Thyrotropin-releasing Hormone Infusion Research Articles

Effects of TRH and high-dose corticosteroid therapy on evoked potentials, and tissue Na+,K+ and water content in experimental spinal injury.

The therapeutic effects of continuous infusion of thyrotropin-releasing hormone (TRH) and methylprednisolone (MP) in experimental spinal cord injury were studied in Swiss albino rats. Thirty rats received a 53-g clip-compression injury on the cord at T1, then were allocated randomly and blindly to one of three treatment groups (ten animals in each): (1) control; received equal volumes of saline solution; (2) MP; received 30 mg/kg methylprednisolone i.v. 1h after trauma, followed by infusion of 5.4 mg/kg/per hour i.v. for 3h; (3) TRH; received 2 mg/kg TRH i.v. 1h after trauma, followed by infusion of 1 mg/kg/per hour i.v. for 3h. MP and TRH treatments significantly improved somatosensory-evoked potentials (SEPs; P < 0.001). Both treatments significantly reduced water content, decreased Na+ content and increased the K+ content of the cord segment that included the centre of the impact (P < 0.01). Our data provide evidence for the beneficial effects of high-dose corticosteroid and TRH in promoting electrophysiological recovery and preserving spinal cord tissue following experimental injury.

Pulsatile TSH Secretion during 48-Hour Continuous TRH Infusions

Thyroid-stimulating hormone (TSH), like other anterior pituitary hormones, is normally secreted in a series of pulses over 24 h. However, the factors that control TSH pulse generation are unknown. We investigated the potential role of thyrotropin-releasing hormone (TRH) in TSH pulse generation by measuring TSH pulses during constant TRH infusions. Two groups of subjects were studied: five healthy subjects and five subjects with treated primary hypothyroidism and normal TSH levels. Each subject underwent four separate studies: (1) TSH levels were measured every 15 min over 24 h (baseline study). (2) TSH levels were measured every 15 min over 48 h during TRH infusions at 0.1 microgram/min (low dose TRH study). (3) TSH levels were measured every 15 min over 48 h during TRH infusion at 0.5 microgram/min (medium dose TRH study). (4) TSH levels were measured every 15 min over 48 h during TRH infusions at 1.0 microgram/min (high dose TRH study). TSH pulses were located by cluster analysis. We found that constant TRH infusions at any of the doses utilized did not alter TSH pulse frequency in normal or treated hypothyroid subjects, although pulse amplitude increased. Normal subjects had lower TSH pulse amplitude than treated hypothyroid subjects at all TRH doses, perhaps due to slightly higher serum T3 levels. This suggests that, at least acutely, pulsatile input of TRH to the pituitary gland does not determine pulsatile TSH release. However, TRH may modulate TSH pulse amplitude.

Thyrotropin-releasing hormone-mediated Mn2+ entry in perifused rat anterior pituitary cells.

Receptor-mediated Ca2+ influx has been shown to exist in several cell types. Thyrotropin-releasing-hormone (TRH)-stimulated Ca2+ entry has also been postulated to exist in rat anterior pituitary cells, but direct evidence has been lacking. We have measured the fluorescence quenching of indo-1 caused by Mn2+ at a Ca(2+)-insensitive wavelength to investigate the actions of TRH on cation entry in dispersed perifused anterior pituitary cells. In indo-1-loaded cells perifused with Ca(2+)-free medium, Mn2+ caused fluorescence quenching in unstimulated cells; TRH caused further quenching. TRH-stimulated Mn2+ entry was transient, and levelled off within a few minutes in the presence of continuous TRH infusion. TRH-stimulated Mn2+ entry was dependent on the concentration of Mn2+ (50 microM-1 mM). TRH (1 microM) caused a larger effect than TRH (10 nM). La3+ and Ni2+ blocked the quenching stimulated by TRH. The rate of basal quenching was not blocked by dopamine, but TRH-stimulated Mn2+ entry was partially blocked by 1 microM-dopamine and almost completely abolished by 10 microM-dopamine. Thapsigargin (1-5 microM), a tumour promotor which depleted intracellular Ca2+ stores, had little effect on Mn2+. F- (20 mM), which activates G-proteins, also had little effect on Mn2+ entry. We conclude that TRH can transiently stimulate Ca2+ entry through a channel than can pass Mn2+ and be inhibited by dopamine. Depleting Ca2+ stores alone is not sufficient to stimulate Ca2+ entry, and so TRH must do so by other mechanisms.

