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.     

AUGMENTATION OF PITUITARY THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE DURING SUBPHYSIOLOGICAL TRI-IODOTHYROININE THERAPY IN HYPOTHYROIDISM

Five hypothyroid patients are reported with increased pituitary TSH response to TRH during administration of T3. In one patient treated with intravenous T3, 50 micrograms daily for 10 days, the peak serum TSH and total pituitary TSH reserve after TRH increased coincident with increases in serum T3 and T4 levels and a decrease in the basal TSH concentration. In four patients treated with oral T3, the peak serum TSH and total pituitary TSH reserve after TRH increased during administration of subphysiological doses of T3. Peak serum T3 levels occurred 4 h after ingestion and increased progressively with increasing T3 doses. Serum TSH levels decreased modestly with the nadir at 4 h after T3 ingestion and then returned to basal levels at 24 h. Augmentation of TSH responses to TRH occurred simultaneously with decreases in serum cholesterol, as well as increases in the pituitary prolactin response to TRH, and increase in the GH and cortisol response to insulin induced hypoglycaemia where these responses could be studied. These data demonstrated a positive effect of subphysiological T3 therapy in these hypothyroid patients on the TSH response to TRH as well as increases in the responses of other pituitary hormones to stimulation.     

Effects of neonatal exposure to TRH on development of the pituitary-thyroid axis in rats

TRH (10 and 1000 micrograms/kg body weight) was administered ip daily to neonatal rats from day 0 to 9 after birth (Neo-TRH rats) and their pituitary-thyroid axis was examined on days 4, 10, 21 and 90. The pituitary TSH content in Neo-TRH rats was significantly smaller than in controls on days 4 and 10. The serum TSH levels in Neo-TRH rats were significantly lower than those in controls on days 4 (male group only), 10 and 21 (only 10 micrograms/kg group). The serum T4 levels in Neo-TRH rats were lower than in controls on day 10. The reduced pituitary TSH content and serum TSH and T4 were restored to control levels on day 90. However, the response of serum TSH to exogenous TRH (10 micrograms/kg/ip) was blunted in Neo-TRH rats on days 10, 21 and 90. It is concluded that repetitive administration of TRH during the neonatal period suppresses the pituitary-thyroid axis in neonatal life, even after the basal hormone level has been restored to normal.     

Use of melatonin and synthetic TRH to determine site of pineal inhibition of TSH secretion.

An experiment was performed on 21-day-old male rats to determine the combined effects of pinealectomy, constant light and darkness, and intraperitoneal (i.p.) thyrotropin-releasing hormone (TRH) on pituitary and plasma radioimmunoassayable thyrotropin (TSH), serum thyroxine (T4), and pituitary, thyroid and body weights at the age of 25 days. In saline-treated rats, pinealectomy or constant illumination decreased pituitary TSH and increased plasma TSH and serum T4. Constant darkness with an intact pineal, however, decreased all 3 of these parameters. When i.p. TRH was injected all rats showed an increase in plasma TSH as compared to saline-treated controls. Another study was performed on 25-day-old male rats to determine the effects of intraventricular administration of melatonin (MEL) alone, and intraventricular MEL plus i.p. TRH on pituitary and plasma TSH. MEL decreased plasma TSH levels as compared to non-treated and saline-treated controls, whereas the concurrent administration of TRH obviated the effect of MEL and increased plasma TSH levels above those of the control animals. The results are interpreted as indicating that the inhibitory effect of the pineal in dark-reared, sham-operated prepuberal male rats is exerted at the level of hypothalamic secretion of TRH.     

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.     

Hypothyroidism of hypothalamic origin in pyridoxine-deficient rats

Pyridoxine-deficient young rats (3 weeks old) had significantly reduced levels of pituitary TSH, serum thyroxine (T4) and tri-iodothyronine (T3) compared with pyridoxine-supplemented rats. The status of the pituitary-thyroid axis of normal, pyridoxine-supplemented and pyridoxine-deficient rats was evaluated by studying the binding parameters of [3H](3-methyl-histidine2)TRH in the pituitary of these rats. The effects of TRH and T4 injections on pituitary TSH and serum TSH, T4 and T3 of these two groups were also compared. The maximal binding of TRH receptors in the pituitary of pyridoxine-deficient rats was significantly higher than that of pyridoxine-supplemented control and normal rats, but there was no change in the binding affinity. Treatment with TRH stimulated TSH synthesis and release. It also increased serum T4 and T3 in both pyridoxine-supplemented and pyridoxine-deficient rats. Treatment with T4 decreased serum and pituitary TSH in both pyridoxine-supplemented and pyridoxine-deficient rats, compared with saline-treated rats. The increased pituitary TRH receptor content, response to TRH administration and the fact that regulation at the level of the pituitary is not affected in the pyridoxine-deficient rat indicates a hypothalamic origin for the hypothyroidism of the pyridoxine-deficient rat.     

