Salivary Diagnostic for Monitoring Strenuous Exercise-A Pilot Study in a Cohort of Male Ultramarathon Runners.

Intense physical stress, such as that in ultramarathon running, affects the immune system. For monitoring in sports medicine, non-invasive methods, e.g., salivary analysis, are of interest. This pilot cohort study aimed to assess changes in salivary parameters in response to an ultramarathon. The results were compared to blood parameters. Male, healthy finishers (n = 9, mean age: 48 ± 8.8 years, mean height: 1.8 ± 0.1 m, mean weight: 72.5 ± 7.2 kg, mean BMI: 23.5 ± 1.9 kg/cm²) of a 160 km ultramarathon were included. Saliva and blood samples were collected at three time points: T1 (baseline), T2 (shortly after the ultramarathon) and T3 (after recovery). In saliva, cortisol, testosterone, IL-1ß, IL-6, IL-8, IL-10, TNF-α, albumin, IgA, α-amylase, aMMP-8, and neopterin were assessed via ELISA. In blood, cortisol, testosterone, IL-1ß, IL-6, IL-8, IL-10, TNF-α, blood cell counts, procalcitonin, CRP, osmolality, albumin, and α-amylase were analyzed. The statistical evaluation comprised longitudinal testing and cross-sectional testing between saliva and blood using ratios of T2 and T3 to baseline values. Various parameters in saliva and blood changed in response to the ultramarathon. Comparing blood and saliva, the longitudinal changes of testosterone (p = 0.02) and α-amylase (p = 0.03) differed significantly. Despite the limitations of the study, it underlines that saliva is an interesting option for comprehensive monitoring in sports medicine and necessitates further studies.

Differences in the Distribution of IGF-I Concentrations Between European and US Populations.

Context: Method-specific reference intervals (RIs) determine utility of IGF-I as a biomarker in GH-related diseases. Differences between populations might affect applicability of RIs. Objective: To compare population-specific RIs derived from IGF-I routine testing in laboratories in the United States and Europe using the same assay. Design and setting: Uncensored routine IGF-I testing results generated over 5 years in 4 accredited laboratories (US, n = 778 173 males/710 752 females; Europe, n = 23 220 males/40 183 females). Main outcome measures: Construction of RIs by indirect statistical methods designed to use routine testing data (modified Hoffmann approach). Comparison to published RIs, between the US and Europe, and between regions in the United States with lower and higher mean body mass indexes (BMIs). Results: Lower limits (LLs) of RIs calculated from all routine data sets do not differ from the published LLs. The same is true for upper limits (ULs) calculated from European routine data. ULs derived from US routine data are significantly higher (children, 10-18 years [mean, %]: boys + 149.3 ng/mL [+34.6%]; girls + 94.9 ng/mL [+19.8%]); adults (19-95 years: males + 45 ng/mL [+20.3%]; and females + 29.7 ng/mL [+13.8%]). Average IGF-I is higher in samples from Colorado (lower mean BMI) compared with Alabama (P < 0.0001), although the difference is smaller than between each of them and Europe. Conclusions: We provide evidence that in large datasets from the same population, direct sampling and the indirect Hoffmann approach provide comparable RIs. Although LLs are comparable between Europe and the United States, the UL is significantly higher in the United States. We suggest use of adapted RIs for the United States.

The ElonginB/C-Cullin5-SOCS-Box-Complex Is a Potential Biomarker for Growth Hormone Disorders.

Insulin-like growth factor 1 (IGF-1) is the standard biochemical marker for the diagnosis and treatment control of acromegaly and growth hormone deficiency (GHD). However, its limitations necessitate the screening for new specific and sensitive biomarkers. The elonginB/C-cullin5-SOCS-box-complex (ECS-complex) (an intracellular five-protein complex) is stimulated by circulating growth hormone (GH) and regulates GH receptor levels through a negative feedback loop. It mediates the cells' sensitivity for GH and therefore, represents a potent new biomarker for those diseases. In this study, individual ECS-complex proteins were measured in whole blood samples of patients with acromegaly (n = 32) or GHD (n = 12) via ELISA and compared to controls. Hierarchical clustering of the results revealed that by combining the three ECS-complex proteins suppressor of cytokine signaling 2 (SOCS2), cullin-5 and ring-box protein 2 (Rbx-2), 93% of patient samples could be separated from controls, despite many patients having a normal IGF-1 or not receiving medical treatment. SOCS2 showed the best individual diagnostic performance with an overall accuracy of 0.93, while the combination of the three proteins correctly identified all patients and controls. This resulted in perfect sensitivity and specificity for all patient groups, which demonstrates potential benefits of the ECS-complex proteins as clinical biomarkers for the diagnostics of GH-related diseases and substantiates their important role in GH metabolism.

