TRH-induced hormonal responses: the effect of pizotifene and naloxone

We examined the effects of the serotonin antagonist pizotifene (4 mg daily for 3 days orally), and the opiate antagonist naloxone-HCI (0.8 mg intravenously) on the TRH-induced thyrotropin (TSH), growth hormone (GH), and prolactin (PRL) response in female psychiatric inpatients with adjustment disorder or alcohol abuse. All the patients were free from interfering endocrine and metabolic illness and had not received major psychotropic medication before the investigation. Pizotifene caused a small but significant decrease of the TRH-induced TSH response in 8 patients, two of them changed their responses from normal (i.e. above 5 mU/l) to blunted. Neither GH nor PRL changed significantly after pizotifene. Naloxone-HCI, 30 min before the TRH challenge, did not produce any significant change in the TSH, GH or PRL responses, nor did it cause any significant change in the plasma level of these hormones by itself. The hormonal responses to TRH remained unaltered in ten other patients who had repeated tests without any drug treatment between the two occasions. The results suggest that serotonin deficiency may play a role in the blunted TSH response to TRH, while opiate mechanisms do not appear to have a primary influence on these endocrine effects of TRH.     

Thyrotropin releasing hormone test in unipolar depressed patients and controls: relationship to clinical and biologic variables

We compared unipolar depressed patients (n = 31) with controls (n = 38) for their responses to the thyrotropin releasing hormone (TRH) test. Depressed patients showed significantly smaller thyrotropin stimulating hormone (TSH) responses to TRH which correlated negatively with post-dexamethasone plasma cortisol levels. Depressed patients also showed significant negative correlations between delta max TSH and urinary outputs of norepinephrine and normetanephrine with similar trends with plasma levels of norepinephrine and 3-methoxy-4-hydroxyphenylglycol. Patients who showed a blunted TSH response, compared with those who did not, had significantly lower platelet serotonin uptake values. These results suggest that the blunted TSH response to TRH seen in depression may be associated with dysregulation of the cortisol, noradrenergic and serotonin systems.     

TRH tests with analyses of TSH, prolactin, and GH responses in subtypes of patients with major depressive disorders

TRH tests were performed on 131 patients with RDC diagnoses of major depressive disorders to study altered endocrine control mechanisms in subtypes of depression. The TSH response to TRH was measured in all patients. In more than a third of the sample the prolactin (PRL) and growth hormone (GH) responses were also analysed. There were no differences between bipolar, primary unipolar and secondary unipolar patients in means of any endocrine variable. However, the expected positive correlation between baseline TSH and delta TSH was absent in the secondary unipolar group, indicating a dysregulation of pituitary TRH receptor sensitivity in this depressive subtype. Only delta TSH was dependent on depressive state, being lower in currently ill primary unipolar patients only. Patients with melancholic features (endogeneity scores high) had blunted TSH responses. Weight loss was connected with TSH blunting in all depressive subtypes. Among patients with blunted delta TSH (less than 5 mU/l) there was no relationship between degree of weight loss and delta TSH. Further, examination of partial correlation coefficients suggests weight loss of affect delta TSH by virtue of its being part of the melancholic syndrome. A significant correlation between blunted delta TSH and nonsuppression of cortisol in the DST was found only among primary unipolar patients, arguing for some independence of the TRH test and the DST in mirroring disturbed endocrine controls in depression.     

Thyrotropin releasing hormone (TRH): a useful tool for psychoneuroendocrine investigation

(1) The hypothalamic tripeptide TRH was injected in normal controls and in schizophrenic, alcoholic and depressed patients. Behavioral and endocrine data were assessed and relationships between the two evaluated. (2) After TRH there was a brief and partial salutary behavioral change in all groups studied, suggesting that the behavioral effects of TRH are not disease specific. (3) A blunted TSH response after TRH was seen in some depressed and some alcoholic patients but not in schizophrenics, indicating that this fault is not simply a nonspecific attribute of mental illness. (4) In depression, but not in alcoholism, the blunting was accounted for by increased levels of serum cortisol. (5) In alcoholic patients, the TSH blunting was related to a favorable behavioral response to TRH. (6) While the relationship between ambient levels of serum cortisol and the TSH response was negative in normal subjects and depressed patients, it was positive in schizophrenic patients. The relative frequency of this finding in the various subtypes of schizophrenia is unknown. (7) The above data, taken together, suggest that both the behavioral and the endocrine effects of TRH render the tripeptide useful for psychoneuroendocrine investigation.     