Intraventricular administration of thyrotrophin-releasing hormone (TRH) suppresses prolactin secretion and synthesis: a possible involvement of dopamine release by TRH from rat hypothalamus.

The administration of thyrotrophin-releasing hormone (TRH) causes a variety of dopamine-related biological events. To understand the specific role of TRH on rat hypothalamic dopamine neurones, we examined the in-vivo effects of intraventricular (i.c.v.) infusion of TRH on the release and synthesis of prolactin in the rat pituitary gland and on the changes in binding of [3H]MeTRH and dopamine turnover rates in rat hypothalamus. We have also examined the in-vitro effects of TRH on the release of [3H]dopamine from dispersed tuberoinfundibular dopamine neurones. Female rats were treated with i.c.v. infusions of 1 mumol TRH/1 daily for 1, 3 and 7 days using Alzet osmotic pumps. Following 7 days of treatment the serum prolactin concentrations were significantly decreased. A reduction in hypothalamic TRH-binding sites (Bmax) was also apparent but the dissociation constant (Kd) was unaffected. Northern blot analysis of total RNA isolated from the pituitary glands of control animals using 32P-labelled prolactin cDNA as a probe indicated the presence of three species of prolactin gene transcripts of approximately 3.7, 2.0 and 1.0 kb in size, and these were decreased by TRH treatment. We examined the turnover rate of dopamine in the rat hypothalamus when TRH was administered i.c.v. for 7 days. There was a significant increase in 3,4-dihydroxyphenylacetic acid/dopamine ratio with TRH treatment. Moreover, exposure to TRH stimulated [3H]dopamine release from rat tuberoinfundibular neurones in a time- and dose-dependent manner. Dopamine receptor antagonists such as SCH23390 and (-)sulpiride, and other neuropeptides such as vasoactive intestinal peptide and oxytocin did not affect TRH-stimulated [3H]dopamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyotrophic lateral sclerosis: Thyroid and prolactin hormone changes in thyrotropin-releasing hormone therapy

13 patients with amyotrophic lateral sclerosis (ALS) were treated with intravenous infusion of thyrotropin-releasing hormone (TRH). In 6 patients 2 mg/day of TRH was i.v. given over 2 hours for 10 days. In 7 others 2 mg/day of TRH was continuously infused by means of a pump. An increase of thyroid hormones related to the duration of the treatment was observed. A surprising finding was the onset of prolactin (PRL) response to growth hormone releasing hormone (GHRH), previously absent.

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 T 3 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.

Prolactin response to growth hormone-releasing hormone during chronic thyrotropin-releasing hormone infusion in the treatment of amyotrophic lateral sclerosis

In six patients suffering from amyotrophic lateral sclerosis we evaluated changes of T4, T3, TSH, PRL, and GH during treatment by continuous iv infusion of TRH for at least 15 days. No clinical improvement was detected. A significant rise of thyroid hormone levels was observed, as well as an upward trend of basal TSH levels and no change of basal PRL and GH levels. TRH acute test-induced TSH and PRL responses became blunted. Treatment provoked also the onset of a responsiveness of PRL to GHRH. The reduced TSH and PRL responses to acute TRH test during treatment could be explained by a down-regulation of TRH pituitary receptors. On the contrary, the onset of PRL responsiveness to GHRH is at present without a satisfactory explanation.

Pressor and sympathetic responses to dorsal raphe nucleus infusions of TRH in rats

Pressor, tachycardic, and sympathoexcitatory responses to intracerebroventricularly (icv) infused thyrotropin-releasing hormone (TRH) were recorded in urethan-anesthetized rats to identify where centrally administered TRH acts in the brain. None of these responses was altered either by electrolytic lesions in the medial preoptic, posterior, or paraventricular hypothalamus or by chemical lesions produced by destroying catecholaminergic neurons with icv infused 6-hydroxydopamine. By contrast, when serotonergic neurons were similarly destroyed with 5,7-dihydroxytryptamine, TRH-induced tachycardia was inhibited. Attendant pressor responses were also inhibited by electrolytic lesions of the dorsal, but not of the median, raphe nucleus. Pressor and sympathoexcitatory responses elicited by infusing TRH directly into the dorsal raphe nucleus resembled those produced by icv infusion, and their magnitude diminished after pentolinium-induced ganglioplegia. These results are compatible with the interpretation that icv infused TRH may produce its cardiovascular and sympathetic effects by acting, at least in part, on serotonergic mechanisms located in the dorsal raphe nucleus.

