TRH Injection Research Articles

Administration of sulpiride to anovulatory mares in winter: effects on prolactin and gonadotropin concentrations, ovarian activity, ovulation and hair shedding

Sixteen seasonally anovulatory mares were randomly allotted to two groups and injected daily with either sulpiride (1 mg/kg body weight) or vehicle from 14 January to 14 February. Sulpiride administration increased daily plasma prolactin concentrations ( P<0.05), although the prolactin response during the 6 h following sulpiride injections decreased markedly from the 1st to the 6th day of treatment (treatment by day, P<0.0001). Plasma concentrations of LH and FSH were not affected by treatment ( P>0.1). Injection of GnRH and TRH on 15 February showed that the response of plasma prolactin to secretagogue was increased in sulpiride-treated mares ( P<0.005), while there was no effect ( P>0.1) of sulpiride treatment on the response of LH or FSH. Both treatment groups had similar changes in numbers of follicles 10–19 and ≥20 mm during the experiment ( P>0.1). Similarly, the mean change in maximal follicular size was not affected by treatment ( P>0.9). No mare ovulated during the study, and plasma progesterone concentrations were similar in both groups ( P>0.1), always at levels <1 ng/ml. Hair shedding increased with time in all mares ( P<0.001) and was increased by sulpiride injections ( P=0.09). It was concluded that sulpiride administration to seasonally anovulatory mares under the conditions of our experiment increased daily plasma prolactin levels but did not stimulate gonadotropin secretion or ovarian activity.

Synergetic effect of pimozide and thyrotropin releasing hormone on prolactin and thyrotropin release during the drying off of ewes

The effect of pimozide and/or TRH was investigated on plasma prolactin, thyrotropin, T 4 and T 3 and udder distension in 38 ewes during drying off by feed restriction. The effect of daily injections of 2 mg pimozide (s.c.), combined or not with TRH stimulation (200 μg, i.v.) on three different days of the drying off period was examined. Blood samples were taken twice daily in each group for 9 days, while blood sampling on the days of TRH injection was also performed at 0, 15, 30 min, and 1, 2 and 4 h post-injection. Plasma was assayed for PRL, TSH, T 4 and T 3 levels. Udder distension and mastitis incidence were recorded at the end of the drying off period. TRH and pimozide both resulted in elevated plasma PRL levels and acted in a synergetic way. Udder distension and the incidence of mastitis was only influenced by pimozide. The TSH as well as the T 3 response to TRH was increased in ewes under a continuous influence of pimozide and T 3 peaks following TRH injection occurred earlier than T 4 peaks. The higher effect of pimozide upon TRH stimulated PRL and TSH release at day 8 compared to days 0 and 3 indicates a progressive involvement of dopamine on the inhibition of PRL and the sensitivity of the thyrotrophs to TRH during drying off.

Central hypocortisolism as part of combined pituitary hormone deficiency due to mutations of PROP-1 gene.

One of the causes of combined pituitary hormone deficiency (CPHD) is represented by Prophet of Pit-1 (PROP-1) gene inactivating mutations. This disorder is generally characterized by GH, TSH, prolactin (PRL), and gonadotropin deficiency, but recent papers have described a concomitant alteration of the corticotrope function. To make a detailed investigation of the hypothalamic-pituitary-adrenal axis in two sisters with PROP-1 gene mutations. Two female siblings (17 and 16 years old) with CPHD, belonging to a Brazilian family of consanguineous parents, presented with growth retardation and central hypothyroidism during childhood, and showed central hypogonadism at the age of puberty. No clear clinical symptoms and signs of hypocortisolism were present. GH, TSH, free thyroxine, total tri-iodothyronine, PRL, LH, FSH, ACTH and cortisol were measured in basal condition and after appropriate testing. The molecular study was performed by PCR amplification and sequencing analysis of PROP-1 gene. Both patients showed GH, PRL, LH and FSH deficiencies, associated with absent responses to an insulin tolerance test (ITT), TRH and GnRH injection. Circulating concentrations of TSH were normal in basal conditions, but failed to respond to a TRH test. Plasma ACTH concentrations were normal, but serum cortisol concentrations were below the lower limit of the normal range, showing a trend to decrease during 6 years of follow-up. The serum ACTH response to ITT was impaired, whereas its response to CRH was normal and prolonged. The cortisol response to both tests, and to the ACTH test, was clearly impaired. In both sisters, the genetic analysis showed the presence of a homozygous 2-bp deletion (296delGA) of PROP-1 gene, which results in the synthesis of a protein with no residual functional activity. In addition to GH, TSH, PRL and gonadotropin deficiency, patients with PROP-1 gene mutations can present with late-onset central hypocortisolism, possibly beause of the lack of important paracrine factors normally produced by the cells surrounding the corticotropes and absent in the pituitary of these patients, or because of progressive corticotrope apoptosis. This finding indicates the need for life-long endocrine monitoring of PROP-1-deficient patients.