Associations among dexamethasone non-suppression and TRH-induced hormonal responses: increased specificity for melancholia?

TRH-induced thyrotropin (TSH), prolactin (PRL), and growth hormone (GH) responses were investigated together with a dexamethasone suppression test in female psychiatric inpatients with major melancholic depression (n = 21), schizophrenic disorder (n = 20), alcohol dependence (n = 11), and adjustment disorder with predominantly depressed mood (n = 13), as well as in 15 healthy women. Abnormal responses for all four endocrine variables were noted most frequently in melancholia; however, a significant number of the non-depressed patients also had abnormal hormonal responses in the individual test. The association of two or three abnormalities proved to be quite specific for the melancholic group. There were no statistically significant differences in TRH-induced TSH responses among the patient subgroups. Non-suppression of cortisol after dexamethasone was associated with blunted TSH-responses only in melancholia. There was a tendency for non-suppressor schizophrenics to show more abnormal GH-responses to TRH administration.     

Use of TSH response to TRH as an independent variable

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

Lack of correlation between cerebrospinal fluid thyrotropin-releasing hormone (TRH) and TRH-stimulated thyroid-stimulating hormone in patients with depression.

BACKGROUND: It has been proposed that elevated central thyrotropin-releasing hormone (TRH) is associated with the blunted thyroid-stimulating hormone (TSH) response to TRH in patients with depression. Few studies have directly evaluated this relationship between central nervous system and peripheral endocrine systems in the same patient population. METHODS: 15 depressed patients (4 male, 11 female, 12 bipolar, and 3 unipolar) during a double-blind, medication-free period of at least 2 weeks duration, underwent a baseline lumbar puncture followed by a TRH stimulation test. Cerebrospinal fluid (CSF) TRH and serial serum TSH, free thyroxine, triiodothyronine, prolactin, and cortisol were measured. A blunted response to TRH was defined as a delta TSH less than 7 microU/mL. RESULTS: There was no significant difference in mean CSF TRH between "blunters" (2.82 +/- 1.36 pg/mL) and "non-blunters" (3.97 +/- 0.62 pg/mL, p = .40). There was no evidence of an inverse relationship between CSF TRH and baseline or delta TSH. There was no correlation between CSF TRH and the severity of depression or any other endocrine measure. CONCLUSIONS: These data are not consistent with the prediction of hypothalamic TRH hypersecretion and subsequent pituitary down-regulation in depression; however, CSF TRH may be from a nonparaventricular nucleus-hypothalamic source (i.e., limbic area, suprachiasmatic nucleus, brain stem-dorsal raphe) and thus, not necessarily related to peripheral neuroendocrine indices.     

Weight loss causes neuroendocrine disturbances: experimental study in healthy starving subjects

A variety of endocrine dysfunctions have been reported for anorexia nervosa, protein caloric malnutrition, and depression. The effect of reduced caloric intake and weight loss on endocrine functions was assessed in an experiment with five healthy female subjects during an initial baseline phase, a 3-week phase of complete food abstinence, weight gain to the original level, and a final baseline phase. During fasting, disturbances in hypothalamic-pituitary-adrenal function were observed, with elevated plasma cortisol levels, increase in the number of secretory episodes, increase in cortisol plasma half-life, and insufficient suppression following 1.5 mg dexamethasone. While all dexamethasone suppression tests (DSTs) were normal at baseline, 7 of 14 DSTs showed insufficient suppression in the fasting phase. During fasting, basal thyroid-stimulating hormone (TSH) values were lowered and the TSH response to thyrotropin-releasing hormone (TRH) was blunted. The plasma level of growth hormone (GH) over 24 hours was elevated during fasting and administration of the alpha 2-adrenergic receptor agonist clonidine resulted in a subnormal GH response after restoration of original body weight. One of the five subjects showed increased irritability, distress, anxiety, and depression as measured by various psychological scales. The results show that reduced caloric intake, weight loss, or catabolic state have powerful effects on several endocrine systems. The specificity of measures of endocrine disturbances (DST, TRH tests, and clonidine tests) as biological markers for certain types of depression must be questioned, and the metabolic state should be given more consideration in future studies.     

