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Bruno Allolio

Publications and source records attributed to Bruno Allolio.

At least 19 recordsLinked to original sources
PubMed2006

Pituitary-interrenal interaction in zebrafish interrenal organ development.

To further elucidate pituitary adrenal interactions during development, we studied the organogenesis of the interrenal organ, the teleost homolog of the mammalian adrenal gland, in zebrafish. To this end we compared wild-type zebrafish interrenal development with that of mutants lacking pituitary cell types including corticotrophs. In addition, we studied the effects of ACTH receptor (Mc2r) knockdown and dexamethasone (dex) on interrenal development and pituitary feedback. Until 2 d post fertilization (2 dpf) interrenal development assessed by transcripts of key steroidogenic genes (cyp11a1, mc2r, star) is independent of proopiomelanocortin (Pomc) as demonstrated in aal/eya1and lia/fgf3 mutants. However, at 5 dpf lack of pituitary cells leads to reduced expression of steroidogenic genes at both the transcriptional and the protein level. Pituitary control of interrenal development resides in corticotrophs, because pit1 mutants lacking pituitary cells except corticotrophs have a phenotype similar to that of wild-type controls. Furthermore, development in mc2r knockdown morphants does not differ from aal/eya1 and lia/fgf3 mutants. Inhibition of steroidogenesis by mc2r knockdown induces up-regulation of pomc expression in the anterior domain of pituitary corticotrophs. Accordingly, dex suppresses pomc in the anterior domain only, leading to impaired expression of steroidogenic genes commencing at 3 dpf and interrenal hypoplasia via reduced interrenal proliferation. In contrast, negative feedback on pituitary corticotrophs by dex is evident at 2 dpf and precedes effects of Pomc on the interrenal primordium. These data demonstrate a gradual transition from early pituitary-independent interrenal organogenesis to developmental control by the anterior domain of pituitary corticotrophs acting via Mc2 receptors.

Animals↗
PubMed2006

A dangerous liaison--pheochromocytoma in patients with malignant disease.

BACKGROUND: Adrenal masses in patients with known malignancy may be interpreted as metastasized disease, although a significant proportion of these tumors are of adrenal origin. Despite improved imaging techniques, it remains difficult to distinguish an adrenal metastasis from a pheochromocytoma or a lipid-poor adrenocortical adenoma. PATIENTS AND METHODS: We report a case series of four patients with established or suspected malignant disease (melanoma, transitional cell carcinoma and prostate carcinoma, thyroid carcinoma, colorectal carcinoma) harboring an adrenal mass. None of these patients showed clinical symptoms indicative for a pheochromocytoma. RESULTS: Surgery unrelated to the adrenal lesion (n = 3) or biopsy of the adrenal mass (n = 1) was performed without prior endocrine work-up. Pronounced hemodynamic instability including hypertensive crisis was observed during surgery in all patients. In contrast, in the same patients preoperative alpha-blockade with phenoxybenzamine and an increased awareness of the potential risks led to improved hemodynamic stability following adrenalectomy for pheochromocytoma. CONCLUSION: Our series is a strong reminder of the risks associated with surgery in patients harboring an unsuspected pheochromocytoma and underscores the need to exclude a pheochromocytoma in all patients with an adrenal mass and without a definitive diagnosis of the mass, especially when they are scheduled for surgery or adrenal biopsy. Otherwise, life-threatening hypertensive crisis can be precipitated even in the previously asymptomatic patient.

Adrenal Gland Neoplasms↗
PubMed2006

Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma.

