Thyrotropin-releasing Hormone 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.

Are thyrotropin-releasing hormone (TRH) and analog taltirelin viable reversal agents of opioid-induced respiratory depression?

Opioid‐induced respiratory depression (OIRD) is a potentially life‐threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin‐releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH‐analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator within the brainstem respiratory network. An additional respiratory excitatory effect may be related to TRH’s analeptic effect. In awake and anesthetized rodents, TRH and taltirelin improved morphine‐ and sufentanil‐induced respiratory depression, by causing rapid shallow breathing. This pattern of breathing increases the work of breathing, dead space ventilation, atelectasis, and hypoxia. In awake and anesthetized humans, a continuous infusion of intravenous TRH with doses up to 8 mg, did not reverse sufentanil‐ or remifentanil‐induced respiratory depression. This is related to poor penetration of TRH into the brain compartment but also other causes are discussed. No human data on taltirelin are available. In conclusion, data from animals and human indicate that TRH is not a viable reversal agent of OIRD in awake or anesthetized humans. Further human studies on the efficacy and safety of TRH’s more potent and longer lasting analog taltirelin are needed as this agent seems to be a more promising reversal drug.

Effect of TRH and TSH on Circulatory Glucose and Fatty Acids Responses in Hypoinsulenemic Male Dwarf Goats

Diabetes mellitus or hypoinsulinemia was induced successfully in the male dwarf goats aged be-tween 2 - 3 years with 2 consecutive administrations of streptozotocin. A comparable group of intact control goats was also maintained. In ruminants including goats unlike non-ruminants, insulin generally displays ineffectiveness or resistance in their biochemical setup to facilitate gluco-neogenesis, the only source of glucose in these animals. In present study almost in the absence of insulin through induced hypoinsulinemia the effects of thyrotropin releasing hormone (TRH) (30 μg/kg body weight) and thyroid stimulating hormone (TSH) (2.5 μg/kg body weight) on circulatory glucose and different fatty acid fractions were studied in insulin resistant ruminant model. Fatty acid fractions were estimated by gas chromatography. Both TRH and TSH administration lowered glycemia in insulin deficient goats compared to the controls but significantly with TSH dose only. In intact goats the detectable circulating long chain fatty acids (LCFAs) fractions of lauric, myristic, palmitic, stearic, oleic and linoleic acid were undetected except linoleic acid in the hypoinsulinemic state, however were found restored following TRH and TSH administrations and some of LCFAs; stearic (6417%), oleic (1676%) and linoleic acid (1225%) increased exceptionally with TSH dose. In Intact goats however the hormones variedly increased the fractions. The volatile fatty acid fractions (VFAs) of formic, acetic, propionic, iso-butyric, n-butyric, iso-valeric, n-valeric, iso-caproic, n-caproic and heptanoic acid were detected in the goats. The most VFAs fractions markedly increased in hypoinsulinemic goats compared to the control goats following TRH and TSH infusion. These results have indicated that endogenously stimulated thyroid hormones with TRH and TSH in insulin deficient state inhibit the mechanisms of utilizing the fatty acids in glucose production. Therefore the study reveals thyroid hormones inhibitory effects on gluconeogenesis in insulin resistance and hyperglycemia.

T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal/mild endometriosis

In the present study, interleukin (IL)-10, IL-12, IL-17, and IL-23 levels were measured in serum and peritoneal fluid of women with minimal or mild endometriosis and compared with levels in controls without endometriosis. Higher IL-23 levels were encountered in the peritoneal fluid of women with endometriosis, suggesting a possible role of this cytokine in these women's infertility.

Regulation of Tissue Iodothyronine Deiodinase Activity in a Model of Prolonged Critical Illness

