Adrenocorticotropic Hormone Hypersecretion Research Articles

Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours.

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical-pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.

Advances in Molecular Pathophysiology and Targeted Therapy for Cushing's Disease.

Cushing's disease is caused by autonomous secretion of adrenocorticotropic hormone (ACTH) from corticotroph pituitary neuroendocrine tumors. As a result, excess cortisol production leads to the overt manifestation of the clinical features of Cushing's syndrome. Severe complications have been reported in patients with Cushing's disease, including hypertension, menstrual disorders, hyperglycemia, osteoporosis, atherosclerosis, infections, and mental disorders. Cushing's disease presents with a variety of clinical features, ranging from overt to subtle. In this review, we explain recent advances in molecular insights and targeted therapy for Cushing's disease. The pathophysiological characteristics of hormone production and pituitary tumor cells are also explained. Therapies to treat the tumor growth in the pituitary gland and the autonomous hypersecretion of ACTH are discussed. Drugs that target corticotroph pituitary neuroendocrine tumors have been effective, including cabergoline, a dopamine receptor type 2 agonist, and pasireotide, a multi-receptor-targeted somatostatin analog. Some of the drugs that target adrenal hormones have shown potential therapeutic benefits. Advances in potential novel therapies for Cushing's disease are also introduced.

MRI-negative Cushing's Disease: Management Strategy and Outcomes in 15 Cases Utilizing a Pure Endoscopic Endonasal Approach.

BackgroundCushing’s disease (CD) is among the most common etiologies of hypercortisolism. Magnetic resonance imaging (MRI) is often utilized in the diagnosis of CD, however, up to 64% of adrenocorticotropic hormone (ACTH)-producing pituitary microadenomas are undetectable on MRI. We report 15 cases of MRI negative CD who underwent surgical resection utilizing a purely endoscopic endonasal approach.MethodsEndoscopic endonasal transsphenoidal surgery (EETS) was performed on 134 CD cases by a single surgeon. Fifteen cases met inclusion criteria: no conclusive MRI studies and no previous surgical treatment. Data collected included signs/symptoms, pre- and post-operative hormone levels, and complications resulting from surgical or medical management. Data regarding tumor diameter, location, and tumor residue/recurrence was obtained from both pre- and post-operative MRI. Immunohistochemistry was performed to assess for tumor hormone secretion.ResultsAside from a statistically significant difference (P = 0.001) in histopathological results between patients with negative and positive MRI, there were no statistically significant difference between these two groups in any other demographic or clinical data point. Inferior petrosal sinus sampling (IPSS) with desmopressin (DDAVP®) administration was performed on the 15 patients with inconclusive MRIs to identify the origin of ACTH hypersecretion via a central/peripheral (C/P) ratio. IPSS in seven, five and three patients showed right, left, and central side lateralization, respectively. With a mean follow-up of 5.5 years, among MRI-negative patients, 14 (93%) and 12 patients (80%) achieved early and long-term remission, respectively. In the MRI-positive cohort, over a mean follow-up of 4.8 years, 113 patients (94.9%) and 102 patients (85.7%) achieved initial and long-term remission, respectively.ConclusionsSurgical management of MRI-negative/inconclusive Cushing’s disease is challenging scenario requiring a multidisciplinary approach. An experienced neurosurgeon, in collaboration with a dedicated endocrinologist, should identify the most likely location of the adenoma utilizing IPSS findings, followed by careful surgical exploration of the pituitary to identify the adenoma.

