Palatopharyngeal incompetence in association with esophageal dysmotility, acquired glucocorticoid deficiency, and deficient tear production.
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An 8 1/2-year-old male is described with the rare triad of acquired adrenal insufficiency, esophageal dysfunction, and alacrima. In addition, he had velopharyngeal insufficiency, which is a previously unreported feature of this syndrome. Although the pathophysiology of this disorder remains to be demonstrated, a defect may be present, linking hormone-receptor cyclic AMP-mediated processes with abnormalities in parasympathetic and voluntary neuronal innervation or transmission.Keywords:
Pathophysiology
Triad (sociology)
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The interrelationships between thyroid hormone and cortisol actions were investigated in GH3 pituitary tumor cells. When GH3 cells were grown in thyroid hormone–deficient medium, cortisol did not affect the concentration of TRH receptors. Both thyroid hormones and TRH normally decrease the number of TRH receptors, and cortisol inhibited down-regulation by both hormones. TRH caused a greater increase in PRL synthesis when TRH receptors were high in the presence of cortisol and T3 than when TRH receptors were low (T3 alone). In the presence of cortisol, higher concentrations of T3 were required to decrease TRH receptors, while lower concentrations were necessary to stimulate GH synthesis. Cortisol and T3 alone stimulated GH synthesis 6- and 10–fold, respectively, while together they caused an 830–fold increase. In contrast, T3 did not alter the inhibition of PRL synthesis by the glucocorticoid. Cortisol did not significantly affect the amount of [125I]T3 bound to nuclei from cells incubated in thyroid hormone-deficient or T3-supplemented medium (-100 and -25 fmol/mg cell protein). The data suggest that cortisol modifies thyroid hormone action at a step subsequent to T3 receptor binding (Endocrinology106: 600, 1980)
Thyroid hormone receptor
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Patients with critical illness or hepatic failure exhibit impaired cortisol responses to ACTH, a phenomenon known as ‘relative adrenal insufficiency’. A putative mechanism is that elevated bile acids inhibit inactivation of cortisol in liver by 5α-reductases type 1 and type 2 and 5β-reductase, resulting in compensatory downregulation of the hypothalamic–pituitary–adrenal axis and adrenocortical atrophy. To test the hypothesis that impaired glucocorticoid clearance can cause relative adrenal insufficiency, we investigated the consequences of 5α-reductase type 1 deficiency in mice. In adrenalectomised male mice with targeted disruption of 5α-reductase type 1, clearance of corticosterone was lower after acute or chronic (eightfold, P <0.05) administration, compared with WT control mice. In intact 5α-reductase-deficient male mice, although resting plasma corticosterone levels were maintained, corticosterone responses were impaired after ACTH administration (26% lower, P <0.05), handling stress (2.5-fold lower, P <0.05) and restraint stress (43% lower, P <0.05) compared with WT mice. mRNA levels of Nr3c1 (glucocorticoid receptor), Crh and Avp in pituitary or hypothalamus were altered, consistent with enhanced negative feedback. These findings confirm that impaired peripheral clearance of glucocorticoids can cause ‘relative adrenal insufficiency’ in mice, an observation with important implications for patients with critical illness or hepatic failure, and for patients receiving 5α-reductase inhibitors for prostatic disease.
Corticosterone
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Corticotropin-releasing hormone (CRH)–deficient (KO) mice provide a unique system to define the role of CRH in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Despite several manifestations of chronic glucocorticoid insufficiency, basal pituitary proopiomelanocortin (POMC) mRNA, adrenocorticotrophic hormone (ACTH) peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. The normal POMC mRNA content in KO mice is dependent upon residual glucocorticoid secretion, as it increases in both KO and WT mice after adrenalectomy; this increase is reversed by glucocorticoid, but not aldosterone, replacement. However, the normal plasma levels of ACTH in CRH KO mice are not dependent upon residual glucocorticoid secretion, because, after adrenalectomy, these levels do not undergo the normal increase seen in KO mice despite the increase in POMC mRNA content. Administration of CRH restores ACTH secretion to its expected high level in adrenalectomized CRH KO mice. Thus, in adrenal insufficiency, loss of glucocorticoid feedback by itself can increase POMC gene expression in the pituitary; but CRH action is essential for this to result in increased secretion of ACTH. This may explain why, after withdrawal of chronic glucocorticoid treatment, reactivation of CRH secretion is a necessary prerequisite for recovery from suppression of the HPA axis.
