Hyperthyroidism due to a thyrotropin-secreting pituitary adenoma. Studies of thyrotropin and subunit secretion.

A 58-year-old man had symptoms of hyperthyroidism and congestive heart failure. While hyperthyroid, his serum thyrotropin (TSH) level was inappropriately elevated at 6.1 microunits/mL. The molar ratio of alpha subunit to TSH was 2.5, suggesting the presence of a TSH-secreting pituitary tumor. Further evaluation disclosed an enlarged sella turcica with posterior erosion, and an intrasellar mass was visualized on computed tomographic scan. Neither serum TSH nor alpha subunit levels became elevated after administration of thyrotropin-releasing hormone, nor were they suppressed by a dopamine infusion. Serum TSH but not alpha subunit levels rose during antithyroid drug therapy. Estrogens produced a partial reduction in serum alpha subunit concentration (presumably reflecting the nontumorous gonadotroph contribution to circulating alpha subunit). Dexamethasone completely suppressed serum TSH level but had no effect on the alpha subunit level, suggesting a differential feedback of glucocorticoids on TSH and alpha secretion. The patient was treated with pituitary irradiation rather than surgery because of his underlying heart disease.

Isolated thyrotropin deficiency with thyrotropin-releasing-hormone induced TSH secretion and thyroidal release.

A patient with isolated thyrotropin (TSH) deficiency was studied. Prior to treatment with thyroid hormone, administration of thyrotropin releasing hormone (TRH) produced no increment in serum TSH and a normal increase in plasma prolactin (PRL). In order to explore whether physiologic increases in serum TSH might be occurring below the limits of detectability of TSH by radioimmunoassay, a double isotope technique of assessing thyroidal secretion secondary to release of TSH was employed. The patient was restudied seven months later, after discontinuing thyroid hormone replacement therapy for two months, and on this occasion repeat TRH administration produced small increments in serum TSH. After administration of 125I and 131I-T4 to assess thyroid hormone secretion, TRH was infused continuously for 6 h. Small increases in serum TSH were again observed, along with significant increases in PG125I/PB131I and urinary 125I/131I, reflecting increased thyroidal iodine secretion, although serum T3 and T4 did not change. These studies indicate that: 1) isolated TSH deficiency need not be complete and may be associated with detectable levels of immunoassayable TSH; 2) the TSH released possesses in vivo biological activity; and 3) therapy with thyroid hormone may have facilitated TSH release.

Absent growth hormone response to L-tryptophan in acromegaly.

In acromegaly, regulation of GH secretion by dopamine pathways appears to be qualitatively abnormal. To determine whether regulation of GH secretion by serotonin pathways is also abnormal in acromegaly, we administered L-tryptophan (5 g orally), the initial precursor of serotonin, to 10 patients with active acromegaly (9 treated and 1 untreated), 3 patients with cured acromegaly, and 8 normal subjects. The normal group showed a significant (P less than 0.05) increase in serum GH after L-tryptophan [peak value, 12.3 +/- 4.0 (se) ng/ml], though the magnitude of the response was highly variable. In contrast, subjects with active acromegaly did not show an increase in serum GH after L-tryptophan [mean integrated percentage change in serum GH, -25 +/- 25% (SE); P = NS]. One patient whose acromegaly had been surgically cured did show a GH rise after L-tryptophan. In acromegaly, the GH response to L-tryptophan is absent, suggesting that regulation of GH secretion by serotonin pathways might be qualitatively abnormal.

Failure of propranolol to alter thyroid iodine release, thyroxine turnover, or the TSH and PRL responses to thyrotropin-releasing hormone in patients with thyrotoxicosis.

A dual isotope method allowing simultaneous analysis of both endogenous thyroidal release and peripheral thyroxine disposal was employed in four patients with thyrotoxicosis before and during propranolol therapy (160 mg/day) to determine whether beta adrenergic blockade with this agent affected the secretion or metabolism of thyroid hormone. Since catecholamines may be involved in the regulation of both thyrotropin (TSH) and prolactin (PRL) release from the pituitary, the effect of propranolol on the TSH and PRL responses to thyrotropin-releasing hormone (TRH) was also examined. In the dosage employed in these patients, propranolol had no demonstrable effect on either thyroid hormone secretion, the peripheral disposal of T4, or the TSH and prl responses to TRH.

Effect of acute increases in serum triiodothyronine on TSH and prolactin responses to TRH, and estimates of pituitary stores of TSH and prolactin in normal subjects and in patients with primary hypothyroidism.