[Transsexualism and transgender medicine - what every internal specialist should know about]. / Transsexualität und Transgender-Medizin ­ Was jeder Internist wissen sollte.

The authors present current findings on transsexualism and its treatment. According to the ICD-10, transsexualism is defined as the "desire to live and be accepted as a member of the opposite sex, usually accompanied by a sense of discomfort with, or inappropriateness of, one's anatomic sex, and a wish to have surgery and hormonal treatment to make one's body as congruent as possible with one's preferred sex." Synonyms of transsexualism are terms such as gender dysphoria reflecting the distress that persons feel due to a mismatch between their gender identity and their sex assigned at birth.The prevalence of transsexualism is estimated to be about 0,6 %. The diagnosis of transsexualism is made by psychiatrists, but at least five more medical specialties (endocrinologist, surgeon, ear, nose and throat specialist, speech therapist and dermatologist) are involved when treating transsexual persons. Hormonal therapy is a very important element of the treatment process; due to the complexity of transsexualism it should be undertaken by endocrinologists with experience and expertise in this field.

Long-term Outcome of Subacute Thyroiditis.

BACKGROUND: Subacute thyroiditis (SAT) is a rare inflammatory disease that presents diagnostic challenges. The underlying pathophysiology and prediction of outcomes are elusive. We investigated the long-term follow-up of SAT for up to 30 years and determined predictors for later hypothyroidism. METHODS: SAT outcome data from 127 patients (age: 47.6 ± 11.0 yrs. , BMI: 24.7±4.8 kg/m²) were analyzed retrospectively. Patients with pre-existing and known causes of hypothyroidism unrelated to SAT were excluded. We also excluded patients without an accelerated erythrocyte sedimentation rate. SAT outcome parameters included anterior neck pain or tenderness of the thyroid, inflammation markers, hypoechoic areas in thyroid ultrasound, hyperthyroidism, fine-needle aspiration, and thyroid scan. Pre-treatment TSH-levels, gender, age, ultrasound findings, anti-thyroid antibodies and markers of inflammation were considered as possible predictors of SAT outcome. RESULTS: More than 26.8% of SAT patients developed permanent hypothyroidism within 3 years of treatment. The patient groups later developing hypothyroidism did not differ in age, BMI, pre-treatment TSH levels or initial dosage of prednisolone treatment. However, high cumulative doses of prednisolone were associated with a higher prevalence of hypothyroidism. Also, women were more likely to develop hypothyroidism (OR: 3.18 (95% CI: 1.14-8.65); p=0.0176). CONCLUSIONS: Our study suggests that one-quarter of patients with SAT develop hypothyroidism in the long-term. Hypothyroidism was predicted by high cumulative doses of prednisolone treatment and female gender. The reported lower prevalence of hypothyroidism in other countries may represent the faster establishment of diagnosis, different treatment protocols, or lower susceptibility to loss of thyroid function. Swift establishment of the diagnosis and rapid tapering of steroids may result in a higher proportion of patients with euthyroidism.

An Update on Addison's Disease.

Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or mineralocorticoid deficiency due to failure of the adrenal cortex which may result in an adrenal crisis with potentially life-threatening consequences. Even though efficient and safe pharmaceutical preparations for the substitution of endogenous gluco- and mineralocorticoids are established in therapy, the mortality in patients with PAI is still increased and the health-related quality of life (HRQoL) is often reduced.PAI is a rare disease but recent data report an increasing prevalence. In addition to the common "classical" causes of PAI like autoimmune, infectious, neoplastic and genetic disorders, other iatrogenic conditions - mostly pharmacological side effects (e. g., adrenal haemorrhage associated with anticoagulants, drugs affecting glucocorticoid synthesis, action or metabolism and some of the novel anti-cancer checkpoint inhibitors) are contributing factors to this phenomenon.Due to the rarity of the disease and often non-specific symptoms at least in the early stages, PAI is frequently not considered resulting in a delayed diagnosis. Successful therapy is mainly based on adequate patient education as a cornerstone in the prevention and management of adrenal crisis. A focus of current research is in the development of pharmacokinetically optimized glucocorticoid preparations as well as regenerative therapies.

Impact of Autoimmune Thyroiditis on Reproductive and Metabolic Parameters in Patients with Polycystic Ovary Syndrome.

BACKGROUND: Autoimmune thyroiditis (AIT) has been found to be associated with polycystic ovary syndrome (PCOS). The aim of this retrospective cohort study using data from a fertility clinic, with patients recruited from 2009 to 2010, was to confirm the higher prevalence of AIT in PCOS and to evaluate the impact of AIT on reproductive and metabolic parameters of PCOS patients. METHODS: Patients comprised 827 PCOS subjects seen for reproductive or metabolic complaints. Patients presenting primarily for thyroid problems were excluded. All patients were tested for the presence of AIT by laboratory testing and thyroid ultrasound. The impact of AIT on PCOS was evaluated by determination of reproductive and metabolic parameters. RESULTS: Patients with PCOS and AIT as compared to those only with PCOS, had a lower prevalence of elevated testosterone (45 vs. 61%; p=0,0001), free androgen index (5,96±5,41 vs. 7,02±7,6; p<0,001) and hyperandrogenemia (66 vs. 78%; p<0,001). Also testosterone levels were lower in PCOS patients with AIT (0,50±0,30 vs. 0,63±0,71; p=0,0006). Consequently, in these patients, hirsutism was less frequent (51 vs. 66%; p=0,0021). There was no difference in the prevalence of acne, alopecia, a-/ or oligomenorrhea or PCO-morphology in the two patient groups. Patients with PCOS and AIT were more obese by 2 kg/m² BMI on average. A higher BMI correlated with a higher TSH value, although all patients were euthyroid. CONCLUSIONS: AIT is more prevalent in PCOS than in controls. PCOS patients with AIT have less severe hyperandrogenemia and hyperandrogenism but are likely to suffer from an elevated metabolic risk.

Reduction in daily hydrocortisone dose improves bone health in primary adrenal insufficiency.

OBJECTIVE: Individuals with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) replacement therapy. Current daily GC doses are still higher than the reported adrenal cortisol production rate. This GC excess could result in long-term morbidities such as osteoporosis. No prospective trials have investigated the long-term effect of GC dose changes in PAI and CAH patients. METHODS: This is a prospective and longitudinal study including 57 subjects with PAI (42 women) and 33 with CAH (21 women). Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and after 2 years. Subjects were divided into three groups (similar baseline characteristics) depending on changes in daily hydrocortisone equivalent dose (group 1: unchanged 25.2±8.2  mg (mean±S.D., n=50); group 2: increased 18.7±10.3 to 25.9±12.0  mg (n=13); group 3: decreased 30.8±8.5 to 21.4±7.2  mg (n=27)). RESULTS: Subjects in group 1 showed normal lumbar and femoral Z-scores which were unchanged over time. Group 2 subjects showed a significant decrease in femoral neck Z-scores over time (-0.15±1.1 to -0.37±1.0 (P<0.05)), whereas group 3 subjects showed a significant increase in lumbar spine and hip Z-scores (L1-L4: -0.93±1.2 to -0.65±1.5 (P<0.05); total hip: -0.40±1.0 to -0.28±1.0 (P<0.05)). No changes in BMI over time were seen within any group. Reduction in GC dose did not increase the risk of adrenal crisis. CONCLUSION: This study demonstrates for the first time that cautious reduction in hydrocortisone equivalent doses leads to increases in BMD, whereas dose increments reduced BMD. These data emphasize the need for the lowest possible GC replacement dose in AI patients to maintain health and avoid long-term adverse effects.

