Effect of Synthetic Thyrotrophin Releasing Hormone (TRH) in Man

Summary: Synthetic TRH (200 μ g) administered intravenously to twelve normal subjects produced a consistent rise in serum thyrotrophin (TSH) levels reaching a peak 20 – 30 mins following the injection. No reproducible effects were seen on plasma levels of GH, LH, FSH or 11 -hydroxycorticoids measured concomitantly with TSH. Mean free thyroxine index following TRH rose by 23% at 60 and 120 mins. Two subjects treated with triiodothyronine and 17 untreated thyrotoxic patients showed marked impairment of TSH response to TRH. Reduced or absent TSH responses were likewise observed in five euthyroid patients with Graves' disease, two with ophthalmopathy as the sole manifestation of the disease. In ten patients with primary hypothyroidism, synthetic TRH evoked further increases of elevated basal TSH levels with exaggerated over-all responses. Five of seven euthyroid patients with pituitary tumours showed blunted TSH responses whereas all six patients with secondary hypothyroidism (resulting from pituitary or suspected hypothalamic lesions) exhibited normal or slightly exaggerated responses.
It is concluded that synthetic TRH is a specific stimulus to pituitary TSH release with considerable potential in the diagnosis of mind disturbances of thyroid function. Its use should promote better understanding of hydothalamic-pituitary-thyroid relationships.     

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

Fourteen 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.     

THE EFFECT OF THYROTROPHIN-RELEASING HORMONE ON PLASMA PROLACTIN AND THYROTROPHIN LEVELS IN PRIMARY HYPOTHYROIDISM

Plasma prolactin and thyrotrophin (TSH) were measured by radioimmunoassay before, at 20 min and 60 min after the intravenous administration of 200 μg thyrotrophin-releasing hormone (TRH) in thirty-two patients with untreated primary hypothyroidism and in sixteen normal volunteers. Whereas basal plasma TSH was markedly elevated in all the patients with hypothyroidism, a slight, but significant increase (P<0.05) in basal plasma prolactin in primary hypothyroidism could only be demonstrated by matching for age, sex and circulating gonadotrophin levels, ten patients with hypothyroidism with ten normal volunteers. There was, however, no significant difference between the two groups, matched or unmatched, in the plasma prolactin levels, in contrast to the plasma TSH levels, following TRH administration. No apparent relationship was found between basal prolactin and follicle-stimulating hormone (FSH), luteinizing hormone (LH) or TSH. Assuming the release of prolactin by TRH to be of physiological significance, the results suggest that TRH secretion by the hypothalamus may be increased in untreated hypothyroidism and that low levels of circulating thyroid hormone increase the sensitivity of the pituitary thyrotrophs, but not the prolactin secreting cells, to TRH. Markedly elevated plasma prolactin levels associated with galactorrhoea were not seen in primary hypothyroidism in the absence of the puerperium or oestrogen therapy.     

THYROID FUNCTION AND ANTIBODY STUDIES IN PERNICIOUS ANAEMIA

Thyroid antibodies were demonstrated in 57% of thirty pernicious anaemia patients without overt thyroid disease. Elevated basal thyroid stimulating hormone (TSH) levels and an enhaced TSH response to thyrotrophin releasing hormone (TRH) only occurred in thyroid antibody positive subjects; by contrast the thyroid antibody negative subjects in the older age group frequently and undetecable basal TSH levels and an impaired TRH response. Thyroid hormone concentrations provided no absolute evidence of hypothyroidism in any of the patients.     

THYROTROPHIN AND PROLACTIN RESPONSIVENESS TO THYROTROPHIN RELEASING HORMONE IN CUSHING'S DISEASE

Serum thyrotrophin response to thyrotrophin releasing hormone was impaired in all of eight subjects with untreated Cushing's disease; while all of six similar subjects tested after adequate treatment by a pituitary implant of ¹⁹⁸ Au then showed a normal response. In all five of the untreated patients studied, the serum prolactin response to TRH was normal. Thus chronically excessive cortisol levels as seen in Cushing's disease inhibit pituitary TSH responsiveness to TRH without affecting the prolactin response to TRH Evidently the release of TSH and of prolactin by TRH are governed by independent mechanisms.     

