Elevated Adrenocorticotropic Hormone Levels Research Articles

Sellar gangliocytoma with adrenocorticotropic and prolactin adenoma

We report a case of a 60-year-old man who presented with weight gain, headaches, dizziness, erectile dysfunction and decreased libido. He was found to have elevated adrenocorticotropic hormone (ACTH) and prolactin serum levels. The imaging studies revealed a 1.4cm sella/suprasellar mass which was compressing the optic chiasm. Histologic slides of the lesion showed a pituitary adenoma, marked by a proliferation of biphenotypic appearing cells, associated with a gangliocytoma, and marked by a proliferation of atypical appearing neuronal cells arranged against a glial-appearing background. Pituitary adenoma-gangliocytomas are benign combination tumors that rarely occur in the sellar region. Adenomas in this setting are sometimes functional, and rare patients with mixed adenomas (adenomas secreting more than one hormone) have been reported. To our knowledge, there has been only one other report of a combined ACTH and prolactin-producing adenoma with gangliocytoma, reported in a patient who also had acromegaly. In our patient, the immunohistochemical stains demonstrated that the bulk of the adenoma cells stained with prolactin antibody, and scattered clusters of cells within the adenoma stained positively for ACTH. The adenoma did not stain with antibodies to any of the other anterior pituitary hormones. Postoperatively, the elevated prolactin and ACTH levels returned to normal levels and there was no evidence of residual tumor. Adequate sampling and immunohistochemistry are important in rendering a correct diagnosis and in identifying the hormone status of mixed adenoma-gangliocytomas.

Effects of chronic sleep deprivation on the extracellular signal-regulated kinase pathway in the temporomandibular joint of rats.

ObjectivesTo examine the possible involvement and regulatory mechanisms of extracellular signal-regulated kinase (ERK) pathway in the temporomandibular joint (TMJ) of rats subjected to chronic sleep deprivation (CSD).MethodsRats were subjected to CSD using the modified multiple platform method (MMPM). The serum levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) were tested and histomorphology and ultrastructure of the TMJ were observed. The ERK and phospho-ERK (p-ERK) expression levels were detected by Western blot analysis, and the MMP-1, MMP-3, and MMP-13 expression levels were detected by real-time quantitative polymerase chain reaction (PCR) and Western blotting.ResultsThe elevated serum CORT and ACTH levels confirmed that the rats were under CSD stress. Hematoxylin and eosin (HE) staining and scanning electron microscopy (SEM) showed pathological alterations in the TMJ following CSD; furthermore, the p-ERK was activated and the mRNA and protein expression levels of MMP-1, MMP-3, and MMP-13 were upregulated after CSD. In the rats administered with the selective ERK inhibitor U0126, decreased tissue destruction was observed. Phospho-ERK activation was visibly blocked and the MMP-1, MMP-3, and MMP-13 mRNA and protein levels were lower than the corresponding levels in the CSD without U0126 group.ConclusionThese findings indicate that CSD activates the ERK pathway and upregulates the MMP-1, MMP-3, and MMP-13 mRNA and protein levels in the TMJ of rats. Thus, CSD induces ERK pathway activation and causes pathological alterations in the TMJ. ERK may be associated with TMJ destruction by promoting the expression of MMPs.