Intraduodenal lipid inhibits central vagal stimulation of gastric acid secretion through activation of CCK a receptor in rats

Background: Intestinal lipids inhibit gastric acid secretion induced by meal in dogs and gastric emptying in rats via CCK and vagal capsaicin-sensitive afferent pathway (Lloyd et al: Gastroenterology, 102: 131,1992. Holzer et al: Am J Physiol267: G625, 1994). Intracisternal injection (ic) ofTRH is widely used to stimulate vagal efferent activity and mimics the cephalic phase of acid secretion. Aim: To investigate I) whether intraduodenal lipids inhibit central vagal gastric acid stimulation-induced by ic TRH analog; 2) whether CCK receptors are involved in these responses. Methods: Male SD rats (270-310 g) fasted for 24 h were anesthetized with urethane. Gastric acid secretion was induced by ic TRH analog, RX 77368 (5 ng) and measured by flushing the stomach through a gastric cannula. Intraduodenal (id) intralipid (0.5 ml) was administered through a duodenal fistula. Results: RX 77368 ic induced a net acid output of 56.8 ± 8.0 /Lmo1/90 min. CCK-8S (0.5 and 1 nmol/kg/h) iv infusion started 10 min before the ic RX 77368 inhibited the acid secretion by 23% and 82% respectively. The inhibitory action of CCK-8S was completely prevented by the CCK A receptor antagonist devazepide (l mg/kg) injected iv 10 min before the CCK-8S infusion. Intraduodenal intralipid (5%, 10% and 20%) administered 20 min before ic RX 77368 dose-dependently reduced by 24%, 83% and 100% the acid response and the inhibitory effect of intralipid was completely prevented by devazepide(l mg/kg). The CCK B receptor antagonist L-365260 (l mg/kg) had no effect on the inhibitory effect of intraduodenal lipid (Table). Conclusion: Intraduodenal lipid inhibits central TRH-induced gastric acid secretion through releasing endogenous CCK and the inhibitory action is mediated by CCK A receptors.

Effect of TRH on beta-gonadotropin subunits in patients with pituitary microincidentalomas.

To explore the hypothesis that most of the pituitary abnormalities compatible with the diagnosis of microadenoma, and detected in about 10% of the normal adult population, represent asymptomatic gonadotropinomas. Patients diagnosed with pituitary microincidentalomas at the Institute of Endocrinology of the Tel Aviv Medical Center were evaluated. Circulating beta-subunits of gonadotropin hormones were measured before and 30, 45, 60 and 90 min after the intravenous injection of 400 microgram TRH. Twenty-two patients with pituitary incidentaloma and 16 normal volunteers were tested. In 16 of the 22 patients, an abnormal beta-subunit response was detected after the TRH challenge. Three patients had an abnormal increase in both beta-FSH and beta-LH after TRH administration. Isolated pathological beta-FSH or beta-LH responses were demonstrated in five and eight patients respectively. Six patients had normal basal and stimulated gonadotropin subunit values, raising the possibility that their lesions were not pituitary microadenomas. There was a significant overall difference between the response to TRH of the patient and control groups. In the gonadotropin positive group, comprising 16 patients, serum beta-FSH increased from 6.4+/-1.6 ng/ml to 9.2+/-1.3 ng/ml (P=0.042) 1 h after TRH stimulation, whereas no changes were detected in the control group after TRH injection (basal: 4.1+/-0.8 ng/ml, peak: 5.1+/-0.8 ng/ml; P=0.15). Serum beta-LH increased from 10.5+/-3.2 ng/ml to 23.4+/-4.9 ng/ml (P=0.0037) at this time, in contrast to a lack of response in controls (basal: 6.4+/-1.5 ng/ml, peak: 8.2+/-2.3 ng/ml; P=0.24). In about 73% of patients with pituitary incidentalomas smaller than 10 mm, TRH elicits an increase in gonadotropin beta-subunits. This observation raises the possibility that non-functioning pituitary micro- and macroadenomas, which share a similar response to TRH, originate in a common ancestor cell type, probably a pituitary gonadotrope.