The low plasma triiodothyronine (T3) observed during prolonged critical illness can be explained in part by suppressed hepatic deiodinase type I (D1) and increased D3 activity. Infusion of thyrotropin-releasing hormone (TRH) can restore D1 and D3 activity in critically ill rabbits, but it remains unknown whether this is a direct effect of TRH or the TRH-induced rise in circulating thyroxine (T4) and T3. To answer this specific question, burn-injured rabbits randomly received a 4-day treatment with saline, T4, T3, T4+T3, or TRH, started on day 4 of the illness. Plasma iodothyronine concentrations, D1 and D3 activity, and T3-responsive gene expression were quantified in liver and kidney. Infusion of T4, T3, or TRH increased circulating T3 levels and hepatic D1 activity. Co-infusion of T3 with T4 enhanced T4 to T3 conversion as demonstrated by lower T4, higher T3, and lower reverse T3 (rT3) levels and tended to further increase hepatic D1 activity. Hepatic D1 activity correlated positively with circulating T3 and the T3/rT3 ratio, but not with T4, rT3, or thyroid-stimulating hormone. During prolonged critical illness, D1 activity is primarily regulated via changes in circulating T3, suggesting that the low plasma T3 concentrations may be important in sustaining low D1 activity in this condition.

Hypothalamic neuronal histamine mediates the thyrotropin-releasing hormone-induced suppression of food intake.

We examined the involvement of thyrotropin-releasing hormone (TRH) and TRH type 1 and 2 receptors (TRH-R1 and TRH-R2, respectively) in the regulation of hypothalamic neuronal histamine. Infusion of 100 nmol TRH into the rat third cerebroventricle (3vt) significantly decreased food intake (p < 0.05) compared to controls infused with phosphate- buffered saline. This TRH-induced suppression of food intake was attenuated partially in histamine-depleted rats pre-treated with α-fluoromethylhistidine (a specific suicide inhibitor of histidine decarboxylase) and in mice with targeted disruption of histamine H1 receptors. Infusion of TRH into the 3vt increased histamine turnover as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH, a major metabolite of neuronal histamine in the brain) in the tuberomammillary nucleus (TMN), the paraventricular nucleus, and the ventromedial hypothalamic nucleus in rats. In addition, TRH-induced decrease of food intake and increase of histamine turnover were in a dose-dependent manner. Microinfusion of TRH into the TMN increased t-MH content, histidine decarboxylase (HDC) activity and expression of HDC mRNA in the TMN. Immunohistochemical analysis revealed that TRH-R2, but not TRH-R1, was expressed within the cell bodies of histaminergic neurons in the TMN of rats. These results indicate that hypothalamic neuronal histamine mediates the TRH-induced suppression of feeding behavior.

Central Thyrotropin-Releasing Hormone Infusion Opposes Cardiovascular and Metabolic Suppression during Caloric Restriction

Inhibition of hypothalamic thyrotropin-releasing hormone (TRH) neuronal activity is a well-established adaptation to caloric restriction (CR) that suppresses pituitary secretion of thyroid-stimulating hormone, but may also participate in modulation of autonomic function. Thus, we hypothesized that decreased hypothalamic TRH activity contributes to CR-induced bradycardia and decreased metabolic rate. To test this hypothesis, male Sprague-Dawley rats were instrumented with telemetry devices for measurement of heart rate (HR) and blood pressure (BP) and a lateral intracerebroventricular (i.c.v.) guide cannula for central infusions. After recovery, rats were housed in metabolic chambers and given either ad libitum(ad-lib) or CR treatments for 7 days; half of each diet group was then given continuous i.c.v. infusions of TRH (25 nmol/h) or saline (0.25 µl/h) for 7 days via osmotic pump. This dose of TRH did not significantly alter peripheral free T₄ levels. In ad-lib rats, TRH infusion produced small reductions in food intake and small increases in HR and BP over saline-infused controls. In CR rats, TRH infusion resulted in an increase in HR and also energy expenditure over saline-infused controls. These results support the hypothesis that suppression of central TRH activity contributes to the homeostatic suppression of energy expenditure and HR observed during CR.

Pituitary responsiveness to gonadotropin- and thyrotropin-releasing hormones in goats treated with recombinant bovine somatotropin

