TRH Infusion Research Articles

360 The Ability of an Enhanced Zeolite-Based Flow Agent to Mitigate the Effects of Ergot-Like Alkaloids Consumed by Beef Cattle

Abstract Aluminosilicate-based flow agents, like zeolites, may impact digestion of ergot-like alkaloids in the ruminant gut. Twenty-four steers (226 ± 27.6 kg) were used in a 21-d experiment to test the effects of an enhanced zeolite-based flow agent (KALLSIL, Kemin Industries, Des Moines, IA) on site of ergot-like alkaloid excretion, serum prolactin, rectal temperature, respiration rate, and nutrient digestibility. Treatments were control (E+) or enhanced zeolite inclusion (E+Z; 2 g/kg, DM basis). Steers were fed a TMR at 1.85% of BW (DM-basis). Tall-fescue seed was included in the diet at 11.14%, providing 465 µg of ergovaline/kg DM. Steers had no ORTS during the experiment. Rectal temperature and respiration rate were recorded daily at 0700 and 1200 h from steers housed tie stalls in a room kept at (18.5°C ± 0.33°C, 32.6% ± 2.19%). Serum was harvested from blood collected on d-1, 7, 14, and 21 to measure prolactin. On d-21 jugular catheters were placed to measure prolactin following the infusion of thyrotropin-releasing hormone (TRH; 1 µg/kg BW). Spot samples of feces and urine were collected every 8 h from d 17-20, with 2-hour advancement each day to determine digestibility, N balance, and recovery of ergot-like alkaloids. Digestion and N balance was not affected by treatment (P ≥ 0.16). Enhanced zeolite tended (P = 0.15) to increase recovery of ergovaline. Prolactin concentration decreased over time (P < 0.01), but was greater (P = 0.01) at each time point for E+Z steers. Following the infusion of TRH, prolactin tended (P = 0.11) to be greater for E+Z. Rectal temperatures and respiration rates were not affected (P ≥ 0.89) by E+Z. Results from this study indicate that enhanced zeolite inclusion tended to increase recovery of ergot-like alkaloids in feces and increased serum prolactin when offered to beef steers in a diet containing ergot-like alkaloids.

Effects of camelina meal supplementation on ruminal forage degradability, performance, and physiological responses of beef cattle1,2,3

Three experiments compared ruminal, physiological, and performance responses of beef steers consuming hay ad libitum and receiving grain-based supplements without (control) or with (CAM) the inclusion of camelina meal. In Exp. 1, 9 steers fitted with ruminal cannulas received CAM (2.04 kg of DM/d; n = 5) or control (2.20 kg of DM/d; n = 4). Steers receiving CAM had reduced (P = 0.01) total DMI and tended to have reduced (P = 0.10) forage DMI compared with control. No treatment effects were detected (P ≥ 0.35) for ruminal hay degradability parameters. In Exp. 2, 14 steers fed CAM (1.52 kg of DM/d; n = 7) or control (1.65 kg of DM/d; n = 7) were assigned to a corticotropin-releasing hormone (CRH; 0.1 μg/kg of BW) and a thyrotropin-releasing hormone (TRH; 0.33 μg/kg of BW) challenge. Steers fed CAM had greater (P < 0.05) serum concentrations of PUFA compared with control before challenges. Upon CRH infusion, plasma haptoglobin concentrations tended (P = 0.10) to be reduced and ceruloplasmin concentrations increased at a lesser rate in CAM steers compared with control (treatment × time; P < 0.01). Upon TRH infusion, no treatment effects were detected (P ≥ 0.55) for serum thyrotropin-stimulating hormone, triiodothyronine, and thyroxine. In Exp. 3, 60 steers were allocated to 20 pens. Pens were assigned randomly to receive CAM (2.04 kg of DM/steer daily; n = 10) or control (2.20 kg of DM/steer daily; n = 10) during preconditioning (PC; d -28 to 0). On d 0, steers were transported for 24 h. Upon arrival, pens were assigned randomly to receive CAM or control during feedlot receiving (FR; d 1 to 29). During PC, CAM steers had reduced (P < 0.01) forage and total DMI, and tended to have reduced (P = 0.10) ADG compared with control. Plasma linolenic acid concentrations increased during PC for CAM steers, but not for control (treatment × day; P = 0.02). During FR, steers fed CAM during PC had reduced (P < 0.01) forage and total DMI, but tended (P = 0.10) to have greater G:F compared with control. Steers fed CAM during FR had greater (P < 0.05) plasma concentrations of PUFA, and reduced rectal temperature and concentrations of haptoglobin and ceruloplasmin during FR compared with control. In summary, CAM supplementation to steers impaired forage and total DMI, did not alter thyroid gland function, increased circulating concentrations of PUFA, and lessened the acute-phase protein reaction elicited by neuroendocrine stress responses.

