The nocturnal thyroid-stimulating hormone surge is absent in overt, present in mild primary and equivocal in central hypothyroidism.

The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%, NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3 +/- 0.4 vs 0.9 +/- 1.0 mU/l, p less than 0.05) and relative (24 +/- 31 vs 63 +/- 51%, p less than 0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight of ten patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54 +/- 33%) and subclinical (92 +/- 69%), but decreased in overt hypothyroidism (2 +/- 10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. In conclusion: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.     

Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders

The circadian pattern of serum TSH in normal children, aged 5-18 yr, is characterized by a nocturnal surge and is presumably related in some way to a biological clock within the central nervous system. To look for patients deficient in the nocturnal TSH surge, we studied 52 children with hypothalamic-pituitary disorders. Thirteen of the children were hypothyroid, as judged by subnormal serum free T4 (FT4). The hypothyroid patients had a mean nocturnal TSH surge of 22% (range, -30% to +114%), significantly less than that of normal controls (mean, 124%; 95% confidence limits, 47-300%; n = 96; P less than 0.01). Only 1 of the hypothyroid children had a value for the nocturnal TSH surge (114%) that was within the normal range. Nineteen of the 52 patients with hypothalamic-pituitary disorders had subnormal nocturnal TSH surges; their mean iodothyronine values were significantly less than those of the 33 patients with normal surges [total T4, 73 +/- 4 (mean +/- SE) vs. 109 +/- 3 nmol/L (P less than 0.01); FT4, 13 +/- 1.0 vs. 19 +/- 0.5 pmol/L (P less than 0.01)]. These data demonstrate a clear association of a deficient nocturnal TSH surge and low iodothyronine concentration in children with hypothalamic-pituitary disorders. We performed both TRH tests and nocturnal TSH surge tests in 11 of the children with central hypothyroidism; TRH was abnormal in only 2, while the nocturnal surge test was abnormal in 10 of the 11. We suggest that the nocturnal surge of TSH is important for maintenance of thyroid function and conclude that the nocturnal TSH surge is a much more sensitive test than the TSH response to TRH for the diagnosis of central hypothyroidism.     

Nocturnal serum thyrotropin (TSH) surge and the TSH response to TSH-releasing hormone: dissociated behavior in untreated depressives

TSH secretion, with particular regard to the nocturnal surge of the hormone, was evaluated in 15 women (age range, 35-66 yr; mean, 50 yr) with untreated major endogenous depression and 15 healthy women (age range, 32-67 yr; mean, 53 yr) using an ultrasensitive assay. Mean morning (0830 h) TSH values did not differ in the 2 groups (1.3 +/- 02 mU/L in depressives and 1.4 +/- 0.1 mU/L in controls), whereas mean nighttime (2400-0200 h) values were significantly reduced in depressives (1.5 +/- 0.3 vs. 3.1 +/- 0.3 mU/L; P less than 0.0005). At variance with the control group, morning and nighttime TSH values did not differ in the depressives. The nocturnal serum TSH surge was abolished in 14 of 15 depressed patients. The mean peak TSH value after TRH was slightly yet significantly lower in the depressives. Patients with subnormal (less than 0.4 mU/L) TSH values in the morning had a serum TSH increase after TRH less than 2 mU/L in 5 of 6 cases and a lack of the nocturnal TSH surge in 6 of 6. Among the 9 patients with normal TSH values in the morning, the nocturnal serum TSH surge was lost in 8 of 9, whereas the response to TRH was normal in all. The depressives, at variance with other reports, showed significantly lower values of total and free thyroid hormones. Mean serum sex hormone-binding globulin (SHBG) and ferritin were also significantly reduced. In conclusion, major endogenous depression is associated with a major impairment of TSH secretion, which baseline TSH measurements in the morning and the evaluation of the TSH response to TRH may not reveal. In this regard, the loss of the nocturnal serum TSH rise would appear to be a more sensitive indicator of hypothalamus-pituitary-thyroid axis alterations in depressives than the TRH test, which is commonly used in the evaluation of these patients. The lack of the nocturnal TSH surge may be responsible for the reduced thyroid hormone secretion and supports the case for some degree of central hypothyroidism in endogenous depression.     

