Sequential changes in the pituitary thyroid axis after chronic TRH administration: effects on euthyroid and thyroxine treated female rats

The effect of chronic oral thyrotrophin-releasing hormone (TRH) administration on thyrotrophin (TSH), L-triiodothyronine (T3) and L-thyroxine (T4) serum levels, pituitary TSH concentration and serum response to acute TRH injection, has been studied in female rats under different thyroidal conditions: sham-operated control animals, and thyroidectomized animals receiving 25 micrograms L-T4/100 g body weight/day. After 30 days, these groups were divided into two subgroups (6-10 animals per group), one receiving the aforementioned treatment and the other the same plus 2 mg TRH/10 ml distilled water (DW), as drinking water. TRH-treated sham-operated animals showed significantly reduced serum and pituitary TSH levels and increased serum T3 levels at most of the times studied (1, 6, 10, 18 and 34 days of oral TRH or DW administration), and a transient elevation in serum T4 between day 1 and 6. Thyroidectomized-L-T4-treated animals showed increased serum and pituitary TSH levels throughout the treatment and reduced T3 and T4 serum levels at the beginning, as compared to thyroidectomized-L-T4-treated animals. TSH response to iv TRH administration on the 10th day of oral TRH administration was reduced in controls chronically treated with oral TRH as compared to non-treated controls, and was increased in thyroidectomized-L-T4-treated animals on chronic TRH vs the same group on oral DW. These results suggest that chronic TRH administration can stimulate TRH synthesis in vivo, bypassing the inhibitory effects of thyroid hormones, the increased pituitary TSH reserve being responsible for the partial restoration of a response to acute TRH injection in the thyroidectomized-L-T4-treated animals.     

RAPID ADAPTATION OF PITUITARY RESPONSIVENESS TO TRH IN THE POST-SURGICAL STATE. THE ROLE OF FREE T3

In eight clinically and biochemically euthyroid patients undergoing routine major non-thyroidal surgery preoperative and daily postoperative serum concentrations of total and free thyroid hormones were measured. Thyrotro-phin-releasing hormone (TRH) tests were performed preoperatively and on the first 3 postoperative days. There was a significant fall in mean serum total and free triiodothyronine (T3) concentrations on the postoperative days and mean reverse T3 concentrations rose reciprocally. There was no significant change in mean basal thyroid-stimulating hormone (TSH) values, but there was a significant increase in the mean TSH response to TRH on the first postoperative day. The mean TSH response then declined sequentially until day 3 while mean free T3 concentrations remained significantly depressed. Mean serum free thyroxine (T4) concentrations remained normal during the study. Intrapituitary conversion of T4 to T3 or other down regulatory mechanisms could explain this rapid adaptation of the pituitary axis.     

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 three-day oral cholecystography on serum iodothyronines and TSH concentrations: comparison of the effects among some cholecystographic agents and the effects of iopanoic acid on the pituitary-thyroid axis

The effects of repeated doses of oral cholecystographic agents on serum thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3) and thyrotrophin (TSH) concentrations were studied in 37 euthyroid male subjects. Iobenzamic acid, tyropanoic acid, iopanoic acid, and ipodate sodium, in a dosage of 3 g for 3 days, respectively, induced a significant decrease in serum T3 and an increase in rT3 within 24 h after the initial dose, followed by an increase in TSH and a slight increase in T4. The extent of the changes in rT3 varied between the agents, ipodate causing the greatest change, but without any relation to the changes in T3 or T4. Responses of serum T4, T3, rT3 and TSH concentrations to exogenous thyrotrophin-releasing hormone (TRH) and bovine TSH were also studied before and after 3-day doses of iopanoic acid. In 11 subjects given iopanoic acid, the response to TSH to TRH (500 micrograms, iv) was increased but the T3 response was unchanged. A dose of TSH (10 U.S.P. units, im) caused a significant increase in serum T3 and a decrease in TSH concentrations in 5 subjects both before and after cholecystography. It is thus suggested that in euthyroid subjects given multiple doses of oral cholecystographic agents, (1) the primary and consistent events are the reciprocal changes of serum T3 and RT3, although the extent of the changes is not coordinately reciprocal; (2) the responsiveness of the pituitary thyrotrophs and thyroid to TRH is preserved; and (3) the high basal and TRH-induced TSH in the serum may be ascribed to the decrease in the serum T3 concentration.     