Clinical validation for the aldosterone-to-renin ratio and aldosterone suppression testing using simultaneous fully automated chemiluminescence immunoassays.

BACKGROUND: As larger numbers of hypertensive patients are screened for primary aldosteronism with the aldosterone-to-renin ratio (ARR), automated analyzers present a practical solution for many laboratories. We report the method-specific ARR cutoff determined with direct, automated chemiluminescence immunoassays allowing the simultaneous measurement of plasma aldosterone concentrations (PACs) and plasma renin concentrations (PRCs). METHODS: Method comparisons to commonly employed assays and tandem mass spectrometry were undertaken. Patients were previously diagnosed based on the local ARR cutoff of 1.2 (ng/dl)/(µIU/ml) in samples collected in upright seated position. Lack of aldosterone suppression in response to salt load to less than 5 ng/dl confirmed primary aldosteronism. For the new assays, the optimal ARR cutoff was established in 152 patients with essential hypertension, 93 with primary aldosteronism and 147 normotensive patients. Aldosterone suppression was assessed in 73 essential hypertensive and 46 primary aldosteronism patients. RESULTS: PAC and PRC were significantly correlated to values determined with currently available methods (P < 0.001). In patients with primary aldosteronism, patients with essential hypertension and controls, mean (95% confidence interval) PAC was 28.4 (25.4-31.8), 6.4 (5.9-6.9) and 6.2 (5.6-6.9) ng/dl, respectively. In the same groups, PRC was 6.6 (5.6-7.7), 12.9 (11.2-14.8) and 26.5 (22.2-31.5) µIU/ml. An ARR cutoff of 1.12 provided 98.9% sensitivity and 78.9% specificity. Employing the new assay aldosterone suppression confirmed the diagnosis of primary aldosteronism and essential hypertension using the cutoff of 5 ng/dl. CONCLUSION: Our data demonstrate that the new assays present a convenient alternative for the measurement of PAC and PRC on a single automated analyzer. Availability of these simultaneous assays should facilitate screening and diagnosis of primary aldosteronism.

Sleep quality in patients with primary aldosteronism.

OBJECTIVE: In subjects at high risk for sleep apnea (SA), aldosterone concentrations correlate with severity of SA and primary aldosteronism (PA) is very often diagnosed. Patients with PA show a high prevalence of SA. Treatment of PA either by adrenalectomy (ADX) or mineralocorticoid receptor (MR) blockade is thought to abolish the increased comorbidities. However, no data are available regarding effectiveness of different PA treatments on quality of sleep. DESIGN: This prospective multi-center study included 15 patients with newly diagnosed PA evaluated before and 0.7 ± 0.2 years after treatment initiation, and a second cohort including 81 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Biochemical parameters, 24h blood pressure and three validated self-assessment questionnaires (Giessen Complaint List (GBB-24), Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality-Index (PSQI)) were analyzed. RESULTS: Z-scores of exhaustion tendency of GBB significantly improved in newly diagnosed PA patients after treatment initiation (1.8 ± 1.4 vs. 1.0 ± 1.2, p=0.034). In the second cohort no differences were found in GBB-24, ESS and PSQI. No differences were found in all three questionnaires independently of type of PA therapy. However, female patients scored significantly higher than males in the PSQI (8.7 ± 3.6 vs 5.7 ± 4.2, p<0.005), indicating lower sleep quality, independently of the type of therapy. CONCLUSIONS: For the first time, we analyzed quality of sleep in patients with PA, demonstrating that therapy initiation improves exhaustion tendency. Surprisingly, female PA patients showed significantly more sleep disturbances than male PA patients several years after treatment initiation.

Arginine vasopressin-dependent and AVP-independent mechanisms of renal fluid absorption during thirsting despite glucocorticoid-mediated vasopressin suppression.

