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Background: So far, investigations of the relationships between suicidality and the activity of the thyrotropic and lactotropic axes are scarce and have yielded conflicting results., Methods: We studied the thyrotropin (TSH) and prolactin (PRL) responses to 0800h and 2300h protirelin (TRH) stimulation tests, carried out on the same day, in 122 euthyroid DSM-5 major depressed inpatients with suicidal behavior disorder (SBD) (either current [n=71], or in early remission [n=51]); and 50 healthy hospitalized controls., Results: Baseline TSH and PRL measurements did not differ across the 3 groups. In SBDs in early remission, the TSH and PRL responses to TRH tests (expressed as the maximum increment above baseline value after TRH [Δ]) were indistinguishable from controls. Current SBDs showed (1) lower 2300h-ΔTSH and lower ΔΔTSH values (differences between 2300h-ΔTSH and 0800h-ΔTSH) than controls and SBDs in early remission; and (2) lower baseline free thyroxine (FT 4B ) levels than controls. In the current SBD group, ΔΔPRL values (differences between 2300h-ΔPRL and 0800h-ΔPRL) were correlated negatively with lethality. Moreover, in current SBDs (1) violent suicide attempters (n=15) showed lower FT 4B levels, lower TSH-TRH responses (both at 0800h and 2300h), and lower ΔΔTSH and ΔΔPRL values than controls, while (2) non-violent suicide attempters (n=56) showed lower ΔΔTSH values than controls and higher TSH-TRH responses (both at 0800h and 2300h) than violent suicide attempters., Conclusions: Our results suggest that central TRH secretion is not altered in depressed patients with SBD in early remission. The findings that current SBDs exhibit both decreased FT 4B levels and decreased evening TSH responses (and consequently, decreased ΔΔTSH values) support the hypothesis that hypothalamic TRH drive is reduced-leading to an impaired TSH resynthesis in the pituitary during the day after the morning TRH challenge. In violent suicide attempters, the marked abnormalities of TRH test responses might indicate a greatest reduction in hypothalamic TRH drive. These results further strengthen the possibility that a deficit in central TRH function may play a key role in the pathogenesis of suicidal behavior., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Hyperthyrotropinemia, which can be either a permanent or a transient state, is an asymptomatic condition and there is a controversy in management and long-term consequences. The aim of this study was to evaluate the results of thyrotropin-releasing hormone (TRH) test in infants with hyperthyrotropinemia., Methods: Data of the patients who underwent a TRH test for mildly elevated thyroid-stimulating hormone (TSH) levels between 2004 and 2011 in a single academic pediatric endocrinology unit were retrospectively reviewed from the case files., Results: Twenty infants (13 female, 7 male) with the median (range) age of 33 days (25-50) were enrolled into the study. The median basal TSH was 7.0 mIU/L (4.9-8.9) and free thyroxine level was 1.4 ng/mL (1.2-1.6) at the time of the TRH test. Thyroid ultrasonography was performed to 10 of the cases, and one of them had thyroid hypoplasia. TRH test revealed normal results in four infants, while sixteen infants had exaggerated response suggestive of primary hypothyroidism. The median follow-up period was 3.5 years (2.3-3.7). Therapy was discontinued in seven cases (2 had normal TRH response, 5 had exaggerated response) with the median age of 3.2 years (2.5-4). Of these seven infants, three had an elevated TSH on follow-up and L-thyroxine was restarted. All of the infants, in whom therapy was restarted, had exaggerated response to TRH., Conclusion: TRH test response could be a useful diagnostic test to evaluate the persistence of the disease during the infantile age period.

Context: A recent trial showed that 1:3 μg:μg liothyronine (L-T3) substitution for levothyroxine (L-T4) achieving near-identical TSH levels resulted in a significant decrease in weight and cholesterol levels with no appreciable changes in cardiovascular parameters, suggesting a differential peripheral response to the therapy., Objective: We characterized the pituitary-thyroid axis in hypothyroid patients receiving equivalent doses of L-T3 or L-T4 by escalating-dose TRH stimulation test., Design: A secondary analysis of a L-T3 vs L-T4 therapy trial was performed., Setting: The study was conducted at the National Institutes of Health., Patients: Thirteen patients were studied., Interventions: Escalating-dose (5, 15, and 200 μg) TRH stimulation test on both treatment arms., Main Outcome Measures: Study outcomes were peak serum TSH concentration (Cmax), time to peak TSH concentration (Tmax), area under the curve from 0 to 60 minutes (AUC₀₋₆₀) after TRH injection., Results: Thirteen patients aged 51.2 ± 8.29 years completed escalating-dose TRH stimulation test. No significant difference between L-T3 and L-T4 treatments was observed in TSH Cmax or area under the curve. L-T4 resulted in a small but significantly shorter Tmax compared to L-T3 (3.5 ± 0.73 min on 200 μg TRH dose, P < .03). In addition, 5 μg TRH dose compared to 200 μg resulted in a shorter Tmax on both treatment arms (6.9 ± 0.59 min L-T3, 4 ± 0.3 min L-T4; P = .0002)., Conclusions: The assessment of the dynamic pituitary response to escalating doses of TRH confirms that substitution of L-T3 for L-T4 on a 1:3 ratio achieves a near-identical degree of pituitary euthyroidism. Furthermore, the data suggest that lower doses of TRH might provide clinically relevant information of thyrotroph function, particularly when investigating partial pituitary insufficiency states.

Six insulin-sensitive and 6 insulin-insensitive mares were used in a replicated 3 by 3 Latin square design to determine the pituitary hormonal responses (compared with vehicle) to sulpiride and thyrotropin-releasing hormone (TRH), 2 compounds commonly used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. Mares were classified as insulin sensitive or insensitive by their previous glucose responses to direct injection of human recombinant insulin. Treatment days were February 25, 2012, and March 10 and 24, 2012. Treatments were sulpiride (racemic mixture, 0.01 mg/kg BW), TRH (0.002 mg/kg BW), and vehicle (saline, 0.01 mL/kg BW) administered intravenously. Blood samples were collected via jugular catheters at -10, 0, 5, 10, 20, 30, 45, 60, 90, and 120 min relative to treatment injection. Plasma ACTH concentrations were variable and were not affected by treatment or insulin sensitivity category. Plasma melanocyte-stimulating hormone (MSH) concentrations responded (P < 0.01) to both sulpiride and TRH injection and were greater (P < 0.05) in insulin-insensitive mares than in sensitive mares. Plasma prolactin concentrations responded (P < 0.01) to both sulpiride and TRH injection, and the response was greater (P < 0.05) for sulpiride; no effect of insulin sensitivity was observed. Plasma thyroid-stimulating hormone (TSH) concentrations responded (P < 0.01) to TRH injection only and were higher (P < 0.05) in insulin-sensitive mares in almost all time periods. Plasma LH and FSH concentrations varied with time (P < 0.05), particularly in the first week of the experiment, but were not affected by treatment or insulin sensitivity category. Plasma GH concentrations were affected (P < 0.05) only by day of treatment. The greater MSH responses to sulpiride and TRH in insulin-insensitive mares were similar to, but not as exaggerated as, those observed by others for PPID horses. In addition, the reduced TSH concentrations in insulin-insensitive mares are consistent with our previous observation of elevated plasma triiodothyronine concentrations in hyperleptinemic horses (later shown to be insulin insensitive as well)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

At doses lower than those needed to stimulate prolactin release directly, TRH almost completely antagonizes the inhibitory effect of dopamine on prolactin release. We have previously reported that prolactin response to administration of 12.5 microg TRH i.v. correlates with prolactin response to 0.5 mg i.m. haloperidol and negatively with 24-h urinary excretion of HVA in normal subjects, suggesting that the response reflects dopamine activity. An association between central dopamine hyperactivity and SANS scores relating to poverty of content of speech and inattention has been suggested by studies utilizing methylphenidate administration in patients with first-episode schizophrenia. The hypothesis that small plasma prolactin responses to administration of 12.5 microg TRH i.v. (Delta prolactin) correlate with SANS scores for these symptoms was tested in 19 drug-naïve patients with first-episode schizophrenia. Significant negative correlations were found between the response and scores relating to poverty of content of speech (r = - 0.55, p = 0.014) and inattention (r = - 0.52, p = 0.022), supporting the hypothesis of increased dopamine activity in association with disorganization symptoms. A significant positive correlation between basal prolactin levels and prolactin response to stimulation by 12.5 microg TRH was also found (r = + 0.61, p = 0.0058). Our previous study in normal subjects found a similar positive correlation between basal prolactin levels and prolactin response to stimulation by 200 microg TRH i.v., but not by 12.5 microg TRH i.v. As far as we know, this is the first study to report an abnormality in TRH-induced prolactin release in acute schizophrenia.