Intra-pituitary administration revisited: Development of a novel in vivo approach to investigate the ovine hypophysis

The anterior pituitary gland regulates physiological processes via the secretion of hormones, which are under the control of factors produced either in the hypothalamus or the pituitary gland itself. Studies investigating how the pituitary gland functions have employed both in vitro and in vivo approaches. Although in vitro analysis has the advantage that it is pituitary specific, the results may be incomplete because the tissue is isolated from other physiological inputs that could affect function under natural conditions. Without vascular input, such studies are inherently of short duration. Conversely, in vivo experiments that rely upon systemic hormone injections require high doses, are non-target specific and the precise hormone concentrations reaching the pituitary gland are difficult to control. Intracerebroventricular hormone infusions are reliant on assumptions that factors are transported to the pituitary gland from the cerebrospinal fluid and are without cerebral effects. Here we describe an innovative method to investigate anterior pituitary function in conscious sheep by direct infusion of peptides into the pituitary tissue surrounding the hypophyseal portal blood vessels. This approach is an adaptation of the hypophyseal portal cannulation technique whereby an indwelling cannula provides direct access to the rostral aspect of the adenohypophysis. Peptide infusions were achieved by insertion of a needle through the implanted cannula such that it penetrated the pituitary. Using this technique, infusion of TRH (17ng/1μl/min for up to 6h) induced a sustained rise in systemic prolactin levels that lasted for the duration of the infusion.

Les dyshormonémies des affections non thyroïdiennes

Abnormalities in the circulating levels of thyroid hormones, without evidence of coexisting thyroid or pituitary gland disease can be observed in all general diseases. These nonthyroidal illnesses (NTIS) are the result of complex mechanisms that combine the effect of some drugs, cytokines, nutritional and endocrine factors at all levels of the thyrotropic axis, from the hypothalamus to the cellular transporters and nuclear receptors of thyroid hormones. The patterns of NTIS depend on the underlying disease and its severity. Thirtyfive years after the initial description, the pathophysiological significance of these anomalies remains controversial. One of the dilemma of NTIS is whether the hormone responses represent an adaptive and normal, physiologic response to conserve energy and protect against hypercatabolism in case of aggression, or whether it is a maladaptive response contributing to a worsening of the disease. This debate is not just a theoretical question, because in the first case the process must be respected, in the other case a vigorous treatment to restore circulating thyroid hormone levels is justified. There have been very few clinical studies designed to address whether the substitution with thyroid hormone is advantageous, and there is at current time no permissive evidence for the use of thyroid hormone replacement in patients with NTIS. But the clinical context, the choice of the molecule or of the dose and the way of administration were not necessarily the most relevant. Theoretically, stimulation of thyreotrope axis used a continuous infusion of TRH seems to provide clinical benefit. With the expectation that randomized clinical trials will provide demonstration of NTIS treatment efficiency, the question might remain unanswered for several more years.

Regulation of type 1 deiodinase activity in prolonged critical illness

The low T3 syndrome invariably observed in prolonged critically ill patients can be explained at least in part by reduced hepatic type 1 deiodinase (D1) activity, whereby the T4 metabolism is shunted away from T3 production into inactive rT3. Infusion of TRH, however, restores the catalytic activity of D1 and concomitantly increases T3 to within the physiological range, indicating that D1 activity during critical illness is regulated via alterations within the thyroid axis [1]. It remains unknown, however, whether this observed reactivation of D1 activity is due to either a direct effect of TRH or the induced rise in circulating T4 and T3 concentrations.