Previous investigators have shown that daily administration of TRH to normal individuals leads to diminishing TSH responses which were believed due to rising serum T3 with subsequent feedback inhibition of the pituitary. Patients with primary hypothyroidism were examined in the present study to test this hypothesis, since their T3 cannot increase after TRH. Bi-daily TRH (100 mug) was given to 4 patients for 3 consecutive days, and repeated on a 4th day following oral T3 (50 mug). TSH and PRL responses were unchanged during these 3days of serial TRH and were unaltered by T3 administration on the fouth day. In 5 other hypothyroid subjects studied before and during 3 consecutive days of T3 administration, TSH but not PRL responses to TRH appeared to decrease slowly but progressively. These observations led us to re-examine TRH responses in normal subjects given T3, since other workers had reported that 50 mug T3 completely abolished TSH response. Responses to TRH in 11 normals on a control day were compared to those observed 1 hour after oral T3. In spite of marked increases in serum T3, there was no significant difference between the mean TSH responses of the two studies.

A radioimmunoassay for 3,3',5'-L-triiodothyronine (reverse T3): assessment of thyroid gland content and serum measurements in conditions of normal and altered thyroidal economy and following administration of thyrotropin releasing hormone (TRH) and thyrotropin (TSH).

The present report describes the development of a radioimmunoassay for 3,3',5'-L-triiodothyronine (reverse T3) which is performed on unextracted serum. Utilizing this radioimmunoassay, 21 normal subjects had a mean (+/-SD) serum reverse T3 level of 60 +/- 12 ng/100 ml, 17 of 19 hyperthyroid patients had elevated serum reverse T3 levels, and 10 of 11 hypothyroid subjects had decreased serum reverse T3 concentrations. Thyroidal secretion of reverse T3 was assessed by measurements in samples obtained from the internal carotid artery and jugular vein of sheep following the administration of thyrotropin releasing hormone (TRH) or bovine thyrotropin (TSH). Reverse T3 levels were increased 45-60 min after TRH administration, but TSH administration produced inconsistent alterations in reverse T3, although 18 of 27 samples obtained after TSH injection were higher than their average respective baseline concentration and the mean peak reverse T3 level was 14% higher than baseline. Following TRH administration to 10 normal human subjects, mean serum reverse T3 levels significantly increased from 53.6 ng/100 ml to 56.3ng/100 ml (P less than .05). The thyroid gland content of reverse T3 in human autopsy material was 6.5 +/- 1.5 microng/g tissue. Both pregnancy and estrogen administration were associated with increases in serum reverse T3 concentrations presumably because of their ability to augment thyroxine binding globulin synthesis.

Sensitivity to lithium in treated Graves' disease: effects on serum T4, T3 and reverse T3.

Seven patients judged to be euthyroid following treatment of diffuse toxic goiter were studied to determine if they were susceptible to lithium induced hypothyroidism. Lithium carbonate was administered for 4-7 weeks in a dosage (900 mg/day) which maintained serum lithium levels between 0.5-1.0 mEq/l. Blood was obtained weekly for the determination of serum 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3',5'-TRIIODO-L-thyronine (reverse T3, rT3) and thyrotropin (TSH). Values observed during lithium therapy were compared to those obtained prior to, and approximately one week after discontinuing lithium. During the pretreatment preiod, mean (+/- SE) serum T3, T4, and rT3 concentrations were 130 +/- 21 ng/100 ml, 7.6 +/- 0.4 mug/100 ml and 48 +/- 8 ng/100 ml, respectively, and decreased during lithium administration with the lowest T3, T4 and reverse T3 concentrations of the lowest T3, T4 and reverse T3 concentrations of 92 +/- 8 ng/100 ml, 4.9 +/- 0.6mug/100 ml, and 33 +/- 6 ng/100, ml, respectively, being reached between the fourth and sixth weeks of study. Thereafter, and in spite of continued treatment with lithium, values for serum concentrations of T3, T4, and rT3 plateaued, or actually increased in 4, 6, and 5 subjects, respectively. Serum TSH concentrations remained 3.0 muU/ml or less throughout the study in 6 patients; 2 of these subjects had no TSH response to thyrotropin-releasing hormone (TRH), even though they had been euthyroid for 3 and 10 months. These data suggest that patients euthyroid following treatment of diffuse toxic goiter display sensitivity to the antithyroid effects of lithium. Furthermore, these observations support the thesis that the inhibitory effects of lithium and iodine upon thyroid hormone synthesis or secretion may involve a similar mechanism of action since increased thyroidal iodine content may be a consequence of therapy with either agent.

Klinefelter's syndrome: examination of thyroid function, and the TSH and PRL responses to thyrotropin-releasing hormone prior to and after testosterone administration.