It is known that ghrelin stimulates the secretion of prolactin in women. The aim of this study was to examine the effect of exogenous thyrotropin-releasing hormone (TRH) on ghrelin-induced prolactin release. Ten healthy normally cycling women were studied in four menstrual cycles. The women were injected intravenously in late follicular phase (follicle size 16-17 mm) with a single dose of normal saline (cycle 1), ghrelin (1 microg/kg) (cycle 2), thyrotropin-releasing hormone (200 microg) (cycle 3), and ghrelin plus thyrotropin-releasing hormone (cycle 4). Blood samples in relation to saline or drugs injection (time 0) were taken at -15, 0, 15, 30, 45, 60, 75, 90, and 120 min. The prolactin and growth hormone responses were assessed. After ghrelin administration (cycles 2 and 4), plasma ghrelin, serum prolactin, and growth hormone levels increased rapidly, peaking at 15-30 min (p<0.001). The injection of thyrotropin-releasing hormone (cycle 3) stimulated prolactin secretion markedly (p<0.001), but reduced growth hormone levels significantly (p<0.05). Ghrelin induced a smaller prolactin increase than thyrotropin-releasing hormone (p<0.05). The combination of ghrelin and thyrotropin-releasing hormone induced a similar increase in prolactin levels as with thyrotropin-releasing hormone alone. No changes in growth hormone and prolactin levels were seen after saline injection. These results demonstrate that the stimulating effect of ghrelin on prolactin secretion is not additive with that of thyrotropin-releasing hormone.

Energy expenditure and thermogenesis are regultated by thyroid and sex hormones. Several parameters of hypothalamic-pituitary-thyroid (HPT) axis function are modulated by 17β-oestradiol (E(2)) but its effects on thyrotrophin-releasing hormone (TRH) mRNA levels remain unknown. We evaluated, by in situ hybridisation and Northern bloting, TRH expression in the paraventricular nucleus of the hypothalamus (PVN) of cycling rats, 2 weeks-ovariectomised (OVX) and OVX animals injected s.c. during 1-4 days with E(2) (5, 50, 100 or 200 μg ⁄ kg) (OVX-E). Serum levels of E(2), thyroid-stimulating hormone (TSH), prolactin, corticosterone and triiodothyronine (T(3)) were quantified by radioimmunoassay. Increased serum E(2) levels were observed after 4 days injection of 50 μg ⁄ kg E(2) (to 68.5 ± 4.8 pg ⁄ ml) in OVX rats. PVN-TRH mRNA levels were slightly higher in OVX than in virgin females at dioestrous 1 or pro-oestrous, decreasing proportionally to increased serum E(2) levels. E(2) injections augmented serum T(3), prolactin, and corticosterone levels. Serum TSH levels augmented with 4 days 50 μg ⁄ kg E(2), but not with the higher doses that enhanced serum T(3) levels. Exposure to cold for 1 h resulted in marked HPT axis activation in OVX rats, increasing the levels of TRH mRNA along the rostro-caudal PVN areas, as well as serum TSH, T(3), corticosterone and prolactin levels. By contrast, no significant changes in any of these parameters were observed in cold-exposed OVX-E (50 μg ⁄ kg E(2)) rats. Very few PVN-TRHergic neurones expressed the oestrogen receptor type-α, suggesting that the effects of E(2) on PVN-TRH expression are indirect, most probably as a result of its multiple modulatory effects on circulating hormones and their receptor sensitivity. The blunted response of OVX-E rats to cold coincides with the effects of E(2) on the autonomic nervous system and increased cold tolerance.

In ruminant species photoperiod regulates prolactin (PRL) secretion. It is hypothesized that the inhibition of PRL secretion resides in dopaminergic neurons of the medial basal hypothalamus (MBH). To test this hypothesis, anterior (AHD), posterior (PHD) and complete (CHD) hypothalamic deafferentation and sham operation control (SOC) surgeries were carried out during May (long-day photoperiod) in beef heifer calves (6-8 mo old) to measure basal PRL secretion and PRL secretion as affected by intravenous secretagogues. On the day of surgery (day 0), PRL secretion reflected stress of anesthesia and surgery in all groups. Thyrotropin-releasing hormone (TRH), alpha-methyl-rho-tyrosine (alphaMrhoT), and haloperidol (HAL) was iv injected on days 11, 13 and 15, respectively. AHD, PHD, CHD, and SOC calves responded to TRH (100 microg) with an acute increase in PRL that peaked within 20 min. All heifers responded to alphaMrhoT (10 mg/kg BW) with an acute elevation in PRL within 10 min and remaining elevated for 3 h. HAL (0.1 mg/kg BW) induced an acute increase in PRL secretion in all groups, peaking within 15-30 min. Seven months later (December, short-day photoperiod) these heifers were ovariectomized. Basal plasma PRL levels were seasonally low, PRL secretion in AHD, PHD and CHD animals abruptly increased within 15 min to iv injection of 100 microg TRH to a greater amount than seen in SOC heifers. Although a biphasic effect on PRL secretion entrains under long-day and short-day photoperiods, hypothalamic deafferentation in cattle did not affect the pituitary gland's responsiveness to secretagogues.

The secretion of prolactin (PRL) is stimulated by thyrotropin-releasing hormone (TRH), and inhibited by dopamine (DA). However, we have recently demonstrated that salsolinol (SAL), a DA-derived endogenous compound, is able to stimulate the release of PRL in ruminants. The aims of the present study were to compare the characteristics of the PRL-releasing response to SAL and TRH, and examine the relation between the effects that SAL and DA exert on the secretion of PRL in ruminants in vivo and in vitro. Three consecutive intravenous (i.v.) injections of SAL (5mg/kg body weight (b.w.): 19.2micromol/kgb.w.) or TRH (1microg/kgb.w.: 2.8nmol/kgb.w.) at 2-h intervals increased plasma PRL levels after each injection in goats (P<0.05); however, the responses to SAL were different from those to TRH. There were no significant differences in each peak value between the groups. The rate of decrease in PRL levels following the peak was attenuated in SAL-treated compare to TRH-treated animals (P<0.05). PRL-releasing responses to SAL were similar to those to sulpiride (a DA receptor antagonist, 0.1mg/kgb.w.: 293.3nmol/kgb.w.). In cultured bovine anterior pituitary (AP) cells, TRH (10(-8)M) significantly increased the release of PRL following both 15- and 30-min incubation periods (P<0.05), but SAL (10(-6)M) did not increase the release during the same periods. DA (10(-6)M) completely blocked the TRH-induced release of PRL for a 2-h incubation period in the AP cells (P<0.05). Sulpiride (10(-6)M) reversed this inhibitory effect but SAL (10(-6)M) did not have any influence on the action of DA. These results show that the mechanism(s) by which SAL releases PRL is different from the mechanism of action of TRH. Furthermore, they also show that the secretion of PRL is under the inhibitory control of DA, and SAL does not antagonize the DA receptor's action.

Objective: Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). The objective of the study was to determine the mechanisms of hypothyroidism in PHP Ia., Design: A prospective study., Patients: Ten patients with PHP Ia., Measurements: The serum concentrations of TSH, free triiodothyronine (FT(3)), free thyroxine (FT(4)), and prolactin (PRL) were measured at baseline and after stimulation with TRH (200 microg i.v)., Results: The median basal serum TSH concentration was 4.92 mU/l. Basal serum TSH concentration was slightly elevated in eight patients (4.22-7.0 mU/l; normal range, 0.4-3.6 mU/l), normal in one patient (2.5 mU/l), and high in one patient (13.1 mU/l). After the TRH test, TSH concentrations increased to 13.4-36.0 mU/l (normal range, 4.0-20.0 mU/l). The absolute values after the test were normal in three patients and high in seven patients. However, TSH responses relative to the baseline value (stimulated/basal TSH and expressed as a fold increase), which reflect the relative increases after TRH stimulation, were low in seven patients (2.3- to 4.3-fold TSH) and normal in three patients. Basal FT(4) concentration was normal in seven patients and low in three patients (range, 8.4-20.0 pmol/l; mean, 14.1+/-4.3 pmol/l; normal range, 10.5-23.0 pmol/l). Basal FT(3) concentration was normal in nine patients and low in one patient (range, 0.9-5.0 pmol/l; mean, 3.8+/-1.1 pmol/l; normal range, 3.3-6.1 pmol/l). FT(4) and FT(3) were not significantly increased after the TRH test. PRL concentration was normal at baseline and increased from 7 to 96 ng/ml after TRH., Conclusion: Our results support the hypothesis that patients with PHP Ia have impaired sensitivity to both TSH and TRH.

Context: A shortage of thyroid hormone during prenatal life and the first years after birth results in a spectrum of neuropsychological disorders, depending on the duration and severity of the deficiency. In the case of congenital hypothyroidism of central origin (CH-C), the majority of patients have multiple pituitary hormone deficiencies (MPHD). This condition poses an additional threat to postnatal central nervous system development, primarily on account of neuroglycopenia due to ACTH/cortisol deficiency with or without additional GH deficiency. Therefore, in CH-C, rapid diagnosis is even more urgent than in congenital hypothyroidism of thyroidal origin., Objective: In the assessment of hypothalamic-pituitary-thyroid function, we considered the pituitary response to iv administration of TRH (TRH test) pivotal. We evaluated the usefulness of the TRH test in a cohort of infants with neonatal congenital hypothyroidism screening results indicative of CH-C by analyzing the results within the framework of investigations of the anatomical and functional integrity of the hypothalamo-hypophyseal system., Design and Setting: The study was a Dutch nationwide prospective study (1994-1996). Patients were included if neonatal congenital hypothyroidism screening results were indicative of CH-C and patients could be tested within 3 months of birth., Patients: Ten male and five female infants with CH-C, detected by neonatal screening, and six infants with false-positive screening results, nonthyroidal illness, or transient hypothyroidism, were included in the study., Main Outcome Measures: Results of TRH tests, within the framework of extensive endocrinological examinations and cerebral magnetic resonance imaging, were measured., Results: All patients with type 3 TSH responses to TRH had MPHD, and the majority (67%) of patients with type 2 responses had isolated TSH deficiency., Conclusions: The TRH test has a pivotal role in the diagnosis of TSH deficiency in young infants. Abnormal TRH test results, especially a type 3 response, urge immediate assessment of integral hypothalamic-pituitary function because the majority of patients have MPHD.

