Adrenal Growth Research Articles

Study of Morphological changes of Adrenals in Suicidal cases, An Autopsybased Study at a Tertiary Care Centre at Odisha

Introduction –Uncertainty and instability are the norm of today’s work envioronment. .Now-a-days suicidal cases account for more than a million deaths each year. This work has been undertaken to study the Morphological adaptive changes in adrenal gland in such stressful conditions .Aim & Objectives :To correlate the Morphological adaptive changes in adrenal gland in response to chronic stress since it is a stress responding organ common to both the HPA axis &Sympathoadrenomedullary axis . Material &Methods : The study was carried out from 5th April 2021 to 5th April 2023 at SCB Medical college,Cuttack,Odisha..Right and Left adrenals of hundred suicidal cases and twentyaccidental cases (control) were studied .Results : On Morphological Analysis it was found that Adrenal gland increases both in weight & dimensions in suicidal cases as compared to Accidental cases . A normal pattern of Adrenal gland is informative of receipt of sudden violence i.e accident. Conclusion :The present study concludes and supports the idea that chronic stress as in suicide usually induces adrenal growth which may have implications for forensic people in revealing the cause of unknown deaths.

Postnatal Exposure to the Endocrine Disruptor Dichlorodiphenyltrichloroethane Affects Adrenomedullary Chromaffin Cell Physiology and Alters the Balance of Mechanisms Underlying Cell Renewal.

Dichlorodiphenyltrichloroethane (DDT) is a wide-spread systemic pollutant with endocrine disrupting properties. Prenatal exposure to low doses of DDT has been shown to affect adrenal medulla growth and function. The role of postnatal exposure to DDT in developmental disorders remains unclear. The aim of the present investigation is to assess growth parameters and the expression of factors mediating the function and renewal of chromaffin cells in the adult adrenal medulla of male Wistar rats exposed to the endocrine disruptor o,p'-DDT since birth until sexual maturation. The DDT-exposed rats exhibited normal growth of the adrenal medulla but significantly decreased tyrosine hydroxylase production by chromaffin cells during postnatal period. Unlike the control, the exposed rats showed enhanced proliferation and reduced expression of nuclear β-catenin, transcription factor Oct4, and ligand of Sonic hedgehog after termination of the adrenal growth period. No expression of pluripotency marker Sox2 and absence of Ascl 1-positive progenitors were found in the adrenal medulla during postnatal ontogeny of the exposed and the control rats. The present findings indicate that an increase in proliferative activity and inhibition of the formation of reserve for chromaffin cell renewal, two main mechanisms for cell maintenance in adrenal medulla, in the adult DDT-exposed rats may reflect a compensatory reaction aimed at the restoration of catecholamine production levels. The increased proliferation of chromaffin cells in adults suggests excessive growth of the adrenal medulla. Thus, postnatal exposure to DDT alters cell physiology and increases the risk of functional insufficiency and hyperplasia of the adrenal medulla.

