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D N Orth

Publications and source records attributed to D N Orth.

At least 37 records · Page 2Linked to original sources
PubMed1994

Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency.

A spontaneous autosomal recessive mutation causing disordered morphogenesis of the adrenal cortex has been identified in DW/J inbred strain mice and named adrenocortical dysplasia (acd). The acd mutant gene has been mapped just proximal to oligosyndactyly (Os) and esterase-1 (Es-1) in the central region of chromosome 8. Both male and female acd/acd mice are characterized by reduced survival, retarded growth, skin hyperpigmentation, poorly developed pelage and focal ureteral blockage leading to hydronephrosis. Morphometric measurements showed that acd/acd cortical cells and nuclei were increased sevenfold in volume; nuclei often showed a variety of inclusions. Cortical cells of acd/acd mice contained large numbers of mitochondria, smooth endoplasmic reticulum and lipid droplets characteristic of steroidogenic cells. While cortical X-zones failed to develop in acd/acd adrenals, medullary cells and nuclei were unaffected by mutant gene action. Resting serum corticosterone levels in female, but not male, mutant mice were significantly lower than in +/? normal littermates, whereas ACTH levels were significantly elevated in mutants of both sexes. Serum aldosterone levels were normal in acd/acd mice. Functional studies of adrenals cultured in vitro revealed that acd/acd adrenals secreted reduced amounts of corticosterone per pair of glands under both basal and ACTH-stimulated conditions. However, correction of the corticosterone secretion data to mg cortical mass in culture showed that the mutant cortical tissue secreted the same amount of glucocorticoid as did their +/? normal littermate glands. We conclude that the acd mutant gene acts in an unknown fashion to cause a fundamental defect in cellular proliferation in the adrenal cortex, leading to compensatory marked hypertrophy of cortical cells and grossly enlarged nuclei. The role of acd action in adrenal cortical development remains to be established.

Adrenal Cortex↗
PubMed1994

Plasma concentrations of immunoreactive proopiomelanocortin peptides and cortisol in clinically normal cats.

We measured immunoreactive (IR) plasma concentrations of the proopiomelanocortin (POMC)-derived peptides (adrenocorticotropic hormone [ACTH]; beta-endorphin/beta-lipotropin [beta END/beta LPH]; and alpha-melanocyte stimulating hormone [alpha MSH]) and of cortisol in 100 clinically normal cats. Median plasma concentration of IR-ACTH was 2.7 pmol/L (range, < or = 1.1 to 22 pmol/L), of beta END/beta LPH was 28 pmol/L (range, 3.8 to 130 pmol/L), of alpha MSH was 36 pmol/L (range, < or = 3.6 to 200 pmol/L), and of cortisol was 35 nmol/L (range, 5 to 140 nmol/L). Plasma concentrations of IR-ACTH, alpha MSH, and beta END/beta LPH were at or below the assay sensitivity in 34, 3, and 0% of the cats, respectively. We did not detect a correlation between plasma concentrations of IR-ACTH and beta END/beta LPH (r = 0.23) or between plasma concentrations of IR-ACTH and alpha MSH (r = 0.19). However, there was a significant (P < 0.001) correlation between plasma concentrations of IR-beta END/beta LPH and alpha MSH (r = 0.81). There was not a significant correlation between plasma concentration of cortisol and plasma concentration of any of the IR-POMC peptides. High plasma concentrations of IR-alpha MSH and beta END, POMC peptides secreted predominantly by melanotrophs in other species, indicate that clinically normal cats have an actively secreting pars intermedia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Cholecystokinin in human cerebrospinal fluid: concentrations, dynamics, molecular forms and relationship to fasting and feeding in health, depression and alcoholism.

