Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy.

PURPOSE: Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI). METHODS: We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19-83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 µg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E). RESULTS: The sensitive 1.8 µg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 µg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 µg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively. CONCLUSION: Saliva cortisol showed acceptable performance only with the 5.0 µg/dL cortisol cutoff, as in overt Cushing's syndrome. Lower cutoffs (1.8 and 2.5 µg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST.

Zona fasciculata 21-hydroxysteroids and precursor-to-product ratios in 21-hydroxylase deficiency: further characterization of classic and non-classic patients and heterozygote carriers.

INTRODUCTION: Although much is known about the increased levels of the 21-hydroxylase substrates 17-hydroxyprogesterone (17OHP) and 21-deoxycortisol (21DF) - the biochemical markers of all forms of 21-hydroxylase deficiency (21OHD), only limited information is available on the zona fasciculata (ZF) products distal to the enzymatic block: 11-deoxycortisol (S), 11-deoxycorticosterone (DOC), and corticosterone (B). OBJECTIVE: To investigate whether basal and post-ACTH levels of S, DOC, and B and the 21-hydroxylase precursor-to-product ratios determined by tandem mass spectrometry preceded by high-performance liquid chromatography separation (liquid chromatography-tandem mass spectrometry) could disclose distinct profiles in genotypically confirmed classic (no.=14) and non-classic (NC) (no.=18) patients, heterozygote carriers (no.=61) and wildtypes (WT) (no.=27) for 21OHD. RESULTS: Salt wasting (SW) and simple virilizing (SV) had higher basal levels of DOC with no further increase in response to ACTH. Stimulated DOC was similar in 21OHD patients and carriers but was reduced as compared to WT. ACTH-stimulated B increased gradually from SW and SV through WT. The post-ACTH 21DF/B ratio was able to detect 92% of the carriers among WT. All NC patients could be detected by post-ACTH 17OHP/DOC and 21DF/B, with no overlap with 21OHD carriers. CONCLUSION: Although 21-hydroxylase is a key enzymatic step in both 17-hydroxy and 17-deoxy pathways of ZF, the reaction is mostly affected in the latter pathway, leading to a significant impairment of B production, which may further characterize the 21OHD subtypes. Also, the precursor-to-product ratios, particularly 21DF/B, can demonstrate the distinctive outline of 21OHD subtypes, including carriers and normal subjects.

Impact of prolonged physical training on the pituitary glucocorticoid sensitivity determined by very low dose intravenous dexamethasone suppression test.

The activity of the hypothalamic-pituitary-adrenal axis is usually modulated by several stress factors, including exercise. Different responses are induced by physical training according to duration and intensity of exercise. During prolonged training, cortisol remains normal or decreased as a consequence of altered cortisol secretion, metabolism and excretion, and possibly by changes in glucocorticoid sensitivity. The aim of this study was to evaluate the impact of prolonged physical training on the glucocorticoid sensitivity. Eighteen cadets of the Air Force Academy, mean (SD) age: 18.7 (1.0) years, underwent an intensive 6-week preparatory training-period considered adequate by inducing significant changes on body composition measured by bioelectrical impedance. Measurement of individual's pituitary glucocorticoid sensitivity was done by an intravenous very low dose dexamethasone suppression test (20 microg/m (2)) that was performed before and after the training period. Cortisol levels were obtained at basal condition and 120 minutes after the dexamethasone infusion. Basal cortisol showed a significant decrease after prolonged training. The percent cortisol suppression after dexamethasone tended to be lower after the training period. Overall, our data suggest that prolonged physical training is able to reduce glucocorticoid sensitivity, which can have a beneficial impact in chronic stress conditions.

Autoantibodies against glutamic acid decarboxylase and 21-hydroxylase in Brazilian patients with type 1 diabetes or autoimmune thyroid diseases.

