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Determination of functional states during sepsis-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis using measurement of ACTH, cortisol, dehydroepiandrosterone-sulfate (DHEAS) and dehydroepiandrosterone (DHEA)
C Marx, M Wendt, S Petros, L Engelmann, M Weise, G H?ffken
Critical Care , 2003, DOI: 10.1186/cc1893
Abstract: Recently, we examined levels of cortisol, DHEAS, DHEA as well as ACTH in 30 patients with severe sepsis (15 survivors, 15 nonsurvivors) and correlated the time course during early and late sepsis to the clinical course and inflammatory markers [1]. Here, we demonstrate and describe different states of HPA activation in characteristic surviving (n = 3) and nonsurviving (n = 3) septic patients of this study by use of hormone and inflammatory profiles.Four functional states of HPA response with prognostic relevance could be differentiated. I) Activation: infection, systemic inflammation and activation of the HPA axis; high cytokine levels lead to release of ACTH and cortisol. II) Immunogenic stimulation: high cytokine levels maintain cortisol release whereas ACTH is suppressed by high glucocorticoid levels. III) Suppression of inflammation or exhaustion and hyperinflammation, respectively: suppression of inflammation by glucocorticoids or development of relative adrenal insufficiency by adrenal exhaustion resulting in relative hyperinflammation. IV) Recovery or insufficiency, respectively: normalisation of cytokine levels and regeneration of the adrenal driven by normalisation of ACTH. Reconstitution of physiologic ACTH-driven regulation or relative adrenal insufficiency with poor prognosis, respectively.The HPA axis reflects the individual prognostic risk of the patient. The clinical course rarely enables the detection of all time-dependent states of HPA response. For individual diagnostic benefit of hormone measurements in septic patients, rapid availability of hormone levels is necessary.
Dehydroepiandrosterone Sulfate (DHEAS) Stimulates the First Step in the Biosynthesis of Steroid Hormones  [PDF]
Jens Neunzig, Rita Bernhardt
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089727
Abstract: Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in human, with the highest concentrations between age 20 and 30, but displaying a significant decrease with age. Many beneficial functions are ascribed to DHEAS. Nevertheless, long-term studies are very scarce concerning the intake of DHEAS over several years, and molecular investigations on DHEAS action are missing so far. In this study, the role of DHEAS on the first and rate-limiting step of steroid hormone biosynthesis was analyzed in a reconstituted in vitro system, consisting of purified CYP11A1, adrenodoxin and adrenodoxin reductase. DHEAS enhances the conversion of cholesterol by 26%. Detailed analyses of the mechanism of DHEAS action revealed increased binding affinity of cholesterol to CYP11A1 and enforced interaction with the electron transfer partner, adrenodoxin. Difference spectroscopy showed Kd-values of 40±2.7 μM and 24.8±0.5 μM for CYP11A1 and cholesterol without and with addition of DHEAS, respectively. To determine the Kd-value for CYP11A1 and adrenodoxin, surface plasmon resonance measurements were performed, demonstrating a Kd-value of 3.0±0.35 nM (with cholesterol) and of 2.4±0.05 nM when cholesterol and DHEAS were added. Kinetic experiments showed a lower Km and a higher kcat value for CYP11A1 in the presence of DHEAS leading to an increase of the catalytic efficiency by 75%. These findings indicate that DHEAS affects steroid hormone biosynthesis on a molecular level resulting in an increased formation of pregnenolone.
Biofeedback treatment in chronically constipated patients with dyssynergic defecation
Simón,Miguel A.; Bueno,Ana M.; Durán,Montserrat;
Revista Latinoamericana de Psicología , 2011,
Abstract: the aim of this study was to evaluate the effects of electromyographic biofeedback training in chronically constipated patients with dyssynergic defecation. with this purpose, ten patients (4 males, 6 females) with dyssynergic defecation unresponsive to dietary corrections and fibre supplements were selected and enclosed in the study on the basis of fulfilled the rome iii criteria for this functional gastrointestinal disorder. the study was carried out following a series of defined phases: clinical and psychophysiological assessment prior to the treatment (4 weeks), emg-biofeedback treatment (8 sessions, two per week) and follow-up (4 weeks) one month later. in all phases, four clinical variables were assessed through selfmonitoring (frequency of defecations per week, sensation of incomplete evacuation, difficulty evacuation level, and perianal pain at defecation); moreover, psychophysiological measures were obtained through electromyography (emg) of the external anal sphincter. results show significant improvements in psychophysiological measures (emgactivity during straining to defecate and anismus index), as well as in clinical variables. biofeedback's benefits were maintained at the follow-up period.
