Oral Thyrotropin-releasing Hormone Research Articles

Calcitonin reserve in different stages of atrophic autoimmune thyroiditis.

The objective of this study was to determine the calcitonin (CT) hormone reserve in different severity of atrophic autoimmune thyroiditis (AAT). Forty-eight female patients with AAT were divided into four groups based on basal and peak thyrotropin (TSH) values (after oral thyrotropin-releasing hormone [TRH], free triiodothyronine (FT3) and free thyroxine (FT4) ranging from normal in group 1 to overt hypothyroidism in group 4. All had thyroid antibodies. The control group comprised euthyroid females of comparable age, without thyroid antibodies. Basal CT and CT response to calcium infusion (area under the curve) were investigated as parameters of CT reserve. Basal CT was lower in groups 2 to 4 of patients with AAT (compared to controls), but the difference was not significant. Stimulated CT levels were lower (p < 0.05) in all groups of patients compared to controls, with markedly reduced CT-secretory reserve in group 4. Thyroid antibody concentrations and, basal and postinfusion calcium levels were not significantly different among the various groups. In conclusion CT deficiency (especially stimulated values) occurs in AAT and is more severe in hypothyroid patients than in earlier stages of AAT.

Inhibitory action of oral thyrotropin-releasing hormone on the glucoregulatory response of the oral glucose tolerance test.

Thyrotropin-releasing hormone (TRH) has been found in the gastrointestinal tract, where it mainly exerts an inhibitory action. We used oral TRH, a stable and powerful formulation, to explore the glucoregulatory response of oral glucose tolerance test (OGTT) on obese patients with impaired glucose tolerance (IGT). Seven obese patients with IGT and eight controls were investigated. Three tests were performed on three separate days. On day 1, An oral TRH test: a 40 mg TRH tablet, was given. Blood samples for blood glucose (BG), proinsulin (PI), insulin (INS), C-peptide (CP), thyroxine (T4), triiodothyronine (T3), and thyrotropin (TSH) were collected every 30 minutes for 3 hours. On day 2, an OGTT with 75 g glucose was performed. On day 3, an oral TRH test was administered 30 minutes before the OGTT, and blood was collected every 30 minutes for 3 hours. Oral-TRH had no effect on basal BG and on pancreatic hormone secretion. Oral TRH, coupled with OGTT in both controls and obese patients, led to a significant inhibition of BG (p < 0.01), of CP (p < 0.001), and of INS (p < 0.001) during the first hour of administration, and afterward, there was only a very slight increase, compared with levels after only OGTT treatment. After OGTT, PI peaked at 90 minutes (9.4+/-3 ng/mL) in controls and at 60 minutes (12.7+/-2.5 ng/mL) in obese patients. TRH application prior to OGTT inhibited PI secretion for 90 minutes in controls, whereas in obese patients PI levels were decreased, not inhibited, during the OGTT. The mechanism of the inhibitory TRH action on OGTT-induced increase of BG and pancreatic hormone secretion is not clear. It could be due to inhibition of gastric motility, and on a paracrine effect that enhances secretion of somatostatin that then suppresses INS, CP, and possibly PI levels. The partial escape of PI from the TRH blockade in obese patients with IGT might indicate a diminished functioning capability of beta-cells and that TRH cannot affect the INS processing within the beta-cells in these patients.

LDL/HDL‐CHANGES IN SUBCLINICAL HYPOTHYROIDISM: POSSIBLE RISK FACTORS FOR CORONARY HEART DISEASE

The aim of the present study was to evaluate the lipid profiles (total cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and the electrophoretic low-density lipoproteins and high-density lipoproteins) in patients with subclinical (n = 52) and overt hypothyroidism (n = 18) in comparison to normal controls (28 and 18, respectively), matched for age, sex and body mass index. Subclinical hypothyroidism was defined as a syndrome with normal free thyroxine and total thyroxine but elevated basal thyrotrophin levels and/or an exaggerated TSH response to oral thyrotrophin releasing hormone. In subclinical hypothyroidism there was an elevated LDL concentration (P less than 0.01), a diminished HDL fraction (P less than 0.05) and a borderline elevated LDL-C (not reaching the limit of significance, P = 0.07). Total cholesterol and triglyceride concentrations remained unaltered. For the whole group of patients and controls significant negative correlations were found between LDL-C and T4 (P less than 0.04), total cholesterol and free thyroxine-index (P less than 0.01); positive correlations could be demonstrated between LDL-C and basal TSH (P less than 0.03), the ratio total cholesterol/HDL-C and basal TSH (P less than 0.03), and triglycerides and basal TSH (P less than 0.01). Our data provide a possible explanation for the higher prevalence of coronary heart disease reported in subclinical hypothyroidism. There may well be a case for the detection and early treatment of such individuals.

