Immune Effects of Corticosteroids in Sepsis.

Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids via non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.

Low-dose sustained-release deoxycorticosterone acetate-induced hypertension in Bama miniature pigs for renal sympathetic nerve denervation.

Recently, the effectiveness of renal sympathetic nerve denervation for treatment of hypertension has been doubted after SYMPLICITY HTN-3 trial. An ideal animal model is still unavailable for preclinical study about catheter-based renal sympathetic nerve denervation for treatment of hypertension. Traditional high-dose deoxycorticosterone acetate (DOCA)-induced hypertension pig model has some problems due to extensive end-organ damage. Based on the similarity in the anatomic characteristics of renal artery between pigs and humans, this study was undertaken to establish a low-dose sustained-release DOCA-induced hypertension model in pigs. A total of 14 pigs were subcutaneously implanted with low-dose DOCA in the abdomen and cannulated from the femoral artery for the measurement of blood pressure (BP). Plasma angiotensin I (Ang I), angiotensin II (Ang II), plasma renin activity (PRA), aldosterone (Ald), creatinine, epinephrine, and norepinephrine (NE) were determined before and after treatments. The kidneys were collected and processed for hematoxylin and eosin staining, Masson-Goldner trichromic, and periodic acid Schiff staining. Ten pigs survived for 1 month. Mean BP significantly increased after 2-week treatment (P < .001). The plasma Ang I, Ang II, PRA, and Ald significantly decreased (Ang I: 6.92 ± 6.06 vs. 2.22 ± 3.08, P = .002; Ang II: 768.85 ± 525.8 vs. 213.76 ± 148.63, P = .003; PRA: 1.68 ± 1.67 vs. 0.29 ± 0.39, P = .008; Ald: 0.37 ± 0.12 vs. 0.25 ± 0.09, P < .001), but norepinephrine significantly increased (7.59 ± 4.57 vs. 16.96 ± 10.38, P = .021). Plasma creatinine remained unchanged. Hisotological examination showed mild damage to the kidney. Low-dose sustained-release DOCA is able to induce hypertension in pigs. A femoral catheter is not only helpful for monitoring BP, but can be used to quickly exchange the renal sympathetic nerve denervation equipment.

Beneficial effects of stress-dose corticosteroid therapy in canines depend on the severity of staphylococcal pneumonia.

PURPOSE: The effects of stress-dose corticosteroid therapy were studied in a canine staphylococcal pneumonia model of septic shock. METHODS: Immediately following intrabronchial bacterial challenge, purpose-bred beagles were treated with stress doses of desoxycorticosterone (DOC), a mineralocorticoid agonist, and dexamethasone (DEX), a glucocorticoid agonist, or with placebo for 96 h. Oxacillin (30 mg/kg every 8 h) was started 4 h after infection onset. Bacterial dose was titrated to achieve 80-90 % lethality (n = 20) using an adaptive design; additional animals (n = 18) were investigated using the highest bacterial dose. RESULTS: Initial analysis of all animals (n = 38) demonstrated that the effects of DOC + DEX were significantly altered by bacterial dose (p = 0.04). The treatment effects of DOC + DEX were different in animals administered high or relatively lower bacterial doses in terms of survival (p = 0.05), shock reversal (p = 0.02), interleukin-6 levels (p = 0.02), and temperature (p = 0.01). DOC + DEX significantly improved the above parameters (p ≤ 0.03 for all) and lung injury scores (p = 0.02) after high-dose bacterial challenges, but not after lower challenges (p = not significant for all). Oxacillin trough levels were below the minimum inhibitory concentration of the infecting organism, and DOC + DEX increased the frequency of persistent staphylococcal bacteremia (odds ratio 3.09; 95 % confidence interval 1.05-9.11; p = 0.04). CONCLUSIONS: Stress-dose corticosteroids were only beneficial in cases of sepsis with high risk for death and even short courses may interfere with host mechanisms of bacterial clearance.