Diagnosis of hidden central hypothyroidism in survivors of childhood cancer

To determine how often central hypothyroidism remains undetected by routine out-patient tests of thyroid hormone, we studied 208 pediatric cancer survivors referred for evaluation because of signs of subtle hypothyroidism or hypopituitarism. Of the 208 (68 females and 140 males), 110 had brain tumors, 14 had other head/neck tumors, 11 had solid tumors remote from head and neck, and 73 had leukemia. Patients were evaluated 1-16 yr (mean, 6.1+/-4.1 yr) after tumor diagnosis. The nocturnal TSH surge and response to TRH were measured. Of 160 patients with free T4 in lowest third of normal, 34% had central hypothyroidism (blunted TSH surge or low/delayed TSH peak or delayed TSH decline after TRH); 9% had central hypothyroidism with mild TSH elevation (mixed hypothyroidism). Another 16% had mild primary hypothyroidism (TSH, 5-15 mU/L). Of 48 with free T4 in the upper two thirds of normal, 14% had central hypothyroidism; 17% had mild primary hypothyroidism. Incidence of central, mixed, and mild primary hypothyroidism 10 yr after tumor diagnosis was significantly related to total cranial radiation dose (P < 0.0001). Of 62 patients with central hypothyroidism, 34% had not developed GH deficiency. TSH surge identified 71%, and response to TRH identified 60% of those with central hypothyroidism. More than half of the slowly growing patients who have received cranial or craniospinal radiation for childhood cancer develop subtle hypothyroidism. In our study group, 92% of patients with central hypothyroidism and 27% with mixed hypothyroidism would have remained undiagnosed using baseline thyroid function tests alone. Both TSH surge and response to TRH must be evaluated to identify all of these patients.     

Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion

Six patients with idiopathic isolated deficit of TSH secretion were examined and reported on. Their clinical symptoms and routine biochemical data were unclear and were not specific for hypothyroidism. Serum triiodothyronine, free thyroxine and TSH levels were slightly low or low-normal. Basal metabolic rate and thyroidal (123)I-uptake were also slightly low or low-normal. The response of serum TSH to TRH stimulation was blunted in all patients. No nocturnal surge of serum TSH level could be seen in any of the patients. Empty sella was revealed in three patients, and pituitary microadenoma in one patient via magnetic resolution imaging. Antihuman pituitary cytosol antibody was seen in five patients. Autoimmunity may have played a role in the pathogenesis of idiopathic isolated TSH deficiency. Routine examination of thyroid function cannot easily detect this disease. TSH response to TRH stimulation and nocturnal surge of TSH should be examined when this disease is suspected.     

Circadian and stimulated thyrotropin secretion in cranially irradiated adult cancer survivors

CONTEXT: It has been claimed that with the use of the TRH test and knowledge of the nocturnal TSH surge, the diagnosis of so-called hidden central hypothyroidism might be uncovered in a substantial proportion of euthyroid cranially irradiated children. STUDY SUBJECTS: We conducted 24-h TSH profiles and TRH tests in 37 euthyroid adult cancer survivors 2-29 yr (median, 11.5) after irradiation (18-64 Gy) and in 33 matched normal controls. RESULTS: Basal and stimulated TSH levels (during the TRH test) were significantly (P < 0.05) higher in the patients who had received craniospinal irradiation, more so in those with severe GH deficiency. Six patients (16%) had a hypothalamic TSH response to TRH. The maximum TSH surge calculated from the highest peak (average of the highest three sequential samples) and the smallest nadir (average of the smallest three sequential samples) in the whole 24-h profile period was above the cutoff value of 50% in all except one control subject and two patients. However, the nocturnal TSH surge was greatly reduced or absent in eight normal subjects (24%) and six patients (16%), not due to a genuine loss of diurnal rhythm, but simply to a shift in the timing of the peak TSH and/or the nadir TSH to outside the recommended sampling times (for the nocturnal surge) of 2200-0400 and 1400-1800 h, respectively; thereby potentially leading to an erroneous diagnosis of hidden central hypothyroidism. Overall, the maximum TSH surge was significantly (P = 0.01) reduced only in the GH-deficient patients (100.7 +/- 11%) compared with normal subjects (154.9 +/- 18.2%). Free T4 levels did not correlate with TSH surge results. CONCLUSIONS: The normality of free T4 levels and the wide discrepancy between the high rate of these TSH abnormalities and the very low rate of overt secondary hypothyroidism (3-6%) after prolonged periods of postirradiation follow-up strongly suggest that in the vast majority of patients, these abnormalities in TSH dynamics represent subtle functional disturbances in the hypothalamic-pituitary axis rather than genuine pathology that may progress with time. We suggest that in this context, use of the term hidden central hypothyroidism is inappropriate, because these subtle changes may not have any clinical significance.     