Tissue Deiodinase Activity during Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone-Releasing Peptide-2

Prolonged critical illness is characterized by reduced pulsatile TSH secretion, causing reduced thyroid hormone release and profound changes in thyroid hormone metabolism, resulting in low circulating T(3) and elevated rT(3) levels. To further unravel the underlying mechanisms, we investigated the effects of exogenous TRH and GH-releasing peptide-2 (GHRP-2) in an in vivo model of prolonged critical illness. Burn-injured, parenterally fed rabbits were randomized to receive 4-d treatment with saline, 60 microg/kg.h GHRP-2, 60 microg/kg.h TRH, or 60 microg/kg.h TRH plus 60 microg/kg.h GHRP-2 started on d 4 of the illness (n = 8/group). The activities of the deiodinase 1 (D1), D2, and D3 in snap-frozen liver, kidney, and muscle as well as their impact on circulating thyroid hormone levels were studied. Compared with healthy controls, hepatic D1 activity in the saline-treated, ill animals was significantly down-regulated (P = 0.02), and D3 activity tended to be up-regulated (P = 0.06). Infusion of TRH and TRH plus GHRP-2 restored the catalytic activity of D1 (P = 0.02) and increased T(3) levels back within physiological range (P = 0.008). D3 activity was normalized by all three interventions, but only addition of GHRP-2 to TRH prevented the rise in rT(3) seen with TRH alone (P = 0.02). Liver D1 and D3 activity were correlated (respectively, positively and negatively) with the changes in circulating T(3) (r = 0.84 and r = -0.65) and the T(3)/rT(3) ratio (r = 0.71 and r = -0.60). We conclude that D1 activity during critical illness is suppressed and related to the alterations within the thyrotropic axis, whereas D3 activity tends to be increased and under the joint control of the somatotropic and thyrotropic axes.

Effects of chronic retinoid administration on pituitary function

It has been reported that retinoids may affect hypothalamic-pituitary-thyroid axis, causing central hypothyroidism. In the present study, we evaluated pituitary function in 11 male psoriatic patients at baseline and after 1 and 3 months of treatment with acitretin (all-trans retinoic acid, 35 mg/day). Serum LH, FSH, testosterone, cortisol, GH and IGF-I levels were not affected by the treatment. By contrast, we observed a significant decrease in TSH levels (from 0.92 +/- 0.3 to 0.80 +/- 0.3 mU/I, p < 0.05) at 1 month, that reverted to baseline after 3 months. No change in free T4 (FT4) levels occurred, while free T3 (FT3) levels were reduced at 1 and 3 months (from 6.7 +/- 0.5 to 6.2 +/- 0.3 and 6.1 +/- 0.6 pmol/l; p < 0.05, respectively). Moreover, acitretin treatment induced a significant reduction of PRL levels after 3 months (from 182 +/- 70 to 150 +/- 56 mU/l, p < 0.05). During treatment, no change in TSH and PRL response either to TRH or dopamine infusion was observed. In conclusion, we demonstrated that treatment with low dose of acitretin induced a series of hormonal modifications that, in addition to a mild and transient reduction of TSH levels, included a persistent reduction of FT3, probably due to changes in thyroid hormone metabolism, and a decrease in PRL levels.

Endocrine and Metabolic Effects of Growth Hormone (GH) Compared with GH-Releasing Peptide, Thyrotropin-Releasing Hormone, and Insulin Infusion in a Rabbit Model of Prolonged Critical Illness

Treatment with recombinant human GH (rhGH) increases the mortality of critical illness. We postulated that combined GH-releasing peptide-2 (GHRP-2), TRH, and insulin infusion is a less toxic anabolic strategy through a putative inability to overstimulate the GH axis and a capacity to normalize thyroid hormone concentrations while foregoing excessive hyperglycemia. Burn-injured, parenterally fed, New Zealand White rabbits were randomized to receive 4-d treatment with saline (n=8); 60 microg/kg.h GHRP-2 and 60 microg/kg.h TRH, i.v. (n=9); or 3.5 mg/kg rhGH, s.c. (n=7). In the GHRP-2+TRH group, insulin was adjusted to maintain blood glucose below 180 mg/dl. Endocrine function and biochemical organ system function markers were studied. Animals were killed for assay of deiodinase activity in snap-frozen liver. Mortality, organ system function, hyperglycemia, and insulin requirement were equal in the three groups. GHRP-2+TRH increased pulsatile rabbit GH (rGH) and TSH release on d 1. After 4 d, rGH secretion and T4 and T3 concentrations were elevated, with a significant increase in hepatic activity of type 1 deiodinase and a decrease in type 3 deiodinase. Exogenous rhGH suppressed endogenous rGH secretion and increased IGF-I more than GHRP-2+TRH without altering thyroid hormone levels. Unlike GHRP-2+TRH, rhGH down-regulated liver type 3 deiodinase and did not affect type 1 deiodinase. We conclude that in experimentally induced critical illness, GHRP-2+TRH reactivated the GH and TSH axes and altered liver deiodinase activity, driving T4 to T3 conversion. In contrast to the human model, high dose rhGH was not rapidly lethal in this rabbit model. Whether this is explained by lack of rhGH-induced insulin resistance and hyperglycemia remains unclear.