The response of the pituitary- thyroid axis, reverse triiodothyronine (rT3), prolactin, and growth hormone (GH) levels following TRH stimulus (Relefact TRH 200 microg 2 amp. i.v.) was examined in patients with autoimmune diabetes type 1 (DM1, n=30), with autoimmune thyroiditis (AT, n=25), and with concurrent DM1 and AT (n=22) to evaluate the influence of DM1 and AT of autoimmune pathogenesis on the above-mentioned hormonal parameters. Statistical analysis (ANOVA) showed that: a) the response of TSH did not differ from control groups (C); b) free triiodothyronine (fT3), free thyroxine (fT4) and their ratio in DM1, DM1+AT and C rose in 120 and 180 min, while a similar increase was not seen in AT (p<0.000001); c) rT3 was not present in any group, with rT3 levels higher in AT (p<0.00002) and lower in DM1 (p<0.02); d) the response of GH had a paradoxical character in some patients in all groups, most often in DM1 (52 %, DM1 vs C, p <0.01). The characteristic response difference was not in the peak GH level, but the delayed return to basal levels in DM1 (p<0.0001) and an abrupt one in AT (p<0.0001). The major findings in DM1 were the differences in GH response, while significant impairment of pituitary-thyroid axis and PRL response to TRH was absent. AT was associated with impairment of TRH stimulated fT3, fT4, fT3/fT4 response and changes in rT3 levels, in spite of preserved TRH-stimulated TSH secretion. GH response in AT patients was also altered.

We recently showed that diencephalic TRH may mediate the central leptin-induced pressor effect. Here, to study the role of TRH in obesity-induced hypertension (OIH), we used a model of OIH produced by a high-fat diet (HFD, 45 days) in male Wistar rats. After 4 wk, body weight and systolic arterial blood pressure (SABP) increased in HFD animals. Plasma leptin was correlated with peritoneal adipose tissue. Then, we treated OIH animals with an antisense oligodeoxynucleotide and small interfering (si)RNA against the prepro-TRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 h posttreatment. Similar effects were observed with siRNA against prepro-TRH but for up to 4 wk. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein, produced no changes. SABP decrease seems to be owing to an inhibition of the obesity-enhanced sympathetic outflow but not to an alteration in thyroid status. Using a simple OIH model we demonstrated, for the first time, that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity. Thus the TRH-leptin interaction may contribute to the strong association between hypertension and obesity.

ProThyrotropin-releasing hormone (proTRH) is a prohormone widely distributed in many areas of the brain. After biosynthesis, proTRH is subjected to post-translational processing to generate TRH and seven non-TRH peptides. Among these non-TRH sequences, we found previously that preproTRH178-199 could regulate the secretion of prolactin in suckled rats by their pups. Dopamine (DA), the main regulator of prolactin secretion, is produced in dopaminergic tyrosine hydroxylase (TH)-positive neurons in the hypothalamic arcuate nucleus (ARC). In this study we investigated whether prolactin release during the estrous sexual cycle is regulated by preproTRH178-199 through its effect on DA neurons of the ARC. We observed that biotinylated preproTRH178-199 bound to neurons in the ARC; this was higher during proestrus than during diestrus. Binding of preproTRH178-199 to DA neurons was seen only during proestrus in the ARC. Using primary neuronal hypothalamic cultures we found that preproTRH178-199 peptide decreased TH levels in a dose-responsive manner, whereas intra-ARC administration of preproTRH178-199 induced a 20-fold increase in plasma prolactin levels. Together, these results suggest a potential role for preproTRH178-199 in regulating dopaminergic neurons involved in the inhibition of pituitary prolactin release.

Objective: To detect any significant alteration of basal and TRH stimulated circulating prolactin levels in those with an extremely dense breast composition as compared to ones with a fatty pattern in mammography in climacteric patients with a low risk probability for developing invasive breast cancer within five years according to a validated risk model., Materials and Method: In this matched pairs case-control trial a total of 67 climacteric patients with an extremely dense breast composition were compared to a control group of 71 climacteric patients with an almost entirely fat pattern composition in terms of basal and TRH stimulated circulating prolactin levels. All participants in the study had an estimated 5 years breast cancer risk less than 1.67% according to the validated model of Gail. Subgroup analysis was done according to menopausal status (premenopausal versus postmenopausal) and according to the hormone replacement therapy (HRT) in postmenopausal patients (current users of HRT versus never used HRT)., Results: We did not detect any statistically relevant differences between groups or subgroups in terms of basal, stimulated and Delta levels (stimulated-basal) of prolactin (ng/ml). The differences between groups of extremely dense composition versus almost fatty pattern in terms of DeltaPRL (ng/ml) (+/-S.D.) were not statistically significant (68.1+/-34.5 versus 69.1+/-43.0; unpaired t test, Welch corrected p=0.88, 95% CI -12.1 to 14.0)., Conclusion: Our results do not suggest a contribution of circulating prolactin to increased mammographic density in climacteric patients with low risk probability to develop breast cancer. A study of similar kind is warranted in high risk patients.

Prolactin-releasing peptide (PrRP) was named for its originally reported effects as a prolactin (PRL) secretagogue in mammals. Carassius RFamide (C-RFa) is an orthologous PRL secretagogue in fishes and a gene encoding a 20-amino acid peptide of identical sequence is present in the chicken. These facts suggest that C-RFa is a putative chicken PrRP. However, no information is available for the physiological effects of C-RFa in chickens. Therefore, in the present study, we compared the effect of intracerebroventricular (ICV) injection of C-RFa and mammalian PrRP (mPrRP) on feeding behavior and plasma PRL, growth hormone (GH), and corticosterone (CORT) concentrations. ICV injection of C-RFa did not affect feeding behavior of chicks while mPrRP was stimulatory. The injection of C-RFa also did not significantly affect plasma PRL, GH, and CORT concentrations. In contrast, ICV injection of mPrRP exerted similar effects to those reported in mammals by increasing plasma CORT and decreasing GH concentrations. Additionally, the peptide induced an unexpected inhibitory effect on plasma PRL concentrations. Overall, these data suggest that an as yet unidentified peptide that shares some functional similarities with mPrRP is present in birds, but that the physiological role of the avian 20-amino acid C-RFa peptide remains to be determined.

We used our nonsurgical technique for collecting pituitary venous blood to relate the dynamics of thyrotrophin-releasing hormone (TRH) secretion to the secretion patterns of both prolactin and thyrotrophin in periovulatory mares, either euthyroid (n = 5) or made hypothyroid by treatment with propyl-thiouracil (n = 5). Pituitary venous blood was collected continuously and divided into 1-min aliquots for 4 h. To test the effect of dopamine on the relationship between secretion patterns, sulpiride, a selective D2 receptor antagonist, was given i.m. after 2 h of sampling. Thorough testing of the model and blood collection procedure revealed no sites of TRH loss. Hypothyroidism increased the mean secretion rates of TRH (P = 0.04) and thyrotrophin (P < 0.0001) but not prolactin. Sulpiride increased prolactin secretion rates in hypothyroid (P < 0.0001) and control (P = 0.007) mares, but did not alter TRH or thyrotrophin secretion rates. In both groups of mares, all three hormones were secreted episodically but not rhythmically. In both groups, the secretion pattern of TRH was almost always significantly related to that of thyrotrophin, as assessed by cross correlation and cross approximate entropy (ApEn) analysis. However, the degree of linear correlation was weak, with only 14% (hypothyroid) or 8% (controls) of the variation in thyrotrophin secretion rates attributable to TRH. Prolactin and TRH secretion patterns before sulpiride were coupled on cross ApEn analysis in both groups, and the minute-to-minute secretion rates of the two hormones were correlated in four hypothyroid and three euthyroid mares. Overall, the small, but significant, degree of association between TRH and prolactin was similar to that between TRH and thyrotrophin. In hypothyroid mares, sulpiride increased (P = 0.02) the synchrony between TRH and prolactin patterns. We conclude that in horses: (i) little TRH degradation occurs during passage through the pituitary or in blood after 1 h at 37 degrees C; (ii) TRH is not the major factor controlling minute-to-minute fluctuations in either thyrotrophin or prolactin; and (iii) reducing two strongly inhibitory inputs (i.e. dopamine and thyroid hormones) may magnify the stimulatory effect of TRH on prolactin secretion.

