The Serum Thyrotropin Research Articles

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.

Thyroxine, Triiodothyronine, and Thyrotropin in Serum during Long-Term Diphenylhydantoin Therapy

Clinical laboratory tests for assessment of thyroid function were performed in 31 patients receiving long-term diphenylhydantoin (DPH) therapy. Reduced serum total thyroxine and free thyroxine index were found. The decrease in serum total triiodothyronine and free triiodothyronine index was smaller but statistically significant. DPH had no significant effect on the serum thyrotropin (TSH) concentration and maximal TSH response to TSH-releasing hormone. The absence of reciprocal changes in TSH and serum thyroxine might be due to the near-normal triiodothyronine concentration. Such an explanation would also conform with previous findings that the pituitary contains specific receptors for triiodothyronine but not thyroxine.

The time course of changes in TRH responsiveness in man following a single dose of liothyronine

The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH, 100 μg i.v.) was evaluated prior to and at various times following the oral administration of single doses of liothyronine (100 μg) given at weekly intervals. The TSH response to TRH was mildly depressed when TRH was given 1 hr after liothyronine administration when the serum triiodothyronine (T 3) concentration was strikingly elevated, was markedly reduced 16 and 24 hr after liothyronine, was essentially abolished 3 days after liothyronine when the serum T 3 concentration was normal, and was normal 7 days after liothyronine administration. These findings suggest that the more prolonged suppression of TRH responsiveness, observed following the withdrawal of long-term excess endogenous or exogenous thyroid hormones, cannot be ascribed to the intrinsic duration of action of the hormone present at the time of withdrawal, but rather to the prolonged extent of the suppression itself.

Reversible Hypothyroidism in Growth Hormone-Deficient Children Treated with Human Growth Hormone

Six children with human growth hormone (hGH) deficiency became hypothyroid during the course of their therapy with hGH. This was accompanied by a decreasing growth rate, clinical symptoms of hypothyroidism and decreased serum T4 concentrations. Three of the 6 patients returned to the euthyroid state, both clinically and biochemically, with cessation of hGH therapy, and reinstitution of hGH precipitated hypothyroidism again in 2 of the three. The patients who remained hypothyroid have evidence of multiple pituitary trophic hormone deficiencies while those who reverted to euthyroidism appear to have isolated hGH deficiency. Evaluation of thyroid function while on hGH showed low T4, free T4 and T3 concentrations. The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was absent or markedly blunted in 4 of 6 patients while receiving long-term hGH therapy but was normal or exaggerated in all patients when tested before or after only 5 days of hGH therapy. These data indicate that exogenous hGH results in an inhibition of the TSH response to TRH. The mechanism of this inhibition is unclear, but we postulate that it may be mediated by somatostatin secretion in response to pulse doses of hGH.

Repetitive administration of thyrotropin-releasing hormone results in small elevations of serum thyroid hormones and in marked inhibition of thyrotropin response.

Repetitive administration of thyrotropin-releasing hormone (TRH) to human subjects was used to produce small elevations of endogenous serum triiodothyronine (T(3)) and thyroxine (T(4)) levels and thereby to determine the effect of these small elevations on the serum thyrotropin (TSH) response to subsequent doses of TRH. Each subject received 13 consecutive doses of 25 mug TRH at 4-h intervals. Serum T(3), T(4), and TSH levels were measured before the 1st, 7th, and 13th doses ("basal levels") and for the 4 h after each of these doses. In 10 normal subjects, the mean TSH response fell from 14.6 muU/ml after the 1st TRH dose to 6.9 and 3.0 muU/ml after the 7th, and 13th doses. These falls in TSH response were accompanied by rises in the mean basal serum T(3) levels from 81 to 115 to 114 ng/100 ml (normal range, 70-150 ng/100 ml) and rises in the mean basal serum T(4) from 6.7 to 8.6 to 9.5 mug/100 ml (normal range, 5-11 mug/100 ml). These data suggest that TRH-induced TSH release is extremely sensitive to inhibition by small elevations, not above the normal ranges, of serum T(3) and T(4) of endogenous origin. In four patients with primary hypothyroidism, the mean TSH responses were 92, 137, and 92 muU/ml after the 1st, 7th, and 13th TRH doses. The corresponding mean basal serum T(3) and T(4) levels at the times of these doses were 34, 30, and 32 ng/100 ml and 1.9, 1.9, and 1.7 mug/100 ml. These data show that repetitive administration of TRH does not result in progressively lower TSH responses in the absence of corresponding increases in serum T(3) and T(4) level. The progressive fall in TSH response observed in the normal subjects, therefore, was apparently due to the corresponding small increases in serum T(3) and T(4) levels and not to progressive depletion of pituitary TSH. In two patients with presumed TRH deficiency, the TSH responses were blunted by repetitive TRH doses but only when the serum T(3) and T(4) levels increased to within the normal ranges. TRH deficiency was thus confirmed for the first time by producing euthyroidism by replacement of TRH.