The condition of neuro-endocrine systems in acute experimental myocardial infarction against the background of various reactivity of the organism

The adequacy of recovery processes in myocardial infarction (MI) significantly depends on the state of reactivity of the organism, which, in turn, is determined by the adequacy of neuro-endocrine regulation, in particular, hypothalamic-pituitary-adrenocortical (HPA) and hypothalamic-pituitary-thyroid (HPT) system system.Purpose of the study. To investigate the condition of HPA and HPT in acute experimental MI against the background of different reactivity of the organism.Material and methods. The study was performed on 20 outbred adult dogs weighing 8-12 kg, in which MI was simulated by ligation of the anterior interventricular artery. Animals were divided into three groups (n =5 in each group). The condition of hyperreactivity was caused by the introduction of pyrogenal (group 2), the state of hyporeactivity - the introduction of azothioprine (group 3), in group 1 drugs were not used (state of normoreactivity). In the control group used 5 falsely operated dogs with thoracopericardiotomy. In animals before surgery, on 1, 4, 7, 11 and 15 days in the blood was determined by the content of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) , cortisol (Cr), aldosterone (Ald), thyroxine and triiodothyronine. Statistical processing was performed using license packages Statistica 5.5 (Stat Soft Rus), Statistica Neural Networks (Statsoft Inc.).Results. Normoreactive course of myocardial infarction was characterized by primary activation of HPA, which was most pronounced for Cortisol, followed by restoration of ACTH and Aldosterone levels and duration of activation of the central link up to 4 days, peripheral - up to 7-11 days; reciprocal in relation to HPA inhibition of the functional activity of the HPT, most pronounced on the 4th day and lasting up to 15 days. Such changes caused the healing of myocardial infarction through the formation of a full-fledged post-infarction scar. The hyperreactive course of myocardial infarction was characterized by hypersecretion of ACTH with hypercorticism and hyperaldosteronism and less pronounced suppression of HPT with the restoration of its functional activity on the 7th day. The hyporeactive course of myocardial infarction was characterized by a minimally pronounced and delayed up to 4 days activation of HPA with Aldosterone hyposecretion on the 15th day; deep hypothyroidism of both central and peripheral genesis. Impaired reactivity was accompanied by an increase in the area of necrosis and a decrease in the thickness of the heart wall with the formation of postinfarction aneurysm.Conclusions. Desynchronization of necrotic and reparative processes with a change in reactivity leads to a disruption in the relationship between necrosis and repair with the formation of postinfarction aneurysm, which is accompanied by different activities of the HPA and HPT.

The Role of Non-Pharmacological Treatment for Osteoporosis at Patients with High Plasmatic Concentration of ACTH

Cushing disease is characterized by the hypersecretion of adrenocorticotropic hormone (ACTH) due to a pituitary adenoma that causes endogenous hypercortisolism by stimulating adrenal glands. Objective of the study was to analyse the benefits of the physical therapy for patients with ACTH-secreting adenomas osteoporosis.This retrospective study was performed at Craiova, Bunavestire Hospital, the patients were monitorized during 6 months and included 17 patients with ACTH-secretingadenomas. Participants in this study group exercised 3 days a week for 6 consecutive months. Each session is intended to take approximately 60 minutes to complete and will comprise of a warm-up, progressive resistance training using medium weights, moderate impact weight-bearing exercises, flexibility and also stretching exercises. Physical therapy for osteoporosis treatment in patients with ACTH-secreting adenomas improved joint mobility and reduced pain, significantly increasing BMD performed by DEXA in group I patients compared to patients included in group II. Pain relief is evident following evaluation using the VAS rating scale. The increase in joint mobility is observed following the goniometric measurement from day 1 to the end of treatment. Applying the physical therapy program the bone pain and joint mobility was improved, physical therapy can modify bone turnover in the sense of increasing the body mass.

MON-468 Selective Inhibition of Epigenetic Pathways Has Anti-Proliferative and Pro-Apoptotic Effects on the Mouse Corticotroph Tumor Cells, AtT20

