Hypothalamic-pituitary Disorders Research Articles

Abnormal catecholamine mechanisms in hypothalamic-pituitary disorders

Patients with growth hormone or prolactin-secreting pituitary tumors failed to show normal plasma catecholamine (especially norepinephrine) responses to oral bromocriptine. These patients had normal basal plasma catecholamine concentrations. Patients with anorexia nervosa had low basal levels of dopamine, norepinephrine, and epinephrine. These data are consistent with disordered catecholamine metabolism in patients with these neuroendocrine disorders.

Glycoprotein hormone alpha subunit secretion by pituitary adenomas: influence of external irradiation.

In ninety-nine patients with pituitary adenomas, forty-six with acromegaly, the serum level of the glycoprotein hormone alpha subunit was elevated in eighteen cases. Thirteen of these were acromegalic and one had an FSH-producing tumour. Alpha levels varied little during the day, from one day to the next and over a 6 month period. In twenty-five patients with a variety of other hypothalamic-pituitary disorders examined, one patient with a craniopharyngioma had a mildly elevated alpha level. External pituitary irradiation was followed by an acute and often transient fall in alpha level in several of these patients. Of the fifty-four patients with pituitary adenomas who had received external irradiation before testing, only five had elevated alpha subunit levels compared with thirteen patients of the forty-five who had not been irradiated. This difference in incidence of elevated alpha level was statistically significant (P less than 0.025). We conclude that external irradiation may reduce alpha subunit level chronically in many patients with pituitary adenoma.

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.

Concordance of Insulin-Induced Hypoglycemia and Phenothiazine-Induced Prolactin Secretion in Man*

Abstract Highly variable pituitary PRL responses have been reported after insulin-induced hypoglycemia in normal subjects. Thus, insulin hypoglycemia has not been widely utilized to ascertain hypothalamic-pituitary PRL reserve. To determine the clinical usefulness of measuring hypoglycemia-induced PRL secretion, serum PRL concentrations after standard insulin tolerance tests were compared to those after phenothiazine (perphenazine) administration in 12 normal subjects and in 24 euprolactinemic patients evaluated for possible hypothalamic-pituitary disorders. In normal subjects, mean PRL levels rose from 12.6 ± 1.0 to 42.6 ± 6.6 (1 SEM) ng/ml after insulin hypoglycemia and from 13.3 ± 1.7 to 52.2 ± 8.4 ng/ml after perphenazine ingestion. The mean maximum increment in PRL was 30.1 ± 6.7 ng/ml after hypoglycemia and 38.9 ± 8.8 ng/ml after perphenazine administration. In the 24 patients evaluated for hypothalamic-pituitary dysfunction, mean PRL concentration rose from 9.6 ± 1.3 to 32.0 ± 5.5 ng/ml after insul...

Plasma TSH and prolactin response to insulin induced hypoglycemia in patients with hypothalamic pituitary disorders.

Plasma TSH and prolactin (PRL) responses to insulin-induced hypoglycemia (ITT) were examined in 37 patients with various hypothalamic pituitary disorders. Four patients showed a definite TSH response to ITT. They were 2 patients with suspected pinealoma with diabetes insipidus (DI), a patient with pituitary adenoma and a patient with acute prophyria. A suspected hypothalamic dysfunction and a slightly impaired pituitary function manifested as GH deficiency were their common endocrinological features. On the contrary, plasma PRL response to ITT was noted in about one third of the patients examined, but no concomitant PRL response was observed in any of the patients with a definite TSH response. This suggested a different mechanism of TSH and PRL secretion may be different under this circumstance and a certain factor related to the hypothalamic disorder may play a modulating role in an unusual TSH response to hypoglycemia in these particular patients.

MULTIFACTORIAL REGULATION OF PROLACTIN SECRETION

The hypothalamus exerts an inhibitory influence on prolactin release from the anterior pituitary. Whether or not peptide hypothalamic prolactin-regulating factors, analogous to those for other pituitary hormones, exist, remains to be confirmed. There is evidence that catecholamines and indolamines directly or indirectly affect prolactin release, This concept may explain the pathogenesis of galactorrhœa-amenorrhœa and other endocrine diseases produced by hypothalamic-pituitary disorders.

Adrenocorticotrophic and growth hormone secretion. Studies during pneumoencephalography.

