Showing papers on "Adrenal cortex published in 2003"
TL;DR: It is suggested that human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.
Abstract: Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin (2 x 10(-5) M). On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99 degrees C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass >50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass <50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.
418 citations
TL;DR: Two different gsp mutations are found in three patients with Cushing's syndrome due to AIMAH, and it is speculated whether they belong to the spectrum of McCune-Albright syndrome or whether these are the first reported cases of AIMah due to gsp mutation.
Abstract: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is an uncommon cause of Cushing’s syndrome characterized by bilateral nodular adrenocortical hyperfunction in the presence of suppressed ACTH levels. We investigated whether activating mutations in the ACTH receptor (MC2-R) or Gsα (GNAS1) genes might be involved in AIMAH genesis. Five women with Cushing’s syndrome due to AIMAH, confirmed by histological studies, and no signs of McCune-Albright syndrome were selected for molecular analysis of these genes. The single exon of the MC2-R gene and exons 8 and 9 of the GNAS1 gene were amplified by PCR in genomic DNA from adrenal nodules and peripheral blood. Direct sequencing revealed only MC2-R wild-type sequences. GNAS1 PCR products at denaturing gradient gel electrophoresis revealed abnormal migration patterns in adrenal tissues of three patients. Automatic sequencing showed two different activating mutations at codon Arg201 of GNAS1, a substitution by histidine in two cases and by serine in one case. ...
172 citations
TL;DR: It is demonstrated that the primate adrenal gland cortex expresses functional mt1 melatonin receptors and shows thatmelatonin inhibits ACTH-stimulated cortisol production, suggesting that melatonin acts through a cAMP-independent signaling pathway.
Abstract: The pineal hormone melatonin participates in circadian, seasonal, and reproductive physiology. The presence of melatonin binding sites in human brain and peripheral tissues is well documented. However, in the mammalian adrenal gland, low-affinity melatonin binding sites have been detected only in the rat by some but not all authors. Conflicting evidence for a regulatory role of melatonin on adrenal cortisol production, prompted us to investigate this possibility in a New World primate, the capuchin monkey. Expression of melatonin receptors in the adrenal cortex was demonstrated through pharmacological characterization and autoradiographic localization of 2-[125I]iodomelatonin binding sites (dissociation constant = 96.9 +/- 15 pM; maximal binding capacity = 3.8 +/- 0.4 fmol/mg protein). The mt1 identity of these receptors was established by cDNA sequencing. Melatonin treatment of dispersed cells and explants from adrenal gland did not affect basal cortisol production. However, cortisol production stimulated by 100 nM ACTH was significantly inhibited by low melatonin concentrations (0.1-100 nM); this inhibitory effect was reversed by the mt1/MT2 melatonin antagonist luzindole. Melatonin also inhibited dibutyril-cAMP-stimulated cortisol production, suggesting that melatonin acts through a cAMP-independent signaling pathway. The present data demonstrate that the primate adrenal gland cortex expresses functional mt1 melatonin receptors and shows that melatonin inhibits ACTH-stimulated cortisol production.
171 citations
TL;DR: Age-dependent reference values for salivary cortisol, 17α-hydroxyprogesterone (17OHP), and progesterone in a large cohort of healthy children are established to improve the applicability of saliva analysis as a diagnostic tool in pediatric endocrinology.
Abstract: Very few reference intervals for salivary steroids in children have been established to date (1). Even the manufacturers of salivary steroid assays do not provide sufficient reference data for their products. This lack of information is surprising because the measurement of salivary steroids has been accepted as being noninvasive and stress-free (2)(3). In particular, psychiatric and neuro-endocrinologic experiments are frequently designed with saliva as the medium of choice for steroid analysis (4)(5)(6).