Comparison of the effects of pulsatile and continuous TRH infusion on TSH release in men

Pulsatile secretion of hypothalamic releasing factors modulates the release of pituitary hormones. To compare the effects of pulsatile and continuous administration of TRH on TSH secretion, we studied six healthy euthyroid 20- to 38-year-old men by obtaining blood samples every 20 minutes for 12 hours (8 AM to 8 PM) during five days of study. TRH was administered according to the following schedule: day 1 (no TRH, control); day 2 and subsequent day 3 (20 micrograms IV bolus of TRH every 96 minutes); 6 to 17 days rest; then consecutive days 4 and 5 (continuous infusion of 20 micrograms TRH/96 minutes) for 12 hours on and 12 hours off. The highest mean serum TSH levels occurred on the first day of pulsatile TRH. Serum TSH on pulsatile days 1 and 2 and continuous day 1 was significantly greater than on the control day. Similarly, the mean TSH on each day of pulsatile TRH was greater than the mean TSH on the corresponding days of continuous TRH administration. The highest serum T4 and T3 levels were observed on pulsatile day 2, suggesting that the decrease in serum TSH on this day was due to thyroid hormone negative feedback at the pituitary. The mean T4 and T3 values on continuous day 1 and 2 did not differ significantly, suggesting that other factors, including "down-regulation" of the pituitary TRH receptors by the continuous TRH infusion may be involved in the further decline of TSH levels on continuous day 2. We conclude that pulsatile TRH infusion releases more TSH, T3, and T4 than the corresponding amount of TRH administered continuously.(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of hypothyroidism and hypoprolactinemia by growth hormone producing rat pituitary tumors.

The GH3 rat pituitary tumor cell line which secretes both growth hormone (GH) and prolactin (PRL) stopped releasing PRL when transplanted to animals; furthermore, it suppressed PRL production by the hosts' pituitary glands. When the same tumor was transferred back to cell culture, PRL production resumed. The PRL to GH ratio in cell culture medium and cells ranged from 5 to 1 while in the tumor and serum of the host animals it averaged 0.09 and 0.001, respectively. To investigate further this phenomenon, female rats were transplanted with GH3 tumors (T) and compared to intact normal (N) and to thyroidectomized (Tx) rats. T animals were larger and had splanchnomegaly but smaller pituitaries and thyroids. Serum PRL concentrations in the basal state were decreased, as were levels of triiodothyronine (T3), thyroxine (T4), and free T4 index. Despite reduced serum thyroid hormone concentrations, and in contrast to Tx animals, the serum thyrotropin (TSH) level in T rats was not elevated and they did not show a supranormal TSH response to thyrotropin-releasing hormone (TRH) administration. The PRL response to TRH in T animals was completely abolished while all N and Tx animals responded by a significant increase in serum PRL. Serum corticosteroids and estrogens were normal in T rats. Pituitary content of PRL was decreased and that of TSH increased in T rats. Tx animals, however, had a reduced pituitary content of PRL, TSH, and GH. When GH3 cells were grown in cell culture media containing serum from T animals, there was a reduction of PRL content in cells and released in the medium. Addition of T3 to the T serum did not alter its suppressive effect on PRL nor did rat GH added to N serum alter PRL production and release in vitro. In a preliminary experiment, rats injected ip with 50 mug hGH in two divided doses for eighteen days, suppressed serum T4 and T3 concentrations; pituitary content of TSH was significantly increased and that of PRL slightly decreased. Injection with 250 mug oPRL or saline, on the same schedule and for the same length of time, had no significant effect on the levels of serum thyroid hormones. Thus, GH, but also possibly other substance(s) secreted by GH3 tumors in vivo a) suppress the production of tumor and pituitary PRL; b) suppress the release of TSH, causing mild hypothyroidism; c) inhibit the PRL and TSH responses to TRH; and d) decrease the production of PRL in tissue culture. Although no simple and unifying theory could explain these findings, an hypothesis implicating somatomedin is presented.     