Thyrotropin and thyroidal responses to consecutive doses of thyrotropin-releasing hormone.

Abstract To determine whether changes in serum triiodothyronine (T3) and thyroxine (T4) following a dose of thyrotropin-releasing hormone (TRH) modified the serum thyrotropin (TSH) response to a second dose of TRH, two iv doses of TRH were administered, 180 min apart, to 22 children. Following the first TRH dose, both in normal and in growth hormone-deficient children, the serum T3 levels rose to peaks in 120 min. The serum TSH responses to the second TRH dose, given 180 min after the first, were no less than to the first TRH dose. These studies demonstrate that the well-documented inhibition of serum TSH response to TRH by rises in serum T3 and T4 levels requires longer than 60 min to develop.

Advances in the laboratory diagnosis of thyroid disease. Part II

<h2>Summary</h2> Thyroid function tests presently available or in development have been reviewed. The Murphy-Pattee T4, T4(D), or the T4 by radioimmunoassay, T4(RIA) are the preferred measurements of circulating serum total thyroxine. These usually are conducted in association with a test to assess T4 binding by TBG; the preferred screening test is the T3-resin uptake (RT3U). This result should be reported fractionally relative to a normal serum pool (e.g., patient RT3U/normal RT3U, referred to as the resin T3 ratio) so that the T4 can be "adjusted" for variations in TBG level. The adjusted T4 value, the product of the resin T3 ratio and T4 values, is referred to as the thyroxineresin T3 index (T4-RT3 index). In subjects with abnormal TBG binding, a measurement of TBG binding capacity, TBG concentration by RIA, TBG(RIA), or a measurement of "free" T4 concentration (FT4) can be conducted. The most sensitive test for primary hypothyroidism is the serum thyrotropin (TSH) concentration measured by RIA, TSH(RIA). The measurement of the serum T3 concentration by RIA, T3(RIA), now is possible and will be increasingly utilized in the diagnosis of thyrotoxicosis and "T3-thyrotoxicosis". The thyrotropin-releasing hormone (TRH) response test is valuable (a) to confirm a diagnosis of thyrotoxicosis, (b) to distinguish pituitary (TSH) from hypothalamic (TRH) deficiency, and (c) to assess pituitary TSH reserve. Radioiodine uptake tests are not usually necessary for routine purposes but may be helpful in selected problem cases. More sophisticated thyroid structure-function studies, including thyroid scanning, perchlorate discharge studies, radioiodine kinetic studies, and special tests are useful in patients with euthyroid or hypothyroid goiters. The laboratory approach to these more difficult diagnostic problems is discussed. Nonbiopsy criteria for the diagnosis of chronic lymphocytic (Hashimoto's) thyroiditis are outlined.

Inhibition of thyrotropin releasing hormone-mediated secretion of thyrotropin by human growth hormone.

The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) was measured in ten patients with short stature prior to, during and after the administration of clinical grade human growth hormone (hGH). TRH-stimulated TSH secretion was significantly lower than baseline values after the ninth consecutive day of hGH administration, and returned to baseline levels 14 days after hGH had been discontinued. Serum thyroxine concentrations did not vary during the study, but the mean serum level of triiodothyronine increased during administration of hGH, and remained elevated after hGH had been discontinued. Clinical grade hGH was found to contain trace quantities of immunoassayable TSH. These data have not elucidated the mechanism by which clinical grade hGH inhibits TRH-mediated TSH secretion.

Thyrotropin response to thyrotropin releasing hormone in normal females over forty.

The serum thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) was determined in 12 normal females, 40–59 yr old and in 12 normal females, 60–79 yr old. The mean maximum incremental responses above baseline (maximum ΔTSH) in these two groups were 16.0 ± 2.5 μU/ml and 16.3 ± 2.4 μU/ml, virtually the same as the mean maximum ΔTSH response (16.7 ± 1.6 μU/ml) in a group of 12 normal, 20–39-yr-old females previously reported. In contrast to males, females demonstrate no agerelated decline in TSH response to TRH.