Prevalence of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not with dementia.

Thyroid disorders are known to manifest occasionally as isolated psychiatric disorders. In order to determine whether thyroid dysfunctions could play a significant role in the pathogenesis of psychiatric disorders in the elderly, the prevalence of thyroid disorders was compared in a group of psychogeriatric patients and in a group of nonpsychiatric elderly patients. Thyroid function screening was performed in 157 patients consecutively admitted to a psychogeriatric unit, and the prevalence of hypothyroidism was determined in the different groups of psychiatric disorders (senile and multi-infarct dementia, organic brain syndrome of other etiologies, psychotic depression, neurotic depression, chronic delusional state, acute confusional state, and personality disorder). Thyroid function screening was performed similarly in 104 unselected elderly patients admitted to the medico-surgical admission unit of the University hospital to assess the prevalence of hypothyroidism in a general, nonpsychiatric, elderly population. Eight patients were diagnosed as hypothyroid based on an elevated basal thyrotropin (TSH) and on thyrotropin-releasing hormone (TRH) test in the total number of patients, two in the nonpsychiatric and six in the psychiatric group. Three had clinical hypothyroidism, with decreased total and free T4 and T3 plasma levels in addition to increased basal TSH, five had biochemical hypothyroidism, with normal T4 and T3 levels and an excess TSH response to oral TRH. The prevalence of hypothyroidism in the two groups did not differ significantly (1.9% in the nonpsychiatric versus 3.8% in the psychiatric group). The prevalence of hypothyroidism in a subgroup of 88 patients with senile and multi-infarct dementia was 2.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-dependent effects of oral thyrotropin-releasing hormone in hyperthyroid female rats.

We have studied the thyrotropin (TSH) and thyroid hormone (T3) response to acute thyrotropin-releasing hormone (TRH) administration in rats previously rendered hyperthyroid by daily ip injection of 25 micrograms L-T4/100 g bw for 30 days. Animals were thereafter put on distilled water or TRH (2 mg/10 ml) as drinking solution for another 18 days, continuing T4 administration. On days 3 and 10 on oral TRH, the serum TSH and T3 response to TRH was studied by administering 2 micrograms of the tripeptide iv. After 3 days, neither the animals on oral DW, nor those on oral TRH showed any response. Nevertheless, after 10 days, animals on oral TRH had a measurable, significant thyrotropin response. At sacrifice (18 days), animals on oral TRH had increased pituitary TSH content. These results confirm and extend a recent report from our laboratory (Iglesias, Llobera and Montoya 1985). We conclude that TRH-mediated thyrotropin accumulation in pituitary is the primary cause for the presence of this response.

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.

Use of a single TSH-measurement after oral thyrotrophin releasing hormone: an economical and highly sensitive thyroid screening test.

The increment of serum TSH after thyrotrophin-releasing hormone (TRH) is usually considered an extremely sensitive thyroid test, particularly useful in borderline disturbances. We evaluated 195 patients by measuring serum TSH before and 3 h after 40 mg TRH po, and by various other thyroid tests. We found a very tight correlation between the TSH- increment and the 3 h TSH. Thus the TSH-increment can reliably be estimated from the 3 h TSH. The mann-Whitney test confirmed that the 3 h TSH identified thyroid dysfunction as well as the TSH-increment. The basal TSH can therefore be omitted and we propose the measurement of the 3 h TSH as an initial screening test. This single measurement economically excludes the many euthyroid patients sent for thyroid evaluation from further costly tests.