Robotic Bilateral Posterior Adrenalectomy Using a New Articulating Vessel Sealer

Introduction: Patients with adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome from unmanageable primary sources may benefit bilateral adrenalectomy. This requires a complete resection of all adrenal tissue for long-term success.1 The laparoscopic posterior retroperitoneal (PR) approach is an alternative to the lateral transabdominal technique for removing adrenal tumors.2 For bilateral adrenal tumors, PR approach might facilitate the surgery, as repositioning of patient and abdominal entry is not required. Nevertheless, the PR technique has certain drawbacks, such as instrument clashing and limitations of working in a small space. We previously showed that a robotic technique could overcome these limitations.3,4 Our initial experience has involved the use of an ultrasonic robotic vessel sealer without articulation. The aim of this video is to show the utility of a new articulating robotic vessel sealer to perform this procedure. Case: A 61-year-old male patient was found to have edema, hypokalemia, and fatigue 3 years ago. He had an elevated serum cortisol and ACTH levels, as well as a high 24-hour urine cortisol level, consistent with ACTH-dependent Cushing's syndrome. No source for ectopic ACTH was identified on extensive imaging. The ketoconazole treatment was unsuccessful. With worsening clinical symptoms, he was referred for bilateral adrenalectomy. The patient was intubated supine and flipped to prone position on the operating room table. Initially, the right retroperitoneal space was entered using an optical trocar. The retroperitoneal space was created with a balloon trocar and insufflated. The additional two trocars were inserted. Intraoperative ultrasound was performed, and the adrenal gland was identified. The robot was docked, and using a robotic vessel sealer and Maryland grasper, the gland was circumferentially dissected. The adrenal vein was divided with the vessel sealer. The specimen was removed using a specimen bag. Hemostasis was obtained and trocars removed. Then, attention was directed to the left side. The left side adrenal was excised as same technique for right side. The pathology showed bilateral adrenal cortical hyperplasia. The patient was discharged home on postoperative day 1 uneventfully. Conclusion: This video illustrates the technical details of bilateral robotic posterior adrenalectomy using a robotic articulating vessel sealer. Bilateral posterior approach was preferred as there was no entry to the abdomen and no need to reposition the patient for the contralateral side. The robotic vessel sealer facilitated the procedure by providing articulation in a small space. All authors declare no conflict of interest. Runtime of video: 5 mins 41 secs

Letter to the Editor Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation:

Letter to the Editor Adrenal function and MC1R gene analysis in a prepubertal girl with generalized hyperpigmentation:

Recurrent Episodes of Hypothermia With Psychiatric Medications

Recurrent Episodes of Hypothermia With Psychiatric Medications

Hypertension, Diabetes, Hypokalemia, and Metabolic Alkalosis

Abstract: Prostate adenocarcinoma is a very rare cause of ectopic adrenocorticotropic hormone (ACTH) syndrome. We report the case of a 70-year-old man who presented with clinical and biochemical features of ACTH-dependent Cushing syndrome secondary to prostate carcinoma. On admission, his blood pressure was 170/100 mm Hg. Physical examination revealed signs of excessive production of cortisol. Laboratory values were consistent with hypokalemia and metabolic alkalosis. Elevated serum cortisol, ACTH, and urine free cortisol levels were found. Cortisol was not suppressed with an overnight 1-mg oral dexamethasone suppression test (DST), 2-day low-dose DST, or overnight 8.0-mg high-dose DST. Chest computed tomography showed multiple parenchymal nodules in the right lung, consistent with metastatic disease. Whole-body bone scintigraphy revealed numerous foci of increased radiotracer uptake in the femur and axial skeleton, consistent with metastatic disease. Bone survey (radiography) showed generalized osteolytic metastases. Histologic analysis of a prostatic biopsy showed prostate adenocarcinoma. Immunostaining of the prostate adenocarcinoma for ACTH was positive. The severe metabolic alkalosis due to glucocorticoid-induced mineralocorticoid excess was treated with potassium supplements and spironolactone. This case is a remarkable example of the complex metabolic endocrine manifestations that can accompany prostate adenocarcinoma.

A Case of Ectopic Adrenocorticotropic Hormone-producing Pancreatic Neuroendocrine Tumor with Multiple Liver Metastases

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.