CONTEXT: Local tumor recurrence is common in adrenocortical carcinoma (ACC) and is the most frequent cause for reoperation. Although radiotherapy is often considered ineffective in the treatment of ACC, the limited number of available studies does not support this statement. OBJECTIVE: The objective of the study was investigation of adjuvant tumor bed irradiation in the treatment of ACC. DESIGN: We performed a retrospective analysis. PATIENTS: The German ACC Registry (n = 285) was screened for patients who had received tumor bed radiotherapy in an adjuvant setting (no macroscopic evidence for residual disease after surgery). Fourteen patients without distant metastases (World Health Organization stage I, one patient; stage II, seven; stage III, three; and stage IV, three) were matched with 14 patients for resection status, adjuvant mitotane treatment, stage, and tumor size. Median follow-up of patients still alive (n = 15) was 37 months. MAIN OUTCOME MEASURE: Survival without local recurrence and disease-free survival was the main outcome measure. RESULTS: Local recurrence was observed in two of 14 patients in the radiotherapy group and in 11 of 14 control patients. The probability to be free of local recurrence 5 yr after surgery differed significantly [79% (95% confidence interval, 53-100) vs. 12% (0-30); P < 0.01]. However, disease-free and overall survival were not significantly different between the two groups. Acute adverse events related to radiotherapy were mostly mild. One patient developed a partial Budd-Chiari syndrome. CONCLUSION: These data from the largest series of ACC patients treated with adjuvant tumor bed irradiation suggest that radiotherapy is effective in reducing the high rate of local recurrence in ACC. A randomized trial in high-risk patients is needed to further evaluate the efficacy of radiotherapy as an adjuvant treatment option in ACC.

Adrenal Cortex Neoplasms↗
PubMed2006

High-dose 17beta-estradiol treatment prevents development of heart failure post-myocardial infarction in the rat.

OBJECTIVES: Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or beta-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. METHODS: Female rats were treated with 17beta-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed. RESULTS: In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen. CONCLUSIONS: High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.

Animals↗
PubMed2006

Comprehensive mutation scanning of NF1 in apparently sporadic cases of pheochromocytoma.

BACKGROUND: Pheochromocytoma is a rare manifestation in patients with neurofibromatosis type 1 (NF 1). The 57-exon susceptibility gene NF1 has so far not been systematically scanned for unexpected germline mutations in individuals with sporadic pheochromocytoma. METHODS: Twenty-seven patients with bilateral adrenal and/or extraadrenal abdominal pheochromocytoma not carrying germline mutations of the genes VHL, RET, SDHB, and SDHD were selected from the European-American pheochromocytoma registry. All 57 exons and flanking intronic regions of the NF1 gene were PCR amplified using newly designed primer pairs to exclude the amplification of pseudogenes. Intragenic mutation scanning was performed using denaturing HPLC and bidirectional direct sequencing. RESULTS: Of the 27 apparently sporadic cases, one (4%) was found to have a pathogenic germline NF1 mutation, Leu303Arg. Clinical reevaluation of this individual, who had bilateral pheochromocytoma, revealed classic, but very mild, features of NF 1, one cutaneous neurofibroma, axillary freckling, and Lisch nodules of the iris as well as a few café-au-lait spots. CONCLUSIONS: In the absence of germline mutations in VHL, RET, SDHD, and SDHB, patients with pheochromocytoma, especially with bilateral disease, should be checked thoroughly for clinical lesions suggestive of underlying syndromes such as the cutaneous and ophthalmological features characteristic of NF 1.

Adolescent↗
PubMed2006

Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock.

CONTEXT: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels. OBJECTIVE: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls. MAIN OUTCOME MEASURES: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation. RESULTS: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322). CONCLUSIONS: The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.

Adrenocorticotropic Hormone↗
PubMed2006

Clinical review: Adrenocortical carcinoma: clinical update.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. virilization, Cushing's syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm). This paper reviews current diagnostic and therapeutic strategies in ACC. EVIDENCE ACQUISITION: Original articles and reviews were identified using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) covering the time period up until November 2005. The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery. EVIDENCE SYNTHESIS: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content. Hormonal analysis reveals evidence of steroid hormone secretion by the tumor in the majority of cases, even in seemingly hormonally inactive lesions. Histopathology is crucial for the diagnosis of malignancy and may also provide important prognostic information. In stages I-III open surgery by an expert surgeon aiming at an R0 resection is the treatment of choice. Local recurrence is frequent, particularly after violation of the tumor capsule. Surgery also plays a role in local tumor recurrence and metastatic disease. In patients not amenable to surgery, mitotane (alone or in combination with cytotoxic drugs) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14-20 mg/liter) is mandatory for optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently being compared in an international phase III trial (www.firm-act.org). Adjuvant treatment options after complete tumor removal (e.g. mitotane, radiotherapy) are urgently needed because postoperative disease-free survival at 5 yr is only around 30%, but options have still not been convincingly established. National registries, international cooperations, and trials provide important new structures for patients but also for researchers aiming at systematic and continuous progress in ACC. However, future advances in the management of ACC will mainly depend on a better understanding of the molecular pathogenesis facilitating the use of modern cancer treatments (e.g. tyrosine kinase inhibitors).