Autoimmune thyroid diseases (ATD) are often associated with Type 1 diabetes mellitus (T1DM) and Addison's disease (AD), characterizing the autoimmune polyendocrine syndrome. We evaluated the frequency of autoantibodies against glutamic acid decarboxylase isoform 65 (GAD65Ab) and 21-hydroxylase (21OHAb) in the sera of 65 [58 females (F)/7 males (M), 17-70 yr] patients with Graves' disease (GD) and 47 (45 F/2 M, 12-77 yr) with Hashimoto's thyroiditis (HT), none of whom had either diabetes or AD. The sera of 30 recently diagnosed T1DM patients (16 M/14 F, 1-39 yr) and of 97 (54 F/43 M, 7-69 yr) healthy controls were also examined. GAD65Ab were detected in the sera of 18 (60%) T1DM, 8 (12%) GD and in none of the HT patients or the controls (p = 0.03 for GD vs HT, p = 0.002 for GD vs controls, and p < 0.001 for GD vs T1DM). 21OHAb were detected in the sera of 2 (3%) GD, 1 (2%) HT and in none of the T1DM patients or the controls. GAD65Ab levels were significantly lower in GD than in T1DM patients (median: -0.06 vs 0.28, p < 0.001). Six of the 8 GD GAD65Ab-positive patients submitted to an intravenous glucose tolerance test showed no diminished first phase insulin secretion. All 21OHAb positive patients had normal basal cortisol and adrenocorticotropin (ACTH), normal cortisol response after ACTH stimulation, but high plasma renin activity. In conclusion, despite the genetic diversity of the Brazilian population, the frequency of GAD65Ab and 21OHAb in our patients is similar to that observed in other countries. GAD65Ab were more prevalent in GD than in HT patients, suggesting a difference in the immune response between these disorders. Long-term follow-up is necessary to determine the clinical relevance of these autoantibodies in the Brazilian population.

Cortisol, DHEAS and aging: resistance to cortisol suppression in frail institutionalized elderly.

Convincing evidences has linked the hypothalamus-pituitary-adrenal (HPA) axis to aging patterns. F excess is implicated in the development of frailty characteristics whereas DHEAS is positively correlated to successful aging. We compared serum F and DHEAS levels of independent community-living (successful group, 19 M and 28 F, 69 to 87 yr) with those of institutionalized elderly (frail group, 20 M and 30 F, 65 to 95 yr). Serum F was determined at 1) baseline (08:00 h, 16:00 h and 23:00 h), 2) after 2 overnight dexamethasone (DEX) suppression tests (DST, using 0.25 and 1.0 mg doses), and 3) 60 min after ACTH stimulation (250 microg i.v. bolus); serum DHEAS was determined at 08:00 h. Basal serum F at 08:00 h, 16:00 h and 23:00 h and serum DHEAS levels were similar in both groups; however F: DHEAS ratio at 08:00 h was higher in the frail, compared to the successful group (mean +/- SD: 0.55 +/- 0.53 and 0.35 +/- 0.41, respectively; p = 0.04). In response to DST, F suppression was less effective in frail elderly after either 0.25 or 1.0 mg doses (9.0 +/- 6.0 and 2.0 +/- 0.9 microg/dl), as compared to the successful group (5.8 +/- 4.4 and 1.5 +/- 0.5 microg/dl) (p = 0.01). In addition, a significant correlation was observed between post-DEX F levels (both doses) and parameters of cognitive and physical frailty. Normal and similar F levels were observed after ACTH stimulation in both groups. Our data suggest a deficient feedback regulation of the HPA axis in frail institutionalized elderly, as demonstrated by a higher set point for F suppression. This augmented HPA tonus enforces the hypothesis that even milder F excess may be related to characteristics of frailty in the elderly.

Autoantibodies against recombinant human steroidogenic enzymes 21-hydroxylase, side-chain cleavage and 17alpha-hydroxylase in Addison's disease and autoimmune polyendocrine syndrome type III.

OBJECTIVE: To evaluate the frequency of autoantibodies (Ab) against 21 hydroxylase (21OH), side-chain cleavage (SCC) and 17alpha-hydroxylase (17OH), in Addison's disease (AD) and autoimmune polyendocrine syndrome type III (APSIII). DESIGN AND METHODS: We used radiobinding assays and in vitro translated recombinant human (35)S-21OH, (35)S-SCC or (35)S-17OH and studied serum samples from 29 AD (18 idiopathic, 11 granulomatous) and 18 APSIII (autoimmune thyroid disease plus type 1 diabetes mellitus, without AD) patients. Results were compared with those of adrenocortical autoantibodies obtained with indirect immunofluorescence (ACA-IIF). RESULTS: ACA-IIF were detected in 15/18 (83%) idiopathic and in 1/11 (9%) granulomatous AD subjects. 21OHAb were found in 14/18 (78%) idiopathic and in the same (9%) granulomatous AD subject. A significant positive correlation was shown between ACA-IIF and 21OHAb levels (r(2)=0.56, P<0.02). The concordance rate between the two assays was 83% (24/29) in AD patients. SCCAb were found in 5/18 (28%) idiopathic (4 of whom were also positive for 21OHAb) and in the same (9%) granulomatous AD subject. 17OHAb were found in only 2/18 (11%) idiopathic and none of the granulomatous AD patients. Two APSIII patients were positive for ACA-IIF, but only one was positive for 21OHAb and SCCAb. 17OHAb were found in another two APSIII patients. CONCLUSIONS: Measurement of 21OHAb should be the first step in immune assessment of patients with AD and individuals at risk for adrenal autoimmunity, in addition to ACA-IIF. Due to their low prevalence in AD, measurement of SCCAb and 17OHAb should be indicated only for 21OHAb negative patients and/or for those with premature ovarian failure, regardless of ACA-IIF results.