The effect of pneumoencephalography on plasma and cerebrospinal fluid (CSF) adrenocorticotrophic (ACTH) and growth hormone concentrations was studied in patients with and without hypothalamicpituitary disorders. In those without hypothalamic-pituitary disease, basal plasma and CSF ACTH levels were approximately equal, whereas plasma growth hormone levels were higher than CSF levels. Associated with the stress of the procedure, both ACTH and growth hormone concentrations increased in the plasma without a corresponding change in CSF levels of these two hormones. In two patients with suprasellar extension of either an ACTH or growth hormone secreting pituitary tumor, basal CSF ACTH or growth hormone levels were higher than in those without suprasellar extension. In contrast, those patients with nonendocrine active pituitary tumors that extended above the sella turcica did not have elevation of CSF ACTH or growth hormone levels.

Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders.

The plasma TSH response to TRH (200 μg iv) was investigated in a group of normal subjects of both sexes and in 108 patients with hypothalamic-pituitary disorders: 89 had pituitary tumors (49 had acromegaly, 36 had pituitary tumors without recognized hormonal secretion, 8 had craniopharyngioma, 1 had hypothalamic-pituitary metastasis from breast cancer, 1 had a hypothalamic- pituitary vascular tumor), 19 had other hypothalamic-pituitary disorders (1 Sheehan's syndrome, 4 primary empty sella, 12 idiopathic hypopituitarism, 2 idiopathic diabetes insipidus). Seventy-two were euthyroid; 32 had secondary hypothyroidism, 4 were thyrotoxic. The pattern of TSH response to TRH was defined with respect to the magnitude of the increase and to the pattern of the response curve. Three thyrotoxic patients did not respond to TRH, while one patient with high basal TSH values had a poor increase. Most of the other patients (88%) showed positive responses and the percentage of absent responses in euthyroid and hypothyroid patients did not significantly differ. Exaggerated responses were more frequently observed in hypothyroid patients (mostly in nontumorous cases). Regular response curves were observed in 55% of euthyroid and in only 19% of hypothyroid patients in whom there was a higher incidence of either delayed or prolonged response (56% and 37%, respectively). Frequently, prolonged responses were, at the same time, delayed and exaggerated. The incidence of these abnormalities was larger in patients with craniopharyngioma, in patients with pituitary tumors with suprasellar extension and in patients with idiopathic hypopituitarism. Therefore, these abnormalities can be considered quite characteristic of hypothalamic disorders.

Effect of synthetic thyrotrophin-releasing factor on pituitary TSH secretion in normal subjects and patients with hypothalamic-pituitary disorders.

ABSTRACT Different doses of thyrotrophin-releasing factor (TRF) were administered by three different routes (intravenous, subcutaneous and oral) to 87 normal subjects in order to standardize the "TRF test" for the pituitary TSH reserve. The results were: 1) Intravenous single injection may be suitable as a routine TRF test because of the stability of TSH response to TRF and the reliability of TRF administration. 2) The maximum TSH increases were dose-related between 50 and 400 μg, so that we can recommend the use of 50 μg of TRF as a screening test for TSH secretion. 3) Oral administration and slow intravenous infusion of TRF with estimation of thyroxine levels can be useful as an indirect test of pituitary TSH reserve when TSH assays are not available. According to these results, the TRF test was performed in patients with hypothalamic-pituitary disorders. A normal increase in plasma TSH occurred in 10 out of 20 patients with operated pituitary chromophobe adenoma following the administration of 50 or 100 μg of TRF. Two patients showed no rise in plasma TSH after receiving 50 or 100 μg of TRF but a normal rise after receiving 400 or 600 μg of TRF. Little or no rise in the plasma TSH levels occurred following the administration of 100 μg TRF in pituitary chromophobe adenoma and Sheehan's syndrome who had a long standing pituitary insufficiency and secondary hypothyroidism. However, some cases with craniopharyngioma and pinealoma, accompanied with a low level of thyroid function, showed a normal TSH responses to 50 μg of TRF. Since the pituitary of these cases remained intact from tumour invasion, they should be assumed to have tertiary (hypothalamic) hypothyroidism. Of particular interest is the fact that the patients with suprahypophyseal tumour surprisingly showed a supernormal TSH response to 50 μg of TRF.

Functional evaluation of prolactin secretion in patients with hypothalamic-pituitary disorders.

