Our data indicate a high prevalence of comorbidities in patients with PA. The hypokalemic variant is defined by a higher morbidity than the normokalemic variant regarding some cardiovascular but not cerebrovascular events. Thus, PA should be sought not only in hypokalemic but also in normokalemic hypertensives because high-excess morbidity occurs in both subgroups.

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.

Background: Glucocorticoids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy. However, the data describing gluco-and mineralo-corticoid (MC) properties of widely applied synthetic GCs are often based on diverse clinical observations and on a variety of in vitro tests under various conditions, which makes a quantitative comparison questionable. Method: We compared MC and GC properties of different steroids, often used in clinical practice, in the same in vitro test system (luciferase transactivation assay in CV-1 cells transfected with either hMR or hGRa expression vectors) complemented by a system to test the steroid binding affinities at the hMR (protein expression in T7-coupled rabbit reticulocyte lysate). Results and Conclusions: While the potency of a GC is increased by an 11-hydroxy group, both its potency and its selectivity are increased by the D1-dehydro-configuration and a hydrophobic residue in position 16 (16-methylene, 16a-methyl or 16b-methyl group). Almost ideal GCs in terms of missing MC effects, as defined by our in vitro assay, are therefore prednylidene, budesonide, beclomethasone and betamethasone. The MC potency of a steroid is increased by a 9a-or a 6a-fluoro substituent. A hydrophilic substituent in position 16 (like 16-hydroxylation in triamcinolone) decreases both MC and GC properties. As no substituent that leads to an isolated reduction of GC activity could be characterized in our experiments, 9a-fluorocortisol, the most frequently used steroid for MC substitution, seems to be the best choice of available steroids for this purpose.

Tetracosactin [corticotropin-(1-24)] is used for clinical testing of adrenocortical responsiveness. The usual dose [high dose test (HDT)] is 250 micrograms. With this test, patients with mild secondary adrenal insufficiency are usually not identified, thus putting them at risk of an adrenal crisis in stressful situations. It was recently reported that a tetracosactin test with approximately 1 micrograms [low dose test (LDT)] identifies patients with mild forms of pituitary-adrenal insufficiency. We performed both the HDT and the LDT in 35 control subjects and in 44 patients with pituitary disease, mostly pituitary tumors. In these patients, more sensitive reference tests for evaluating the pituitary-adrenal axis (insulin-induced hypoglycemia, metyrapone, and CRH tests) were also performed. In the HDT, plasma cortisol was measured 30 and 60 min after tetracosactin injection; in the LDT (0.5 microgram/m2 body surface area), plasma cortisol was measured 20, 30, 40, 50, and 60 min postinjection. In 6 control subjects, tetracosactin plasma levels were also measured after injection. In the HDT, the correlation between 30 and 60 min cortisol levels was extremely high (r = 0.991; P < 0.0001), but the correlation of the LDT with the HDT at 30 min was also highly significant (r = 0.948; P < 0.0001). The lower normal limit of cortisol responses (means of controls minus 2 SD) at 30 min was lower in the LDT by 3.1 micrograms/dL (85 nmol/L) than in the HDT. Compared with the reference tests, the diagnostic sensitivities of the HDT and the LDT were almost identical. Both tests identified patients with moderately to severely pathological insulin and metyrapone tests, but not those with slightly pathological reference tests. In the HDT, plasma tetracosactin rose to more than 60,000 pg/mL shortly after injection. In the LDT, it rose to 1,900 pg/mL. Both concentrations stimulate cortisol (supra-) maximally. Together, these data show that in pituitary disorders the results of the LDT and the HDT are almost identical. Plasma tetracosactin levels in the LDT still rise to levels that maximally stimulate the adrenal. Tetracosactin testing with low or high doses cannot generally replace the more expensive and cumbersome insulin or metyrapone tests.

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) system plays a pivotal role in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11beta-HSD activities are important determinants for the efficacy of synthetic MCs and GCs, corresponding pharmacokinetic data are scanty. Therefore, we characterized 11beta-HSD profiles for a wide range of steroids often used in clinical practice. 11beta-HSD1 and 11beta-HSD2 were selectively examined in 1) human liver and kidney cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with 11beta-HSD1 or 11beta-HSD2 expression vectors. Both systems produced concordant evidence for the following conclusions. Oxidation of steroids by 11beta-HSD2 is diminished if they are fluorinated in position 6alpha or 9alpha (e.g. in dexamethasone) or methylated at 2alpha or 6alpha (in methylprednisolone) or 16alpha or 16beta, by a methylene group at 16 (in prednylidene), methyloxazoline at 16, 17 (in deflazacort), or a 2-chlor configuration. Whereas the methyl groups also decrease reductase activity (steric effects), fluorination increases reductase activity (negative inductive effect), leading to a shift to reductase activity. This may explain the strong MC activity of 9alpha-fluorocortisol and should be considered in GC therapy directed to 11beta-HSD2-expressing tissues (kidney, colon, and placentofetal unit). 11beta-HSD2 oxidation of prednisolone is more effective than that of cortisol, explaining the reduced MC activity of prednisolone compared with cortisol. Reduction by 11beta-HSD1 is diminished by 16alpha-methyl, 16beta-methyl, 2alpha-methyl, and 2-chlor substitution, whereas it is increased by the Delta(1)-dehydro configuration in prednisone, resulting in higher hepatic first pass activation of prednisone compared with cortisone. To characterize a GC or a MC as substrate for the different 11betaHSDs may be essential for an optimized steroid therapy.

Adult PAI and CAH patients on low glucocorticoid doses showed normal BMD within the normal reference range. The use of longer acting prednisolone resulted in significantly lower BMD in PAI. In addition, DHEA treatment may have a beneficial effect on bone in Addison's women.