Novel insights into the neuroendocrinology of critical illness.

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically accrued. This 'wasting syndrome' often persists after the underlying disease has been resolved and thus perpetuates intensive care dependency. Although the crucial role of an intact hypothalamus-pituitary axis for homeostasis during stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recently described. Novel insights in this area are reviewed here. The initial endocrine stress response consists primarily of a peripheral inactivation of anabolic pathways while pituitary activity is essentially amplified or maintained. These responses presumably provide the metabolic substrates and host defense required for survival and to delay anabolism, and thus should be considered as adaptive and beneficial. Persistence of this acute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been observed in protracted critical illness, causing diminished stimulation of several target organs. Impaired pulsatile secretion of anterior pituitary hormones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing factors evoked immediate and pronounced pituitary hormone release. A reduced availability of TRH, one of the endogenous ligands of the GH-releasing peptide (GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay critically ill men, also of GHRH, appear to be involved. This hypothesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of GH, TSH and PRL was re-amplified by relevant combinations of releasing factors which also substantially increased circulating levels of IGF-I, GH-dependent binding proteins, thyroxine and tri-iodothyronine (T3) while avoiding a rise in reverse T3. Active feedback-inhibition loops prevented overstimulation of target organs and metabolic improvement was noted with the combined infusion of GHRP and TRH. Whether this novel endocrine strategy will also enhance clinical recovery from critical illness remains to be explored.

Pituitary Hormone Secretion in Normal Male Humans: Acute Responses to a Large, Oral Dose of Monosodium Glutamate

Numerous studies have shown that the administration of a glutamate receptor agonist or a high dose of glutamate stimulates pituitary hormone secretion in animals. However, only a single human study has reported that an oral load of glutamic acid induced the secretion of prolactin and probably adrenocorticotropic hormone (ACTH) (but not other pituitary hormones). Because of glutamate's use in foods as monosodium glutamate (MSG), a flavoring agent, and the limited amount of human data, we studied the effect of a large oral dose of MSG in humans on the secretion of prolactin and other pituitary hormones. Fasting male subjects bearing venous catheters received on separate days each of the following four treatments: a vehicle, MSG (12.7 g), a high protein meal (a physiologic stimulus of prolactin secretion) by mouth, or an intravenous infusion of thyrotropin-releasing hormone (TRH, a pharmacologic stimulus of prolactin secretion). Plasma hormone responses were quantitated by RIA at 20-min intervals for 4 h. The protein meal induced a modest increase and TRH infusion a substantial increase in plasma prolactin, whereas MSG ingestion did not. MSG ingestion also did not raise the plasma concentrations of any of the other pituitary hormones measured (luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, growth hormone) or of cortisol. Ingestion of MSG raised plasma glutamate concentrations 11-fold; the protein meal did not raise plasma glutamate. The results demonstrate that MSG ingestion in humans does not modify anterior pituitary hormone secretion. One implication is that diet-derived glutamate may not penetrate into hypothalamic regions controlling anterior pituitary function.

GHRP-2 + TRH infusion for 5 days during protracted critical illness: Endocrine and metabolic effects

GHRP-2 + TRH infusion for 5 days during protracted critical illness: Endocrine and metabolic effects

Short-term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male subjects.

Fasting male subjects received each of four treatments on different days: a large oral dose of monosodium L-glutamate (MSG; 12.7 g), the MSG vehicle, an iv injection of TRH, or a high protein meal. Blood samples were drawn via an indwelling venous line before and at 20-min intervals after each treatment for 4 h. Plasma glutamate levels rose 11-fold within 1 h of MSG ingestion, but did not change appreciably with any of the other treatments. Plasma PRL levels rose 10-fold after TRH infusion and 2-fold after the protein meal, but did not rise significantly after MSG ingestion. No effects resulted from any of the treatments on plasma LH, FSH, testosterone, GH, or cortisol concentrations. Plasma levels of TSH, T4, and T3 showed minimal changes after any of the treatments except TRH; TRH elevated plasma TSH and T3 levels. Self-rating instruments of mood and side-effects revealed no treatment-related effects on mood or physical state for up to 48 h after each treatment. Together, these results suggest that acute pharmacological elevations of plasma glutamate levels in adult men produce minimal, if any, effects on hypothalamic or pituitary function.

