subjects showed significantly enhanced GH responses to GHRH (100 micrograms i.v. at 0 min) after the pretreatment with PD (60 mg, -30 min), no such enhancement was observed in acromegalic patients. In contrast, the decrement in plasma TSH after SMS 201-995 administration was similar between normal subjects (5 young 5 old) and 7 acromegalic patients. Further, the maximal plasma GH decrement after administration was significantly greater in acromegalic patients than in the 5 normal young and 5 old subjects p < 0.01). In conclusion, hypothalamic SS tone does not appear to be elevated in acromegalic patients compared to normal young and probably old subjects.

Thyrotropin response to thyrotropin-releasing hormone in patients with dementia of the Alzheimer type

Eleven patients with senile dementia of the Alzheimer type and 11 age-matched control subjects were given the thyrotropin-releasing hormone (TRH) test. The two groups did not differ with respect to peak thyrotropin (TSH) response or TSH levels at baseline, 20, 30, and 45 min after TRH injection. There were significant differences between the groups on Hamilton Depression Rating Scale scores (p < 0.03), although neither group met clinical criteria for depression. Items that were significantly different pertained to depressed mood, loss of interest, loss of insight, suicidal ideation, and obsessional symptoms.

Thyrotropin-releasing hormone increases serum levels of growth hormone-releasing hormone and growth hormone in patients with acromegaly.

The effect of intravenous injection of thyrotropin-releasing hormone (TRH) on the plasma concentrations of growth hormone (GH) and growth hormone-releasing hormone (GHRH) was studied in seven patients with acromegaly and in five control subjects. TRH had no effect on plasma GH or GHRH in the five control subjects. A 'paradoxical' increase in plasma GH in response to TRH was observed in four of the seven patients with acromegaly. In these four patients plasma GHRH also increased in response to TRH. No TRH-induced increase in GHRH levels was observed in the other three patients with acromegaly who did not display an increase in GH in response to TRH. The present results imply that GHRH may be involved in the plasma GH response to TRH in patients with acromegaly.

Effect of pretreatment with pyridostigmine on the thyrotropin response to thyrotropin-releasing hormone in patients with Cushing's disease.

Effect of pretreatment with pyridostigmine on the thyrotropin response to thyrotropin-releasing hormone in patients with Cushing's disease.

Turnover of thyrotropin-releasing hormone in patients with chronic renal failure and chronic alcoholic liver disease

Homogenates of liver and kidney tissues are efficient in degrading TRH, but the liver contains only membrane-bound pyroglutamyl aminopeptidase, active in degrading TRH at the extracellular side of cell membranes. In the present study the effect of liver and kidney failure on the degradation of infused TRH was investigated in man. In 7 uremic patients (group I) and 7 patients with chronic alcoholic liver disease (group II) plasma clearance rate, half-time of disappearance (t1/2) and half time of disappearance of TRH in serum in vitro (t1/2p) was determined. The plasma clearance rate, t1/2 and t1/2p were, respectively, 19.8 +/- 6.2 ml.kg-1.min-1, 6.6 +/- 1.5 min and 16.4 +/- 6.2 min in group I versus 28.2 +/- 4.8 ml.kg-1.min-1, 9.3 +/- 2.6 min and 25.3 +/- 15 min (mean +/- SD) in group II. The volume of distribution of TRH was 19.3% of the body weight in group I and 36.5% in group II. The calculated half-time in the extravascular tissue compartment (t1/2) was 5.4 +/- 1.4 min in group I and 9.2 +/- 2.7 min in group II patients (mean +/- SD). TRH metabolism in the uremic patients was almost identical to that previously reported in normal subjects. In the patients with chronic liver disease plasma clearance rate was significantly greater than in normal subjects, indicating an increased TRH-degrading enzyme activity in the tissue compartment. However, owing to the very large expansion of this compartment, the t1/2 and t1/2t were significantly prolonged. Hence, half-time determination of TRH is no reliable indicator of overall TRH degradation in patients with liver disease.

Triiodothyronine administration reduces serum growth hormone levels and growth hormone responses to thyrotropin-releasing hormone in patients with anorexia nervosa

The aim of this study was to test the hypothesis that low serum T 3 concentrations may promote an abnormal growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in patients with anorexia nervosa. Eight anorexic women and two anorexic men, ages 15–25 years, with low free T 3 circulating levels (mean ± SEM = 2.8 ± 0.3 pmol/l) were studied. A TRH test (200 μg IV) was carried out under basal conditions and repeated following treatment with oral T 3 (1.5 μg/kg BW/day) for eight days. Following T 3 administration, GH levels dropped significantly from a baseline of 7.1 ± 1.3 μg/l to 3.1 ± 0.7 μg/l ( p<0.02), as did GH peak responses to TRH (9.0±1.0 μg/l vs. 4.4 ± 0.8 μg/l, p<0.01). ANOVA and analysis of area under the curve (AUC) confirmed that after T 3 treatment there was a significant reduction in TRH-induced GH release in these patients (GH AUC: 902±132 μg/l vs. 456±91 μg/l, p<0.02). TSH responses to TRH, which were normal prior to T 3 treatment, completely disappeared following it, and PRL responses to TRH also were diminished. Although our experimental approach does not permit a conclusion that low T 3 levels were the primary reason for these changes, the data support the theory that low T 3 circulating levels may facilitate abnormal GH secretion and the GH-releasing activity of intravenous TRH.