Adrenal Cortex Neoplasms↗
PubMed2006

Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements.

OBJECTIVE: Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements. DESIGN: Cross-sectional study in the outpatient department of a university teaching hospital. PATIENTS: Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years). MEASUREMENTS: Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement. RESULTS: Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied. CONCLUSIONS: Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.

Absorptiometry, Photon↗
PubMed2006

Intraoperative haemodynamic stability in patients with phaeochromocytoma--minimally invasive vs conventional open surgery.

OBJECTIVE: There is conflicting evidence, whether or not minimally invasive adrenalectomy (MA) is associated with an increased perioperative cardiovascular instability in phaeochromocytomas compared to conventional open adrenalectomy (CA). DESIGN AND PATIENTS: In a retrospective analysis of 49 patients with phaeochromocytoma we compared 27 cases of MA to 22 cases of CA by assessing intraoperative haemodynamic parameters and perioperative complications. Patients undergoing MA for adrenocortical adenomas (aldosteronomas n = 15, inactive adenomas n = 13) served as controls. Additionally, we investigated the effect of phenoxybenzamine (POB) pretreatment on intraoperative cardiovascular stability in 42 patients (ranked by maximum daily POB-dose) by comparing the highest (n = 10) with the lowest (n = 10) POB dose quartile (0.32 +/- 0.2 and 2.17 +/- 0.6 mg/kg/day, P < 0.001). RESULTS: In phaeochromocytomas we found no significant difference in intraoperative haemodynamic parameters or complications when comparing MA with CA. In comparison to adrenocortical adenomas, MA in phaeochromocytomas was associated with a significantly higher maximum systolic BP (188 +/- 29 vs 154 +/- 22 mmHg, P < 0.001), more frequent hypertensive episodes (1[0-4]vs 0[0-1], P < 0.001), more episodes of systolic BP > 200 mmHg (0[0-4]vs 0[0-1], P = 0.03) and a higher demand for intraoperative fluids (3194 ml vs 1750 ml, P < 0.001). Most haemodynamic parameters did not differ significantly between high-dose POB pretreatment and low-dose POB pretreatment, but high-dose POB pretreatment was associated with a significantly higher intraoperative heart rate (120 +/- 19.5 vs 94 +/- 15.2 min(-1), P < 0.01). CONCLUSION: There is no significant difference in haemodynamic stability between MA and CA in phaeochromocytomas, but it is significantly inferior when compared to MA for cortical adenomas. We could not detect a beneficial effect of high-dose compared to low-dose POB pretreatment on intraoperative cardiovascular stability.

Adenoma↗
PubMed2006

Peripheral administration of the N-terminal pro-opiomelanocortin fragment 1-28 to Pomc-/- mice reduces food intake and weight but does not affect adrenal growth or corticosterone production.