FRI254 Unconventional Pre-operative Management Of Congenital Adrenal Hyperplasia

Abstract Disclosure: M.A. Ortiz-Rivera: None. L.N. Madera Marin: None. A. Rosado-Burgos: None. L. El Musa Penna: None. W. Medina-Torres: None. L.R. Sepulveda-Garcia: None. L.A. Gonzalez-Rodriguez: None. M. Ramirez-Vick: None. M. Alvarado-Santiago: None. A.J. Grana Santini: None. M. Feliciano-Emmanuelli: None. Management of classic salt-wasting congenital adrenal hyperplasia [CAH] warrants suppression of the hypothalamic-pituitary-adrenal axis through glucocorticoid and mineralocorticoid supplementation. Preferred glucocorticoid replacement is generally hydrocortisone [HC] 3 times daily but caring for these patients often involves unconventional choices of glucocorticoid preparation regimens tailored to meet patient needs. A 41-year-old female with history of long-standing poorly controlled classic salt-wasting CAH associated to secondary amenorrhea and hypothyroidism, presenting with bilateral myelolipomas was consulted to our service for pre-op optimization. She underwent evaluation by Urology due to worsening right-sided back pain for which an abdominal-pelvic CT was performed showing large bilateral adrenal gland lesions (left mass measuring 11.5 x 10.3 x 10.6 cm and right mass measuring 8.1 x 10.4 x 7.7 cm) consistent with adrenal myelolipomas. Endocrine surgeon favored adrenalectomy due to mass effect brought about by massive adrenal growth secondary to inadequate therapeutic regime. Patient had been lost to follow-up after transitioning from pediatric to adult Endocrinology and was managed by her primary care physician who kept her on an unmodified therapeutic regime. During a pharmacy shortage of HC, she was switched from HC 25 mg TID to 5 mg daily. Furthermore, use of fludrocortisone 0.1 mg daily had been inadvertently halted in the past year. There had been progressive skin hyperpigmentation since the age of 20, significant hirsutism and salt cravings which made her add soy sauce to meals. At the age of 12 a vaginoplasty was performed, with menstrual periods ceasing at age 15. Physical examination was remarkable for grave voice, broad shoulders, bronze skin and coarse terminal hairs on chin, upper lip, sides of face and upper back. Hormonal workup revealed a direct renin > 300 pg/mL (nl 3.6 – 81.6), ACTH 463 pg/mL (nl 0.00 – 46.00), androstenedione > 10 ng/mL (nl 0.6 – 3.10), total testosterone [TT] 419 ng/dL (nl 13 – 53) and 17-hydroxyprogesterone [17-OHprog] > 20 ng/mL (nl 0.20 – 2.6). Frequent increases in medication dosing, up to HC 20mg TID and fludrocortisone 0.1mcg BID, did not attain adequate hormonal control. Dexamethasone 0.25 mg was then added at bedtime and the patient was finally able to achieve restoration of menses, resolution of salt cravings and hormonal profile control with decreases in renin to 23.02 pg/mL, androstenedione to < 0.30 ng/mL, TT to 11 ng/dL and 17-OHprog to 3.15 ng/mL. Alternative treatment strategies are sometimes warranted to achieve control of CAH. In this patient with prominent androgen excess and amenorrhea who failed to meet goals on high doses of hydrocortisone and fludrocortisone, combination therapy with a small dose of long-acting glucocorticoid at bedtime achieved the desired goal. Presentation: Friday, June 16, 2023

Impact of Classic Adrenal Secretagogues on mRNA Levels of Urotensin II and Its Receptor in Adrenal Gland of Rats.

Urotensin 2 (Uts2) is a biologically active peptide involved in the regulation of a variety of physiological and pathophysiological processes. In both the human and rat adrenal gland, the expressions of the Uts2 gene and its receptor (Uts2r) have been described. This paper focuses on the description of the hormonal control of the mRNA levels of urotensin II and its receptor in the adrenal gland of the rat, both in vitro and in vivo. The initial in vitro experiments were carried out on freshly isolated rat adrenocortical cells and their primary culture. The obtained results indicated a stimulating PKA-independent effect of ACTH on the Uts2 mRNA level in the tested cells, with no changes in the Uts2r transcript. Subsequent in vivo experiments showed that ACTH-induced adrenal growth was accompanied by an elevated level of the Uts2 mRNA, with unchanged expression of Uts2r. In the other types of in vivo gland growth studied, enucleation-induced adrenal regeneration and compensatory growth of the gland, the mRNA levels of the studied genes showed no significant differences. The only exception was hemiadrenalectomy, which led to a significant increase in Uts2 mRNA expression level 24 h after surgery. In 12-week-old rats of both sexes, gonadectomy led to a significant increase in the level of Uts2 mRNA in the adrenal gland, an effect that was prevented by sex hormones' replacement. No changes in Uts2r transcript levels were observed under these conditions. Thus, this study suggests that the regulation of Uts2 and Uts2r mRNA levels differs significantly in the rat adrenal gland. While Uts2 transcript levels appear to be mainly dependent on ACTH action, Uts2r mRNA levels are not under the control of this hormone.