TSH response to TRH and family history of alcoholism

The thyrotropin (TSH) response to intravenous thyrotropin-releasing hormone (TRH) was evaluated in 10 sons of alcoholic fathers (FHP group) and 10 matched controls (FHN group). No differences were observed between the two groups in basal TSH, peak TSH levels, on the incidence of TSH-blunting to TRH. Though there was a trend for a less intense TSH response over time after the TRH infusion, the difference between the family groups was not significant. These results are not consistent with some previous reports of an increased percentage of blunted TSH response to TRH for children of alcoholics. The clinical and research implications of these findings are discussed.

Hyperprolactinemia in clinically asymptomatic, fertile men: Report of two cases

Although the role of prolactin (PRL) in men is undefined, hyperprolactinemia has been associated with decreased reproductive potential. Two healthy, fertile, asymptomatic men with hyperprolactinemia are reported. Both men had normal puberty. Both were euthyroid and had normal gonadotropin levels and androgen profiles. Semen analyses were normal and both had fathered children. The serum PRL level (mean +/- standard error of the mean) (N = 5) of subject 1 was 48 +/- 12 ng/mL, and of subject 2 was 214 +/- 5 ng/mL. Sella turcica computed tomography scans with contrast were normal. The two subjects underwent a thyrotropin-releasing hormone stimulation test. Serum PRL and TSH were measured by radioimmunoassay. At time 0 and at 15 minutes, PRL bioactivity was measured in the Nb2 node rat lymphoma assay. Both subjects showed a normal TSH response to thyrotropin-releasing hormone. Subject 1 had baseline PRL immunoactivity and bioactivity measuring 41 and 50 ng/mL, respectively, peaking at 76 and 70 ng/mL 15 minutes after infusion of thyrotropin-releasing hormone. Subject 2 had baseline PRL immunoactivity of 200 ng/mL and bioactivity of 67 ng/mL, neither of which were altered by infusion of thyrotropin-releasing hormone. Administration of L-dopa decreased the serum PRL of subject 1 from 33 to 7 ng/mL, but had no clinically significant effect in subject 2. Prolactin and gonadotropin secretion may be dissociated in men so that hyperprolactinemia may not always manifest as reproductive dysfunction.

Clinical applications of the contralateral components of the brain-stem auditory evoked potentials

The thyrotropin (TSH) response to intravenous thyrotropin-releasing hormone (TRH) was evaluated in 10 sons of alcoholic fathers (FHP group) and 10 matched controls (FHN group). No differences were observed between the two groups in basal TSH, peak TSH levels, on the incidence of TSH-blunting to TRH. Though there was a trend for a less intense TSH response over time after the TRH infusion, the difference between the family groups was not significant. These results are not consistent with some previous reports of an increased percentage of blunted TSH response to TRH for children of alcoholics. The clinical and research implications of these findings are discussed.

Stimulation of duodenal mucosal bicarbonate secretion in the rat by brain peptides

Bicarbonate secretion by duodenal mucosa free of Brunner's glands was titrated in situ in anesthetized rats. Intracerebroventricular infusion of thyrotropin-releasing hormone (0.01–1 μg/h), bombesin, gastrin-releasing peptide, or corticotropin-releasing factor increased the bicarbonate secretion and the transmucosal electrical potential difference. The increase in secretion in response to thyrotropin-releasing hormone and bombesin was prevented by cervical vagotomy. Intravenous administration of the α-adrenoceptor antagonist phentolamine increased the magnitude and duration of the response, suggesting that these two peptides in addition to eliciting vagal stimulation of the duodenal secretion, by sympathetic activation, inhibit the secretion. Intravenous thyrotropin-releasing hormone (3.6 mg/kg) did not affect the secretion, further indicating that effects were elicited within the central nervous system. Intracerebroventricular infusion of cholecystokinin-octapeptide or β-endorphin had no effect on duodenal bicarbonate secretion or on the potential difference. The latter peptide was a potent stimulant of the secretion when injected intravenously and probably acts at a peripheral site. The central nervous control of duodenal mucosal bicarbonate secretion is thus influenced by some specific peptides that are known to occur in brain tissue, and duodenal protection against acid might be modulated by agents affecting this control.