Involvement of a dopaminergic mechanism in the response of growth hormone to thyrotropin releasing hormone in patients with major depression.

In an attempt to establish whether, in patients with major depression, dopaminergic receptors are involved in the release of growth hormone (GH) induced by thyrotropin releasing hormone (TRH), eleven subjects were tested with TRH (200 micrograms in an i.v. bolus) with or without concomitant treatment with domperidone (10 mg in an i.v. bolus 10 min before TRH), an antidopaminergic agent which does not readily cross the blood-brain barrier. In 7 out of the 11 patients, TRH strikingly increased GH levels (responders) (the mean peak level was 9 times higher than basal value), whereas it was without effect in the remaining 4 patients (non-responders). When the responders were treated with domperidone before TRH injection, TRH-induced GH increase was still present, but it was significantly lower (the mean peak level was 5.3 times higher than basal value) than in the TRH test (p less than 0.02). These data suggest that the paradoxical response of GH or TRH in patients with major depression involves a dopaminergic mechanism active at sites situated outside the blood-brain barrier.

Intravenous Thyrotropin-Releasing Hormone in Patients with Amyotrophic Lateral Sclerosis: Dose-Response and Randomized Concurrent Placebo-Controlled Pilot Studies

Focal, small-to-moderate and transient improvement occurred in the muscle strength and function of patients with ALS who received TRH in dose-response and screening studies. In a small pilot study of 12 patients, 3 months administration of TRH at 10 mg per kg on alternate days resulted in localized increased strength of jaw muscles as well as significant improvement in lower extremity function. Aerobic exercise capacity was particularly improved in patients with ALS following administration of TRH. Autonomic effects of TRH on heart rate, respiration, and blood pressure were not serious and attenuated slightly over the course of the study.

Pirenzepine inhibits growth hormone, but not thyrotropin response to thyrotropin-releasing hormone in patients with endogenous depression

In order to evaluate whether in endogenous depression the anomalous growth hormone (GH) response to thyrotropin-releasing hormone (TRH) is mediated by muscarinic cholinergic receptors, 12 patients were tested with TRH (200 μg iv) with and without previous treatment with the muscarinic cholinergic receptor blocker pirenzepine (40 mg iv 10 min before TRH). Control tests with normal saline also were performed. Administration of normal saline did not alter serum GH levels. In contrast, TRH injections significantly increased serum GH concentrations by about three-fold. This response was inhibited by pretreatment with pirenzepine. Another neuroendocrine marker of endogenous depression, the low TSH increase in response to TRH ( Δ ⩽ 7 μU/ml), was observed in our patients. Pretreatment with pirenzepine did not modify this response. These data indicate that in patients with endogenous depression a muscarinic cholinergic mechanism is involved in the GH response but not in the TSH response to TRH.

Reduced TSH and prolactin responses to TRH in patients with panic disorder.

The authors studied the TSH and prolactin responses to a standard 500-micrograms thyrotropin-releasing hormone (TRH) stimulation test in 12 patients with panic disorder and 10 control subjects. As a group, panic disorder patients had lower mean TSH and prolactin responses, and female patients accounted for the lower prolactin response. The clinical and theoretical implications of these findings are discussed.

Pituitary-thyroid function and thyrotropin, prolactin and growth hormone responses to TRH in patients with chronic alcoholism.

Basal plasma concentrations of thyroxine (T4), 3,3',5-triiodothyronine (T3), free T4 index (TF4I), free T3 index (FT3I) reverse T3, 3,3',5-triiodothyronine (rT3), resin T3 uptake (TR3U), thyroxine-binding globulin (TBG), thyrotropin (TSH), prolactin (PRL) and growth hormone (GH) as well as thyrotropin releasing hormone (TRH) stimulated TSH, PRL and GH were investigated in 31 consecutive male patients (mean age 41 years) with chronic alcoholism. According to the histology of their liver biopsies the patients were divided into three groups: patients with normal livers, steatosis and cirrhosis. The control group consisted of 30 healthy males. The patients had abstained from alcohol for at least one week when studied, and they were on a nutritionally adequate diet. All had consumed a daily minimum of 52 g ethanol for at least 5 years. None of the patients had severe or decompensated liver disease. The patients had significantly reduced T3 and rT3 plasma levels compared to normals. Patients with cirrhosis of the liver had increased TBG and normal RT3U levels, while those without cirrhosis had increased RT3U and normal TBG levels. Plasma concentrations of basal as well as TRH-stimulated TSH and PRL were unchanged in alcoholic patients, whereas basal as well as stimulated GH levels were increased in cirrhotic alcoholics. It is concluded that alcohol per se influences T3 levels, but not the part of the hypothalamic-pituitary axis studied, and that the binding proteins are mostly determined by the degree of liver disease.