Management of primary bilateral macronodular adrenal hyperplasia causing primary hyperaldosteronism and Cushing's syndrome: Case report and review of the literature

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a very heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression. Both in terms of cortisol excess and adrenal hyperplasia with mild forms of asymptomatic and oligosymptomatic cases with less impressive imaging phenotypes. Activation of the cAMP/PKA pathway, either due to alteration of various downstream signaling pathways or by aberrantly expressed G protein-coupled receptors, is linked to both cortisol secretion and adrenal growth. Germline mutations in ARMC5 are a frequent genetic defect. We report the case of a 35 -year-old female patient with primary hyperaldosteronism associated with Cushing's syndrome in the setting of macronodular adrenal hyperplasia treated by left adrenalectomy in the first instance and whose evolution was marked by a clinical and biological improvement of hypercorticism and hyperaldosteronism questioning the indication of controlteral adrenalectomy. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifelong steroid dependence. And is best reserved for patients with severe Cushing’s syndrome. Unilateral adrenalectomy may be considered in selected patients. In cases where regulation of cortisol secretion is mediated by aberrant receptors, there is some potential for medical therapy

Sonic Hedgehog signaling pathway is expressed in normal human adrenal cortices and up-regulated in adrenocortical carcinomas

The Sonic Hedgehog (Shh) signaling pathway is involved in mouse adrenal growth and differentiation. However, it remains unclear whether this pathway plays a similar role in human especially because we previously showed that this organ displays a significant capacity for tissue regeneration from differentiated cells. The expression of the components of the pathway was examined in 38 normal adult adrenal glands and 23 adrenocortical carcinomas (ACCs). We found that Shh is widely expressed in steroidogenic cells. Shh-positive cells also expressed the Shh receptor Patched-1 as well as the receptor-like signal transducer Smoothened. Moreover, expression of the transcription factors Gli1, Gli2 and Gli3 was detected in the nucleus of the steroidogenic cells. Our data identified Shh pathway as a new autocrine/paracrine loop in human steroidogenic cells. However, we cannot exclude that a subpopulation of cells may correspond to stem/progenitor cells since non-steroidogenic cells located in the capsule express components of the Shh pathway. ACCs exhibited an increased expression of all components of Shh pathway with the exception of Gli2 indicating a possible involvement in the tumorigenic process. In addition, the Smoothened inhibitor NVP-LDE225 potently inhibited tumor growth and reduced cortisol and aldosterone secretion by H295R cells. We also showed that LDE225 acts by targeting mitochondria leading to a decrease in transmembrane potential and an increase in ROS production. Collectively, our findings show that Shh pathway is expressed in normal human steroidogenic cells and is activated in carcinomas. Shh may be a promising target for the treatment of this aggressive cancer.

Corticosteroid-binding Globulin (SERPINA6) Establishes Postpubertal Sex Differences in Rat Adrenal Development.

Encoded by SerpinA6, plasma corticosteroid-binding globulin (CBG) transports glucocorticoids and regulates their access to cells. We determined how CBG influences plasma corticosterone and adrenal development in rats during the pubertal to adult transition using CRISPR/cas9 to disrupt SerpinA6 gene expression. In the absence of CBG, total plasma corticosterone levels were ∼80% lower in adult rats of both sexes, with a greater absolute reduction in females than in males. Notably, free corticosterone and adrenocorticotropic hormone were comparable between all groups. Between 30 and 90 days of age, wild-type female rats showed increases in adrenal weight and the size of the corticosterone-producing region, the zona fasciculata (zf), in tandem with increases in plasma CBG and corticosterone concentrations, whereas no such changes were observed in males. This sex difference was lost in rats without CBG, such that adrenal growth and zf expansion were similar between sexes. The sex-specific effects of CBG on adrenal morphology were accompanied by remarkable changes in gene expression: ∼40% of the adrenal transcriptome was altered in females lacking CBG, whereas almost no effect was seen in males. Over half of the adrenal genes that normally exhibit sexually dimorphic expression after puberty were similarly expressed in males and females without CBG, including those responsible for cholesterol biosynthesis and mobilization, steroidogenesis, and growth. Rat adrenal SerpinA6 transcript levels were very low or undetectable. Thus, sex differences in adrenal growth, morphology and gene expression profiles that emerge during puberty in rats are dependent on concomitant increases in plasma CBG produced by the liver.