EFFECT OF EXOGENOUS CORTISOL UPON THE SERUM CORTISOL LEVEL
Zoran Pavlovic,Voja Pavlovic
Acta Medica Medianae , 2001,
Abstract: The effect of high doses of cortisol upon the serum cortisol level is studied. Theexperiment is done upon male guinea-pigs of bodily weight of 300 to 400 g. Cortisolis applied in the subcutaneous way to a kilogram of bodily weight, namely, A group -5, B group - 20, C group - 40 and D group - 80. The control group guinea-pigsreceived one ml of the physiological solution. After the six days application the bloodsamples were taken by the cordial puncture. The exogenous cortisol application leadsto an increase of its level in all the cortisol treated groups. The greatest cortisolconcentration is verified twelve hours after the exogenous cortisol application. Withan increasing dose of the applied cortisol the serum cortisol level also rises.
Hirschsprungs Disease: a Clinical and Pathologic Study in Iranian Constipated Children
Maryam Monajemzadeh,Mehdi Kalantari,Bahareh Yaghmai,Roya Shekarchi
Iranian Journal of Pediatrics , 2011,
Abstract: Objective:Hirschsprung's disease (HD) is a complex disorder resulting from absence of ganglion cells in the bowel wall leading to functional obstruction and bowel dilatation proximal to the affected segment. The aim of our study was to evaluate rectal biopsies from constipated children in different age groups to see in which age it is more likely to encounter HD to avoid unnecessary rectal biopsy. Methods: Records of all children with chronic constipation undergoing a rectal biopsy to exclude HD were obtained from the files of Childrens Medical Center in Tehran, Iran. A detailed retrospective demographic review, including age of beginning of signs and symptoms was made of all cases. Findings: Totally, 172 biopsies were taken from 168 children in a five year period, of which 127 cases (75%) had HD. The mean age of constipated patients at biopsy was 39 months and the mean age of patients with proven HD was 18 months. Males were affected more than females. Congenital anomalies associated with HD were found in 9.6%. In 85 (91%) cases constipation had begun in neonatal period. Conclusion:Our data supports previous studies that if constipation begins after the neonatal period, the child is unlikely to have HD. In neonates delay in meconium passage is the most important clinical sign of HD.
Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms  [PDF]
Guangju Zhai equal contributor,Alexander Teumer equal contributor,Lisette Stolk equal contributor,John R. B. Perry equal contributor,Liesbeth Vandenput equal contributor,Andrea D. Coviello equal contributor,Annemarie Koster equal contributor,Jordana T. Bell,Shalender Bhasin,Joel Eriksson,Anna Eriksson,Florian Ernst,Luigi Ferrucci,Timothy M. Frayling,Daniel Glass,Elin Grundberg,Robin Haring,?sa K. Hedman,Albert Hofman,Douglas P. Kiel,Heyo K. Kroemer,Yongmei Liu,Kathryn L. Lunetta,Marcello Maggio,Mattias Lorentzon,Massimo Mangino,David Melzer,Iva Miljkovic,MuTHER Consortium,Alexandra Nica,Brenda W. J. H. Penninx,Ramachandran S. Vasan,Fernando Rivadeneira,Kerrin S. Small,Nicole Soranzo,André G. Uitterlinden,Henry V?lzke,Scott G. Wilson,Li Xi,Wei Vivian Zhuang,Tamara B. Harris ?,Joanne M. Murabito ?,Claes Ohlsson ?,Anna Murray ?,Frank H. de Jong ?,Tim D. Spector ,Henri Wallaschofski ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002025
Abstract: Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10?36), SULT2A1 (rs2637125; p = 2.61×10?19), ARPC1A (rs740160; p = 1.56×10?16), TRIM4 (rs17277546; p = 4.50×10?11), BMF (rs7181230; p = 5.44×10?11), HHEX (rs2497306; p = 4.64×10?9), BCL2L11 (rs6738028; p = 1.72×10?8), and CYP2C9 (rs2185570; p = 2.29×10?8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Primary chemotherapy for operable breast cancer: the NSABP experience
HD Bear
Breast Cancer Research , 2005, DOI: 10.1186/bcr1221