Blunted TSH response to TRH and seizure duration in ECT

The relationship between the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) and the duration of seizures induced by electroconvulsive therapy (ECT) in depressed patients was investigated. In a balanced-order cross-over design, 16 depressed women were given 0.4 mg TRH or placebo intravenously, 20 min before ECT in the first two sessions. In the third ECT session TRH was given just prior to ECT. Thyrotropin (TSH) levels at various sampling times, as well as the duration of seizures, were measured. There was a significant inverse correlation between plasma TSH concentrations 20 min after TRH administration (deltaTSH) and seizure duration. Furthermore, when patients were categorized according to their TSH response to TRH, the group with blunted responses (deltaTSH <6 microIU/ mL, n = 7) had a longer seizure time during ECT than the group with non-blunted responses (deltaTSH > 6 microIU/mL, n = 9). Finally, the seizure duration in the group with blunted TSH responses was reduced significantly when TRH was co-administered, while it remained unchanged in the group with non-blunted TSH responses. It is concluded that a blunted TSH response to TRH might indicate a seizure susceptibility as measured by the duration of seizures induced by ECT. The fact that TRH pre-administration had a reducing effect suggests that this substance might be involved in the pathophysiology of ECT-induced seizures.     

Thyrotropin and prolactin response to thyrotropin-releasing hormone in depressed and nondepressed alcoholic men

Thyrotropin-releasing hormone (TRH) stimulation tests were performed on 81 alcoholic men after at least 3 weeks of abstinence. Subjects were given 500 micrograms of TRH intravenously, and thyroid-stimulating hormone (TSH) and prolactin (PRL) were measured at baseline, and then 15 and 30 min later. Comparisons were made among alcoholics with (n = 27) and without (n = 54) a lifetime history of depression as determined by the Diagnostic Interview Schedule. Nine nondepressed, nonalcoholic subjects served as controls. Alcoholics with or without a depression history did not differ from each other or from control in TSH or PRL response area under the curve. Blunted TSH responses were present in 10 (12%) of the alcoholics and none of the controls when blunting was defined as a delta max TSH less than 5 microU/ml. When blunting was defined as a delta max TSH less than 7 microU/ml, 18 (22%) of the alcoholics and 1 (1%) of the controls were blunted. Conversely, 2 (2.5%) of the alcoholics had a delta max TSH greater than 32 microU/ml. All subjects were clinically euthyroid. Contrary to expectation, depressed subjects were slightly less likely to show blunted responses than nondepressed subjects. No relationship was found between neuroendocrine measurements and several measurements of alcoholism or depression. Some alcoholic subjects show a blunted TSH response to TRH injection, which may be a function primarily of the alcoholism itself. The precise mechanism remains unknown.     

Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia

Disturbances in the hypothalamo-pituitary-adrenal (HPA) and other endocrine axes were assessed in 24 women with bulimia and healthy controls. Overnight blood samples for measuring nocturnal plasma cortisol, prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were obtained at 30-min intervals. A 1.5 mg dexamethasone suppression test (DST) and a TRH-test were performed. Patients were monitored closely while their nutritional intake was recorded over 21 days. Compared with healthy controls, nocturnal cortisol plasma levels were not elevated in the bulimics. There was a trend toward insufficient cortisol suppression in the DST in patients with bulimia, which was most pronounced in patients with signs of restricted caloric intake. Plasma dexamethasone levels were significantly reduced in bulimics compared with healthy controls. There was a trend for blunted thyrotropin stimulating hormone (TSH) responses to thyrotropin releasing hormone (TRH) in bulimia. The prolactin response to TRH was significantly reduced in bulimics with a history of anorexia nervosa. Plasma LH and plasma FSH were significantly reduced in bulimics with signs of reduced caloric intake [low T3, high levels of beta-hydroxy-butyric acid (BHBA), reduced daily caloric intake, high number of fasting days] as compared with healthy controls. Bulimics with high BHBA levels had significantly reduced nocturnal prolactin plasma levels. Results show that multiple neuroendocrine disturbances exist in bulimia in a milder form than in anorexia nervosa. Evidence for the impact of caloric intake on endocrine functions is presented. Endocrine dysfunctions in our bulimic sample did not show a positive association with the presence of depressive symptoms.     

