Robert D. Utiger

The effect of glucocorticoids on thyrotropin secretion

The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.TSH responses to steroid were also studied in rats. In hypothyroid rats given dexamethasone intravenously, plasma TSH fell to 63% of control in 30-90 min and then returned to normal or above in 3-4 hr. Dexamethasone also reduced plasma TSH concentrations in normal rats but no rebound was observed in these animals. Dexamethasone did not block the increase in plasma TSH produced by thyrotropin releasing factor (TRF) administration in vivo. Neither basal nor TRF-mediated TSH release from hemipituitaries in vitro was reduced by dexamethasone or corticosterone. These studies indicate that glucocorticoids reduce TSH secretion and suggest that this effect occurs at a suprahypophyseal level.

Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones.

Inhibition of thyrotropin (TSH) release by chronic treatment with small quantities of triiodothyronine (T(3)) and thyroxine (T(4)) was evaluated by determining the serum TSH response to thyrotropin-releasing hormone (TRH) in normal subjects and hypothyroid patients. Response to TRH was determined before treatment and after each dosage of a synthetic combination of T(3) + T(4) had been given for 3-4 wk. Treatment of eight normal subjects with 15 mug T(3) + 60 mug T(4) reduced the maximum increase in serum TSH above baseline (maximum DeltaTSH) by 76% in response to 400 mug TRH and by 87% in response to 25 mug TRH. The average serum T(3) level during a 24 hr period in normal subjects who had been taking 15 mug T(3) + 60 mug T(4) for 3-4 wk was 129+/-10 ng/100 ml (mean +/-SEM), well within the normal range, 70-150 ng/100 ml, although higher than the pretreatment level, 98+/-7 ng/100 ml. The average serum T(4) level was unchanged from the pretreatment level. Treatment of the same subjects with 30 mug T(3) + 120 mug T(4) reduced the maximum DeltaTSH further.Six patients with primary hypothyroidism were treated, sequentially, with 15 + 60, 22.5 + 90, and 30 mug T(3) + 120 mug T(4). For each patient there was one increase in dosage of 7.5 mug T(3) + 30 mug T(4) which abruptly converted a maximum DeltaTSH that was greater than, or at the upper limit of, normal to one that was subnormal. Concurrent with these six abrupt changes in TSH response, the mean serum T(3) level increased only from 105+/-5 to 129+/-9 ng/100 ml, and the mean serum T(4) level increased only from 4.9+/-0.8 to 6.3+/-0.5 mug/100 ml. These data demonstrate the extreme sensitivity of TRH-induced TSH release to inhibition by the chronic administration of quantities of T(3) + T(4) which do not raise serum T(3) and T(4) levels above the normal ranges.

Thyroid Hormone Inhibition of the Prolactin Response to Thyrotropin-Releasing Hormone

A B S T R A C T The influence of serum triiodothvronine (T3) and thyroxine (T4) concentrations on the release of prolactin in man was studied by determining the prolactin response to synthetic thyrotropin-releasing hormone (TRH) in hypothyroid and hyperthyroid patients before and after correction of their serum thyroid hormone abnormalities. The maximum increment in serum prolactin above the basal level (maximum A prolactin) was used as the index of response to TRH. In 12 patients with primary hypothyroidism, the maximum A prolactin in response to TRH fell from 100.5± 29.1 ng/ml (mean +SEM) before treatment to 36.1±6.0 ng/ml (P< 0.01) during the 4th Nk of treatment with 30 jug T3 + 120 jug T4 daily. The mean serum T3 level increased from 57±8 to 138+10 ngl100 nml! and the mean serum T4 level increased from 3.0±0.4 to 7.2±0.4 Ag/lOO ml during this treatment. In eight normal subjects the maximum Aprolactin in response to TRH was not significantly different during the 4th wk of treatment with 30 Ag T3 + 120 /g T4 daily from the response before treatment. In 10 patients with hvperthyroidism, the maximum Aprolactin in response to TRH increased from 14.2±2.9 ng/ml before treatment to 46.9±6.7 nig/ml (P < 0.001) during antithyroid treatment. The mean serum T3 level fell from 313±47 to 90±8 ng/100 ml, and the mean serum T4 level fell from 20.8±2.5 to 6.8+ 0.6 Ig/100 ml during this treatment. These results show that changes from normal serum levels of T3 and T4 are associated with changes in prolactin responses to TRH; subnormal serum levels of T3 and T4 increase TRH-induced prolactin release,

Diagnostic Value of Thyrotrophin-Releasing Hormone in Pituitary and Hypothalamic Diseases: Assessment of Thyrotrophin and Prolactin Secretion in 100 Patients

Abstract The clinical utility of synthetic thyrotrophin-releasing hormone (TRH) in assessing thyrotrophin (TSH) and prolactin secretion was evaluated in 100 patients with pituitary and hypothalamic...

Hypothyroidism in workers exposed to polybrominated biphenyls

THE polybrominated biphenyls (PBBs) and polybrominated biphenyl oxides (FBBOs) are brominated hydrocarbons that have been used commercially as fire retardants. PBBs in particular are highly lipo...