Do we still need the TRH stimulation test?

OBJECTIVE: To evaluate the diagnostic value of the thyrotropin-releasing hormone (TRH) stimulation test in the diagnosis of central hypothyroidism in patients with Sheehan's syndrome. DESIGN: TRH stimulation test was performed in 72 patients with Sheehan's syndrome. Basal free triiodothyronine (fT(3)) and free thyroxine (fT(4)) levels were measured. Serum thyrotropin (TSH) concentration was determined before and 30, 60, 90, and 120 minutes after 200 mug TRH IV bolus injection. The peak TSH values <5.5 microIU/ml were defined as inadequate response. A peak TSH at 60 minutes or later was considered as delayed response. If TSH (60 minutes after peak), was more than 40% of the peak value it was considered as prolonged response. The diagnosis of central hypothyroidism (CH) was made if either serum fT(4) concentration was subnormal with an inappropriately low serum TSH concentration or inadequate response to TRH stimulation test and/or a delayed or prolonged response to TRH stimulation test. MAIN OUTCOME: Fifty-six (77.7%) of the patients had low serum fT(4) and fT(3) levels with an inappropriately low serum TSH levels were defined as CH (CH0 group). Ten (13.8%) patients with normal and low-normal fT(4) levels had no response and/or delayed or prolonged response to TRH stimulation test (CH1group). Six (8.3%) patients had fT(3), fT(4), and TSH levels within normal limits and peak TSH responses >/=5.5 microIU/ml consistent with euthyroidism (euthyroid group). Thus, 66 (91.6%) of 72 patients with Sheehan's syndrome had CH. Although fT(4) levels were within normal reference range, TRH stimulation test revealed that 10 (13.8%) of these had CH. CONCLUSION: TRH stimulation test is useful in the diagnosis of central hypothyroidism, especially in whom fT(4) and/or TSH is low-normal and known to have hypothalamo-pituitary pathology.     

The lack of nocturnal serum thyrotropin surge in patients with nontoxic nodular goiter may predict the subsequent occurrence of hyperthyroidism

TSH secretion, with particular regard to the nocturnal TSH surge, was evaluated in 115 subjects with non-toxic nodular goiter. All patients were clinically and biochemically euthyroid. After 18-36 months of follow-up (mean, 24 months), hyperthyroidism occurred in 21 (18%; group 1), while the remaining 94 remained euthyroid (82%; group II). The analysis of hormonal data at the time of first observation showed that the 2 groups had similar total and free T4 and T3 serum concentrations. Morning serum TSH values in group I were lower than those in group II patients (0.6 +/- 0.1 vs. 1.1 +/- 0.1 mU/L; P less than 0.001); this difference was even more striking for the nocturnal values (0.6 +/- 0.1 vs. 2.2 +/- 0.2 mU/L; P less than 0.0001); nocturnal values were significantly lower than morning values in group II, but not in group I. The mean peak TSH value after TRH was also significantly reduced in group I (5.5 +/- 0.4 vs. 9.2 +/- 0.7 mU/L; P less than 0.001). Morning TSH values in group II did not differ from those in controls (1.3 +/- 0.1 mU/L), whereas nocturnal and TRH stimulated peak TSH values were slightly but significantly lower. The nocturnal serum TSH values in control subjects were 62-390% higher than morning values. The nocturnal TSH surge was abolished in 18 of 21 (86%) group I patients and in 7 of 94 (8%) group II patients. TRH testing resulted in an absent or blunted TSH responses in 5 subjects in group I and 6 in group II. Analysis by the Galen and Gambino predictive model; comparing the abolition of the nocturnal TSH surge and the abnormal TRH test as predictors of the subsequent occurrence of hyperthyroidism, showed that the former had higher sensitivity (86% vs. 24%) and predictivity (72% vs. 45%). In conclusion, the results of the present study demonstrate that the evaluation of the nocturnal TSH surge may be useful in identifying patients with nontoxic nodular goiter in whom hyperthyroidism may eventually occur. Patients who lack the nocturnal serum TSH surge are more prone to develop thyroid hyperfunction; their thyroid status should, therefore, be more carefully and frequently monitored.     