Very little is known about the physiologic significance of the gut-brain hormone cholecystokinin (CCK) in the human central nervous system, although the hormone has been hypothesized to be involved in the regulation of both appetite and anxiety. We continuously collected lumbar cerebrospinal fluid (CSF) via indwelling subarachnoid catheters in ten normal volunteers, ten patients with major depression and five abstinent alcoholic humans, while fasting and after eating. Five other healthy subjects were fasted throughout the experiment. We quantified CSF immunoreactive cholecystokinin (IR-CCK) and glucose concentrations at 10-min intervals from 11.00 to 17.00 h. No difference in CSF IR-CCK concentration, half-life or rhythm was observed between normal volunteers and either depressed or alcoholic patients. Fasting CSF IR-CCK concentrations were 1.3 +/- 0.18, 1.3 +/- 0.21 and 1.2 +/- 0.21 fmol/ml (mean +/- S.E.M.) in normal volunteers, depressed patients and alcoholic patients, respectively. After eating, CSF IR-CCK concentrations rose to 1.5 +/- 0.21, 1.5 +/- 0.24 and 1.4 +/- 0.26 fmol/ml, respectively. Normal volunteers who did not eat had similar basal CSF IR-CCK concentrations (1.1 +/- 0.1 fmol/ml) which similarly rose to 1.4 +/- 0.13 fmol/ml during the sampling interval. In contrast, CSF glucose concentrations rose only in the subjects who ate, beginning to rise after about 1 h and remaining elevated for at least 3 h after eating. These data suggest the existence of a diurnal rhythm of IR-CCK release into CSF, as opposed to a response to feeding. The disappearance half-time of CCK in human CSF is less than 13 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Thyroid and adrenal dysfunction in abstinent alcoholic men: locus of disturbance.

Certain neuroendocrine abnormalities (e.g., blunted plasma adrenocorticotropic hormone [ACTH] response to corticotropin-releasing hormone [CRH] administration and blunted serum TSH response to thyrotropin-releasing hormone [TRH] administration) are common in alcoholic patients. It was the objective of this study to evaluate whether they are centrally mediated: that is, whether they are secondary to increased activity of CRH and/or TRH neurons. We evaluated the nocturnal secretion (2200 hours to 1000 hours, q 15 min) of plasma ACTH, serum cortisol, and serum TSH, and their responses to the combined administration of CRH and TRH, in 28 acutely abstinent alcoholic (age range: 32 to 57 years; mean: 42.4 years) and 19 normal men (age range: 21 to 52 years; mean: 32.1 years). To assess the validity of administering CRH and TRH simultaneously, we gave 10 additional abstinent alcoholic men (age range: 36 to 53 years; mean: 45.8 years), in random order and at least 4 days apart, either CRH, TRH, placebo, or CRH plus TRH. Nocturnal ACTH, cortisol, and TSH secretion, as well as cortisol and TSH responses after CRH plus TRH administration, were similar in alcoholic and normal men. However, ACTH peak responses to CRH plus TRH were reduced in the alcoholic men (p < 0.05). The ACTH, but not cortisol, response was greater after combined CRH plus TRH administration than after CRH alone (p < .002). The blunted ACTH response does not appear to be the result of increased endogenous CRH activity, because all parameters of nocturnal ACTH pulsatility were normal in the alcoholics. It rather appears to be secondary to an intrinsic defect in the CRH responsiveness of the pituitary corticotroph, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Adrenal Cortex Hormones↗
PubMed1993

Chromogranin A does not mediate glucocorticoid inhibition of adrenocorticotropin secretion.

It has recently been proposed that chromogranin A (CgA), a 50-kilodalton acidic glycoprotein that is costored and cosecreted with hormones and neurotransmitters in a variety of tissues, mediates glucocorticoid inhibition of ACTH secretion from AtT20/D16v mouse anterior pituitary corticotroph tumor cells by an undefined autocrine mechanism. We used AtT20/D16v cells, RIAs for murine CgA and ACTH, complementary DNA probes for CgA and POMC, the precursor of ACTH, antiserum that reacts with murine CgA, highly purified bovine CgA, and synthetic rat and porcine pancreastatin, a bioactive cleavage product of CgA in some systems, to study the kinetics of the effect of glucocorticoids on CgA and ACTH synthesis and secretion and of CgA's subsequent effects on ACTH secretion. Exposure to 100 nM dexamethasone (DEX) did not alter the size of CgA or POMC messenger RNA (mRNA) transcripts but increased cell CgA mRNA content 42% by 3 h and 192% by 48 h. DEX decreased cell POMC mRNA content 22% by 6 h and 57% by 48 h. These divergent effects of DEX on steady state mRNA levels were accompanied by similar divergent effects on the production of CgA and ACTH protein. Thirty-minute exposure to 10 nM ovine CRF increased CgA and ACTH release to 300% and 360% of basal levels, respectively. One-hour DEX pretreatment inhibited CRF-stimulated CgA and ACTH release 58% and 49% at 30 min and 67% and 66% at 60 min, respectively. There was a positive correlation between CgA and ACTH release under all conditions at both times (r = 0.976 and 0.964, respectively, P < 0.001), consistent with costorage and cosecretion of the two proteins. The ratio of secreted ACTH to CgA decreased progressively with DEX treatment. Purified bovine CgA (100 nM) had little or no effect on basal or CRF-stimulated ACTH secretion from AtT20/D16v cells, 100 nM synthetic pancreastatin had no significant effect on basal or CRF-stimulated ACTH release from AtT20/D16v cells or dispersed normal male rat anterior pituitary cells, and anti-CgA sera had no significant effect on basal or CRF-stimulated ACTH release from AtT20/D16v cells. These results indicate: 1) that DEX stimulates CgA synthesis, whereas it inhibits POMC synthesis; 2) that CgA and ACTH are cosecreted; 3) that DEX increases CgA secretion relative to ACTH secretion, but decreases the absolute secretion of both proteins; and 4) that neither CgA nor its proteolytic product, pancreastatin, inhibits ACTH secretion. Thus, CgA does not mediate the inhibitory effect of DEX on ACTH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1993