Sensitivity and Specificity of Coupled Dexamethasone Suppression and TRH Infusion Tests in 90 Postsuicide Hospitalized Adolescents with Depression

In order to reduce the possible confounding effect of suicidality on studies of biological markers in adolescents, we examined a sample consisting solely of adolescents hospitalized following a suicide attempt. Of 112 adolescents hospitalized after a suicide attempt, 90 met DSM-III-R criteria for a depressive disorder: major depression presented in 54% of these cases, dysthymia in 11%, and both (double depression) in 35%. The 22 adolescents who did not have depression formed the psychiatric control group. All patients were administered a dexamethasone suppression test and a TRH infusion test after several days in the hospital. There were no significant differences in DST or TRH responses among the adolescents with major depression, dysthymic disorder, or double depression. Among the depressed adolescents, cortisol nonsuppression was found in 42%, and blunted TSH response was noted in 51%; one of the two tests was abnormal in 74% of the depressed adolescents, and both tests were abnormal in 19%. Among the nondepressed adolescents, 18% manifested cortisol nonsuppression (a result which differs from the depressed group, p < 0.05) and 14% showed blunted TSH response (p < 0.01); one of the two tests was abnormal in 27% of the nondepressed adolescents (p < 0.0001), and both tests were abnormal in only one nondepressed patient (NS). For identifying depressed adolescents, the DST had a sensitivity of 42% and a specificity of 82%. The TRH test had a sensitivity of 51% and a specificity of 86%. An abnormality on one of the two tests had a sensitivity of 74% and a specificity of 73%. The sensitivity of the coupled tests was 19%, and the specificity was 95%. These figures do not provide a basis to support the use of these tests, singly or coupled, as a major clinical aid in the identification of depressed adolescents, even among postsuicide depressed adolescents.

Effects of a sustained release formulation of thyrotropin-releasing hormone on behavioral abnormalities in senescence-accelerated mice

Effects of a sustained release formulation of thyrotropin-releasing hormone (TRH-SR) on reduced anxiety-like behavior and learning impairment in senescence-accelerated mice (SAM) were examined. SAMP8/Ta (SAMP8) mice showing age-related emotional changes as well as learning and memory impairments, and SAMRITA (SAMR1) mice exhibiting normal aging were used at 8 months of age. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immunoreactive plasma TRH levels up to about 4 weeks after dosing in SAMP8. TRH-SR antagonized the reduced neophobia to novel food in SAMP8 in a dose-dependent manner when tested 10 days but not 3 days after the injection. In the elevated plus-maze test, the SAMP8 control group treated with vehicle had significant increases in the number of entries into open arms and the time spent in open arms in comparison to SAMR1 mice. TRH-SR showed dose-dependent decreases in the number of entries into open arms, and reduced the time spent in open arms in SAMP8 mice. Furthermore, TRH-SR significantly improved the impairment of water maze learning in SAMP8 mice. In contrast, bolus administration of TRH had no significant effects on behavioral abnormalities in SAMP8 even at high doses, implying that long-term and continuous infusion of TRH may be important for amelioration of the behavioral abnormalities. These results suggest that TRH-SR may be useful for treatment of age-related emotional disorders and memory disturbance in dementia.

Effects of sustained release formation of thyrotropin-releasing hormone on learning impairments caused by scopolamine and AF64A in rodents

The efffects of a sustained-release formulation of thyrotropin-releasing hormone (TRH-SR) on learning impairment induced by scopolamine and a cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), were examined on rodents. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immonoreactive plasma TRH levels up to about 2 weeks after dosing in rats. TRH-SR (0.56 and 2.8 mg/kg) given subcutaneously 7 days before the aquisition trial markedly ameliorated scopolamine-induced amnesia in mice, as evaluated with a passive avoidance task. Repeated administration of TRH for 7 days at doses of 0.2–6 mg/kg s.c. elicited a dose-dependent recovery from amnesia induced by scopolamine, whereas only the group treated with 5 mg/kg/day showed a significant improvement. The rat with bilateral intracerebroventricular injection of AF64A (3.75 nmol/brain) showed a significant impairment in the water maze task 2 weeks after surgery. TRH-SR (0.56 and 2.8 mg/kg) also exhibited a dose-dependent ameliorating action on the deficit. These findings indicate that TRH-SR ameliorates learning impairments produced by scopolamine and AF64A, and suggest that continuous infusion of TRH may have a potent learning and memory improving action at low doses.

