Use Of Thyrotropin-releasing Hormone Research Articles

New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent

Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood–brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones’ levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide’s actions to improve symptoms and the progression of several pathologies.

The forgotten effects of thyrotropin-releasing hormone: Metabolic functions and medical applications

Thyrotropin-releasing hormone (TRH) causes a variety of thyroidal and non-thyroidal effects, the best known being the feedback regulation of thyroid hormone levels. This was employed in the TRH stimulation test, which is currently little used. The role of TRH as a cancer biomarker is minor, but exaggerated responses to TSH and prolactin levels in breast cancer led to the hypothesis of a potential role for TRH in the pathogenesis of this disease. TRH is a rapidly degraded peptide with multiple targets, limiting its suitability as a biomarker and drug candidate. Although some studies reported efficacy in neural diseases (depression, spinal cord injury, amyotrophic lateral sclerosis, etc.), therapeutic use of TRH is presently restricted to spinocerebellar degenerative disease. Regulation of TRH production in the hypothalamus, patterns of expression of TRH and its receptor in the body, its role in energy metabolism and in prolactin secretion are addressed in this review.

Discovery of a dual action first-in-class peptide that mimics and enhances CNS-mediated actions of thyrotropin-releasing hormone

Thyrotropin-releasing hormone (TRH) displays multiple CNS-mediated actions that have long been recognized to have therapeutic potential in treating a wide range of neurological disorders. Investigations of CNS functions and clinical use of TRH are hindered, however, due to its rapid degradation by TRH-degrading ectoenzyme (TRH-DE). We now report the discovery of a set of first-in-class compounds that display unique ability to both potently inhibit TRH-DE and bind to central TRH receptors with unparalleled affinity. This dual pharmacological activity within one molecular entity was found through selective manipulation of peptide stereochemistry. Notably, the lead compound of this set, l-pyroglutamyl- l-asparaginyl- l-prolyl- d-tyrosyl- d-tryptophan amide (Glp-Asn-Pro- d-Tyr- d-TrpNH 2), is effective in vivo at producing and potentiating central actions of TRH without evoking release of thyroid-stimulating hormone (TSH). Specifically, this peptide displayed high plasma stability and combined potent inhibition of TRH-DE ( K i 151 nM) with high affinity binding to central TRH receptors ( K i 6.8 nM). Moreover, intraperitoneal injection of this peptide mimicked and augmented the effects of TRH on behavioural activity in rat. Analogous to TRH, it also antagonized pentobarbital-induced narcosis when administered intravenously. This discovery provides new opportunities for probing the role of TRH actions in the CNS and a basis for development of novel TRH-based neurotherapeutics.

Effects of thyrotropin-releasing hormone on human myometrium and umbilical vasculature in vitro

Objective The purpose of this study was to investigate the direct effects of thyrotropin-releasing hormone on isolated human myometrium that was obtained during pregnancy and on human umbilical vasculature in vitro. Study design Isolated human myometrial strips were dissected from biopsy specimens that were obtained at elective cesarean delivery and suspended for isometric recording under physiologic conditions. The effects of cumulative additions of thyrotropin-releasing hormone (10 −9-10 −4 mol/L) on oxytocin-induced myometrial contractility were evaluated. The effects of thyrotropin-releasing hormone (10 −9-10 −4 mol/L) on umbilical vessel (artery and vein) resistance in vitro were investigated with the use of isolated ring preparations. Results Thyrotropin-releasing hormone exerted a significant concentration-dependent relaxant effect on pregnant human myometrial tissue, which ranged from 3.54% (10 −9 mol/L, P = .935) to a net cumulative total of 21.06% (10 −4 mol/L, P<.001). Thyrotropin-releasing hormone also exerted a concentration-dependent relaxant effect on human umbilical vasculature that ranged from 12.51% (10 −9 mol/L, P = .994) to a net cumulative total of 23.27%±4.87% (SEM, 10 −4 mol/L, P<.01) in umbilical artery. For umbilical vein, the relaxant effect ranged from 1.80% (10 −9 mol/L, P = .998) to a net cumulative total of 14.64% (10 −4 mol/L, P<.009). Conclusion Thyrotropin-releasing hormone exerts a significant relaxant effect in human myometrium and in human umbilical vasculature and highlights a potential physiologic role for this neuropeptide in these tissues. These findings have clinical implications for the therapeutic use of thyrotropin-releasing hormone antenatally.

