Steroidogenesis and androgen/estrogen signaling pathways are altered in in vitro matured testicular tissues of prepubertal mice.

Children undergoing cancer treatments are at risk for impaired fertility. Cryopreserved prepubertal testicular biopsies could theoretically be later matured to produce spermatozoa for assisted reproductive technology. A complete spermatogenesis has been obtained from mouse prepubertal testicular tissue, although with low efficiency.

Ectopic localization of CYP11B1 and CYP11B2-expressing cells in the normal human adrenal gland.

The sharp line of demarcation between zona glomerulosa (ZG) and zona fasciculata (ZF) has been recently challenged suggesting that this interface is no longer a compartment boundary. We have used immunohistochemical analyses to study the steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) pattern of expression and investigate the remodeling of the adrenal cortex in relation to aging. We analyzed human adrenal glands prepared from 47 kidney donors.

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis.

Aims/hypothesis: 26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis.

Expression of LHCGR in Pheochromocytomas Unveils an Endocrine Mechanism Connecting Pregnancy and Epinephrine Overproduction.

Background: The mechanisms by which pregnancy may unmask pheochromocytomas and paragangliomas are not totally understood. We hypothesized that gestational hormones may participate in the pathophysiology of catecholamine excess during pregnancy. We report a case of silent pheochromocytoma revealed in a pregnant woman by life-threatening adrenergic myocarditis.

Steroidogenic cell microenvironment and adrenal function in physiological and pathophysiological conditions.

The human adrenal cortex is a complex organ which is composed of various cell types including not only steroidogenic cells but also mesenchymal cells, immunocompetent cells and neurons. Intermingling of these diverse cell populations favors cell-to-cell communication processes involving local release of numerous bioactive signals such as biogenic amines, cytokines and neuropeptides. The resulting paracrine interactions play an important role in the regulation of adrenocortical cell functions both in physiological and pathophysiological conditions.

The neuropeptide substance P regulates aldosterone secretion in human adrenals.

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.

Role of Mast Cells in the Control of Aldosterone Secretion.

Mast cells are immune cells present in adrenals from various species. Proliferation and activation of adrenal mast cells seem to be influenced by environment, since they increase during summer and in response to sodium restriction in frogs and mouse, respectively. Although the physiological factors regulating adrenal mast cell activity have not been identified, they might involve neurotransmitters and the renin-angiotensin system.

Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels.

Context: In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors.

Paracrine Regulation of Aldosterone Secretion in Physiological and Pathophysiological Conditions.

Aldosterone secretion by the zona glomerulosa of the adrenal cortex is controlled by circulating factors including the renin angiotensin system (RAS) and potassium. Mineralocorticoid production is also regulated through an autocrine/paracrine mechanism by a wide variety of bioactive signals released in the vicinity of adrenocortical cells by chromaffin cells, nerve endings, cells of the immune system, endothelial cells and adipocytes. These regulatory factors include conventional neurotransmitters and neuropeptides.

Autoantibodies reactive to adrenocorticotropic hormone can alter cortisol secretion in both aggressive and nonaggressive humans.

Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11-24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1-13).

Dysregulation of Aldosterone Secretion in Mast Cell-Deficient Mice.

Resident adrenal mast cells have been shown to activate aldosterone secretion in rat and man. Especially, mast cell proliferation has been observed in adrenal tissues from patients with aldosterone-producing adrenocortical adenoma. In the present study, we show that the activity of adrenal mast cells is stimulated by low-sodium diet and correlates with aldosterone synthesis in C57BL/6 and BALB/c mice.

Role of cAMP/PKA pathway and T-type calcium channels in the mechanism of action of serotonin in human adrenocortical cells.

In human adrenal, serotonin (5-HT), produced by mast cells located in zona glomerulosa, stimulates production of corticosteroids through a paracrine mechanism involving the 5-HT receptor type 4 (5-HT). The aim of the present study was to investigate the transduction mechanisms associated with activation of 5-HT receptors in human adrenocortical cells. Our results show that 5-HT receptors are present in the outer adrenal cortex, both in glomerulosa and fasciculata zonae.

PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A () gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters.

Role of ACTH in the Interactive/Paracrine Regulation of Adrenal Steroid Secretion in Physiological and Pathophysiological Conditions.