Endocrine morbidity in adults treated with cerebral irradiation for brain tumours during childhood.

Hypothalamic-pituitary function was assessed in 20 adult subjects who were treated with cerebral irradiation for brain tumours during childhood between 8 and 32 years earlier. Nine patients showed impaired growth hormone (GH) responses to hypoglycaemia, of whom, 7 are below the third centile for standing height. All GH deficient subjects received more than 2950 rads to the hypothalamic-pituitary axis with a maximum dose of approximately 5000 rads being used in one case. Three subjects have an elevated basal serum thyroid stimulating hormone (TSH) level and 2 of these show an exaggerated TSH response to thyrotrophin releasing hormone (TRH) but no patient was clinically or biochemically hypothyroid. The rest of hypothalamic-pituitary function was essentially normal. This study shows that multiple pituitary hormone deficiencies do no develop with time when the radiation dose is below a critical level. Thus it appears that there is a gradation of radiation damage to the hypothalamic-pituitary axis which is dependent primarily on the dose received rather than the time interval after radiotherapy.     

Prolactin and thyrotrophin responses to thyroliberin (TRH) in patients with growth hormone deficiency: study in 167 patients

Both thyrotrophin (TSH) and prolactin (Prl) were studied under thyroliberin (TRH) stimulation tests in 167 hypopituitary dwarfs out of GH or T4 treatment. TSH and/or Prl responses were either low, normal or exaggerated and/or protracted. Various abnormal patterns were observed in most of the patients with low T4 but also in many patients with normal T4. The TSH response should be considered together with the value of T4. A normal response of TSH with a low T4 reflects a relative TSH deficiency from pituitary or hypothalamic origin. There was no clear relationship between the cause or type of hypopituitarism and the pattern of the responses of either TSH or Prl. The abnormalities of TSH and Prl were not related to each other except in patients with a past history of breech delivery. Then both TSH and Prl have to be measured after TRH in order to obtain full information from the test about hypothalamo-pituitary function. The frequency of the exaggerated and/or delayed or protracted responses of TSH and Prl with normal or low T4 is probably mostly related to hypothalamo-pituitary dysfunction. Abnormal responses of TSH or Prl, seldom of both hormones, were observed in otherwise isolated growth hormone (GH) deficiency, leading to a modification of such a diagnosis after the TRH test. Actually, the TRH test may be useful to ascertain the diagnosis of GH deficiency when the GH responses to provocative tests are borderline.     

THE SECRETION OF THYROTROPHIN WITH IMPAIRED BIOLOGICAL ACTIVITY IN PATIENTS WITH HYPOTHALAMIC–PITUITARY DISEASE

We describe here two patients with hypothyroidism due to pituitary-hypothalamic disease in whom basal thyrotrophin (TSH) levels measured by radioimmunoassay (RIA) were elevated yet when measured by a cytochemical bioassay (CBA) were found to be normal. This finding and the absence of the normal rise of thyroid hormones in response to thyrotrophin-releasing hormone (TRH) mediated release of TSH confirms for the first time the secretion of TSH with impaired biological activity. Primary thyroid disease as a cause for the elevated immunoreactive TSH was excluded by the absence of circulating thyroid antibodies and by a normal thyroidal radioiodine uptake response to exogenous TSH.     

Prolactin and TSH responses to TRH, chlorpromazine and L-dopa in children with human growth hormone deficiency.

