Effect of prolonged oral administration of TRH on plasma levels of thyrotrophin and prolactin in normal individuals and in patients with primary hypothyroidism.

Forty mg TRH/day was given orally for 3 weeks to 10 euthyroid women and 10 women with primary hypothyroidism on low replacement doses of thyroxine. Once weekly oral TRH was replaced by an iv TRH-test (0.4 mg) with measurement of serum concentration of TSH, prolactin (PRL), thyroxine (T4), triiodothyronine (T3) and cholesterol. In the normal group, mean serum T4 concentration increased after one week and remained elevated. Serum TSH concentration showed a slight tendency to decline. Maximal rise in TSH concentration after iv TRH (deltaTSH) fell from a mean of 4.0 ng/ml to 1.4 ng/ml within one week and stayed low. T3, cholesterol, PRL and deltaprl were normal and unchanged throughout. In the hypothyroid group T4, T3, cholesterol, PRL and deltaPRL were not influenced by the TRH administration. In 2 patients (with the highest serum T4 concentrations) serum TSH concentration was normal and resistant to iv TRH. Of the 8 patients with elevated TSH, basal level and deltaTSH did not change in 2 (with subnormal T4 levels and the highest TSH levels). In the other 6 (with intermediate T4 levels) basal TSH fell from a mean of 10.1 ng/ml to 4.2 ng/ml, and deltaTSH from 10.0 ng/ml to 3.3 ng/ml after three weeks. It is concluded that in addition to feed-back effect of thyroid hormones, the pituitary response to long-term administration of TRH is determined by other factors. Among these may be reduced pituitary TRH receptor capacity and the activity of the TSH producing cells.     

Alterations in circulating thyroid hormones and thyrotropin in euthyroid patients with Graves' disease after total thyroidectomy: comparison between responders and nonresponders to TSH-releasing hormone

Eleven euthyroid patients with severe exophthalmos of Graves' disease who had been treated with antithyroidal drugs for one to three years prior to total thyroidectomy were studied. All patients were clinically and biochemically euthyroid at the time of operation. According to their responses of TSH to TRH prior to operation, the patients were divided into two groups: (1) five responders and (2) six nonresponders. In group 1, serum TSH levels increased significantly on the third day after thyroidectomy (from 1.5 +/- 0.3 to 8.6 +/- 1.4 microU/mL: P less than 0.05); serum T4 concentrations decreased significantly and were in the hypothyroid range by the third day. In group 2, serum TSH levels rose from 0.5 +/- 0.01 to 3.2 +/- 0.5 microU/ml (P less than 0.05) on the ninth postoperative day; serum T4 concentrations decreased on the third day after operation but did not attain hypothyroid levels until the 12th day. Thus after total thyroidectomy the following are concluded: (1) serum TSH levels even in treated euthyroid patients with Graves' disease, rose more gradually in TRH-nonresponders in comparison with TRH responders; (2) the time when serum TSH elevation occurs is dependent upon serum concentrations of thyroid hormones (serum T3 and T4).     

Effect of thyrotrophin releasing hormone (TRH) in patients with pituitary disorders.

The secretion and biological activity of thyroid stimulating hormone (TSH) were studied in 22 patients with a pituitary tumour (17 acromegalics and 5 patients with a chromophobe adenoma) and in 36 hypophysectomized patients (16 acromegalics and 20 with a chromophobe adenoma). Thyroid function was assessed by serum thyroxine (T4), serum triiodothyronine (T3), and thyroxine-binding globulin (TBG) concentration. Serum TSH was measured before and after injection of TSH releasing hormone (TRH), and in 19 hypophysectomized patients the T3 response after TRH was measured. In addition a TRH test was performed 1-2 weeks after surgery in 11 patients. The basal serum TSH did not differ from euthyroid control values in any of the groups and no late effect of hypophysectomy was observed. Subnormal peak TSH values were seen in 10 out of 37 euthyroid patients, whereas 9 out of 11 hypothyroid patients responded normally. Hypophysectomy caused an immediate but transient decrease in peak TSH in patients with a chromophobe adenoma only. The rise in serum T3 after TRH was significantly lower in hypophysectomized patients than in controls. An increase in TSH was followed by a T3 response in all patients except in 4 out of 8 euthyroid acromegalics. In patients operated on for a chromophobe adenoma the T3 response was correlated with serum T4, whereas this was not the case in acromegalics.     