Studies using releasing factors in Klinefelter's Syndrome: The responses of LH and FSH to luteinizing hormone-releasing hormone and of prolactin and TSH to thyrotropin-releasing hormone before and after testosterone

(1) During an investigation of their pituitary function, the TSH prolactin (PRL) and gonadotropin, (LH, FSH) response to TRH was measured in four patients with documented euthyroid Klinefelter's syndrome. (2) In all four patients, the serum testosterone was low, the gonadotropins were elevated and thyroid antibodies undetectable. (3) The identical study was repeated after each patient had received intramuscular testosterone cypionate 200 mg bi-weekly for three doses. This raised the serum testosterone at least four-fold. (4) Basal TSH was normal in all four patients but its response to TRH was blunted (mean peak TSH 9.6 μU/ml), compared with normal controls (mean peak TSH 18 μU/ml). Following testosterone this response to TRH was further suppressed to a mean peak of 3.4 μU/ml TSH. (5) Basal PRL levels were also normal and the mean peak response to TRH, 28 ng/ml. When repeated after testosterone, TRH produced a mean peak PRL of 58 ng/ml. (6) LH and FSH, both elevated basally, did not change with TRH administration, but both were stimulated by LHRH 100 μg i.v., LH briskly, FSH more variably. (7) FSH was suppressed sharply but LH only partially with testosterone therapy. (8) Our studies indicate that the TSH response to TRH in Klinefelter's syndrome is blunted and further suppressed with short term testosterone replacement. The PRL response to TRH under these same circumstances, however, is enhanced. Previous reports of abnormal LH feedback control are confirmed. (9) Klinefelter's syndrome is associated with subtle abnormalities in hypothalamic pituitary regulation not expected in typical primary hypogonadism.     

Abnormal thyroid stimulating hormone, prolactin, and growth hormone responses to thyrotropin releasing hormone in abstinent alcoholic men with cerebral atrophy

The thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) responses to thyrotropin releasing hormone (TRH), the Wechsler Adult Intelligence Scale (WAIS) for cognitive impairment, and computed tomographic scans were evaluated in 15 nondepressed alcoholic men after 4 weeks of abstinence and in 10 normal controls. Both cognitive impairment and cerebral atrophy were found in 13 of the alcoholics. Eight alcoholics (seven with cerebral atrophy) had blunted TSH and PRL responses to TRH and a TRH-induced paradoxical increase of GH. This study demonstrates that besides affecting the TSH response to TRH, alcoholism often induces alterations of the PRL and GH secretory patterns in response to TRH. The severe brain damage caused by long-term alcoholism might be involved in the pathogenesis of these neuroendocrine alterations.     

Thyroid stimulating hormone and prolactin responses to thyrotropin releasing hormone in nondepressed alcoholic inpatients.

Thyroid stimulating hormone (TSH) and prolactin (PRL) responses to thyrotropin releasing hormone (TRH) stimulation are sometimes blunted in alcoholic subjects; however, the mechanisms involved in these phenomena have not been established. We hypothesized that elevations in free thyroid concentrations might be related to these abnormal responses and then tested that hypothesis in a sample of nondepressed alcoholic inpatients (n = 21). Four alcoholic patients had delta max TSH responses that were < 7 mIU/l; three had PRL responses at or below 8 micrograms/l. Baseline TSH was the only significant predictor of peak TSH; however, free thyroxine (FT4) and baseline TSH both were significant predictors of peak PRL. The average baseline FT4 concentration in alcoholic patients was significantly higher than that in healthy control subjects (n = 10). Our data, thus, suggest that small elevations of FT4 play a role in the inhibition of TSH and PRL responses to TRH among nondepressed, abstinent alcoholic patients.     