Objective: Severe hyponatremia due to hypopituitarism and adrenal insufficiency can be lifethreatening, and treatment with glucocorticoids is very effective once the diagnosis of the underlying disorder has been made. In our experience, the diagnosis of hypopituitarism in hyponatremic patients is often overlooked. Methods: In a retrospective study we screened the files of 185 patients with severe hyponatremia (,130 mmol/l) that had been seen in one endocrinological unit of a university hospital between 1981 and 2001 in order to describe the clinical spectrum of patients with hyponatremia and hypopituitarism including secondary adrenal insufficiency. Results: In 139 cases it was possible to clearly ascribe the patients to the pathophysiological groups of (i) primary sodium deficiency, (ii) edematous disorders, and (iii) normovolemic disorders including the 'syndrome of inappropriate secretion of antidiuretic hormone' (SIADH). Twenty-eight patients with severe 'normovolemic hyponatremia' (serum sodium: 116^7 mmol/l, mean^S.D.) had hypopituitarism and secondary adrenal insufficiency as shown by basal cortisol measurements and dynamic tests of adrenal function. In 25 cases of this group hypopituitarism (mostly due to empty sella, Sheehan's syndrome and pituitary tumors) had not been recognized previously, and in 12 cases recurrent hyponatremia during previous hospital admissions (up to four times) could be documented. The mean age of these patients (21 women, seven men) was 68 years. The most frequently occurring clinical signs were missing or scanty pubic and axillary hair, pale and doughy skin, and small testicles in the men. Frequent symptoms like nausea and vomiting, confusion, disorientation, somnolence or coma were similar to those in 91 patients with SIADH. Basal serum cortisol levels in the acutely ill state ranged from 20 to 439 nmol/l (mean^S.D.: 157^123), while in 30 other severely hyponatremic patients it ranged from 274 to 1732 nmol/l (732^351 nmol/l). In most patients with hyponatremic hypopituitarism, plasma antidiuretic hormone levels were inappropriately high, probably due to a failure of endogenous cortisol to suppress the hormone in a stressful situation. All patients recovered after low-dose hydrocortisone substitution. Most patients had other pituitary hormone deficiencies and were appropriately substituted subsequently. Conclusions: Hypopituitarism including secondary adrenal insufficiency seems to be a frequently overlooked cause of severe hyponatremia. A high level of suspicion is the best way to recognize the underlying disorder. Treatment with hydrocortisone is very effective.

Objective: Selective inhibitors of 11b-hydroxysteroid-dehydrogenase type I may be of therapeutical interest for two reasons: i) 9a-Fluorinated 11-dehydrosteroids like 11-dehydro-dexamethasone (DH-D) are rapidly activated by human kidney 11b-hydroxysteroid-dehydrogenase type II (11b-HSD-II) to dexamethasone (D). If the same reaction by hepatic 11b-HSD-I could be selectively inhibited, DH-D could be used for selective renal immunosuppressive therapy. ii) Reduction of cortisone to cortisol in the liver may increase insulin resistance in type 2 diabetes mellitus, and inhibition of the enzyme may lead to a decrease in gluconeogenesis.Therefore, we characterized the metabolism of DH-D by human hepatic 11b-HSD-I and tried to find a selective inhibitor of this isoenzyme. Methods: For kinetic analysis of 11b-HSD-I, we used microsomes prepared from unaffected parts of liver segments, resected because of hepatocarcinoma or metastatic disease. For inhibition experiments, we also tested 11b-HSD-II activity with human kidney cortex microsomes. The inhibitory potency of several compounds was evaluated for oxidation and reduction in concentrations from 10 ¹9 to 10 ¹5 mol/l. Results: Whereas D was not oxidized by human liver microsomes at all, cortisol was oxidized to cortisone with a maximum velocity (V max ) of 95 pmol/mg per min. The reduction of DH-D to D (V max = 742 pmol/ mg per min, Michaelis-Menten constant (K m ) = 1.6 mmol/l) was faster than that of cortisone to cortisol (V max =187 pmol/mg per min). All reactions tested in liver microsomes showed the characteristics of 11b-HSD-I: K m values in the micromolar range, preferred cosubstrate NADP(H), no product inhibition. Of the substances tested for inhibition of 11b-HSD-I and -II, chenodeoxycholic acid was the only one that selectively inhibited 11b-HSD-I (IC 50 for reduction: 2.8 × 10 ¹6 mol/l, IC 50 for oxidation: 4.4 × 10 ¹6 mol/l), whereas ketoconazole preferentially inhibited oxidation and reduction reactions catalyzed by 11b-HSD-II. Metyrapone, which is reduced to metyrapol by hepatic 11b-HSD-I, inhibited steroid reductase activity of 11b-HSD-I and -II and oxidative activity of 11b-HSD-II. These findings can be explained by substrate competition for reductase reactions and by product inhibition of the oxidation, which is a well-known characteristic of 11b-HSD-II. Conclusions: Our in vitro results may offer a new concept for renal glucocorticoid targeting. Oral administration of small amounts of DH-D (low substrate affinity for 11b-HSD-I) in combination with chenodeoxycholic acid (selective inhibition of 11b-HSD-I) may prevent hepatic first pass reduction of DH-D, thus allowing selective activation of DH-D to D by the high affinity 11b-HSD-II in the kidney. Moreover, selective inhibitors of the hepatic 11b-HSD-I, like chenodeoxycholic acid, may become useful in the therapy of patients with hepatic insulin resistance including diabetes mellitus type II, because cortisol enhances gluconeogenesis.