Time of Day-Dependent Effects of Thyroliberin and Thyrotropin on Thymocyte Proliferation in Rats

Our earlier studies have shown that thyroliberin (TRH) as well as thyrotropin (TSH) enhanced thymus cell proliferation. The aim of the present study was to investigate whether the effects of TRH and TSH on thymocyte proliferation depend on time of day. A single subcutaneous injection of TRH (25 μg/animal) or TSH (3 IU/animal) was made at 9:00 h (1 h after light onset) or at 18:00 h (10 h after light onset) in 3-month-old male Wistar rats. The animals were killed 24 h later. The proliferation of thymocytes was assessed by incorporation of bromodeoxyuridine into cell nuclei. Thymocyte proliferation was significantly increased by TSH administration at 9:00 h, whereas treatment given at 18:00 h was ineffective. TRH enhanced the proliferation when injected at 9:00 h, but had an inhibitory effect when administered at 18:00 h. These data indicate that the effects of TRH and TSH on thymocyte proliferation are dependent on time of day.

Electroconvulsive seizures increase levels of pGlu-Glu-Pro-NH2 (EEP) in rat brain

We have previously reported that electroconvulsive seizures (ECS) increases the level of prepro-TRH-derived peptides in hippocampus, amygdala and pyriform cortex but not the striatum of male rats and that this increase is significantly correlated with reduced immobility (increased swimming) in the Porsolt forced swim test. An abstract by Mabrouk and Bennett published in 1993 described increased locomotor activity in rats following IP injection of TRH (pGlu-His-Pro-NH2) and EEP (pGlu-Glu-Pro-NH2). We have examined the effect of three daily transcorneal ECS on the levels of EEP in various brain regions and their correlation with results from the Porsolt forced swim test. The EEP level (ng/g wet weight) was measured by RIA in 6 brain regions: amygdala (AY), hippocampus (HC), pyriform cortex (PYR), anterior cortex (AC), striatum (STR) and motor cortex (MC). ECS significantly increased EEP levels in AY, HC and PYR. The increased swim behavior following ECS, as measured in the Porsolt test, correlated significantly with the EEP levels in HC and MC within individual subjects. Intraperitoneal (IP) injection of EEP (1.0 mg/kg) resulted in a rapid and sustained rise in EEP levels throughout the brain and a clearance half-time from blood of 2.0 h. Intracardiac injection of 0.5 mg EEP resulted in a peak EEP level in CSF at 2 h followed by a t1/2 of 0.35 h. A 3 compartment model for EEP transport from blood into CSF and then brain was developed. This model revealed a 1.75 h delay in the transit time of EEP from blood to CSF followed by rapid clearance from the CSF but long retention time within various brain tissues. We conclude that (1) ECS significantly increases EEP levels in limbic regions, but not in striatum, of the rat brain, (2) EEP, like TRH, is a potential mediator of the antidepressant effect of ECS and (3) EEP, after IP or IV administration, is readily taken up by, and has a long residence time in, brain tissue.

Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats.

Cold exposure increases TRH gene expression in hypothalamic and raphe nuclei and results in a vagal activation of gastric function. We investigated the role of medullary TRH receptors in cold (4-6 C, 90 min)-induced stimulation of gastric motor function in fasted conscious rats using intracisternal injections of TRH receptor (TRHr) antisense oligodeoxynucleotides (100 microg twice, -48 and -24 h). The gastric emptying of a methyl-cellulose solution was assessed by the phenol red method. TRH (0.1 microg) or the somatostatin subtype 5-preferring analog, BIM-23052 (1 microg), injected intracisternally increased basal gastric emptying by 34% and 47%, respectively. TRHr antisense, which had no effect on basal emptying, blocked TRH action but did not influence that of BIM-23052. Cold exposure increased gastric emptying by 64%, and the response was inhibited by vagotomy, atropine (0.1 mg/kg, i.p.), and TRHr antisense (intracisternally). Saline or mismatched oligodeoxynucleotides, injected intracisternally under similar conditions, did not alter the enhanced gastric emptying induced by cold or intracisternal injection of TRH or BIM-23052. These results indicate that TRH receptor activation in the brain stem mediates acute cold-induced vagal cholinergic stimulation of gastric transit, and that medullary TRH may play a role in the autonomic visceral responses to acute cold.