Dexamethasone suppression (DST), thyroid-stimulating hormone (TSH) and prolactin (PRL) responses to thyrotropin-releasing hormone (TRH) and growth hormone (GH) response to L-DOPA tests were evaluated in 19 depressed inpatients before the commencement of the antidepressant treatment and after the clinical response to examine: (i) the functional relationships among the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axis and dopaminergic system in depression, (ii) any alterations in these hormonal functions with the antidepressant treatment. TSH responses to TRH showed a tendency to increase from pre- to posttreatment period, while TRH-induced PRL and L-DOPA-induced GH responses did not change with treatment in depressed patients who responded to the treatment. Females showed significantly higher TSH and PRL responses to TRH compared to males. No interconnections were found among the responses in DST, TRH stimulation test and L-DOPA-induced GH test in the patients. The results do not support the interrelations between the abnormalities in the HPT and HPA axes and central dopaminergic activity in depression.

To determine the value of the TRH test, we analyzed the unstimulated serum T(4) and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T(4), total T(4), and basal TSH concentrations were 0.6 ng/dl, 4.0 microg/dl, and 2.8 microU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase (delta) in TSH, 4.5-17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk (deltaTSH, >17.8), absent/blunted (deltaTSH, <4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T(4) measurements.

Polychlorinated biphenyl compounds (PCBs) are global environmental contaminants that cause disruption of the endocrine system in humans and wildlife. Recently, we reported that acute exposures to ortho-PCB congeners 95 (2,3,6-2',5') or 101 (2,4,5,-2',5') causes changes in the performance of the hypothalamo-pituitary-thyroid (HPT)-axis in developing rats through mechanism(s) not yet clear. The functionality of the HPT-axis was evaluated by using the thyrotropin releasing hormone (TRH) test following acute exposure to PCBs 95 or 101. Weanling female rats received PCBs 95 or 101 intraperitoneally (ip) at 32 mg/kg for 2 consecutive days and synthetic TRH was given 48 h after the last dose. Serum thyroxine (T4) levels decreased following exposure to both the congeners. In PCB 95-treated rats, serum thyroid stimulating hormone (TSH) levels were elevated in response to TRH, but were only 40% of the control response to TRH. No significant changes were seen in serum prolactin (PRL), hypothalamic dopamine (DA), thyroid gland morphology, or epithelial cell proliferation. It is suggested that these congeners, interfere with the HPT-axis by causing a subnormal response of the pituitary and thyroid to TRH stimulation.

Light horse mares, stallions, and geldings were used to 1) extend our observations on the thyrotropin releasing hormone (TRH) inhibition of GH secretion in response to physiologic stimuli and 2) test the hypothesis that stimulation of endogenous TRH would decrease the normal rate of GH secretion. In Exp. 1 and 2, pretreatment of mares with TRH (10 microg/kg BW) decreased (P < 0.001) the GH response to exercise and aspartate infusion. Time analysis in Exp. 3 indicated that the TRH inhibition lasted at least 60 min but was absent by 120 min. Administration of a single injection of TRH to stallions in Exp. 4 increased (P < 0.001) prolactin concentrations as expected but had no effect (P > 0.10) on GH concentrations. Similarly, 11 hourly injections of TRH administered to geldings in Exp. 5 did not alter (P > 0.10) GH concentrations either during the injections or for the next 14 h. In Exp. 5, it was noted that the prolactin and thyroid-stimulating hormone responses to TRH were great (P < 0.001) for the first injection, but subsequent injections had little to no stimulatory effect. Thus, Exp. 6 was designed to determine whether the inhibitory effect of TRH also waned after multiple injections. Geldings pretreated with five hourly injections of TRH had an exercise-induced GH response identical to that of control geldings, indicating that the inhibitory effect was absent after five TRH injections. Retrospective analysis of pooled, selected data from Exp. 4, 5, and 6 indicated that endogenous GH concentrations were in fact lower (P < 0.01) from 45 to 75 min after TRH injection but not thereafter. In Exp. 7, 6-n-propyl-2-thiouracil was fed to stallions to reduce thyroid activity and hence thyroid hormone feedback, potentially increasing endogenous TRH secretion. Treated stallions had decreased (P < 0.01) concentrations of thyroxine and elevated (P < 0.01) concentrations of thyroid-stimulating hormone by d 52 of feeding, but plasma concentrations of GH and prolactin were unaffected (P > 0.10). In contrast, the GH response to aspartate and the prolactin response to sulpiride were greater (P < 0.05) in treated stallions than in controls. In summary, TRH inhibited exercise- and aspartate-induced GH secretion. The duration of the inhibition was at least 1 h but less than 2 h, and it waned with multiple injections. There is likely a TRH inhibition of endogenous GH episodes as well. Reduced thyroid feedback on the hypothalamic-pituitary axis did not alter basal GH and prolactin secretion.

The roles of endogenous angiotensin II (AII), thyrotropin-releasing hormone (TRH) and prolactin-releasing peptide (PrRP) on the estrogen-induced prolactin (PRL) surge and the diurnal change of tuberoinfundibular dopaminergic (TIDA) neuronal activity were assessed in this study. Ovariectomized, estrogen-primed rats implanted with intracerebroventricular cannula received daily injection of antisense oligodeoxynucleotide (ODN, 10 microg/3 microl) against the mRNA of AII, TRH or PrRP for two days. Artificial cerebrospinal fluid or the sense ODN were used as the control. In the first experiment, serial blood samples (0.3 ml each) were obtained hourly from each rat through a pre-implanted intraatrial catheter from 1100 to 1700h. Half of the rats pretreated with respective antisense ODN received single injections of AII, TRH or PrRP (1 microg each, i.v.) at 1400h. In the second experiment, groups of rats were decapitated either at 1000 or 1500h. The hypothalamic median eminence tissue of each rat was dissected out and its DOPAC content was used as the index for TIDA neuronal activity. Plasma and serum PRL levels were determined by radioimmunoassay. Pretreatment of antisense ODN against the mRNA of either AII or TRH significantly attenuated the PRL surge; replacement injection of AII or TRH restored the surge. The effect of antisense ODN against PrRP was less significant. None of the treatments significantly affected the diurnal changes of TIDA neuronal activity. In summary, both AII and TRH may play an important role as the PRL-releasing hormone involved in the estrogen-induced afternoon PRL surge.

A series of experiments was performed to determine the factor(s) responsible for an apparent inhibition of GH secretion in mares administered the GH secretagogue EP51389 in combination with GnRH, thyrotropin-releasing hormone (TRH), and sulpiride. Experiment 1 tested the repeatability of the original observation: 10 mares received EP51389 at 10 microg/kg BW; five received TRH (10 microg/kg BW), GnRH (1 microg/kg BW), and sulpiride (100 microg/kg BW) immediately before EP51389, and five received saline. The mixture of TRH, GnRH, and sulpiride reduced (P = 0.0034) the GH response to EP51389, confirming the inhibitory effects. Experiment 2 tested the hypothesis that sulpiride, a dopamine antagonist, was the inhibitory agent. Twelve mares received EP51389 as in Exp. 1; six received sulpiride before EP51389 and six received saline. The GH responses in the two groups were similar (P > 0.1), indicating that sulpiride was not the inhibitory factor. Experiment 3 tested the effects of TRH and(or) GnRH in a 2 x 2 factorial arrangement of treatments. Three mares each received saline, TRH, GnRH, or the combination before EP51389 injection. There was a reduction (P < 0.0001) in GH response in mares receiving TRH, whereas GnRH had no effect (P > 0.1). Given those results, Exp. 4 was conducted to confirm that TRH was inhibitory in vivo as opposed to some unknown chemical interaction of the two compounds in the injection solution. Twenty mares received TRH or saline and(or) EP51389 or saline in a 2 x 2 factorial arrangement of treatments. Injections were given separately so that the two secretagogues never came in contact before injection. Again, TRH reduced (P < 0.0001) the GH response to EP51389. In addition, TRH and EP51389 each resulted in a temporary increase in cortisol concentrations. Experiment 5 tested whether TRH would alter the GH response to GHRH itself. Twelve mares received porcine GHRH at 0.4 microg/kg BW; six received TRH prior to GHRH and six received saline. After adjustment for pretreatment differences between groups, the GHRH-induced GH response was completely inhibited (P = 0.068) by TRH. Exp. 6 was a repeat of Exp. 5, except geldings were used (five per group). Again, pretreatment with TRH inhibited (P < 0.0001) the GH response to GHRH. In conclusion, TRH inhibits the GH response not only to EP51389 but also to GHRH in horses, and in addition to its known secretagogue action on prolactin and TSH it may also stimulate ACTH at the dosage used in these experiments.

The authors examined the concentration of thyrotropic hormone (TSH) and prolactin (PRL) before and after stimulation with synthetic thyroliberine (0.2 mg TRH i.v.) in a group of 72 women with primary hypothyroidism (mean age 45 years, range 17-69 years) and 12 controls (mean age 35 years, range 17-49 years). According to the total thyroxin concentrations (TT4) and TSH they divided the group into three smaller subgroups: developed primary hypothyroidism (n = 8, mean age 50 years, TT4 < 65 nmol/l, basal TSH concentration > 15.0 mIU/l nmol/l), subclinical hypothyroidism, severe grade (n = 23, mean age 36 years, TT4 > 65 nmol/l, basal TSH concentration < 4.5 mIU/l), subclinical hypothyroidism mild degree (n = 39, mean age 42 years, TT4 > 65 nmol/l, basal TSH concentration < 4.5 mIU/l, TSH after TRH stimulation > 25 mIU/l). Mean basal PRL concentrations were in all three patient groups significantly higher than in the control group (P < 0.01) but mutually they did not differ significantly. Poststimulation PRL concentrations were also significantly higher than in controls however the values in developed hypothyroidism were significantly higher than in subclinical patients. No correlation was found between TSH and PRL concentrations.