Prolactin (PRL) and TSH responses to TRH, chlorpromazine (CPZ) and L-DOPA were studied in 23 children (15 male and 8 female) with human growth hormone (HGH) deficiency. Eight patients (group I) showed normal PRL response to TRH and CPZ but TSH response to TRH was delayed in 4 of this group. Twelve patients (group II) had normal (4 patients) or higher (8 patients) baseline PRL level and showed lower PRL response to CPZ than that to TRH. TSH response to TRH was normal in 3, blunted in 1, and delayed in 8 patients. Three patients (group III) had no PRL response to either TRH or CPZ. TSH response to TRH was normal in 1 but blunted in 2 patients. Of 8 patients with a higher baseline PRL level (group II and III), L-DOPA suppressed PRL secretion to less than 50% of the initial value in 7 patients, but not in 1 patient, in whom the diagnosis of hypothalamic tumour was established on brain surgery following these examinations. These results suggest that hypothalamic disorders are involved in more than half of 23 children with HGH deficiency.     

THYROTROPHIN, PROLACTIN AND GROWTH HORMONE RESPONSES TO TRH IN BARBITURATE COMA AND IN DEPRESSION

The effects of 200 microgram thyrotrophin-releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear-cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderated rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TRH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.     

Failure of luteinizing hormone-releasing hormone and insulin to further augment thyrotrophin release in primary hypothyroidism.

The effect of luteinizing hormone-releasing hormone (LH-RH) and insulin-induced hypoglycaemia on the release of thyrotrophin (TSH) was studied in five patients with primary hypothyroidism. All five patients had elevated TSH levels with an exaggerated rise in response to thyrotrophin-releasing hormone (TRH). No rise over control values was found after LH-RH or insulin indicating that despite the augmentation of TSH release in primary hypothyroidism there is no alteration of the specificity of the thyrotroph response.     

Is the thyrotropin-releasing hormone test necessary in the diagnosis of central hypothyroidism in children

To determine the value of the TRH test, we analyzed the unstimulated serum T(4) and TSH concentrations in 54 children with central hypothyroidism. A TRH test was performed in 30 patients. Midline brain defects (septo-optic dysplasia, 28; holoprosencephaly, 2) and combined pituitary hormone deficiencies were present in 30 and 52 patients, respectively. The mean serum free T(4), total T(4), and basal TSH concentrations were 0.6 ng/dl, 4.0 microg/dl, and 2.8 microU/ml, respectively. Five patients demonstrated elevated basal serum TSH concentrations. A normal TRH test [increase (delta) in TSH, 4.5-17.8], based on data from 30 controls, was documented in 23.3% of patients. Brisk (deltaTSH, >17.8), absent/blunted (deltaTSH, <4.5), and delayed responses were documented in 16.7%, 30%, and 30% of patients, respectively. The mean age at diagnosis was 2.8 yr, with 8 patients evolving into TSH deficiency. It was not possible to differentiate patients as having pituitary or hypothalamic disease based solely on the TRH test results. Patients with septo-optic dysplasia were diagnosed earlier and had elevated basal serum TSH and PRL concentrations, diabetes insipidus, and evolving disease. Although full pituitary function assessment is mandatory to identify combined pituitary hormone deficiencies, a TRH test is not essential, and the diagnosis should be made by serial T(4) measurements.     

The nocturnal thyroid-stimulating hormone surge is absent in overt, present in mild primary and equivocal in central hypothyroidism.

The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%, NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3 +/- 0.4 vs 0.9 +/- 1.0 mU/l, p less than 0.05) and relative (24 +/- 31 vs 63 +/- 51%, p less than 0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight of ten patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54 +/- 33%) and subclinical (92 +/- 69%), but decreased in overt hypothyroidism (2 +/- 10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. In conclusion: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.     

Thyrotropic function in patients with a hypothalamic or pituitary tumor. Possibility of the secretion of a TSH with reduced biological activity

Thyrotropic function was studied in 100 patients with hypothalamic or pituitary tumours before treatment. Eighteen patients with thyroid deficiency showed no signs of primary hypothyroidism. This was also showed in 4 other hypothyroid patients who had pituitary tumours studied later on. Only 4 of these 22 patients had TSH deficiency. The other 18 had normal or high plasma TSH levels, and the TSH response to TRH was normal but often delayed and/or prolonged. This pattern, suggestive of secretion of TSH with reduced biological activity, might however be due to other factors. Tumoral invasion of the hypothalamus, present in these 18 cases, could reduce secretion of TRH and dopamine. Hypothyroidism would then be secondary to TRH deficiency if TRH is considered to have a direct thyroid-stimulating action, and, like dopamine deficiency, could contribute to maintaining normal or high TSH secretion.     