THE EFFECT OF MINOR INCREMENTS IN PLASMA THYROXINE ON HEART RATE AND URINARY SODIUM EXCRETION

We studied day/night (D:N) patterns of urinary sodium excretion and the 24 hour ambulatory electrocardiogram in seven normal subjects before and during the administration of T4. Thyroxine increased thyroid hormone levels within the normal range and inhibited the plasma TSH response to TRH. This was associated with a significant decrease in D:N sodium excretion (P less than 0.01) and D:N urine flow (P less than 0.01), a significant increase in mean nocturnal heart rate (P less than 0.01), and a lesser increment in mean daytime heart rate (P less than 0.05). These responses to small changes in thyroid hormone levels suggest that the anterior pituitary is not alone in recognising minor thyroid hormone excess. The clinical implication is that some patients with a normal T3 and T4 but an impaired TSH response to TRH might benefit from antithyroid treatment.     

Age-related alterations of pituitary-thyroid function in normal female subjects and in female patients with simple goitre

Age-related alterations in pituitary-thyroid function were studied in 173 female patients with simple goitre and in 70 normal female subjects. They were divided into 4 groups according to age: A group, less than 19 years; B group, 20 to 29 years; C group, 30 to 39 years; D group, 40 to 59 years. Serum triiodothyronine (T3) concentrations decreased progressively but insignificantly with age in female patients with simple goitre and in normal female subjects, whereas serum thyroxine (T4) concentrations remained constant throughout the studied age range. Only in female patients with simple goitre, did basal serum TSH concentrations show a tendency to increase with age. However, thyrotrophin-releasing hormone (TRH)-stimulated increase of serum TSH was progressively augmented with age both in female patients with simple goitre and in normal female subjects; the magnitude of change was greater in the former group. As reflected by acute increases of serum T3 and T4 concentrations, thyroidal responsiveness to endogenous TSH was progressively depressed with age in female patients with simple goitre and in normal female subjects. This age-related thyroidal refractoriness to TSH was more apparent when the changes were expressed as delta T3 (stimulated T3 - basal T3)/delta TSH (maximum TSH after TRH - basal TSH), and delta T4 (stimulated T4 - basal T4)/delta TSH. Delta T4/delta TSH was lower in female patients with simple goitre than in normal female subjects in all age groups. However, the difference was significant only for delta T4/delta TSH in group A. Thyroidal responsiveness to exogenous TSH also gradually declined with age in female patients with simple goitre.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

PITUITARY AND PERIPHERAL RESISTANCE TO THYROID HORMONE

A 32-year-old Caucasian male, clinically euthyroid, with paranoid schizophrenia and granulocytopenia, had elevated total and free serum T4 and T3; serum TSH was normal (2.7 +/- 0.7 micronU/ml). There was no goitre present, no evidence of Graves' disease, and no evidence of pituitary tumour. He had a normal response to methyl-TRH, with a TSH increment of 14.6 micronU/ml, T3 increment of 212 ng/dl, and T4 increment of 4.7 microgram/dl; baseline value and decreased the TSH increment in response to methyl-TRH. T3 therapy (100 microgram/day) decreased the thyroidal radioactive iodine uptake to less than half the baseline prolactin was normal with a normal response to methyl-TRH to 4.1 micronU/ml. Iodine therapy caused an increase in his baseline TSH with an increase in the TSH response to TSH. The metabolic clearance rates (MCR) and production rates (PR) of T3 and T4 were increased. Baseline serum levels of glycoprotein hormone alpha-subunit were normal and showed a slight increase in response to methyl-TRH, similar to normal subjects. This patient has evidence of partial pituitary and peripheral resistance to thyroid hormone; his only evidence for hyperthyroidism is the elevated MCR and PR of T3 and T4.     

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.     