Controlled trial of prenatal Thyrotropin-Releasing Hormone (TRH) and Betamethasone (B) for prevention of Respiratory Distress Syndrome (RDS).• 965

The use of TRH in conjunction with corticosteroids to prevent RDS in preterm pregnancies remains controversial. We conducted a multicenter, double-blind, randomized, controlled trial of prenatal administration of TRH(400 mg iv in 50 ml NS, q 8 h × 4) or placebo (PLC, 50 ml NS iv at same times) in women with singleton pregnancies ≤ 32 weeks' gestational age (GA) with threatened preterm delivery. All women in the trial received B (12 mg im q 24 h × 2). Live-born neonates < 1.0 kg received Exosurf soon after birth, whereas those ≥ 1.0 kg only received Exosurf as rescue therapy. The primary outcome of the study was RDS. A total of 370 women entered the trial(TRH n=190, PLC n=180) and 85% of them received all doses of TRH or PLC. GA at entry were 29.0 ± 2.2 vs 28.2 ± 2.3 d (mean ± SD), respectively. No benefits of maternal use of TRH were seen in either all neonates in the study or in the subgroup delivered between 1-10 days from entry. Air leaks were more common in the TRH group (7.0% vs 1.9%, respectively, RR= 1.38 i1.20-2.09, 95% C.I.ý).Other maternal or neonatal complications were similar in both groups. These data do not support the use of TRH in conjunction with B to prevent RDS when there is widespread surfactant availability. Funded by FONDECYT grant 193-0854.Table

Hormonal Regulation of the Thyrotropin Releasing Hormone (TRH) Gene

Significant advances in understanding the function, distribution, and hormonal regulation of TRH gene expression have occurred since the cloning of the TRH gene. TRH gene expression is widespread in the CNS and peripheral sites but only TRH mRNA located in the paraventricular nucleus is under negative regulation by thyroid hormone. Molecular biological experiments using gene transfer of TRH promoter-reporter mini' genes reproduce the in vivo transcriptional repression by thyroid hormones. In vitro binding studies using the TRH promoter demonstrate binding sites for transcriptional trans-acting factors including thyroid hormone receptor, CREB, and c-jun. The divergent hormonal response of the TRH gene in the thyrotropic area of the hypo-thalamus compared to peripheral sites illustrate the importance in hormonal regulation of the distribution of cell-specific factors including nuclear hormone receptors and transcription factors.The TRH stimulation test has been replaced by second and third generation TSH assays in the diagnosis of hypothyroidism. The paradoxical response of some pituitary adenomas to exogenous TRH administration allows the use of the TRH test as a marker for these tumors. The studies demonstrating the widespread distribution and function of TRH have provided information that has led to the new and exciting field of the therapeutic use of TRH in a wide array of clinical disorders.

NS-3, a TRH analog, reverses repeated ECS-induced deficits in water maze performance in the rat

Rats given five consecutive daily electroconvulsive shock (ECS) treatments and trained to run in the Morris water maze, starting three days posttreatment, showed deficits in learning and memory functions. Treatment before each training session with the thyrotropin-releasing hormone (TRH) analog NS-3 [(CG-3703), (3R),(6R)-6-methyl-5-oxo-3-thiomorphorinyl-histidyl-l-prolinamide tetrahydrate] reversed these behavioral deficits. The possible use of TRH and its analogs as therapeutic treatment for the cognitive dysfunctions resulting from electroconvulsive shock treatment for depression and the possible involvement of central cholinergic systems in the cognitive dysfunctions are discussed.

Evaluation of thyrotropin releasing hormone as a therapeutic intervention for endotoxemia

Thyrotropin releasing hormone (TRH) has been reported to reduce endotoxin-induced hypotension and mortality rate in conscious rats. Limited data are available to explain these effects. We evaluated hemodynamic parameters, metabolic function, tissue injury, and survival rate in three groups of instrumented conscious rats following intravenous endotoxin (20 mg/kg, LD/90-24 h) challenge. Pretreatment with TRH (2.0 mg/kg, i.v.) was administered 10 min before endotoxin ( n = 10) and control ( n = 10) animals were given an equivalent volume of saline. The post-treated group ( n = 7) was given TRH at the nadir of the hypotensive response following endotoxin to duplicate published protocols. 5 min after endotoxin blood pressure and cardiac output were significantly higher in the post and pre-treatment groups, respectively, compared to the untreated group. There were no differences at other times. Systemic vascular resistance was not affected by either treatment mode at any time. TRH treatment following endotoxin resulted in transient increases in heart and respiration rates and decreased central venous pressure during the first 30 min. Metabolic function indicated by measurements of glucose, lactate, hematocrit, pH, PO 2, and PCO 2 at 60 and 240 min after endotoxin was not modified by TRH. The hemorrhagic small intestine characteristic of this model was not improved by either treatment mode. Mortality rates at 4 h after endotoxin were 20% for the untreated, 40% for the pre-treated, and 43% for the post-treated. These results suggest TRH exerts early transient effects on cardiovascular responses evoked by endotoxin in the conscious rat but no lasting beneficial effects were found to support the use of TRH as a mono-therapy for endotoxemia.