Evaluation of the nocturnal serum thyrotropin (TSH) surge, as assessed by TSH ultrasensitive assay, in patients receiving long term L-thyroxine suppression therapy and in patients with various thyroid disorders

Circadian variations of serum TSH concentrations have been reported, with higher values occurring in the late evening or early morning. In patients receiving long term L-T4 suppression therapy, it may be important to achieve suppression of TSH secretion throughout the day. To investigate whether undetectable serum TSH values in the morning are associated with undetectable serum TSH levels at night, serum TSH concentrations were measured by an ultrasensitive immunoradiometric assay in 16 normal subjects, 20 hyperthyroid patients, 10 patients with primary hypothyroidism (either untreated or inadequately treated with L-T4), 1 patient with central hypothyroidism, 10 patients with nontoxic nodular goiter, 5 patients with functioning thyroid adenoma, 20 patients receiving L-T4 replacement therapy, and 30 patients receiving L-T4 suppression. In 6 subjects blood was drawn at hourly intervals for 24 h; in 2 normal subjects a major TSH surge occurred between 2300-0100 h, with other minor peaks, and the same pattern was found in two patients receiving L-T4 replacement, whereas in 2 patients receiving L-T4 suppression, serum TSH was constantly below the limit of detection of the assay (i.e. less than 0.07 mU/L). In the remaining patients blood was drawn at hourly intervals between 2300-0200 h and on the next morning before (0830-0900 h) and 30 min after iv TRH administration. In normal subjects, in patients receiving L-T4 replacement therapy, and in hypothyroid patients, serum TSH values at night were higher than in the morning, with normal responses to TRH in the first 2 groups and exaggerated responses in the latter. The patient with central hypothyroidism had no nocturnal TSH surge and no TSH response to TRH. In all hyperthyroid patients, serum TSH was undetectable both at night and during the day, and none had a serum TSH response to TRH. Among patients with nontoxic goiter, 7 had detectable serum TSH in the morning, with higher values at night, and a normal response to TRH; the remainder had undetectable serum TSH both at night and in the morning, and subnormal or absent TSH responses to TRH. All 5 patients with a functioning thyroid adenoma had undetectable serum TSH levels in the morning and during the night, and subnormal or absent TSH responses to TRH. Of the 30 patients receiving long term (greater than 6 months) L-T4 suppression therapy, 28 had undetectable serum TSH both during the night and in the morning and unresponsiveness to TRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Decreased nocturnal surge of thyrotropin in nonthyroidal illness