Effect of protein kinase-C depletion on inositol trisphosphate-mediated and cyclic adenosine 3',5'-monophosphate-dependent protein kinase-mediated adrenocorticotropin secretion.

We studied the effect of Ca2+/phospholipid-dependent protein kinase-C (protein kinase-C) down-regulation by chronic exposure to phorbol 12-myristate 13-acetate (PMA) on ACTH secretion by dispersed male rat anterior pituitary cells in a microperifusion system. Preincubation for 24 h and preperifusion for 3 h with 0.1 and 1 microM PMA significantly inhibited (by 85% and 91%, respectively) the specific cell binding of [3H]phorbol 12,13-dibutyrate, an index of protein kinase-C concentration, and significantly reduced (by 101% and 20%, respectively) the sustained plateau (final 15-min) phase of the ACTH response to arginine vasopressin (AVP) and (by 56% and 54%, respectively) the sustained (full 20-min) response to dioctanoylglycerol (DOG), both of which are mediated by protein kinase-C activation. In contrast, the spike (initial 5-min) phase of the response to AVP, which is mediated by intracellular Ca2+ release from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores, was significantly increased (by 112% and 99%, respectively), but the spike-type response to ionomycin, which releases intracellular Ca2+ by an InsP3-independent mechanism, was unaffected. AVP significantly stimulated inositol bisphosphate and InsP3, but not inositol monophosphate, accumulation, and PMA pretreatment significantly enhanced their AVP-stimulated accumulation (by 86%, 34%, and 78%, respectively), an effect that was abolished by simultaneous preperifusion with PMA and cycloheximide to inhibit new protein synthesis. Enhancement of the spike phase response to AVP and AVP-stimulated InsP3 accumulation were lost within 1 h of PMA removal, but [3H]phorbol 12,13-dibutyrate binding and the sustained responses to AVP and DOG remained suppressed after 3 h. Pretreatment with 0.1 and 1 microM PMA slightly reduced the sustained responses to CRF (by 29% and 16%, respectively) and 8-bromo-cAMP (by 8% and 12%, respectively), which are mediated by protein kinase-A activation and extracellular Ca2+ influx via L-type voltage-sensitive Ca2+ channels, but not the response to KCl, which is mediated by extracellular Ca2+ influx via all types of voltage-sensitive Ca2+ channels. The sustained response to CRF was still suppressed 1 h after PMA removal, but returned to the control level by 3 h. When new protein synthesis was inhibited by preperifusion with cycloheximide alone for 3 h after 24-h PMA pretreatment, recovery from the effects of PMA was abolished. Three-hour exposure to cycloheximide without PMA pretreatment inhibited the sustained responses to CRF, AVP, and DOG, but not the spite response to AVP.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Two patients with Cushing's disease in a kindred with multiple endocrine neoplasia type I.

Cushing's disease (pituitary ACTH-dependent Cushing's syndrome) has been described in association with the syndrome of multiple endocrine neoplasia type I (MEN-I). Cushing's disease is uncommon in MEN-I and has not been reported in more than one member of a kindred. Here we describe a mother and her daughter with Cushing's disease and major depressive disorder. The mother, her other daughter, and two other relatives also had primary hyperparathyroidism. We believe this to be the first reported instance of hereditary Cushing's disease as a manifestation of MEN-I.

