Effect of dexamethasone on prolactin and TSH responses to TRH and metoclopramide in man.

We studied the effects of administration of dexamethasone, 2 mg orally every 6 h, for 5 days on the thyrotropin-releasing hormone (TRH)-induced release of prolactin (PRL), thyrotropin (TSH), triiodothyronine (T3) and thyroxine (T4) in 9 normal men and on the metoclopramide-induced release of PRL in 7 normal men. Dexamethasone suppressed the baseline serum levels of PRL, TSH and T3. The administration of dexamethasone blunted the PRL and TSH response to TRH; the blunted TSH response resulted in a decreased T3 and T4 response to TRH after dexamethasone. Following dexamethasone administration, the PRL response to metoclopramide, a dopamine antagonist which acts at the hypothalamicpituitary level to stimulate PRL secretion, was blunted in 7 normal men. The data suggest that short-term administration of pharmacological doses of glucocorticoids suppress the secretion of PRL and TSH by a direct effect on the anterior pituitary gland.     

External pituitary irradiation as a cause of TRH deficiency in patients with pituitary adenomas

The influence of external pituitary irradiation (XRT) on thyrotroph function and PRL secretion was studied in twenty-five patients with pituitary adenomas, of whom eight had acromegaly. Twenty-one patients had undergone subtotal operative removal of their adenomas 8-190 weeks (median 12 weeks) before XRT. Following irradiation there was a significant reduction in peak serum TSH levels in response to i.v. TRH (P less than 0.05, compared with before XRT). Peak TSH levels returned to normal at 3 months. Similarly a transient reduction in TRH-stimulated beta-TSH release was observed. Serum T3 and T4 concentrations also fell after XRT, the levels at 3 months being significantly lower than control values (P less than 0.02), though no difference was seen at 6 and 12 months. A delayed (hypothalamic) serum TSH response to TRH (60 greater than 20-min level) developed at 6 months. In contrast, PRL concentrations (basal and TRH stimulated) were not altered during the 12 months following XRT. These findings demonstrate that thyrotroph function can be transiently impaired following external pituitary irradiation. None of the patients studied required T4 replacement therapy. The development of a delayed TSH response to i.v. TRH may indicate endogenous TRH deficiency. It was not associated with supra-sellar tumour enlargement in our patients and may be due to hypothalamic damage by irradiation.     

Effect of Pyridostigmine on the Thyroid-Stimulating Hormone Response to Thyrotropin-Releasing Hormone in Abstinent Alcoholics

Alcoholism is sometimes associated with a blunted thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH; peak minus baseline < 5 mlU/liter), despite basal TSH and thyroid hormone levels within the normal range. In light of the inhibitory effect of somatostatin on TSH secretion, we examined whether this condition is caused by an increased hypothalamic somatostatinergic tone in alcoholic subjects. To answer this question, 16 euthyroid male alcoholics (aged 38 to 50 years) with normal [ n = 8; normal responder alcoholics (NRAs)] or blunted [ n = 8; low responder alcoholics (LRAs)] TSH response to TRH were selected in a preliminary TRH test (200 μg in an intravenous bolus). In addition, 8 age- and weight-matched normal men were tested with TRH and used as normal controls (NCs). NCs and alcoholic patients showed similar basal serum TSH, free triiodothyronine, and free thyroxine levels. All subjects were tested again with TRH, 60 min after treatment with 180 mg of pyridostigmine orally. According to selection criteria, NCs and NRA groups showed similar TSH responses to TRH, whereas TRH-induced TSH rise was strikingly lower in LRAs than in NCs and the NRA group. Pyridostigmine did not change the basal levels of TSH in any group, whereas it enhanced in a similar manner the TRH-induced TSH rise in the NC and NRA groups. No significant change in the TSH response to TRH was observed in LRA patients after pyridostigmine treatment. These data argue against the possibility that an enhanced somatostatinergic tone is responsible for the blunted TSH response to TRH observed in some alcoholic patients. This phenomenon might be attributed to alcohol-related defects of stimulated pituitary thyrotroph secretory capacity in some individuals, possibly due to genetic vulnerability and/or the toxic effects of prolonged alcohol abuse.     