THE TRIIODOTHYRONINE AND THYROXINE RESPONSE TO THYROTROPHIN-RELEASING HORMONE IN THE ASSESSMENT OF THE PITUITARY-THYROID AXIS

The thyroidal component of the response to thyrotrophin releasing hormone (TRH) has been studied by measurement of serum triiodothyronine (T3) and thyroxine (T4).
In normal subjects a significant increase in serum T3 followed intravenous administration of TRH 200 μg. A less consistent increase was detected in serum T4 concentration.
Oral TRH at a dose of 40 mg caused a significant rise in serum T4 in normal subjects. The increase in T4 at 24 hr was considered to provide a convenient index of pituitary and thyroidal response.
Fourteen patients with pituitary disease, of whom twelve were euthyroid, were investigated by an oral TRH test. The majority of these patients retain a normal pituitary TSH reserve though a small group can be identified in whom it is diminished.
A significant correlation was obtained between the T4 and TSH response to oral TRH. It is suggested that measurement of serum concentration of thyroid hormone is of value in the assessment of the pituitary response to TRH and the integrity of the pituitary-thyroid axis.     

Effect of neonatal hyperthyroidism upon the regulation of TSH secretion in rats

The neo-T4 syndrome was induced in rats by administration of 30 micrograms T4/in 5 doses starting on the first day of life. In the first experiment (A), neo-T4 and saline-control rats were divided into two populations, one of which was thyroidectomized on day 25. All rats then received 5 micrograms T4/100 g b.w. on days 42, 43 and 44, and were sacrificed on day 45. In the second experiment (B), neo-T4 and saline-control rats were thyroidectomized at 25 days of age and were sacrificed 10, 20 and 40 days after the operation. In both experiments, pituitary and plasma TSH and pituitary GH were determined. T4 administration has the same effect on plasma and pituitary TSH regulation in neo-T4 and control rats, thyroidectomized or not. The increase in pituitary GH produced by T4 is smaller in the thyroidectomized neo-T4 animals. The comparison between T4-induced increases of pituitary TSH in thyroidectomized neo-T4 and saline control-rats, and the corresponding decreases in non-thyroidectomized animals suggests an alteration in TSH synthesis which has previously been compared with that found in rats with lesions of the hypothalamus. However, the changes in pituitary and plasma TSH levels in neo-T4 rats at different intervals after thyroidectomy do not coincide with those described for rats with hypothalamic lesions. The possible perturbation in pituitary TSH synthesis proposed for neo-T4 rats accords with the lack of response to TRH found in adult animals treated with thyroxine, an effect which remains even when plasma T4 levels decrease.     

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.     

Peripheral resistance to thyroid hormone in an infant

Peripheral resistance to thyroid hormone, a syndrome characterized by elevated serum total and free thyroid hormone levels and abnormal TSH suppression without manifestations of hyperthyroidism, was studied in a clinically euthyroid 6-month-old infant. Initial serum concentrations of T4, T3, and TSH were 22.1 micrograms/dl, 334 ng/dl, and 7.6 microunits/ml, respectively; infusion of synthetic TRH increased the serum TSH to 47.4 microunits/ml, an exaggerated response. Pituitary insensitivity to T3 was investigated by measuring these parameters in response to consecutive 7-day courses of increasing doses of T3. Four times the calculated replacement dose of T3 (40 micrograms/day) was required to normalize the serum T4 and the serum TSH response to TRH. After administration of 80 micrograms/day T3, the serum TSH response to TRH was virtually abolished, but no clinical signs of thyroid hormone excess were observed. High doses of T4 blunted the serum TSH response to TRH in a manner similar to T3. Prednisone also decreased the TSH response to TRH but had no effect on serum thyroid hormone concentrations. In an attempt to determine the mechanism of thyroid hormone resistance, specific nuclear T3 binding was compared in cultured skin fibroblasts from the patient and a normal infant. Normal fibroblast nuclei had a single binding site with a Ka of 3.1 X 10(9) M-1. In contrast, the Scatchard plot of the patient's T3 binding was curvilinear, compatible with a high affinity site that had a Ka (4.2 X 10(9) M-1) similar to that of the normal fibroblasts and a second low affinity site (Ka = 2.7 X 10(8) M-1). Supraphysiological concentrations of T3 elicited a dose-related increase in fibroblast glucose consumption, which was similar in cells from both the patient and from a normal infant. In conclusion, pituitary and peripheral resistance to thyroid hormone has been demonstrated in this infant, but despite the abnormality of nuclear T3 binding, the cellular mechanisms remain unclear.     