Dopamine-Regulated Adrenocorticotropic Hormone Secretion in Lactating Rats: Functional Plasticity of Melanotropes

Pro-opiomelanocortin (POMC) is processed to adrenocorticotropic hormone (ACTH) and β-lipotropin in corticotropes of the anterior lobe, and to α-melanocyte-stimulating hormone (α-MSH) and β-endorphin in melanotropes of the intermediate lobe (IL) of the pituitary gland. While ACTH secretion is predominantly under the stimulatory influence of the hypothalamic factors, hormone secretion of the IL is tonically inhibited by neuroendocrine dopamine (NEDA) neurons. Lobe-specific POMC processing is not absolute. For example, D₂ type DA receptor (D2R)-deficient mice have elevated plasma ACTH levels, although it is known that corticotropes do not express D2R(s). Moreover, observations that suckling does not influence α-MSH release, while it induces an increase in plasma ACTH is unexplained. The aim of the present study was to investigate the involvement of the NEDA system in the regulation of ACTH secretion and the participation of the IL in ACTH production in lactating rats. Untreated and estradiol (E₂)-substituted ovariectomized (OVX) females were also studied. The concentration of ACTH in the IL was higher in lactating rats than in OVX rats, while the opposite change in α-MSH level of the IL was observed. DA levels in the IL and the neural lobe were lower in lactating rats than in OVX rats. Suckling-induced ACTH response was eliminated by pretreatment with the DA receptor agonist, bromocriptine (BRC). Inhibition of DA biosynthesis by α-methyl-p-tyrosine (αMpT) and blockade of D2R by domperidone (DOM) elevated plasma ACTH levels, but did not influence plasma α-MSH levels in lactating rats. The same drugs had opposite effects in OVX and OVX + E₂ animals. In lactating mothers, BRC was able to block ACTH responses induced by both αMpT and DOM. Surgical denervation of the IL elevated basal plasma levels of ACTH. Taken together, these data indicate that melanotropes synthesize ACTH during lactation and its release from these cells is regulated by NEDA neurons.

The genetics of familial glucocorticoid deficiency

Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from defects in the action of adrenocorticotropic hormone (ACTH) to stimulate glucocorticoid synthesis in the adrenal. Production of mineralocorticoids by the adrenal is normal. Patients present in early life with low or undetectable cortisol and--because of the failure of the negative feedback loop to the pituitary and hypothalamus--grossly elevated ACTH levels. About half of all cases result from mutations in the ACTH receptor (melanocortin 2 receptor) or from mutations in the melanocortin 2 receptor accessory protein (MRAP), but other genetic causes of this potentially lethal disorder remain to be discovered.

Strongyloides Hyperinfection Syndrome Complicating (Ectopic) Cushing Syndrome

Strongyloidiasis can present with a wide variety of symptoms and can lead to a potentially fatal hyperinfection. Although any factors that suppress the host defense mechanisms can potentially trigger hyperinfection, prolonged steroid use has been quite well described. A patient with disseminated small cell lung cancer suffered a Strongyloides stercoralis hyperinfection syndrome complicating ectopic adrenocorticotropic hormone (Cushing syndrome). Evaluation revealed lymphopenia, elevated levels of adrenocorticotropic hormone in the setting of elevated cortisol levels, a normal pituitary, and metastatic malignancy. S. stercoralis larval forms were seen in the stool and sputum. At autopsy, S. stercoralis larval forms were seen in the lung along with evidence of metastatic small cell lung carcinoma.

A Rare Case of Ectopic Adrenocorticotropic Hormone Syndrome in Small Cell Carcinoma of the Vagina

To describe ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) to increase awareness of this condition when treating patients with gynecological small cell carcinoma (SmCC). This is a review of a 61-year-old woman with primary vaginal SmCC and an atypical presentation of Cushing syndrome. This case describes the molecular rationale, caveats in clinical presentation, pathological diagnosis, and management options for patients with this rare syndrome. After treatment with primary chemotherapy, the patient presented acutely with delirium and metabolic disturbances. This was associated with elevated ACTH and gastrin levels without any tumor staining for ACTH. The patient was initially managed with ketoconazole to control the EAS. Complications developed related to her Cushing syndrome, and she succumbed to complications of her disease. Vaginal SmCC complicated by EAS is a rare paraneoplastic syndrome, and this case history outlines the management options for patients with this condition and reviews the pertinent literature.