Adolescent↗
PubMed1992

Psychiatric phenomenology in Cushing's disease.

We evaluated 20 patients with Cushing's disease (i.e., Cushing's syndrome due to ACTH-secreting pituitary microadenoma) and 20 patients with Major Depressive Disorder (MDD) using the Structured Clinical Interview for DSM-III-R (SCID) and Research Diagnostic Criteria. The diagnosis of Generalized Anxiety Disorder (GAD) was most common in Cushing's disease (79%), followed by MDD (68%), and Panic Disorder (PD) including subthreshold PD (53%). The combination of MDD and GAD and/or PD was also common in Cushing's disease (63%). Behavioral symptoms, if present, usually first occurred at or after the onset of the first physical symptoms. However, the onset of PD was associated with more chronic stages of Cushing's disease. In both Cushing's disease and MDD, more female than male relatives suffered from MDD, whereas more male than female relatives suffered from substance abuse. The data demonstrate a syndrome of anxious depression in patients with active Cushing's disease; such comorbidility has not been previously noted. The data also point to intriguing epidemiological, clinical, and biological associations between Cushing's disease, MDD and substance abuse.

Adolescent↗
PubMed1992

Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats.

Cells of the immune system can produce and respond to peptide hormones associated with the endocrine system. However, the physiological significance of these endocrine-immune interactions is not known. It has been postulated that cells of the immune system, when stimulated with viruses that induce interferon-alpha, produce sufficient levels of ACTH to stimulate adrenal steroidogenesis and, thus, function as an auxiliary source of ACTH that may have a role in the response to stress. However, we have confirmed that levels of ACTH-related peptides produced by immunocompetent cells are far lower than those produced by the pituitary, raising questions about the ability of lymphocyte-derived ACTH to stimulate adrenal function. Furthermore, we have rigorously examined this issue using intact and hypophysectomized rats treated with Newcastle disease virus. Although high levels of interferon-alpha were produced by both intact and hypophysectomized rats, and the plasma corticosterone concentration increased dramatically in intact animals, corticosterone remained undetectable in hypophysectomized rats. The lack of a corticosterone response in these animals was not due to adrenal insensitivity to ACTH, as shown by a normal rise in corticosterone following Cosyntropin injection 8 h after hypophysectomy. The findings demonstrate that levels of ACTH produced by nonpituitary sources in response to viral infection are not sufficient to stimulate adrenal steroidogenesis.

Adrenal Cortex Hormones↗
PubMed1992

Serial cerebrospinal fluid corticotropin-releasing hormone concentrations in healthy and depressed humans.

CRH, a hypothalamic peptide that is the most potent ACTH secretagogue known, also appears to be produced in the cerebral cortex and spinal cord. Depressed patients have blunted responses to exogenous CRH and normal to high concentrations of CRH immunoreactivity in single morning samples of lumbar cerebrospinal fluid (CSF). Although these data suggest that depression may be associated with hypersecretion of CRH, it has also been postulated that central nervous system insufficiency of CRH might have a pathophysiological role in certain depressive syndromes. We continuously sampled lumbar CSF via indwelling subarachnoid catheters from 1100-1700 h and measured CRH at 10-min intervals in depressed patients and normal subjects. A standardized mixed liquid meal was administered at 1300 h. CSF CRH was strikingly reduced in depressed patients compared to normal subjects [4.2 +/- 1.1 pmol/L vs. 13 +/- 2.1 pmol/L (mean +/- SEM), respectively, P less than 0.01 by Wilcoxon test]. CSF CRH concentrations rose progressively during the experiment in both groups, suggesting a diurnal rhythm and, possibly, response to a test meal. CRH had a very brief half-life in CSF (less than 10 min), suggesting that the spinal cord is the origin of CRH in lumbar CSF. The rapid transients in CSF CRH concentration demonstrate that single samples provide very limited information. There were no intraindividual correlations between CSF CRH concentrations and those of either plasma ACTH or cortisol, both of which rose in response to eating. The present data show that impaired central nervous system secretion of CRH can exist during states of severe depression.

Adrenocorticotropic Hormone↗
PubMed1992

Effects of synthetic ovine corticotropin-releasing hormone on plasma concentrations of immunoreactive adrenocorticotropin, alpha-melanocyte-stimulating hormone, and cortisol in dogs with naturally acquired adrenocortical insufficiency.