Thyroid-stimulating hormone response to thyrotropin-releasing hormone in unipolar depression before and after clinical improvement

Fourteen patients with unipolar depression who had a blunted thyroid- stimulating hormone (TSH) response to infusion of 500 μg of thyrotropin- releasing hormone (TRH) and who showed marked clinical improvement after pharmacotherapy and/or electroconvulsive therapy had the TRH test repeated after improvement. The mean (± SD) maximal TSH response to TRH (Δ TSH) increased significantly from 4.0± 1.9 to 8.1± 3.5 μ IU/ml. The number of patients with Δ TSH ≤ 7.0 μIU/ml increased significantly from 0 to 9 of 14 after improvement. Eleven of the patients were followed for 5 to 19 months, and none showed clear relapse. The results suggest that the blunted TSH response to TRH has features of both a state marker for active unipolar depression and a trait marker for vulnerability to this illness, and support the suggestion that the TRH test may be useful in diagnosis and treatment planning.     

Violent suicidal behavior and the thyrotropin-releasing hormone-thyroid-stimulating hormone test: a clinical outcome study

A relation between abnormal response of thyroid-stimulating hormone (TSH) to thyrotropin-releasing hormone (TRH) and a personal history of violent suicidal behavior was observed in a sample of 60 depressive women. Patients with a blunted TSH response to TRH were also at greater risk for subsequent suicide. There was no relationship between TSH response to TRH and age, severity of depression and polarity of the illness.     

Delayed TSH release in anorexia nervosa following injection of thyrotropin-releasing hormone (TRH)

We studied plasma concentrations of thyrotropin (TSH), prolactin and growth hormone (GH) after injection of 500 microgram of thyrotropin-releasing hormone (TRH) in 10 patients with acute anorexia nervosa, subsequent to initial nutritional stabilization and again after weight recovery. Plasma thyroxine levels were normal throughout, whereas plasma triiodothyronine levels were low initially but rose with weight gain. The TSH secretory response to TRH was delayed and prolonged during the initial study but showed a normal overall quantitative response, except for two patients who showed no TSH rise. Following weight gain the TSH response was more rapid, and positive correlations were found between body weight and peak TSH levels and rapidity of TSH response. Six of 10 patients, however, continued to exhibit a delayed TSH peak response, the average response was markedly increased in comparison with that in normal females. The prolactin response curves were normal at both times. Rises in GH following TRH were observed in two patients prior to and in one patient after weight gain. We conclude that acute anorexia nervosa, with its concomitant profound weight loss, is accompanied by abnormalities in the hypothalamo-pituitary-thyroid axis, which are reversed only in part with improvement in the illness and weight gain, suggesting the persistence of disordered neuroendocrine function in this illness.     

The TRH test during dopamine receptor blockade in depressed patients

In an evaluation of the possible role of dopamine on TRH test results, 21 depressed patients were given TRH before and after one week of treatment with a low dose of haloperidol. Haloperidol significantly increased serum prolactin (both basal and after TRH) and cortisol levels, decreased body temperature, and had no effect on serum TSH, growth hormone, or thyroid hormone levels. Five of six patients with initial TSH blunting were retested with TRH; in four patients the TSH response remained blunted. These data render it unlikely that dopamine exerts a major inhibitory input on TSH secretion in depression.     

TRH stimulation test in obsessive-compulsive patients

Serum thyroid stimulating hormone (TSH), prolactin (PRL), and growth hormone (GH) levels were measured before and after stimulation with 200 micrograms of thyrotropin releasing hormone (TRH) in 10 patients with obsessive-compulsive disorder (OCD) and in 10 control subjects. There were significantly more blunted TSH responses among OCD patients than control subjects. PRL and GH responses to TRH challenge did not differ between OCD patients and controls. These results may indicate dysregulation of the hypothalamic-pituitary-thyroid axis in OCD.     

Thyroid status in senile dementia of the Alzheimer type (SDAT)

Thyroid function was investigated in a group of 21 patients with severe senile dementia of the Alzheimer type (SDAT) and in a group of 17 age and sex matched normal controls. Free thyroid hormone levels (triiodothyronine (T3) and thyroxine (T4) were measured, as were also the thyrotrophin (TSH), prolactin (PRL) and growth hormone (GH) responses to thyrotrophin releasing hormone (TRH)). When compared to controls, patients demonstrated a significantly lower free T3 value (but not free T4), a blunted TSH response to TRH, slightly elevated basal PRL and GH values and a small GH response to TRH. However, all differences were small in biological terms and were within the laboratory's normal range. This emphasizes the relative normality of neuroendocrine function, particularly thyroid status, in SDAT.