TRH In Patients Research Articles

Gspmutation in acromegaly and its influence on TRH-induced paradoxical GH response

We recently reported that paradoxical GH response to TRH administration reflects biological characteristics in patients with acromegaly. The aim of this study is to elucidate the relationship between gsp mutations and the paradoxical GH response to TRH. Sixty-seven patients with acromegaly were included for analysis. Paradoxical increase in serum GH level to TRH, GH suppression by octreotide and bromocriptine, radiological profiles and histopathological findings were analysed with respect to tumour gsp-mutation status. Twenty-six (38·8%) gsp mutations were detected, and the number of paradoxical GH responders to TRH, defined as an increase of 100% or more in GH after TRH, was 49 (73·1%). Among the paradoxical GH responders to TRH, 21 patients (42·9%) had a gsp mutation and 28 patients (57·1%) did not. The percentage of paradoxical GH responders to TRH in gsp-positive and gsp-negative patients was not significantly different (80·8% and 68·3%, respectively). The gsp-positive group showed a significantly higher paradoxical increase in serum GH level by TRH administration (1830% vs 650% GH increase, P = 0·045) and greater GH suppression by octreotide (88·7% vs 75·4% GH decrease, P = 0·003) than the gsp-negative group. Paradoxical GH response to TRH was observed regardless of gsp mutation, although the rate of increase was significantly higher in gsp-positive patients. These results suggest that gsp mutation is not sufficient to cause the paradoxical GH response to TRH, while other unidentified factors have a strong influence on paradoxical GH response to TRH in patients with acromegaly.

Biological Characteristics of Growth Hormone-Producing Pituitary Adenomas Are Different According to Responsiveness to Thyrotropin-Releasing Hormone

The paradoxical response of GH to TRH in patients with acromegaly has been previously reported. However, few reports have focused on tumor characteristics reflected by this response. This study aimed to clarify the relationship between TRH-induced GH responsiveness and other tumor characteristics. Patients with acromegaly who underwent initial surgery between 2000 and 2012 were divided into TRH-responder and nonresponder groups. Clinical features were compared between the two groups with respect to tumor size, Knosp grade, endocrinological profiles, and histopathological findings revealed by cytokeratin staining. Tumor size was quantitatively evaluated with volumetry. Cytokeratin staining patterns were categorized into three groups: sparsely granulated type, densely granulated type, and intermediate type. Sixty-two patients were included in the study. TRH responders (n = 45) showed significantly smaller tumor size than nonresponders (n = 17) (2.78 ± 4.71 vs. 7.56 ± 9.00 ml, P < 0.005). In addition, TRH responders showed significantly higher preoperative basal GH per volume ratio than nonresponders (10.1 ± 8.4 vs. 7.72 ± 11.85 ng/ml(2), P < 0.05). Logarithmic regression modeling showed significant correlation between TRH responsiveness and tumor volume (r = -0.341; P < 0.01). The difference between cytokeratin staining patterns was also significant: sparsely granulated-type adenomas were found in only 13% of TRH responders but in 64% of nonresponders (P < 0.0005). TRH responders showed higher GH suppression rates in the octreotide test compared with nonresponders (86 vs. 68%, P < 0.01). The present data suggest that the responsiveness of serum GH level to TRH reflects significant tumor biological characteristics.

Exaggerated TSH Responses to TRH in Patients with Goiter and ‘Normal’ Basal TSH Levels

Background/Aim: The availability of sensitive thyrotropin (TSH) assays decreased the diagnostic value of thyrotropin-releasing hormone stimulation tests (TRH-ST) in subclinical hypothyroidism. In this study we aimed to evaluate the relation between basal and stimulated serum TSH levels on TRH-ST and to determine the prevalence of patients with normal basal serum TSH and exaggerated TSH responses. Methods: 179 patients (117 girls, 123 pubertal) with a median age of 12 (2.7–21.4) years who presented with goiter were enrolled and evaluated for their pubertal stage, height, thyroid autoimmunity, ultrasonography, thyroid function, and TRH-ST. Serum TSH concentrations were determined by sensitive assays. At TRH-ST, a peak serum TSH level >25 mIU/l was considered as an exaggerated response. Results: 30 (17%) patients had an exaggerated TSH response. In patients with serum TSH levels between 2 and 4.68 mIU/l (upper half the normal range), an exaggerated TSH response was observed in 19.5%. A positive correlation between basal and TRH-stimulated TSH levels was determined (r = 0.536, p < 0.01). In patients with an exaggerated TSH response, 23 had normal (discordant) and 7 had high basal TSH levels (concordant). The mean basal serum TSH level was lower in the discordant group compared to the concordant group (p < 0.01). Conclusion: Basal serum TSH levels might not be sufficient for diagnosing subclinical hypothyroidism. Stimulated TSH levels on TRH-ST are valuable, especially when serum TSH concentrations are in the upper half of the normal range.