We evaluated the effect of ovine corticotropin-releasing hormone (CRH) on plasma immunoreactive (IR) concentrations of ACTH, alpha-melanocyte-stimulating hormone, and cortisol in 8 dogs with naturally acquired adrenocortical insufficiency. Of the 7 dogs with primary adrenal insufficiency, 6 had markedly high basal plasma IR-ACTH concentrations and exaggerated ACTH responses to CRH administration, whereas 1 dog that was receiving replacement doses of prednisone at the time of testing had normal basal IR-ACTH concentrations and a nearly normal response to CRH. In contrast, the 1 dog with secondary adrenocortical insufficiency had undetectable basal plasma IR-ACTH concentrations, which failed to increase after administration of CRH. Basal plasma alpha-melanocyte-stimulating hormone concentrations in the dogs with adrenal insufficiency were within normal range and were unaffected by CRH administration. In all 8 dogs with adrenal insufficiency, plasma cortisol concentrations were low and did not increase after administration of CRH. Therefore, stimulation with CRH produced 2 patterns of plasma IR-ACTH response when administered to dogs with naturally acquired adrenal insufficiency. Dogs with primary adrenal insufficiency had high basal plasma IR-ACTH concentrations and exaggerated responses to CRH, whereas the dog with secondary adrenal insufficiency had undetectable basal plasma concentrations of IR-ACTH that did not increase after stimulation with CRH.

Adrenal Cortex Hormones↗
PubMed1991

Adrenal function in abstinent alcoholic men.

1. The nocturnal secretion of plasma ACTH and serum cortisol and their responses to ovine corticotropin-releasing hormone (oCRH) were studied in acutely abstinent alcoholic and normal men. 2. Nocturnal cortisol secretion was similar in alcoholic and normal men, but nocturnal ACTH secretion tended to be decreased during the early morning hours (0600h-0900h) in alcoholic men. ACTH, but not cortisol, responses after oCRH administration tended to be attenuated in alcoholic men. CLUSTER ANALYSIS showed that the changes were not due to alterations in ACTH pulse frequency, amplitude, or interpulse interval. 3. The data suggest an intrinsic defect in response to CRH by the pituitary corticotroph cell, possibly due to genetic vulnerability or to the toxic effects of prolonged alcohol abuse.

Adrenal Glands↗
PubMed1991

Distinct classes of corticotropes mediate corticotropin-releasing hormone- and arginine vasopressin-stimulated adrenocorticotropin release.

ACTH release from the anterior pituitary gland is principally driven by the two hypothalamic hormones, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). Using the reverse hemolytic plaque assay, we have compared the effects of CRH and AVP on ACTH release from individual, dispersed pituitary cells. A small percent (0.36 +/- 0.06%) of pituitary cells formed plaques when exposed to medium alone. AVP caused 3.44 +/- 0.10% of cells to form plaques (P less than 0.01 compared with medium alone), CRH produced 4.85 +/- 0.20% plaque-forming cells (P less than 0.01 compared with AVP), and the combination of CRH and AVP produced a still greater percent of plaque-forming cells (5.80 +/- 0.20%, P less than 0.01 compared with CRH alone). A double reverse hemolytic plaque assay was then employed to examine whether some cells formed plaques only in the presence of one or other secretagogue. Using this technique we found clear evidence of cells that formed plaques in response to CRH but not AVP (P less than 0.005); CRH or AVP (P less than 0.0001), and CRH and AVP (P less than 0.05). There was no evidence of a corticotrope forming a plaque with AVP but not CRH (P = 0.52). Thus there appears to be functionally distinct classes of corticotropes. These findings have important implications for our understanding of the relative responsiveness of the pituitary to hypothalamic secretagogues and provide a new physiological perspective on recent reports of stress-specific hypothalamic responses regulating ACTH release.

Adrenocorticotropic Hormone↗
PubMed1991

Effects of intracellular Ca2+ depletion and glucocorticoid on stimulated adrenocorticotropin release by rat anterior pituitary cells in a microperifusion system.

