Prolactin and TSH response to TRH and metoclopramide before and after l-thyroxine therapy in subclinical hypothyroidism

The effects of the dopamine (DA) receptor antagonist metoclopramide on the plasma thyroid stimulating hormone (TSH) and prolactin (PRL) levels were studied in 8 patients with subclinical hypothyroidism (defined as absence of clinical signs of hypothyroidism with normal thyroid hormone levels, normal or slightly increased basal plasma TSH levels and increased and long-lasting TSH response to TRH) before and after l-thyroxine replacement therapy. Metoclopramide induced a significant (p less than 0.01) TSH release in the subclinical hypothyroid patients. Two weeks after l-thyroxine replacement therapy (50 micrograms/day), the TSH response to metoclopramide was completely blunted in subclinical hypothyroidism. In these patients a significant (p less than 0.01) inhibition of TSH response to intravenous thyrotropin-releasing hormone (TRH) was also observed after treatment with thyroid hormone. In analogy to the TSH behavior, plasma PRL secretion in response to metoclopramide and TRH administration was significantly (p less than 0.05) inhibited in the subclinical hypothyroid patients after l-thyroxine replacement therapy.     

Differential response of amphibian PRL and TSH pituitary cells to in vitro TRH treatment.

Hypophysial prolactin (PRL) and thyrotropin (TSH) cells of Rana perezi were examined after treatment in vitro with synthetic thyrotropin-releasing hormone (TRH). Ultrastructural morphometry applied to PRL and TSH immunoidentified cells estimated the volume density (Vv) of the secretory granules (SG), rough endoplasmic reticulum (ER), and Golgi complex (GC) as well as the numerical density (Nv) of the granules. Hemipituitaries were cultured in a superfusion system with or without 100 ng TRH/ml for 4, 14, or 24 hr. PRL cells showed significant degranulation (42%) of medium size SG after 14 hr of stimulation, whereas the biosynthetic machinery (ER and GC) was significantly developed after 4 hr of TRH culture (increase of Vv of GC, 1.5-fold, and ER, 1.3-fold, in comparison to the control). Most of these changes remained after 24 hr of TRH treatment. Compared with controls, TRH-treated TSH cells differed only after 24 hr when SG showed degranulation (40%), mainly of the medium size ones, and Vv of GC (1.6-fold) and ER (1.3-fold) increased. These results suggest that TRH acts directly on amphibian PRL and TSH cells stimulating hormonal synthesis and release. The time courses of responses to TRH differed in that PRL cells gave an immediate response while TSH cells gave a more delayed reaction.     

TSH response to TRH in euthyroid insulin-dependent diabetics

Summary In order to establish the exact profile of thyroid function in Insulin Dependent Diabetics (IDD), we have measured T4, T3 basal and TRH stimulated TSH concentrations in 22 IDD. Four patients with positive thyroid antibodies showed increased basal and TRH stimulated TSH concentrations; this situation may be indicative of subclinical hypothyroidism.     

Serum reduces the TSH content in rat pituitary cells in culture

Euthyroid rat pituitary cells were plated on a natural extracellular matrix (ECM) and cultured in either a medium supplemented with hormones and growth factors (SM) or in an unsupplemented medium (USM). Hormone supplementation resulted in a marked increase in the number of cells and in a less pronounced increase in the TSH content. Addition of 10% dehormonized serum (DHS) to the medium caused a further increase in the cell number as well as a significant elevation in the GH content but, surprisingly, it caused also a dramatic decrease in the TSH content. Time course experiments revealed that the serum doubled the rate of suppression of the TSH. DHS prepared from rat serum was as effective as that prepared from foetal calf serum and heat-inactivation of the serum did not change its suppressive effect on the production of TSH. This effect was confined to the serum fraction which was precipitable with 45% ammonium sulphate but did not bind to Con-A. It is suggested that a high molecular weight protein fraction of serum reduces the number of thyrotrophs in the culture and/or decreases the rate of TSH production by these cells.     

Changes of pituitary thyrotropin releasing hormone (TRH) receptor level and prolactin response to TRH during the rat estrous cycle.