Caloric restriction does not alter thyrotropin secretion in hypothyroidism

The effect of caloric restriction, as a model of nonthyroid illness, on serum thyroid hormone and TSH concentrations in hypothyroid patients was studied to determine if pituitary-thyroid function is altered in such patients, as it is in euthyroid subjects. Serum T4, T3, and TSH concentrations and serum TSH responses to TRH were measured in 5 untreated hypothyroid patients and 10 hypothyroid patients receiving T4 replacement therapy before and after restriction of caloric intake to 500 cal daily for 7 days. In 5 untreated hypothyroid patients, the mean serum T3 concentration declined 17%, from 75 +/- 14 (+/- SE) to 62 +/- 11 ng/dl. The mean basal serum TSH concentrations were 154 +/- 67 (+/- SE) microU/ml before and 161 +/- 75 microU/ml at the end of the period of caloric restriction, and the serum TSH responses to TRH were similar on both occasions. In 10 T4-treated hypothyroid patients, the mean serum T3 concentration declined 35%, from 110 +/- 8 to 71 +/- 8 ng/dl. In this group, mean basal serum TSH concentrations were 17 +/- 5.1 microU/ml before and 18.2 +/- 7.0 microU/ml at the end of the period of caloric restriction, and as in the untreated hypothyroid patients, the serum TSH responses to TRH were similar on both occasions. Mean serum T4 concentrations and serum free T4 index values did not change in either group. These results indicate that caloric restriction in both untreated and T4-treated hypothyroid patients is accompanied by 1) reduced serum T3 concentrations, as it is euthyroid subjects, and 2) no alterations in basal or TRH-stimulated TSH secretion.     

Pituitary-thyroid function in spironolactone treated hypertensive women.

Four weeks high dose spironolactone treatment (Aldactone Searle, 100 mg q. i. d.) significantly enhanced the TSH (delta max. 8.5 +/- 4.1 vs. 4.6 +/- 3.1 microunits/ml, P less than 0.05) and T3 (delta max. 32 +/- 27 vs. 11 +/- 16 ng/100 ml, P less than 0.05) responses to an intravenous TRH/LH-RH bolus injection in 6 eumenorrhoeic euthyroid hypertensive women, without affecting basal serum TSH, T3 or T4 levels or the basal and stimulated LH, FSH and prolactin values (P greater than 0.10). The mean serum testosterone, 17-hydroxyprogesterone and oestradiol levels were also similar before and during therapy. Spironolactone, possibly by virtue of its antiandrogenic action, may exert its enhancing effect on pituitary-thyroid function by modulating the levels of receptors for TRH in the thyrotrophs or by altering the T3 receptor in the pituitary permitting a greater response to TRH.     

Familial thyroid hormone resistance

Eight patients with thyroid hormone resistance were found in four generations of a kindred containing 19 members. Results of studies in this family are consistent with an autosomal dominant mode of inheritance for this disorder. The affected family members were clinically euthyroid but all had goiters and markedly increased serum thyroid hormone levels: thyroxine (T4) = 21.1 +/- 2.1 microgram/dl; triiodothyronine (T3) = 323 +/- 60 ng/dl; free T4 = 5.4 +/- 0.9 ng/dl; and free T3 = 1,134 +/- 356 pg/dl (mean +/- SD). Serum thyrotropin (TSH) levels were normal or slightly elevated in six patients and responded normally to the administration of thyrotropin-releasing hormone (TRH) and L-triiodothyronine. Two patients who had previously undergone subtotal thyroidectomy had elevated baseline serum TSH levels and exaggerated TSH responses to the administration of TRH suggesting subclinical hypothyroidism despite elevated total and free thyroid hormone levels. The absence of thyrotoxicosis and normal serum TSH levels despite elevated serum free T3 and T4 levels in the untreated members of this family are consistent with resistance of pituitary and peripheral tissues to the actions of thyroid hormones. In addition, the absence of hypothyroidism and normal responsiveness of serum TSH to TRH and L-triiodothyronine administration in untreated family members suggest that the thyroid has compensated for the hormone resistance by increased secretory activity under the control of pituitary TSH secretion.     