Seventeen seasonally anovulatory light horse mares were treated daily, starting January 5 (d 1), for 28 d with GnRH analog (GnRH-A; 50 ng/kg BW) and(or) thyrotropin-releasing hormone (TRH; 5 microg/kg BW) in a 2 x 2 factorial arrangement of treatments to test the hypothesis that combined treatment may stimulate follicular growth and development. Ovaries were examined via ultrasonography and jugular blood samples were collected every 3 d. Frequent blood samples were collected after treatment injections on d 1, 2, 4, 7, 11, 16, and 22; on d 29, all mares received an i.v. mixture of GnRH, TRH, sulpiride, and EP51389 (a growth hormone secretagogue) to assess pituitary responsiveness. No consistent effects (P > 0.1) of treatment were observed for plasma LH, FSH, prolactin, or thyroxine concentrations in samples collected every 3 d. The only effect on ovarian follicle numbers was a reduction in number of follicles 11 to 19 mm in diameter due to TRH treatment (P = 0.029). No mare ovulated during treatment. On the days of frequent sampling, mean LH (P = 0.0001) and FSH (P = 0.001) concentrations were higher in mares receiving GnRH-A and tended to increase from d 1 through 7. In contrast, mean prolactin (P = 0.001) and thyroid-stimulating hormone (P = 0.0001) concentrations were high in mares receiving TRH on d 1 but rapidly decreased thereafter. When mares were administered the secretagogue mixture on d 29, the LH response was greater (P = 0.0002) in mares that had previously received GnRH-A but the FSH response was not affected (P > 0.1); the prolactin response was greater (P = 0.014) and the TSH response was smaller (P = 0.0005) in mares that had previously received TRH. Surprisingly, an immediate growth hormone response to EP51389 was absent in all mares. In conclusion, daily GnRH-A treatment stimulated plasma LH and FSH concentrations immediately after injection; although no long-term elevation in preinjection concentrations was achieved, the responses gradually increased over time, indicating a stimulation of gonadotropin production and storage. Daily treatment with TRH stimulated plasma TSH and prolactin concentrations, but the response diminished rapidly and was minimal within a few days, indicating a depletion of pituitary stores and little or no stimulation of production. There was no beneficial effect of adding TRH treatment to the daily GnRH-A regimen.

The aim of this study was to assess GH response to oral glucose tolerance test (OGTT) and TRH stimulation test in a group of 10 patients with active post-operative acromegaly before and after long-term slow-release (SR) lanreotide therapy (30 mg im every 10-14 days). Seven patients (2 males, 5 females, 29-71 yr), who during therapy maintained plasma GH and IGF-I concentrations under 5 microg/l and 450 microg/l, respectively, were considered as responders and studied for 24 (1 patient) to 36 months (6 patients). Three patients (1 male, 2 females, 46-61 yr) with levels of GH and IGF-I above those values were studied for 12 months. The OGTT (75 g po) and TRH test (400 microg iv) were repeated before and after 6, 12, 24 and 36 months. The GH response to OGTT was abnormal (nadir: >2 microg/l) at 6 and 12 months in poorly responsive patients. This response was normalized in all responsive patients. Nonetheless, 2 responsive patients showed abnormal GH values after OGTT once each throughout the 36-month study period. The GH response to TRH was characterized by great variability and exhibited unpredictable behavior throughout the study period both in responsive and in poorly responsive patients. Only 2 patients in the responsive group showed persistent normal GH levels (peak: < or =5 microg/l) after TRH for 3 yr. In conclusion, SR lanreotide treatment gave rise to a correct control of GH hypersecretion and to a normalization of GH response to oral glucose in 7 out of 10 patients, although it did not abolish the paradoxical reaction of GH to TRH in all responders. The effect of SR lanreotide on GH response to glucose tolerance test was not paralleled by GH response to TRH.

The authors evaluated serum level of prolactin (PRL) and interleukin 2 (IL-2) before and after i.v. application of tyreoliberin (TRH) 0.2 mg in 10 women as controls and 10 women with primary hypothyreoidism. In controls, there was a significant increase of IL-2 20 min following application of TRH (IL-2 0 min: 17.95 +/- 11.69, IL-2 in 20 min: 33.36 +/- 17.73 fmol/l), in patients with hypothyreoidism the serum level of IL-2 decreased (IL-2 0 min: 31.32 +/- 19.0, IL-2 in 20 min: 19.11 +/- 17.8 fmol/l). The basal concentration of IL-2 in patients with hypothyreoidism was significantly higher as in controls (p < 0.01). The presented finding indicated relation between the neuroendocrine and immune system but its value is not yet apparent. (Tab. 4, Fig. 1, Ref. 7.)

To define the role of somatostatin and dopamine in TSH suppression induced by L-thyroxine, 16 children (12 F, 4 M) on suppressive doses of L-thyroxine (3-4 microg/kg/day) for endemic goiter were studied. Firstly a conventional TRH test was performed in all subjects, in order to evaluate TSH, PRL and GH (basal study). A week later a second TRH test was carried out; one hour before the test, however, group A (9 patients) was given 60 mg pyridostigmine bromide po (pyridostigmine study) and group B (7 patients) 10 mg metoclopramide po (metoclopramide study). In the basal study, TSH was suppressed in both groups and levels did not increase following TRH administration, while PRL increased significantly and GH levels remained stable. In the pyridostigmine study, TSH levels did not increase following TRH administration, while PRL and GH levels were both significantly raised. In the metoclopramide study, TSH and GH levels were not raised following TRH administration, while a significantly greater increase of PRL was observed. In conclusion, suppressive doses of L-thyroxine inhibit the TSH response to TRH, while they do not seem to affect GH and PRL secretion. Somatostatin and/or dopamine do not seem to play a significant role in the L-thyroxine-induced TSH suppression.

Objective: Our aim has been to evaluate the effects of i.v. infusion of recombinant human erythropoietin (rhEPO) on the responses of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) stimulation in acromegalic patients., Methods: We studied 16 patients (8 females, aged 29-68 years) with active acromegaly and 12 control subjects (7 females, 24-65 years). All participants were tested with TRH (400 microg i.v. as bolus) and with TRH plus rhEPO (40 U/kg at a constant infusion rate for 30 min, starting 15 min before TRH injection) on different days. Blood samples were obtained between -30 and 120 min for GH and PRL determinations, and between -30 and 90 min for TSH determinations. Hormone responses were studied by a time-averaged (area under the secretory curve (AUC)) and time-independent (peak values) analysis., Results: Twelve patients exhibited a paradoxical GH reaction after TRH administration with great interindividual variability in GH levels. When patients were stimulated with rhEPO plus TRH there were no changes in the variability of GH responses or in the peak and AUC for GH secretion. Infusion with rhEPO did not induce any significant change in GH secretion in normal subjects. Baseline and TRH-stimulated PRL concentrations in patients did not differ from those values found in controls. When TRH was injected during the rhEPO infusion, a significant (P<0.05) increase in PRL concentrations at 15-120 min was found in acromegalic patients. Accordingly, the PRL peak and the AUC for PRL secretion were significantly increased in patients. Infusion with rhEPO had no effect on TRH-induced PRL release in control subjects. Baseline TSH concentrations, as well as the TSH peak and the AUC after TRH, were significantly lower in patients than in controls. Infusion with rhEPO modified neither the peak TSH reached nor the AUC for TSH secretion after TRH injection in acromegalic patients and in healthy volunteers., Conclusion: Results in patients with acromegaly suggest that (i) the paradoxical GH response to TRH is not modified by rhEPO infusion, (ii) rhEPO has no effect on TRH-induced TSH release, and (iii) acute rhEPO administration increases the TRH-induced PRL release in acromegalic patients.

The effects of TRH administration (400 microg, i.v.) on the release of prolactin were examined in 15 patients who met DSM-III-R criteria for panic disorder and 15 normal control subjects. Four hundred micrograms TRH was given via IV route. Blood samples were taken before TRH administration (baseline values) and at 15, 30 and 60 min. The results demonstrate that prolactin responses to TRH did not differ between panic disorder patients and normal control subjects. When only women were evaluated, the findings indicate that women with PD tend to show excessive prolactin responses to TRH. The findings are discussed in view of findings from earlier reports.

The present study examined in rats how prolactin-releasing peptide (PrRP), a new hypothalamic hormone, infused centrally during the dark period affects sleep and plasma levels of prolactin (PRL). At a dose of 0.1 nmol, PrRP increased only rapid eye movement (REM) sleep, whereas with 1.0 nmol both non-REM sleep and REM sleep were enhanced. However, 10.0 nmol of PrRP increased only non-REM sleep with a febrile response. The levels of plasma PRL were elevated during the infusion of PrRP with 0.1 and 1.0 nmol. Consequently, the increased release of PRL correlated with significant increases in REM sleep, but not in non-REM sleep.