Effects of TRH on gastric acid secretion: A model for human study

The possible effects of TRH administration on different parameters of gastric function were studied in 10 patients with different gastrointestinal complaints. Basal (BAO) and pentagastrin stimulated (6 μg pentagastrin/kg bw sc) maximal (MAO) acid output were determined and serum levels of TSH, total and free thyroxine (T4 and FT4), triiodothyronine (T3) were measured. After determinations of BAO and MAO and the hormones indicated above, one group of patients received a TRH injection (0.2 mg protirelin) intravenously. The second group of patients was injected with atropine (atropinum sulfuricum, 1 mg, iv). At different times following the injections in both groups of patients BAO, MAO and serum levels of TSH, total and free T4, T3, gastrin were determined. Injection of TRH resulted in an increase in TSH and with some delay in thyroxine and gastric acid levels. Atropine treatment was followed by a decrease in gastric acid secretion and a small decrease in TSH and no changes in the values of the other studied hormones. The results suggest a complex interrelationship between TRH, vagal system and pentagastrin-dependent gastric acid secretion operating in human subjects.

Intracisternal TRH and RX 77368 Potently Activate Gastric Vagal Efferent Discharge in Rats

O-Lee, T. J., J. Y. Wei and Y. TachÉ. Intracisternal Trh and Rx 77368 potently activate gastric vagal efferent discharge in rats. Peptides 18(2) 213–219, 1997.—The influence of intracisternal (ic) TRH and the stable TRH analog, RX 77368, on gastric vagal efferent discharge (GVED) was investigated in urethane-anesthetized rats. Consecutive IC injections of TRH (3, 30, and 300 ng) at 60 min intervals stimulated dose dependently multi-unit GVED with a peak increase of 90 ± 21%, 127 ± 18% and 145 ± 16% respectively. In two separate studies, IC injection of RX 77368 at 1.5 or 15 ng stimulated multi-unit GVED by 142 ± 24% and 244 ± 95% respectively. Saline injection IC had no effect on GVED. RX 77368 (1.5 ng, ic) action was long lasting (84 ± 13 min) compared with TRH (3 ng: 44 ± 7 min). Single-unit analysis also showed that 13 of 13 units responded to ic RX 77368 (1.5 ng) by an increase in activity. These data indicate that low doses of TRH injected ic stimulate vagal efferent outflow to the rat stomach and that RX 77368 action is more potent than TRH.

Percutaneous ethanol injection therapy for autonomously functioning thyroid nodule.

Four patients with solitary autonomously functioning thyroid nodule (AFTN; 2 toxic and 2 subclinically toxic) received ultrasonography (US)-guided percutaneous ethanol injection therapy (PEIT). The pretreatment scintigraphic appearance of the nodule was hot, and radioactivity in the extranodular tissue was completely suppressed throughout. Ninety-nine percent ethanol was slowly injected under US guidance. As a rule, the injection was performed in fractionated sessions and the treatment was repeated until the total amount of ethanol exceeded the baseline nodular volume. The therapy was successful. Complete remission of hyperthyroidism was observed among the patients with toxic nodule. The basal level of TSH and its response to TRH injection was normalized in the patients with subclinically toxic nodule. Posttreatment scintigrams revealed that the extranodular tissue recovered and radioactivity in the hot nodule had noticeably decreased. The rate of reduction in the nodular volume was more than 80% in all. There was no recurrence or development of hypothyroidism during a follow up of 10 to 23 months. The main side effect was mild and transient pain and/or a burning sensation at injection. No severe or permanent complications occurred. Although the number of our cases was small, the results suggest that PEIT is a useful program in treating AFTN.

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.