Effect of dexamethasone on prolactin and TSH responses to TRH and metoclopramide in man.

We studied the effects of administration of dexamethasone, 2 mg orally every 6 h, for 5 days on the thyrotropin-releasing hormone (TRH)-induced release of prolactin (PRL), thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) in 9 normal men and on the metoclopramide-induced release of PRL in 7 normal men. Dexamethasone suppressed the baseline serum levels of PRL, TSH and T3. The administration of dexamethasone blunted the PRL and TSH response to TRH; the blunted TSH response resulted in a decreased T3 and T4 response to TRH after dexamethasone. Following dexamethasone administration, the PRL response to metoclopramide, a dopamine antagonist which acts at the hypothalamicpituitary level to stimulate PRL secretion, was blunted in 7 normal men. The data suggest that short-term administration of pharmacological doses of glucocorticoids suppress the secretion of PRL and TSH by a direct effect on the anterior pituitary gland.     

Thyrotropin dysregulation during a non-thyroidal illness: transient hypothalamic hypothyroidism?

Both the basal TSH concentration and the TSH response to iv TRH administration are noted to be decreased at the peak of an acute critical illness. Moreover, an impaired release from hypothalamus has been documented in rats with uncontrolled diabetes, suggesting hypothalamic dysfunction in a non-thyroidal illness. However, the exact inference and mechanism of this impaired TSH secretary pattern is not well defined in humans during a non-thyroidal illness. Therefore, this study assessed hypothalamic pituitary thyroid axis by determination by T4, T3, and T3 resin uptake prior to and TSH concentrations, prior to, as well as following, iv TRH administration at an interval of 30 min up to 2 hours on three successive mornings during a severe, critical, fatal illness in five previously known euthyroid subjects. TSH response to iv TRH administration was expressed as a maximal absolute change (delta TSH) and a cumulative response (CR TSH), calculated as the sum of changes from the basal level at each specific time period for up to 120 min. Serum T4, T3 and TSH concentrations on day 1 of the TRH administration were significantly lower than normal values as well as the values documented previously in the same individuals prior to hospitalization. T3 resin uptake was increased simultaneously. Moreover, serum T4, T3, and T3 resin uptake remained significantly unaltered on three successive days of iv TRH administration. However, basal serum TSH rose significantly with a parallel TSH response to iv TRH administration, as reflected by a progressive rise in delta TSH as well as CR TSH over this three-day period, with normalization of the TSH responses by the third day. Therefore, impaired TSH secretary pattern and altered thyroid hormone concentrations noted in subjects with acute critical illness may be attributed to the presence of a transient hypothalamic hypothyroidism.     

The effect of 3,5,3'-triiodothyronine or thyrotropin-releasing hormone on pituitary hormone responses to arginine infusions in hypothyroid patients

Serum PRL and GH responses to a control arginine infusion were determined in seven hypothyroid patients. During the infusion, basal TSH levels fell slightly but significantly. On a following day, a second arginine infusion was performed, 5 min after iv injection of 500 micrograms TRH. The mean peak PRL response was enhanced 6-fold and occurred earlier, while the mean peak GH response remained unaffected. Mean peak TSH levels were only 128% above baseline after TRH. On a third day, a third arginine infusion was performed 4 h after oral administration of 100 micrograms T3; mean serum T3 levels were increased from 57 to a peak of 481 ng/dl 5 h after T3. The mean GH response was significantly reduced by 71% at 90 min, with an overall reduction of the GH output of 47%, while the PRL response remained unaffected. Thus, acute elevation of serum T3 levels in hypothyroidism appear to inhibit the mean GH response to arginine.     

Reduced thyroid function after thyrotropin stimulation.