To evaluate the regulation of TSH secretion in nonthyroidal illness (NTI) we studied the nocturnal TSH surge in 11 healthy controls and 26 NTI patients; none of the patients was on medication known to interfere with TSH secretion. The presence of a nocturnal TSH surge was defined as a mean nighttime TSH (the mean of 5 samples taken hourly from 0000-0400 h) significantly greater than the mean daytime TSH (the mean of 5 samples taken from 1500-1900 h). A nocturnal TSH surge was present in 11 of 26 NTI patients and in 11 of 11 controls (P less than 0.01). Both the absolute (0.3 +/- 0.1 vs. 1.0 +/- 0.2 mU/L; P less than 0.01) and relative (11 +/- 6% vs. 71 +/- 12%; P less than 0.001) nocturnal TSH surges were lower in NTI patients than in controls. NTI patients had lower plasma T3 (1.11 +/- 0.08 vs. 1.84 +/- 0.11 nmol/L; P less than 0.001) and higher plasma rT3 (0.81 +/- 0.24 vs. 0.23 +/- 0.01 nmol/L; P less than 0.001) concentrations than controls, but T4, FT4, and TSH values were similar in both groups. No differences were found between the 15 NTI patients without nocturnal TSH surge and the 11 patients with a nocturnal TSH surge in sex distribution, age, caloric intake, or plasma T4 and T3, but hospital mortality was slightly, although not significantly, higher in those with an absent nocturnal TSH surge. An absent nocturnal TSH surge occurred in 2 of 2 patients with a low TSH (less than 0.4 mU/L), in 11 of 20 patients with a normal TSH (0.4-4.0 mU/L), and in 2 of 4 patients with a high TSH (greater than 4.0 mU/L). Pituitary TSH responsiveness to TRH was similar in patients with or without a nocturnal TSH surge. We conclude that NTI is frequently associated with a decreased nocturnal TSH surge. This phenomenon is not related to ambient plasma T4, T3, or TSH concentrations or pituitary TSH responsiveness to TRH. A decreased nocturnal TSH surge appears to be one of the features of the sick euthyroid syndrome and is probably related to hypothalamic dysregulation.     

DOPAMINERGIC MODULATION OF TSH AND ITS SUBUNITS: IN VIVO AND IN VITRO STUDIES

We have studied the effects of dopamine on the secretion of TSH and its subunits in vivo and in vitro. Four normal controls, seven patients with primary hypothyroidism, two patients with peripheral resistance to thyroid hormone (PRTH), and two patients with alpha-secreting pituitary tumours underwent a 3-h dopamine infusion (4 micrograms/kg/min). Serial blood samples were drawn for TSH, PRL, alpha, and TSH-beta subunit. In normal subjects, TSH fell from 2.1 +/- 0.9 (+/- SE) to 0.7 +/- 0.1 microU/ml (P less than 0.05), and alpha declined from 1.5 +/- 0.4 to 1.0 +/- 0.1 ng/ml (P less than 0.01). TSH-beta was at or slightly above the detection limits of the assay before and after dopamine. In hypothyroidism, basal serum TSH was 81 +/- 14 microU/ml. With dopamine, TSH fell to 35 +/- 8 microU/ml (P less than 0.001), while alpha decreased from 3.2 +/- 0.4 to 2.0 +/- 0.3 ng/ml (P less than 0.01). Serum TSH-beta also declined from 0.97 +/- 0.06 to 0.57 +/- 0.05 ng/ml (P less than 0.001). A similar fall in TSH and alpha was seen in the two patients with PRTH. In normals and hypothyroid patients, the percentage change in alpha concentration was significantly less than that observed for intact TSH. This is due presumably to the contribution of the gonadotrophs to the circulating alpha pool. TSH and TSH-beta were undetectable in the two pituitary tumour patients, and alpha declined only slightly in each patient after dopamine. The in vitro effects of dopamine were studied using cultured bovine anterior pituitary cells. Dopamine (10(-4)-10(-8) mol/l) did not change basal TSH, alpha, or TSH-beta release. However, dopamine at all doses significantly blunted TRH (10(-7) mol/l)-stimulated TSH and TSH-beta release, and blunted TRH-mediated alpha release at the two highest dopamine doses. These data suggest that dopamine modulates both TSH and TSH subunit secretion. These effects may be exerted directly at the level of the thyrotroph.     