Prolactin secretion was assessed in 23 patients with hypothalamic-pituitary disorders using L-Dopa suppression, chlorpromazine (CPZ), and thyrotropin-releasing hormone (TRH) stimulation tests. Based on the responses to these tests, three groups of patients were identified: those with panhypopituitarism (group I) and those with partial hypopituitarism either with (group II) or without (group III) evidence of hypothalamic involvement. Panhypopituitary patients (group I) consistently had low serum prolactin values and failed to respond to all tests. Patients with hypothalamic involvement (group II) exhibited (a) elevated basal prolactin values. (b) an increase in serum prolactin after TRH stimulation. (c) blunted response to L-Dopa, and (d) lack of response to chlorpromazine stimulation. Patients with partial hypopituitarism but without hypothalamic involvement (group III) had normal serum prolactin levels and suppressed normally after L-Dopa; although the magnitude of response to both stimulatory agents was significantly lower than normally found the ratio of prolactin levels post-CPZ and TRH (Delta prolactin CPZ/Delta prolactin TRH) was similar to the ratio of normal individuals suggesting that these patients (group III) had a normal hypothalamic-pituitary prolactin axis. In the 23 patients studied, the most consistent disorder of pituitary function proved to be an abnormal response to one or other of the three tests employed for the evaluation of prolactin secretion. Hence these tests have considerable potential as a sensitive screening procedure in the evaluation of patients suspected of having hypothalamic-pituitary disease.

TRF test in patients with hypothalamic-pituitary disorders.

TRF test with 50-100μg of synthetic TRF was performed in 57 patients with hypothalamic-pituitary disorders. According to the degree and the pattern of TSH response, they were classified as an absent, subnormal, normal or supernormal response and/or delayed pattern of TSH response. 9 of 21 patients with pituitary chromophobe adenoma showed an absent or a subnormal response. Six of them were hypothyroid. 21 of 23 patients with hypothalamic lesions had normal or supernormal TSH response. 5 with a normal response and all of the six with a supernormal response showed clinical or biochemical evidence of hypothyroidism. Since the pituitary of these cases remained intact from tumor invasion, they should be postulated as hypothalamic hypothyroidism. A delayed pattern of TSH response to TRF, where the peak TSH response occurred after 20min, was observed in 17 of 23 in hypothalamic lesions. 6 of 7 patients with diabetes insipidus showed just the same pattern of TSH response as observed in the patients with determined hypothalamic lesions. This delayed pattern of response and normal or supernormal response to a small dose of TRF, such as 50-100μg, could be used to distinguish hypothalamic lesions from pituitary diseases.

Clinical study of TRF test. 7. TRF test response in hypothalamic pituitary disorders

Clinical study of TRF test. 7. TRF test response in hypothalamic pituitary disorders

The usefulness of TRF (thyrotropin releasing factor) test in patients with hypothalamic-pituitary disorders

合成thyrotropin releasing factor (TRF) 50～100μgを視床下部下垂体疾患々者57例に投与し, TSH放出反応の程度,様式により分類検討した.下垂体障害例ではTRFに対して正常反応するものと低下あるいは無反応の症例が相半ばした. 8例が反応遅延を示したが,この内7例は開頭手術後であつた.視床下部障害症例23例中21例が正常あるいは過大反応を示し,しかも21例中17例が反応遅延を呈した.したがつて少量のTRFに十分なTSH放出反応を呈し,しかも反応遅延を示す症例は,視床下部障害の存在を示唆するものである.

20 Growth Hormone (GH) Responsiveness to Stimulation by Insulin Hypoglycemia, 2. Arginine, 3. Piromen in normal and Growth Deficient Children

Plasma GH levels in 11 normal children, in 5 children with hypothalamic-pituitary disorders, in 8 children with idiopathic GH deficiency and in 4 children with a constitutional growth delay were examined in the fasting state and following stimulation with insulin hypoglycemia, arginine, and bacterial pyrogen (Piromen). Normal children exhibited a marked fluctuation in fasting GH levels (radioimmunoassay). An elevated prestimulatory GH value was associated with a diminished response. Of the 3 stimuli, insulin hypoglycemia resulted in the highest GH levels. In normal children, GH responses to Insulin Hypoglycemia (x 20.4±6.4) Arginine (x 15.2±4.3) and Piromen (x 9.9±2.8) were not significantly different because of the marked variability observed within each group. In children with a constitutional growth delay, both fasting and poststimulatory GH values were indistinguishable from normal. In idiopathic GH deficiency, GH values prior to stimulation (x 2.4±0.4) and after the three stimuli (x 3.6±1.0) were significantly lower than those values observed in the normal or constitutional delay groups. The data suggest 1. Insulin Hypoglycemia, Arginine and Piromen are suitable stimuli with which to evaluate GH responsiveness; 2. failure to respond to stimuli in normal children is associated with elevated resting levels of GH; 3. children with idiopathic GH deficiency have significantly lower pre and post stimulatory GH values than do the normal but do respond better to stimulation than children with pituitary-hypothalamic disorders; 4. constitutional delay in growth is not associated with abnormal GH responsiveness; 5. normal GH secretion can be diagnosed if a resting GH level 6 mμg/ml. (APS)