Results of oral TRH test in the differentiation of compensated and decompensated autonomous thyroid nodules.

In 17 patients with compensated autonomous adenomas of the thyroid, iv thyrotropin releasing hormone (TRH) tests (200 microgram) and oral TRH tests (40 mg) were performed. In nine of these patients, thyroid-stimulating hormone (TSH) 30 min after iv TRH showed a normal (greater than 2.7 microU/ml) and in eight patients a subnormal (less than 2.7 microU/ml) or negative response. However, after prolonged oral stimulation with 40 mg TRH, after 120-180 min TSH was normal (greater than 2.7 microU/ml) in 15 and subnormal (less than 2.7 microU/ml) in two patients. In 20 patients with decompensated autonomous thyroid nodules. TSH was not detectable (less than 0.8 microU/ml) after iv or oral TRH stimulation. Therefore, the oral TRH stimulation test seemed to be superior to the iv TRH test in the discrimination of compensated and decompensated autonomous adenomas of the thyroid.

Interaction of prolactin and testosterone in the human prostate.

Three experiments were performed to determine whether human prolactin (hPr) affects prostatic uptake and metabolism of testosterone (T). 1) Patients with prostatic cancer were infused twice with radio-labelled androgens, the first time with basal hPR, the second time with oral thyrotrophin-releasing hormone (TRH)-elevated hPr. In 5/7, significant increases in metabolic clearance of dihydrotestosterone (DHT) and in conversion of T to DHT accompanied increased hPR. 2) The incorporation of labelled T into minced benign prostatic hypertrophy (BPH) tissue from subjects with high (40 ng/ml) hPR was measured and was found to be more than twice the uptake into tissue from those with low hPR (6.5 +/- 1.9 ng/ml). 3) Uptake and metabolism in vivo of a bolus of 3H-T by BPH and carcinomatous prostates was measured and was far greater in subjects whose hPR was elevated by chlorpromazine than in untreated controls. It is concluded that prolactin increases prostatic uptake and metabolism of T. It is suggested that the best management of prostatic cancer should include depletion of prolactin as well as androgen.

Oral administration of TRH in puerperal women: effect on insufficient lactation, thyroid hormones and on the responses of TSH and prolactin to intravenous TRH.

Thirteen puerperal women with insufficient lactation were treated with thyrotrophin releasing hormone (TRH) 20 mg twice daily for two weeks. Intravenous (iv) TRH stimulation tests were done before the TRH therapy and within 3-5 h after the last dose of oral TRH. Plasma samples were assayed for prolactin (Prl), thyrotrophin (TSH), triiodothyronine (T3) and thyroxine (T4) by radioimmunoassays, and the lactational response was objectively monitored in 11 women. Oral TRH treatment was associated with significantly (P less than 0.05) depressed Prl levels (23.0 +/- 7.9 microgram/l vs. 61.4 +/- 26.2, mean +/- SEM), no change in TSH levels (3.7 +/- 0.4 IU/l vs. 4.0 +/- 0.4) but significantly (P less than 0.01) elevated T3 (2.17 +/- 1.14 nmol/l vs. 1.83 +/- 0.09) and T4 (131.6 +/- 7.9 nmol/l vs. 96.6 +/- 5.8) levels. Oral TRH entirely blocked the TSH response and significantly (P less than 0.01) blunted the Prl response to iv TRH stimulation. No improvement in lactation was observed.

Effects of oral thyrotropin-releasing hormone, exogenous thyroid-stimulating hormone, and withdrawal of triiodothyronine on 131I uptake after subtotal thyroidectomy.

To characterize the effects of oral TRH, exogenous TSH, and length of time of T3 withdrawal on I3II uptake, 16 patients who had undergone subtotal thyroidectomy for differentiated thyroid cancer were administered T3 (75-100 μg/day) for 8–15 weeks before 131I remnant ablation. T3 was withdrawn for 10 days in 8 patients (group 1) and for 24 days in 8 patients (group 2) before a baseline 24-h 131I uptake (study day 2), with repeat uptakes (study days 5 and 7) after the sequential administration of oral TRH (80 mg 3 times a day for 3 days) and after bovine TSH (10 U im each day for 2 days). Baseline serum TSH values were 30 ± 8 μU/ml in group 1 and 73 ± 14 in group 2 (P < 0.02), and the values did not increase at the end of the study (day 7; 36 ± 9 and 77 ± 12, respectively). Four hours after doses 1 and 7 of oral TRH, changes in serum TSH values were 10 ± 4 and 9 ± 2 in group 1, respectively, and 17 ± 6 and 10 ± 3 in group 2, respectively. The 131I uptake increased 2.8 ± 0.7% after oral TRH in group 1 (an in...

Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from <5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 μg of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 ± 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.

Psychologic and Psychosocial Aspects of Medical Practice

Excerpt In 1976Annals of Internal Medicinepublished a series of suggested readings for physicians reviewing medicine and its subspecialty fields, including neurology and dermatology, in preparation...

Effect of synthetic thyrotropin-releasing hormone on ovulation in baboons

Twice daily oral thyrotropin-releasing hormone administered to female baboons throughout the menstrual cycle had no significant influence on cycle length or upon estrogen levels but produced blunted midcycle LH peaks and luteal phase progesterone levels in three fourths of the treatment cycles. Mean plasma prolactin levels were increased approximately 2.5-fold relative to untreated, ovulatory control cycles. CB-154 alone did not alter cycle length or endocrine parameters examined (mean prolactin levels were decreased but not significantly). Cycles during which CB-154 was administered concomitantly with TRH were characterized by normal ovulation as evidenced by luteal phase progesterone levels. Since the effect on LH secretion was reversed by concomitant CB-154 administration, TRH-induced anovulation in animals given long-term treatment appeared to be mediated through physiologic mechanisms sensitive to elevated circulating prolactin levels. However, this conclusion must be considered equivocal since prolactin levels were also elevated during ovulatory cycles following long-term TRH therapy. Finally, these data do not exclude the alternative possibility that anovulation in baboons given long-term TRH treatment was a reflection of thyroid disturbance and not directly attributable to elevated prolactin.

Treatment of endogenous depressions with Thyrotropin‐Releasing Hormone (TRH) under oral administration

In a double-blind study among six patients suffering from endogenous depression, three patients received thyrotropin-Releasing Hormone (TRH) administered orally in doses of 20 mg three times a day for 3 weeks. In an open controlled study of three patients suffering from endogenous depression, two patients received oral TRH 20 mg four times a day for 2 weeks. Degree of depression according to Hamilton's Rating Scale measured during the study showed that TRH had no antidepressant effect. Thyroxine concentration in serum (T4) increased during the period of TRH treatment.

Long-Term Administration of Thyrotropin-Releasing Hormone and its Effect on Gonadotropin Secretion in Eumenorrheic Women

Thyrotropin-releasing hormone (TRH) was administered orally in doses of 60 mg/day to six women for two consecutive menstrual cycles. Daily serum samples were obtained for radioimmunoassay of luteinizing hormone, follicle-stimulating hormone, prolactin (PRL), and 17beta-estradiol secretory response. TRH was ineffective in interfering with normal gonadotropin and estradiol secretion, and failed to inhibit ovulation. The length of the luteal phase was not affected by TRH in the two cycles of treatment as demonstrated by basal body temperature, pregnanediol excretion, and endometrial biopsy. Long-term TRH administration induced an elevation of PRL serum levels that were not persistent and showed wide spikes. From these studies it is concluded that oral TRH at a dosage of 60 mg/day is unable to modify gonadotropin secretion and ovarian responsiveness in normally menstruating women.