Thyroid function in survivors of childhood acute lymphoblastic leukaemia: the significance of prophylactic cranial irradiation.

Focus on long-term side-effects after cancer therapy in childhood has become of the utmost importance. The hypothalamic-pituitary thyroid (HPT) axis is exposed to irradiation when some children are treated for acute lymphoblastic leukaemia (ALL) with prophylactic cranial irradiation (CIR). Whether this treatment causes hypofunction of the HPT axis remains controversial. We measured plasma levels of total T3 (T3), total T4 (T4) and TSH before stimulation with TRH and plasma levels of TSH, 30 and 150 minutes after stimulation with TRH in 95 patients in first continuous remission of childhood ALL. Patients diagnosed with ALL before the age of 15 years between 1970 and 1991 and who were in first continuous remission and off treatment for at least one year were studied. The children were aged between 0.5 and 14.8 years (median: 3.9) at diagnosis of ALL. Thyroid function was assessed between 1.2 and 18.3 years (median: 7.6) after completion of therapy. We measured T4 levels before, and compared TSH levels before and after, stimulation with TRH in patients who were treated with prophylactic CIR (15-24 Gy) (n = 38) (CIR group) with patients who were treated with chemotherapy only (n = 57) (non-CIR group). We found that T3 and T4 levels were normal in all individuals (excluding the women who were on oral contraceptives). The median time from end of treatment to time at follow-up was 9.1 years in the non-CIR group vs. 4.2 years in the CIR group (P < 0.001), and the effect on follow-up time was significant (P = 0.04). It was estimated that just after irradiation, the TSH levels before and 30 and 150 minutes after TRH stimulation was 49% lower in the CIR group; however, after 4.0 years, TSH levels were not significantly different between the two groups. Although within normal limits, the T4 levels were significantly higher in the CIR group compared to the non-CIR group (P = 0.003). It was estimated that, just after the end of treatment, T4 was 19.9% higher in the CIR group. However, in the CIR group, the T4 level decreased significantly over time with -1.5% per year (P = 0.025), while the difference in the non-CIR group was not significant. There was no correlation between T4 and TSH levels and sex, age at diagnosis, age at the end of treatment or age at follow-up. We conclude that, in our cohort of survivors of childhood ALL, prophylactic cranial irradiation of the central nervous system did not have an adverse effect on hypothalamo-pituitary-thyroid function within a median follow-up time of 8 years.

Serum alpha-subunit levels in patients with pituitary adenomas.

We investigated preoperative and postoperative serum alpha-subunit levels and the alpha-subunit response to TRH in patients with various types of pituitary tumour and correlated the data with histological findings in order to clarify the significance of alpha-subunit measurement in pituitary adenomas. We examined 59 patients with pituitary tumours (22 with GH cell adenomas, 30 with clinically nonfunctioning adenomas and seven with other tumours) treated at Toranomon Hospital between 1996 and 1998. The basal alpha-subunit level was supranormal in six out of 22 (27%) patients with a GH cell adenoma and in nine out of 30 (30%) patients with a nonfunctioning adenoma. A paradoxical alpha-subunit response to TRH was found in seven out of 22 (32%) patients with a GH cell adenoma. These seven patients also showed a paradoxical GH response to TRH administration. In addition, paradoxical response to TRH was found in eight out of 30 (27%) patients with a clinically nonfunctioning adenoma. In contrast, patients with other types of pituitary tumour showed neither a supranormal alpha-subunit level nor a paradoxical response to TRH. The supranormal alpha-subunit level and the abnormal response to TRH were normalized in both GH cell adenoma and nonfunctioning adenoma patients after successful surgery. Immunohistochemical studies showed alpha-subunit positive cells in 51% of GH cell adenomas or nonfunctioning adenomas and there was a good concordance with the serum alpha-subunit levels in both GH cell adenoma and nonfunctioning adenoma patients. These findings suggest that supranormal serum alpha-subunit levels are mainly due to hypersecretion by the tumour itself, while the paradoxical alpha-subunit response to TRH is an associated phenomenon in patients with a GH cell adenoma or nonfunctioning adenoma. The alpha-subunit level and the response to TRH may be useful indicators for assessing the operative outcome, especially in nonfunctioning adenoma patients who have no other definite endocrine markers.

