The thyrotropin-releasing hormone (TRH)-immune system homeostatic hypothesis.

Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend far beyond its role as a regulator of the hypothalamic-pituitary-thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A., Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410-416.] and Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses 69(6):1249-1256.] provided a functional framework, predicated on its global homeostatic influences, to conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system. Herein, we profer a similar analysis to interactions of TRH with the immune system. Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical role for TRH during the developmental stages of the immune system as well as its numerous interactions with the fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of the inflammatory process with specific relevance to the "cytokine-induced sickness behavior" paradigm. These findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of TRH-based therapeutics in select inflammatory disorders. Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with the immune system is consonant with the large body of available data. Recent advances in the field of immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics for certain medical and psychiatric disorders involving immune dysfunction.

Oxytocin induces maternal behavior in virgin female rats.

Intracerebroventricular administration of oxytocin to virgin female rats that had been ovariectomized and primed with estrogen 48 hours previously induced a rapid onset of full maternal behavior. The maternal behavior persisted and its incidence was dose-related. Tocinoic acid, the ring structure of oxytocin, also rapidly induced the onset of persistent, full maternal behavior. Arginine vasopressin induced persistent maternal behavior, but this behavior had a later onset. Prostaglandin F2 alpha induced strong partial maternal behavior, which showed early onset but did not persist. Many other peptides, ovarian steroids, and prostaglandin E2 were no more effective than saline. These findings suggest that the release of oxytocin and prostaglandin F2 alpha during labor may promote maternal behavior in rats.

Thyrotropin releasing hormone: enhancement of dopa activity by a hypothalamic hormone.

Thyrotropin releasing hormone potentiates the behaviorial effects of dopa plus pargyline in mice. Because the potentiation occurs in hypophysectomized mice, as well as in normal mice, the phenomenon is independent of the release of thyroid stimulating hormone from the pituitary. Possible mechanisms and clinical implications are discussed.

Regional brain concentrations of neuropeptides in Huntington's chorea and schizophrenia.

To ascertain whether Huntington's chorea and schizophrenia are associated with specific regional alterations in neurotensin, somatostatin, and thyrotropin-releasing hormone, the concentrations of these putative neurotransmitters were measured by radioimmunoassay in postmortem brain samples from patients with Huntington's chorea or schizophrenia. Compared to 50 patients without psychiatric or neurological disease, the patients with Huntington's chorea showed significantly elevated concentrations of all three neuropeptides in the nucleus caudatus. In the nucleus accumbens somatostatin levels were increased threefold, while in the amygdala thyrotropin-releasing hormone levels were elevated. In contrast, the schizophrenics exhibited reduced levels of thyrotropin-releasing hormone in two frontal cortical regions, reduced somatostatin levels in one frontal cortical area, and increased neurotensin levels in one frontal cortical area. None of the differences between the diseased brains and the controls could be accounted for by differences in age, sex, or time between death and autopsy.

Cholecystokinin inhibits tail pinch-induced eating in rats.

Peripheral administration of the COOH-terminal octapeptide of cholecystokinin in doses from 1 to 100 micrograms per kilogram of body weight (0.25 to 25.0 micrograms per rat) significantly antagonized tail pinch-induced eating in rats, an animal model for stress-induced human hyperphagia. Centrally administered cholecystokinin was effective only in high doses (3 micrograms into the cerebral ventricle). The finding that the minimal effective dose of cholecystokinin in suppressing stress-induced appetitive behavior is smaller after peripheral than central administration suggests that the peptide is acting on peripheral, as opposed to central nervous system, substrates.

Thyrotropin-releasing hormone can relieve cancer-related fatigue: hypothesis and preliminary observations.

Fatigue in cancer patients is highly prevalent, predominantly idiopathic, difficult to manage, and has a significant negative impact on quality of life. Thyrotropin-releasing hormone (TRH) exerts normotrophic, state-dependent therapeutic effects in a variety of experimental and clinical situations. To evaluate TRH as a treatment for cancer-related fatigue, an ongoing randomized, placebo-controlled, crossover pilot study of breast cancer patients has been initiated and this report presents preliminary observations conducted with three of these patients over 4 consecutive weeks, thereby involving a total of six TRH treatments and six saline controls. Global assessment using both subjective and objective parameters showed that TRH exerted clear anti-fatigue effects in four of the six TRH treatments. These responses were rapid in onset and persisted through the 24 h observation period. No anti-fatigue responses were seen in five of the six saline controls. No unexpected side-effects were seen with TRH administration. These initial findings support the proposal that TRH can ameliorate cancer-related fatigue.

Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions.