Non-lactating, crossbred Alpine goats, of similar age and body weight were used to evaluate the effects of bovine somatotropin (bST) administration on pituitary function. Following ovarian synchronization, treated goats ( n=4) received a subcutaneous injection of 160 mg rbST, three times, at 14-day intervals, while control goats ( n=4) remained uninjected. The day after the last rbST injection ovarian synchronization was repeated and the following day all animals were challenged with 50 μg gonadotropin-releasing hormone (GnRH) and 100 μg thyrotropin-releasing hormone (TRH), intravenously. Blood samples were collected at −10, 0, 30, 60, 90, 120, 180, 270 and 360 min after challenge. Additionally, blood sampling was conducted three times per week throughout the experimental period for the detection of peripheral somatotropin, progesterone, T 3 and T 4 concentrations. Treatment with rbST significantly increased somatotropin concentrations in treated animals (21.2±1.3 ng/ml) as compared to controls (5.2±0.4 ng/ml). GnRH and TRH infusions resulted in similar LH, TSH, T 3 and T 4 responses in both groups, in terms of the area under the curve (AUC), the peak value (PV) and the time to peak (PT). Plasma progesterone concentrations during the treatment period did not differ between groups. Treatment with rbST did not affect T 4 levels during the experimental period, but a highly significant effect of treatment was observed for T 3 levels, particularly after the second rbST administration (1.47±0.06 ng/ml versus 2.01±0.1 ng/ml) for the control and treated group. In conclusion, it has been shown that rbST treatment did not affect pituitary responsiveness to GnRH or TRH challenge, demonstrating that the pituitary control of ovarian and thyroid function is not influenced by bST administration.

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.

Physiological effects of electroconvulsive therapy and transcranial magnetic stimulation in major depression.

Major depressive episodes are associated with dysregulation of various physiologic systems. Antidepressant medications alter regulation of the hormonal and sleep systems. A thorough understanding of these changes may elucidate the pathophysiologic basis of the disorder [Amsterdam et al., 1989: Psychoneuroendocrinology 14:43-62], and interventions targeted directly at these systems are being increasingly recognized as possible treatments for depression [Wong et al., 2000: Proc Natl Acad Sci USA 97:325-330; Szuba et al., 1996: Proc Am Coll Neuropsychopharmacol Ann Meet]. These physiologic systems are regulated by the major neurotransmitters implicated in the etiology of mood disorders--norepinephrine, serotonin, and dopamine. Many of the hormones of import for this article also act as neurotransmitters and thus alter cerebral activity themselves [Owens and Nemeroff, 1993: Ciba Found Symp 172:296-308; Weitzner, 1998: Psychother Psychosom 67:125-132]. Parenteral infusion of hydrocortisone [DeBattista, 2000: Am J Psychiatry 157:1334-1337] and thyrotropin-releasing hormone (TRH) [Prange et al., 1972: Lancet 2:999-1002; Marangell et al., 1997: Arch Gen Psychiatry 54:214-222; Szuba, 1996: Proc Am Coll Neuropsychopharmacol Ann Meet.] produce acute antidepressant effects. Antagonists to corticotropin-releasing hormone and repeated parenteral infusion of TRH may have antidepressant activity when given during several weeks [Wong, 2000: Proc Natl Acad Sci USA 97:325-330; Arborelius et al., 1999: J Endocrinol 160:1-12; Callahan et al., 1997: Biol Psychiatry 41:264-272]. Manipulations of the sleep system through sleep deprivation can ameliorate depression [Szuba et al., 1994: Psychiatry Res 51:283-295; see Wirz-Justice et al., 1999: Biol Psychiatry 46:445-453 for review]. Sleep deprivation has been shown in more than three dozen studies published in the last three decades to produce marked, acute antidepressant effects in the majority of depressed individuals [Wirz-Justice, et al., 1999: Biol Psychiatry 46:445-453]. Thus, examination of the effects the two nonpharmacologic treatments, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), produce in these physiologic systems may help elucidate their mechanisms of action, while enhancing understanding of the neurobiology of depressive illness. We will review these physiologic changes associated with depression, the effects that manipulations of these systems can have on depressive disorders, and then describe the effects the two techniques that can stimulate the human brain in vivo, ECT and TMS, exert on these systems.

Effects of Prenatal Maternal TRH Stimulation on the Postnatal Ability of Neonatal Piglets to Cope with a Cold Challenge

The effect of administering thyrotropin-releasing hormone (TRH) before farrowing on the ability of their newborn piglets to withstand a cold challenge was studied. Sows received intravenous infusions of TRH (5 µg kg^–1; TRH group) or physiological saline (0.9% NaCl; control group) from day 105 of gestation until farrowing. The plasma concentrations of thyroxine and triiodothyronine increased in sows treated with TRH. There were no differences in thyroxine and triiodothyronine between pigs born to sows in the TRH group and those of the control group. The rectal temperature of piglets born to TRH-treated sows decreased less than that of piglets born to controls as a consequence of a 1-hour cold challenge. Piglets born to sows in the TRH group had higher body weights at birth, and by day 28 they were an average 600 g heavier than those born to sows in the control group. Summarizing, prenatal maternal treatment with TRH appears to increase piglets’ resistance to cold as well as to have beneficial effects on birth and weaning weights.