IGF-I levels rise and GH responses to GHRH decrease during long-term prednisone treatment in man.

Glucocorticoid excess is associated with a blunted GH response to GHRH. IGF-I levels in hypercortisolism are controversial and have been reported as low, normal or high. The aim of this study was to evaluate longitudinally time-dependent changes in the GH response to GHRH, IGF-I, IGFBP-3 and albumin values in patients during corticotherapy. Six patients received GHRH before and after one week and one month of prednisone administration (20-60 mg/d, orally). IGF-I, IGFBP-3 and albumin were determined in each test, at time 0. Ten normal controls were also evaluated in one occasion. There were no differences in basal GH values, GH response to GHRH, IGF-I and IGFBP-3 levels between controls and patients before starting corticotherapy. Albumin (g/l; mean+/-SE) values were lower in patients before treatment (31+/-4) than in controls (43+/-1). After one week of prednisone administration there was a significant decrease in peak GH (microg/l) levels (before: 18.8+/-7.4; 1 week: 5.0+/-1.3), which was maintained after one month (8.1+/-3.5). IGF-I (microg/l) levels increased significantly, from 145+/-23 to 205+/-52 after one week of therapy, reaching levels of 262+/-32 after one month. IGFBP-3 (mg/l) values did not increase significantly (before: 2.1+/-0.2; 1 week: 2.5+/-0.3; 1 month: 2.8+/-0.2). Albumin levels showed a significant rise both after one week (36+/-4) and one month (42+/-3) of corticotherapy. In summary, we observed a marked decrease in the GH response to GHRH after one week and one month of prednisone administration associated with an increase in circulating IGF-I and albumin values. The physiological implications of these findings are still uncertain. It is possible that glucocorticoids increase hepatic IGF-I and albumin synthesis, although other mechanisms may have a role.

Detection of adrenocortical autoantibodies in Addison's disease with a peroxidase-labelled protein A technique

Adrenocortical autoantibodies (ACA), present in 60-80 percent of patients with idiopathic Addison's disease, are conventionally detected by indirect immunofluorescence (IIF) on frozen sections of adrenal glands. The large-scale use of IIF is limited in part by the need for a fluorescence microscope and the fact that histological sections cannot be stored for long periods of time. To circumvent these restrictions we developed a novel peroxidase-labelled protein A (PLPA) technique for the detection of ACA in patients with Addison's disease and compared the results with those obtained with the classical IIF assay. We studied serum samples from 90 healthy control subjects and 22 patients with Addison's disease, who had been clinically classified into two groups: idiopathic (N = 13) and granulomatous (N = 9). ACA-PLPA were detected in 10/22 (45 percent) patients: 9/13 (69 percent) with the idiopathic form and 1/9 (11 percent) with the granulomatous form, whereas ACA-IIF were detected in 11/22 patients (50 percent): 10/13 (77 percent) with the idiopathic form and 1/9 (11 percent) with the granulomatous form. Twelve of the 13 idiopathic addisonians (92 percent) were positive for either ACA-PLPA or ACA-IIF, but only 7 were positive by both methods. In contrast, none of 90 healthy subjects was found to be positive for ACA. Thus, our study shows that the PLPA-based technique is useful, has technical advantages over the IIF method (by not requiring the use of a fluorescence microscope and by permitting section storage for long periods of time). However, since it is only 60 percent concordant with the ACA-IIF method, it should be considered complementary instead of an alternative method to IIF for the detection of ACA in human sera

Detection of adrenocortical autoantibodies in Addison's disease with a peroxidase-labelled protein A technique.