Deficient nocturnal surge of thyrotropin in central hypothyroidism

In normal individuals, serum TSH concentrations have a circadian pattern characterized by a nocturnal surge which begins in the late afternoon and reaches its peak after midnight. We assessed the nocturnal surge of TSH in 16 patients with pituitary and/or hypothalamic diseases, 6 of whom were judged to be hypothyroid. To assess the magnitude of the nocturnal surge in individual patients, TSH was measured in 5 serum samples obtained during the normal time of the TSH nadir in the late afternoon and in 5 samples obtained during the normal time of the peak of serum TSH after midnight. A significant nocturnal surge of TSH was defined as a significantly greater mean nighttime TSH level than the mean daytime TSH concentration. The nocturnal TSH surge was absent in the 6 patients with central hypothyroidism, while it was present in the 10 euthyroid patients with central lesions. In 6 hypothyroid patients who did not have pituitary or hypothalamic lesions, the nocturnal TSH surge was intact, indicating that hypothyroidism per se does not account for the deficient nocturnal TSH surge in central hypothyroidism. We conclude that central hypothyroidism is characterized by a deficient nocturnal surge of TSH, and accordingly, we suggest that evaluation of the circadian pattern of TSH may be a useful adjunct in making the diagnosis of hypothyroidism in patients with diseases involving the pituitary or hypothalamus.     

Circadian changes in pulsatile TSH release in primary hypothyroidism

OBJECTIVE: We evaluated pulsatile and circadian TSH secretion in primary hypothyroidism. DESIGN: In a prospective study, blood was sampled every 10 minutes during 24 hours for assay of TSH (IRMA). Thyroid hormones and TSH responsiveness to TRH were then measured. SUBJECTS: Nine patients with overt primary hypothyroidism, seven patients with subclinical hypothyroidism and 16 healthy controls. MEASUREMENTS: Computer-assisted analysis by the Desade and Cluster programs. RESULTS: Both computer-assisted programs revealed an increased TSH pulse amplitude in both overt and subclinical hypothyroidism versus controls (Desade: 36.9 +/- 31.4 (mean +/- SD) (P < 0.001) and 2.8 +/- 1.9 (P < 0.001) vs 0.4 +/- 0.2 mU/l; Cluster: 25.6 +/- 25.1 (P < 0.001) and 2.4 +/- 1.4 (P < 0.001) vs 0.4 +/- 0.2 mU/l). TSH pulse frequency remained unchanged with approximately 10 pulses/24 hours. A highly significant correlation was found between the mean 24-hour TSH concentration and the TSH pulse amplitude in all controls and patients but not to TSH pulse frequency. The nocturnal TSH surge was absent in six out of nine patients with overt primary hypothyroidism. The deficient nocturnal rise of TSH in primary hypothyroidism vs controls (22 +/- 51 vs 82 +/- 41%, P < 0.001), was associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency. CONCLUSIONS: Mean 24-hour TSH pulse amplitude is increased in primary hypothyroidism, but TSH pulse frequency remains unchanged. The decrease of the nocturnal TSH increase in primary hypothyroidism is associated with a loss of the usual nocturnal increase in TSH pulse amplitude and frequency.     

Circadian variation of thyrotropin in childhood

We evaluated the circadian variation of serum TSH in 96 normal children, aged 5-18 yr. Blood samples were obtained hourly for 24 h, and serum TSH was measured using an immunoradiometric assay with a sensitivity of 0.2 mU/L and an intraassay coefficient of variation of 4.9%. The nadir serum TSH value, defined by the three consecutive hourly TSH concentrations having the lowest mean, occurred between 1000 and 1900 h, while the peak TSH value, defined by the three consecutive hourly TSH concentrations having the greatest mean, occurred between 2100 and 0600 h. The mean nadir serum TSH was 1.6 +/- 0.1 mU/L, and the mean peak TSH was 3.7 +/- 0.2 mU/L. The mean nocturnal TSH surge (percent increase in TSH from nadir to peak) was 144% (95% confidence limits, 50-300%) and did not correlate with serum T4, free T4, or T3 concentrations. Seventy-six children were given TRH (7 micrograms/kg). The mean peak serum TSH after TRH was 16.0 +/- 1.1 mU/L (95% confidence limits, 9.0-42.0 mU/L), and it occurred by 30 min after TRH administration in 92% of the children. The absolute peak nocturnal serum TSH and peak post-TRH serum TSH values correlated significantly (r = 0.62; P less than 0.001), while age, gender, and pubertal status did not correlate with either the nocturnal TSH surge or the TSH response to TRH. We conclude that normal children have a circadian variation of serum TSH characterized by a nocturnal TSH surge, and that the peak of serum TSH, which occurs at night, correlates with the peak serum TSH level after TRH administration.     