THYROTROPHIN RESPONSES TO INTRAVENOUS THYROTROPHIN-RELEASING HORMONE IN PATIENTS WITH HYPOTHALAMIC AND PITUITARY DISEASE

Plasma immunoreactive thyrotrophin (TSH) responses to synthetic thyrotrophin releasing hormone (TRH) have been measured in forty-five patients with pituitary or hypothalamic disease (largely non-functioning and functioning pituitary tumours) tested before and/or after ablative treatment. Subnormal TSH responses usually indicated impaired pituitary function but were less sensitive indices than those of human growth hormone (HGH) after hypoglycaemia. High basal TSH values with exaggerated rises after TRH were occasionally found with hypothyroidism and impaired HGH and cortisol secretion. Delayed TSH responses were indicative of hypothalamic disease in some cases, but in others were associated with pituitary tumours without overt hypothalamic disease. Normal TRH tests were found with hypothyroidism, while five abnormal tests (four delayed) were found in euthyroid patients. Patterns of TSH response to TRH in hypothalamic-pituitary disease are complex and their significance is not always clear.     

Effect of pyridoxine on plasma levels of HGH, PRL, and TSH in normal women.

The effect of chronic administration of pyridoxine (vitamin B6) on HGH, basal and TRH stimulated PRL and TSH levels was studied in seven healthy female volunteers. HGH and TSH basal levels remained unaffected. Basal PRL and TRH stimulated PRL and TSH levels were slightly reduced without statistical significance (P greater than 0.05). The results indicate, that stimulation of the hypothalamic dopaminergic pathway by pyridoxine is highly variable and unpredictable. Therefore it seems meaningless to recommend vitamin B6 for the treatment of hyperprolactinaemia.     

Growth hormone secretory status is a determinant of the thyrotropin response to thyrotropin-releasing hormone in euthyroid patients with hypothalamic-pituitary disease

To assess the influence of endogenous GH secretion on the TSH and T3 responses to TRH administration in patients with hypothalamic-pituitary disease, we analyzed tests in a selected group of 26 euthyroid patients with hypothalamic-pituitary disease and in 15 normal controls. Basal TSH levels and the TSH response to TRH were significantly greater in GH-deficient patients (group 1) than in patients with normal anterior pituitary function and unimpaired GH reserve (group II). However, the T3 response to TRH was significantly less in group 1 than in group II patients. In acromegaly (group III), the TSH response to TRH was blunted, while basal and stimulated T3 levels were no different compared to control levels. These findings suggest that endogenous GH depresses the TSH response to TRH while enhancing the thyroid secretion of T3 in response to the evoked TSH released.     

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.     

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 effects of pyridoxine on pituitary hormone secretion in amenorrhea-galactorrhea syndromes

Six patients with amenorrhea, five of whom had galactorrhea and elevated PRL levels, were evaluated on a metabolic ward. All had normal sella tomograms, normal thyroid functions, and routine laboratory evaluations. None of the patients had taken any medication in the previous 6 months. On alternate days, five patients received 500 microgram of TRH iv with the measurement of PRL, TSH, FSh, LH, and hGH; 500 mg L-dopa orally with the measurement of PRL, FSH, and LH; a bolus infusion of 300 mg pyridoxine (B6) with measurement of PRL, hGH, TSH, FSH, and LH; and 25 mg chlorpromazine (CPZ) im with the measurement of PRL, LH, and FSH. The patients were then discharged on 600 mg oral pyridoxine/day and were readmitted for a repeat of the complete protocol 21 days later. The patients were continued on 600 mg oral pyridoxine for 3-4 months with monthly evaluations of serum PRL, LH, and FSH levels. These evaluations continued for 3 months after discontinuing pyridoxine. There was no demonstrable change in serum PRL after acute or chronic B6 therapy, mor was there a significant change in the response of PRL to CPZ, L-dopa, or TRH. The mean basal PRL was 97.5 +/- 9.7 ng/ml and after 3-4 months of oral pyridoxine was 97.1 +/- 14.8. In addition, there was no significant change in LH or FSH levels in response to acute or chronic B6, TRH, L-dopa, or CPZ. Neither acute B6 infusion nor chronic B6 therapy had any effect on TSH or the TSH response to TRH. Finally, acute B6 infusion had no effect on hGH levels and there were no paradoxical hGH responses to TRH. Two patients began having regular menses while on chronic pyridoxine. Their hormonal responses did not differ from those of the group, however.     