Adrenocortical autoantibodies (ACA), present in 60-80% of patients with idiopathic Addison's disease, are conventionally detected by indirect immunofluorescence (IIF) on frozen sections of adrenal glands. The large-scale use of IIF is limited in part by the need for a fluorescence microscope and the fact that histological sections cannot be stored for long periods of time. To circumvent these restrictions we developed a novel peroxidase-labelled protein A (PLPA) technique for the detection of ACA in patients with Addison's disease and compared the results with those obtained with the classical IIF assay. We studied serum samples from 90 healthy control subjects and 22 patients with Addison's disease, who had been clinically classified into two groups: idiopathic (N = 13) and granulomatous (N = 9). ACA-PLPA were detected in 10/22 (45%) patients: 9/13 (69%) with the idiopathic form and 1/9 (11%) with the granulomatous form, whereas ACA-IIF were detected in 11/22 patients (50%): 10/13 (77%) with the idiopathic form and 1/9 (11%) with the granulomatous form. Twelve of the 13 idiopathic addisonians (92%) were positive for either ACA-PLPA or ACA-IIF, but only 7 were positive by both methods. In contrast, none of 90 healthy subjects was found to be positive for ACA. Thus, our study shows that the PLPA-based technique is useful, has technical advantages over the IIF method (by not requiring the use of a fluorescence microscope and by permitting section storage for long periods of time). However, since it is only 60% concordant with the ACA-IIF method, it should be considered complementary instead of an alternative method to IIF for the detection of ACA in human sera.

Randomised controlled trial of growth effect of hydrocortisone in congenital adrenal hyperplasia.

The influence of 15 or 25 mg/m2 of daily oral hydrocortisone with fludrocortisone 0.1 mg/day on growth and laboratory findings was evaluated in a prospective randomised crossover trial over 12 months in 26 children with 21-hydroxylase deficiency. Nine non-salt losers had fludrocortisone stopped for a further six month period. Height velocity was significantly decreased during treatment with 25 mg/m2 as compared with 15 mg/m2. This was the most sensitive indicator of corticosteroid treatment excess. A dose dependent effect upon plasma concentrations of 17-hydroxyprogesterone, testosterone, and androstenedione was found but increased values were still detected in more than half of the determinations made during the 25 mg/m2 period. Height velocity and 17-hydroxyprogesterone concentrations were positively correlated. Growth hormone response to clonidine stimulation and insulin-like growth factor-1 concentrations were both within reference values and there was no difference between treatment periods. Withdrawal of fludrocortisone did not result in any difference for the non-salt losers. It was concluded that 25 mg/m2 of hydrocortisone depressed growth in children with congenital adrenal hyperplasia, and that full suppression, or even normalisation, of plasma concentrations of 17-hydroxyprogesterone and androgens should not be considered a treatment goal, but instead an indication of corticosteroid treatment excess.

Growth hormone axis in cushing's syndrome.

All levels of the growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor (IGF) and IGF binding protein (IGFBP) axis are influenced by chronic hypercortisolism. Thus, there is a blunted response to GHRH alone or together with other stimuli associated with a marked suppression of endogenous GH secretion but accompanied by normal GHBP, normal to low IGF-1 and GHBPs 1 and 3 with the correspondent 41.5 and 38.5-kD molecular forms of the latter presenting values similar to normal. These findings may suggest enhanced GH sensitivity with normal or increased IGF-1 bioavailability to the correspondent tissue receptors. In conclusion, the glucocorticoid (GC)-induced target tissue resistance can neither be attributed to the suppression of the GH axis nor to changes in circulating GHBPs 1 and 3. However, it may be related either to the described 12-to-20-kD inhibitor(s) which antagonizes postbinding IGF-1 bioactivity (gene expression) and/or by the downmodulation of activator protein-1 (Fos/Jun) activity by the GC-GC receptor complex.

Acute adrenal haemorrhage: diagnosis, treatment and follow-up.

Acute adrenal haemorrhage (AAH) is a rare disorder with different aetiologies. Aiming to discuss this condition, this report deals with four different cases that will be analysed and examined below, each one of them confirmed by biopsy or surgery and followed clinically and radiologically. In these cases it was found that the patients suffered from localized abdominal pain (4/4) and fever (2/4); one patient had adrenal insufficiency due to bilateral massive AAH. Therefore we concluded that AAH is an uncommon condition with variable clinical manifestations.