The plasma PRL and TSH responses to TRH injected iv at different stages of the estrous cycle in normal rats under Surital anesthesia were maximal during the afternoon of proestrus and morning of estrus and lowest on diestrus I. As calculated from the areas under the plasma response curves, a 10-fold difference was found between the maximal and minimal PRL responses while a 2-fold difference was measured for TSH. The plasma PRL and TSH responses to TRH showed a correlation with the binding of [3H]TRH to anterior pituitary gland, a 3-fold difference being observed between the minimal binding measured on the morning of diestrus II and the maximal value found on the evening of proestrus. Contrary to findings with LHRH and LH, repeated injections of a small dose (10 ng) of TRH in the afternoon of proestrus abolished PRL and TSH responses to subsequent injection of the neurohormone.     

神经型地方性克汀病患者TSH对TRH应答性的研究

本文应用 TRH 兴奋试验来了解地方性神经型克汀病患者下丘脑—垂体—甲状腺轴的功能状态和垂体 TSH 的储备功能。通过对37例分别来自未补碘和已补碘地区的神经型克汀病的研究,认为神经型克汀病与甲低症关系密切,不仅有原发性甲低,而且还有继发性甲低,部分患者垂体 TSH 储备功能较差,同时补碘可改善一部分患者甲状腺功能状态。     

Heterogeneity of prolactin and TSH response to TRH in hypotonadotropic hypogonadism.

To evaluate prolactin and TSH secretion in isolated gonadotropin deficiency, thyrotropin-releasing hormone (TRH), in a dose of 500 microgram, was administered iv to fifteen male subjects with this disorder. In 4 out of 8 untreated patients, TRH-mediated prolactin release was significantly blunted and this attenuated response was not improved in one patient after treatment with testosterone for 1 year. In 7 patients who were treated with testosterone for 2 to 8 years, four failed to show a normal prolactin response after TRH injection. TRH-induced TSH secretion, on the other hand, was attenuated in two out of 8 untreated and in two of 8 treated patients with hypogonadotropic hypogonadism. The decreased TSH reserve was not necessarily associated with the poor prolactin response to TRH. It was concluded that heterogeneity exists in TRH-mediated prolactin and TSH release in "isolated" gonadotropin deficiency syndrome.     

The relationship between TSH response to TRH and GH response to dopaminergic agents in patients with acromegaly]

The role of dopaminergic agents (DA) in the regulation of growth hormone (GH) secretion was investigated in patients with untreated acromegaly. TRH (0.5 mg iv), bromocriptine (Br) (2.5 mg orally) or L-Dopa (500 mg orally) loading tests were performed, and serum levels of TSH, GH and prolactin (PRL) were measured. Patients were defined as responders to TRH when peak TSH level after TRH test was higher than 5 microU/ml. Br or L-Dopa was considered to be effective when serum GH or PRL levels were suppressed more than 50% of the basal value. The patients were classified into large adenoma group with suprasellar extension or cisternal herniation (L group, n = 7) and intrasellar small adenoma group (S group, n = 11) which was further divided into TRH responder (Sr group, n = 4) and TRH non-responder with suppressed TSH (Ss group, n = 7). Br was effective in 7 or 100% of 7 patients in the Ss group but only in one or 25% of 4 patients in the Sr group. Br was also effective in 5 or 71% of 7 patients in the L group, although most of them were responders to TRH. Percent inhibition of serum GH levels by Br was significantly higher in the Ss group (82.3 +/- 12.3%, p less than 0.001) and in the L group (64.7 +/- 20.5%, p less than 0.05) compared with that in the Sr group (29.3 +/- 21.6%). Suppression of serum GH level by L-Dopa was also observed in the Ss group. In contrast to the difference in the response of GH, serum PRL level was equally suppressed by Br or L-Dopa in each group. Suppression of TSH by administration of exogenous T4 had no effect on the GH suppression effect of Br in the Sr group. Considering the dual effects of DA to enhance growth hormone-releasing hormone (GHRH) secretion in the hypothalamus and to suppress GH secretion in the pituitary gland, these findings suggest that the paradoxical effect of DA to suppress serum GH level is observed when the hypothalamo-pituitary axis is disturbed mechanically by large adenoma in the L group or functionally in the Ss group probably due to enhanced secretion of somatostatin which suppresses TSH secretion and impairs the effect of GHRH.     