The influence of long-term low dose thyrotropin-releasing hormone infusions on serum thyrotropin and prolactin concentrations in man

The purpose of the present study was to evaluate in man the relative thyrotroph and lactotroph response to a 48-h low dose constant TRH infusion. Before, during, and after the 75 ng/min TRH constant infusion, serum samples were obtained every 4 h in six euthyroid ambulating male subjects for measurements of TSH, PRL, T4, and T3. The TSH response, employing a specific and sensitive human TSH RIA, demonstrated a significant rise from the mean basal pre-TRH value of 2.35 +/- 0.64 microU/ml (+/- SEM) to 3.68 +/- 0.80 (P < 0.005) during the TRH infusion; this value fell below the basal level to 1.79 +/- 0.47 (P < 0.05) post infusion. Serum T4 values were increased above basal both during (P < 0.025) and after (P < 0.025) TRH infusion, whereas serum T3 values were not significantly changed throughout the entire study period. The daily TSH nocturnal surge was augmented in both absolute and relative terms during the first 24 h or the TRH infusion, unchanged during the second 24 h of infusion, and inhibited during the first postinfusion day. Other than a minimal increase in serum PRL during the first few hours of the infusion, no significant alteration in the mean basal concentration or circadian pattern of PRL secretion was evident during or after the low dose TRH infusion. These findings would indicate that 1) near-physiological stimulation of the pituitary with TRH produces a greater stimulation of TSH release than of PRL release and 2) the factor or factors producing the circadian TSH surge may not be mediated through fluctuations in endogenous TRH.     

Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin.

TSH concentration was measured in plasma before and after TRH administration (200 micrograms, iv) in 89 patients with documented hypothyroidism consequent to various hypothalamic-pituitary disorders. Basal plasma TSH was less than 1.0 microI/ml in 34.8%, between 1.0-3.6 microU/ml in 40.5% and slightly elevated (3.7-9.7 microU/ml) in 24.7% of the cases. The plasma TSH response to TRH was absent in 13.5%, impaired in 16.8%, normal in 47.2%, and exaggerated in 22.5% of the cases, with delayed and/or prolonged pattern of response in 65% of the cases. The dilution curves of several plasmas drawn before and after TRH were parallel to those obtained with TSH standard preparation. After gel filtration, the elution pattern of TRH-stimulated plasmas from 4 patients did not show any major difference from that of pooled plasmas from normal subjects given TRH or from that of patients with primary hypothyroidism. Plasma TSH values determined by cytochemical bioassay on both basal and TRH-stimulated samples of 5 patients were markedly lower than those obtained by RIA. The serum T3 response to TRH was absent or low in 40 out of 53 patients in whom it was evaluated. The administration of T3 (100 micrograms/day for 3 days) or dexamethasone (3 mg/day for 5 days) respectively suppressed or reduced both basal and TRH-induced plasma TSH levels. Two patients became hypothyroid shortly after pituitary surgery in spite of basal and TRH-induced plasma TSH levels similar to or higher than those before surgery. Though thyroid atrophy due to chronic understimulation could explain the low T3 response to TRH in secondary hypothyroidism, it is difficult to reconcile thyroid understimulation with normal or increased plasma TSH unless the immunoreactive material has low biological activity. Present data suggest that several patients with hypothyroidism consequent to hypothalamic-pituitary diseases secrete a material which is immunologically similar to pituitary standard TSH and responds to stimulatory and suppressive agents in a manner similar to normal TSH but has low or absent biological activity. Thus, hypothyroidism due to insufficient TSH stimulation can be termed central hypothyroidism and can be due 1) to pituitary insufficiency (secondary hypothyroidism), 2) to a hypothalamic defect (tertiary hypothyroidism), or 3) to the secretion of biologically inactive TSH.     

Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children

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.     