A large variety of stressors can rapidly affect the adrenal cortex, causing increased adrenal steroid concentrations. For example, hypoglycemia (7) or physical exercise (8) are potent physiologic stressors, whereas fear (9), feelings of inferiority (10)(11), or experiences at school (12)(13) can affect the adrenal cortex activity as psychologic stressors. The taking of blood can also influence adrenal steroid concentrations in children; saliva collection, however, is almost stress-free (14). The use of saliva for steroid analysis in children is therefore an excellent alternative to blood.
The aim of our study was to establish age-dependent reference values for salivary cortisol, 17α-hydroxyprogesterone (17OHP), and progesterone in a large cohort of healthy children. The availability of such reference intervals will improve the applicability of saliva analysis as a diagnostic tool in pediatric endocrinology.
We collected 252 saliva profiles from healthy children and adolescents (125 boys; age range, 4 days to 15 years; 127 girls; age range, 6 days to 13 years) with normal body length/height and weight. None of the girls had developed a regular menstrual cycle. The parents of the children gave informed consent.
Saliva was collected either with the Salivette®, using polyester swabs (Sarstedt), from children >1 year of age or with modified medical pacifiers (Buttner-Frank; see Fig. 1⇓ in the Data Supplement that accompanies the …
135 citations
TL;DR: The major corticosteroids aldosterone and cortisol (corticosterone in rodents) are secreted from the adrenal cortex under the regulation of the renin–angiotensin system and the hypothalamic–pituitary–adrenal axis.
Abstract: 1. The major corticosteroids aldosterone and cortisol (corticosterone in rodents) are secreted from the adrenal cortex under the regulation of the renin-angiotensin system and the hypothalamic-pituitary-adrenal axis. 2. In addition to their accepted roles in such processes as blood pressure regulation, glycogenesis, hepatic glyconeogenesis and immunosuppression, the corticosteroids have been implicated in the development of cardiac fibrosis, modulation of hippocampal neuron excitability, memory formation and neurodegeneration. 3. The advent of sensitive molecular biological techniques has produced a wealth of evidence to support the existence of extra-adrenal corticosteroidogenic systems. Most attention has been paid to the cardiovascular system and the central nervous system, where the full array of enzymes required for the de novo synthesis of corticosteroids from cholesterol has been identified. 4. Although the evidence for local corticosteroid production is strong, the quantities of steroid would be small compared with adrenal production. Therefore, it is still a matter of debate as to whether extra-adrenal corticosteroids are of any physiological significance. This will depend on factors such as local concentration, proximity to target cells and, possibly, to tissue-specific control mechanisms.
132 citations
TL;DR: After 30 years of intensive research in this field, cAMP remains the first obligatory second messenger of ACTH action, however, recent work emphasizes that cell environment probably interacts with cAMP to coordinate functions other than steroid secretion.
Abstract: ACTH is the major regulator of adrenal cortex function, having acute and chronic effects on steroid synthesis and secretion. The precise molecular mechanisms by which ACTH stimulates steroid synthesis and secretion, as well as cell hypertrophy, survival, and migration are still poorly understood. Several studies have shown that ACTH action is mediated not only by cyclic adenosine monophosphate (cAMP), but also by calcium (Ca(2+)), both interacting closely through positive feedback loops to enhance steroid secretion. However, in spite of the evidence that ACTH could stimulate other signaling pathways, such as inositol phosphates and diacylglycerol or mitogenic-activated protein kinase pathway (MAPK), none is as potent as cAMP. Recent data indicate that duration and potency of the cAMP production could be modulated by several isoforms of adenylyl cyclases and phosphodiesterases. In addition, calcium is probably not a first second messenger per se; rather, there are several arguments indicating that its increase occurs following cAMP production. Finally, in addition to steroid secretion, ACTH, through cAMP, is a survival factor, protecting cells against apoptosis. All of the effects of ACTH are dependent on cytoskeleton integrity. In summary, after 30 years of intensive research in this field, cAMP remains the first obligatory second messenger of ACTH action. However, recent work emphasizes that cell environment (matrix and cytoskeleton) probably interacts with cAMP to coordinate functions other than steroid secretion.