Effect of thyroid status and paraventricular area lesions on the release of thyrotropin-releasing hormone and catecholamines into hypophysial portal blood

TRH is a potent stimulator of pituitary TSH release, but its function in the physiological regulation of thyroid activity is still controversial. The purpose of the present study was to investigate TRH and catecholamine secretion into hypophysial portal blood of hypothyroid and hyperthyroid rats, and in rats bearing paraventricular area lesions. Male rats were made hypothyroid with methimazole (0.05% in drinking water) or hyperthyroid by daily injections with T4 (10 micrograms/100 g BW). Untreated male rats served as euthyroid controls. On day 8 of treatment they were anesthetized to collect peripheral and hypophysial stalk blood. In euthyroid, hypothyroid and hyperthyroid rats plasma T3 was 1.21 +/- 0.04, 0.60 +/- 0.04, and 7.54 +/- 0.33 nmol/liter, plasma T4 50 +/- 3, 16 +/- 2, and 609 +/- 74 nmol/liter, and plasma TSH 1.58 +/- 0.29, 8.79 +/- 1.30, and 0.44 +/- 0.03 ng RP-2/ml, respectively. Compared with controls, hyperthyroidism reduced hypothalamic TRH release (0.8 +/- 0.1 vs. 1.5 +/- 0.2 ng/h) but was without effect on catecholamine release. Hypothyroidism did not alter TRH release, but the release of dopamine increased 2-fold and that of noradrenaline decreased by 20%. Hypothalamic TRH content was not affected by the thyroid status, but dopamine content in the hypothalamus decreased by 25% in hypothyroid rats. Twelve days after placement of bilateral electrolytic lesions in the paraventricular area plasma thyroid hormones and TSH levels were lower than in control rats (T3: 0.82 +/- 0.05 vs. 1.49 +/- 0.07 nmol/liter; T4: 32 +/- 4 vs. 66 +/- 3 nmol/liter; TSH: 1.08 +/- 0.17 vs. 3.31 +/- 0.82 ng/ml). TRH release in stalk blood in rats with lesions was 15% of that of controls, whereas dopamine and adrenaline release had increased by 50% and 40%, respectively. These results suggest that part of the feedback action of thyroid hormones is exerted at the level of the hypothalamus. Furthermore, TRH seems an important drive for normal TSH secretion by the anterior pituitary gland, and thyroid hormones seem to affect the hypothalamic release of catecholamines.     

Preserved thyroidal secretion of thyroxione in acromegalic patients with suppressed hypophyseal secretion of thyrotrophin

OBJECTIVE--We have assessed the mechanisms which maintain euthyroidism in acromegalic patients despite the suppression of thyrotrophin (TSH) secretion. MATERIALS--Fourteen untreated patients with acromegaly were analysed. Ten patients were also studied after pituitary surgery. METHODS--Thyroid hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and thyroidal uptake of radioactive iodine, thyrotrophin releasing hormone (TRH) test and basal metabolic rate (BMR) were measured before and after pituitary surgery. RESULTS--Nine patients had palpable goitres. The TSH response to TRH stimulation was suppressed in eight patients, who maintained normal serum levels of total T3, T4 and free T4. The patients with normal TSH response had lower levels of free and total T4 than controls. The response of TSH to TRH correlated inversely with the serum level of total and free T4, and also with the plasma level of IGF-I (r = -0.74, P less than 0.05, n = 9). After pituitary surgery, the serum levels of total and free T4 were elevated for at least up to 6 months, with a decrease in the T3/T4 ratio and the BMR. CONCLUSION--GH may have a direct stimulatory action on the thyroid secretion of T4 possibly via increased IGF-I, despite suppressed TSH secretion. The post-operative elevation of serum T4 suggests the persistent secretion of T4 from the thyroid gland, in spite of instantaneous normalization of the accelerated conversion of T4 to T3, even after reduction of excess GH secretion.     

Effects of oestradiol benzoate on the pituitary secretion and peripheral kinetics of thyrotrophin in the rat