Corticotrophinomas, which are neuroendocrine tumors (NETs) and represent >10% of all surgically removed pituitary adenomas, cause Cushing’s disease that is associated with hypersecretion of adrenocorticotropic hormone (ACTH) leading to excessive production of glucocorticoids by the adrenal cortex. Trans-sphenoidal hypophysectomy is the treatment of choice for corticotrophinomas, with medical treatments being reserved for patients who have contraindications for surgery. However, these treatments are often ineffective. Improved therapeutic approaches are required, and we have therefore assessed the efficacy of epigenetic modulators, a new class of anti-cancer drugs that have been reported to be effective in treating pancreatic NETs. Specifically, we assessed the anti-proliferative and pro-apoptotic effects of the bromo and extra terminal domain (BET) inhibitors JQ1 and PFI-1, in the mouse corticotrophinoma cell line AtT20, using Cell Titer Blue and Caspase Glo assays, respectively. JQ1, after 96h treatment, was more efficacious than PFI-1. Thus, JQ1 significantly decreased proliferation by 95%, (p<0.0005), and significantly increased apoptosis >50-fold (p<0.0005), compared to control treated cells; whereas PFI-1 decreased proliferation by 43% (p<0.0005), but did not significantly alter apoptosis. Furthermore, AtT20 cells did not resume proliferating for up to 96 hours after the removal of JQ1 from the media. In addition, RNA-sequence (RNA-Seq) analysis revealed that JQ1 treatment significantly altered the expression of genes involved in apoptosis, including Nuclear Factor Kappa B Subunit 1 (Nfκb1) and Baculoviral IAP Repeat Containing 3 (Birc3), as well as genes associated with the somatostatin receptor type 2 (SSTR2) anti-proliferative signaling pathway, including Sstr2. The down regulation of these genes was confirmed using quantitative PCR, which showed decreases in Nfkb1, Birc3 and Sstr2 mRNA of 2.9-fold (p<0.0009), 1.7-fold (p<0.005), and 1.5-fold (p<0.005), respectively. In addition, Western blot analysis showed decreases in Nfkb1, cIAP2 and SSTR2 protein expression of 1.5-fold (p<0.05), 1.9-fold (p<0.05), and 2.3-fold (p<0.05), respectively. Thus our results, which demonstrate that JQ1 treatment is both anti-proliferative and pro-apoptotic in ACTH-secreting cells, reveal that BET inhibition may provide a novel approach for the treatment of corticotrophinomas.

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells.

Cushing's disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing's disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease.

MORPHOFUNCTIONAL STATE OF THE ADRENAL GLANDS IN LABORATORY ANIMALS UNDER EXPERIMENTAL INTOXICATION WITH CYPERMETHRIN

The research objective was to evaluate the morphofunctional state of the adrenal glands in laboratory animals in conditions of acute and chronic intoxication with cypermethrin. Studies were performed on 140 male rats of the Wistar line. To simulate an acute intoxication cypermethrin was single injected into the stomach in a dose of half of LD50 followed by observation of the animals for 30 days. In the study of chronic intoxication cypermethrin was administered to rats in a dose of 1/100 of LD50. The experiment has lasted for 120 days.At the initial stage of the experiment the acute intoxication of rats with cypermethrin caused hyper- and then hyposecretion of adrenocorticotropic hormone. The content of progesterone in the blood serum and adrenal tissue decreased in animals. During the first three days after the poisoning there was an increase in the concentration of corticosterone in the blood serum. To the end of the 7th day the concentration of this hormone in adrenal tissue decreased sharply and did not reach the control background after a month. Chronic intoxication with cypermethrin caused hypersecretion of adrenocorticotropic hormone for two months with the subsequent normalization of its level in the blood. The disturbance of progesterone synthesis in the adrenal glands during chronic intoxication is indicated by fluctuation of its concentration in blood 30 days after the start of the experiment. There was found high level of corticosterone in blood and adrenal glands for two months, and then it decreased to a control level. Morphological criteria for amplification and then suppression of adrenal function are the dimension of endocrine cells and their nuclei, the intensity of cell vacuolation suggesting the degree of lipids accumulation, and the severity of blood filling in the vessels of the beam and reticular zones.