Hypothalamo-hypophyseal thyroid and gonadal function before and after erythropoietin therapy in dialysis patients.

We examined the effects of administration of two hypothalamic neurohormones, TRH and GnRH, for 3 days in five anemic male dialysis patients and five age-matched normal male volunteers. Patients on chronic hemodialysis have abnormal hypothalamo-hypophyseal thyroid and gonadal functions, including blunted TSH response to TRH, hyperprolactinemia, elevated basal levels of LH with exaggerated response to GnRH, and depressed FSH secretory response to GnRH. After correction of anemia with exogenous erythropoietin, these dialysis patients were given a single injection of the same hypothalamic hormones. The repeat studies after the correction of anemia showed normalization of 1) the TSH response to TRH, 2) basal GH and PRL levels, and 3) the FSH response to GnRH. Although these patients appear to have biochemical evidence of testicular failure, the gonadotropin response (FSH) to GnRH was not exaggerated. In addition, there was no increase in total T4 and free T4 after TRH administration. Although a free T3 response to TRH was present, it was remarkably blunted compared to that of controls. At the present time, it is not known whether these hormonal responses after the correction of anemia are due to better oxygenation or a trophic action of the erythropoietin.     

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.     

PROLACTIN RESPONSE TO METOCLOPRAMIDE AND CHLORPROMAZINE IN PRIMARY TESTICULAR FAILURE AND ISOLATED GONADOTROPHIN DEFICIENCY

The aim of the present study was to measure the PRL response to metoclopramide (MET) and chlorpromazine (CPZ) in seventeen patients with primary testicular failure and eight patients with isolated gonadotrophin deficiency (IGD). The responses were compared with those to TRH. Basal gonadotrophins and peak responses to LHRH were increased in testicular failure and reduced in IGD. Basal PRL levels were normal in both groups of patients. However, when compared with controls, the PRL response to both MET and CPZ as well as to TRH was exaggerated in primary testicular failure, whereas the responses were decreased in IGD. In both patient groups, as well as in the controls, the PRL response to MET exceeded that to TRH and CPZ. It is suggested that alterations in the steroid milieu are responsible for the exaggerated PRL response to MET, CPZ and TRH in primary testicular failure and the reduced response observed in IGD.     

STUDIES ON THE ROLE OF HISTAMINE IN HUMAN PITUITARY FUNCTION

To elucidate further the role of histamine in pituitary regulation, TRH and L-DOPA stimulation tests were performed with and without diphenhydramine, cimetidine, or betazole pre-treatment. Betazole blunted the GH response to L-DOPA and slightly enhanced the T3 response to TRH without altering the TSH or PRL increments. Neither diphenhydramine nor cimetidine had any acute effect on the hormonal responses examined. Histamine appears to play only a limited role in these aspects of human pituitary regulation.     

THE ACUTE EFFECTS OF A DOPAMINE ANTAGONIST (DOMPERIDONE) ON LUTEINISING HORMONE, FOLLICULE STIMULATING HORMONE, PROLACTIN AND THYROTROPHIN SECRETION IN POLYCYSTIC OVARIAN SYNDROME: DIFFERENTIAL EFFECT OF OVULATION

An alteration of the hypothalamic dopaminergic regulation of LH secretion has been implicated in the abnormal LH secretion of polycystic ovarian syndrome (PCOS). To investigate this, the acute effect of dopamine (DA) receptor blockade on LH, FSH, PRL and TSH secretion was determined. No effect was observed on either LH or FSH secretion in the PCOS patients or in normal women and LH pulsatility appeared to be maintained. When the PCOS patients were divided into those who ovulated in the preceding cycle and those who were anovulatory, it was observed that the ovulatory patients had a normal PRL and TSH response; whereas in the anovulatory patients, the PRL rise was blunted and the TSH response was absent. We conclude that this study gives no evidence to support the hypothesis of altered hypothalamic DA regulation of LH secretion in PCOS. The lack of LH response to DA blockade suggests that a physiological role of DA in the control of LH secretion seems unlikely as determined under these experimental conditions. The differences in PRL and TRH response may reflect anovulation rather than a fundamental abnormality in PCOS.     