119 citations
TL;DR: Ghrelin and GHS‐R are both expressed in the rat adrenal cortex, ghrelin binding sites being very abundant in the ZG, and gh Relin does not affect the secretory activity of rat adrenocortical cells, but significantly enhances the proliferation rate of cultured ZG cells, without affecting apoptotic deletion rate.
116 citations
TL;DR: Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders of adrenal steroidogenesis in which each disorder is characterized by a specific enzyme deficiency that impairs cortisol production by the adrenal cortex.
110 citations
TL;DR: Calretinin is the most sensitive among all the adrenal markers tested and may have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.
103 citations
TL;DR: It is hypothesized that Wnt-dependent signaling cascades regulate SF-1-dependent transcription of genes required for adreno-gonadal development and the data demonstrate that β-catenin synergizes withSF-1 to activate the α-inhibin promoter through formation of a transcriptional complex support the recent observation thatβ-Catenin can participate in nuclear receptor-mediated transcriptional activation and extend the findings to the monomer binding class of orphan nuclear receptors.
96 citations
TL;DR: The intimate relationship between serotonin and the hypothalamic–pituitary–adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue.
Abstract: Serotonin (5-hydroxytryptamine, 5-HT)-containing neurons in the midbrain directly innervate corticotropin-releasing hormone (CRH)-containing cells located in paraventricular nucleus of the hypothalamus. Serotonergic inputs into the paraventricular nucleus mediate the release of CRH, leading to the release of adrenocorticotropin, which triggers glucocorticoid secretion from the adrenal cortex. 5-HT1A and 5-HT2A receptors are the main receptors mediating the serotonergic stimulation of the hypothalamic-pituitary-adrenal axis. In turn, both CRH and glucocorticoids have multiple and complex effects on the serotonergic neurons. Therefore, these two systems are interwoven and communicate closely. The intimate relationship between serotonin and the hypothalamic-pituitary-adrenal axis is of great importance in normal physiology such as circadian rhythm and stress, as well as pathophysiological disorders such as depression, anxiety, eating disorders, and chronic fatigue.
TL;DR: Evidence of leptin receptor gene expression in central and peripheral tissues of the bovine is reported by reverse transcription and polymerase chain reaction analysis and reveals that leptin may have multiple physiological functions in the Bovine.
TL;DR: Although there is currently no direct evidence that environmental exposure to endocrine‐disrupting chemicals has actually caused adverse human health effects, lessons have been learned on their potential from the diethylstilboestrol case and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes.
Abstract: Current testing strategies to assess the endocrine disrupting properties of chemicals have omitted examination of the adrenal gland and do not adequately cover the process of steroidogenesis Steroidogenesis is critical for adrenocortical function as well as that of the testes and ovaries, and presents multiple molecular targets for toxicity, ranging from general effects on all steroidogenic tissues (eg via StAR protein or CYP11A1 cholesterol side-chain cleavage) through to specific targets affecting only adrenocortical function (eg CYP11beta/18 and glucocorticoid synthesis) Numerous chemicals of environmental relevance are now being shown to affect adrenocortical function both in vivo in aquatic species and in vitro in human cell lines, and given the vital role of the adrenal gland to human health and development, there is a strong case for including dedicated assessment techniques in screening batteries for endocrine-disrupting chemicals, not least to assist in general data interpretation (eg whether adrenal hypertrophy is due to stress or to a more sinister adrenocortical insufficiency) Cell lines such as H295R (derived from a human adrenocortical adenocarcinoma) currently exist that will allow assessment of cortisol production and most of the major enzymes and functional proteins in the steroidogenic pathway (eg StAR; CYP11A1/scc; CYP11beta/18; CYP17; CYP19; CYP21; 3beta-hydroxysteroid dehydrogenase) Adequate assessment of adrenocortical function, as with any component of the integrated endocrine system, probably also will require the development of specific in vivo methodology to include effects on hypothalamo-pituitary function Finally, although there is currently no direct evidence that environmental exposure to endocrine-disrupting (oestrogenic) chemicals has actually caused adverse human health effects, lessons have been learned on their potential from the diethylstilboestrol case Similar evidence exists from aminoglutethimide and etomidate on the lethal impact of unpredicted chemically induced adrenal insufficiency in sensitive human subgroups, and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes
TL;DR: It is proposed that zU is the stem cell zone of the adult rat adrenal cortex and the recent success in isolating novel cell lines, which display an undifferentiated phenotype similar to that of zU cells, could facilitate the exploration of molecular mechanisms for the differentiation and development of the adrenocortical cells.