TRH-induced secretion of adrenocorticotropin and cortisol in dogs with pituitary-dependent hypercortisolism

Background: In dogs, spontaneous Cushing’s syndrome is most often pituitary-dependent and caused by hypersecretion of adrenocorticotropic hormone (ACTH), resulting in increased adrenocortical glucocorticoid secretion similar to horses. In horses with Cushing’s syndrome (or pituitary pars intermedia dysfunction [PPID]) a thyrotropin-releasing hormone (TRH) stimulation test can be used for diagnosis, as TRH administration results in increased circulating ACTH and cortisol concentrations in affected horses.Objective: The aim of this study was to investigate the effect of TRH administration on the circulating ACTH and cortisol concentrations in dogs with pituitary-dependent hypercortisolism (PDH).Methods: Ten clinically normal control dogs and 10 dogs with PDH, all client owned, underwent a TRH stimulation test with measurement of plasma concentrations of ACTH and cortisol, before and after intravenous administration of 10 μg TRH/kg bodyweight.Results: Plasma ACTH concentration did not rise significantly after TRH stimulation, neither in PDH dogs nor in clinically normal dogs. In contrast, the plasma cortisol concentration did increase significantly after TRH stimulation in both groups (p = .003 in PDH and p < .001 in control). Immunohistochemistry of normal adrenal glands demonstrated the presence of TRH receptors in the whole adrenal cortex.Conclusions: The results of this study demonstrate that the TRH stimulation test should be rejected as a tool to diagnose PDH in dogs. The observed TRH-induced increase in plasma cortisol concentration without a significant rise in plasma ACTH concentration may be explained by a direct effect of TRH on adrenocortical cells mediated by adrenocortical TRH receptors.

Hypersecretion of ACTH and PRL from pituitary adenoma in MEN1, adequately managed by medical therapy.

SummaryA 54-year-old man had gastrinoma, parathyroid hyperplasia and pituitary tumor. His family history indicated that he might have multiple endocrine neoplasia type 1 (MEN1). MEN1 gene analysis revealed a heterozygous germline mutation (Gly156Arg). Therefore, we diagnosed him with MEN1. Endocrinological tests revealed that his serum prolactin (PRL) and plasma adrenocorticotropic hormone (ACTH) levels were elevated to 1699 ng/mL and 125 pg/mL respectively. Immunohistochemical analysis of the resected pancreatic tumors revealed that the tumors did not express ACTH. Overnight 0.5 and 8 mg dexamethasone suppression tests indicated that his pituitary tumor was a PRL-ACTH-producing plurihormonal tumor. Before transsphenoidal surgery, cabergoline was initiated. Despite no decrease in the volume of the pituitary tumor, PRL and ACTH levels decreased to 37.8 ng/mL and 57.6 pg/mL respectively. Owing to the emergence of metastatic gastrinoma in the liver, octreotide was initiated. After that, PRL and ACTH levels further decreased to 5.1 ng/mL and 19.7 pg/mL respectively. He died from liver dysfunction, and an autopsy of the pituitary tumor was performed. In the autopsy study, histopathological and immunohistochemical (IHC) analysis showed that the tumor was single adenoma and the cells were positive for ACTH, growth hormone (GH), luteinizing hormone (LH) and PRL. RT-PCR analysis showed that the tumor expressed mRNA encoding all anterior pituitary hormones, pituitary transcription factor excluding estrogen receptor (ER) β, somatostatin receptor (SSTR) 2, SSTR5 and dopamine receptor D (D2R). PRL-ACTH-producing tumor is a very rare type of pituitary tumor, and treatment with cabergoline and octreotide may be useful for controlling hormone levels secreted from a plurihormonal pituitary adenoma, as seen in this case of MEN1.Learning points:Although plurihormonal pituitary adenomas were reported to be more frequent in patients with MEN1 than in those without, the combination of PRL and ACTH is rare.RT-PCR analysis showed that the pituitary tumor expressed various pituitary transcription factors and IHC analysis revealed that the tumor was positive for PRL, ACTH, GH and LH.Generally, the effectiveness of dopamine agonist and somatostatin analog in corticotroph adenomas is low; however, if the plurihormonal pituitary adenoma producing ACTH expresses SSTR2, SSTR5 and D2R, medical therapy for the pituitary adenoma may be effective.

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension.

Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA). We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT). One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs. Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group. A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Comparative Analysis of Clinical, Hormonal and Morphological Studies in Patients with Neuroendocrine ACTH-Producing Tumours.