Background: We recently have reported the first randomized, controlled study on the effects of short-term recombinant human growth hormone (rhGH|| therapy on the nutritional status of a group of malnourished adult dialysis patients. In order to evaluate whether rhGH administration exerts any influence on GH, thyrotropin (TSH|| and prolactin (PRL|| responses to TSH-releasing hormone (TRH||, we assessed these responses before and after rhGH therapy., Methods: GH, PRL and TSH responses to TRH before and 1 month after rhGH therapy in a group of adult dialysis patients were evaluated. Seventeen dialysis patients (11 on continuous ambulatory peritoneal dialysis/six on haemodialysis|| were studied (rhGH group, n=8; control group, n=9||. In the rhGH group, 0.2 IU/kg/day rhGH was administered subcutaneously. Each patient was tested with TRH (400 microg bolus i.v.|| on two separate occasions, just before and immediately after the treatment period., Results: rhGH treatment did not modify baseline serum GH concentrations (6.6+/-2.7 vs 4.1+/-1.1 microg/l||, paradoxical GH responses to TRH (six out of eight patients||, GH peak (11.9+/-4.6 vs 11.2+/-5.3 microg/l, NS|| or area under the secretory curve of GH (GH AUC; 19.1+/-4.5 vs 12.1+/-3.1 microg/h/l||. Both basal PRL (35.5+/-7.1 vs 36.7+/-8.6 microg/l|| and TSH (2.3+/-1.1 vs 2.8+/-1.7 mU/l|| concentrations, as well as their responses to TRH stimulation (PRL peak, 59.9+/-16.6 vs 59. 5+/-11.8 microg/l; TSH peak, 6.2+/-2.6 vs 7.1+/-3.9 mU/l||, were also unaffected by rhGH therapy., Conclusion: These results suggest that short-term rhGH therapy does not significantly influence the magnitude of the somatotropic, lactotropic or thyrotropic response to TRH in adult dialysis patients. However, this finding has to be interpreted with caution due to the two different patient groups included in this study.

Leptin, a hormone which is produced by adipose tissue, has been shown to inhibit food intake, increase energy expenditure and influence the function of hypothalamo-pituitary-gonadal, -thyroid, and -adrenal systems. We have examined the association between leptin concentrations (RIA method) and levels of different hormones using standard Gn-RH, TRH and CRF tests (at 0, 30, 60, and 120 min) in regularly menstruating 10 lean and 10 obese premenopausal women in follicular phase. FSH, LH, estradiol (E2) and progesterone (P) concentrations in Gn-RH test; TSH, PRL, fT3, fT4 in TRH test; ACTH, DHEA-S, cortisol in CRF test were measured by RIA, ELISA or IRMA methods. The obese subjects had thicker four skinfolds, higher fat content in the body, and bigger BMI, compared to the lean females. Gn-RH test: We have noted higher basal leptin values in obese women than in lean subjects, which was stable during the Gn-RH test. In the same blood specimen, basal insulin concentrations did not differ between the tested groups of patients. There were no correlations between E(2), P, or gonadotropins and plasma leptin concentrations between both groups of patients. We have revealed the negative correlation between LH mobilization (maximal incremental values over basal levels; Delta%) and baseline leptin concentrations in all observed subjects. TRH test: In both groups of patients the leptin levels decreased at 120 min of TRH administration. We have noted diminished PRL and TSH mobilisation in obese subjects in comparison to the controls. In all females (n = 20) the correlations between TSH or PRL mobilization and BMI, skinfold thickness and the mass of body fat in kg were negative. In obese subjects only we observed the positive correlations between fT(3)concentrations at 60 and 120 min of the test or Delta% of fT(3)and leptin levels. CRF test: In obese females, we noted higher basal ACTH and cortisol concentrations with decreased mobilization (Delta%) of ACTH or cortisol, as compared to the controls. Basal leptin values were also higher in obese women comparing controls and did not significantly change within 2 h after CRF injection. In all the observed subjects (n = 20), we noted positive correlations between baseline values of leptin and ACTH, as well as negative correlation between basal concentrations of leptin and mobilisation of cortisol. The obtained results show that the hypothalamic neuropeptides may influence leptin secretion in humans., (Copyright 2000 Harcourt Publishers Ltd.)

Previous in vitro studies have demonstrated zinc (Zn++) inhibition of basal and of potassium (K+) or thyrotropin-releasing hormone (TRH)-stimulated prolactin (PRL) secretion, in a selective, reversible, and dose-dependent manner. Thus, Zn++ may regulate physiologically pituitary PRL secretion. Furthermore, studies with patients with uremia, cirrhosis or prolactinoma, have shown the coexistence of hypozincemia and hyperprolactinemia and zinc supplementation did not correct hyperprolactinemia in these patients. In normal individuals Zn++ administration produced controversial results on PRL secretion. Here, we investigated whether zinc administration affects TRH-stimulated PRL in healthy men. We found that Zn++ administration does not change the TRH-stimulated PRL. Therefore, in normal conditions, Zn++ does not inhibit TRH-stimulated prolactinemia. In addition, we found that acute increases of blood PRL and TRH do not alter blood Zn++ levels.

Acetylcholine (ACh), synthesized in the pituitary, can act locally to modulate pituitary function. We used rat primary anterior pituitary (AP) cells to investigate how ACh affects pituitary prolactin (PRL) secretion in the presence or absence of known PRL regulators: thyrotropin-releasing hormone (TRH), 17beta-estradiol (E(2)) and triiodothyronine (T(3)). Cultured AP cells were prepared from ovariectomized rats and pretreated with diluent, 0.6 nM E(2), 10 nM T(3), or E(2) plus T(3) for 5 days, then challenged with various doses of ACh or muscarinic receptor agonists (oxotremorine or carbachol) and TRH (100 nM) for 20 min. Significant ACh (10(-5) M) suppression of both basal and TRH-induced PRL secretion was not evident in diluent-, E(2)- or T(3)-pretreated cells, but observed only in cells pretreated with both E(2) and T(3). Moreover, in E(2) plus T(3)-pretreated cells, oxotremorine and carbachol, like ACh (10(-7)-10(-5) M), suppressed both responses in a dose- related manner. Pertussis toxin (PTX; 100 ng/ml) as well as atropine (a muscarinic receptor antagonist; 1 mM) blocked these effects of cholinomimetics. ACh also inhibited both PRL responses elicited by drugs elevating intracellular cAMP (10 microM forskolin) or Ca(2+) (1 microM Bay K-8644) in a PTX-sensitive manner. ACh inhibition of basal PRL secretion was unaltered by intracellular Ca(2+) mobilization blockers, TMB-8 (100 microM) and thapsigargin (1 microM), but abrogated by the nitric oxide synthase inhibitor (300 microM L-NAME). ACh inhibition of TRH-induced PRL secretion was accentuated by TMB-8 and alleviated by thapsigargin or L-NAME. In summary, muscarinic inhibition of either basal or TRH-induced PRL secretion was augmented by E(2) and T(3), and involved the PTX-sensitive cAMP/Ca(2+) pathways. Furthermore, nitric oxide mediated the basal rather than TRH-induced PRL response to ACh, whereas the intracellular Ca(2+) mobilization concerned the TRH-induced rather than the basal PRL response to ACh. Thus, ACh synthesized in the AP appears to inhibit basal vs. TRH-induced PRL secretion via different mechanisms., (Copyright 1999 S. Karger AG, Basel.)

Background: In patients with hyperprolactinemia, the thyrotropin-releasing hormone (TRH) stimulation test is widely applied to distinguish prolactinoma from other causes of hyperprolactinemia. In the present study, we established reference values for the plasma concentration of prolactin (PRL) and its response to TRH., Methods: Basal PRL and the PRL response to 400 micrograms TRH i.v. was determined in 50 subjects recruited from the general population, equally distributed according to sex and age between 20 and 69 years. PRL was determined by a fluoroimmunometric assay. Reference values are given as the observed range., Results: Plasma concentrations of PRL were 4.0-25 micrograms/l (median: 10.0 micrograms/l) in women and 0.5-19.0 micrograms/l (median: 8.5 micrograms/l) in men (p = 0.11). The peak PRL concentration after stimulation with TRH was slightly higher in women (median: 51 micrograms/l) than in men (median: 41 micrograms/l; p = 0.04) and was reached at t = 20 min in all subjects. The relative increase in plasma PRL (median: 440%) did not show a statistically significant effect of age or sex. In 12 subjects (24%), the relative increase in plasma PRL was lower than 250%, which has traditionally been considered the minimum cutoff for a normal response. There were no effects of smoking and alcohol, but regular ingestion of liquorice was associated with lower basal (p = 0.03) and lower stimulated (p = 0.05) plasma concentrations of PRL., Conclusions: The present study provides reference values for basal and TRH-stimulated plasma concentrations of PRL.

Functional interaction between the immune and neuroendocrine systems is mediated by humoral mediators, neurotransmitters, and cytokines, including TRH and PRL. We examined the role of neuroendocrine changes, particularly TRH and PRL, during the T cell-dependent immune response. After immunization of rats with sheep red blood cells (SRBC, a T cell-dependent antigen), an increase of hypothalamic TRH messenger RNA (mRNA) was observed at 4-24 h post immunization, in contrast to the decrease observed after treatment with lipopolysaccharide (LPS). During the above period, with SRBC, there was an increase in pituitary TRH receptor mRNA and plasma PRL levels but no changes in TSH and GH. Also, in contrast to the early corticosterone peak induced by LPS, the activation of the hypothalamic-pituitary-adrenocortical suppressive response appears in a late phase, 5-7 days after SRBC. Intracerebroventricular injection of antisense oligonucleotide complementary to rat TRH mRNA in conscious freely-moving rats immunized with SRBC resulted in a significant inhibition of specific antibody production and a concomitant inability to produce the peak in plasma PRL levels. These studies demonstrate, for the first time, that the T cell-dependent immune response is critically dependent on the early activation of TRH and PRL and that the neuroendocrine changes occurring during it are profoundly different from those occurring during the T cell-independent and inflammatory responses (LPS model).