Nearly four decades of research have yielded thousands of publications on the physiology, pharmacology and therapeutic effects of TRH and TRH mimetic analogs. This work addresses both the neuroendocrine and the extrahypothalamic actions and functions of the tripeptide. The many reports of clinical effects of TRH in diverse medical conditions, unrelated to pituitary or thyroid function, can appear bewildering, as can its widespread involvement in a plethora of neuronal and physiological processes. Herein, we hypothesize that a logical and causal interrelationship exists between the fundamental molecular and cellular actions of TRH, its broader physiological functions and the therapeutic effects that attend the administration of exogenous TRH and TRH analogs. When viewed from this perspective, the basic neurobiological actions and functions of TRH provide a rational basis for understanding its diverse therapeutic effects. We posit: that the fundamental excitatory actions of TRH throughout the neuroaxis result from blocking various K+ channels linked to G-protein coupled TRH receptors in neurons and pituitary cells in distinct TRH-innervated anatomical pathways; that the functional consequences of blockade of these K+ channels are to enhance neuronal and secretory outputs in TRH regulatory circuits to modulate behavioral and energy homeostasis, and; that in clinical situations the resultant broad and useful therapeutic effects following administration of TRH reflect the state-dependent normalizing effects of activation of these regulatory circuits. In this light, the spectrum of reported clinical effects of TRH agonism remains unique and impressive but is less enigmatic. With the understanding that the neurobiological actions of TRH underlie and are rationally antecedent to its documented, extensive clinical 'normotrophic' effects, continued empirical efforts to assess the medical uses of TRH and related drugs seem rational and warranted. We predict that the range of disorders whose symptoms are alleviated by TRH therapy will continue to expand and that TRH agonism could conceivably become a near-universal therapeutic adjunct, particularly in the practice of neuropsychiatric medicine.

A hypothesis of thyroid-catecholamine-receptor interaction. Its relevance to affective illness.

Recent prospective studies suggest that thyroid state plays a role in affective disorders. A lack of thyroid hormones can lower the threshold for depression; an excess can contribute to a state of tense dysphoria. Thyroid function in some persons also appears to influence the course of affective disorders. Adequate mobilization of thyroid hormones favors recovery from depression; excess mobilization increases the risk of mania in vulnerable individuals. Although other mechanisms may be involved, evidence suggests that the modulation by thyroid hormones of the beta-adrenergic receptor response to catecholamines may contribute to these effects. Norepinephrine stimulates such receptors; thyroid hormones increase their ability to receive stimulation. The plausibility of such interactions between catecholamines and thyroid hormones occurring in the CNS is strengthened by their common origin in the amino acid tyrosine and by their synergism in many metabolic processes.

Peptides and psychoneuroendocrinology. A perspective.

Research indicates that brain peptides exert both behavioral and endocrinologic effects in humans and animals. This review summarizes the best known behavioral actions of four endogenous peptides: luteinizing hormone-releasing hormone (LHRH), adrenocorticotrophic hormone (ACTH), vasopressin, and angiotensin. The hypothalamic-releasing hormones play a role in modulating pituitary-end organ systems. Behavioral disorders may, in the future, be susceptible to formulation in terms of changes in brain peptides. Peptide research in psychiatry may be approached in several ways.

TRH (protirelin) in depressed alcoholic men. Behavioral changes and endocrine responses.

Chronic alcoholics with secondary depression were treated with protirelin in a double-blind, placebo-controlled study. Behavioral data, collected only during the acute alcohol withdrawal state, indicated a beneficial effect of protirelin three hours after injection, but not during subsequent days. Injections caused only mild and infrequent subjective side effects and no cardiovascular effects. Endocrine data were recorded in the acute withdrawal state and after clinical remission. Findings in the acute state suggested thyroid activation and increased central dopaminergic activity, as evidenced by elevated baseline levels of growth hormone, low baseline levels of prolactin, and blunted thyroid-stimulating hormone (TSH) response to protirelin. The first two abnormalities returned to normal levels in the remission state. A blunted TSH response was observed in both the acute and the remission states. Partial persistence of this finding suggests that TSH blunting may not be solely state-dependent. In the acute withdrawal state, TSH blunting was associated with favorable behavioral responses to protirelin.

Behavioral and endocrine responses of schizophrenic patients to TRH (protirelin).

We studied the effects of intravenous protirelin (thyrotropin-releasing hormone) in 17 schizophrenic patients and 17 normal subjects. A total of 12 patients received protirelin, 0.5 mg, and, on another occasion, niacin, 2 mg, in a double-blind, crossover design. Both behavioral and endocrine data were collected. Five patients received protirelin in an open trial; only endocrine data were collected. Protirelin caused about a 50% prompt decrease in psychotic symptoms. Patients then tended slowly to experience a relapse. Side effects were about as infrequent after protirelin as after niacin. We assayed serum prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), L-triiodothyronine (T3) and thyroxine (T4). Free T4 (FT4) index was calculated. The values for PRL, GH, and TSH at baseline and after protirelin stimulation were normal. Patients showed lower T3 values at baseline, but a brisker T3 response to protirelin, than controls. Their FT4 indices were higher at baseline. Patients showed diminished T4 binding sites rather than increased total T4. The causes of these alterations in thyroid dynamics are unidentified.

Dose-response studies with protirelin.