EFFECT OF SEVERE, CHRONIC ILLNESS ON THYROID FUNCTION

Most clinically euthyroid patients with severe, chronic, non-thyroidal illnesses (i.e., " sick euthyroid " patients) have abnormal thyroid-function tests, and consequently assessment of their thyroidal status may be very difficult. The most striking abnormality detected in 75 sick euthyroid patients was a highly significant reduction in the mean total serum-triiodothyronine (T3) levels, with most patients having total T3 levels in the hypothyroid range. The severity of the illness correlated well with the reduction in total serum-T3 levels. The mean absolute free serum-T3 concentration was significantly lower than in the control patients. The mean total serum-thyroxine (T4) levels were also significantly reduced, although, unlike the total serum-T3 levels, they remained within the normal range. The total serum-T4/T3 ratios were generally higher in the sick euthyroid patients compared with the controls. The absolute free serum-T4 concentrations (as measured by the effective-thyroxine-ratio test) were normal, and serum-T.S.H. was not increased in any patient. The mean effective binding capacity of thyroid binding proteins in 11 sick euthyroid patients and the control patients was not significantly different. 3 patients had normal T.S.H. and T3 responses to oral thyrotrophin-releasing hormone (T.R.H.) and 2 other patients had normal T3 responses to intramuscular T.S.H. The major cause of the low total and absolute free serum-T3 concentrations in the sick euthyroid patients seemed to be inhibition of extrathyroidal conversion of T4 to T3. Decreased concentrations of binding proteins are unlikely to contribute greatly to the abnormalities of thyroid-function tests in the patients studied. Depressed production of T.R.H., secondary to stress or undernutrition consequent upon chronic illness, may also contribute by reducing thyroidal hormone output.

A DOUBLE-BLIND CROSSOVER SEQUENTIAL TRIAL OF ORAL THYROTROPHIN-RELEASING HORMONE IN DEPRESSION

In a double-blind, crossover, sequential trial, oral thyrotrophin-releasing hormone (T.R.H.) (40 mg.) given daily for a week was no more effective than placebo in treating twenty-nine depressed outpatients. There was no clinical or biochemical evidence that patients continuing on oral T.R.H. (40 mg. daily) maintenance therapy after completion of the trial became hyperthyroid, even when T.R.H. was administered for 12 weeks.

SERUM TSH RESPONSES TO INTRAVENOUSLY AND ORALLY ADMINISTERED TRH IN MAN AFTER THYROIDECTOMY FOR CARCINOMA OF THE THYROID

SUMMARYFourteen patients whose thyroid glands had been ablated for carcinoma were given intravenous or oral thyrotrophin releasing hormone (TRH) at intervals after stopping replacement thyroid hormone. Despite continuing the TRH infusion, serum thyrotrophin (TSH) rose to reach a peak at 120 min after the start of the infusion, and then fell again towards the pre‐treatment values. Significant responses were seen by 4 days after stopping triodothyronine (T3), but progressively increased with longer intervals off T3. Oral TRH gave a similar pattern of responses. Patients maintained on thyroxine (T4) and changed to T3 4 weeks prior to treatment had smaller TSH responses to TRH than patients maintained continuously on T3. It would seem that: (1) TRH promotes TSH release faster than it promotes synthesis of new hormone under the conditions studied, and (2) that long‐term administration of T3 suppresses TSH secretion from the pituitary in response to TRH less than thyroxine. While it is possible to elevate the serum TSH levels of these patients with thyroid carcinoma into the rane normally seen in primary hypothyroidism by the use of TRH prior to administration of radioiodine without production of clinical symptoms of hypothyroidism, we do not yet know whether such elevation is of benefit in treatment.

Response to orally administered synthetic thyrotropin-releasing hormone in man.

ABSTRACT Serum TSH, T4, PB125I and thyroidal radioiodine uptake were measured in response to orally administered thyrotropin-releasing hormone (TRH). Doses of 1, 2 and 4 mg were given to 10 normal male subjects at 3–5-day intervals; 8 mg were given to 9 of the 10 subjects 3 days to 10 weeks following the 4 mg-dose. The serum TSH response to oral TRH was doserelated. The mean maximum increments ±sem in serum TSH produced by 1, 2, 4 and 8 mg were 0.7 ± 0.3, 1.7 ± 0.3, 2.9 ± 0.7 and 6.7 ± 1.0 μU/ml, respectively. The repetitive dosage schedule used in this study produced small, progressive increments in serum levels of T4 and increments in serum radioactive inorganic iodide, but clear increments in thyroidal radioiodine uptake and serum PB125I levels did not occur. No symptoms or toxic effects were observed. Oral administration of TRH will be a useful method of determining pituitary TSH reserve when the releasing factor is more readily available.