Two consecutive nucleotide substitutions resulting in the T3 receptor β gene resulting in an 11-amino acid truncation in a patient with generalized resistance to thyroid hormone

We identified unusual mutations in the T3 receptor (TR) β gene in a 6-year-old Japanese girl with generalized resistance to thyroid hormone. Two consecutive base substitutions, T to A and C to A at nucleotide positions 1637 and 1638, respectively, changed the 451st codon coding for Phe(TTC) to stop codon (TAA), resulting in an 11-amino acid carboxyl(C)-terminus truncation. The patient was a heterozygote. Western blotting using an anti-TR antibody demonstrated the truncated receptor protein. The patient showed severe mental retardation (IQ41), disturbance in speech development, and attention deficit hyperactivity disorder. Thyroid functional status by clinical evaluation was considered within the normal range in spite of high serum thyroid hormone levels (T4 725.9 nmol/l, T3 12.7 nmol/l, FT4 166.0 pmol/l). TSH increased from 0.6 to 24 mU/L after TRH (150 μg) injection. TSH secretion as well as 123I-uptake was suppressed only partially by T3 (75 μg/day for a week). Close examination of thyroid functions and TRβ gene analysis were not possible in the family, except for paternal grandmother and one of her two sisters who showed no abnormality. The patient's truncated TRβ showed very low T3 binding activity ( K a = 0.1 × 10 −10 M), transcriptional activity, and a very strong dominant negative effect. When co-expressed with wild-type TRβ at the molar ratio 1:1 in CV-1 cells, the mutant receptor inhibited the wild-type TRβ transcriptional activity by 74% at 10 nM T3. Even 1 μM T3 could not normalize these impaired functions.

Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone in juvenile obesity before and after hypocaloric diet

This study was performed on 36 obese subjects aged 8.5-17.4 yr, 14 boys and 22 girls (prepubertal: 5 boys and 5 girls [stage I, according to Tanner]; BMI: 35.5 +/- 1.4 [mean +/- SEM] and 35 +/- 1.3 respectively; pubertal: 9 boys and 17 girls [stage IV-V]; BMI: 36.2 +/- 1.8 and 36 +/- 1.5 respectively) before and after 8 weeks of a 1000 kCal/day diet. The responses of serum TSH and PRL to TRH (200 micrograms iv as a bolus) were evaluated as Area Under the Curve (AUC) and net increase in respect to basal values (delta TSH and delta PRL). Serum T4, fT4 and rT3 were assayed at the baseline and T3 and fT3 at the baseline and 120' after TRH injection. A similar analysis was performed on 14 age- and sex-matched lean subjects as controls. In females at baseline fT4 serum levels were greater than controls and were significantly reduced after weight loss; rT3 increased after weight loss in the whole study group. In patients of both sexes the PRL peak after TRH injection was earlier but not greater (15') than in controls (30'). After weight loss PRL peak after TRH was found at 30' (as controls) in females only. Taking into consideration the stage of pubertal development, the results were the following: a) in puberal girls, after weight loss, TSH and PRL peaks after TRH were delayed with respect to baseline and to the other considered subgroups; b) in prepubertal girls TSH and PRL peaks, delta TSH, delta PRL, AUC-TSH and AUC-PRL were blunted with respect to pubertal ones; c) the other considered variables were unchanged after the period of caloric deprivation. No correlation between BMI and the AUC of TSH and PRL was found. These data suggest that thyroid function is substantially normal in adolescent obese subjects and not influenced by a prolonged period of caloric restriction, even though a reduced hypothalamic dopaminergic tone on pituitary thyreotrophs and lactotrophs could cause subtle alterations on TSH and PRL release, partially influenced by gender and sexual development.

Characterization of the paradoxical growth hormone inhibitory effect of galanin in acromegaly.