OBJECTIVE: Glucocorticoids seem to modify the release and effects of plasma arginine vasopressin (pAVP). However, underlying processes are not well understood. This study aimed to evaluate the mechanism of the modulating effects of glucocorticoids on pAVP and renal water reabsorption. DESIGN: Fluid deprivation tests were performed without (d0) and after one (d1) and five days (d5) of oral prednisolone (Pred) pretreatment in a dosage relevant to drug therapy (30 mg/day). PATIENTS: Twelve healthy male volunteers participated in this trial. MEASUREMENTS: Plasma and urinary osmolality, pAVP, renin, aldosterone, plasma atrial natriuretic peptide (ANP) as well as urinary secretion of aquaporin-2 (AQP2) and prostaglandin E(2) (PGE2) were analysed. RESULTS: An appropriate rise in pAVP was observable during thirsting (P < 0.001), which was absent after Pred pretreatment. However, the plasma and urinary osmolality after Pred treatment did not differ when compared with the basal thirsting test. Unchanged urinary AQP2 excretion suggests AVP-independent mechanisms of renal fluid reabsorption. Plasma renin concentration as well as ANP was substantially increased after Pred intake at d1 and d5 (both P < 0.05), which may mediate such AVP-independent mechanisms. Urinary PGE2 secretion was not influenced by Pred pretreatment, making a PGE2-mediated effect on renal AQP2 translocation and water permeability unlikely. Increased efficacy of exogenous desmopressin at d1 and d5 indicates also a relative increase in AVP sensitivity of the tubular cells after Pred intake. CONCLUSIONS: The here presented data are compatible with an increased AVP sensitivity and a partially AVP-independent regulation of AQP2 translocation and renal fluid reabsorption during glucocorticoid treatment.

BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy.

CONTEXT: Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD). OBJECTIVES: To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH. DESIGN AND PATIENTS: A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured. RESULTS: Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum ß-CrossLaps (0.37 ± 0.34 µg/l; P < 0.05) and urinary collagen crosslinks (NTX, 68.1 ± 32.4 nmol/g; P < 0.005) despite receiving the lowest average daily hydrocortisone dose of 9.9 ± 3.7 mg/m(2) (P < 0.05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6.7, 95% CI = 1.78-25.38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes. CONCLUSIONS: Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity.

Effectiveness of eplerenone or spironolactone treatment in preserving renal function in primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce. DESIGN AND METHODS: This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; n=86); spironolactone (n=65); and eplerenone (n=18)). RESULTS: GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications. CONCLUSIONS: Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

Rosiglitazone increases fatty acid Δ9-desaturation and decreases elongase activity index in human skeletal muscle in vivo.

The ratio of unsaturated to saturated long-chain fatty acids (LC-FAs) in skeletal muscle has been associated with insulin resistance. Some animal data suggest a modulatory effect of peroxisome proliferator receptor γ (PPARγ) stimulation on stearoyl-CoA desaturase 1 (SCD1) and LC-FA composition in skeletal muscle, but human data are rare. We here investigate whether treatment with a PPARγ agonist affects myocellular SCD1 expression and modulates the intramyocellular fatty acid profile in individuals with impaired glucose tolerance. Muscle biopsies and hyperinsulinemic-euglycemic clamps were performed in 7 men before and after 8 weeks of rosiglitazone treatment. Intramyocellular saturated, monounsaturated, and polyunsaturated intramuscular fatty acid profiles were measured by gas chromatography. Effects on SCD1 messenger RNA expression were analyzed in C2C12 cells and in human biopsies before and after rosiglitazone treatment. As expected, treatment with the PPARγ activator rosiglitazone improved insulin sensitivity in humans. Myocellular SCD1 messenger RNA expression was increased in human biopsies and C2C12 cells. Although the total content of myocellular LC-FA was unchanged, a relative shift from saturated LC-FAs to unsaturated LC-FAs was observed in human biopsies. Particularly, the amount of stearate was reduced, whereas the amounts of palmitoleate as well as oleate and vaccenate were increased, after rosiglitazone therapy. These changes resulted in an increased fatty acid Δ9-desaturation index (16:1/16:0 and 18:1/18:0) in skeletal muscle and a decreased elongase activity index (18:0/16:0). The PPARγ associated phenotypes may be partially explained by an increased Δ9-desaturation and a decreased elongase activity of skeletal muscle.