Hypothalamic secretion of thyrotropin releasing hormone declines in aging rats

Young and aged male rats were used in experiments to investigate a possible decline in hypothalamic secretion of thyrotropin releasing hormone (TRH) to the anterior pituitary of aging mammals. We observed a 66% decrease in basal TRH release by incubated rat hypothalami with aging. Thyroid hormone-responsive hepatic alpha-glycerophosphate dehydrogenase (GPD) and malic enzyme (ME) levels in aged rats did not differ from 5-month-old controls in spite of a significant fall in serum thyroxine (T4) levels with aging. Other results suggest that these particular indicators of thyroidal status should not change in the aging rat because serum T3 is maintained in the normal range. Serum thyrotropin (TSH) levels, which normally rise when serum T4 levels decline, did not change with aging. These data suggest that gradual loss of the essential TRH stimulation of TSH release with aging may be compensated for by a decline in T4 inhibition of TSH release at the pituitary.     

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.     

Preclinical hyperthyroidism--a graded condition

In 65 consecutive surgical patients with multinodular goitre and with preclinical hyperthyroidism (TRH-resistant suppression of TSH in the presence of normal circulating thyroid hormones) the individual values of the FT4-index (FT4-I) and FT3-index (FT3-I) showed a wide range form low normal to high normal with mean values not differing from those in TRH-responsive goitre patients and from controls. Thirty-five patients underwent repeated pre-operative TRH tests: 11 (group A) were TRH-unresponsive on one occasion, and TRH-responsive at another time. Fifteen (group B) were TRH-unresponsive on two occasions. Nine patients (group C) were preclinically hyperthyroid on one occasion and had supranormal individual thyroid hormone concentrations at another time. In multinodular goitre patients with preclinical hyperthyroidism a significant T3 increase was observed after oral TRH. In spite of a TRH-resistant suppression of TSH small amounts of TSH are thus still secreted. The degree of TSH suppression may be the result of a varying degree and pattern of continued, fluctuating or elapsed increase in thyroid hormone supply. The T3 response to oral TRH depends not only on the degree of TSH suppression, but also subtlely on the thyroidal reserve: in euthyroid TRH-TSH negative goitre patients a decrease of the TSH-regulated follicular mass by goitre resection abolished the pre-operatively significant T3 response to TRH during the post-operative phase of transient TSH deficiency.     

The effect of a low-calorie diet alone and in combination with triiodothyronine therapy on weight loss and hypophyseal thyroid function in obesity

The effect of a low-calorie diet (200 kcal) composed of about 50 per cent glucose and 50 per cent protein on body weight, thyroid hormone levels and pituitary thyrotrophin response was studied in 18 grossly obese subjects (relative weight 131-205 per cent) for 28 d; during the last 14 d eight subjects (Gp B) served as controls, while in the other ten subjects (Gp A) the low T3-high rT3 state was treated by T3 supplementation (150 micrograms daily). During the first 14 d (period 1) weight loss (corrected for the sodium diuresis) appeared to be constant and to be equal for both groups. The thyroid hormone concentration and the basal and TRH stimulated TSH concentrations were similar to the results from previous total starvation studies. Despite marked changes in serum T3 levels a normal pituitary TSH response was maintained and no delayed response of TSH to TRH occurred. During T3 supplementation the serum T3 levels increased to high values, the rT3 concentration declined to below initial values, the T4 and TSH concentrations were depressed and the response of the TSH concentration to TRH disappeared; apparently these 'high normal' levels of serum T3 must be considered inappropriate for this condition of severe calorie restriction. In the controls the serum T3 levels remained constant after the end of the first period; the serum rT3 concentration declined from day 14 to day 28, but remained above the initial values. The serum T4 concentration remained almost constant during the whole study; basal and TRH stimulated TSH concentrations did not change during the whole study. During period 2 weight loss diminished in the control group, but remained constant in Gp A (T3 supplemented); the correlation between the weight loss and the increase of the serum T3 concentration during triiodothyronine supplementation was significantly negative (r = -0.64; P less than 0.05). The well-being of the subjects did not change during T3 administration and no signs of hyperthyroidism developed. One could speculate this reflects a decrease in number or sensitivity of intracellular receptor sites. It is concluded that at the peripheral level no complete resistance develops against T3 administration; in the low T3 state the hypothalamic-pituitary axis reacts as if euthyroidism exists.     