Thyroid function before and after four-week light treatment in winter depressives and controls

Thyroid function in patients in a current major depressive episode during the course of recurrent major mood disorder with seasonal pattern according to DSM-IIIR was compared to that of controls before and after 4 weeks' light treatment, and to that of controls at baseline and after 4 weeks' of arising early without exposure to bright light. No consistent abnormalities in thyroxine, free thyroxine index, triiodothyroine, reverse triiodothyronine, thyrotropin, thyrotropin response to TRH infusion, or thyroid autoantibodies were seen in depressives at baseline. No differences in these parameters were seen at baseline between depressives and controls. No intergroup differences were seen with treatment, although reverse T 3 decreased significantly during the protocol in all groups. These data do not support the hypothesis that the thyroid axis plays a role in the pathogenesis of winter depressive symptoms or their response to light treatment.

Is thyrotropin-releasing hormone immunoreactivity in peripheral blood an estimate for hypothalamic thyrotropin-releasing hormone release?

The significance of TRH for pituitary function is still unresolved mainly due to limitations in determining in vivo hypothalamic TRH release. We therefore examined whether TRH immunoreactivity (TRH-IR) in peripheral blood is an index for hypothalamic TRH release. Peripheral TRH-IR varied between 10 and 55 pmol/l and was similar in euthyroid and hypothyroid rats, but lower in hyperthyroid rats. Destruction of the hypothalamic paraventricular area reduced peripheral TRH-IR, while stimulation of this area increased it. Clearance of TRH during continuous TRH infusion was 1.9 +/- 0.2, 3.5 +/- 0.3 and 5.9 +/- 0.8 ml/min in hypothyroid, euthyroid and hyperthyroid rats, respectively. These and previous data on TRH in hypophysial portal blood indicate that 5-25 pmol TRH/l peripheral blood is of hypothalamic origin. Chromatography revealed that TRH-IR from hypothalamus and portal blood co-eluted with TRH, but in peripheral blood two peaks were found, one of which was authentic TRH. Thus, peripheral TRH-IR alters in experimental conditions and part of it seems to be of hypothalamic origin. However, the presence of TRH-like material in peripheral blood not identical to TRH and the fact that experimental conditions alter TRH clearance indicate that peripheral TRH-IR is not an index for hypothalamic TRH release.

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.

Cerebral and peripheral blood flow effects of TRH in the rat—A role of vagal nerves

The cardiovascular effects of the IV infusion of TRH were studied in the rat. TRH tended to increase the MAP and markedly increased the CBF tot in the control group, in vagotomized animals and in methylatropine-pretreated rats. A marked vasodilation was noted in the pancreas, gastric mucosa, duodenum and cardiac muscle. This effect was turned to vasoconstriction, the heart excluded, in vagotomized animals. Muscarinic blockade attenuated the vasodilating effect of TRH in the duodenum and gastric mucosa. The results indicate that TRH elicits cerebral vasodilation and a partly nonmuscarinic parasymphathetically mediated vasodilation in several gastrointestinal organs in parallel with a vasoconstriction which is unmasked by vagotomy.

Chronic administration of thyrotropin-releasing hormone enhances the sensitivity of lumbar motoneurons to 5-hydroxytryptophan in the rat

The influence of a single intraperitoneal injection or of a three-week excitatory effect of DL-5-hydroxytryptophan (5-HTP) (20–100 mg/kg IP) on lumbar motoneurons. This effect was studied by recording the integrated spontaneous electromyographic (EMG) activity of the hindlimb muscles in spinalized rats previously denervated with an intrathecal injection of 5,7-dihydroxytryptamine. A single injection of TRH 10 mg/kg IP caused by itself a stimulation of the EMG activity but failed to modify the subsequent EMG response to 5-HTP one hour or one day later. However, a three-week infusion of TRH in the lumbar subarachnoid space caused a 300% increase in the response to 5-HTP, while denervation alone caused only an increase of 160%. A similar potentiation of the effect of 5-HTP was seen on the Wet Dog Shake phenomenon which we believe is elicited in the forebrain. Therefore, chronic but not acute stimulation of lumbar motoneurons or forebrain structures by THR appears to facilitate the serotonergic excitating response. This effect of TRH does not appear to necessitate the actual coexistence of 5-HT and TRH in the same nerve fibers.