The diagnosis and treatment of primary hyperaldosteronism in Germany: results on 555 patients from the German Conn Registry.

BACKGROUND: Primary hyperaldosteronism (Conn's syndrome) is being diagnosed increasingly often. As many as 12% of patients with hypertension have the characteristic laboratory constellation of Conn's syndrome. Its diagnosis and treatment have not been standardized. METHODS: The authors retrospectively analyzed data of 555 patients (327 men and 228 women, aged 55 +/- 13 years) who were treated for primary hyperaldosteronism in 5 different centers from 1990 to 2006. The objective was to determine center-specific features of diagnosis and treatment. RESULTS: 353 (63%) of the patients had the hypokalemic variant of primary hyperaldosteronism; 202 never had documented hypokalemia. The centers differed markedly with respect to the patients' clinical presentation, diagnostic testing of endocrine function, and diagnostic imaging techniques, including adrenal venous sampling. The adrenalectomy rate ranged from 15% to 46%. CONCLUSIONS: The registry data reveal an unexpected heterogeneity in the diagnostic evaluation and treatment of primary hyperaldosteronism. National or international guidelines are needed so that these can be standardized.

Risk factors associated with a low glomerular filtration rate in primary aldosteronism.

CONTEXT: Primary aldosteronism (PA) is associated with vascular end organ damage. OBJECTIVE: We evaluated the newly established German Conn's Registry for evidence of renal impairment and compared the data with those from hypertensive subjects of a population-based survey. DESIGN: We conducted a case-control study. PATIENTS AND CONTROLS: A total of 408 patients with PA from the Conn's registry treated in five German centers were matched for age, sex, and body mass index in a 1:1 ratio with 408 hypertensive control subjects from the population-based F3 survey of the Kooperative Gesundheitsforschung in the region of Augsburg (KORA). MAIN OUTCOME MEASURES: We measured serum creatinine and calculated glomerular filtration rate (GFR). RESULTS: The percentage of patients with a serum creatinine concentration above the normal range of 1.25 mg/dl was higher in patients with PA than in hypertensive controls (29 vs. 10%; P < 0.001). Regression analysis showed that age, male sex, low potassium, and high aldosterone concentrations were independent predictors of a lower GFR. Adrenalectomy reduced systolic blood pressure from a mean of 160 to 144 mm Hg. In parallel, we observed an increase in serum creatinine and a decrease of GFR from 71 to 64 ml/min (P < 0.001). A similar trend was seen after spironolactone treatment. CONCLUSIONS: In a large cohort of patients with PA, markers of disease activity such as plasma aldosterone and serum potassium are independent predictors of a lower GFR. Specific interventions, such as adrenalectomy or spironolactone treatment, are associated with a further decline in GFR.

Cell-type specific regulation of the human 11beta-hydroxysteroid dehydrogenase type 1 promoter.

The intracellular enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone into the more active metabolite cortisol. Overexpression of 11beta-HSD1 was associated with features of the metabolic syndrome such as obesity or impaired glucose tolerance. Despite this considerable impact of 11beta-HSD1, the human 11beta-HSD1 promoter has not been described in detail yet. We therefore cloned eight different promoter fragments of the 5'-upstream region of the known transcription/translation-start up to -3034 bp into the luciferase-reporter vector pGL3. A low-cost in-house assay was developed and validated to detect firefly and renilla luciferase activity. Promoter fragments were analysed in human HepG2 and undifferentiated and differentiated murine 3T3-L1 cells. A differential regulation of the human 11beta-HSD1 promoter depending upon the cell type was observed. Specifically, a strong repressor of the basal promoter activity was found between -85 and -172 bp in HepG2 cells only, while an additional repressor appeared to be active between -342 and -823 bp in both, the hepatic and the adipose cell line. The presented data suggest a cell-type specific regulation of the 11beta-HSD1 promoter, which is in agreement with existing expression data from animal and human studies. The described promoter constructs will allow subsequent studies about the role of specific hormonal, metabolic and transcription factors to finally characterise the regulation of the human 11beta-HSD1-promoter in more detail.