Potassium restores vasorelaxation of resistance arterioles in non-hypertensive DOCA/salt fed mice.

BACKGROUND: Potassium-enriched diets exert renal and cardiovascular protective effects, but the underlying mechanisms are largely unknown. METHODS: Using the dorsal skinfold chamber model for intravital microscopy, we examined endothelium-dependent vasorelaxation of precapillary resistance arterioles in response to acetylcholine or the NO donor SNAP in awake mice. Experiments were performed in uni-nephrectomized one renin gene (Ren-1c) C57BL/6 mice (control group) and in mice having received a continuous administration of deoxycorticosterone acetate and a dietary supplementation of 1% sodium chloride for 8 weeks (DOCA/salt group). An additional group of DOCA/salt treated animals received a dietary supplement of 0.4% KCl for 3 weeks prior to the experiments (DOCA/salt + potassium group). RESULTS: DOCA/salt treatment for 8 weeks resulted in hypokalemia, but blood pressure remained unchanged. In DOCA/salt mice, relaxation of resistance arterioles was blunted in response to acetylcholine, and to a lesser extent to SNAP, suggesting endothelial dysfunction. Endothelium-dependent vasorelaxation was restored by the potassium-enriched diet. CONCLUSION: This study is the first to demonstrate a protective effect of potassium on endothelium-dependent vasorelaxation in the absence of confounding anti-hypertensive effects, as observed in most animal models and the clinical situation. We propose that the known cardio- and nephro-protective effects of potassium might - at least in part - be mediated by the salutary effects on endothelium-dependent arteriolar relaxation.

Corticosteroid physiology and principles of therapy.

The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics. Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects, prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in patients receiving systemic high dose GC therapy must be borne in mind.

Mineralocorticoid treatment upregulates the hypothalamic vasopressinergic system of spontaneously hypertensive rats.

Mineralocorticoid effects in the brain include the control of cardiovascular functions, induction of salt appetite, interaction with the vasoactive neuropeptides arginine vasopressin (AVP) and angiotensin II and development or aggravation of hypertension. In this regard, mineralocorticoids may play a pathogenic role in rats with a genetic form of hypertension (spontaneously hypertensive rats, SHR). Our objective was to compare the response of the hypothalamic vasopressinergic system to mineralocorticoid administration in SHR and control Wistar-Kyoto (WKY) rats. Sixteen-week-old male SHR showing a systolic blood pressure of 190 +/- 5 mm Hg and normotensive WKY rats (130 +/- 5 mm Hg) were treated subcutaneously with oil vehicle or a single 10-mg dose of deoxycorticosterone acetate (DOCA). After 2 h, rats were sacrificed and brains prepared for immunocytochemistry of Fos and vasopressin V1a receptor (V1aR) and for non-isotopic in situ hybridization of AVP mRNA. In the basal state, SHR demonstrated a higher number of AVP mRNA- and V1aR-immunopositive cells in the magnocellular division of the paraventricular hypothalamic nucleus (PVN) than WKY rats. After DOCA injection, SHR responded with a significant increase in both parameters with respect to vehicle-injected SHR. In WKY rats, DOCA was without effect on AVP mRNA although it increased the number of V1aR-positive cells. Changes in the number of Fos-positive nuclei were measured in the PVN, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a circumventricular region showing anatomical connections with the PVN. In vehicle-injected rats, the PVN of SHR showed a higher number of Fos-positive nuclei than in WKY rats, whereas after DOCA treatment, a significant increment occurred in the OVLT but not in the PVN or MnPO of the SHR group only. These data suggest that the enhanced response of the vasopressinergic system to mineralocorticoids may contribute to the abnormal blood pressure of SHR.

Diminished renal kallikrein responses to mineralocorticoid stimulation in African Americans: determinants of an intermediate phenotype for hypertension.