Dietary Thyrotropin-Releasing Hormone Stimulates Growth Rate and Increases the Insulin: Glucagon Molar Ratio of Broiler Chickens

The effects of thyroid manipulation on growth, feed efficiency, and plasma hormone levels were determined in rapidly growing chickens. Beginning at 3 weeks of age, eight broiler cockerels were provided with control feed (CF) or feed containing either 1 ppm of triiodothyronine (T3), 1 ppm of thyroxine (T4), 0.3% propylthiouracil (PTU), or 5 ppm of thyrotropin-releasing hormone (TRH) for 3 weeks. Blood samples were taken at 4, 5, and 6 weeks for determination of plasma levels of growth hormone, insulin-like growth factor, T3, T4, insulin, glucagon, glucose, and nonesterified fatty acids. Dietary TRH increased (P less than 0.05) the growth rate of chickens by 14% when compared with the CF group. Plasma growth hormone levels were reduced (P less than 0.05) 65% by dietary T3 and 33% by treatment with either T4 or TRH when compared with the CF group. Plasma insulin-like growth factor levels were 16% lower (P less than 0.05) in PTU-fed birds than the other treatment groups. Plasma T3 levels were elevated (P less than 0.05) 3-fold by dietary T3 and 38% by TRH whereas plasma T3 in the PTU group was 38% below the average of CF birds. Plasma T4 levels were increased (P less than 0.05) by 12-fold in T4-fed birds, decreased 48% in TRH-fed birds, and nondetectable in birds treated with either T3 or PTU. Compared with the other treatments, dietary PTU increased (P less than 0.01) plasma insulin levels 4.3-fold whereas TRH provided a 2.7-fold increase in plasma insulin. Plasma glucagon levels were 26% higher (P less than 0.05) in T3-fed birds than those fed either T4 or PTU. These observations indicate that thyroid activity plays an important role in regulating secretion of GH and the pancreatic hormones. Furthermore, our study demonstrates the potential use of TRH as an orally active growth promoter for poultry.

Systemic toxicity of diphtheria toxin-related fragments (CRM26, CRM45), a hormone-toxin hybrid protein (TRH-CRM45), and ricin A.

As a preliminary step in evaluating the use of thyrotropin releasing hormone (TRH) linked to toxin fragments for systemic treatment of pituitary disease, we have examined the metabolic degradation, tissue distribution, renal excretion, and toxicity in rats of TRH-CRM45 which consists of TRH coupled to CRM45, a diphtheria toxin-related polypeptide. For comparison, we have similarly studied CRM45, CRM26 (a smaller diphtheria toxin-related fragment), and ricin A. All four proteins were found to concentrate in the kidney and liver relative to blood (in comparison to bovine serum albumin), tissue:plasma ratios for the kidney being much higher than those observed for the liver. Radioiodinated CRM45 and ricin A were rapidly cleared from the circulation with similar patterns. Systemic toxicity studies showed that at doses greater than 2 micrograms/100 g body wt (bw), CRM45 caused a decrease in growth rate and caused renal damage. CRM45 modified with 2-pyridyldithio(propionate) groups as well as TRH-CRM45 was significantly less toxic than CRM45, as was TRH-CRM45. CRM26 had no discernible effect on the growth rate of the animals. Ricin A, at a dose of 50 micrograms/100 g bw slowed the growth rate of rats, but specific liver or kidney damage could not be detected. These findings define an upper range of doses for possible therapeutic use.

Postoperative Management and Acute Rehabilitation of Patients with Spinal Cord Injuries

The mortality and morbidity rates of patients with spinal cord injury have decreased greatly. Prior to World War II, few patients survived their acute injuries. Now even severely involved respiratory-dependent patients may return to live in the community. Advanced surgical procedures, when appropriately applied, are decreasing the time of immobility and preventing late spinal deformities. Exciting new developments in basic science research such as the use of thyrotropin-releasing hormone and functional electrical stimulation may alter the whole course of recovery for patients within the foreseeable future. It is likely, however, that the acute management of the patient with spinal cord injury will still demand systematic care by an experienced, multidisciplinary team of professionals.