Effects of Galp and alarin peptides on HPA axis gene expression and adrenal function: In vivo experiments.

Many experimental data indicate interactions between peptides involved in the control of food intake, energy homeostasis and adrenocortical hormone release. Glucocorticoids stimulate or inhibit the secretion of orexigenic and anorexigenic peptides, which in turn are involved in the regulation of adrenal growth, structure and function. Galanin-like peptide (Galp) and alarin (Ala) are involved in the regulation of food intake. Galp and Ala mRNAs have already been shown to be present in the arcuate nucleus (ARC) of the hypothalamus in both rats and mice. To investigate the expression of Ala, Galp and their receptors in the hypothalamus and pituitary and adrenal glands of the rat hypothalamic-pituitary-adrenal (HPA) axis after intraperitoneal administration of peptides in vivo. Experimental in vivo models were used: acute and long-term exposure to peptides. The expression of Galp, Ala, their receptors, and steroidogenesis enzymes was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Statistically significant expression changes were found in the hypothalamus and pituitary after 1-hour exposure to the peptides, such as a decrease in corticotropin-releasing hormone (CRH) expression after Ala, Galp and adrenocorticotropic hormone (ACTH) administration, and a decrease in the expression of receptors for galanin (Gal) (Galr1 and Galr2). In the pituitary, there was a statistically significant increase in the expression of Ala, Galr1, Galr2, and Galr3 receptors 1 h after Galp administration. In the adrenal glands, only a statistically significant decrease in Galr2 expression was observed after 1 h of Ala 0.5 administration. The mRNA expression of steroidogenesis enzymes also changed: for example, the expression of cholesterol desmolase increased 24 h after Ala peptide administration. The results indicate that the peptides tested under in vivo conditions can alter the expression of the peptides tested, as well as of Galp, Ala and Gal receptors and steroidogenesis enzymes - Cyp11a1 (cholesterol desmolase), Cyp11b1 (11β-hydroxylase) and Cyp11b2 (aldosterone synthase).

Embryonic osteocalcin signaling determines lifelong adrenal steroidogenesis and homeostasis in the mouse

Through their ability to regulate gene expression in most organs, glucocorticoid (GC) hormones influence numerous physiological processes and are therefore key regulators of organismal homeostasis. In bone, GC hormones inhibit expression of the hormone Osteocalcin for poorly understood reasons. Here, we show that in a classical endocrine feedback loop, osteocalcin in return enhanced the biosynthesis of GC as well as mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivation of osteocalcin signaling in adrenal glands significantly impaired adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin was necessary for normal Sf1 expression in fetal adrenal cells and adrenal cell steroidogenic differentiation and therefore determined the number of steroidogenic cells present in the adrenal glands of adult animals. Embryonic, not postnatal, osteocalcin also governed adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium, and the rise in circulating corticosterone levels during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurred even in the absence of a functional hypothalamus/pituitary/adrenal axis and explains why osteocalcin administration during pregnancy promoted adrenal growth and steroidogenesis and improved the survival of adrenocorticotropic hormone signaling–deficient animals. This study reveals that a bone-derived embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency.