BACKGROUND: Hypertension is a complex trait with an ill-defined genetic predisposition, in which renal mechanisms seem to be involved even at the early stages. Renal kallikrein excretion is diminished in patients with hypertension, and perhaps even in the early, prehypertensive phases of the syndrome. African Americans, a group at increased risk of developing hypertension, have especially diminished kallikrein expression, coupled with decreased renal excretion of K(+), a known stimulant of kallikrein expression, suggesting an environmental mechanism for their kallikrein deficit. We, therefore, tested whether short-term indirect (K(+)) or direct (fludrocortisone) stimulation of mineralocorticoid activity might be capable of restoring kallikrein excretion in African Americans. METHODS: Nineteen healthy normotensive young men (n = 10 white, n = 9 African Americans) were treated with the following sequence of four oral medications, each for 1 week: placebo, KCl (120 mEq/day), placebo, and the mineralocorticoid fludrocortisone (0.4 mg/day). At each stage, we measured vital signs, excretion of kallikrein, aldosterone and electrolytes, and serum renin. Results were evaluated by two-way, repeated measures ANOVA. RESULTS: African Americans had diminished urinary excretion of not only kallikrein (P =.007), but also K(+) (P <.001) and aldosterone (P =.015). Kallikrein responses to mineralocorticoid stimulation were substantially blunted in African Americans, whether achieved indirectly (by supplemental K(+); P =.019) or directly (by the exogenous mineralocorticoid fludrocortisone; P =.027), despite achievement of substantial increments in K(+) excretion after KCl (P =.002), and multiple other mineralocorticoid effects after fludrocortisone (P =.005). The kallikrein increment after KCl was best predicted by renin activity (P =.001) rather than ethnicity. Potassium chloride did not lower blood pressure (BP) in either group (P >.4). CONCLUSIONS: Restoration of K(+) and aldosterone secretion to levels found in whites does not normalize kallikrein excretion or lower BP in African Americans, at least in the short term. Nor does exogenous mineralocorticoid stimulation fully restore kallikrein expression in African Americans. Therefore, the diminution of kallikrein biosynthesis in African Americans seems to involve mechanisms at or distal to the aldosterone receptor, and perhaps at the level of the kallikrein gene itself.

Variable mapping of structure-activity relationships: application to 17-spirolactone derivatives with mineralocorticoid activity.

Fifty-four steroid homologs, belonging to the series of 17-spirolactones, were modelled by molecular and quantum mechanics. We studied the affinity of these compounds for the cytosolic mineralocorticoid receptor by way of various parameters describing each structure and its molecular properties. After the failure of a classic preliminary QSAR study, demonstrating the nonlinear relationships between affinity and structural descriptors, we constructed a model allowing us to predict the affinity of new compounds. Our method is based on simple graphic tools coupled to a cluster significance analysis. A complementary study of the activity relating the prediction of the antagonist/agonist character of 37 high-affinity compounds was also carried out using the same methodology. The principal electronic and structural characteristics leading to a selective activity were revealed.

No alteration in the primary structure of the mineralocorticoid receptor in a family with pseudohypoaldosteronism.

We have studied the molecular structure of the mineralocorticoid receptor (MR) complementary DNA (cDNA) in a kindred affected by pseudohypoaldosteronism (PHA). In this family, the clinical symptoms included salt wasting and failure to thrive, accompanied by high urinary levels of sodium despite hyponatremia, hyperkalemia and metabolic acidosis, elevation of PRA, and high plasma aldosterone levels. The patients were resistant to mineralocorticoid administration, but their symptoms ameliorated after a period of sodium supplementation, which was discontinued in older patients. Binding studies performed on mononuclear leukocytes of the members of the family have shown the absence of MR in two siblings and a marked reduction in another sibling of the father, suggesting either the absence of MR or a defect of the ligand-binding domain of the MR in these patients. Southern analysis of patient's DNA did not show any major rearrangement of the MR gene. To search for point mutations in the cDNA of the MR, we performed amplification of the MR cDNA by the polymerase chain reaction and direct sequencing of amplified products. No mutation was found in the entire coding sequence of the MR in patients affected by PHA. Although these results do not exclude a molecular abnormality present on the MR gene, they indicate that PHA in this family is not related to a modification of the MR primary structure.