TL;DR: After subtotal bilateral adrenalectomy left 15% to 30% of adrenal tissue in situ, functional recovery could be observed in all patients and subclinical impairment of the adrenocortical function with questionable clinical significance has to be considered in some of the patients.
TL;DR: A significant effect of genistein on steroidogenesis in the adrenal gland and testis of rats is suggested, and this effect appeared to be more evident on steroid production in adrenals than in testis in vivo.
TL;DR: In this paper, the expression of CYP11B2 mRNA in the failing or hypertensive human ventricle was investigated using real-time reverse transcription-polymerase chain reaction.
Abstract: Background— Although previously thought to be synthesized solely in adrenal cortex, we have recently showed that aldosterone is also produced in and the expression of CYP11B2 mRNA was induced in the failing or hypertensive human ventricle. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones with wide biological effects, including inhibition of renin and aldosterone production. We hypothesized that natriuretic peptides reduce the expression of CYP11B2 mRNA in the heart. Methods and Results— To test this hypothesis, we examined whether endogenous or exogenous natriuretic peptides reduce the expression of CYP11B2 mRNA using real-time reverse transcription-polymerase chain reaction. By using HS 142–1, a functional guanylyl cyclase-A type receptor antagonist, we showed that angiotensin II (AngII) pretreated with HS 142–1 increased CYP11B2 mRNA expression (1.62±0.12-fold, HS 142–1+AngII 10−7 mol/L versus AngII 10−7 mol/L alone, P<0.0001). The treatment with exogenous (10−6 ...
01 Jan 2003
TL;DR: The data suggest that E(2), acting through its receptors in the ZG, reduces AT(1)R density and Ang II-induced aldosterone release, primarily by inhibiting AT( 1)R translation, possibly by blocking ribosomal scanning caused by increased steric hindrance from 5'LS RBPs.
Abstract: Hypertension and associated cardiovascular disease increase after menopause. Angiotensin AT1 receptor (AT1R) antagonists are effective treatments, in part, by inhibiting angiotensin II (Ang II)-induced aldosterone release from the adrenal zona glomerulosa (ZG). Estrogen decreases the number of AT1Rs in the adrenal gland and attenuates acute Ang IIinduced aldosterone release. Here, we examined the effects of 17-estradiol (E2 )o n AT 1R gene regulation in the rat adrenal cortex (AC). Female rats were ovariectomized and injected with vehicle or E2. Immunohistochemistry revealed the presence of both estrogen receptor (ER) and ER in the ZG, and E2 treatment increased the intensity of their nuclear staining. Under conditions in which AT1R maximal binding capacity was decreased by 46%, chronic miniosmotic pump Ang IIinduced aldosterone secretion was reduced by 43%. E2 treatment had no effect on AT1aR and AT1bR mRNA levels in the AC, whereas the AT1R mRNA polysome distribution in sucrose gradients was shifted to lighter fractions, indicating that E2 treatment reduces AT1R translation. RNA binding proteins (RBPs) in AC extracts formed complexes with the 5 leader sequence (5LS), coding region, and the 3-untranslated region (3UTR); however, only the activity of 5LS RBPs was regulated by E2 treatment. These data suggest that E2, acting through its receptors in the ZG, reduces AT1R density and Ang II-induced aldosterone release, primarily by inhibiting AT1R translation, possibly by blocking ribosomal scanning caused by increased steric hindrance from 5LS RBPs. Dysregulation of this posttranscriptional mechanism may contribute to the increased incidence of cardiovascular disease associated with menopause. (Endocrinology 144: 3251–3261, 2003)
TL;DR: In this article, the effects of 17β-estradiol (E2) on AT1R gene regulation in the rat adrenal cortex (AC) were examined, and female rats were ovariectomized and injected with vehicle or E2.