Galanin is a 29-amino acid straight-chain biologically active peptide which has been found to decrease circulating GH levels in some acromegalic patients, whereas is able to increase GH secretion in normal subjects. The aim of our study was to ascertain the incidence, entity and mechanism of the paradoxical GH inhibitory effect of galanin in acromegaly also looking at possible correlations between the GH responses to galanin and the main clinical and biochemical features of the patients. Finally, the effects of either successful or unsuccessful neurosurgical intervention on the GH inhibitory effect of galanin in acromegaly were investigated. A series of 23 consecutive patients with active acromegaly seen at the Endocrine Section of the Department of Internal Medicine of the University of Brescia (Italy) between 1991 and 1994 was examined. The acromegalic patients were subdivided in group 1 (i.e. patients who were 1) untreated, 2) evaluated before surgery, and 3) not cured after surgery and radiotherapy) and group 2 (i.e. surgically cured). All patients were submitted at least once to the following biochemical and radiological evaluations: 1) baseline serum insulin-like growth factor-I and PRL samples, 2) iv infusion of synthetic porcine galanin (500 micrograms in 100 mL saline) from -10 to 30 min, 3) iv bolus injection of TRH (200 micrograms) at time zero, 4) oral glucose tolerance test (75 g glucose, orally) at time zero, and 5) magnetic resonance of the pituitary sella. Adenomatous tissue obtained during neurosurgery in four patients was cultured in vitro, and the effect of the addition of galanin in the culture medium on GH secretion was tested. During galanin infusion in 19 of 21 group 1 patients, serum GH levels were lower with respect to baseline (range of GH decrease, -6.2 to -85.4% with respect to basal levels). During galanin infusion, no reductions in GH levels were observed in the acromegalic patients cured after neurosurgery (group 2); on the contrary, 6 of 7 patients displayed a normal stimulatory response to galanin (range of GH increase, +120-1533.3% of the basal level). A significant correlation between the percent decrease in GH levels after galanin treatment and the percent increase after TRH was found in group 1 patients (r = -0.783; P < 0.05). In three of the four adenomas examined, galanin determined a clear decrease in GH secretion (mean nadir, 63.3 +/- 12% of the baseline secretion rate). In conclusion, we demonstrated that the large majority of numerous patients with active acromegaly show a decrease in serum GH levels after galanin administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical significance of the growth hormone response to vasoactive intestinal peptide and gonadotropin-releasing hormone in acromegaly

GH-secreting pituitary adenomas causing acromegaly can be classified into at least two types, i.e. the lactotroph-like adenoma and somatotroph-like adenoma. From a functional point of view, the lactotroph-like adenoma is characterized by positive GH responses to TRH and bromocriptine (Br) with a GH increase or decrease, respectively, whereas the somatotroph-like adenoma is characterized by a high GH response to GHRH and a low GH response to TRH and Br. In this study, we examined whether the loading of vasoactive intestinal peptide (VIP) and GnRH, another hypothalamic hormone capable of stimulating GH secretion in acromegaly, have a pathophysiological significance as TRH, GHRH, and Br tests. In 52 patients with active acromegaly, we performed iv bolus injections of TRH (500 μg), GHRH (100 μg), VIP (100 μg), and GnRH (100 μg), and a peroral administration of Br (2.5 mg), in order to compare the GH responses to these loads. There was a significant correlation that the higher was the GH response after TRH the greater was the GH decrease after Br. Although statistically insignificant, there was a trend (0.05 < p < 0.1) that the higher was the GH response after GHRH the smaller was the GH decrease after Br. In addition, as novel findings, we observed that the GH responses to GHRH, VIP, and GnRH were in significant positive correlations to each other, and that the higher were the GH responses after VIP and GnRH the smaller was the GH decrease after Br. In agreement with this, we also found that a simultaneous GH responsivity to VIP and/or GnRH in TRH-responsive acromegalics significantly enhanced the GH response to GHRH and lowered the Br responsiveness compared to the data of pure TRH-responders. From these results, we hypothesize that the positive GH responsiveness to VIP and GnRH, like that to GHRH, may be a feature of the somatotroph-like pituitary adenoma causing acromegaly. The present results appear to be of some help in understanding the basis of the great variabilities in the GH responses to various dynamic testings in acromegaly.

Unconsciousness due to Hyponatremia in a Patient of Short Stature with Panhypopituitarism

An unconscious woman of short stature (141 cm) was admitted to our hospital in March, 1994. She had hyponatremia (120 mEq/l) and had experienced massive bleeding during delivery. No increment of either plasma ACTH or cortisol levels was observed after insulin-induced hypoglycemia. However, urinary 17OHCS levels gradually increased after repeated intramuscular injections of ACTH. Plasma free T3 and free T4 levels were low. Neither plasma TSH nor prolactin (PRL) levels increased after an intravenous injection of TRH. Basal plasma LH, FSH and growth hormone (GH) levels were low and there were no observable responses to any of the stimulation tests. A magnetic resonance image (MRI) of her pituitary gland showed an empty sella. These results showed that she had a panhypopituitarism with primary empty sella. Replacement therapy with glucocorticoid was started and serum sodium levels normalized immediately. Levothyroxine was also administered. The possibility of pituitary dwarfism during her youth and a gradual postpartum reduction of other pituitary hormones may have caused an impairment of the hypothalamo-pituitary-adrenal axis.

