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\"The Adrenal Reset Diet is the first scientifically sound, patient-tested weight-loss plan developed by a natural endocrinologist, Dr. Alan Christianson. He heals readers in any of the three stages of adrenal impairment--Stressed, Wired and Tired, or Crashed. Readers learn their stage and receive distinct strategies for diet, activity, and lifestyle change to bring them to Thriving. Recent study participants halved their cortisol levels in just 30 days--and lost an average of 9 pounds!\"-- Provided by publisher.

The benefit of adjuvant use of corticosteroids in patients with septic shock remains controversial. In this international, multicenter, double-blind, placebo-controlled trial, adjunctive therapy with hydrocortisone in nearly 500 patients with septic shock was not found to be clinically helpful. This lack of benefit was also found in a subgroup of patients who did not have a response to a corticotropin test. Adjunctive therapy with hydrocortisone in nearly 500 patients with septic shock was not found to be clinically helpful. This lack of benefit was also found in a subgroup of patients who did not have a response to a corticotropin test. Severe sepsis is a major cause of mortality and morbidity worldwide. 1 , 2 Septic shock, the most severe manifestation, occurs in 2 to 20% of inpatients. 3 The incidence of the condition has been rising, 4 and a death rate of 33 to 61% has been reported in the placebo groups of multicenter trials. 5 – 8 The use of corticosteroids as an adjunctive therapy has been controversial for decades. 9 After the study by Schumer, 10 a short course of high-dose corticosteroids became accepted therapy. Subsequent studies, however, did not confirm a survival benefit with this regimen and suggested an increase in superinfection-related mortality. 11 – 13 Studies . . .

BACKGROUNDMetastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODSOur prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTSPatients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSIONThese data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDINGNational Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1 st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes. Adrenal aldosterone production is regulated by plasma angiotensin and potassium levels. Here the authors report that the neuropeptide substance P stimulates aldosterone production via neurokinin type 1 receptors (NK1R), and report a proof-of-concept placebo controlled clinical trial showing that a NK1R antagonist decreases aldosterone levels.

Neuroblastoma (NB) is a tumor of the sympathoadrenal system arising in children under 15 years of age. In Germany, NB accounts for 7% of childhood cancer cases, but 11% of cancer deaths. It originates from highly migratory progenitor cells that leave the dorsal neural tube and contribute neurons and glial cells to sympathetic ganglia, and chromaffin and supportive cells to the adrenal medulla and paraganglia. Clinically, histologically and molecularly, NBs present as extremely heterogeneous, ranging from very good to very poor prognosis. The etiology of NB still remains unclear and needs to be elucidated, however, aberrant auto- and paracrine embryonic cell communications seem to be likely candidates to initiate or facilitate the emergence, progression and regression of NB. The wingless-type MMTV integration site (WNT) family of proteins represents an evolutionary highly conserved signaling system that orchestrates embryogenesis. At least 19 ligands in the human, numerous receptors and co-receptors are known, which control not only proliferation, but also cell polarity, migration and differentiation. Here we seek to interconnect aspects of WNT signaling with sympathoadrenal and paraganglionic development to define new WNT signaling cues in the etiology and progression of NB.

Gap junctions (GJs) are important in the regulation of cell growth, morphology, differentiation and migration. However, recently, more attention has been paid to their role in the pathogenesis of different diseases as well as tumorigenesis, invasion and metastases. The expression pattern and possible role of connexins (Cxs), as major GJ proteins, under both physiological and pathological conditions in the adrenal gland, were evaluated in this review. The databases Web of Science, PubMed and Scopus were searched. Studies were evaluated if they provided data regarding the connexin expression pattern in the adrenal gland, despite current knowledge of this topic not being widely investigated. Connexin expression in the adrenal gland differs according to different parts of the gland and depends on ACTH release. Cx43 is the most studied connexin expressed in the adrenal gland cortex. In addition, Cx26, Cx32 and Cx50 were also investigated in the human adrenal gland. Cx50 as the most widespread connexin, along with Cx26, Cx29, Cx32, Cx36 and Cx43, has been expressed in the adrenal medulla with distinct cellular distribution. Considerable effort has recently been directed toward connexins as therapeutically targeted molecules. At present, there exist several viable strategies in the development of potential connexin-based therapeutics. The differential and hormone-dependent distribution of gap junctions within adrenal glands, the relatively large gap junction within this gland and the increase in the gap junction size and number following hormonal treatment would indicate that gap junctions play a pivotal role in cell functioning in the adrenal gland.

The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single‐nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular‐endothelial cells and cortical‐neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/β‐catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single‐nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma‐specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal‐related pathologies. This study unveils the cellular diversity within the adult human adrenal gland using single‐nuclei RNA sequencing and spatial transcriptome data. Analysis of the adult human adrenal gland identifies new cell populations and key pathways governing adrenal homeostasis. Significant cellular and transcriptomic heterogeneity is discovered when comparing adrenocortical adenomas to healthy adrenal glands, shedding light on adrenocortical tumorigenesis and steroid hormones regulation.

Adrenal cortical carcinomas (ACC) are rare but aggressive tumours associated with poor prognosis. The two most frequent alterations in ACC in patients are overexpression of the growth factor IGF2 and constitutive activation of Wnt/β-catenin signalling. Using a transgenic mouse model, we have previously shown that constitutive active β-catenin is a bona fide adrenal oncogene. However, although all these mice developed benign adrenal hyperplasia, malignant progression was infrequent, suggesting that secondary genetic events were required for aggressive tumour development. In the present paper, we have tested IGF2 oncogenic properties by developing two distinct transgenic mouse models of Igf2 overexpression in the adrenal cortex. Our analysis shows that despite overexpression levels ranging from 7 (basal) to 87 (ACTH-induced) fold, Igf2 has no tumour initiating potential in the adrenal cortex. However, it induces aberrant accumulation of Gli1 and Pod1-positive progenitor cells, in a hedgehog-independent manner. We have also tested the hypothesis that Igf2 may cooperate with Wnt signalling by mating Igf2 overexpressing lines with mice that express constitutive active β-catenin in the adrenal cortex. We show that the combination of both alterations has no effect on tumour phenotype at stages when β-catenin-induced tumours are benign. However, there is a mild promoting effect at later stages, characterised by increased Weiss score and proliferation. Formation of malignant tumours is nonetheless a rare event, even when Igf2 expression is further increased by ACTH treatment. Altogether these experiments suggest that the growth factor IGF2 is a mild contributor to malignant adrenocortical tumourigenesis.

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues.

Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as \"pseudo-hypoxic drive\". Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissue-specificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1α pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the \"pseudo-hypoxic\" response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21(WAF1/Cip1) will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1α in tumorigenesis.