Abstract: Hypertension and associated cardiovascular disease increase after menopause. Angiotensin AT1 receptor (AT1R) antagonists are effective treatments, in part, by inhibiting angiotensin II (Ang II)-induced aldosterone release from the adrenal zona glomerulosa (ZG). Estrogen decreases the number of AT1Rs in the adrenal gland and attenuates acute Ang II-induced aldosterone release. Here, we examined the effects of 17β-estradiol (E2) on AT1R gene regulation in the rat adrenal cortex (AC). Female rats were ovariectomized and injected with vehicle or E2. Immunohistochemistry revealed the presence of both estrogen receptor (ER)α and ERβ in the ZG, and E2 treatment increased the intensity of their nuclear staining. Under conditions in which AT1R maximal binding capacity was decreased by 46%, chronic miniosmotic pump Ang II-induced aldosterone secretion was reduced by 43%. E2 treatment had no effect on AT1aR and AT1bR mRNA levels in the AC, whereas the AT1R mRNA polysome distribution in sucrose gradients was shifted ...
TL;DR: The restricted expression of activin receptor subunits and Smad2 in cells of the adrenal x zone, together with the elevated activin levels in INH−/−-LH-CTP mice, supports the conclusion that activin inhibits adrenal tumor growth by inducing x-zone regression.
Abstract: Inhibin and activin are members of the transforming growth factor β (TGF-β) family of ligands produced and secreted primarily by the gonads and adrenals. Inhibin-null (INH−/−) mice develop gonadal tumors and—when gonadectomized—adrenocortical carcinoma. The mechanisms leading to adrenal tumorigenesis have been proposed to involve the lack of a gonadal factor and/or a compensatory increase in gonadotropins. In order to achieve elevation of gonadotropins without the concomitant loss of a gonadal hormone, we crossed INH−/− mice with a transgenic mouse strain that has chronically elevated luteinizing hormone (LH) levels (LH-CTP). Compound INH−/−-LH-CTP mice die within 6 weeks of age from severe cancer cachexia induced by large, activin-secreting ovarian tumors. Unexpectedly, INH−/−-LH-CTP mice not only fail to develop adrenal tumors but have smaller adrenals, with a regressed x zone, indicating that elevated LH levels are not sufficient to induce adrenal tumor formation. However, following gonadectomy, INH−/−-LH-CTP mice develop large, sex steroid-producing adrenal tumors that arise from the x zone, indicating a growth-promoting effect of high levels of LH on the adrenal cortex in the absence of ovarian tumors. In addition, in vivo and in vitro data indicate that activin induces apoptosis specifically in the adrenal x zone. The restricted expression of activin receptor subunits and Smad2 in cells of the adrenal x zone, together with the elevated activin levels in INH−/−-LH-CTP mice, supports the conclusion that activin inhibits adrenal tumor growth by inducing x-zone regression.
TL;DR: It is indicated that sex and/or gonadal steroid environment can affect the stress-induced ACh release in the hippocampus and CS release from the adrenal cortex.
Abstract: To assess sex differences in stress-induced acetylcholine (ACh) release in the hippocampus and corticosterone (CS) release from the adrenal cortex, an in vivo microdialysis study was performed in inta
TL;DR: Results show an overexpression of the 5-HT4 receptor in cisapride-responsive AIMAH and Cushing's syndrome, and the level of expression of the receptor in the hyperplastic adrenal cortex was similar to that of normal adrenal gland.