The pituitary TSH response to TRH is inversely related to the plasma TSH concentration and directly related to the pituitary TSH content during hypothyroidism in the rat

We studied the effects of degree and duration of hypothyroidism on the pituitary TSH concentration and the pituitary TSH secretory response to TRH. Varying degrees of hypothyroidism were achieved in thyroparathyroidectomized rats (THYREX) by continuous sc infusion of T3 (0.2, 0.3, 0.4, or 0.5 microgram/100 g X day) or T4 (0.6, 1.2, or 1.8 microgram/100 g X day). While T3 was more potent than T4, both resulted in a dose-dependent suppression of the post-thyroidectomy rise in TSH. After 7 or 14 days of severe hypothyroidism (nonreplaced THYREX rats) the pituitary TSH secretory response to TRH (250 ng/100 g body weight, iv) was found to be decreased when compared to that of euthyroid rats. Decreasing the degree of hypothyroidism increased the pituitary secretory response to TRH and the pituitary TSH content. The results indicate that in the hypothyroid rat: severe hypothyroidism results in a blunted pituitary TSH response to TRH through 14 days after thyroidectomy, at 7 and 14 days after thyroidectomy the pituitary TSH response to exogenous TRH is inversely related to the basal plasma TSH concentration, the pituitary TSH concentration increases with the duration of hypothyroidism, the pituitary TSH content is increased by low rates of thyroid hormone replacement, and the pituitary TSH response to exogenous TRH is directly related to the pituitary TSH content.     

Decreased TSH response to TRH induced by amiodarone

In order to test the reactivity of TSH to TRH during amiodarone treatment we investigated 7 hypothyroid subjects treated with 50 micrograms T3/day. A TRH test (200 micrograms iv) was performed before and after 6 weeks of treatment with 400 mg amiodarone/day. Amiodarone treatment induced a significant increase in serum total and free T3 (from 2.17 +/- 0.13 to 3.55 +/- 0.58 nmol/l and from 5.6 +/- 0.61 to 9.46 +/- 1.41 pmol/l). Basal TSH levels were significantly decreased and the maximal stimulation of TSH 20 min after TRH injection was only 20.0 +/- 3.3 mU/l during amiodarone treatment compared with 61.4 +/- 10.4 mU/l before treatment. These results indicate that in hypothyroid patients treated with amiodarone, the TSH response to TRH is blunted and that this is likely to be related to the higher total and free T3 levels or to a direct effect of amiodarone at the pituitary level.     

Persistent pituitary resistance to thyroid hormone in congenital versus later-onset hypothyroidism

The pituitary and peripheral responses to L-T4 and L-T3 therapy were studied in 12 patients with congenital goitrous hypothyroidism, in 10 patients with an ectopic thyroid and onset of hypothyroidism at 3-8 years of age, and in 6 patients with adult-onset hypothyroidism, after they had had their chronic thyroid hormone replacement therapy discontinued for 30 days. They were first treated with increasing L-T4 (0.1, 0.2 and 0.4 mg daily) followed by L-T3 (0.05 and 0.2 mg daily) after stopping thyroid medication for another month. Ten normal subjects were treated identically. In normal individuals the peak TSH, alpha, and TSH-beta response to TRH was significantly decreased with 0.1 mg L-T4 or 0.05 mg L-T3 daily and was suppressed with 0.2 and 0.4 mg L-T4 or 0.2 mg L-T3 daily; serum cholesterol and triglyceride decreased significantly with 0.2 or 0.4 mg L-T4 or 0.2 mg L-T3 daily; testosterone-estradiol binding globulin (TeBG) increased significantly at the same doses. In congenitally hypothyroid patients receiving 0.2 mg L-T4 daily, the mean peak TSH after TRH was 24 +/- 17 microU/ml, whereas in patients with an ectopic thyroid or adult-onset hypothyroidism the peak TSH was significantly less at 5.9 +/- 8.8 and 5.5 +/- 5.7 microU/ml, respectively. Only at the highest doses of L-T4 (0.4 mg/day) or L-T3 (0.2 mg/day) was the TSH response to TRH suppressed in the congenitally hypothyroid group. The alpha and TSH-beta subunit levels followed those of TSH.(ABSTRACT TRUNCATED AT 250 WORDS)