Ultra-sensitive TSH and the TRH test in the follow-up of thyroid and pituitary diseases

Basal TSH values measured by an ultra-sensitive method (TSH-US) were compared with the response of TSH under TRH (delta TSH) in 178 patients. In all thyroid pathologies and in patients without thyroid or hypophyseal pathology, results are in good agreement, i.e., delta TSH is proportional to basal TSH-US (r = 0.93). In 92 patients with hypophyseal diseases, no correlation between delta TSH and basal TSH-US could be found.     

Serum free thyroid hormones and response of TSH to TRH in nonthyroidal illnesses

The change in the levels of free thyroid hormones and the pathophysiology of the hypothalamo-pituitary-thyroid axis of patients with nonthyroidal illness (NTI) have not been clearly elucidated so far. Therefore, it was thought of interest to investigate this problem by determining free thyroid hormones and TSH in serum and the response of TSH to TRH in these patients. The subjects employed in this study were 71 cases with hemodialysis, 40 cases with diabetes mellitus, 24 cases with liver cirrhosis, 12 cases with various cancers, 10 cases with anorexia nervosa and 110 normal subjects as controls. The serum total protein, albumin, free T4, free T3, TSH and other parameters of thyroid function were determined, and the TRH test was performed on about 10 patients of each group. Serum TSH was not only determined by a conventional assay system, but with a highly sensitive method, and the data were compared with one another. It was found that the serum free T3 levels were significantly low in all the groups investigated, but the serum free T4 levels were significantly low only in the groups with hemodialysis, decompensated liver cirrhosis, cancers and anorexia nervosa. No significant lowering of serum free T4 was observed in the patients with diabetes mellitus, acute hepatitis and compensated liver cirrhosis. However, serum TSH levels tended to be higher in all the groups studied, though they were not significant. The response of TSH to TRH was low or delayed in about 20-50% of patients with hemodialysis, diabetes mellitus, liver cirrhosis, cancers and anorexia nervosa. It was observed that the serum rT3 concentration was significantly high in the patients with diabetes mellitus and anorexia nervosa but significantly low in the patients on hemodialysis. In the rest of the groups, there were found many cases who showed high levels of serum rT3 although they were not statistically significant. These results indicate that low concentrations of serum free T3 observed in the majority of the patients with severe NTI were, at least in part, due to the decrease in the peripheral conversion of T4 to T3 and the lowered sensitivity of the anterior pituitary to thyroid hormones and TRH.     

Antihypertensive effect of dilevalol is directly related to dose and plasma concentrations

Dilevalol is a novel antihypertensive agent combining vasodilation due to selective beta 2-adrenergic receptor agonism with nonspecific beta antagonism. To determine the relation of dilevalol dose and plasma concentration to antihypertensive effect, dilevalol (n = 15) or placebo (n = 3) was administered to 18 hypertensive subjects. The study was performed under blinded conditions during a 21-day hospitalization after a 3-week drug-free outpatient phase. In the 15 hypertensive patients receiving dilevalol orally in single morning doses of 200, 400 and 800 mg each for 5 days, the drug was shown to reduce blood pressure effectively for 24 hours at all doses. The antihypertensive effect was significantly related to dose administered and to the concentration of unchanged dilevalol measured in plasma. Dilevalol did not cause excessive changes in heart rate at rest and did not produce postural hypotension. The antihypertensive effectiveness of dilevalol was essentially the same after the first and fifth (steady state) doses at each dose level. Finally, no tendency toward rebound hypertension or tachycardia was observed after the abrupt discontinuation of dilevalol in these patients.     

The effect of iodized oil on the TSH response to TRH in endemic goiter patients.