Sex Specific Associations between Common Glucocorticoid Receptor Gene Variants and Hypothalamus-Pituitary-Adrenal Axis Responses to Psychosocial Stress

Alterations in glucocorticoid (GC) signaling have been associated with a number of psychiatric disorders. Genetic variation of the glucocorticoid receptor (GR) might be one of the factors underlying susceptibility to stress related disease. We investigated 206 healthy subjects and assessed associations between four common GR gene (NR3C1) polymorphisms (ER22/23EK, N363S, BclI, 9beta) and hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress (Trier Social Stress Test, TSST) and glucocorticoid sensitivity measured by a dexamethasone suppression test (DST). Male 9beta AG carriers displayed the highest adrenocorticotropic hormone (ACTH) and total cortisol TSST responses (for ACTH: main effect genotype p = .02) whereas male BclI GG carriers showed diminished responses. Remarkably, the BclI GG genotype in women (all using oral contraceptives) was associated with the highest total cortisol TSST responses, resulting in a significant sex by genotype interaction (p = .03). Following the DST, male 9beta AG carriers had elevated ACTH levels (sex by genotype interaction p = .03). We observed significant sex specific associations between GR gene polymorphisms and HPA axis responses to psychosocial stress as well as GC sensitivity. These findings support the relevance of GR gene polymorphisms in HPA axis regulation. Genetic variations of the GR might constitute a risk factor in development of HPA axis related disorders.

Gamma Knife surgery for adrenocorticotropic hormone–producing pituitary adenomas after bilateral adrenalectomy

Patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas may require a bilateral adrenalectomy to treat their Cushing's disease. Approximately one third of these patients, however, will experience progressive enlargement of the residual pituitary adenoma, develop hyperpigmentation, and have an elevated level of serum ACTH. These patients with Nelson's syndrome can be treated with Gamma Knife surgery (GKS). The prospectively collected University of Virginia Gamma Knife database of patients with pituitary adenomas was reviewed to identify all individuals with Nelson's syndrome who were treated with GKS. Twenty-three patients with a minimum of 6 months of follow up were identified in the database. These patients were assessed for tumor control (that is, lack of tumor growth over time) with neuroimaging studies (median follow-up duration 22 months) and for biochemical normalization of their ACTH levels (median follow-up duration 50 months). Neuroimaging follow-up studies were available for 22 patients, and endocrine follow up was available for 15 patients in whom elevation of ACTH levels was documented prior to GKS. In the 22 patients in whom neuroimaging follow-up studies were available, 12 had a decrease in tumor size, eight had no tumor growth, and two had an increase in tumor volume. Ten of 15 patients with elevated ACTH levels prior to GKS showed a decrease in their ACTH levels at last follow up; three of these 10 patients achieved normal ACTH levels (< 50 pg/ml) and the other five patients with initially elevated values had an increase in ACTH levels. Ten patients were thoroughly evaluated for post-GKS pituitary function; four were found to have new pituitary hormone deficiency and six did not have hypopituitarism after GKS. One patient suffered a permanent third cranial nerve palsy and four patients are now deceased. Gamma Knife surgery may control the residual pituitary adenoma and decrease ACTH levels in patients with Nelson's syndrome. Delayed hypopituitarism or cranial nerve palsies can occur after GKS. Patients with Nelson's syndrome require continued multidisciplinary follow-up care. Given the difficulties associated with management of Nelson's syndrome, even the modest results of GKS may be helpful for a number of patients.

Attenuation of stress-induced elevations in plasma ACTH level and body temperature in rats by green odor

To investigate the effect of green odor on the elevation of the plasma adrenocorticotropic hormone (ACTH) levels and body temperature (Tb) induced by stress, adult male rats were subjected to a 2-h immobilization stress and exposed to green odor or its vehicle only. In comparison with the vehicle group, animals in the green odor group showed a significant reduction in plasma ACTH levels at the end of the stress when green odor was applied during the stress. The elevated plasma ACTH levels 2 days after the stress were reduced by green odor applied 0, 1, 2, 4 or 6 h after the beginning of the stress. Neither the immediate nor the long-lasting plasma ACTH response was affected by a prestress treatment of green odor. Tb elevation was evident following the end of the stress and during the light phase the day after the stress. Both the immediate and the long-lasting elevations in Tb were attenuated by green odor. These data suggest that green odor extracted from green leaves has a relieving effect on plasma ACTH and Tb levels induced by an immobilization stress for not only immediate but also long-lasting periods.