Effects of diabetes, beta-hydroxybutyric acid and metabolic acidosis on the pituitary-thyroid axis in the rat

Previous studies demonstrated alterations of thyroidal economy in untreated diabetes mellitus both in man and experimental animals. To test the role of beta-hydroxybutyric acid (BHB) and acidosis in generating such changes, we studied the pituitary-thyroid axis of streptozotocin-diabetic rats, BHB or ammonium chloride (NH4Cl)-treated normal rats. Serum TSH, pituitary content and pituitary concentration of TSH, serum T4, T3 and free T4 (FT4), were all measured by RIA. In short term (2 days) diabetic rats the pituitary content of TSH was normal whereas the concentration (per mg of protein) was elevated (p less than 0.05 versus control group). Serum TSH (p less than 0.05), serum T4 (p less than 0.05), serum T3 (p less than 0.01) and serum FT4 (p less than 0.05) were all significantly decreased. In long term (30 days) untreated diabetic rats serum changes were similar to the short term diabetic group, though the pituitary content of TSH was significantly decreased (p less than 0.05). Animals treated with NH4Cl had no variations from controls. However, rats treated with BHB displayed a significant decrease in pituitary content of TSH (p less than 0.05), pituitary concentration of TSH (p less than 0.05) and in plasma TSH (p less than 0.01), and normal thyroid hormones in serum. No significant changes were seen in the TSH response to TRH in 2 or 30 days untreated diabetic and in BHB - treated animals. The data suggest that BHB, although not NH4Cl acidosis, may be capable of inducing a moderate depression of pituitary and plasma TSH of a lesser magnitude of that accompanying the full, long term diabetic state in the rat.     

Transient TRH deficiency after prolonged thyroid hormone therapy.

A patient who had been treated with large doses of thyroid hormone for several years developed features of secondary hypothyroidism after thyroid hormone withdrawal. These findings were low serum T4 (3.8 micrograms/dl), T3 (23 ng/dl), and a failure of serum TSH to rise after TRH injection. Serum PRL values rose normally after TRH administration, and evaluation of other pituitary hormones was normal. When retested 3 months later, at which time the serum T4 was 5.5 micrograms/dl, the patient was somewhat less hypothyroid and there was an exaggerated TSH response to exogenous TRH, indicating recovery of pituitary TSH reserve. Indirect assessment of endogenous TRH reserve capacity was consistent with impairment of endogenous TRH activity. Repeat studies performed 7 months later indicated some improvements in this indirect assessment of endogenous TRH reserve capacity but a continued exaggerated TSH response to exogenous TRH administration. Further testing at 28 months revealed a serum T4 value of 7.8 micrograms/dl and a serum T3 value of 141 ng/dl. At this time, the TSH response to TRH was normal and the patient was considered fully recovered. A causal relationship between high doses of thyroid hormone and the presumptive impairment of endogenous TRH reserve is suggested.     

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.     

Effect of starvation on hypothalamic-pituitary-thyroid function in the rat.

Total starvation in the rat for 2 days did not alter the hypothalamic content of thyrotropin-releasing hormone (TRH), but did decrease both pituitary TSH content and serum TSH concentration. Five days starvation resulted in a significant decrease in serum TSH and a slightly enhanced serum TSH response to exogenous TRH, suggesting that the pituitary retains its sensitivity to TRH. Fasting for 5 days resulted in a decreased 1 and 4th, but an increased 24th thyroid 131I uptake. Other starvation-induced abnormalities of intrathyroid 131I metabolism were a consistent increase in the percent of organified 131I present as MIT and DIT and a decreased percent 131I labeled T4 AND T3. These alterations in the intrathyroid metabolism of 131I in the starved rat probably reflect both a decrease in serum TSH concentration and a decrease in urinary and fecal loss of administered 131I. The serum total and free T4 and total and free T3 concentrations were decreased following 2 and 5 days of starvation.     