Previous works from this laboratory have demonstrated that oestradiol benzoate (EB) in euthyroid male and female rats induced a significant decrease in the pituitary content of TSH while serum levels of this hormone remained normal. The present work studied the effects of EB (25 micrograms/100 g body weight, during 9 days) on the peripheral metabolism of [125I]rTSH and on the pituitary and plasma concentration of TSH in euthyroid and hypothyroid rats. No significant variations were observed in [125I]rTSH kinetics of EB-treated euthyroid rats vs untreated controls: fractional turnover rate 2.8 +/- 0.2 vs 3.0 +/- 0.3%/min, distribution space 6.5 +/- 0.4 vs 6.8 +/- 0.5 ml/100 g body weight, disposal rate 18.4 +/- 2.4 vs 18.1 +/- 1.9 microU/100 g/min and extrapituitary pool 645 +/- 42 vs 614 +/- 43 microU/100 g body weight. Similarly, in hypothyroid rats oestrogens induced no changes in TSH kinetics except for an increase in distribution space (P less than 0.025). However, oestrogens decreased the pituitary pool of TSH (P less than 0.001) in both euthyroid and hypothyroid rats and increased the plasma TSH in hypothyroid animals (P less than 0.01), all vs their respective controls. Neither hypothyroid group had detectable plasma levels of T4 and T3. In summary: 1) the marked decrease of pituitary TSH with normal plasma TSH induced by EB appears unrelated to the peripheral metabolism of TSH, 2) the results from hypothyroid rats suggest that EB stimulates the release of TSH from the pituitary gland.     

Thyrotropin-releasing hormone stimulates growth hormone release from the anterior pituitary of hypothyroid rats in vitro

We have examined the interaction of thyroid hormone and TRH on GH release from rat pituitary monolayer cultures and perifused rat pituitary fragments. TRH (10(-9) and 10(-8)M) consistently stimulated the release of TSH and PRL, but not GH, in pituitary cell cultures of euthyroid male rats. Basal and TRH-stimulated TSH secretion were significantly increased in cells from thyroidectomized rats cultured in medium supplemented with hypothyroid serum, and a dose-related stimulation of GH release by 10(-9)-10(-8) M TRH was observed. The minimum duration of hypothyroidism required to demonstrate the onset of this GH stimulatory effect of TRH was 4 weeks, a period significantly longer than that required to cause intracellular GH depletion, decreased basal secretion of GH, elevated serum TSH, or increased basal secretion of TSH by cultured cells. In vivo T4 replacement of hypothyroid rats (20 micrograms/kg, ip, daily for 4 days) restored serum TSH, intracellular GH, and basal secretion of GH and TSH to normal levels, but suppressed only slightly the stimulatory effect of TRH on GH release. The GH response to TRH was maintained for up to 10 days of T4 replacement. In vitro addition of T3 (10(-6) M) during the 4-day primary culture period significantly stimulated basal GH release, but did not affect the GH response to TRH. A GH stimulatory effect of TRH was also demonstrated in cultured adenohypophyseal cells from rats rendered hypothyroid by oral administration of methimazole for 6 weeks. TRH stimulated GH secretion in perifused [3H]leucine-prelabeled anterior pituitary fragments from euthyroid rats. A 15-min pulse of 10(-8) M TRH stimulated the release of both immunoprecipitable [3H]rat GH and [3H]rat PRL. The GH release response was markedly enhanced in pituitary fragments from hypothyroid rats, and this enhanced response was significantly suppressed by T4 replacement for 4 days. The PRL response to TRH was enhanced to a lesser extent by thyroidectomy and was not affected by T4 replacement. These data suggest the existence of TRH receptors on somatotrophs which are suppressed by normal amounts of thyroid hormones and may provide an explanation for the TRH-stimulated GH secretion observed clinically in primary hypothyroidism.     

Responses to TRH and T3 suppression tests in euthyroid subjects with a family history of Graves' disease.

The relationship of Graves' disease and heredity was studied in 97 clinically and biochemically euthyroid relatives (resin T3 uptake and serum T3, T4, and TSH within normal ranges) who had more than two thyrotoxic relatives within the second degree relationship. TRH tests were preformed in all 97 cases. In 56 of the 97, T3 suppression tests were performed shortly after the TRH test. Results revealed that 29 of the 97 (29.9%) showed an abnormal response to TRH. fourteen of these (14.4%) revealed no response or a hyporesponse, and 15 (15.5%) revealed a hyperresponse to TRH. Four of 56 (7.1%) were T3 nonsuppressible. Seven individuals who showed no response or a hyporesponse to TRH consisted of 2 nonsuppressible and 5 suppressible subjects. In 14 non- or hyporesponsive cases, serum T3 (1.51 +/- 0.05 ng/ml; mean +/- SE) and T4 (9.91 +/- 0.31 micrograms/dl) were significantly higher compared with those of normal responders (1.30 +/- 0.04 ng/ml, 8.57 +/- 0.21 micrograms/dl; P less than 0.001) or hyperresponders (1.16 +/- 0.06 ng/ml, 7.77 +/- 0.63 micrograms/dl; P less than 0.01). There was no correlation between TRH responsiveness and T3 suppressibility. A relatively high occurrence of thyroglobulin and microsomal antibodies was observed, further suggesting a hereditary predisposition. The findings indicate that even in euthyroid relatives with a family history of Graves' disease who have no clinical or biochemical abnormalities of thyroid dysfunction, many have abnormalities in TRH responsiveness, T3 suppressibility, and thyroidal antibodies.     