PITUITARY FUNCTION IN ISOLATED GONADOTROPHIN DEFICIENCY

Hypothalamic-pituitary function was assessed in 24 individuals with isolated gonadotrophin deficiency (IGD). Thirteen had normal olfaction (Group I) while 11 (Group II) had anosmia (Kallmann's syndrome). In response to a 10 micrograms intravenous (i.v.) bolus of GnRH, the minimal dose required to evoke a consistent gonadotrophin response in normal subjects, the patients responded with significant LH and FSH increases over baseline (P less than 0.01). In Group II patients, large doses (150 micrograms) of GnRH, which elicit maximal release of gonadotrophin in normal subjects did not increase gonadotrophin release beyond that produced by a 10 micrograms bolus. In response to two 10 micrograms GnRH doses, at times 0 and 120 min, the IGD patients responded with similar LH increases to both boluses (both P less than 0.01 compared to baseline). The maximal PRL responses to arginine infusion and to TRH in the male patients were similar to those of normal males. However, in the IGD females, the PRL response to TRH was less than in normal females. The TSH responses to TRH in IGD males and females were similar to each other and similar to normal. The IGD male GH response to arginine infusion was comparable to that in normal males. We conclude that (1) IGD patients appear to retain minimal endogenous GnRH secretion so that the IGD pituitary responds to a minimal dose of GnRH without priming; (2) IGD is a heterogeneous syndrome in which affected individuals with and without normal olfaction represent parts of the spectrum of the same disease; and (3) except for the PRL response in females, the PRL, TSH and GH responses demonstrate that the IGD pituitaries are largely intact.     

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.     

LONG-TERM FOLLOW-UP OF''CURED''PROLACTINOMA PATIENTS AFTER SUCCESSFUL ADENOMECTOMY

The long-term follow-up (greater than or equal to 4 years) of clinical, hormonal and radiological aspects in 22 'cured' prolactinoma patients after adenomectomy was studied. Dynamic secretion of PRL and TSH was also evaluated, in order to identify the persistence of any underlying abnormality of hypothalamic pituitary control and to predict relapses. A relapse into hyperprolactinaemia was shown in 36% of patients 5-90 months (mean 46) after surgery. This was accompanied by reappearance of clinical symptoms but not by the radiological demonstration of the adenoma in any patients. A significant PRL rise after domperidone, a dopaminergic antagonist drug, was shown in cured patients after surgery (mean +/- SEM peak, 2977 +/- 645 mU/l) but this was markedly lower than that observed in control subjects (5732 +/- 440 mU/l). In fact, normal PRL increments were shown in only 6/16 (37%) patients. TSH hyper-responsiveness to domperidone normalized in only 46% of patients. Similar PRL responses to those obtained with domperidone were shown when a TRH test was given. A relapse into hyperprolactinaemia was observed in six of ten (60%) non-responders to domperidone and in four of seven (57%) non-responders to TRH, whereas six normal responders to domperidone and TRH had not relapsed at that time. Plasma PRL levels during pregnancy showed increments lower than those observed in normal pregnant women only in domperidone and TRH non-responder patients. These results indicate that a relapse into hyperprolactinaemia and a blunted PRL rise during pregnancy were present only in patients with persistently reduced PRL response to dynamic tests.     

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.     

Abnormal Growth Hormone Responsiveness to Stimuli in Women with Active Celiac Sprue

Baseline somatomedin C (Sm-C) and responses of growth hormone (GH), prolactin (PRL), and thyrotropin (TSH) to TSH-releasing hormone (TRH) and to L-dopa were evaluated in 10 untreated and nine treated women with celiac sprue, and in 10 normal women. Mean basal Sm-C, GH, PRL, and TSH levels were similar in all groups of subjects. In all subjects, L-dopa decreased PRL levels, without affecting TSH, and TRH increased PRL and TSH levels. In both controls and treated patients, TRH did not influence GH secretion, whereas L-dopa significantly increased GH levels. In untreated patients, GH levels paradoxically increased after TRH (8/10) but were unaffected by L-dopa (7/10). Because L-dopa would stimulate hypothalamic GH-releasing hormone (GHRH) secretion, four untreated patients, unresponsive to L-dopa, received GHRH, and GH levels rose markedly. These data suggest that, in untreated celiac sprue patients, hypothalamic control of GH secretion is reversibly impaired.     

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.