IntroductionAdrenocorticotropic hormone (ACTH) is produced from proopiomelanocortin, which is predominantly synthetized in the corticotroph and melanotroph cells of the anterior and intermediate lobes of the pituitary gland and the arcuate nucleus of the hypothalamus. Although ACTH clearly has an effect on adrenal homeostasis and maintenance of steroid hormone production, it also has extra-adrenal effects that require further elucidation.MethodsWe comprehensively reviewed English language articles, regardless of whether they reported the presence or absence of adrenal and extra-adrenal ACTH effects.ResultsIn the present review, we provide an overview on the current knowledge on adrenal and extra-adrenal effects of ACTH. In the section on adrenal ACTH effects, we focused on corticosteroid rhythmicity and effects on steroidogenesis, mineralocorticoids and adrenal growth. In the section on extra-adrenal effects, we have analyzed the effects of ACTH on the osteoarticular and reproductive systems, adipocytes, immune system, brain and skin. Finally, we focused on adrenal insufficiency.ConclusionsThe role of ACTH in maintaining the function of the hypothalamic–pituitary–adrenal axis is well known. Conversely, if we broaden our vision and analyze its role as a potential treatment strategy in other conditions, it will be evident in the literature that researchers seem to have abandoned this aspect in studies conducted several years ago. We believe it is worth re-evaluating the role of ACTH considering its noncanonical effects on the adrenal gland itself and on extra-adrenal organs and tissues; however, this would not have been possible without the recent advances in the pertinent technologies.

Changes in Transcriptional Regulation of Postnatal Morphogenesis of the Adrenal Zona Fasciculata Caused by Endocrine Disruptor Dichlorodiphenyltrichloroethane.

We studied the expression of transcriptional factors regulating postnatal morphogenesis of the adrenal zona fasciculata in rats after developmental exposure to endocrine disruptor DDT. It was found that tissue reparation after trophic disorders and cell death triggered by prenatal and postnatal exposure to DDT was accompanied by an increase in the number of Oct4- and Shh-expressing cells forming a pool located outside the regeneration zones and involved in the maintenance of tissue homeostasis in the zona fasciculata. DDT exposure also disrupted the expression of antiproliferative factor Hhex. The data showed that proliferation of fasciculata cells after termination of adrenal cortex growth was downregulated by inhibition of the expression of Oct4 and Shh and suppression of canonical Wnt signaling, i.e. due to a decrease in the reserve cell pool essential for physiological regeneration, which can reduce the reactive potential of the zona fasciculata.

Effect of long term inhaled corticosteroid therapy on adrenal suppression, growth and bone health in children with asthma

BackgroundInhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. However adverse effects of ICS on Hypothalamo Pituitary Adrenal (HPA) axis, growth and bone metabolism are a concern. Hence the primary objective of this study was to describe the effects of long term inhaled corticosteroid therapy (ICS) on adrenal function, growth and bone health in children with asthma in comparison to an age and sex matched group of children with asthma who were not on long term ICS. Describing the association between the dose of ICS and duration of therapy on the above parameters were secondary objectives.MethodSeventy children with asthma on ICS and 70 controls were studied. Diagnosis of asthma in selected patients was reviewed according to the criteria laid down by GINA 2018 guidelines. The estimated adult heights were interpreted relative to their Mid Parental Height (MPH) range. Serum calcium, alkaline phosphatase and vitamin D levels were analyzed in both groups and cortisol value at 30 min following a low dose short synacthen test was obtained from the study group. The average daily dose of ICS (Beclamethasone) was categorized as low, medium and high (100–200, 200–400, > 400 μg /day) respectively according to published literature.ResultsHeights of all children were within the MPH range. There was no statistically significant difference in the bone profiles and vitamin D levels between the two groups (Ca: p = 0.554, vitamin D: p = 0.187) but vitamin D levels were insufficient (< 50 nmol/l) in 34% of cases and 41% of controls. Suppressed cortisol levels were seen in 24%. Doses of ICS were low, medium and high in 56, 32 and 12% of children respectively. The association between adrenal suppression with longer duration of therapy (p < 0.01) and with increasing dose of ICS (p < 0.001) were statistically significant.ConclusionICS had no impact on the growth and bone profiles but its dose and duration were significantly associated with adrenal suppression.

Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing’s syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

OP08.10: Longitudinal adrenal gland measurements and growth trajectories as risk markers for late preterm delivery

OP08.10: Longitudinal adrenal gland measurements and growth trajectories as risk markers for late preterm delivery

Incidental Adrenocortical Carcinoma in Dogs: Clinical, Tomographic and Histopathological

Background: Adrenal incidentalomas are masses accidentally discovered during imaging examinations performed when there is no suspicion of adrenal disease. Even with a low prevalence, it is important to perform a reliable evaluation observing biological behavior and determining whether the hormonal activity is stimulated. Frequently, these masses are not functional, but in some cases, there is increased cortisol activity, and patients with adrenal incidentalomas may present hyperadrenocorticism. This report aims to describe the clinical, tomographic, and histopathological aspects of a case of adrenal incidentaloma detected in a routine abdominal ultrasound.Case: An 8-year-old, male, maltese dog with occasional emesis, halitosis, claudication of the left pelvic limb, and previous compensated and untreated cardiomyopathy was treated at the Veterinary Hospital of the Federal University of Mato Grosso (HOVET-UFMT). Physical examination revealed arterial hypertension and claudication, with the positive posterior drawer test suggesting rupture of the cruciate ligament. The blood count showed no alteration, and the serum biochemistry revealed a slight increase in the activity of alanine aminotransferase. In order to investigate this increase, an abdominal ultrasound was performed. Slight hepatomegaly and a heterogeneous mass of irregular edges were observed with a moderate and difficult-to-delimit vascularization of the adrenal gland. Left knee radiography raised the suspicion of rupture of the cranial cruciate ligament due to the cranial displacement of the tibia in relation to the femur. Computed tomography was performed to define the extent and delimitation of the mass, which was compatible with a tumor of the right adrenal gland characterized by the visualization of an abdominal mass between the kidneys, extending from the hepatic region to the cranial pole of the left kidney. On follow-up, the patient was reported to have diarrhea with black stools, and a low-dose dexamethasone suppression test was ordered. Unilateral adrenalectomy was recommended due to the suspicion of pheochromocytoma. During the surgical procedure, the mass adhered to the abdominal wall and the diaphragm resulting in the death of the animal. Histopathological analysis revealed a cellular proliferation of cortical adrenal cells forming multiple cell nests separated by a small amount of fibrovascular stroma. Proliferated cells were polyhedral, with densely eosinophilic cytoplasm and well-defined edges, and were occasionally vesicular. They had globular nuclei, slightly stained chromatin, and inconspicuous nucleoli. Pleomorphism, anisocytosis, and anisokaryosis were accentuated, and eight mitosis figures were observed in ten high-power fields (40×), leading to a diagnosis of adrenocortical carcinoma.Discussion: When there is no suspicion or characteristic clinical sign, and adrenal growth is observed on imaging examination, the finding may be called an incidentaloma. Here, the incidentaloma was a non-functional adrenal carcinoma, because the tests were not conclusive. Adrenal carcinomas grow by infiltrating adjacent tissues, such as the caudal vena cava. In this case, it infiltrated the abdominal wall and diaphragm. Therefore, imaging, ultrasound, and tomography examinations were important for the characterization of the adrenal incidentaloma in this dog. This adrenal incidentaloma, which was a carcinoma with metastasis to the adjacent tissues, required other hormonal tests to rule out further endocrine dysfunctions.

Expression profile of Galp, alarin and their receptors in rat adrenal gland.

Galanin-like peptide (Galp) and alarin (Ala) are 2 new members of the galanin peptide family. Galanin (Gal), the "parental" peptide of the entire family, is known to regulate numerous physiological processes, including energy and osmotic homeostasis, reproduction, food intake, and secretion of adrenocortical hormones. Galp and Ala are known to regulate food intake. In the rat, Galp mRNA has been found in the brain, exclusively in the hypothalamic arcuate nucleus (ARC) and median eminence, which are involved in the regulation of energy homeostasis. Alarin-like immunoreactivity is present in the locus coeruleus (LC) and the ARC of rats and mice. The aim of the study was to investigate the expression of Ala, Galp and their receptors in the organs of the hypothalamo-pituitary-adrenal (HPA) axis of the rat. The expression of the examined genes was measured in different models of adrenal growth of the rat in vivo (postnatal ontogenesis, compensatory adrenal growth, adrenocortical regeneration, adrenocorticotropic hormone (ACTH) administration). The expression was evaluated using the Affymetrix® microarray system or quantitative polymerase chain reaction (qPCR). The expression of Ala gene was observed in each organ of the HPA axis (the hypothalamus, hypophysis and adrenal gland). The elevated level of expression of this gene was observed in the pituitary of 2-day rats, while very low levels of Ala mRNA were observed in the adrenals. Galp mRNA expression was observed only in the hypothalamus and the hypophysis during postnatal ontogenesis. The expression of Gal receptors was demonstrated in the hypothalamus, the hypophysis and the adrenal gland. In different compartments of the adrenal glands of adult, intact male and female rats, the expression of Ala, Galp and galanin receptor 1 (Galr1) genes was negligible, but the expression of galanin receptor 2 (Galr2), galanin receptor 3 (Galr3) and neurotrophic receptor tyrosine kinase 2 (Ntrk2) genes was noticeable. The examined genes showed different expression levels within the studied HPA axis; some of them were neither expressed in the hypothalamus or the pituitary gland, nor in the adrenal gland.