Reduction of proteinuria by adrenalectomy and its restoration by glucocorticoids in rats bearing functioning pituitary tumor.

Intense proteinuria in rats bearing a functioning pituitary tumor MtT SA5 was considered to be evoked by overproduction of albumin due to elevated serum growth hormone (GH). The present study revealed a striking reduction of proteinuria by bilateral adrenalectomy. Supplementation for about 6 weeks with glucocorticoids to adrenalectomized tumor-bearing rats again induced marked proteinuria, but supplementation with mineralocorticoids failed to augment proteinuria. An analysis of systemic blood pressure and renal blood flow did not yield any conclusive result. In spite of an assumption that glucocorticoids enhance GH production of the tumor based on the presence of glucocorticoid receptor in the tumor tissue, no difference was found in serum GH levels between glucocorticoid- and mineralocorticoid-supplemented adrenalectomized rats. The mechanism remains to be clarified, but modification of glomerular permeability or a change in glomerular hydraulic pressure by glucocorticoids might be considered.

Modulation of angiotensin II binding sites in neuronal cultures by mineralocorticoids.

Previous studies have determined that mineralocorticoid hormones are able to increase the number of angiotensin II (ANG II)-specific binding sites in rat diencephalon and in neuronal cultures and also increase the drinking response elicited by centrally injected ANG II. In the present study, we have examined the specificity and mechanisms of this mineralocorticoid action. In neuronal cultures from the hypothalamus and brain stem (H/BS), both D-aldosterone and deoxycorticosterone acetate (DOCA) caused significant time- and dose-dependent increases in 125I-labeled ANG II-specific binding. This effect was not mimicked by the synthetic glucocorticoid dexamethasone, or by testosterone, beta-estradiol or progesterone. However, the steroid corticosterone induced a moderate increase in [125I] ANG II binding. This may have occurred as a result of its high affinity for the mineralocorticoid type I receptor. DOCA was ineffective in increasing [125I]ANG II specific binding both in neuronal cultures prepared from the cerebellum and in pure astrocytic glial cultures, indicating that this mineralocorticoid effect is specific both for neurons and for certain brain regions. The increase in [125I]ANG II-specific binding elicited by DOCA was abolished by cotreatment with the mineralocorticoid receptor blockers mespirenone or ZK97894 and by cotreatment with cycloheximide. Taken together, these observations suggest that the mineralocorticoid-induced increase in [125I]ANG II-specific binding in H/BS neuronal cultures is a specific event, which is mediated via mineralocorticoid type I receptors and which requires protein synthesis.

Mineralocorticoid-induced kaliuresis in type-II pseudohypoaldosteronism.

Type II pseudohypoaldosteronism is an uncommonly reported disorder. The authors recently evaluated a patient who in many respects appeared to have this syndrome. He had hyperkalemia, a normal glomerular filtration rate, "normal" serum and urinary aldosterone levels, and low plasma renin activity. In addition, he had a hyperchloremic metabolic acidosis and hypertension. Fractional excretion of potassium was reduced in response to sodium chloride loading. However, renal potassium excretion in response to administration of sodium sulfate was normal. Thiazide diuretic restored the serum potassium, the low bicarbonate, and blood pressure to normal. He developed marked natriuresis and kaliuresis in response to high-dose exogenous mineralocorticoid. The magnitude of the kaliuretic response achieved to exogenous mineralocorticoid has been reported only once previously.

Expression of the renal kallikrein gene in mineralocorticoid-treated and genetically hypertensive rats.