Prolactin response to TRH in patients with panic disorder

The effects of TRH administration (400 μg, 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.

Tues-P102 - Prolactin response to TRH in patients with panic disorder

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Combined beta FSH and beta LH response to TRH in patients with clinically non-functioning pituitary adenomas.

'Paradoxical' responses of LH, FSH, alpha-subunits and beta LH to TRH have previously been reported in individuals with clinically non-functioning pituitary tumours (NFT). The present study was designed to assess the in vivo and in vitro responses of beta FSH to TRH in NFT. We further examined the possibility that a TRH challenge with combined measurement of beta FSH and beta LH will identify a common anomalous secretory pattern in patients with NFT. Forty patients with NFT underwent a standard TRH test (400 micrograms intravenously). Blood samples for the determination of beta FSH, beta LH, FSH and LH were collected prior to TRH as well as 15, 30, 45, 60 and 90 minutes following injection. Additionally, cultured adenomatous cells from eight to these patients were exposed to TRH in the absence and presence of octreotide and gonadotropin subunits were determined. TRH elicited a marked rise in circulating beta FSH in 29 of 40 individuals and in beta LH in 28 of 36 patients with NFT. In a subgroup of eight individuals whose tumours were harvested during surgery and cultured for 7-21 days, TRH increased beta FSH or beta LH and alpha-subunit release in cultured adenomatous cells in all cases, including tumours from subjects not responding to TRH in vivo. In this subgroup of patients octreotide inhibited basal beta FSH secretion but not basal beta LH secretion both in vivo and in primary cultures of NFT cells. Both the in vivo and in vitro beta FSH, beta LH and alpha-subunit responses to TRH were entirely inhibited by octreotide. In all, 38 of the 40 subjects could be identified by either elevated basal beta FSH or beta LH levels and/or an abnormal rise in either beta FSH or beta LH in response to TRH. The measurement of basal and TRH-stimulated beta-FSH and beta-LH levels identifies an abnormal hormonal secretory pattern in the vast majority (> 90%) of patients with clinically nonfunctioning pituitary tumours.

Human TRH receptor messenger ribonucleic acid levels in normal and adenomatous pituitary: analysis by the competitive reverse transcription polymerase chain reaction method

Little is known about the mechanism of diversity in in-vivo hormonal responsiveness to TRH in patients with functional pituitary adenomas. In order to clarify the relation between the responsiveness to TRH and TRH receptor messenger ribonucleic acid (mRNA) expression, we attempted to measure TRH receptor mRNA levels in human pituitary adenoma tissues by competitive reverse transcription polymerase chain reaction (RT-PCR) method. Pituitary tissue samples were obtained at autopsy from 5 patients without pituitary disease. Pituitary adenoma tissue samples were obtained at surgery from 18 patients with pituitary adenoma (4 non-functioning, 8 prolactinoma, 4 acromegaly, 1 Cushing's disease and 1 FSH producing adenoma). Partial TRH receptor cDNA from a human GH producing adenoma cDNA library was amplified by PCR under low stringency conditions using primers encoding the transmembrane domains III and VI of pituitary TRH receptor cDNA. The partial sequence of the amplified cDNA determined by a dideoxy-chain termination method was identical to the corresponding sequence of human TRH receptor cDNA. A competitor was generated by deleting the inner 111 bp from the amplified TRH receptor cDNA and subcloning. RNA extracted from human pituitary was reverse transcribed and co-amplified with competitor by PCR under higher stringency conditions. The TRH receptor mRNA levels, expressed as the relative intensity against the amplified levels of competitor, were compared among various pituitary tissues. The relative TRH receptor mRNA levels of pituitary tissues in patients without pituitary disease were detectable and variable (M +/- SD) (0.370 +/- 0.231, n = 5), and slightly but not significantly lower than those in patients with pituitary tumours (0.598 +/- 0.265, n = 18). In patients with prolactinoma, the relative levels of TRH receptor mRNA were quite variable (0.02-1.170, 0.604 +/- 0.358, n = 8) and not correlated with PRL responsiveness to TRH (responder 0.457; non-responder 0.340-0.950). In patients with acromegaly, TRH receptor mRNA was detectable not only in the paradoxical GH responder to TRH (0.718) but also in the non-responder (0.758 and 0.765). In one patient with Cushing's disease, a relatively low level of TRH receptor mRNA could be detected (0.415). In the patient with a FSH producing tumour whose plasma FSH did not respond to TRH, a small amount of TRH receptor mRNA was detectable (0.447). In patients with functioning pituitary adenomas, hormonal responsiveness to TRH in vivo might not be assessable by TRH receptor mRNA levels in the adenoma cells.