Functional central hypothyroidism in the elderly

BACKGROUND AND AIMS: Previous studies have shown that blood concentrations of free thyroxin and basal thyroid-stimulating hormone (TSH) decrease during adult life. Suggested mechanisms include reduced thyroid activity resulting from decreased serum TSH concentrations, impairment of peripheral 5'-deiodinase, and an increase in reverse 3,5,3'-triiodothyronine due to non-thyroidal illness. However, testing of pituitary reserves leads to contradictory results and has infrequently been evaluated in studies. METHODS: We investigated whether the response of TSH to thyrotropin-releasing hormone (TRH) is preserved during aging. This was tested in a cohort of 387 subjects aged 13 to 100 years in whom thyroid disease was excluded by normal thyroid ultrasound, normal values for free thyroxin, free triiodothyronin, TSH, and negative thyroid peroxidase antibodies. RESULTS: Serum concentrations of free thyroxin remained almost unchanged, whereas free triiodothyronin and TSH levels were lower in older subjects. In addition, the TSH response to TRH was blunted in older subjects, especially in male individuals. CONCLUSIONS: There is evidence that the decreased thyroid hormone levels observed in aging are due to lower TSH concentrations, and that lower TSH concentrations may be linked to an impaired pituitary activity.     

Preclinical hyperthyroidism in multinodular goiter.

The thyrotropin (TSH) response to thyrotropin-releasing hormone(TRH) (200 mug iv) was determined in 80 surgical patients with nontoxic multinodular goiter. The TSH reserve was normal in multinodular goiter. The TSH reserve was normal in 55 and elavated in 8 patients. No TSH response to TRH (deltaTSH less than or equal to 1 muU/ml) was detectable in 17 patients (21%). Individual and mean serum T4, FT4I and serum T3 values did not differ from normal in 13 of the TRH unresponsive patients; in 4 patients FT4I or serum T3 was marginally elevated. No statistical differences were noted for I131-uptake, PBI131 and conversion rate between controls and TRH unresponsive patients. All patients who failed to respond to TRH were euthyroid on clinical evaluation. Goiters were large multinodular and long-standing in most instances. In 12 tested subjects TRH responsiveness recovered following partial thyroidectomy. In 3 of 7 TRH unresponsive euthyroid patients tested 9-12 days post surgery a transient lack of TSH to respond to TRH was observed. Recovery of TRH responsiveness was accompanied by a significant (P IS LESS THAN 0, 02) decrease in serum T4and FT4I in the euthyroid range, whereas no change in serum T3 occurred. It is suggested that TRH unresponsiveness represents a state of preclinical hyperthyroidism maintained by autonomously functioning goiter compartments.     

THE ROLE OF A HIGHLY SENSITIVE AMPLIFIED ENZYME IMMUNOASSAY FOR THYROTROPHIN IN THE EVALUATION OF THYROTROPH FUNCTION IN HYPOPITUITARY PATIENTS

Using a highly sensitive amplified enzyme-linked immunoassay (AEIA) for thyrotrophin (TSH), we have assessed the ability of a single basal measurement of TSH to predict the subsequent response of TSH to TRH in a group of 11 patients with known pituitary pathology and some evidence of hypopituitarism. All patients were clinically euthyroid. Basal levels of AEIA-TSH ranged from less than 0.2 mU/l ('undetectable') to 0.9 mU/l; within this range there was no correlation with the subsequent TSH levels at 30 min in the TRH test. The TSH response in the TRH test did not correlate with the direct measurements of prevailing thyroid hormone levels (Total T4 or Free T4). We suggest that in patients with pituitary disease, the formal TRH test yields additional information regarding residual thyrotroph function that cannot reliably be predicted by a single basal TSH value, even when measured by a sensitive method. The current and potential thyroid status in patients with hypopituitarism must continue to rest on the overall picture provided by clinical assessment, direct measurement of thyroid hormones and the TRH test response. A basal TSH alone gives little useful information regarding thyroid status in such patients.