Pro-opiomelanocortin (POMC) is a polypeptide precursor that undergoes extensive processing to yield a range of peptides with biologically diverse functions. POMC-derived ACTH is vital for normal adrenal function and the melanocortin alpha-MSH plays a key role in appetite control and energy homeostasis. However, the roles of peptide fragments derived from the highly conserved N-terminal region of POMC are less well characterized. We have used mice with a null mutation in the Pomc gene (Pomc(-/-)) to determine the in vivo effects of synthetic N-terminal 1-28 POMC, which has been shown previously to possess adrenal mitogenic activity. 1-28 POMC (20 mug) given s.c. for 10 days had no effect on the adrenal cortex of Pomc(-/-) mice, with resultant cortical morphology and plasma corticosterone levels being indistinguishable from sham treatment. Concurrent administration of 1-28 POMC and 1-24 ACTH (30 mug/day) resulted in changes identical to 1-24 ACTH treatment alone, which consisted of upregulation of steroidogenic enzymes, elevation of corticosterone levels, hypertrophy of the zona fasciculate, and regression of the X-zone. However, treatment of corticosterone-depleted Pomc(-/-) mice with 1-28 POMC reduced cumulative food intake and total body weight. These anorexigenic effects were ameliorated when the peptide was administered to Pomc(-/-) mice with circulating corticosterone restored either to a low physiological level by corticosterone-supplemented drinking water (CORT) or to a supraphysiological level by concurrent 1-24 ACTH administration. Further, i.c.v. administration of 1-28 POMC to CORT-treated Pomc(-/-) mice had no effect on food intake or body weight. In wild-type mice, the effects of 1-28 POMC upon food intake and body weight were identical to sham treatment, but 1-28 POMC was able to ameliorate the hyperphagia induced by concurrent 1-24 ACTH treatment. In a mouse model which lacks all endogenous POMC peptides, s.c. treatment with synthetic 1-28 POMC alone can reduce food intake and body weight, but has no impact upon adrenal growth or steroidogenesis.

Adrenal Glands↗
PubMed2005

Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP.

Aldosterone production in zona glomerulosa (ZG) cells of adrenal glands is regulated by various extracellular stimuli (K(+), ANG II, ACTH) that all converge on two major intracellular signaling pathways: an increase in cAMP production and calcium (Ca(2+)) mobilization. However, molecular events downstream of the increase in intracellular cAMP and Ca(2+) content are controversial and far from being completely resolved. Here, we found that Ca(2+)/calmodulin-dependent protein kinases (CaMKs) play a predominant role in the regulation of aldosterone production stimulated by ANG II, ACTH, and cAMP. The specific CaMK inhibitor KN93 strongly reduced ANG II-, ACTH-, and cAMP-stimulated aldosterone production. In in vitro kinase assays and intact cells, we could show that cAMP-induced activation of CaMK, using the adenylate cyclase activator forskolin or the cAMP-analog Sp-5,6-DCI-cBIMPS (cBIMPS), was not mediated by PKA. Activation of the recently identified cAMP target protein Epac (exchange protein directly activated by cAMP) by 8-pCPT-2'-O-Me-cAMP had no effect on CaMK activity and aldosterone production. Furthermore, we provide evidence that cAMP effects in ZG cells do not involve Ca(2+) or MAPK signaling. Our results suggest that ZG cells, in addition to PKA and Epac/Rap proteins, contain other as yet unidentified cAMP mediator(s) involved in regulating CaMK activity and aldosterone secretion.

Adrenocorticotropic Hormone↗
PubMed2005

Androgen receptor-mediated regulation of the alpha-subunit of the epithelial sodium channel in human kidney.

Rodents studies suggest that androgens are involved in sex-specific differences in blood pressure. In humans, there is no difference in blood pressure between boys and girls, but after puberty, blood pressure increases more in men than in women. We investigated androgen-dependent regulation of the alpha-subunit of the epithelial sodium channel (alphaEnaC) in human kidney and in the human renal cell line immortalized human renal proximal tubular cell line (HKC-8). We used microarray technique to analyze androgen-dependent gene regulation and performed quantitative RT-PCR for verification. Promoter constructs for human alphaENaC were used in transfection studies to analyze the regulation by testosterone. We investigated the in vivo effect of testosterone on alphaENaC in a rat model and used the mouse collecting duct cell line M-1 for transepithelial electrophysiological measurements. The androgen receptor (AR) was expressed in male kidney and HKC-8 cells. AlphaENaC mRNA expression increased 2- to 3-fold after treatment with testosterone in HKC-8 cells. The induction by testosterone was completely blocked by adding the AR antagonist flutamide. Analysis of the alphaENaC promoter sequence identified a putative AR response element (ARE) located 140 nucleotides upstream from the transcription start site. HKC-8 cell transfection studies showed that testosterone directly upregulated gene expression via this ARE. In vivo, testosterone treatment of orchiectomized rats resulted in an increased renal alphaENaC mRNA expression. In testosterone-treated mouse M-1 cells, amiloride caused a significant stronger decrease in short circuit current than in control cells. These data show that alphaENaC expression is directly regulated by androgens in vitro and in vivo and highlight a potential mechanism explaining the reported gender differences in blood pressure.