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Corticotropin-releasing hormone
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The influences of glucocorticoid administration or increased serum corticoid concentration on TRF-induced TSH release was studied in patients receiving glucocorticoids and in patients with Cushing's syndrome. The TRFinduced TSH release was inhibited in patients who had received glucocorticoids for long periods or in high doses. These patients had received more than 60 mEq of cortisol per day for more than six months. Definite plasma TSH increases by TRF were observed in patients receiving shortterm, low doses or intermittent, low doses administration of glucocorticoid. Little or no rise of plasma TSH occurred following TRF administration to patients with Cushing's syndrome. From these observations it is possible to conclude that the mechanism of the glucocorticoid suppressive action on TSH secretion after short-term, low doses of glucocorticoid administration may be an impaired secretion of endogenous TRF, which results in a supernormal TSH response induced by exogenous TRF. With long-term and high doses of glucocorticoid therapy, TSH secretion appears to be inhibited not only at the suprahypophyseal level but also at the pituitary level.
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Journal Article Adrenocorticotropin Deficiency: Correction of Hyponatremia and Hypoaldosteronism with Chronic Glucocorticoid Therapy Get access GEORGE R. MERRIAM, GEORGE R. MERRIAM 1Department of Medicine, Columbia University College of Physicians and Surgeons, and Presbyterian Hospital New York, New York 10032 Search for other works by this author on: Oxford Academic Google Scholar LESLIE BAER LESLIE BAER 1Department of Medicine, Columbia University College of Physicians and Surgeons, and Presbyterian Hospital New York, New York 10032 Search for other works by this author on: Oxford Academic Google Scholar The Journal of Clinical Endocrinology & Metabolism, Volume 50, Issue 1, 1 January 1980, Pages 10–14, https://doi.org/10.1210/jcem-50-1-10 Published: 01 January 1980 Article history Received: 15 March 1979 Published: 01 January 1980
Mineralocorticoid
Hypoaldosteronism
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Abstract. In patients with deficient endogenous glucocorticoid production due to primary adrenal insufficiency (n = 4) or bilateral adrenalectomy (n = 2) a rise in LRH-stimulated concentrations of LH was seen following withdrawal of substitution therapy for 84 h. Consecutive re-administration of glucocorticoids (dexamethasone 2.0 mg/day for 3 days) resulted in increased basal concentrations of LH and FSH and a diminished secretory response of LH upon iv LRH (100 μg). Five patients substituted with glucocorticoids because of adrenocortical insufficiency presented upon the administration of exogenous ACTH 1-24 with unchanged basal and LRH-stimulated concentrations of LH and FSH as compared to a placebo experiment. These data suggest that the withdrawal and subsequent re-administration of glucocorticoid substitution alters basal and stimulated concentrations of gonadotrophins in patients with adrenocortical insufficiency, thus providing evidence for the importance of adequate glucocorticoid supply in the regulation of gonadotrophin secretion.
Adrenocortical Insufficiency
Basal (medicine)
Primary Adrenal Insufficiency
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Plasma cortisol, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and androstenedione (delta4-A) were measured by RIA during ACTH infusion in preadrenarchal children with constitutional short stature, normal adults, and patients with secondary adrenal insufficiency resulting from hypothalamic-pituitary disease or corticosteroid therapy. The plasma levels of all four steroids were decreased in patients with secondary adrenal insufficiency compared to normal adults, but the decrease in DHA and DHAS was considerably greater than that in cortisol and delta4-A, resulting in significant decreases in the plasma ratios of DHA to cortisol, DHAS to cortisol, DHA to delta4-A, and DHAS to delta4-A (P less than 0.00001). The decreased DHA and DHAS responses to ACTH persisted in one glucocorticoid-treated patient after glucocorticoid therapy was terminated and the cortisol response to ACTH had normalized. The data suggest that adrenal atrophy due to hypothalamic-pituitary disease or corticosteroid therapy is associated with a greater impairment in the secretion of the delta5 adrenal androgens DHA and DHAS than in the secretion of cortisol and delta4-A, and that the capacity to secrete cortisol and delta4-A recovers more rapidly than the capacity to secrete the delta5 adrenal androgens when corticosteroid therapy is withdrawn.