In the normal human adrenal gland, steroid secretion is regulated by a complex network of autocrine/paracrine interactions involving bioactive signals released by endothelial cells, nerve terminals, chromaffin cells, immunocompetent cells, and adrenocortical cells themselves. ACTH can be locally produced by medullary chromaffin cells and is, therefore, a major mediator of the corticomedullary functional interplay. Plasma ACTH also triggers the release of angiogenic and vasoactive agents from adrenocortical cells and adrenal mast cells and, thus, indirectly regulates steroid production through modulation of the adrenal blood flow.

Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal.

Mast cells are present in the human adult adrenal with a potential role in the regulation of aldosterone secretion in both normal cortex and adrenocortical adenomas. We have investigated the human developing adrenal gland for the presence of mast cells in parallel with steroidogenic enzymes profile and serotonin signaling pathway. RT-QPCR and immunohistochemical studies were performed on adrenals at 16-41 weeks of gestation (WG).

Cell-to-cell communication in bilateral macronodular adrenal hyperplasia causing hypercortisolism.

It has been well established that, in the human adrenal gland, cortisol secretion is not only controlled by circulating corticotropin but is also influenced by a wide variety of bioactive signals, including conventional neurotransmitters and neuropeptides, released within the cortex by various cell types such as chromaffin cells, neurons, cells of the immune system, adipocytes, and endothelial cells. These different types of cells are present in bilateral macronodular adrenal hyperplasia (BMAH), a rare etiology of primary adrenal Cushing's syndrome, where they appear intermingled with adrenocortical cells in the hyperplastic cortex. In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells.

Mast cell hyperplasia is associated with aldosterone hypersecretion in a subset of aldosterone-producing adenomas.

Context: Adrenal mast cells can stimulate aldosterone secretion through the local release of serotonin (5-HT) and activation of the 5-HT4 receptor (5-HT4). In aldosterone-producing adenomas (APAs), 5-HT4 receptor is overexpressed and the administration of 5-HT4 receptor agonists to patients with APA increases plasma aldosterone levels. These data and the well-documented role of mast cells in tumorigenesis suggest that mast cells may be involved in the pathophysiology of APA.

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.

Background: Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia.

Evaluation of endocrine testing of Leydig cell function using extractive and recombinant human chorionic gonadotropin and different doses of recombinant human LH in normal men.

Background: The functional testing of endocrine testis uses extractive human chorionic gonadotropin (ehCG). Recombinant human hCG (rhCG), avoiding any contamination, should replace ehCG. Moreover, a functional evaluation with recombinant human LH (rhLH) would be closer to physiology than a pharmacological testing with hCG.

Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome.

Context: In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol secretion is controlled by illegitimate membrane receptors.

Objective: The aim of the present study was to characterize the pharmacological properties and the transduction mechanisms of illegitimate receptors, i.e.

Circulating EM66 is a highly sensitive marker for the diagnosis and follow-up of pheochromocytoma.

We have previously demonstrated that measurement of tissue concentration of the novel secretogranin II-derived peptide EM66 may help to discriminate between benign and malignant pheochromocytomas. The aim of the present study was to characterize EM66 in plasma and urine of healthy volunteers and pheochromocytoma patients, in order to further evaluate the usefulness of this peptide as a circulating marker for the management of the tumors. HPLC analysis of plasma and urine samples demonstrated that the EM66-immunoreactive material coeluted with the recombinant peptide.

Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: in vivo and in vitro studies.

Two patients with incidentally discovered adrenocortical adenomas underwent a series of pharmacological and physiological tests after pretreatment with dexamethasone. Illicit plasma cortisol responses to the serotonin (5-HT)4 receptor agonist cisapride were observed in the two patients. Significant increases in plasma cortisol levels were also noticed after glucagon and combined TRH/GnRH/GHRH stimulation tests in patient 1 and after administration of the lysine vasopressin precursor terlipressin in patient 2.

In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism.

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1-H4) preoperatively underwent a series of pharmacological and/or physiological tests.

Characterization of endozepines in the human testicular tissue: effect of triakontatetraneuropeptide on testosterone secretion.

Previous studies have shown that endozepines, i.e. endogenous ligands of benzodiazepine (BZD) receptors, stimulate steroidogenesis in adrenocortical and Leydig cells.