Normal response to thyrotrophin releasing hormone (TRH) in familial thyroxine-binding globulin deficiency.

The response in serum thyrotrophin (TSH) to thyrotrophin releasing hormone (TRH) has been studied in 5 euthyroid patients with familial thyroxine-binding globulin (TBG) deficiency. Total serum thyroxine (T4), serum triiodothyronine (T3) and free T4 index and free T3 index were significantly and equally decreased, but in spite of these findings the serum TSH and response to TRH was normal. The TRH test seems to be a better indicator of the euthyroid state in familial TBG deficiency than the measurement of free T4 and free T3 in serum.     

The influence of dexamethasone on serum thyrotrophin and thyrotrophin synthesis in the rat

Glucocorticoid hormones suppress circulating concentrations of thyrotrophin (TSH), but their effect on synthesis of TSH in the pituitary gland is unclear. We have examined the influence of the glucocorticoid dexamethasone on serum TSH, pituitary TSH content and TSH beta- and alpha-subunit mRNA concentrations in pituitary cytoplasm in both the euthyroid and hypothyroid rat, and following triiodothyronine (T3) treatment in the hypothyroid rat. The rise in serum TSH in hypothyroidism was attenuated in animals treated with dexamethasone; in addition the suppression of serum TSH 6 h after T3 administration to hypothyroid rats was enhanced by dexamethasone. In contrast to the changes in serum TSH, pituitary TSH content was unaffected by dexamethasone. Furthermore dexamethasone had no significant effect on changes in pituitary cytoplasmic TSH beta- and alpha-subunit mRNA levels with thyroid status. These findings demonstrate that dexamethasone exerts differential effects on serum TSH levels and TSH biosynthesis which contrast with those of thyroid hormones.     

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.     

Hyperthyroidism caused by a pituitary thyrotrophin-secreting tumour with excessive secretion of thyrotrophin-releasing hormone and subsequently followed by Graves' disease in a middle-aged woman

A 46-year-old woman had signs of thyrotoxicosis and galactorrhoea. Serum immunoreactive TSH and its alpha-subunit increased in the presence of high serum triiodothyronine (T3), thyroxine (T4), and free T4 concentrations, whereas beta-subunit TSH was undetectable. Exogenous TRH failed to increase serum TSH. Serum TSH was markedly suppressed by glucocorticoid, but was increased by antithyroid drug. L-Dopa or bromocriptine partially suppressed, but nomifensine had no influence on serum TSH. Serum prolactin (Prl) was above normal and markedly increased by TRH, but depressed by bromocriptine and not suppressed by nomifensine. Plasma TRH was normal in the hyperthyroid state, but was increased by glucocorticoid and antithyroid drug. Excess thyroid hormone depressed plasma TRH concentrations. Basal serum GH levels were constantly low. Transsphenoidal removal of the tumour normalized serum hormones (T3, T4 free T4, TSH, alpha-subunit and Prl), and eradicated the clinical signs of hyperthyroidism and galactorrhoea. Histological study of the tumour tissue demonstrated both thyrotrophes and somatotrophes. A reciprocal relationship between serum TSH and T4 concentrations shifted to a higher level before but was normalized after removal of the tumour. Ten months later, the clinical signs of thyrotoxicosis and the increase in serum thyroid hormone recurred without a concomitant increase in serum TSH and its alpha-subunit. Thyroidal auto-antibodies were slightly positive, but thyrotrophin-binding inhibitor immunoglobulin (TBII) was negative. Administration of antithyroid drug produced a euthyroid state, but 3 years later, discontinuation of the treatment resulted in recurrent hyperthyroidism without suppressed plasma TRH and with no evidence of regrowth of the pituitary tumour. It is suggested that the patient initially had hyperthyroidism owing to excessive TSH secretion from the tumour caused by abnormal TRH secretion, and subsequently had hyperthyroidism owing to Graves' disease.     