MATERNAL HYPOTHYROIDISM AND FETAL DEVELOPMENT

Thyroid deficiency during the latter two thirds of gestation and the first months after delivery can result in mental retardation and sometimes neurologic deficits. Whether thyroid hormone is neede...

Metabolism and Excretion of Exogenous Thyrotropin-Releasing Hormone in Humans

To study the metabolism of thyrotropin-releasing hormone (TRH) in vivo, 400 mug TRH was administered intravenously to eight normal male subjects. Multiple plasma and urine samples were obtained before and after TRH administration. Serum TSH concentrations increased after TRH administration in all subjects. Plasma TRH levels, measured by radioimmunoassay, were undetectable (< 0.4 ng/ml) before TRH administration. Plasma TRH concentrations averaged 33+/-7 ng/ml (mean +/-SEM) 2 min after TRH injection. Thereafter, they decreased rapidly so that the mean plasma TRH level was 2.9 ng/ml 20 min after TRH administration. The fall in plasma TRH levels was linear during this interval. Thereafter TRH levels declined more slowly. The mean half-life (t(1/2)) of TRH was 5.3+/-0.5 min. The mean distribution volume was 15.7+/-3.8 liters, an average of 16.5% of body weight in these subjects. In the urine, 5.5+/-0.9% of the administered TRH was recovered in the 3 h after TRH administration. Of the total urinary TRH recovered, 84.9% was excreted in the first 30 min. These results indicate that TRH is distributed in a large volume, that it is rapidly metabolized and that a significant quantity of administered TRH is excreted in the urine.

STUDIES ON HUMAN GROWTH HORMONE. II. THE PHYSIOLOGICAL DISPOSITION AND METABOLIC FATE OF HUMAN GROWTH HORMONE IN MAN

The metabolic effects of human growth hormone have received much attention, but little is known regarding the metabolism of the hormone itself in man. Studies of growth hormone metabolism carried out in experimental animals suggest that both bovine growth hormone and human growth hormone have rapid turnovers. Van Dyke, Simpson, Li and Evans (1) and Gemzell, Heijkenskjdld and Str6m (2) injected rats with large doses of bovine growth hormone and determined plasma levels of growth hormone by the tibial cartilage width assay. The half-lives of disappearance were 26 and 40 minutes, respectively, in the two studies, and the volume of distribution of the hormone was roughly equivalent to the extracellular fluid space. Isotopic methods have also been applied to the study of growth hormone metabolism. Sonenberg and co-workers (3) injected rats with radioiodinated bovine growth hormone and, although their work was principally concerned with tissue localization, they published a graph depicting the disappearance of radioactivity from plasma after a single intravenous injection. The half-life of disappearance was approximately 25 minutes. In the experiments of Salmon, Utiger, Parker and Reichlin (4), radioiodinated human growth hormone had a half-life of disappearance from plasma of 17 minutes when injected into rabbits. Only preliminary reports of the disappearance

Treatment of primary hyperparathyroidism.

Hypercalcemia, and subsequently primary hyperparathyroidism, is discovered in two ways. Most commonly, hypercalcemia is discovered when serum calcium is measured as a screening test or in patients ...

Estimation of the Secretion Rate of Thyrotropin in Man

The plasma concentration of a pituitary hormone is determined by the rate of secretion, degradation, and the volume of distribution of that hormone. Using a radioimmunoassay for human thyrotropin (TSH) and human TSH-(131)I, we have estimated the rates of degradation and distribution of TSH in man and calculated the rate of secretion. Either 0.5 or 5 mug of TSH-(131)I with specific activities of 1 to 50 muc per mug was administered intravenously to 12 euthyroid subjects. Serial determinations were made of TSH-(131)I, and the half-time of disappearance (t((1/2))) was thus estimated. The average t((1/2)) in euthyroid subjects was 53.9 minutes with a volume of distribution averaging 5.8% of body weight. The mean endogenous plasma TSH concentration was 1.8 mmug per ml (2.7 muU per ml in terms of the human TSH reference standard A). The mean total TSH pool, excluding the pituitary, was 5.8 mug (8.7 mU). From these data the mean secretion rate of TSH in euthyroid man was calculated to be 110.1 mug per day (165.2 mU). Similar data were estimated for 3 mildly hypothyroid patients. The t((1/2)) were 75.1, 97.1, and 83.6 minutes, with a mean of 85.3 minutes (1.6 times normal). The mean TSH pool was 58.1 mug (10 times normal). The secretion rate was 688.7 mug per day (1,033.1 mU). In other hypothyroid patients, plasma TSH levels ranging from 6 to 230 mmug per ml (9 to 345 muU) have been found. If similar half-times and a normal distribution volume are assumed, the secretion rate of TSH in hypothyroid patients can be estimated to range from about 260 to 15,350 mug per day (390 to 23,025 mU) or from about 2 to 307 times normal. Therefore, the elevated plasma TSH levels found in hypothyroidism are a result of both slower degradation and increase in rate of secretion.