The hypothesis that glucocorticoids have a direct central inhibitory effect on the reproductive axis is sutained by the identification of glucocorticoid receptors on GnRH-secreting neurons and gonadotropic pituitary cells. It has been proposed that glucocorticoids and opioids interact centrally in the regulation of the GnRH-LH axis. The inhibitory effect of glucocorticoids may manifest not only directly through the hormone-receptor link, but also indirectly through an increase in opioid tone. The aim of this study was to evaluate the role of glucocorticoids and glucocorticoids combined with an opioid antagonist, in the regulation of basal and GnRH- and TRH-stimulated secretion of LH, FSH and Prl in 7 women with normal menstrual cycles. Blood samples were obtained every 10 min for an hour. GnRH (50 microgram) and TRH (200 microgram) were administered and blood sampling was continued every 15 min for 2 h (day 1). At 5 a.m. the next day, naltrexone (50 mg) was given and at 8 a.m. the GnRH-TRH test was repeated (day 2). At 5 a.m. on day 3, the patients took 2 mg oral dexamethasone and the test was repeated. At 5 a.m. on day 4, the patients took naltrexone and dexamethasone and at 8 a.m. the GnRH-TRH test was repeated. Administration of naltrexone did not cause significant changes in basal concentrations of LH and FSH and their response to GnRH. The area under the curve of the LH response to GnRH on day 3 was significantly less than on days 1, 2 and 4. Administration of naltrexone (day 2) did not cause any significant increase in basal and TRH-stimulated levels of Prl with respect to day 1. On day 3, dexamethasone caused a reduced response of Prl to TRH. Pretreatment with naltrexone (day 4) prevented this reduction. These results suggest that suppression of the response of LH to GnRH induced by dexamethasone may be partly mediated by endogenous opioids. Dexamethasone led to a reduction in the response of Prl to TRH, and naltrexone blocked this suppression. Hence the suppression of Prl and LH by dexamethasone must be partly mediated by endogenous opioids, which must therefore inhibit pituitary secretion of Prl.

To evaluate the integrated hypothalamic-pituitary function of euprolactinemic secondary amenorrhea, blood samples of 23 patients were taken every 15 min for 4 hours in examination of pulsatile LH, FSH, PRL secretions and then 2 hours GnRH, TRH tests were performed. Nine normal cycling women (group I) served as the controls. Thirteen amenorrheic women (group II) revealed responsive bleeding to progestin injection and the other 10 women (group III) were nonresponsive. The LH frequency, amplitude, and LH response to GnRH of groups II and I were comparable, whereas delta PRL after TRH in group II (60.8 +/- 18.9 ng/ml) exhibited a significantly (P < 0.05) exaggerated response, as compared with that of group I (43.6 +/- 11.4 ng/ml). The LH frequency (1.3 +/- 0.4/4h) and amplitude (1.7 +/- 0.4 mIU/mL) of group III were significantly lower (P < 0.01) than those in group I (2.4 +/- 0.5 and 2.5 +/- 0.5, respectively), but their delta LH and delta FSH responses to GnRH showed no differences from those of controls. The frequency, amplitude of PRL and delta PRL response to TRH in group III were no significant difference with those of group I. These results suggest that masked PRL hypersecretion and loss of the regulatory pulsatility of gonadotropin release may be responsible in part for the causes resulting to euprolactinemic secondary amenorrhea. The analysis of these hormonal environments is useful for the understanding of clinical perspectives, pathophysiology and management.

Because of its ability to cause the release of thyrotropin (TSH), prolactin (PRL), and, under particular circumstances, also of other adenohypopyseal hormones, from the pituitary, thyrotropin-releasing hormone (TRH) has been widely used as a diagnostic tool for about 30 years. The recent introduction of an ultrasensitive TSH assay, able to clearly distinguish suppressed from unsuppressed TSH levels, has rendered the use of the TRH test obsolete in the diagnosis of classic hyperthyroidism. On the contrary, the TRH test is still extremely useful in hyperthyroid patients with inappropriate secretion of thyrotropin, allowing the distinction between TSH-secreting pituitary tumors (usually unresponsive) and the pituitary variant of resistance to thyroid hormone (PRTH) syndrome (always responsive). In hypothyroidism, the TRH test is still of value in patients with preclinical primary hypothyroidism, as they show exaggerated TSH response, and in those with central hypothyroidism, allowing the differentiation between pituitary (secondary) and hypothalamic (tertiary) hypothyroidism. The availability of high-resolution imaging techniques such as magnetic resonance has rendered the use of the TRH test obsolete, to distinguish microprolactionomas from functional hyperprolactinemia. The TRH test still has great clinical value in the follow-up of patients with pituitary tumors (in particular somatotropinomas and clinically nonfunctioning pituitary adenomas) showing abnormal responses of anterior pituitary hormones other than TSH.

The mechanism of action of the synthetic growth hormone (GH)releasing peptide hexarelin is not yet fully understood. Although a direct effect on pituitary cells has been demonstrated, the peptide is also active at hypothalamic level, where specific binding sites have been found. The observation that hexarelin acts synergistically with GH-releasing hormone (GHRH) in releasing GH has suggested that it might suppress endogenous somatostatin secretion. As somatostatin is also inhibitory on TSH secretion, to verify the occurrence of modifications of the somatostatinergic tone induced by hexarelin, we studied its effects on TRH-induced TSH secretion. Seven normal subjects (4 women and 3 men aged 24-29 years) underwent the following tests on 3 different days: a) TRH (200 micrograms/l i.v.) + placebo; b) hexarelin (1 microgram/Kg bw i.v.) + placebo c) combined TRH + hexarelin administration. Hexarelin induced significant and similar increases in serum GH levels when given in combination either with placebo or with TRH (1217 +/- 470 vs 986 +/- 208 micrograms/min/l p:NS), while no modifications of GH levels were seen after TRH + placebo. Serum TSH levels were unmodified by hexarelin + placebo injection. The TSH increase elicited by hexarelin + TRH was superimposable to that elicited by TRH + placebo (1124 +/- 530 and 1273 +/- 380 mU/min/l respectively). Circulating PRL levels slightly increased after hexarelin + placebo too (897 micrograms/min/l), and the PRL response to hexarelin + TRH was slightly, although not significantly, greater than that observed after TRH + placebo (2680 +/- 1517 and 2243 +/- 1108 micrograms/min/l, respectively). In conclusion, our data show that hexarelin does not alter basal and TRH-stimulated TSH secretion, thus suggesting that it does not inhibit somatostatin release. Furthermore a modest PRL-releasing effect of this peptide has been confirmed.

The effect of thyrotropin-releasing hormone (TRH; 200 ng i.c.v.) on oxytocin (OT), vasopressin (AVP) and prolactin (PRL) release was estimated in female Wistar rats during midlactation. The hypothalamo-neurohypophysial radioimmunoassayed OT and AVP storage as well as blood plasma level of both neurohypophysial hormones and PRL in females suckled or not suckled have been studied. I.c.v. administration of TRH increased AVP content both in the hypothalamus and neurohypophysis of suckled females; however, plasma AVP level did not change. TRH increased the hypothalamic as well as neurohypophysial OT content during suckling. Simultaneously, TRH inhibited OT release into the blood plasma. On the contrary, in not suckled females TRH increased OT plasma concentration. I.c.v. TRH raised the PRL concentration in plasma of lactating but, at the moment, not suckled females. On the contrary, i.c.v. TRH injection into females just suckled was followed by a decrease in PRL plasma level. TRH probably acts in the central nervous system as an inhibitory neuromodulating factor for the vasopressin release. Also, it cannot be excluded that TRH--otherwise known to enhance the PRL release--suppresses the oxytocin-prolactin positive feedback mechanism when activated temporarily by suckling.

Objective: Our purpose was to determine the transplacental transfer of thyrotropin-releasing hormone at the time of fetal blood sampling., Study Design: Four hundred micrograms of thyrotropin-releasing hormone was given intravenously to 13 pregnant women between 24 and 35 weeks' gestation and maternal-to-fetal transfer of thyrotropin-releasing hormone was determined at fetal blood sampling 1 to 93 minutes later. The fetal thyrotropic response to thyrotropin-releasing hormone was determined by measuring thyroid-stimulating hormone, thyroxine, and prolactin. For comparison, endogenous fetal and maternal levels of thyrotropin-releasing hormone, thyroid-stimulating hormone, thyroxine, and prolactin levels were determined in a further 20 patients undergoing fetal blood sampling between 19 and 35 weeks' gestation. The concentration of thyrotrophin-releasing hormone was measured by radioimmunoassay and thyroid-stimulating hormone, thyroxine, and prolactin by chemiluminescence assay., Results: Thyrotropin-releasing hormone was undetectable in the maternal circulation, whereas endogenous levels were detectable in the fetus from 19 weeks' gestation (median 150; range 50 to 276 pmol/L) and did not correlate with gestational age. After thyrotropin-releasing hormone injection as an intravenous bolus, peak levels in the mother were attained at 3 minutes (50,000 pmol/L). Maximal transplacental transfer of thyrotropin-releasing hormone occurred within 5 minutes of maternal administration but accounted in fetal blood for only 0.01% of initial dose administered (median 250; 30 to 550 pmol/L). Thyrotropin-releasing hormone-stimulated fetal peak thyroid-stimulating hormone levels occurred within 13 minutes and were higher than maternal values (p < 0.001). There was no change in fetal prolactin level with thyrotropin-releasing hormone therapy., Conclusion: Although maternally administered thyrotropin-releasing hormone crosses the placenta sparingly, it still elicits a thyroid-stimulating hormone but not a prolactin response in the human fetus.