Endocrine effects of intravenous TRH in patients with panic disorder

Endocrine effects of intravenous TRH in patients with panic disorder

Cholinergic mediation of growth hormone secretion induced by thyrotropin-releasing hormone in cirrhotic patients.

In order to evaluate the possible involvement of muscarinic cholinergic receptors in the GH response to TRH in patients with liver cirrhosis, 8 males with post-hepatitic cirrhosis and 11 males with post-alcoholic cirrhosis were primed with the anticholinergic agent pirenzepine and tested with TRH. In addition, 10 male patients affected by piecemeal necrosis were tested in a similar manner. High basal concentrations of GH were found in all groups. None of the patients with piecemeal necrosis responded to TRH, whereas in patients with post-hepatitic and in post-alcoholic cirrhosis, TRH induced a significant rise in GH levels. The priming with pirenzepine (40 mg given iv 10 min before TRH) completely blocked the TRH-induced GH increase, but did not affect the TRH-induced TSH release. These data suggest that a muscarinic cholinergic pathway is involved in the anomalous response of GH to TRH in patients with liver cirrhosis. The lack of effect of pirenzepine on the TRH-stimulated TSH release suggests that the muscarinic cholinergic mediation is peculiar for the effect of TRH on GH secretion.

Serum PRL Responses to TRH in Patients with Anorexia Nervosa

Serum PRL Responses to TRH in Patients with Anorexia Nervosa

Free thyroid hormone levels and TSH response to TRH in patients with autonomous thyroid adenomata and normal T3 and T4.

Free thyroid hormone levels together with basal and TRH stimulated TSH levels, have been determined in 50 patients with autonomous thyroid adenomata, who had normal serum total T3 and T4 values. Similar measurements were made in 33 healthy subjects. FT3 and FT4 plasma levels were significantly higher (P less than 0.01 and P less than 0.05 respectively), and basal and TRH stimulated TSH were significantly lower (P less than 0.05 and P less than 0.001 respectively) in the patients than in the controls. The TSH response to TRH was decreased in spite of normal free thyroid hormones in 25 patients and in a further ten both the delta TSH after TRH and the free fractions were normal. Eighteen patients were studied over periods from 4 37 months by repeating thyroid hormone levels and TRH tests. In six of them a change of these parameters toward toxicity was observed. The data obtained in the longitudinal study indicate that the values of free thyroid hormones and the result of the TRH test obtained by a single determination may represent different steps in the evolution of autonomous thyroid adenomata rather than a distinct pathophysiological condition.

Drs. Rubinow and Roy-Byrne Reply

Drs. Rubinow and Roy-Byrne Reply

Estrogenic treatment does not modify the TSH and PRL responses to domperidone and TRH in patients with tumoral hyperprolactinemia.

To verify if the low estrogen regimen could condition the TSH hyperresponsivity and PRL hyporesponsivity to antidopaminergic drugs seen by us and others in patients bearing prolactinoma, the effect of ethynilestradiol treatment (50 micrograms/day/14 days) on TSH and PRL responses to domperidone in 6 women with tumoral hyperprolactinemia and hypoestrogenemia were studied. Estrogenic treatment was unable to modify the TSH and PRL responsiveness either to domperidone and TRH. These data do not support the hypothesis that hypoestrogenemia could cause the peculiar TSH and PRL pattern in response to antidopaminergic drugs, in patients bearing prolactinoma. Also the TRH releasable pool of TSH and PRL in these patients seems to be unaffected by estrogenic treatment.

Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression.