Effects of Antenatal Thyrotropin-Releasing Hormone on Fetal Heart Rate and Breathing Movements

Objective: To determine the effect of maternally administered thyrotropin-releasing hormone (TRH) on fetal heart rate (FHR) pattern and fetal breathing movements (FBM). Methods: Prospective observational study of 75 pregnant women between 26 and 34 weeks’ gestation in whom pharmacological fetal lung maturation was clinically indicated. Forty-minute recordings were made of FBM or FHR patterns before and after drug administration. Twenty-five received TRH 400 µg as an intravenous bolus, 25 TRH 400 µg in 50 ml 0.9% saline as an intraveous infusion, and 25 acted as controls. Recordings were processed digitally to calculate the change in FHR (n = 45) and FBM parameters (n = 30). The main outcome measures for FHR were number of accelerations and decelerations, baseline rate, overall and short-term variation and duration of high and low variability, while for FBM they were rate, breath-to-breath interval and incidence. Results between groups were compared by analysis of variance. Results: There was no significant change in FHR, accelerations or variation in any of the groups. Similarly, there was no change in the incidence of FBM. TRH administered as a bolus produced a small statistically but not clinically significant increase in breathing rate (mean Δ = 35 breaths/h, p = 0.004), which was not seen in the TRH infusion and control groups. Conclusions: Maternally administered TRH as used to enhance fetal lung maturation has no clinically significant direct effect on FHR or FBM patterns.

Movement-related cortical potentials and contingent negative variation in olivopontocerebellar atrophy.

Movement-related cortical potentials (MRCPs) and contingent negative variation (CNV) were recorded in 8 cases of olivopontocerebellar atrophy (OPCA) and 8 age-matched healthy controls. The amplitude of the negative slope (NS') was smaller in the OPCA group than in the healthy control group. The amplitude of late CNV was smaller in OPCA group than in the healthy control group. These abnormalities in MRCPs and CNV were improved by intravenous infusion of thyrotropin releasing hormone.

P300 And cerebral blood flow before and after trh in olivopontocerebellar atrophy

Ten cases of olivopontocerebellar atrophy (OPCA) (mean age 56 × 9 years) and 8 healthy controls (mean age 58 × 9 years) were studied. The P300 was measured with a Synax 1100 evoked potential recorder and the regional cerebral blood flow was measured using the stable xenon computed tomography method. The P300 latency was significantly longer in the OPCA group than in the healthy control group. The P300 latency after the intravenous infusion of thyrotropin releasing hormone (TRH) in the OPCA group was significantly shorter than that before the intravenous infusion of TRH. The blood flows in all the measured areas (the cerebellar cortex, the cerebellar white matter, the brainstem, the thalamus, the basal ganglia, the frontal lobe cortex and the frontal lobe white matter) were significantly lower in the OPCA group than in the healthy control group. The blood flows in the cerebellar cortex and in the frontal lobe cortex after the intravenous infusion of TRH were significantly higher than those before the intravenous infusion of TRH. The prolongation of P300 latency in the OPCA group suggests that subclinical disturbance in recognition function is present in OPCA and may be related to the blood flow decrease outside the cerebellum.

Pituitary responses to thyrotropin releasing hormone stimulation in depressed women with thyroid gland disorders.