Stereotactic radiosurgery for patients with ACTH-producing pituitary adenomas after prior adrenalectomy

Purpose : To review the results of stereotactic radiosurgery for patients with adrenocorticotropic hormone (ACTH)-producing pituitary adenomas after bilateral adrenalectomy. Methods and Materials : Eleven patients with ACTH-producing pituitary adenomas after bilateral adrenalectomy underwent radiosurgery between 1990 and 1999. Nine patients had documented tumor growth, hyperpigmentation, and elevated ACTH levels (median 920 ng/mL) at the time of radiosurgery. Five of these patients had tumor enlargement despite prior fractionated radiotherapy (median dose 50 Gy). Two patients were treated prophylactically within 1 month of their adrenalectomies to prevent future tumor growth. The median follow-up was 37 months (range 22–74). Results : Tumor growth control was achieved in 9 patients (82%); 2 patients had had continued tumor growth after radiosurgery. The ACTH levels decreased a median of 66% (range −99% to +27%); 4 patients had normal ACTH levels. Three patients had radiation-related complications, including diplopia ( n = 2), ipsilateral blindness ( n = 1), testosterone/growth hormone deficiency ( n = 1), and asymptomatic temporal lobe radiation necrosis ( n = 1): all had received prior radiotherapy. One patient who had undergone three prior resections and radiotherapy died 59 months after radiosurgery despite two additional attempts at tumor resection. Conclusion : Although our experience is limited, it appears that radiosurgery provides tumor control for most patients with ACTH-producing pituitary adenomas who have undergone bilateral adrenalectomy.

Opposing actions of adrenal androgens and glucocorticoids on alternative splicing of Slo potassium channels in bovine chromaffin cells.

Pituitary ablation (hypophysectomy) in rats was previously reported to cause a precipitous change in the relative abundance of two alternative splice variants of the "BK"- or "Maxi K"-encoding Slo gene in adrenal chromaffin cells. Inclusion of the optional "STREX" exon (STRess axis-regulated EXon) in a C-terminal splice site was reduced, in preference to the variant lacking an insert at this site. Adrenocorticotropic hormone (ACTH) injections prevented the drop in STREX inclusion, implicating stress-axis function, as opposed to other pituitary functions. Because ACTH promotes synthesis and release of glucocorticoids (corticosterone or cortisol, depending on species), we hypothesized that glucocorticoids applied directly would promote STREX inclusion. Contrary to predictions, we report that direct application of glucocorticoids to bovine cells in vitro decreased STREX inclusion. This effect was blocked by the glucocorticoid receptor antagonist RU38486. As with glucocorticoids, synthesis and release of the adrenal androgen dehydroepiandrosterone (DHEA) increases in response to stress or elevated ACTH levels in some species. We report that direct application of DHEA increased expression of the STREX variant in cultured bovine cells. Two other androgens, androstenedione and testosterone, had similar effects. We hypothesize that Slo splicing in adrenal chromaffin cells in vivo is differentially regulated by the integrative, concentration- and time-dependent actions of glucocorticoids and androgens, with potentially important ramifications for stress-evoked catecholamine secretion.

Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma

Ectopic adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing hormone (CRH) are associated with a growing list of tumors. We report a 69-year-old white man with a history of high-grade prostate carcinoma and widely metastatic adenocarcinoma who presented with metabolic alkalosis, hypokalemia, and hypertension secondary to ectopic ACTH and CRH secretion. Laboratory values were consistent with hypokalemia and metabolic alkalosis. Markedly elevated serum cortisol (135 μg/dL), ACTH (1,387 pg/dL), CRH (69 pg/dL), and urine free cortisol (16,276 μg/24 h) levels were found. Chest computed tomographic (CT) scan showed small noncalcified parenchymal densities; however, bronchoscopy and bronchoalveolar lavage washings were unremarkable for a neoplastic process. Abdominal CT scan and magnetic resonance imaging showed multiple small liver lesions and multiple thoracic and lumbar intensities consistent with diffuse metastatic disease. Histological analysis of a biopsy specimen from the thoracic spine showed an undifferentiated adenocarcinoma consistent with a prostate primary tumor. The severe metabolic alkalosis secondary to glucocorticoid-induced excessive mineralocorticoid activity was treated with potassium supplements, spironolactone, and ketoconazole. In this case report, we describe an unusual tumor associated with ectopic ACTH and CRH production and the pharmacodynamic relationship of plasma cortisol levels and urinary cortisol excretion with ketoconazole treatment.

Functional adrenocorticotropic hormone receptor in cultured human vascular endothelial cells : possible role in control of blood pressure.

Hypertension is a prominent feature of patients with Cushing's disease and ectopic adrenocorticotropic hormone (ACTH) syndrome, who have elevated ACTH levels. Chronic administration of ACTH (1-24) also raises blood pressure in humans. This effect has been postulated to be due to ACTH-induced increases in cortisol secretion in the adrenal gland. It is well known that cortisol increases vascular tone by potentiating the vasoconstrictor action of a number of pressor hormones. In the present study, we show direct evidence that human aortic endothelial cells possess the ACTH receptor. 11beta-Dehydrogenation, converting cortisol to its inactive metabolite, cortisone, mediated by vascular 11beta-hydroxysteroid dehydrogenase type 2 is essential for the control of vascular tone, and the reduced activity may be relevant to the pathogenesis of hypertension. We found that ACTH (1-24) dose-dependently decreased the gene expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 2 in these cells, and the decrease was partially abolished by a selective ACTH receptor antagonist. This may indicate that ACTH potentiates the action of cortisol through its direct effect on the vasculature. Therefore, the present study provides important information for understanding the mechanism of ACTH-induced hypertension.

The expression of the ACTH receptor.

Adrenal glucocorticoid secretion is regulated by adrenocorticotropic hormone (ACTH) acting through a specific cell membrane receptor (ACTH-R). The ACTH-R is a member of the G protein superfamily-coupled receptors and belongs to the subfamily of melanocortin receptors. The ACTH-R is mainly expressed in the adrenocortical cells showing a restricted tissue specificity, although ACTH is recognized by the other four melanocortin receptors. The cloning of the ACTH-R was followed by the study of this gene in human diseases such as familial glucocorticoid deficiency (FGD) and adrenocortical tumors. FGD is a rare autosomal recessive disease characterized by glucocorticoid deficiency, elevated plasma ACTH levels and preserved renin/aldosterone secretion. This disorder has been ascribed to an impaired adrenal responsiveness to ACTH due to a defective ACTH-R, a defect in intracellular signal transduction or an abnormality in adrenal cortical development. Mutations of the ACTH-R have been described in patients with FGD in segregation with the disease. The functional characterization of these mutations has been prevented by difficulties in expressing human ACTH-R in cells that lack endogenous melanocortin receptor activity. To overcome these difficulties we used Y6 cells, a mutant variant of the Y1 cell line, which possesses a non-expressed ACTH-R gene allowing the functional study without any background activity. Our results demonstrated that the several mutations of the ACTH-R found in FGD result in an impaired cAMP response or loss of sensitivity to ACTH stimulation. An ACTH-binding study showed an impairment of ligand binding with loss of the high affinity site in most of the mutations studied.

Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS.

Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 micrograms/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine production in the peritoneal cavity, markedly reduced plasma ACTH, corticosterone, and IL-6 levels after 5 micrograms/kg LPS. Our results suggest that circulating endotoxin is required for the activation of the HPA axis. They also favor a role for circulating IL-6 in this response.