Thyroid function and prolactin (PRL) responsiveness to thyrotropin-releasing hormone (TRH) were examined in 6 patients with Klinefelter's syndrome prior to and after therapy with testosterone. The thyroid function tests, including serum triiodothyronine (T3), thyroxine (T4), thyroxine binding globulin (TBG), resin T3 uptake (RT3U), radioactive iodine uptake (RAIU), thyrotropin (TSH) stimulation and the TSH response to TRH were normal during both periods of study. Testosterone treatment had no significant effect on any of these parameters with the exception of the RT3U which increased. PRL response to TRH were significantly higher than those observed in normal men (P less than 0.05). Despite the fact that mean plasma PRL responses to TRH were decreased when the patients were restudied during testosterone therapy, they remained greater than those of normal men. Mean serum estradiol concentrations were normal and did not increase significantly during testosterone therapy. These studies suggest that: (1) thyroid function may be normal in patients with Klinefelter's syndrome more often than previously reported, and (2) patients with Klinefelter's syndrome may manifest PRL hyper-responsiveness to TRH that is decreased but not normalized during testosterone therapy. Because estradiol levels failed to increase despite a marked rise in testosterone, further studies are warranted to examine testosterone and estradiol clearance and conversion rates in patients with Klinefelter's syndrome.

Measurement of 3,3',5'-Triiodothyroinine (reverse T3), 3,3'-L-diiodothyronine, T3 and T4 in human amniotic fluid and in cord and maternal serum.

In order to assess fetal function at term, we have investigated parameters of thyroid hormone secretion and degradation in human amniotic fluid and in cord and maternal sera at delivery. The parameters measured included 3,3' L-diiodothyronine (3,3'T2), 3,3',5'-triiodothyronine (reverse T3), 3,3',5'-triiodothyronine (T3), thyroxine (T4), dialyzable T3 and T4, thyroxine binding globulin (TBG),and total iodine. The mean (+/- SE) 3,3'T2 concentrations in cord sera, amniotic fluid, and maternal sera were 20 +/- 1 ng/100 ml, 20 +/- 2 ng/100 ml,and 27 +/- 3 ng/100 ml, respectively. The normal range of this metabolite in the sera of non-pregnant adult subjects was 7 to 29 ng/100 ml. The mean (+/- SE) concentration of reverse T3 was higher in cord sera (315 +/- 16 ng/100 ml), amniotic fluid (82 +/- 25 ng/100 ml) and maternal sera (79 +/- 5 ng/100 ml) than in the sera of normal subjects (mean +/- 2 SD; 60 +/- 12 ng/100 ml). In amniotic fluid, T3, T4, and TBG were low, per cent dialyzable T3 and T4 were increased, and iodine concentrations were relatively normal in comparison to their respective serum levels in euthyroid adults. Since T3 and T4 were low in amniotic fluid our data indicate that measurements of 3,3'T2, reverse T3, or per cent dialyzable T3 and T4 in amniotic fluid would be the potentially most useful in establishing the diagnosis of congenital hypothyroidism before birth. In addition, these studies demonstrate that 3,3'T2 is normally present in the peripheral circulation and suggest that reverse T3 is the major source of 3,3'T2 in both amniotic fluid and cord blood.

Studies on the nature of thyroidal suppression during acute falciparum malaria: integrity of pituitary response to TRH and alterations in serum T3 and reverse T3.

The nature of the suppression of the pituitary-thyroid axis during infection was studied by testing the integrity of thyrotropin (TSH) and prolactin (PRL) responses to thyrotropin-releasing hormone (TRH) during acute falciparum malaria in human volunteers. During infection, TSH responses to TRH were found to be intact while PRL secretion was slightly increased. That serum T3 levels abruptly declined during infection while serum T4 was stable or increasing suggested an alteration in peripheral degradative pathways and prompted the measuremnt of reverse T3. Changes in serum T3 concentration were found to be accompanied by reciprocal changes in reverse T3. These observations allow some clarification of previously unknown aspects of thyroidal economy during infection.

Effect of an oral water load on serum TSH in normal subjects, and on TSH and prolactin response to thyrotropin-releasing hormone (TRH) in patients with primary hypothyroidism.

Reports of suppression of plasma prolactin (PRL) in humans by water loading led us to examine the effect of a 20 cc/kg water load on serum TSH in 21 normal volunteers. In addition, the effects of a water load on basal and TRH-stimulated TSH and PRL levels were evaluated in seven patients with primary hypothyroidism. The water load had no effect on pasal serum TSH levels in either normal or hypothyroid subjects, and did not alter the TSH response to TRH in hypothyroid subjects. Basal or TRH-stimulated plasma PRL was also unaffected by water loading in the hypothyrpid subjects. These data suggest that a water load of 20 cc/kg does not significantly affect TSH release by the anterior pituitary, and also provide further evidence that water loading does not consistently suppress PRL secretion.

Failure of 3,3'-diiodothyronine administration to alter TSH and prolactin responses to TRH stimulation.