From an endocrine outpatient clinic and psychiatric outpatient clinic in Kaunas, Lithuania, 41 women with major depression were selected for study. Three groups of depressed women were established: 15 with autoimmune thyroiditis (AIT); 13 with diffuse non-toxic goiter (DNG); 13 with no thyroid disease (NTD). Standard biochemical tests were used to exclude patients with overt hypothyroidism or overt hyperthyroidism. At baseline the three groups were similar in age and almost identical in severity of depression. In part because of exclusion criteria, all baseline biochemical measures were similar. However, a slight elevation of thyroid-stimulating hormone (TSH) in the AIT group was noted and considered to indicate a tendency toward subclinical hypothyroidism. After thyrotropin-releasing hormone (TRH) administration, six AIT women and six DNG women, but no NTD women, showed blunted TSH responses. As a group DNG women showed smaller TRH responses than other women. Four AIT women showed exaggerated TSH responses. In all three groups basal TSH correlated positively with TSH response to TRH. Basal prolactin (PRL) responses to TRH infusion were similar in all three groups. However, the four AIT women with enhanced TSH responses also showed enhanced PRL responses. Indeed, in the AIT group, but only in this group, PRL responses were correlated with both TSH and basal TSH. In all groups of women the PRL response was unrelated to basal PRL.

Effect of continuous infusion of thyrotrophin-releasing hormone on plasma prolactin and on ovarian activity in melatonin-treated ewes.

Twelve anoestrous ewes maintained under natural photoperiod at 57 degrees N received an oral dose of 3 mg melatonin daily at 15:00 h from 1 May. Starting 41 days later and extending from 11 June until 5 September, six of the ewes were also infused continuously with 0.8 mg thyrotrophin-releasing hormone (TRH) day-1 via subcutaneous osmotic minipumps. The remaining six ewes acted as controls. Behavioural oestrus, ovulation rate and luteal function were determined by exposure to a vasectomized ram, laparoscopy and the measurement of progesterone in peripheral plasma, respectively. TRH infusion stimulated a sustained increase (P < 0.001) in plasma concentrations of thyroxine, tri-iodothyronine and prolactin (thyroxine: 158 +/- 9.3 and 65 +/- 7.7 nmol l-1 for TRH-infused and control ewes, respectively; tri-iodothyronine, 2.6 +/- 0.12 and 1.1 +/- 0.19 nmol l-1 and prolactin, 57 +/- 12 and 11 +/- 2 micrograms l-1). No ewes were in oestrus before TRH infusion and the mean number of behavioural oestrous cycles per ewe during the infusion period was 1.3 +/- 0.33 and 2.5 +/- 0.34 for TRH-infused and control ewes, respectively (P < 0.05). Corresponding mean intervals from 1 May to the onset of the first luteal phase (progesterone > 1 ng ml-1) were 88 +/- 8.9 and 79 +/- 3.5 days (not significant). TRH infusion had no effect on the mean numbers of corpora lutea (1.7 +/- 0.14 and 1.6 +/- 0.20 for TRH-infused and control ewes, respectively), but was associated with a lower mean incidence of normal luteal phases (1.5 +/- 0.43 versus 2.7 +/- 0.21, P = 0.052). Abnormalities in luteal function included delayed initial expression, extended ovarian cycles, suprabasal periovulatory progesterone concentrations and protracted periods of low progesterone secretion between successive ovarian cycles. Thus continuous TRH infusion suppressed plasma prolactin, doubled the circulating concentrations of thyroxine and tri-iodothyronine, and was associated with a wide range of abnormalities in ovarian function and endocrine status, the nature of which varied between ewes.

Sudomotor functional dissection of neurodegenerative diseases

We performed a quantitative sudomotor function test using thermal stimulation (40°C) and thyrotropin-releasing hormone (TRH) in 14 patients with multiple system atrophy (MSA), 10 patients with Parkinson's disease (PD), 11 patients with amyotrophic lateral sclerosis (ALS) and in 11 age-matched control subjects. There was thermal sudomotor dysfunction in the lower extremities of the MSA patients. The PD patients failed to increase their local sweating and frequency of sweat expulsions with TRH infusion, in spite of the fact that they still had normal thermal sweating. ALS patients had mild thermoregulatory sweat dysfunction in their lower extremities. These results suggest that in MSA the lesion most responsible for sudomotor dysfunction is the intermediolateral column cells of the spinal cord and postganglionic sympathetic neurons. There may be an impairment of TRH-induced sympathetic responses in PD, and there is a mild postganglionic sympathetic lesion in the lower extremities of ALS patients.