This paper highlights the problem of neuroendocrine tumours (NETs) with clinical symptoms of hypercorticism caused by hypersecretion of adrenocorticotropic hormone (ACTH) by tumour cells. In most cases (85%), the tumours were localized in the pituitary gland (Cushing's disease); 15% of the patients had an extrapituitary tumour that manifest as an ectopic ACTH secretion (EAS). Comparative analysis of clinical, hormonal, histological, and immunohistochemical characteristics of pituitary and extrapituitary ACTH-secreting NET was performed. It included 46 patients with CD and 38 ones exhibiting ectopic ACTH secretion (EAS). Results of the study suggest differences between CD and EAS in terms of the severity of clinical manifestations and duration of the disease. Hormonal studies showed that EAS unlike CD was associated with high plasma ACTH and cortisol levels, late-evening salivary cortisol and daily urinary free cortisol, the absence of a 60% or greater reduction of cortisol in the HDDST test, and the presence of a low (less than 2) ACTH gradient in response to desmopressin administration with catheterization of cavernous sinuses. The study of morphofunctional characteristics of the removed NET demonstrated the ability of both pituitary and extrapituitary NETs to express ACTH as well as GH, PRL, LH, and FSH. The angiogenic markers (CD31 and VEGF) were detected with equal frequency regardless of the NET localization. The histological structure of all corticotropinomas suggested their benign origin, but extrapituitary NETs were represented by different morphological types with varying malignancy, invasiveness, and metastatic properties. A higher cell proliferation potential (Ki-67) was documented for NET in patients presenting with an ectopic ACTH secretion compared to those having corticotropinomas.

Pituitary-Adrenal Functions in a Hereditary Hypothyroid (rdw) Rat

The rdw rat is a hereditary hypothyroid strain isolated from Wistar-Imamichi rats. In the present study, adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint stress (120 min) were examined in rdw adult male rats. ACTH response to restraint stress was higher in rdw rats than in hetero control rats. The plasma concentrations of corticosterone were lower in rdw rats than in control rats during the first 30 min after the onset of stress. Both ACTH and corticosterone responses to restraint stress in rdw rats recovered to control levels after thyroxine (T4) replacement therapy. These results suggest that hereditary hypothyroidism causes adrenal dysfunction directly and that hypersecretion of ACTH is a result of reduced corticosterone in rdw rats.

Simultaneous ectopic adrenocorticotropic hormone syndrome and adrenal metastasis of a medullary thyroid carcinoma causing paraneoplastic Cushing's syndrome.

Medullary thyroid carcinomas (MTC) constitute about 5 to 7 % of thyroid neoplasms. They originate from parafollicular C-cells which can secrete adrenocorticotropic hormone (ACTH) and/or corticotropin-releasing factor (CRF) in abnormally high concentrations, potentially causing paraneoplastic Cushing's Syndrome (CS).We report on a 42-year-old male patient with a ten year history of metastatic medullary thyroid carcinoma suffering from paraneoplastic Cushing's Syndrome caused by ectopic hypersecretion of ACTH and a simultaneous Cortisol producing adrenal metastasis.

Long-term Remission of Cyclic Cushing's Disease that was Diagnosed and Treated Surgically in Non-active Phase

Cyclic Cushing's disease is a rare clinical entity that is defined as a periodic excessive production of adrenocorticotropic hormone (ACTH) and cortisol. Only 42 cases with cyclic Cushing's disease have been reported in the literature. The diagnosis is very difficult because of the fluctuating secretion of ACTH and cortisol. We report a 78-year-old woman with a pituitary adenoma presenting with cyclic Cushing's disease. In the present case, several interesting issues are pointed out: 1) MRI study detected the presence of an adenoma and selective venous sampling in the cavernous sinus disclosed the hypersecretion of ACTH from a pituitary adenoma. These neuroimaging and endocrinological studies were helpful for the diagnosis, even in the remission phase. 2) The disease was in the long-term remission phase after transsphenoidal surgery despite the high recurrence rate in this clinical entity, although it recurred four years later. Even in the remission phase of cyclic Cushing's disease, meticulous endocrinological and neuroimaging examinations can reveal the presence of a pituitary adenoma, which should be treated surgically.