EFFECTS OF IODIDES ON THE HYPOTHALAMIC-PITUITARY-THYROID AXIS IN NEUROLOGICAL ENDEMIC CRETINISM: EVIDENCE FOR COMPENSATED THYROIDAL FAILURE IN ADULT LIFE

Thyroid function studies, performed after iodide administration to five patients with neurological endemic cretinism, were indicative of hypothyroidism. All five subjects had either a low serum thyroxine (T4) or a high basal thyrotrophin (TSH) level and a clearly exaggerated TSH response to thyrotrophin releasing hormone (TRH). These findings are in sharp contrast with those we have previously described in goitrous patients without cretinism from the same geographical area. One interpretation of our observations is that there is an underlying mild defect in thyroid hormone synthesis in endemic cretinism predisposing to iodine induced hypothyroidism.     

Sex differences in circadian control of LH secretion

We have studied the secretion of TSH and prolactin from perifused rat anterior pituitary glands in vitro in response to single pulses of thyrotrophin releasing hormone (TRH) and KCl after prior exposure to TRH. Anterior pituitary fragments were incubated in normal medium or in medium containing 28 nmol TRH/1 for 20 h before perifusion. Thyrotrophin releasing hormone (28 nmol/l), administered as a 3-min pulse, stimulated TSH and prolactin release from control tissue to a peak value four or five times that of basal. After exposure of the pituitary tissue to TRH for 20 h, the subsequent response of TSH to a 3-min pulse of TRH was, however, markedly reduced; in contrast, the prolactin response was not significantly reduced. In a similar series of experiments KCl (60 mmol/l) was administered to both control and TRH-'treated' pituitary tissue as a 3-min pulse; no significant differences in TSH responses or prolactin responses were observed. These data indicate that TRH desensitizes the pituitary thyrotroph to a subsequent TRH stimulus but has very little effect on prolactin secretion.     

Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin.

TSH concentration was measured in plasma before and after TRH administration (200 micrograms, iv) in 89 patients with documented hypothyroidism consequent to various hypothalamic-pituitary disorders. Basal plasma TSH was less than 1.0 microI/ml in 34.8%, between 1.0-3.6 microU/ml in 40.5% and slightly elevated (3.7-9.7 microU/ml) in 24.7% of the cases. The plasma TSH response to TRH was absent in 13.5%, impaired in 16.8%, normal in 47.2%, and exaggerated in 22.5% of the cases, with delayed and/or prolonged pattern of response in 65% of the cases. The dilution curves of several plasmas drawn before and after TRH were parallel to those obtained with TSH standard preparation. After gel filtration, the elution pattern of TRH-stimulated plasmas from 4 patients did not show any major difference from that of pooled plasmas from normal subjects given TRH or from that of patients with primary hypothyroidism. Plasma TSH values determined by cytochemical bioassay on both basal and TRH-stimulated samples of 5 patients were markedly lower than those obtained by RIA. The serum T3 response to TRH was absent or low in 40 out of 53 patients in whom it was evaluated. The administration of T3 (100 micrograms/day for 3 days) or dexamethasone (3 mg/day for 5 days) respectively suppressed or reduced both basal and TRH-induced plasma TSH levels. Two patients became hypothyroid shortly after pituitary surgery in spite of basal and TRH-induced plasma TSH levels similar to or higher than those before surgery. Though thyroid atrophy due to chronic understimulation could explain the low T3 response to TRH in secondary hypothyroidism, it is difficult to reconcile thyroid understimulation with normal or increased plasma TSH unless the immunoreactive material has low biological activity. Present data suggest that several patients with hypothyroidism consequent to hypothalamic-pituitary diseases secrete a material which is immunologically similar to pituitary standard TSH and responds to stimulatory and suppressive agents in a manner similar to normal TSH but has low or absent biological activity. Thus, hypothyroidism due to insufficient TSH stimulation can be termed central hypothyroidism and can be due 1) to pituitary insufficiency (secondary hypothyroidism), 2) to a hypothalamic defect (tertiary hypothyroidism), or 3) to the secretion of biologically inactive TSH.     