Animals↗
PubMed2005

Sex steroid metabolism in human peripheral blood mononuclear cells changes with aging.

CONTEXT: Dehydroepiandrosterone (DHEA) mainly exerts indirect action via downstream conversion toward sex steroids within peripheral target cells including immune cells. In vitro DHEA has been shown to enhance IL-2 release from T lymphocytes, whereas it inhibits IL-6 secretion. Conversely, aging is associated with a decline in both DHEA and IL-2, whereas IL-6 increases. OBJECTIVE: The objective of the study was to investigate age-related differences in expression and functional activity of steroidogenic enzymes involved in downstream conversion of DHEA in peripheral blood mononuclear cells (PBMCs). DESIGN: This study was cross-sectional. PARTICIPANTS/SETTING: Healthy young men (n = 8; age range, 23-29 yr) and healthy middle-aged men (n = 8; age range, 52-66 yr) were studied in an academic setting. MEASURES: mRNA expression of steroidogenic enzymes in PBMCs was measured by qualitative and quantitative RT-PCR analysis and enzyme activity assays after incubation of PBMCs with radiolabeled DHEA, 4-androstene-3,17-dione (androstenedione), and testosterone. RESULTS: RT-PCR analysis showed expression of all enzymes required for DHEA conversion toward active androgens and to the immune-stimulatory metabolite androstenediol. Steroid conversion patterns indicated a particularly increased activity of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5) in the older men, demonstrated by significantly higher conversion rates of DHEA to androstenediol and of androstenedione to testosterone (all P < 0.05). By contrast, conversion of DHEA to androstenedione via 3beta-HSD occurred at a similar rate. Quantitative RT-PCR analysis revealed increased expression of 17beta-HSD 5 mRNA in PBMCs from the older men. CONCLUSIONS: Our results provide evidence for significant changes in sex steroid metabolism by human PBMCs with aging, which may represent an endocrine link to immune senescence.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

AKT is highly phosphorylated in pheochromocytomas but not in benign adrenocortical tumors.

CONTEXT: Activation of AKT plays a major role in a variety of human neoplasias. In mice, a heterozygous deletion of the Pten gene is associated with increased activation of AKT and with development of pheochromocytomas. OBJECTIVE: The objective of this study was the investigation of the role of AKT in the pathogenesis of pheochromocytomas and adrenocortical tumors. DESIGN, SETTING, AND PARTICIPANTS: Total AKT and phosphorylated AKT (pAKT) in 15 pheochromocytomas, nine aldosterone-producing adenomas, nine cortisol-producing adenomas, eight adrenocortical carcinomas (ACC), and 15 normal adrenals were investigated by Western blot analysis. Immunohistochemistry for total AKT and pAKT was performed in pheochromocytomas (n = 8), ACC (n = 4), and normal adrenal glands (n = 2). In addition, in pheochromocytomas PTEN protein expression and PTEN loss of heterozygosity were analyzed. MAIN OUTCOME MEASURES: Determination of pAKT/total AKT ratio in adrenal tissues was the main outcome. RESULTS: In comparison to normal adrenals, total AKT expression was elevated in both pheochromocytomas (193 +/- 22%) and ACC (176 +/- 36%). The pAKT/AKT ratio was significantly increased in pheochromocytomas (338 +/- 49% vs. 100 +/- 11%) but not in ACC, aldosterone-producing adenomas, and cortisol-producing adenomas. No loss of heterozygosity of PTEN and no decrease in PTEN protein was detected in pheochromocytomas. Immunohistochemistry showed strong and homogeneous AKT and pAKT staining in pheochromocytomas and focal staining in ACC. CONCLUSION: Our findings provide evidence for increased activation of AKT in pheochromocytomas but not in adrenocortical adenomas.

Adrenal Cortex Neoplasms↗
PubMed2005

No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies.