Abstract: The serotonin4 (5-HT4) receptor agonists cisapride and/or metoclopramide have been shown to stimulate cortisol secretion in some patients with ACTH-independent bilateral macronodular adrenal hyperplasias (AIMAH) causing Cushing’s syndrome. In the present study, we have investigated quantitatively and qualitatively the expression of the 5-HT4 receptor in both normal adrenal cortex and tissues removed from six patients (P1–P6) with cisapride-responsive AIMAH and Cushing’s syndrome. Real-time quantitative PCR assay revealed that the 5-HT4 receptor was overexpressed in four of the six hyperplasias studied when compared with normal adrenal cortex. In these tissues, 5-HT4 receptor mRNA expression was 3 to 16 times higher than in normal glands, likely explaining the abnormal in vivo cortisol response to cisapride. Characterization of 5-HT4 receptor splice variants by RT-PCR in both hyperplastic and normal adrenals showed that the variants present in the two hyperplasias that did not overexpress the 5-HT4 recepto...
TL;DR: Strain susceptibility to adrenocortical tumorigenesis (DBA/2J >> FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenoc Cortical neoplasia in response to continuous gonadotropin stimulation.
Abstract: Certain inbred strains of mice, including DBA/2J, develop adrenocortical tumors in response to gonadectomy. Spindleshaped cells with limited steroidogenic capacity, termed A cells, appear in the subcapsular region of the adrenal gland, followed by sex steroid-producing cells known as B cells. These changes result from unopposed gonadotropin production by the pituitary, but the adrenocortical factors involved in tumorigenesis have not been characterized. GATA-4, a transcription factor normally expressed in fetal, but not adult, adrenocortical cells, was found in neoplastic cells that proliferate in the adrenal cortex of gonadectomized DBA/2J mice. GATA-4 mRNA was detected in the adrenal glands of female mice 0.5 months after ovariectomy and reached a maximum by 4 months. Castrated male mice developed adrenocortical tumors more slowly than gonadectomized females, and the onset of GATA-4 expression in the adrenal was delayed. In situ hybridization and immunohistochemistry revealed GATA-4 mRNA and protein in A and B cells, but not in normal adrenocortical cells. mRNA encoding another factor associated with adrenocortical tumorigenesis, LH receptor (LHR), was detected in A and B cells. In addition, transcripts for P450 17-hydroxylase/C17-C20 lyase, an enzyme essential for the production of sex steroids, and inhibin- were found in B cells. Unilateral ovarian regeneration, a phenomenon known to occur in gonadectomized mice, was observed in a subset of DBA/2J mice undergoing complete ovariectomy. In these animals, adrenocortical tumor progression was arrested; A cells and GATA-4 expression were evident, but there was no expression of LHR or P450 17-hydroxylase/C17-C20 lyase. Strain susceptibility to adrenocortical tumorigenesis (DBA/2J FVB/N) correlated with the expression of GATA-4 and LHR, implicating these factors in the process of adrenocortical neoplasia in response to continuous gonadotropin stimulation. (Endocrinology 144: 4123– 4133, 2003)
TL;DR: It is proposed that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia, which might be responsible for the long-term development of the phenotype of hypertension with a raised ratio.
Abstract: Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position −344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11β-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio. In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism.
TL;DR: Findings demonstrate integral roles for MKP-1 and ERK1/2 via regulation of the phosphorylation state of steroidogenic factor-1 (SF-1) in mediating ACTH/cAMP-dependent transcription of hCYP17, thereby maintaining the balance between transcriptional activation and repression.
TL;DR: Activin/inhibin signaling components are coexpressed in the zona reticularis and the innermost zona fasciculata indicating full signaling potential for adrenal activins and inhibins in these layers.