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The regulation of growth hormone (GH) cell development by thyroid and glucocorticoid hormones in the fetal rat pituitary gland was examined. Dexamethasone (Dex) treatment of dams induced GH and GH mRNA accumulation in the fetal pituitary gland on day 17 or 18 of gestation when substantial GH expression has not yet occurred in the control fetus. The additional thyroxine injections apparently enhanced the effect of Dex, whereas it exhibited no effect when given alone. The reduction of fetal thyroid hormone level by methimazole suppressed either the Dex induction of GH expression on day 18 or the spontaneous onset of GH expression on day 19 of gestation. The results suggest that 1) thyroid hormone exerts its stimulatory action on fetal GH gene expression only in the presence of glucocorticoid, 2) this synergistic action of these two hormones is evident as early as day 17 of gestation, and 3) rapid maturation of GH cells seen on day 19 in the normal fetus is considered to be induced by concomitant increase in both serum thyroid and glucocorticoid hormone levels.
Endocrine gland
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To clarify the mechanism underlying abnormal vasopressin (AVP) secretion in glucocorticoid deficiency, we examined the response of AVP secretion to osmotic stimulus produced by 5% saline infusion and analyzed the possible causative factors in seven patients with hypoosmolal hyponatremia resulting from adrenal insufficiency. In all patients, urinary sodium excretion persisted with urine osmolality exceeding plasma osmolality, and plasma AVP levels relative to plasma osmolality were elevated. Blood urea nitrogen, plasma creatinine, and PRA ranged from low to normal. All patients had nausea or vomiting, three had hypotension, and two had hypoglycemia; however, the primary cause of increased AVP secretion was attributed to none of these stimuli. After 5% saline infusion, patterns of changes in plasma AVP levels in individual patients were variable: levels decreased with increasing plasma osmolality in two patients and remained unchanged in the other five patients. Despite hyponatremia and absence of hypovolemia, thirst was present in the five patients, who responded normally to questions. This abnormality in AVP secretion and thirst was corrected after glucocorticoid replacement with normalization of plasma sodium concentrations and osmolality. Thus, glucocorticoid deficiency in man results in a clinical picture almost indistinguishable from that of the syndrome of inappropriate secretion of antidiuretic hormone. Persistent AVP secretion in this pathological state is due to a loss of hypotonic suppression of the osmostat for AVP release, which may be occasioned primarily by glucocorticoid deficiency per se and aggravated secondarily by multiple nonosmotic stimuli including nausea, hypotension, and hypoglycemia.
Plasma osmolality
Hypertonic saline
Urine osmolality
Hypernatremia
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Summary OBJECTIVE Patients with adrenal crisis are at risk of severe hypotension not responding to administration of catecholamines. As glucocorticoids may be a prerequisite for intact β‐adrenoceptor function, impaired adrenoceptor activity may explain the hypotension and reduced cardiac performance in adrenal insufficiency. The aim of our study was, therefore, to further elucidate the permissive action of glucocorticoids on adrenergic function and cardiac performance. DESIGN Prospective randomized controlled study. PATIENTS Nine patients with adrenal insufficiency were investigated before and 48 hours after glucocorticoid withdrawal. Mineralocorticoid therapy remained unchanged during the study period. MEASUREMENTS Lymphocyte β 2 ‐adrenoceptor density, intracellular c‐AMP response to isoprenaline, platelet α 2 ‐receptor density, plasma catecholamines, serum Cortisol, plasma ACTH, echocardiography. RESULTS Glucocorticoid depletion was demonstrated by a fall in serum Cortisol from mean ± SEM 441 ± 62 to 45 ± 18 nmoI/I. Glucocorticoid withdrawal decreased lymphocyte β 2 ‐receptor density from 798±111 to 498 ± 54 binding sites/cell ( P <0.05) and the intracellular c‐AMP response to isoprenaline from 15.0 ± 4.2 to 8.2 ± 1.7 pmol/10 6 cells ( P < 0.05). Echocardiography showed impaired diastolic relaxation after glucocorticoid withdrawal with prolongation of the rapid filling period (80.3 ± 12.5 vs 138.3 ± 11.8 ms, P < 0.05). Plasma catecholamines, platelet α 2 ‐receptor density and systolic left ventricular function were not affected by glucocorticoid deficiency. CONCLUSIONS This study demonstrates the importance of normal glucocorticoid levels for β 2 ‐adrenoceptor function and helps to explain the decreased responsiveness to catecholamines and the impaired cardiac performance in adrenal crisis.
Isoprenaline
Mineralocorticoid
Corticosterone
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