In order to determine whether elevations in serum 3,3'-diiodothyronine (3,3'T2) concentrations influence the hypothalamic-pituitary--thyroid axis, thyrotropin (TSH) and prolactin responses to thyrotropin-releasing hormone (TRH) were assessed in five patients both prior to and during 3,3'T2 administration. Mean (+/- SE) peak TSH responses to TRH were 168 +/- 64 microU/ml during 3,3'T2 administration and 168 +/- 65 muU/ml during 3,3'T2 administration. Mean basal and peak prolactin concentrations after TRH were 6 +/- 3 ng/ml and 54 +/- 26 ng/ml, whereas during 3,3'T2 administration the basal and peak prolactin levels were 6 +/- 2 ng/ml and 55 +/- 28 ng/ml, respectively. Hypothyroid rats administered triiodothyronine (10 migrogram b.i.d.) for 5 days had a mean TSH response to TRH stimulation of 0.051 +/- 0.003 mU/ml, whereas rats to whom saline or 3,3'T2 (50 microgram b.i.d.) had been given for the same time interval had mean TRH-induced TSH responses of 1.127 +/- 0.179 mU/ml and 1.324 +/- 0.286 mU/ml, respectively. None of the TSH or prolactin responses to TRH, in either human or rat studies, were apparently altered by 3,3'T2. These observations suggest that elevation of serum 3,3'T2 levels are not associated with alterations in the hypothalamic--pituitary--thyroid axis in the experimental systems employed.

Parameters of thyroid function in patients with active acromegaly.

In order to determine if acromegaly per se may be associated with abnormalities in thyroidal economy, serum thyroxine-binding globulin (TBG), resin T3 uptake, total and free T4, T3, and reverse T3 concentrations were measured in 21 patients with active acromegaly. Mean (+/- SE) total T4, T3, and reverse T3 levels were 7.1 +/- 0.2 microgram/dl, 111 +/- 4 ng/dl, and 45 +/- 2 ng/dl, respectively, and the mean TBG concentration was 3.6 +/- 0.2 mg/dl. Similarly, mean free T4, T3, and reverse T3 concentrations were 2.4 +/- 0.09 ng/dl, 383 +/- 22 pg/dl, and 118 +/- 7 pg/dl, respectively. None of these values is significantly different from normal and the thyrotropin response to thyrotropin-releasing hormone was also normal. In contrast to several earlier reports, these data suggest that parameters of thyroid function are generally normal in patients with active acromegaly.

Nature of suppressed TSH secretion during undernutrition: effect of fasting and refeeding on TSH responses to prolonged TRH infusions.

TSH responses to 4-hr continuous TRH infusions of approximately 0.8 microgram/min were assessed during feeding (1500 Kcal), fasting, and refeeding (1500 Kcal) intervals in 9 euthyroid obese subjects. The total area under the TSH response curve was 1854 +/- 322 muU/ml . 4-hr during feeding, decreased to 1359 +/- 199 muU/ml . 4-hr (p less than 0.01) on the 10th day of fasting, and remained low, being 1405 +/- 185 muU/ml . 4-hr, despite refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) for 5 days. Baseline serum T3 concentrations were 167 +/- 11 ng/dl during feeding, 86 +/- 8 ng/dl during fasting, and 119 +/- 12 ng/dl during refeeding. The observed decreases in TSH release appeared to correlate with decreased biologic action on the thyroid gland since the net rise in T3 during the infusion was less in fasting and refeeding than in the control (fed) period. Basal serum rT3 levels were 42 +/- 5 ng/dl during feeding, rose as expected to 56 +/- 5 ng/dl during fasting (p less than 0.005), and were completely restored to normal during refeeding (36 +/- 5 ng/dl). These data suggest that: (1) TSH responsiveness to prolonged TRH infusion is diminished during fasting and does not return to control (fed) values despite 5 days of refeeding a 1500 Kcal diet; (2) net T3 increases observed during the TRH infusion are greater in the fed period than in the fasting or refeeding periods; and (3) 5 days of refeeding a 1500 Kcal diet (40% carbohydrate, 40% fat, 20% protein) did not return the T3 to its original fed value whereas rT3 was completely restored to control values. Lastly, since the TSH response was lower both during the early and late phases of the infusion, the decrease in delta TSH to a bolus of TRH during fasting appears to represent one manifestation of a more general suppression of TSH neogenesis associated with caloric deprivation.

Prolactin, thyrotropin, and growth hormone release during stress associated with parachute jumping.

Prolactin, growth hormone, and thyrotropin (TSH) release during the stress of parachute jumping has been evaluated in 14 male subjects. Subjects were studied at several times before and immediately after their first military parachute jump. All three hormones had risen significantly 1 to 14 min after the jump, compared to mean levels measured immediately beforehand. Earlier studies of physical exercise by ourselves and others would suggest that emotional stress played a role in producing changes of this magnitude. We conclude that prolactin, TSH, and growth hormone are released in physiologically significant amounts in association with the stress of parachute jumping.