Abstract: Activins and inhibins are structurally related glycoprotein hormones modulating pituitary FSH secretion and gonadal steroidogenesis. Activins and inhibins are also produced in the adrenal cortex where their physiological role is poorly known. Hormonally active human adrenocortical tumors express and secrete inhibins, while in mice adrenal inhibins may function as tumor suppressors. To clarify the significance of adrenal activins and inhibins we investigated the localization of activin/inhibin signaling components in the adrenal gland, and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis. Activin receptor type II/IIB and IB, activin signal transduction proteins Smad2/3, and inhibin receptor betaglycan were expressed throughout the adrenal cortex, whereas Smad4 expression was seen mainly in the zona reticularis and the innermost zona fasciculata as evaluated by immunohistochemistry. Treatment of cultured adrenocortical carcinoma NCI-H295R cells with activin A inhibited steroidogenic acute regulatory protein and 17alpha-hydroxylase/17,20-lyase mRNA accumulation as evaluated by the Northern blot technique, and decreased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate secretion as determined by specific enzyme immunoassays. Activin A increased apoptosis as measured by a terminal deoxynucleotidyl transferase in situ apoptosis detection method. Inhibins had no effect on steroidogenesis or apoptosis. In summary, activin/inhibin signaling components are coexpressed in the zona reticularis and the innermost zona fasciculata indicating full signaling potential for adrenal activins and inhibins in these layers. Activin inhibits steroidogenic enzyme gene expression and steroid secretion, and increases apoptosis in human adrenocortical cells. Thus, the activin-inhibin system may have a significant role in the regulation of glucocorticoid and androgen production and apoptotic cell death in the human adrenal cortex.
TL;DR: The present coupled RT-PCR, RIA and autoradiographic findings could suggest the involvement of ghrelin in the autocrine-paracrine regulation of human adrenal growth.
Abstract: Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), which was originally isolated from rat stomach. Ghrelin and GHS-R are also expressed in several peripheral tissues, including adrenal glands, and this prompted us to study ghrelin expression and ghrelin-binding site localization in the human adrenal cortex, and the possible effect of this peptide on corticosteroidhormone secretion. Reverse transcription-polymerase chain reaction (RT-PCR) and radioimmune assay (RIA) showed sizeable expression of ghrelin mRNA and protein in six human adrenal cortexes. Autoradiography evidenced abundant [ 1 2 5 I]ghrelin binding sites in the adrenal zona glomerulosa and outer zona fasciculata. However, ghrelin (10 - 6 M) did not significantly affect either basal or agonist (ACTH and angiotensin-II)-stimulated early and late steps of steroidhormone synthesis from adrenocortical slices (as measured by quantitative high pressure liquid chromatography). Since zona glomerulosa is the cambium layer involved in the growth maintenance of adrenal cortex, the present coupled RT-PCR, RIA and autoradiographic findings could suggest the involvement of ghrelin in the autocrine-paracrine regulation of human adrenal growth.
TL;DR: The results provide evidence that synthetic 1-28-POMC induces adrenal tumor cell proliferation, inhibits adrenal steroidogenesis, and mediates its action by signaling via the extracellular signal-regulated kinase pathway.
Abstract: There is evidence that proopiomelanocortin (POMC)-derived peptides other than ACTH are involved in pituitary-dependent adrenal growth. We have synthesized the human N-terminal POMC fragment 1-28-POMC with the disulfide bridges in the correct position between cysteine residues 2-24 and 8-20 and studied the activity of these peptides in adrenocortical tumor cells in vitro. 1-28-POMC stimulated cell proliferation in human NCI-h295 and mouse Y-1 adrenal cancer cell lines and also in primary cultures of bovine adrenocortical cells in a concentration-dependent manner. 1-28-POMC led to rapid activation of the MAPKs extracellular signal-regulated kinases-1 and -2, but not c-Jun N-terminal kinase and p38, pathways. Steroid hormone production (cortisol, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate) in NCI-h295 cells was decreased by 1-28-POMC in a concentration-dependent fashion. However, protein levels of important regulators of steroidogenesis [steroidogenic factor-1, DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X-chromosome 1), steroidogenic acute regulatory protein, and cytochrome P450 side-chain cleavage enzyme] remained unaffected by 1-28-POMC treatment. Our results provide evidence that synthetic 1-28-POMC induces adrenal tumor cell proliferation, inhibits adrenal steroidogenesis, and mediates its action by signaling via the extracellular signal-regulated kinase pathway. The distinct roles of 1-28-POMC and ACTH in the regulation of adrenal growth and steroidogenesis suggest that the adrenal cortex is under the dual opposing control of fragments from the same mother peptide POMC.