Arginine vasopressin (AVP), oxytocin (OT), and angiotensin-II (AII) elicit a biphasic ACTH secretory response by perifused anterior pituitary cells consisting of an initial transient (less than 3-min) spike phase and a subsequent sustained plateau phase. In contrast, CRF produces a monophasic sustained plateau type of ACTH secretory response. We have previously demonstrated that 1) influx of extracellular Ca2+ (Cae2+) via L-type voltage-sensitive Ca2+ channels is involved in both the response to CRF and the sustained phase of the response to AVP and OT; 2) release of intracellular Ca2+ (Cai2+) is involved in the spike phase of the response to AVP, OT, and AII; and 3) activation of protein kinase-C is required for the sustained phase, but not for the spike phase, of the response to AVP. CRF action is mediated by activation of protein kinase-A. In this study we further examined the role of Cai2+ by exploiting the fact that a low concentration (1 microM) of ionomycin, a potent Ca2+ ionophore, releases Cai2+ from nonmitochondrial inositol-1,4,5-trisphosphate (IP3)-sensitive Cai2+ stores without causing Cae2+ influx. Pretreatment with ionomycin for 10 min decreased the spike phase of the response to 100 nM AVP, OT, and AII, but had no effect on the response to 10 nM CRF or the sustained phase of the responses to the other agonists. The combination of CRF plus AVP induced a biphasic and synergistic release of ACTH. Ionomycin pretreatment reduced the spike phase, especially the first 1 min, without any effect on the sustained phase. These results indicate that Cai2+ release, but not Cae2+ influx, is involved in the spike phase of the response to AVP, OT, and AII and that Cai2+ is not involved in the synergistic effect of the combination of CRF plus AVP. Having established these relationships, we examined the effect of 2-h perifusion with 100 nM dexamethasone (DEX) on stimulated ACTH release. DEX pretreatment reduced the total response to CRF, the sustained phase of the responses to AVP and OT, and the sustained phase of the synergistic response to CRF plus AVP. However, DEX had no effect on the spike phase of the responses to AVP, OT, or AII or the spike phase of the response to CRF plus AVP. These results indicate that DEX inhibits ACTH release mediated by activation of either protein kinase-A or protein kinase-C, but does not affect inositol-1,4,5-trisphosphate/Cai2(+)-mediated ACTH release.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗
PubMed1991

Effects of short and long duration hypothyroidism and hyperthyroidism on the plasma adrenocorticotropin and corticosterone responses to ovine corticotropin-releasing hormone in rats.

We report here a study of the plasma ACTH and corticosterone responses to synthetic ovine CRH (oCRH) in hypothyroid and hyperthyroid rats studied 7, 15, and 60 days after either thyroidectomy or the administration of pharmacological doses of T4. The purpose of this study was to further clarify the time-dependent effects of alterations in thyroid status on the functional integrity of the hypothalamic-pituitary-adrenal axis and to aid in the interpretation of the oCRH stimulation test in hypo- and hyperthyroid states. Our data demonstrate that hypothyroid rats have a significant reduction in the cerebrospinal fluid (CSF) levels of corticosterone and a significant decrease in adrenal weight in association with significant increases in the plasma ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during the oCRH stimulation test was significantly reduced in hypothyroidism. With increasing duration of thyroidectomy-induced hypothyroidism, there was a progressive fall in CSF corticosterone levels, a progressive increase in the plasma ACTH response to oCRH, and a gradual normalization of the corticosterone responses to the ACTH released during oCRH stimulation. Our findings in hyperthyroid rats were generally the converse of those seen in hypothyroidism. Hence, there was a significant increase in the CSF levels of corticosterone and a significant increase in adrenal weight in association with an initial slight decrease in the ACTH response to oCRH. On the other hand, the corticosterone response to the ACTH released during oCRH stimulation was significantly increased. There was a gradual increase in the magnitude of the rise in CSF corticosterone levels with time, as well as a gradual normalization of adrenocortical responses during oCRH stimulation. The ACTH plasma clearance rates were similar in hypo-, hyper-, and euthyroid rats. Our data do not permit definitive identification of the precise locus in the hypothalamic-pituitary-adrenal axis that is principally affected by experimentally induced alterations in thyroid status. However, these data are most compatible with a subtle hypothyroid-induced centrally mediated adrenal insufficiency and a subtle hyperthyroid-induced centrally mediated hypercortisolism. These data also suggest that alterations in hypothalamic-pituitary-adrenal function in states of disturbed thyroid function become somewhat more pronounced as the duration of thyroid dysfunction increases. The fact that pituitary-adrenal responses to oCRH are consistently altered in states of thyroid dysfunction may be relevant to the clinical interpretation of oCRH stimulation tests.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenocorticotropic Hormone↗