Estímulo do eixo hipófise-adrenocortical com o hormônio liberador de corticotrofina (CRH) na síndrome de imunodeficiência adquirida: evidência de ativaçäo do sistema imune-neuroendócrino / Stimulus of hypophyseal-adrenocortical axis with the corticotropin releasing hormone (CRH) in acquired immunodeficiency syndrome: evidence for activation of the immune-neuroendocrine system

Portadores de AIDS podem apresentar alteraçöes primárias e/ou secundárias do eixo hipotálamo-hipofisário-adrenocortical (EHHA), com manifestaçöes clínicas que väo de crises addisonianas a quadros de hipercortisolismo. Objeto. Avaliar o EHHA de 20 pacientes de AIDS e 17 controles normais, mediante testes de estímulo com ACTH exógeno (cosintropina, 250µg IV em bolo, com dosagem de cortisol basal e 60min após) e, subseqüentemente, teste de estímulo com hormônio liberador de corticotrofina ovino sintético (oCRH, 1µg/kg IV em bolo, com dosagens de ACTH e cortisol basais e a intervalos de 15-30min durante duas horas). Resultados. Diferente dos voluntários normais, pacientes de AIDS apresentaram estado de hipercortisolismo basal e após estímulo, tanto com cosintropina como com o CRH; cortisol (em µg/dL, média + or - cosintropina - basal 22,5 + or - 7,1 x 10,6 + or - 3,6 (p < 0,01) e após estímulo, 36,0 + or - 12,8 x 28,3 + or - 7,6 (p< 0,05); teste de oCRH - basal 19,7 + or - 9,0 x 10,1 + or - 3,4 (p < 0,01) e no pico de resposta, 27,5 + or - 8,9 x 18,3 + or 0 5,1 (p < 0,05). Além disso, a secreçäo de ACTH encontrava-se também significantemente mais elevada nos pacientes de AIDS após o teste de estímulo com o CRH; ACTH (em pg/mL) nos pacientes com AIDS x normais: teste de oCRH - basal 42,2 + or - 33,5 x 28,9 + or - 12,7 (NS) e no pico de resposta, 104,7 + or - 62,2 x 59,3 + or - 17,6 (p < 0,05). Conclusöes. Pela condiçäo de estresse continuado, os pacientes de AIDS apresentam estado de hipercortisolismo e de hipersecreçäo de ACTH, revelando resistência ao mecanismo de feedback negativo. Este fenômeno pode ser explicado pela interaçäo do sistema imunológico com o EHHA, com ativaçäo deste eixo pela liberaçäo de linfocinas circulantes que estimulariam, diretamente, hipotálamo e hipófise a produzir CRH e ACTH, respectivamente

[Stimulus of the hypophyseal-adrenocortical axis with corticotropin releasing hormone (CRH) in acquired immunodeficiency syndrome. Evidence for activation of the immune-neuroendocrine system]. / Estímulo do eixo hipófise-adrenocortical com o hormônio liberador de corticotrofina (CRH) na síndrome de imunodeficiência adquirida. Evidência de ativação do sistema imune-neuroendócrino.

Ten-20% of patients with AIDS may present clinical evidence of primary or secondary adrenal insufficiency. PURPOSE--To evaluate the hypothalamic-pituitary-adrenocortical axis (HPAA) with CRH in patients with AIDS. METHODS--We studied 20 patients with AIDS and 17 normal subjects (NS) with exogenous ACTH (cosyntropin, 250 micrograms IV bolus) followed one week later by ovine corticotropin releasing hormone (oCRH 1 microgram/kg BW IV bolus). Basal and 60' cortisol (micrograms/dL) were determined in the former whereas ACTH (pg/mL) and cortisol were measured every 15-30' for 2 hours in the latter. RESULTS--Basal and peak values (mean +/- SD) of ACTH and cortisol for both tests were: cosyntropin test (AIDS x NS): basal cortisol 22.5 +/- 7.1 x 10.6 +/- 3.6 (p < 0.01), peak 36.0 +/- 12.8 x 28.3 +/- 7.6 (p < 0.05); oCRH test: basal ACTH 42.2 +/- 33.5 x 28.9 +/- 12.7 (NS), peak 104.7 +/- 62.2 x 59.3 +/- 17.6 (p < 0.05); basal cortisol 19.7 +/- 9.0 x 10.1 +/- 3.4 (p < 0.01), peak 27.5 +/- 8.9 x 18.3 +/- 5.1 (p < 0.05). CONCLUSION--AIDS patients had elevated basal and CRH stimulated ACTH levels and an intact glucocorticoid pathway with elevated basal and peak cortisol levels to both stimulation tests. This situation is probably due to the stressful disease condition, where lymphokines may play a role activating the hypothalamic-pituitary axis.