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.

Thyrotropin releasing hormone uptake into serum and cerebrospinal fluid following intravenous or subcutaneous administration.

Intravenous thyrotropin releasing hormone (TRH) was administered to 6 amyotrophic lateral sclerosis (ALS) patients at the dose rate of 10 mg/kg. Blood samples were obtained prior to and at 10, 20, 40, 60, and 120 min during the TRH infusions. Lumbar punctures were performed at 90 min following the start of infusion. The mean serum TRH concentration rose from 0.03 +/- 0.02 (SD) to 17 +/- 2 ng/ml by 60 min and remained constant to 120 min. The mean CSF TRH concentration rose 10-fold from 0.02 +/- 0.01 to 0.2 +/- 0.02 ng/ml at 90 min and increased further to 0.5 +/- 0.2 ng/ml at 120 min. Subcutaneous TRH was administered to 4 ALS patients at 2.5 mg/kg and to 5 ALS patients at 5.0 mg/kg. The mean serum TRH concentration increased to 1.4 +/- 0.6 ng/ml (2.5 mg/kg) and 3.2 +/- 1.1 ng/ml (5.0 mg/kg) by 60 min. The mean CSF TRH concentration at 60 min increased to 0.3 +/- 0.08 ng/ml following 2.5 mg/kg TRH and 0.8 +/- 0.04 ng/ml following 5.0 mg/kg TRH. TRH entry into the CSF is comparable following subcutaneous or intravenous administration.

A comparison of the effects of intrathecally administered 5-hydroxytryptamine and thyrotropin-releasing hormone on renal and muscle sympathetic nerve activity

Thyrotropin-releasing hormone (TRH) has been shown to coexist with 5-hydroxytryptamine (5-HT) in spinally projecting raphe neurones, some of which terminate in the sympathetic nuclei of the spinal cord. In an attempt to mimic the actions of these neurones, the effects of intrathecal administration of 5-HT was compared to that of TRH on activity in two sympathetic postganglionic nerves, the renal nerve and sympathetic fibres to skeletal muscle of the hind limb. In chloralose-urethane anaesthetised rats intrathecal infusion of TRH at the T 9 level in doses of 5–30 μg increased activity in renal nerve as did low doses (20–100 gmg) of 5-HT. In contrast, intrathecal infusion of TRH in doses of 5–30 μg and 5-HT in doses of 20–800 μg at L 4 level decreased activity in sympathetic fibres to muscle. The results show that TRH, unlike 5-HT, has an excitatory but not an inhibitory action on renal sympathetic activity whereas both substances have only an inhibitory action on muscle sympathetic activity.

Combined effects of corticosteroid, thyroid hormones, and beta-agonist on surfactant, pulmonary mechanics, and beta-receptor binding in fetal lamb lung.

We studied the interactions of corticosteroids, thyroid hormones, and beta-agonist on surfactant phospholipids, pulmonary mechanics, and beta-receptor binding in fetal lambs. We infused cortisol (450 micrograms/h for 48 h), thyrotropin-releasing hormone (TRH) (25 micrograms/h for 48 h), and ritodrine (1.3 micrograms/kg/min for 24 h) independently, and in double (cortisol plus beta-agonist, cortisol plus TRH), and in triple (cortisol plus TRH plus beta-agonist) combinations into chronically catheterized fetal lambs between 0.88 and 0.90 gestation. Infusion of the triple combination of cortisol plus TRH plus beta-agonist resulted in a 20.9-fold increase in the saturated phosphatidylcholine content of fetal lung lavage, in a 5.8-fold increase in the saturated phosphatidylcholine content of whole fetal lung, and in a 13.3-fold increase in the saturated phosphatidylcholine content of fetal tracheal fluid. In addition, lung stability to inflation increased 3-fold, and lung stability to deflation increased 8-fold. The increases in the saturated phosphatidylcholine content of fetal lung lavage and tracheal fluid were greater than the effects of each hormone acting independently, or in the double combinations. The beta-receptor maximal binding capacity was increased 30% by the combined infusion of cortisol and TRH. In addition, the maximal binding capacity after cortisol plus TRH plus beta-agonist infusion was 54% greater than the maximal binding capacity after beta-agonist infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Selective Suppression of Pressor and Sympathetic Responses to Centrally Infused TRH in Hypothyroid Rats