Serum levels of thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5-triiodothyronine (rT3), 3,5-diiodothyronine (3,5-T2), 3,3'-diiodothyronine (3,3'-T2) and 3',5'-diiodothyronine (3',5'-T2) were studied in 80 patients with endogenous depression before and after electroconvulsive treatment (ECT). Compared to the values found after recovery, the patients when depressed had significant increased serum levels of T4, rT3, 3,3'-T2 and 3',5'-T2. Serum concentrations of T3 and 3,5-T2 were not significantly altered. Similarly the free T4 index (FT4I) was increased, while the free T3 index (FT3I) was unaffected. Previous studies have shown a reduced TSH response to TRH in patients with endogenous depression and that the long-term outcome after ECT is strongly related to changes in the TSH response. However, patients with increased TSH response to TRH (n = 23) had a pattern of serum iodothyronine concentrations similar to those (n = 57) with an unchanged TSH response. A similar pattern was also found in 7 patients with nonendogenous psychosis, in whom the TSH response to TRH was unchanged after recovery. It is concluded that the alterations of the TSH response to TRH found in endogenous depression cannot be explained by changes of FT4I or FT3I.

Studies on hypophyseo-thyroid function in patients with chronic thyroiditis (author's transl)

It is well known that serum TSH levels are elevated in most patients with chronic thyroiditis, even if the patient exhibits normal thyroid function tests. The determination of serum TSH levels in these patients is thought to be the most sensitive indicator of subclinical hypothyroidism. In this study, the hypophyseo-thyroid functions of untreated euthyroid patients with chronic thyroiditis were evaluated. Serum T3 levels in most of these patients were raised or at high normal levels, although serum T4 levels were in the low normal range. Serum T4 levels in patients with raised basal TSH were distributed in the low normal range. Hence, it is suggested that the decreased serum T4 stimulates TSH secretion which in turn stimulates T3 (and T4) secretion from the thyroid and the elevated T3 maintains the patient's euthyroid condition. Basal TSH levels in these patients varied from 2.5 to 37.0 muU/ml and mean +/-SD was 12.9+/-9.6 muU/ml. Thirteen out of 30 patients (43%) with normal free T4 indices showed elevated basal TSH levels. TSH responses to TRH injection were exaggerated in all euthyroid patients with raised basal TSH levels, as well as in 11 out 14 patients (78.6%) with normal basal TSH levels as well. But the maximum TSH responses after TRH injection were well correlated with basal TSH levels (gamma=0.79). The percent increases of serum T3 after TRH injection in those patients were less than those of the normal person, and there was no difference in T3 response between the normal TSH group and the group with raised TSH. Eight patients who suffered from collagen diseases (SLE:6, RA:1, PSS:1) without any evidence of thyroid disease also exhibited exaggerated TSH responses to TRH. In five out of these eight patients (62.5%) antithyroglobulin antibody was positive. This may indicate the presence of the so-called asymptomatic autoimmune thyroiditis in these patients. It is suggested that the elevated basal TSH levels in euthyroid patients with chronic thyroiditis are a much more sensitive indicator of thyroid failure than any other routine thyroid function tests. Moreover, the exaggerated TSH responses to TRH in patients with normal basal TSH levels indicated that the TRH-test is more useful for the detection of minimal thyroid failure, especially in patients having such conditions as asymptomatic automimune thyroiditis.

Species specificity in the TSH response to the administration of L-dopa.

SummaryAcute administration of l-dopa (500-750 mg) lowered plasma TSH concentration and depressed an increase of plasma TSH in response to TRH in patients with primary hypothyroidism. In contrast, chronic administration of small or large doses of l-dopa failed to depress the development of goiter in rats treated with methimazole, indicating that plasma TSH concentration was not lowered by l-dopa in methimazole fed animals. Acute administration of l-dopa also failed to prevent an increase of intrathyroidal colloid droplets produced by an increase of TSH secretion in response to TRH. It is suggested that there is species specificity in the TSH response to the administration of l-dopa.

A sensitive radioimmunoassay for thyrotropin releasing hormone

A sensitive radioimmunoassay for TRH is described which is capable of detecting 100 pg/ml. Antibody was produced by injection of TRH coupled to bovine serum albumin by a diazonium compound (BDB). Radioiodinated TRH was purified by gel filtration chromatography. Separation of antibody bound from free TRH was accomplished by dextran-coated charcoal as well as by double antibody precipitation. Measurement of TRH in patients undergoing TRH stimulation tests for evaluation of pituitary function showed rapid disappearance of TRH from the blood with substantial amounts recovered in the urine.

Normal serum triiodothyronine concentration and the lack of TSH response to TRH in patients with euthyroid Graves' disease.

In four patients with euthyroid Graves' disease, serum T3 concentration and TRH response were tested. All four patients showed T3 concentration within normal range, albeit representing TRH-refractoriness. The results suggest the possibility that thyroid hormone concentration is not a sole determinant of TRH-responsiveness in Graves' disease, implying currently undetermined pathologic process underlying the abnormality.