On the basis of both clinical observations and experimental studies it has been proposed that renal kallikrein is a mineralocorticoid regulated protein. In other studies, changes in renal kallikrein activity have been implicated in the genesis of, and/or response to, hypertension. Using a cloned complementary DNA (cDNA) to rat pancreatic kallikrein (pcXP39) for hybridization histochemistry, and both Northern and dot blot analysis, we studied expression of the kallikrein gene in steroid-treated control animals, and in three strains of genetically hypertensive rats. No differences in renal kallikrein messenger RNA (mRNA) levels were found between adrenalectomized rats and those treated for 5-14 days with 9 alpha-fludrocortisone, corticosterone or dexamethasone, or between hypertensive rats and their appropriate controls. Since mRNA levels appear essentially invariant under such circumstances, the change in renal kallikrein activity/immunoreactivity after chronic mineralocorticoid elevation, or in hypertensive rats, presumably reflects modulation at the post-transcriptional level.

Mineralocorticoid regulation of sodium and potassium transport by the cortical collecting duct.

Chronic high-dose mineralocorticoid hormone treatment of rabbits results in marked alterations of the structure and function of the cortical collecting duct. Most importantly, the reabsorption of Na+ and the secretion of K+ are increased. Intracellular microelectrode measurements provide evidence consistent with the idea that the increased transport of these ions is a result of changes in the membrane conductances and electrochemical driving forces for passive ion movement and of the activity of the Na+,K+-ATPase. Specifically, the Na+ and K+ conductances of the apical membrane are increased, and the cellular potential profile is altered to promote transcellular movement of K+ from the peritubular to the luminal fluid compartments. The associated increase in the activity of the Na+,K+-ATPase facilitates extrusion of Na+ from and accumulation of K+ into the cell. The resistance of both the apical and basolateral cell membranes are reduced with DOCA treatment, while the resistance of the paracellular pathway is increased. Consequently, the electrophysiological properties of the tubule epithelium reflect to a greater degree the properties of the transcellular pathway.

Role of the renin-angiotensin system in the regulation of late steps in aldosterone biosynthesis by sodium intake of potassium-deficient rats.

The role of the renin-angiotensin system in the adaptation of late steps in aldosterone biosynthesis to sodium intake was studied in potassium-deficient rats. Capsular portions of adrenal glands were incubated with [3H]corticosterone and conversion to aldosterone and 18-hydroxycorticosterone was measured by double isotope dilution and multiple paper chromatography. Sodium loading of sodium- and potassium-depleted rats resulted in a rapid and extensive fall in PRA but only in a delayed and gradual suppression of aldosterone biosynthesis. Treatment with the converting enzyme inhibitor, captopril, did not affect aldosterone biosynthesis in rats with established sodium and potassium deficiency, but blocked the stimulation of the conversion of corticosterone to aldosterone and 18-hydroxycorticosterone by sodium restriction of potassium-depleted rats. Infusion of a high dose of angiotensin II into potassium-deficient rats stimulated aldosterone biosynthesis depending upon the concurrent sodium intake. Accordingly, the renin-angiotensin system plays an important but limited role in the control of late steps of aldosterone biosynthesis by sodium intake. Angiotensin II seems to be essential for the induction but not for the maintenance of a high activity of the enzyme(s) involved in the conversion of corticosterone to aldosterone during combined sodium and potassium restriction. The sensitivity of the zona glomerulosa to the long term stimulatory action of angiotensin II varies with the sodium intake and appears to be regulated by the plasma potassium concentration and unknown other mediators.

Role of adrenal steroids on electroacupuncture analgesia and on antagonising potency of naloxone.