Chronologic study of free T3 and T4, of responses to TRH and of the suppression test during treatment of Basedow's disease]

32 patients with Graves' Disease were investigated before treatment, during ATD therapy and after recovery with a normal T3 suppression test. Before treatment, TRH response was negative with elevated values of plasma TT4, AFT4, TT3 and AFT3. The 3d, 6 - 9 and 12-18 months and after recovery, several patients remained unresponders to TRH despite normal AFT4 and AFT3 in serum. In an opposite way some patients were responders, 1 month after ATD withdrawal, at the 6-9 month, with elevated values of AFT4 or AFT3. The discrepancy between TRH response and T3 suppression test is pointed out after recovery. The unresponsiveness of TSH to TRH unexplained by serum AFT4 or AFT3 may be due to : 1) a decrease in pituitary TSH stores. 2) an unknown factor inhibiting TSH release during Graves' disease 3) an hypersensitivity of thyreotrop cells to T3.     

Low serum triiodothyronine (T3) and hypothyroidism in anorexia nervosa.

Measurements of serum thyroid hormones were compared in 22 patients with typical anorexia nervosa and 22 euthyroid control subjects. Serum total triiodothyronine (T3) was (mean +/- (SE) 62.1 +/- 7.1 ng/100 ml in anorexia patients and 115.2 +/- 8.4 ng/100 ml in control subjects (P less than 0.001). Serum adjusted thyroxine (T4Adj) was significantly different in the anorexia (7.1 +/- 0.4) and control (8.2 +/- 0.4) groups. Serum T3 was subnormal in 63% and T4Adj subnormal in 36% of the 22 anorexia patients. The mean serum T4/T3 in anorexia patients (158 +/- 19) was higher than that in the control subjects (88 +/- 5.5, P less than 0.005) or in 18 patients with hypothalamic or pituitary hypothyroidism (77.9 +/- 10.1, P less than 0.001). Following weight gain in 6 anorexia patients, there was a significant rise in serum T3 without change in T4Adj concentration. The Achilles reflex half-relaxation time (ART) in 38 anorexia patients was 348.6 +/- 10 msec compared with 280 +/- 30 msec in 168 normal age-matched subjects (P less than 0.001), and was prolonged (greater than 340 msec) in 65% of these 38 patients. In 18 anorexia patients with measured ART, T3 and T4Adj, the mean ART was longer 376.1 +/- 20 msec) in 10 with subnormal T3 than in 8 patients with a normal T3 (294.7 +/- 13.2 msec, P less than 0.01). There was no significant difference in the mean ART between patients with a normal or low serum T4Adj. Administeration of oral T3 40 mug/day for 4 weeks to 11 anorexia patients caused a significant reduction (P less than 0.001) in mean ART of 108.7 +/- 9.6 msec compared with 17.7 +/- 3.3 msec in 18 normal subjects. There was a normal peak serum TSH and a rise in mean total serum T3 of 47 +/- 12 ng/100 ml (range 11-100 ng/ml) in 7 of 8 patients following 200 mug of iv thyrotropin releasing hormone (TRH). The fall in serum TSH was delayed in 6 patients. Assessment of hypothalamic control of thyroid function in 3 patients using the method of thyroidal iodide release (TIR) showed impairment of the normal diurnal variation and response to administered glucocorticoids. In the absence of a space-occupying pituitary lesion, the TRH and TIR data suggest a central inhibition of thyroid function, possibly by impairment of hypothalamic TRH release. In addition, a probable decrease of peripheral T4 to T3 conversion leads to low serum T3 concentrations. The prolonged basal ART and the marked ART reduction in response to T3 administration is attributed to correction of tissue thyroid hormone deficiency in the anorexia patients.     