Hyperthyroidism without Clinical Symptoms Found in Turner Syndrome During Human Growth Hormone Therapy

A nine-year-old Japanese girl with Turner syndrome (45, X/46, Xr (X)) showed poor GH secretion, normal response of TSH, and slightly increased secretion of LH and FSH with increased basic levels, after injection of insulin, TRH, and LH-RH respectively. Since then, r-hGH at 0.5 IU/kg/W has been given for five years under the diagnosis of pituitary dwarfism with Turner syndrome, and an increase of 26 cm in height has been obtained, though menstruation has not been observed till now. Autoimmune diseases such as diabetes mellitus, Addison's disease or thyroid dysfunction have not been observed, up to the age of 14 years. At 15 years, however, regular examination for side-effects of r-hGH revealed hyperthyroidism with 0.1 μU /ml of TSH, 15.7 μg/dl of T4, 4.22 ng/dl of free T4, positive thyroid test, positive microsome test, increased TSAb (1.4 μU/ml) and +32% of BMR, though she has not complained of any kind of clinical symptoms for six months.

Fluoxetine pretreatment potentiates intracisternal TRH analogue-stimulated gastric acid secretion in rats

Central injection of TRH or its metabolically stable analogue RX 77368 has been demonstrated to produce a vagal-dependent stimulation in gastric acid secretion. Accumulating evidence exists regarding the interaction of serotonin (5HT) with TRH containing neuronal systems. This study was performed to assess the effect of pretreatment with the 5HT uptake inhibitor fluoxetine on the TRH analogue-induced gastric acid secretory response. Systemic fluoxetine (30 μmol/kg, i.v.) produced a 43–85% increase in the intracisternal RX 77368 (78–780 pmol)-induced gastric acid output, while not affecting the basal acid response. The acid response to a lower dose of RX 77368 (26 pmol) was not altered. In addition, intracisternal fluoxetine (180 nmol) produced a 71% augmentation of the acid secretory response of i.c. RX 77368 (260 pmol). Intracisternal injection of lower doses (60, 120 nmol), or intravenous injection of 180 nmol of fluoxetine was ineffective in altering the intracisternal RX 77368-induced acid response. Pretreatment with the noradrenergic or dopaminergic uptake inhibitor desipramine or GBR 12909 did not alter the RX 77368-stimulated gastric acid secretory response. The results show that fluoxetine pretreatment potentiates the effect of intracisternal RX 77368 on acid secretion. The effect appears to be impulse dependent, and central sites of action are involved. The data suggest an interaction of synaptic serotonin with a RX 77368-elicited event (activation of TRH receptors, second messenger systems and/or firing of the motor vagus) results in potentiation of the RX 77368-induced gastric response.

Preferential release of tri-iodothyronine following stimulation by thyrotrophin or thyrotrophin-releasing hormone in sheep of different ages

The influence of TRH and TSH injections on plasma concentrations of tri-iodothyronine (T3) and thyroxine (T4) was investigated in neonatal (injection within 0.5 h after delivery) and growing lambs and in normal, pregnant and lactating adult ewes (all 2 years old and originating from Suffolk, Milksheep and Texal crossbreeds). Neonatal lambs had higher levels of T3, T4 and GH compared with all other groups, whereas prolactin and TSH were higher in lactating ewes. In all animals, injections of TRH increased plasma concentrations of prolactin and TSH after 15 min but not of GH at any time. Small increases in T3 and T4 were observed in neonatal lambs, without any effect on the T3 and T4 ratio, after prolactin administration, whereas prolactin did not influence plasma concentrations of T3 or T4 in all other experimental groups. Similar results for thyroid hormones were obtained after TRH or TSH injections. It was therefore concluded that the effects observed after TRH challenge were mediated by the release of TSH. With the possible exception of neonatal lambs, plasma concentrations of T3 after administration of TRH or TSH were always increased before those of T4; the increase in T3 occurred within 0.5-1 h compared with 2-4 h for T4 in all experimental groups. This resulted in an increased ratio of plasma T3 to T4 up to 4 h after injection. It is concluded that, in sheep, TRH and TSH preferentially release T3 from the thyroid gland probably by a stimulatory effect of TSH on the intrathyroidal conversion of T3 to T4.