Electroacupuncture (EA), a form of transcutaneous electrical stimulation, produces opiate-like antinociception and catalepsy in rats. This effect of EA cannot be produced in hypophysectomised rats, whereas adrenalectomised rats show increased sensitivity. In intact rats, adrenocorticotrophic hormone and dexamethasone have been found to be effective to sensitise the animals to the analgesic effect of EA. Deoxycorticosterone, on the contrary, attenuates this effect. Spironolactone is also effective to potentiate EA response, which is accompanied with severe respiratory depression. Drugs that are known to affect adrenal aldosterone secretion also modulate the effect of EA. Naloxone administration, 15 min prior to the initiation of EA stimulation, potentiates the effect of EA, whereas it counteracts the effect of EA if administered after initiation of EA stimulation. Moreover, this counteracting ability of naloxone increases with the increase in time interval between initiation of stimulation and naloxone challenge. Pretreatment with drugs that impair adrenal mineralocorticoid response to physiological stimuli inhibits the counteracting effect of naloxone. On the contrary, mineralocorticoid supplemented rats show greater sensitivity to naloxone counteraction.

Mineralocorticoid-induced membrane proteins in MDCK cells.

The Madin-Darby canine kidney (MDCK) cell line, which exhibits properties indicative of a distal tubule origin, evidently binds and responds to mineralocorticoid hormones. We investigated the effects of aldosterone and deoxycorticosterone on protein synthesis in MDCK cells grown either in medium supplemented with serum or in a hormonally defined, serum-free medium. Aldosterone induced the synthesis of at least 2 membrane proteins with molecular weights of 35000 and 14000. The MDCK line may prove a useful model system for examining the mechanism of mineralocorticoid-regulated sodium transport and, in particular, the identification and study of hormone-induced proteins in a homogeneous cell population.

Binding of glycyrrhetinic acid to kidney mineralocorticoid and glucocorticoid receptors.

Whether the mineralocorticoid effect of glycyrrhetinic acid is mediated by the adrenal glands or is due to a direct action on the renal tubule remains controversial. The affinity of glycyrrhetinic acid for mineralocorticoid receptors has been studied by several types of competition experiments. When rat kidney slices were incubated with 2 times 10- minus 9 M [3H]aldosterone, glycyrrhetinic acid (2 times 10- minus 5 M) was able to compete with aldosterone for the cytosolic receptor and to decrease the formation of a chromatin-[3Hi1 aldosterone-receptor complex. In cytosol, in vitro, 6 times 10- minus 4 M glycyrrhetinic acid was able to inhibit aldosterone binding by 70 percent, whereas the same dose produced only a 20 percent inhibition of dexamethasone binding. The apparent KDiss of glycyrrhetinic acid for the mineralocorticoid receptor was 2 times 10- minus 6 M. That glycyrrhetinic acid appeared to compete mainly with mineralocorticoid receptors was confirmed by sedimentation in the sucrose gradients: [3H]Aldosterone specifically bound to an 8 S peak was displaced by 5 times 10- minus 5 M glycyrrhetinic acid, whereas the [3H]dexamethasone peak was not affected by this compound. Glycyrrhizic acid showed no significant affinity for mineralocorticoid or glucocorticoid kidney receptor sites. Glycyrrhetinic acid and glycyrrhizic acid had no affinity for rat cortisol binding globulin. Glycyrrhetinic acid has a low but definite affinity for mineralocorticoid receptors and thus appears to have a direct mineralocorticoid action. The low affinity of this compound for mineralocorticoid receptors is in good agreement with the very high doses required to exhibit its biological activity.

The effect of glucocorticoids on thyrotropin secretion.

The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.TSH responses to steroid were also studied in rats. In hypothyroid rats given dexamethasone intravenously, plasma TSH fell to 63% of control in 30-90 min and then returned to normal or above in 3-4 hr. Dexamethasone also reduced plasma TSH concentrations in normal rats but no rebound was observed in these animals. Dexamethasone did not block the increase in plasma TSH produced by thyrotropin releasing factor (TRF) administration in vivo. Neither basal nor TRF-mediated TSH release from hemipituitaries in vitro was reduced by dexamethasone or corticosterone. These studies indicate that glucocorticoids reduce TSH secretion and suggest that this effect occurs at a suprahypophyseal level.