Abstract: NSABP Protocol B-18 was designed to compare pre-operative chemotherapy with doxorubicin (adriamycin) and cyclophosphamide (AC) given every 3 weeks for four cycles versus the same chemotherapy treatment given in the adjuvant setting. In protocol B-18, 1523 women with operable breast cancer were randomized to receive four cycles of AC followed by surgery or surgery followed by four cycles of AC. Women 50 years of age or older also received tamoxifen for 5 years, starting after chemotherapy.Subsequently, NSABP Protocol B-27 was conducted with the intent to determine the effect of adding docetaxel (taxotere [T]) after four cycles of preoperative AC on disease-free survival (DFS) and overall survival (OS) of women with operable breast cancer. A total of 2411 women with operable primary breast cancer were randomized to receive either four cycles of preoperative AC followed by surgery (group I) or four cycles of AC followed by four cycles of T, followed by surgery (group II), or four cycles of AC followed by surgery and then four cycles of T (group III). Tamoxifen was given to all patients, starting concurrently with chemotherapy.In protocol B-18, mean tumor size was 3.5 cm. Preoperative AC produced objective clinical responses in 79% of the treated patients and clinical complete responses (cCR) in 36%. Pathologic complete responses (pCR, defined as no invasive cancer in the breast) were observed in 13%. OS and DFS were similar in the two randomized treatment groups. Preoperative chemotherapy resulted in a statistically significant increase in the rate of breast conserving therapy (BCT), from 60% to 68%. This was particularly notable in the patients with tumors >5 cm, in whom BCT was increased from 8% to 22% [1]. Although there was a trend toward increased ipsilateral breast tumor recurrence (IBTR) in preoperative chemotherapy patients who were downstaged to lumpectomy compared with patients treated preoperatively who were considered to be candidates for BCT at the outset
Testosterone- and Cortisol-Secreting Adrenocortical Oncocytoma: An Unusual Cause of Hirsutism  [PDF]
Serap Baydur Sahin,Ahmet Fikret Yucel,Recep Bedir,Sabri Ogullar,Teslime Ayaz,Ekrem Algun
Case Reports in Endocrinology , 2014, DOI: 10.1155/2014/206890
Abstract: Objective. Oncocytomas of the adrenal cortex are usually benign and nonfunctional. They are rarely seen as the cause of hirsutism. Therefore, we aimed to report a case of adrenocortical oncocytoma presenting with hirsutism. Methods. We report a testosterone- and cortisol-secreting adrenal oncocytoma in a 23-year-old female patient presenting with hirsutism. Results. The patient had the complaint of hirsutism for the last year. Laboratory tests revealed total testosterone level of 4.2?ng/mL, free testosterone of >100?pg/mL, and DHEAS level of 574?μg/dL. There was no suppression in cortisol levels with 2?mg dexamethasone suppression test (5.4?μg/dL). Adrenal MRI revealed a ?mm isointense solid mass lesion in the left adrenal gland and the patient underwent laparoscopic left adrenalectomy. Pathological examination confirmed the diagnosis of benign adrenocortical oncoyctoma. Conclusion. This well-characterized case describes a testosterone- and cortisol-secreting adrenocortical oncocytoma as a possible cause of hirsutism. To our knowledge, this is the second report in the literature. Adrenal oncocytomas should always be considered in the differential diagnosis of hirsutism. 1. Introduction Hirsutism, defined as excessive male-pattern hair growth, affects between 5 and 10% of women of reproductive age and most women with hirsutism have polycystic ovary syndrome [1, 2]. Androgen-secreting tumors are rarely seen as the cause of hirsutism. In an epidemiological study, the frequency of androgen-secreting tumors was 0.2% in 950 hirsute women [3]. Most testosterone-secreting tumors arise from the ovary and rarely origins from the adrenal gland. Oncocytic neoplasms or oncocytomas usually arise in the kidneys or thyroid, parathyroid, salivary, or pituitary glands [4]. Oncocytomas of the adrenal cortex are extremely rare and usually detected incidentally [5]. Adrenal oncocytomas are usually benign and nonfunctional in most of cases. Herein, we report a testosterone- and cortisol-secreting adrenal oncocytoma in a 23-year-old female patient presenting with hirsutism. 2. Case Report A 23-year-old female patient admitted to endocrinology outpatient clinic with the complaint of hirsutism for the last year. Excessive hair growth was identified to originate from facial and mandibular areas initially and then to spread to abdominal and thoracic regions. She had regular menstrual cycles since her first period by the age of 12. Medical background and family history were unremarkable. Physical examination revealed that body temperature was 37°C, pulse rate was 80 beats/min,