To determine whether hypothyroidism alters responsiveness to centrally infused thyrotropin-releasing hormone (TRH), blood pressure and sympathetic nerve responses to various stimuli were recorded in urethane-anesthetized rats. Four weeks after thyroidectomy or treatment with propylthiouracil, pressor responses elicited by intracerebroventricular- (ICV)-infused TRH or by electrical stimulation of the posterior or ventromedial hypothalamus were always accompanied by increased sympathetic nerve activity in all rats. When serum thyroxine levels were lowered in hypothyroid rats, pressor responses to most stimuli, including intravenous injections of norepinephrine, angiotensin, and vasopressin, were inhibited, indicating that peripheral pressor responsiveness had been reduced. For centrally acting stimuli, pressor inhibition was also considered partly caused by a selective decrease in sympathetic vasomotor tone because sympathetic excitation was reduced only during ICV infusions of TRH, but not during posterior hypothalamic stimulation. On the other hand, there was no obvious explanation why both pressor and sympathetic responses to ventromedial hypothalamic stimulation were spared from inhibition. Because sympathetic nerve responses to ICV-infused TRH were reduced by thyroid suppression, these results imply that sympathetic activation by TRH in intact rats is mediated, at least in part, indirectly by way of TRH stimulation of thyroid activity.

Thyrotrophin-releasing hormone-induced growth hormone secretion in ducks: Independence of peripheral plasma somatostatin, insulin, and glucagon

In young, but not old, ducks the iv infusion of thyrotrophin-releasing hormone (TRH) markedly increased peripheral plasma growth hormone (GH) concentrations, which remained elevated throughout the 30-min period of infusion. This GH response to TRH was suppressed by the simultaneous infusion of somatostatin, which increased the level of circulating somatostatin-like immunoreactivity (SLI) to supraphysiological levels. Basal concentrations of plasma SLI in both young and old birds were suppressed by TRH infusion. Concentrations of glucagon-like immunoreactivity (GLI) were increased by the infusion of TRH in young birds but not in adults, whereas plasma immunoreactive insulin (IRI) was decreased in young birds and increased in adults following TRH infusion. These results indicate that TRH-induced GH secretion in ducks is unrelated to changes in peripheral plasma SLI, GLI, or IRI induced by TRH infusion.

Prolonged intrathecal infusion of thyrotropin releasing hormone in amyotrophic lateral sclerosis.

Prolonged intrathecal infusion of thyrotropin releasing hormone in amyotrophic lateral sclerosis.

Effects of thyrotropin releasing hormone on human sudomotor and cutaneous vasomotor activities.

At an ambient temperature of 34-41 degrees C (rh = 40%) forearm sweat rates were measured by capacitance hygrometry in 9 male volunteers. Thyrotropin releasing hormone (TRH) was infused intravenously at 0.1 mg.min-1 for 20 to 30 min. Sweat rate increased rapidly within a minute after initiation of TRH infusion, decreased rapidly after the peak sweat rate was attained in 2-5 min of TRH infusion, and then levelled off in 6-10 min near the level before TRH infusion. Core temperature (Tre, Tty) started to decline at the time of the peak sweat rate and levelled off almost coincidentally with the levelling off in sweat rate. Average values for the rate of sweat expulsions (Fsw), sweat rate and mean body temperature (Tb) were obtained from the data of the last 10 min period of TRH infusion. The regression line for the relationship of Fsw to Tb shifted during the TRH infusion to the left of the line for the control; that of sweat rate to Fsw hardly shifted. At an ambient temperature of 24-27 degrees C TRH produced vasodilation as evidenced by an increase in skin blood flow (measured by means of thermal distribution), an increase in amplitude of the photoelectric plethysmogram and an elevation of skin temperature in the finger tips. It is suggested that TRH may act, either directly or indirectly, on the central thermoregulatory mechanism (or on the thermoreceptive mechanism) to lower the reference temperature for heat dissipation.