4493828 Use of thyrotropin releasing hormone and related peptides as poultry growth promotants: Frederick Leung, Roger M Weppelman assigned to Merck & Co Inc

4493828 Use of thyrotropin releasing hormone and related peptides as poultry growth promotants: Frederick Leung, Roger M Weppelman assigned to Merck & Co Inc

The therapeutic potential of thyrotropin releasing hormone (TRH) in Alzheimer's disease (AD)

1. In recent years It has been established that patients with AD have a relatively specific loss of cerebral cortical and hippocampal chollnergic nerve terminals. This may be a reflection of degeneration of cholinergic neurons originating In the nucleus basalls of Meynert and septum Which project to the cortex and hippocampus, respectively. 2. In view of the long-standing association of chollnergic mechanisms with cognitive processes and the recognition of selective chollnergic deficits in AD, therapeutic attempts to enhance CNS chollnergic function have been undertaken In patients with AD. 3. While only limited success with this strategy has been achieved to date, the use of TRH may offer a novel, yet rational, approach to treating AD. This assumption is predicated on the extensive literature documenting unique, facilltatory interactions of this peptide with chollnergic neurons throughout the neuraxis. 4. Furthermore, the same rationale may account for the recently reported therapeutic benefit of TRH in patients with amyotrophic lateral sclerosis, which like AD, is a disease whose symptoms are manifested through a progressive degeneration of a subpopulation of CNS cholinergic neurons.

Opiate antagonists in shock and trauma

Circulatory shock and pain were associated as frequent consequences of surgery and trauma prior to the development of anesthetics. The recent discovery of the endogenous opioid systems affords the opportunity to link the occurrence of pain and circulatory shock at a functional level. The involvement of opioid systems in endogenously and exogenously induced analgesia is well established. In this review, evidence is presented indicating that endogenously activated opioid systems contribute to the pathophysiology of circulatory shock following such diverse causes as endotoxemia, hemorrhage, and spinal cord trauma. The opiate antagonist naloxone (Narcan ®), acting to oppose endogenous opiates, rapidly reverses the hemodynamic, metabolic, and biochemical sequelae of shock in experimental animal models. Additionally, naloxone has been shown to prevent paralysis following acute cervical spinal cord injury. As with all drugs, several physiologic and pathophysiologic circumstances limit the usefulness of naloxone in reversing shock and improving tissue perfusion. They include acidosis, hypothermia, interactions with administered sterolds, and the potential for antagonizing opioid-induced analgesia, which may exacerbate pain in the traumatized patient. Two approaches have yielded potential ways to circumvent these limitations: first, the development of specific opioid-receptor antagonists, which reverse shock without affecting opioid analgesia, and second, the pharmacologic use of thyrotropin releasing hormone (TRH), which acts through its own effector system, independent of endogenous opioid receptors, to produce autonomic effects that reverse shock in experimental animals without affecting analgesia.

The use of thyrotropin-releasing hormone in distinguishing prolactin-secreting pituitary adenoma

In order to differentiate between a prolactin-secreting adenoma and a nonneoplastic etiology for galactorrhea, a single stimulatory dose of 500 μg of thyrotropin-releasing hormone (TRH) was employed to assess the prolactin (PRL) response of 50 women. The results were compared to those obtained in 19 control subjects (10 with subsequent surgical removal of a PRL-secreting adenoma and nine women stimulated in the early follicular phase). All patients were grouped according to normal or elevated serum PRL, and normal, equivocal, or abnormal findings by tomography of the sella turcica. Patients with a normal baseline PRL had a normal PRL response to TRH of at least 200% above baseline. This normal response was independent of findings by tomography of the sella turcica. A highly significant difference in response (p < 0.001) was illustrated by all patients with elevated PRL and abnormal tomograms, and in some patients with elevated PRL and normal or equivocal tomograms. These responses were identical to those of the control patients who had histologic evidence of a PRL-secreting adenoma. The findings indicate that a PRL-secreting adenoma in patients with galactorrhea can be identified on the basis of the PRL response to TRH stimulation.

Use of Thyrotropin-Releasing Hormone In Clinical Medicine

Use of Thyrotropin-Releasing Hormone In Clinical Medicine

Clinical use of thyrotropin-releasing hormone

Clinical use of thyrotropin-releasing hormone