Flavonoids of St. John’s Wort Reduce HPA Axis Function in the Rat

A common biological alteration in patients with major depression is the activation of the hypothalamic-pituitary-adrenal (HPA) axis, manifested as hypersecretion of adrenocorticotropic hormone (ACTH) and cortisol. The hyperactivity of the HPA axis in depressed patients can be corrected during clinically effective therapy with standard antidepressant drugs such as imipramine, indicating that the HPA axis may be an important target for antidepressant action. We previously showed that a methanolic extract of St. John's Wort (SJW) and hypericin, one of its active constituents, both have delayed effects on the expression of genes that are involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis , whereas the phloroglucinol derivative hyperforin was inactive in the same model . Since flavonoids of SJW are also discussed as active constituents it was of interest to determine whether these compounds can modulate HPA axis function. Imipramine (15 mg/kg), hypericin (0.2 mg/kg), hyperoside (0.6 mg/kg), isoquercitrin (0.6 mg/kg) and miquelianin (0.6 mg/kg) given daily by gavage for two weeks significantly down-regulated circulating plasma levels of ACTH and corticosterone by 40 - 70 %. However, none of the compounds tested had an effect on plasma ACTH and corticosterone levels after chronic treatment (daily gavage for 8 weeks). Our data suggest that besides hypericin, flavonoids of SJW play an important role in the modulation of HPA axis function. Furthermore, the results support the hypothesis that flavonoids are involved in the antidepressant effects of SJW.

Mortality in 7B2 null mice can be rescued by adrenalectomy: Involvement of dopamine in ACTH hypersecretion

The serine protease prohormone convertase 2 (PC2), principally involved in the processing of polypeptide hormone precursors in neuroendocrine tissues, requires interaction with the neuroendocrine protein 7B2 to generate an enzymatically active form. 7B2 null mice express no PC2 activity and release large quantities of uncleaved ACTH, resulting in a lethal endocrine condition that resembles pituitary Cushing's (Westphal, C. H., Muller, L., Zhou, A., Bonner-Weir, S., Schambelan, M., Steiner, D. F., Lindberg, I. & Leder, P. (1999) Cell 96, 689). Here, we have compared the 7B2 and PC2 null mouse models to determine why the 7B2 null, but not the PC2 null, exhibits a lethal disease state. Both 7B2 and PC2 nulls contained highly elevated pituitary adrenocorticotropic hormone (ACTH); the neurointermediate lobe content of ACTH in 7B2 nulls was 13-fold higher than in WT mice; that of the PC2 null was 65-fold higher. However, circulating ACTH levels were much higher in the 7B2 null than in the PC2 null. Because hypothalamic inhibitory dopaminergic control represents the major influence on intermediate lobe proopiomelanocortin-derived peptide secretion, dopamine levels were measured, and they revealed that 7B2 null pituitaries contained only one-fourth of WT pituitary dopamine. Adrenalectomized 7B2 null animals survived past the usual time of death at 5 weeks; a month after adrenalectomy, they exhibited normal levels of pituitary dopamine, circulating ACTH, and corticosterone. Elevated corticosterone, therefore, seems to play a central role in the lethal phenotype of the 7B2 null, whereas a 7B2-mediated dopaminergic deficiency state may be involved in the actual ACTH hypersecretion phenomenon. Interestingly, adrenalectomized 7B2 nulls also developed unexpectedly severe obesity.

Multiple pituitary hormone gradients from cavernous sinus sampling in patients with Cushing's disease.