Spontaneous regression of adrenal metastasis from renal cell carcinoma after sunitinib withdrawal: case report and literature review

BackgroundThe spontaneous regression of metastatic renal cell carcinoma is a rare phenomenon, with an estimated incidence of < 1%. We report a case of post-nephrectomy renal cell carcinoma adrenal metastasis, followed by the spontaneous regression of the metastasis after withdrawal of sunitinib.Case presentationThe patient was a 55-year-old male with clear cell type renal cell carcinoma who previously underwent a left laparoscopic radical nephrectomy. After 51 months of follow up, a recurrence in the left renal fossa was observed and subsequently excised. Four months after excision, an abdominal Computerized tomography (CT) identified an adrenal metastasis of 1.6 cm. The patient was treated with sunitinib. However, the treatment was discontinued because of gastrointestinal side effects and fatigue. Eleven months after the discontinuation of sunitinib treatment, a progression in the adrenal metastasis growth (5.7 cm) was observed, whereas 16 months after the discontinuation, a regression of the adrenal metastasis growth (3.4 cm) was observed. During subsequent follow-ups, a gradual reduction in the size of the adrenal metastasis (1.8 cm) was observed. After 44 months from the discontinuation of sunitinib treatment, the patient was still alive and followed up in the outpatient department.ConclusionsSunitinib is a multi-targeted inhibitor of vascular endothelial growth factor (VEGF) receptors. This compound reduces tumor angiogenesis and has been approved worldwide for the treatment of advanced renal cell carcinoma. To our knowledge, this is the fourth case of the spontaneous regression of metastatic renal cell carcinoma after the discontinuation of sunitinib treatment.

Abstract 3746: Targeting adrenal androgen to treat prostate cancer

Abstract Background: Adrenal androgens are the most abundant androgens in humans, with dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) being the major adrenal androgens in circulation. Significantly, adrenal androgens may serve as substrates for intratumoral (intracrine) production of testosterone (T) and/or dihydrotestosterone (DHT), the ligands for androgen receptor (AR). However, adrenal androgens also have functions that are independent of AR. The present study addressed the capability of prostate cancer tissue to use adrenal androgens for T/DHT production, delineated signaling pathways activated by adrenal androgens, and determined whether adrenal androgens sustained tumor growth after androgen-deprivation therapy (ADT). Experimental Procedures: Metabolism of adrenal androgen was evaluated ex vivo using fresh clinical prostate tissue specimens. The production of DHT or DHEA was determined using ELISA. Human prostate cancer cells lines were used for in vitro experiments. The effects of adrenal androgens on tumor growth were evaluated in vivo using xenografts of the human prostate cancer cell line VCaP in castrated or intact mice. Results: 1) Human prostate tissue was able to produce DHT using DHEA-S at a physiologic concentration (3.5 μM). The production of DHT from DHEA-S was absolutely dependent on the activity of steroid sulfatase (STS). DHEA at a physiologic concentration (10 nM) was not a suitable substrate for DHT production, but was used by prostate tissue when available at a supra-physiologic concentration (3.5 μM) to produce DHT. 2) DHEA-S was able to stimulate growth of prostate cancer cells in vitro. The growth stimulatory effect of DHEA-S was mediated by AR-dependent and AR-independent signaling pathways. A subset of the genes modulated specifically by DHEA-S were distinctive from the T-modulated genes. 3) DHEA sustained tumor growth after castration. DHEA-stimulated growth was attributed to activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. Conclusions: Prostate tissue can use adrenal androgens for DHT production. Adrenal androgens may stimulate prostate cancer growth using AR-dependent pathways that are mediated via intratumoral T/DHT production, or using AR-independent signaling pathways such as the IGF1R signaling pathway. Identification of targets and therapeutics to block the adrenal androgen-stimulated pathways may help develop novel strategies to treat prostate cancer. Citation Format: Yue Wu, Jianmin Wang, Li Tang, Elena Pop, John J. Stocking, Kristopher M. Attwood, Gary J. Smith. Targeting adrenal androgen to treat prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3746.