TL;DR: Microarray studies on RNA from microdissected zona reticularis and zona fasciculata/zona glomerulosa derived from adult human adrenal glands showed that a gene of the dickkopf family, DKK3, is differentially expressed in the zones, suggesting that it could be involved in zonal differentiation or growth.
Abstract: The mechanisms underlying the differentiation of the adrenal cortex into zones are unclear. Microarray studies on RNA from microdissected zona reticularis (ZR) and zona fasciculata/zona glomerulosa (ZF/ZG) derived from adult human adrenal glands showed that a gene of the dickkopf family (DKK), DKK3, is differentially expressed in the zones. The Dickkopf proteins are morphogens involved in Wnt signalling. Northern blotting showed higher DKK3 transcript levels in ZF/ZG than ZR samples. In situ hybridization on adult human adrenal gland sections showed that DKK3 expression was much higher in the ZG than in the ZF or ZR. DKK3 expression was also higher in the medulla. We screened for expression of other members of the DKK family and the related Wingless-type mouse mammary tumor virus integration site gene family (WNT), frizzled (FZD), and dishevelled (DVL) gene families. Among dickkopf family members, only DKK3 was expressed at a detectable level in both human and mouse adrenocortical RNA samples. Consistent with previously published data on the effects of Wnt4 gene disruption in the mouse, we found only WNT4 expression within the WNT family in both human and mouse RNA. Northern blotting showed that WNT4 was expressed at a higher level in ZF/ZG cells than in ZR. The higher level of DKK3 and WNT4 expression in ZF/ZG cells was confirmed by real-time PCR. In the frizzled and dishevelled families we found FZD1, FZD2 and DVL3 transcripts in human adrenocortical RNA, and FZD2 and DVL3 in mouse adrenocortical RNA. These data show that a variety of genes of the Wnt signalling pathways are expressed in the adrenal cortex. The zonal distribution of DKK3 expression suggests that it could be involved in zonal differentiation or growth.
TL;DR: The term ACTH-independent used to designate primary adrenal Cushing's syndrome may be inappropriate in some cases of bilateral macronodular adrenal hyperplasia with hypercortisolism and undetectable plasma ACTH levels, because it may be dependent upon ACTH produced within adrenocortical tissue.
Abstract: Adrenochromaffin cells have been shown to physiologically synthesize and secrete ACTH. We have thus hypothesized that excessive intraadrenal ACTH production may be involved in the pathogenesis of primary adrenal Cushing's syndrome. In this report we describe a case of Cushing's syndrome due to bilateral adrenocortical macronodular hyperplasia associated with suppression of plasma ACTH levels. HPLC analysis of adrenal tissue extracts revealed the presence of a peptide coeluting with bioactive ACTH. Immunohistochemical studies showed that ACTH immunoreactivity was detectable in a subpopulation of steroidogenic cells, but not in chromaffin cells. ACTH-positive cells were also labeled by antibodies against relaxin-like factor, a marker of Leydig cells. The presence of ACTH in the hyperplastic tissue resulted from local expression of the gene encoding the ACTH precursor proopiomelanocortin. Finally, hyperplasia fragments, contrary to normal adrenal cortex explants, appeared to release in vitro measurable amounts of ACTH. In conclusion, this observation shows that Cushing's syndromes associated with suppressed plasma ACTH levels may be dependent upon ACTH produced within adrenocortical tissue. The term ACTH-independent used to designate primary adrenal Cushing's syndrome may therefore be inappropriate in some cases of bilateral macronodular adrenal hyperplasia with hypercortisolism and undetectable plasma ACTH levels.