Cavernous sinus sampling in patients with adreno-corticotropic-hormone (ACTH) secreting pituitary adenomas has been used to identify directly ACTH hypersecretion from the pituitary and to predict the lateralization of a microadenoma. In our previous series, cavernous sinus sampling provided a sufficient central/peripheral (c/p) ratio of ACTH and the correct laterality of the pituitary lesion in all microadenomas situated in the lateral wing. To clarify the diagnostic value of other anterior pituitary hormones in relation to ACTH gradients, we evaluated multiple pituitary hormone gradients between a cavernous sinus and a peripheral vein and between both cavernous sinuses in patients with Cushing's disease. Cavernous sinus sampling was done in 11 patients with clinical and biochemical features of ACTH-dependent Cushing's syndrome. In 9, pituitary adenoma was detected during trans-sphenoidal surgery and histologically confirmed, while 2 others were suspected of having ectopic lesions. Serum ACTH, prolactin (PRL), thyroid stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from catheters in both cavernous sinuses and from a peripheral vein were measured. The c/p ratios of each hormone and the intercavernous gradients were evaluated. The c/p ratio of ACTH indicated the presense of pituitary lesions in all 9 patients with ACTH-secreting microadenomas. In addition, the intercavernous gradients of ACTH indicated the correct localization of microadenomas in all 6 patients with lateralized lesions. As for other hormones, the c/p ratios of GH, PRL, TSH and LH were significantly high in number 7, 6, 6 and 3 patients, respectively. In contrast, the significant step up of FSH was observed only in one patient. The intercavernous gradients of GH and PRL were significantly high in number 5 and 4 patients, respectively. The intercavernous gradients of GH and PRL tend to indicate the lateralization of a microadenoma. The measurement of GH and PRL during cavernous sinus sampling may provide additional information, in the lateralization of ACTH-secreting microadenomas.

Stressor- or drug-induced sensitization of the corticosterone response is not critically involved in the long-term expression of behavioural sensitization to amphetamine

Repeated exposure to drugs of abuse induces long-lasting behavioural sensitization, which is thought to play a role in the persistence of drug-seeking behaviour. Recently, we showed that repeated exposure of rats to cocaine resulted in a long-lasting (weeks) sensitization of the hypothalamus–pituitary–adrenal axis, i.e. hypersecretion of adrenocorticotropic hormone and of the glucocorticoid corticosterone. Moreover, we found that the administration of a glucocorticoid receptor antagonist abolished the expression of psychostimulant-induced behavioural sensitization. In the present study we tested whether stressor- or drug-induced long-term hypersecretion of corticosterone is associated with the long-term expression of behavioural sensitization to psychostimulant drugs. To that end, groups of male Wistar rats were exposed once to interleukin-1β or to footshocks, treatments that are known to induce long-term sensitization of the hypothalamus–pituitary–adrenal axis, or were treated with amphetamine or morphine, according to protocols known to induce long-lasting behavioural (locomotor) sensitization. Three weeks later, the groups and their controls were challenged with amphetamine or vehicle. Previous exposure to interleukin-1β or footshocks enhanced adrenocorticotropic hormone and corticosterone responses, but did not affect the long-term locomotor sensitization to amphetamine. Prior amphetamine treatment enhanced the locomotor response and the adrenocorticotropic hormone and corticosterone responses to amphetamine. Prior morphine treatment resulted in long-term locomotor sensitization, whereas the adrenocorticotropic hormone and corticosterone responses to amphetamine were decreased. From these findings and the absence of within-group correlation between corticosterone and locomotor responses in interleukin-1β and morphine-pretreated rats, we conclude that there is no correlation between sensitization of the corticosterone response and behavioural sensitization to amphetamine. Apparently, sensitization of the corticosterone response is not a prerequisite for the long-term expression of behavioural sensitization, which suggests that drug-induced long-term behavioural sensitization may involve corticosteroid receptor-dependent (central) mechanisms that occur independent of hypothalamus–pituitary–adrenal axis responsiveness.

Cushing's Disease in a Patient With a 'Nonfunctioning' Pituitary Tumor

A 40-year-old woman had visual loss and a large nonfunctioning pituitary tumor. After partial surgical resection and radiation treatment, clinical and biochemical evidence of Cushing's disease developed. The pituitary source of her adrenocorticotropic hormone hypersecretion was documented on selective venous sampling. After 18 months of medical therapy with metyrapone and aminoglutethimide, the patient experienced a spontaneous remission of her hypercortisolism. A "nonfunctioning" pituitary tumor has a hypersecretory potential.