Objective: Our purpose was to determine whether adding antenatal thyrotropin-releasing hormone to prenatal corticosteroids reduces the frequency of respiratory distress syndrome., Study Design: A randomized, multicenter, double-blind, placebo-controlled trial was conducted of thyrotropin-releasing hormone (400 micrograms intravenously every 8 hours four times) in women with singleton pregnancies < 33 weeks of gestation who received antenatal betamethasone (12 mg intramuscularly every 24 hours two times). Neonates weighing < 1.0 kg received prophylactic surfactant and those above that weight received rescue therapy., Results: One hundred ninety women received thyrotropin-releasing hormone and 180 were given placebo. There were no differences in the frequency of respiratory distress syndrome (relative risk 1.17 [95% confidence interval 0.93 to 1.48]), use of oxygen at age 28 days (1.14 [0.80 to 1.62]), or neonatal mortality (1.05 [0.79 to 1.38]). Air leaks were more frequent in the thyrotropin-releasing hormone group (1.57 [1.23 to 2.01])., Conclusions: The combination of antenatal thyrotropin-releasing hormone and corticosteroids does not reduce the frequency of respiratory distress syndrome or improve the outcome of preterm neonates compared with the use of corticosteroids alone.

Methods: We studied a group of 36 fertile women affected with moderate-to-severe cyclical mastalgia (mean age: 26.0 years) showing a normal menstrual history and normal basal levels of circulating hormones, including prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), progesterone (P), testosterone (T), dehydroepiandrosterone sulphate (delta HEAs), androstenedione (A). Using serial measurements of PRL plasma levels after an intravenous injection of thyrotropin-releasing hormone (TRH), (TRH test), patients were divided in two groups: 19 patients with abnormal PRL response to TRH and the remaining 17 with normal response., Results: Bromocriptine treatment, 2.5 mg b.i.d. for 3-6 months, was effective in 73.6% of patients with abnormal TRH test and in 23.5% of patients with normal TRH test: the difference was statistically significant. On the other hand, 76.9% of patients with either normal TRH test or resistant to bromocriptine therapy had a favourable response to percutaneous progesterone and systemic non-steroidal antiinflammatory drugs (NSAIDs)., Conclusions: These results seem to confirm the hypothesis that PRL response to TRH could be used to identify patients affected with cyclical mastalgia that are likely to benefit by bromocriptine treatment.

For the purpose of obtaining an integral picture of anterior pituitary function in canine pituitary-dependent hyperadrenocorticism (PDH), 47 dogs with PDH and eight control dogs received combined administration of four hypophysiotropic hormones (CRH, GHRH, GnRH and TRH) and measurements were made of ACTH, cortisol, GH, LH, PRL and TSH. Basal plasma levels in 47 dogs with PDH were higher for ACTH, cortisol and PRL, lower for GH, and not different for LH (n = 25 noncastrated dogs) and TSH compared with controls (n = 8). In dogs with PDH the responses to combined hypophysiotropic stimulation, measured as increment and area under the curve (AUC), were not different for ACTH, lower for GH and TSH (increments and AUC) and higher for cortisol (increments), LH (AUC, n = 25 noncastrated dogs) and PRL (increments and AUC) than in controls. We conclude that pituitary function is altered in several respects in dogs with PDH. 1) In spite of persisting hypercortisolemia and the neoplastic transformation of the corticotropic cells, these cells usually remain responsive to combined hypophysiotropic stimulation. 2) Basal plasma GH concentrations and GH responsiveness in the combined stimulation test are decreased, probably as a result of the glucocorticoid-induced increase in somatostatin tone. 3) Plasma PRL concentrations and the PRL response to stimulation are increased, probably as a result of cosecretion with ACTH by the transformed corticotropic cells. 4) Despite the well known effect of glucocorticoids of decreasing circulating concentrations of gonadal steroids and thyroxine, the basal plasma concentrations of LH and TSH remain unchanged and there is a tendency to hyperresponsiveness to stimulation for LH and hyporesponsiveness for TSH. The most likely explanation for these changes is a dual effect of glucocorticoids: a direct effect on the gonads and thyroids and/or the transport and metabolism of their secretory products, and an influence on the sensitivity of the feedback control at the hypothalamic-pituitary level.

Objective: To determine the pharmacokinetics and pharmacodynamics of thyrotropin-releasing hormone (TRH) in pregnant women., Methods: Twenty-four pregnant and eight nonpregnant women were given 400 micrograms TRH as either intravenous infusion or bolus. Serial venous samples were collected for TRH, TSH, thyroxine, and prolactin assay., Results: When given as bolus, mean (+/- standard error of the mean) peak plasma concentration (50 +/- 5.2 and 73 +/- 5.1 ng/mL, P < .01), elimination half life (4.3 +/- 0.3 and 6.3 +/- 0.4 minutes, P < .001), and area under the curve (156.4 +/- 14.8 and 340.1 +/- 32.8 ng/mL/minute, P < .001) in pregnant subjects were reduced compared with controls, whereas plasma clearance (45.4 +/- 6.5 and 23.6 +/- 2.1 mL/kg/minute, P < .01) and volume of distribution (27.8 +/- 1.8 and 19.0 +/- 1.3% body weight, P < .01) were increased. When given by infusion, steady-state concentration (6.6 +/- 0.5 and 9.8 +/- 0.9 ng/mL, P < .01) and elimination half-life (4.6 +/- 0.5 and 6.3 +/- 0.3 minutes, P < .05) were lower in pregnant subjects than in controls. Thyrotropin-releasing hormone kinetics were independent of mode of administration. Although basal TSH and thyroid hormone concentrations were similar in patients and controls, the TSH response to TRH was blunted in pregnant subjects compared with controls (9.3 +/- 0.6 and 16.4 +/- 1.4 microIU/mL, P < .001). The basal (3187 +/- 488 and 147 +/- 16 mIU/L) and maximal prolactin response (6193 +/- 426 and 1316 +/- 106 mIU/L) were increased in pregnant subjects compared with controls (P < .001)., Conclusion: The peak plasma concentration and elimination half-life of TRH are reduced during pregnancy because of the increased volume of distribution and rapid clearance. Mode of administration does not affect TRH pharmacokinetics, but the maternal pharmacodynamic response differs in patients receiving bolus compared with infusion.

A corticotropin release-inhibiting factor (CRIF) in brain has been postulated for several decades, based on increased plasma levels of ACTH and corticosterone after hypothalamic-pituitary disconnection. Recent in vitro studies indicate that prepro-TRH178-199 may function as an endogenous CRIF, prompting us to examine stress-related neuroendocrine and behavioral responses after in vivo administration to the adult male rat. Animals that were administered prepro-TRH178-199 intravenously 5 min before restraint stress exhibited a significant attenuation of stress-induced elevations of ACTH, corticosterone, and prolactin, as compared with controls infused with vehicle, whereas thyroid-stimulating hormone (TSH) secretion was not changed. In behavioral studies of stress responsiveness, either the vehicle or prepro-TRH178-199 was administered intracerebroventricularly (ICV) 5 min before testing. In the open field, prepro-TRH178-199 significantly increased grooming, locomotor activity, rearing, and sniffing behaviors. In the light/dark box, it significantly increased the time animals spent in the light compartment and increased the number of crossings between the light/dark compartments. In the plus maze, the peptide significantly increased the amount of time animals spent in the open arms. The same dose of peptide, administered ICV, had no effect on peripheral hormone release in response to restraint stress. Overall, these results support a role for prepro-TRH178-199 in the inhibition of the neuroendocrine responses to stress at the level of the pituitary and indicate that it has central modulatory influences over stress-related behaviors.

To clarify whether plasma somatostatin affects thyrotropin secretion in critical illness, plasma somatostatin and thyrotropin responses to thyrotropin-releasing hormone were studied in forty-three critically ill patients. High somatostatin levels were associated with blunted thyrotropin secretion in critically ill patients. There was an inverse correlation between plasma somatostatin levels and the maximum increment of thyrotropin after stimulation by thyrotropin-releasing hormone. Decreased somatostatin and increased thyrotropin secretion before discharge from the intensive care unit were demonstrated in survivors. On the other hand, non-survivors maintained high somatostatin levels and had blunted thyrotropin secretion during their intensive care admission. These results suggest that high plasma somatostatin levels may play a role in the blunted thyrotropin secretion observed in critical illness.