BACKGROUND: A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (protirelin [TRH]) has been found consistently in a portion of patients with major depression. One hypothesis to explain this observation is that pituitary TRH receptors are down-regulated in major depression. One prediction stemming from this hypothesis is that prolactin (PRL) as well as TSH responses to TRH should be attenuated. To adequately test the pattern of protirelin-induced TSH and PRL responses with a protirelin dose-response design is necessary. METHODS: Four doses of protirelin (25, 100, 500, and 800 micrograms) were infused in an ascending schedule at intervals of 3 to 7 days in patients with major depression and in control subjects. Seven women and six men with major depression were compared with age- and gender-matched controls (five women and seven men). The TSH and PRL responses were measured at regular intervals following each dose of protirelin. RESULTS: No significant group differences in baseline levels of thyroid hormones or cortisol were present. Depressed men exhibited significant reductions in both TSH and PRL responses to protirelin across all doses compared with control men. Depressed women exhibited significant reductions in TSH responses but not in PRL responses compared with control women. CONCLUSIONS: The findings that men with major depression exhibit reductions in both protirelin-induced TSH and PRL responses support the hypothesis that TRH receptors are downregulated in depression. The findings in women are less clear and may represent the greater variance in the protirelin-induced PRL responses found in women.

Proposal for summing the incapacity status or environmental status scores.

Factor analysis was performed on the scores of variables of the Incapacity Status (ISS) and the Environmental Status Scale (ESS) in 184 MS patients. The aim of the study was to examine the relation between these variables and to examine the possibilities of using a summation process on scores. It proved that summing scores of the ISS conceals important information on communication disorders and on bladder, bowel and sexual dysfunctions. It was suggested to use three, composed variables of the ISS and the five variables of the ESS in the summation to produce a figure which reflects the handicaps of the patients.

Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression?

Several investigators have reported a paradoxical growth hormone (GH) response to thyrotropin-releasing hormone (TRH) in depressed patients, but other studies have failed to confirm this. In the present study, the GH response to TRH was studied in depressed patients and normal subjects. The rate of paradoxical GH response to TRH in depression was no different than that observed in control subjects. This was the case whether the data was examined using mean values or using frequency of abnormal responses. Patients with blunted thyrotropin (TSH) responses did not differ in GH release from patients with normal TSH response. A variety of factors may have contributed to the earlier reports of a positive GH response to TRH, including the definition of paradoxical GH release and the fact that depressed patients exhibit more frequent spontaneous diurnal GH release than do normal subjects.

Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review.

In 1972 it was reported that in some euthyroid depressed patients the serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was deficient. Since then, 41 reports describing 917 depressed patients have confirmed this finding. Although it is useful to report differences between mean response values of patient populations, it is necessary to identify those individuals in whom the fault occurs so that sensitivity, specificity, state-trait distribution, and clinical correlates can be determined. Present data allow some tentative conclusions: 1) the fault usually reflects a defect in central regulation of the pituitary-thyroid axis, 2) in some patients the fault may be a trait marker, and 3) it may represent a biological bridge between some depressed patients and some patients with other mental disorders.

Use of TSH response to TRH as an independent variable.

The thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was assessed in 35 consecutive male admissions. Patients with TSH blunting were identified; they were compared with patients without blunting and with normal subjects. Patients without TSH blunting were normal as regards all endocrine variables. Patients with TSH blunting showed reduced TSH (but normal prolactin) levels before and after TRH administration, although their thyroid hormone levels and cortisol levels were normal. Height, weight, and body surface were unrelated to TSH blunting. The test-retest reliability of a blunted TSH response was acceptable.

Long-term predictors of outcome in abstinent alcoholic men.

Twenty-nine alcoholic men who had been abstinent for more than 2 years were evaluated behaviorally and neuroendocrinologically and then followed for 2 years. Mean length of abstinence at intake was shorter in the eight patients with histories of depression (3.3 years) than in the patients without such histories (6.8 years). Six patients relapsed during follow-up, all of whom had been sober less than 5 years. None of the neuroendocrine variables studied was predictive of outcome. In summary, abstinence of less than 5 years and comorbidity with depression were most predictive of poor outcome.

Organic brain syndrome associated with marginal hypothyroidism.

The authors report organic brain dysfunction in two psychiatric patients with grade 2 hypothyroidism; one was depressed and one had a paranoid psychosis with depressive features. The depression and psychosis responded to psychotropic medication and L-thyroxine, but the cognitive dysfunction improved only partially.

Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders.

Six women and 6 men who were treated in double-blind fashion major depressive illness did not respond to imipramine or amitriptyline, 150-300 mg/day, during periods of 26-112 days. After the addition of 25 micrograms/day (10 patients) or 50 micrograms/day (2 patients) of L-triiodothyronine (T3), 9 patients showed statistically significant improvement in depression scores; in 8 patients the response was marked. Improvement generally began within 1-3 days and was noted in all aspects of the depressive syndrome; side effects were minimal. T3 did not change plasma levels of imipramine or desipramine or their ratio but did suppress serum thyroxine.

Subclinical hypothyroidism: a modifiable risk factor for depression?

The authors assessed the lifetime history of major depression in 16 subjects with subclinical hypothyroidism and 15 subjects whose thyroid function was completely normal. The lifetime frequency of depression was significantly higher in the subjects who met the criteria for subclinical hypothyroidism (56%) than in those who did not (20%), suggesting that subclinical hypothyroidism may lower the threshold for the occurrence of depression.