The role of epithelial growth factors and insulin growth factors in the adrenal neoplasms.

Human fetal and adult adrenal gland express both insulin growth factor-1 (IGF-1) and IGF-2, their receptors (IGF-Rs) and a variety of specific IGF binding proteins suggesting their potential role in the regulation of adrenal growth and function. IGF-2 overexpression is essential for the growth of monoclonal lesions, such as large benign adenomas (ACA) and adrenocortical carcinomas (ACC) and has been found to contribute to tumorigenesis in Beckwith-Wiedemann syndrome. IGF-2 is the most highly expressed gene observed in more than 85% of ACCs. However, no significant differences in clinical, biological and transcriptomic traits were found between tumors with high and low expression of IGF-2. On the contrary, the expression of IGF-1R, mediating the IGF-2 effects in vivo, was more discriminant between malignant (overexpression) and benign tumors. Data on the role of epithelial growth factor (EGF) and its receptor (EGF-R) in adrenocortical tumorigenesis are controversial. Several studies have shown EGF-R overexpression in ACCs but not in benign ACAs, suggesting that EGF-R could potentially be used as a marker for the differential diagnosis of ACAs and ACCs. Although, in vitro and animal studies provide promising results in the therapeutic role of IGF and EGF pathway inhibitors, the available data in humans are still not encouraging. Herein, we aim to present recent data on the role of IGF and EGF pathways in adrenal development and tumorigenesis and their potential implication in the treatment of the ACC, a rare malignancy with very poor prognosis.

Transcriptome Profile in Unilateral Adrenalectomy-Induced Compensatory Adrenal Growth in the Rat.

Compensatory adrenal growth evoked by unilateral adrenalectomy (hemiadrenalectomy) constitutes one of the most frequently studied in vivo models of adrenocortical enlargement. This type of growth has been quite well characterized for its morphological, biochemical, and morphometric parameters. However, the molecular basis of compensatory adrenal growth is poorly understood. Therefore, the aim of this study was to investigate the rat adrenal transcriptome profile during the time of two previously described adrenocortical proliferation waves at 24 and 72 h after unilateral adrenalectomy. Surgical removal of the left adrenal or a sham operation was accomplished via the classic dorsal approach. As expected, the weight of the remaining right adrenal glands collected at 24 and 72 h after hemiadrenalectomy increased significantly. The transcriptome profile was identified by means of Affymetrix® Rat Gene 2.1 ST Array. The general profiles of differentially expressed genes were visualized as volcano plots and heatmaps. Detailed analyzes consisted of identifying significantly enriched gene ontological groups relevant to adrenal physiology, by means of DAVID and GOplot bioinformatics tools. The results of our studies showed that compensatory adrenal growth induced by unilateral adrenalectomy exerts a limited influence on the global transcriptome profile of the rat adrenal gland; nevertheless, it leads to significant changes in the expression of key genes regulating the circadian rhythm. Our results confirm also that regulation of compensatory adrenal growth is under complex and multifactorial control with a pivotal role of neural regulatory mechanisms and a supportive role of other components.