Transient recurrence of hyperthyroidism after delivery in Graves' disease

Four patients with Graves' disease whose hyperthyroidism was in remission following antithyroid therapy were studied without any treatment during and after pregnancy. In the 8-9th month of pregnancy, they were in a euthyroid state with serum levels of thyroxine (T4) of 18.9, 11.9, 11.2 and 14.5 mug/100 ml, triiodothyronine (T3) of 273, 190, 162 and 244 ng/100 ml and T3 resin sponge uptake (RT3U) of 22, 14, 19 and 16% respectively (normal pregnant range: T4, 7.0-15.0, T3 140-250, RT3U 15-25). At 1-3 months after delivery, hyperthyroidism recurred, as manifested by T4 levels of 17.2, 14.5, 16.7 and 21.7 mug/100 ml, T3 levels of 320, 225, 390 and 464 ng/100 ml and RT3U levels of 34, 34, 43, and 41% respectively (normal non-pregnant range: T4 5.0-12.0, T3 90-190, RT3U 24-37). The recurrence of hyperthyroidism was also demonstrated by serial measurements of serum free T4 and free T3. The thyroid function of all four patients returned spontaneously to the normal range at 4-6 months after delivery. One patient developed hypothyroidism for a short period before regaining the euthyroid state. The titers of serum anti-thyroid microsomal antibodies and levels of serum immunoglobulins decreased during pregnancy and increased transitorily at the time of hyperthyroidism after delivery. Similarly, increases in the levels of thyroid hormones, anti-thyroid antibodies and immunoglobulins were observed transitorily following spontaneous abortion after 4 months' pregnancy in one case. We suggest that the transient recurrence of hyperthyroidism in Graves' disease may be induced by immunological changes after delivery.     

Blunted nocturnal TSH surge does not indicate central hypothyroidism in patients after pituitary surgery.

The thyrotropin-releasing hormone stimulation test (TRH test) is commonly used as part of the endocrine evaluation after pituitary surgery. However, some patients with a normal thyrotropin (TSH) response to TRH after pituitary surgery develop central hypothyroidism during follow-up. On the other hand, hypothyroidism does not necessarily ensue in patients with a blunted TSH response. As TSH is secreted in a pulsatile fashion with maximum secretion in the early morning, we investigated whether measurement of the nocturnal TSH surge is useful for predicting development of thyrotropic function after pituitary surgery. Serum TSH concentrations were measured at hourly intervals from 16.00 h to 06.00 h in 13 healthy volunteers and in 10 patients within 2 weeks after pituitary surgery. A standard TRH test using i.v. injection of 200 microg synthetic TRH was performed the next morning. Three and six months later thyroid function was reassessed in all patients by measuring thyroid hormones and TSH. Healthy volunteers showed a clear nocturnal TSH surge from a nadir of 0.55 +/- 0.27 microIU/ml at 18.00 h to a peak concentration of 1.82 +/- 0.97 microU/ml at 06.00 h (p = 0.0015). DeltaTSH during TRH test was 6.31 +/- 2.27 microIU/ml. In contrast, following pituitary surgery, patients invariably showed a blunted nocturnal increase in TSH concentration, which was 0.27 +/- 0.20 microIU/ml at 18.00 h and 0.33 +/- 0.26 microIU/ml at 06.00 h (p = 0.044). DeltaTSH during TRH test was 1.99 +/- 2.51 microIU/ml and was subnormal in 8 out of 10 patients. Levothyroxine supplementation was initiated in two of these patients, because free T4 levels were also subnormal and clinical hypothyroidism was present. In the remaining patients with subnormal TRH response, no case of central hypothyroidism was identified at the follow-up visits after 3 and 6 months. We conclude from these data that both nocturnal TSH surge and TRH test are subnormal after pituitary surgery and do not indicate that central hypothyroidism will develop.     

Thyrotropin receptor autoantibodies are associated with continued thyrotropin suppression in treated euthyroid Graves' disease patients

Antithyroid treatment effectively restores euthyroidism in patients with Graves' hyperthyroidism. After a few months of treatment, patients are clinically euthyroid with normal levels of thyroid hormones, but in many patients TSH levels remain suppressed. We postulated that TSH receptor autoantibodies could directly suppress TSH secretion, independently from thyroid hormone levels, via binding to the pituitary TSH receptor. To test this hypothesis, we prospectively followed 45 patients with Graves' hyperthyroidism who were treated with antithyroid drugs. Three months after reaching euthyroidism, blood was drawn for the analysis of thyroid hormones, TSH, and TSH binding inhibitory Ig (TBII) levels. After 6.7 +/- 1.5 months since start of antithyroid treatment, 20 patients still had detectable TBII levels, and 25 had become TBII negative. The two groups had similar levels of free T(4) and T(3), but TBII-positive patients had lower TSH values than TBII-negative patients: median 0.09 (range < 0.01-4.30) mU/liter vs. 0.84 (0.01-4.20; P = 0.015). In addition, TSH levels correlated only with TBII titers (r = -0.424; P = 0.004), and not with free T(4) or T(3) values. Our findings suggest that TBII suppress TSH secretion independently of thyroid hormone levels, most likely by binding to the pituitary TSH receptor.