The pituitary TSH response to TRH is inversely related to the plasma TSH concentration and directly related to the pituitary TSH content during hypothyroidism in the rat

We studied the effects of degree and duration of hypothyroidism on the pituitary TSH concentration and the pituitary TSH secretory response to TRH. Varying degrees of hypothyroidism were achieved in thyroparathyroidectomized rats (THYREX) by continuous sc infusion of T3 (0.2, 0.3, 0.4, or 0.5 microgram/100 g X day) or T4 (0.6, 1.2, or 1.8 microgram/100 g X day). While T3 was more potent than T4, both resulted in a dose-dependent suppression of the post-thyroidectomy rise in TSH. After 7 or 14 days of severe hypothyroidism (nonreplaced THYREX rats) the pituitary TSH secretory response to TRH (250 ng/100 g body weight, iv) was found to be decreased when compared to that of euthyroid rats. Decreasing the degree of hypothyroidism increased the pituitary secretory response to TRH and the pituitary TSH content. The results indicate that in the hypothyroid rat: severe hypothyroidism results in a blunted pituitary TSH response to TRH through 14 days after thyroidectomy, at 7 and 14 days after thyroidectomy the pituitary TSH response to exogenous TRH is inversely related to the basal plasma TSH concentration, the pituitary TSH concentration increases with the duration of hypothyroidism, the pituitary TSH content is increased by low rates of thyroid hormone replacement, and the pituitary TSH response to exogenous TRH is directly related to the pituitary TSH content.     

EFFECT OF CIMETIDINE ON SERUM PROLACTIN IN NORMAL WOMEN AND PATIENTS WITH HYPERPROLACTINAEMIA

In normal women, intravenous injection of the H₂-antihistamine, cimetidine, provoked a 3–4 fold rise in serum prolactin, without changes in serum growth hormone, thyrotrophin, or gonadotrophins. Hyperprolactinaemic patients with pituitary tumours, idiopathic hyperprolactinaemia or hypothalamic lesions demonstrated little or no rise in serum prolactin (expressed as a percentage increment) in response to cimetidine; these responses were significantly more blunted than the prolactin responses to intravenous TRH in the same subjects. Post-partum women also demonstrated blunted percentage prolactin responses to cimetidine, although responses to TRH were, in most patients, normal. Dynamic testing of prolactin secretion with cimetidine is no more useful than TRH in distinguishing tumourous from non-tumourous hyperprolactinaemia.     

Anterior pituitary function before and after treatment in twenty-three patients with isolated adrenocorticotropic hormone (ACTH) deficiency reported in Japan (author's transl)

Anterior pituitary function in 23 patients (16 men and 7 women, aged 27 to 68) with isolated ACTH deficiency was analyzed. Four were our own cases while the other 19 cases were ascertained by questionnaire. Both the baseline TSH levels and the peak TSH responses to TRH were high before treatment in more than half the cases but were normalized after treatment. This abnormality was found in patients younger than 50. The peak prolactin responses to TRH were excessive before and after treatment in three-fourths of the cases but decreased after treatment. The peak HGH responses to ITT were excessive in 3 patients before treatment an increased after treatment in 5 out of 6 cases. The peak LH and FSH responses to LH-RH were low or high in 20-30% of cases, but these abnormal responses were reduced to half after treatment. These results demonstrate that many disorders of the anterior pituitary function were found in patients with isolated ACTH deficiency but that these disorders became normal after treatment.