The course of serum T4 and T3 return to baseline after TSH stimulation was studied in two groups at six normal subjects over 28 days after im bovine TSH (b TSH; 0.15 U/kg). In the first group of six subjects, serum bTSH rose from undetectable levels to a mean peak of 5.6 +/- 0.5 ng/ml (mean +/- SE) at 2 h, and fell below detectable levels by 24 h with a t1/2 of 7 +/- 1 h. T4 rose to a peak 59 +/- 10% above basal levels within 24 h, returned to basal levels on day 7, then dropped below basal levels on days 9-24, with a nadir of -16 +/- 4% on day 14. Free T4 paralleled T4 levels. T3 rose to a peak 104 +/- 28% above basal at 24 h, then fell faster than T4, reaching basal levels by day 4. During the period of low T4, T3 was at or below basal levels. Human TSH (h TSH) concentration dropped when T4 and T3 rose, but did not rise above basal levels when T4 and T3 fell below basal levels. Neither a T3 elevation nor an increased percentage of free T4 was present during the time of reduced T4 levels. The same pattern of thyroidal response was seen in the second group of six subjects. In this second group, hTSH response to repeated TRH challenge was studied. During the period of reduced T4 and T3, hTSH response to TRH was diminished. On day 28, T4, T3, hTSH, and hTSH response to TRH returned to basal levels. We conclude that the brief elevation of T4 and T3 after bTSH stimulation exerts a suppressive effect on the pituitary which extends beyond the period of elevated thyroid hormone levels, and that delay in pituitary recovery is the mechanism of the decreased thyroid function after acute bTSH stimulation.     

Thyrotropin secretion in thyrotoxic and thyroxine-treated patients: assessment by a sensitive immunoenzymometric assay

A new TSH immunoenzymometric assay was found to be capable of discriminating between the serum TSH values of normal subjects [2.28 +/- 1.02 (+/-SD); range, 0.6-6.5 microU/ml] and those of clinically euthyroid, antithyroid drug-treated (n = 22) or clinically thyrotoxic (n = 34) patients. While a wide spectrum of basal TSH values was found in the antithyroid drug group [ranging from undetectable (less than 0.05 microU/ml: 57%) to 17.9 microU/ml], all clinically thyrotoxic patients had undetectable values. In 33 patients receiving chronic oral T4 therapy for treatment of goiter (n = 15) or thyroid cancer (n = 18), 48% (6 of 33) had undetectable basal TSH levels and no TSH response to TRH stimulation. Detectable TSH levels were found in 42% (14 of 33), and TRH responsiveness was found in 52% (17 of 33). The TSH response to TRH stimulation was less than 2.0 microU/ml in 7 patients. Serum free T4 index, free T3 index, and free T4 levels and oral T4 dosage were inferior predictors of TRH responsiveness compared to the basal TSH value. No patient receiving more than 0.2 mg T4 daily or having a free T4 index above 18, a free T3 index above 205 or a free T4 level above 3.0 ng/dl had a TSH response to TRH. Seventy-six percent (16 of 21) of the patients, when reevaluated 1-6 weeks after increased oral T4 dosage, had a significant reduction in their serum thyroglobulin level. This was true of both patients with initially detectable (11 of 14) as well as undetectable (5 of 7) basal serum TSH levels. These findings support the concept that subnormal and, for that matter, as yet undetectable levels of circulating TSH may exert stimulatory effects on thyroid tissue.     

Prolactin release in man: influence of cimetidine, thyrotrophin-releasing hormone and acute hypercalcaemia

The responsiveness of anterior pituitary lactotrophs and thyrotrophs to cimetidine (Cim) was investigated in healthy volunteers. Four-hundred mg Cim, injected iv, raised the serum prolactin level (Prl) from 14 +/- 2 to 58 +/- 9 ng/ml (P less than 0.001), but left the serum thyrotrophin level (TSH) unaffected. Acute hypercalcaemia, induced by iv infusion of calcium, blunted this Cim-elicited Prl response by 35 +/- 4% (P less than 0.01). Iv injection of 25 micrograms thyrotrophin-releasing hormone (TRH) had similar Prl-releasing potency as 400 mg Cim, and raised the Prl level from 14 +/- 1 to 51 +/- 6 ng/ml (P less than 0.001). In contrast to Cim, TRH also increased the TSH level significantly. Although oral pre-treatment with Cim for 3 days (1000 mg/day) failed to affect the Prl response to TRH in this study, iv injection of the drug more than doubled the above mentioned Prl response to TRH. The TSH response to TRH remained unaffected both by oral and by iv administration of Cim. These results imply that acute changes in serum calcium affect the release pattern of Prl, and that iv administration of Cim may add Prl-releasing power to TRH in healthy individuals.     