The effects of moderate alcohol supplementation on estrone sulfate and DHEAS in postmenopausal women in a controlled feeding study
Somdat Mahabir, David J Baer, Laura L Johnson, Joanne F Dorgan, William Campbell, Ellen Brown, Terryl J Hartman, Beverly Clevidence, Demetrius Albanes, Joseph T Judd, Philip R Taylor
Nutrition Journal , 2004, DOI: 10.1186/1475-2891-3-11
Abstract: Postmenopausal women (n = 51) consumed 0 (placebo), 15 (1 drink), and 30 (2 drinks) g alcohol (ethanol)/ day for 8 weeks as part of a controlled diet in a randomized crossover design. Blood samples were drawn at baseline, at 4 weeks and at 8 weeks. Changes in estrone sulfate and DHEAS levels from placebo to 15 g and 30 g alcohol per day were estimated using linear mixed models.At week 4, compared to the placebo, estrone sulfate increased an average 6.9% (P = 0.24) when the women consumed 15 g of alcohol per day, and 22.2% (P = 0.0006) when they consumed 30 g alcohol per day. DHEAS concentrations also increased significantly by an average of 8.0% (P < 0.0001) on 15 g of alcohol per day and 9.2% (P < 0.0001) when 30 g alcohol was consumed per day. Trend tests across doses for both estrone sulfate (P = 0.0006) and DHEAS (P < 0.0001) were significant. We found no significant differences between the absolute levels of serum estrone sulfate at week 4 versus week 8 (P = 0.32) across all doses. However, absolute DHEAS levels increased from week 4 to week 8 (P < 0.0001) at all three dose levels.These data indicate that the hormonal effects due to moderate alcohol consumption are seen early, within 4 weeks of initiation of ingestion.Epidemiological evidence consistently shows a positive association between alcohol, even low to moderate intake, and breast cancer risk [1]. However, during the past two decades, it has become evident that moderate drinking is associated with longer life [2], reduced rates of heart disease [3] and stroke [4]. What does this mean for women when the epidemiologic data show an exposure is associated with both benefits and harms? Recommendations regarding the use or avoidance of moderate alcohol, must take into consideration both its potential benefit on cardiovascular disease, as well as its potential risk for breast cancer. To understand the biologic parameters potentially influenced by alcohol, there is a need for well-controlled mechanistic studie
Operable malignant jaundice: To stent or not to stent before the operation?  [cached]
Rungsun Rerknimitr,Pinit Kullavanijaya
World Journal of Gastrointestinal Endoscopy , 2010,
Abstract: Traditionally, pre-operative biliary drainage (PBD) was believed to improve multi-organ dysfunction, and for this reason, was practiced worldwide. Over the last decade, this concept was challenged by many reports, including meta-analyses that showed no difference in morbidity and mortality between surgery with, and surgery without PBD, in operable malignant jaundice. The main disadvantages of PBD are seen to be the additional cost of the procedure itself, and the need for longer hospitalization. In addition, many studies showed the significance of specific complications resulting from PBD, such as recurrent jaundice, cholangitis, pancreatitis, cutaneous fistula, and bleeding. However, the results of these studies remain inconclusive as to date there has been no perfect study that equally randomized comparable patients according to the level of obstruction and technique used for PBD. Generally, endoscopic stent insertion (ES) is preferred for common duct obstruction, whereas endoscopic nasobiliary drainage and percutaneous biliary drainage is reserved for hilar obstruction, since ES in hilar block confers a high rate of cholangitis. Although, there is no guideline which either supports or refutes this approach, certain subgroups of patients, including those with symptomatic jaundice, cholangitis, impending renal failure, hilar block requiring preoperative portal vein embolization, and those who need pre-operative neoadjuvant therapy, are suitable candidates for PBD.
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