Thyrotropin-releasing hormone (TRH) and CNS regulation of anorectal motility in the rat

The effect of thyrotropin-releasing hormone (TRH) upon anorectal motility was investigated in acute male rat preparations. Micromolar doses of TRH were intrathecally (i.t.) infused at the L6 spinal level at a rate of 1 μl/min over 8 min. TRH infusions in 1.0–1000 μM concentrations elicited biphasic, dose-dependent anorectal contractions as measured by a rectal manometer. The 100 μM dose yielded the most significant increase in contractions over the greatest period of time. Atropine, administered as a pretreatment (100 μg s.c.), blocked contractions normally produced by i.t. infusion of TRH (1000 μM). Intravenous infusions of atropine (10 μg) through a jugular catheter immediately blocked anorectal contractions produced by i.t. infusion of 100 μM TRH. Sectioning of the hypogastric nerve, which supplies sympathetic innervation to the colon and internal anal sphincter, did not significantly affect contractions induced by 100 μM TRH applied intrathecally. Disruption of the major pelvic ganglion fibers, however, completely abolished the contractions induced by 100 μM TRH, either through the interruption of preganglionic parasympathetic fibers in the pelvic nerve, or by disrupting postganglionic fibers. These findings extend the role of TRH in the regulation of defecatory behaviors.

Copulsatile release of thyrotropin and prolactin in normal and hypothyroid subjects.

In healthy subjects, thyroid-stimulating hormone (TSH) and prolactin (PRL) are secreted in a pulsatile fashion. However, the factors that control the generation of these pulses are unknown. Since thyrotropin-releasing hormone (TRH) and dopamine (DA) affect levels of both hormones, pulsatile TRH or DA input to the pituitary gland may lead to pulsatile secretion of both TSH and PRL. In this case, TSH and PRL should exhibit significant nonrandom pulse concordance rates. To test this hypothesis, we studied 11 healthy subjects (5 women in the early follicular phase and 6 men) and 11 subjects with primary hypothyroidism (5 untreated and 6 euthyroid on 1-thyroxine therapy). To further test the specific hypothesis that pulsatile TRH entrains pulsatile TSH and PRL secretion, we restudied the 6 treated hypothyroid subjects on the final day of a 9-day constant infusion of TRH. In each study, blood samples were drawn every 15 min for 24 h, and TSH and PRL levels were measured by immunoradiometric assays. Hormone pulses were located by Cluster analysis. Nonrandom TSH and PRL pulse coincidence rates were assessed by a statistically based computer algorithm, which compares observed pulse concordance rates to those expected by chance. In the healthy men and women and the treated hypothyroid subjects, TSH and PRL were copulsatile in a significantly nonrandom fashion. Of TSH pulses 36-45% occurred within 15 min of PRL pulses, while 37-67% of PRL pulses occurred within 15 min of TSH pulses. Similar pulse concordance rates were seen in treated hypothyroid subjects receiving constant TRH infusions. Thus, there appears to be a central factor or factors that stimulate the copulsatile release of TSH and PRL. However, TRH does not appear to play a role in this phenomenon, and the underlying pulse generator(s) for both hormones remains to be elucidated.

Effects of acute ethanol administration and cold exposure on the hypothalamic-pituitary-thyroid axis

A single dose of ethanol increases cellular levels of the mRNA encoding thyrotropin-releasing hormone (TRH) in neurons of the paraventricular nucleus (PVN), but blocks the cold-induced increase in the levels of this mRNA. Because the thyrotropic response to cold is dependent upon TRH secretion, we hypothesized that ethanol uncouples the stimulus-induced regulation of TRH secretion from the stimulus-induced regulation of TRH expression. We employed two complementary strategies to test this hypothesis. The first was to determine whether ethanol alters pituitary sensitivity to TRH. Animals given a single intraperitoneal injection of ethanol (3 g/kg) that produced a blood alcohol concentration of nearly 300 mg/100 mL exhibited the same increase in circulating levels of TSH following an intravenous infusion of TRH. Thus, ethanol does not appear to alter pituitary sensitivity to TRH. Second, we tested whether ethanol blocks the cold induction of c-fos expression in TRH neurons of the PVN. Both cold exposure and ethanol induced the expression of c-fos in the PVN and in TRH neurons; the effects of cold and ethanol on c-fos expression were additive. Thus, ethanol clearly does not block the cold activation of TRH neurons.