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS inter-convert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependent conversion of DHEA (0.1-2 mum) to DHEAS but no conversion of DHEAS (0.1-2 mum). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.

Adolescent↗
PubMed2005

Management of adrenal insufficiency in different clinical settings.

Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent cause of primary adrenal insufficiency in western countries is autoimmune adrenalitis, whereas secondary adrenal insufficiency is most often caused by pituitary tumours and their treatment (e.g., surgery). Chronic glucocorticoid replacement consists of hydrocortisone 15-25 mg/day in divided doses and dose monitoring is largely based on clinical judgement. Fludrocortisone 0.05-0.2 mg/day is given for substitution in mineralocorticoid deficiency aiming at normotension, normokalaemia and a plasma renin activity in the upper normal range. It has recently been shown that, despite adequate glucocorticoid and mineralocorticoid replacement well being in patients with adrenal insufficiency is still impaired. Several studies have demonstrated that dehydroepiandosterone 25-50 mg/day p.o. may improve mood, fatigue, well-being and, in women, also sexuality, suggesting that dehydroepiandosterone should become part of the standard treatment regime. However, large Phase III trials of dehydroepiandosterone for adrenal insufficiency are still lacking and it has not yet been approved for the treatment of this disease. Patients with adrenal insufficiency are at risk of adrenal crisis, usually precipitated by major stress, such as severe infection or surgery. Early dose adjustments are required to cover the increased glucocorticoid demand in stress. Careful and repeated education of patients and their partners is the best strategy to avoid this life-threatening emergency. Some recent studies suggest that during sepsis some patients with intact adrenal function may develop transient relative adrenal insufficiency and benefit from administration of hydrocortisone plus fludrocortisone. However, the pathophysiology and diagnosis criteria of relative adrenal insufficiency and its treatment remain unsettled issues.

Acute Disease↗
PubMed2005

Evidence against a role of human airway trypsin-like protease--the human analogue of the growth-promoting rat adrenal secretory protease--in adrenal tumourigenesis.

OBJECTIVE: A serine protease from rat adrenal cortex was recently characterized and named adrenal secretory protease (AsP). AsP is expressed in the adrenal cortex and is capable of cleaving pro-gamma-melanocyte-stimulating hormone (1-76 N-terminus of pro-opiomelanocortin) into fragments that act as adrenal mitogens. AsP may therefore play a crucial role in adrenal growth and tumourigenesis. The aim of this study was to further characterize the human homologue of AsP and its possible role in adrenal tumourigenesis. METHODS AND RESULTS: Starting with the rat cDNA sequence of AsP we detected high homology to the catalytic C-terminus of the human airway trypsin-like protease (HAT). Further analysis revealed that the HAT gene is the human homologue of a long splice variant of AsP, which we recently described as rat airway trypsin-like serine protease 1. In contrast to rodents, no short isoform of HAT was found in humans due to a stop codon in exon 6 which prevents the expression of a short isoform. While high expression of HAT mRNA was found in the trachea and in the gastrointestinal tract, expression in the adrenal was only very weak. RT-PCR and real-time PCR analysis revealed a complex tissue expression pattern of HAT, indicating a role for this protease in multiple tissues. We further investigated HAT expression in five normal adrenal glands, 15 adrenocortical adenomas (five hormonally inactive adenomas, five aldosterone-producing adenomas and five cortisol-producing adenomas), nine adrenocortical carcinomas, five phaeochromocytomas and two adrenal hyperplasias. Weak HAT expression was detectable in only two out of five normal adrenal glands, in one out of twenty-four adrenocortical tumours and four out of five phaeochromocytomas. However, the expression in the adrenal tissue was several orders of magnitude lower than in the trachea. In addition, we could not detect any HAT transcripts in a sample of fetal adrenal. CONCLUSION: Gene structure and tissue distribution of HAT, the human homologue of the rat adrenal secretory protease AsP, reveal major interspecies differences. The observation of very low expression levels in normal adrenal tissue and adrenocortical tumours casts doubt about a role for HAT in the physiological and pathological growth of adrenocortical cells.

Adenoma↗