The thyrotrophin response to thyrotrophin releasing hormone during treatment in patients with Graves' disease.

Thyrotrophin releasing hormone (TRH) tests were performed at 4 or 8 weeks intervals, after the initiation of anti-thyroid treatment in 15 patients with Graves' disease. All TRH test were negative as long as the serum levels of thyroxine (T4) and triiodothyronine (T3) were elevated, and normalization of the serum levels of these hormones always occurred before the response to iv TRH was restored. In 13 patients the time from the patients for the first time were registered as biochemically euthyroid varied from 0-9 months (mean 3.1 months), before TRH response was restored. Two patients were still TRH non-responsive at the end of the study, even though they had been biochemically euthyroid for as long as 17 and 18.5 months. The TRH test, therefore, is not helpful in the evaluation of the effect of anti-thyroid treatment in patients with Graves' disease. There was an increase in the serum level of (TSH) from 3.4 +/- 0.3 (SEM) to 4.3 +/- 0.5 (SEM) ng/ml (P less than 0.05), and a decrease in the serum level of total T4 from 19.4 +/- 1.1 (SEM) to 5.8 +/- 0.8 (SEM) microng/100 ml in 13 patients from the first examination until the last time they were examined before restored TRH response. This finding shows that the pituitary gland has retained its ability to synthesize and secrete TSH even though no TSH could be released by iv TRH. In 6 TRH non-responsive patients with Graves' disease, serum TSH levels were suppressed from 2.5 +/- 1.2 (SEM) ng/ml before the administration of a single dose of 3 mg T4 orally, to 0.9 +/- 0.2 (SEM) ng/ml, 7 days after the T4 administration. Thus, the negative feed-back effect on the pituitary gland of the thyroid hormones is operating in these patients. This finding indicates that the TRH non-responsiveness in euthyroid patients with Graves' disease is not due to pituitary depletion of TSH, since the negative feed-back effect of the thyroid hormones is operating normally.     

Impairment of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-alpha (cachectin)

Tumor necrosis factor-alpha (TNF; cachectin), a peptide secreted from stimulated macrophages, mediates some of the metabolic derangements in inflammatory and neoplastic disorders. To determine whether TNF is responsible for the changes in hypothalamic-pituitary-thyroid (HPT) function in nonthyroid illnesses, we administered synthetic human TNF to male Sprague-Dawley rats. The rats were given TNF or saline (control; both pair fed and nonpair fed) iv (six to eight per group). HPT function was tested 8 h after administration of 200 micrograms TNF/kg BW, 8 h after 5 days of 150 micrograms TNF/kg BW, and 8 h after a 3-day series of 50, 200, and 800 micrograms TNF/kg BW. The single injection of 200 micrograms TNF/kg significantly reduced (all P less than 0.05) serum TSH, T4, free T4, T3, and hypothalamic TRH compared to the corresponding hormone levels in saline-injected control rats. Serum TSH and hypothalamic TRH recovered to normal levels after 5 days of 150 micrograms/kg TNF treatment. With the increasing daily doses of TNF, serum TSH and hypothalamic TRH fell significantly. Hepatic 5'-deiodinase activity was reduced after 1 day of TNF treatment, but increased after the 3-day series of injections. TNF treatment reduced pituitary TSH beta mRNA, but did not affect alpha-subunit mRNA. TNF treatment also reduced thyroid 125I uptake and reduced thyroidal release of T4 and T3 in response to bovine TSH, but did not change the TSH response to TRH. TNF treatment reduced the binding of pituitary TSH to Concanavalin-A, indicating that it alters the glycosylation of TSH. The TSH with reduced affinity for this lectin had reduced biological activity when tested in cultured FRTL-5 rat thyroid cells. In vitro, TNF inhibited 125I uptake by cultured FRTL-5 rat thyroid cells and blocked the stimulation of [3H]thymidine uptake by these cells. The data indicate that TNF acts on the HPT axis at multiple levels and suggest that TNF is one of the mediators responsible for alterations in thyroid function tests in patients with nonthyroidal illnesses.