The TSH and T3 response to synthetic TRH was evaluated in 4 groups of patients: normal controls and goitrous subjects from the urban area of Sao Paulo (urinary iodine excretion: 172.2 +/- 48.3 mug I/g creatinine) and nongoitrous and goitrous subjects from the endemic areas of Sao Bento (urinary iodine excretion: 53.8 +/- 17.1 mug I/g). Plasma T4 and T3 were within our normal range in all groups of patients. The mean plasma TSH was significantly higher (5.2 +/- 3.3 muU/ml) in goitrous subjects living in Sao Bento as compared to normal control groups both in urban or endemic areas, and after TRH these patients had an exaggerated and sustained TSH response with a significantly higher peak level (21.1 +/- 7.9 muU/ml). T3 concentration rose in all subjects following TRH and all patients from the Sao Bento endemic areas had a significantly higher proportionate increase in plasma T3 at 120 min. After an injection of iodized oil basal plasma TSH returned to the normal range in the goitrous subjects from Sao Bento. The mean peak TSH response to TRH was 9.1 +/- 3.8 muU/ml at 3 months after the iodized oil injection, and only at 6 months after the iodized oil TSH response was significantly reduced (peak level: 6.1 +/- 2.4 muU/ml). It is confirmed that plasma TSH levels are increased in endemic goitrous patients but not in normal controls living in the same endemic area and it is suggested that the pituitary threshold for inhibition of secretion of TSH by T4 and T3 has been reset in these goitrous subjects to achieve a persistently higher secretion rate of TSH.     

Age modifies the pituitary TSH response to thyroid failure.

OBJECTIVE: To investigate the association between serum TSH, total T4 and various patient characteristics when hypothyroidism is diagnosed in a population, and to study how age, sex and serum T4 levels influenced pituitary TSH response. DESIGN: A computer-based register linked to laboratory databases prospectively identified all patients with new, biochemically overt hypothyroidism (n = 685) in an open cohort in Denmark. The diagnosis was verified in each patient, and disease was classified into nosological type. Serum TSH and total T4 were recorded at the time of diagnosis in untreated patients with spontaneous autoimmune hypothyroidism (n = 578). MAIN OUTCOME: In untreated primary, spontaneous autoimmune hypothyroidism, we observed a four fold difference in average serum TSH levels between the youngest (0-20 years: TSH = 100 mU/l) and the oldest (80+ years: TSH = 24.4 mU/l) group of patients. No age dependent variation was observed in serum total T4. Log TSH showed an inverse linear correlation with age. An inverse linear correlation was present between log TSH and total T4 in both young and old patients, but for all total T4 values we observed lower median serum TSH values in elderly patients. CONCLUSIONS: For the same degree of thyroid failure, the serum TSH is lower among the elderly. This is most likely caused by a decrease in the hypothalamic/pituitary response to low serum T4. A certain increase in serum TSH may indicate more severe hypothyroidism in an old than in a young patient, and longer time may be needed after thyroid hormone withdrawal before elderly patients with thyroid cancer reach sufficiently high TSH values to allow for an effective radio-iodine treatment.     

Developmental and patterns of pituitary and plasma TSH in the normal and hypothyroid female rat.

The developmental patterns of thyroid-stimulating hormone (TSH) was examined in female Long-Evans rats by radioimmunoassay of pituitary and plasma from 5 through 80 days of age. The effects of hypothyroidism on normal TSH levels were examined in animals radiothyroidectomized at birth. Control animals showed a peak in circulating TSH levels at day 12 followed by lower levels through day 30, and even lower levels at day 80 when values were those of adult animals. Hypothyroid females had higher plasma TSH levels than controls from days 10 through 30 with no distinct peak at day 12. Pituitary content reached a peak at day 18 and was always higher in control than hypothyroid animals.     

Anterior pituitary function in patients with cerebrovascular diseases with special reference to TSH secretion in response to TRH administration (author's transl)]

TSH secretion in response to TRH was studied in patients with cerebrovascular diseases in order to elucidate the influence of cerebrovascular lesions on the hypothalamus-anterior pituitary function. Blood specimens were obtained before and at intervals of 10, 20, 30, 40, 60, 90 and 120 minutes after the intravenous administration of 500 microgram of TRH. Serum TSH was measured using the RIA method. In 20 normal subjects, the serum TSH level before TRH administration was 1.0 +/- 1.4 microunits/ml (MEAN +/- SD). Following the intravenous administration of TRH, serum TSH increased and reached the maximum level of 9.0 +/- 2.3 microunits/mil at 30 minutes and returned near to the original level at 120 minutes. The response was the same for both male & female patients. In 17 patients with cerebral hemorrhage, the response of serum TSH to TRH was variable, including the types of excess, delayed or low response besides the normal response. In severe cases, cases of acute phase and male patients, a marked variability in the response was observed. In 8 patients with cerebral infarction, a low response of serum TSH to TRH was observed in all cases. There was no difference of the response with regard to severity of the diseases, duration after onset or sex difference of the patients.