Systematic evaluation of the adrenocortical function in patients with paracoccidioidomycosis.

Limited cortisol response to ACTH stimulation has been documented in 22 to 48% of patients with paracoccidioidomycosis (PM). Different approaches to interpret the test and inadequate selection of patients preclude an accurate appraisal of the actual incidence of adrenal insufficiency in PM. Rapid cosyntropin (ACTH) stimulation tests were performed in 38 consecutive patients (9 with the localized and 29 with the disseminated form of PM) and 40 normal controls. Subnormal cortisol responses to ACTH (60 minutes post-ACTH values below 455 nmol/l, 95% confidence limits) were found in only 4 patients (14%) with disseminated PM. If a retrospective sample of 6 patients studied previously (in whom tests were indicated due to clinical suspicion of Addison's disease) were included, or if the absolute cortisol increment above baseline was used for interpretation, we would find figures closer to those previously reported (23 and 24%, respectively). These data reflect that non-systematic evaluation or selection of a substandard criterion to interpret the test overestimates the frequency of adrenocortical insufficiency in PM.

Disorders of steroid 17 alpha-hydroxylase deficiency.

The human P450c17 alpha gene (CYP17) is a single copy gene located in chromosome 10, consisting of 8 exons and 7 introns. 17 alpha-Hydroxylase/17,20-lyase deficiency is one of two hypertensive forms of congenital adrenal hyperplasia and is inherited as an autosomal recessive trait; although rare, it probably exists with twice the frequency of the 11 beta-hydroxylase deficiency. Deficient 17 alpha-hydroxylation of pregnenolone and progesterone and subsequent deficiency of the cleavage of the C-17,20 carbon bond result in the absence of sex hormone formation in both the adrenal glands and the gonads, causing hypogonadism and male pseudohermaphroditism. Elevated and glucocorticoid-suppressible levels of the ZF 17-deoxysteroids--DOC and corticosterone--as well as their 18-hydroxylated products--18-OHDOC and 18-OHB (in addition to 19-nor-DOC)--are responsible for hypertension, hypokalemia, and renin and aldosterone suppression. A few cases, reported primarily among Japanese families, have basal hyperaldosteronism, an enigmatic condition that still demands adequate explanation. Like other forms of congenital adrenal hyperplasia, treatment of 17 alpha-hydroxylase deficiency consists of replacement doses of glucocorticoid hormones and supplemental estrogen therapy in the young adult patient. Heterozygotes may be detected by slightly exaggerated responses of some or all the ZF 17-deoxysteroids to ACTH stimulation, and by the elevated ratio of total urinary metabolites of corticosterone to the total metabolites of cortisol.

Comparative study of two tests of renal diluting ability in Bartter's syndrome.

1. Different results concerning distal NaCl reabsorption have been reported for patients with Bartter's syndrome in tests of renal diluting ability. We describe clearance studies performed on 3 patients with Bartter's syndrome using different routes for body fluid content expansion: water was given orally and 0.45% NaCl solution intravenously. The impact of fluid composition was evaluated in one patient who additionally underwent a "reverse test": i.e., intravenous 5% glucose in water and an oral load of 0.45% NaCl solution. 2. Urine flow per ml glomerular filtration rate (GFR) reached higher levels when the iv route was used (20.6 +/- 1.8 vs 11.8 +/- 5.7%, P < 0.05). Fractional excretion of Na+, Cl- and osmoles increased during NaCl infusion but not during the oral load. Also, distal delivery of solute increased and was greater than that observed in the oral test (21.9 +/- 5.5 vs 11.4 +/- 2.1%, P < 0.05). 3. In contrast, fractional distal chloride reabsorption in the iv test reached subnormal values which were lower than in the oral load test (65.0 +/- 11.2 vs 86.8 +/- 11.0%, P < 0.05). A positive correlation was observed between distal delivery and Cl- fractional excretion (r = 0.87; P < 0.005). In one patient, the 5% glucose infusion resulted in greater urine flow and distal delivery when compared to distilled water or 0.45% NaCl taken orally (28.1 vs 13.3 ml/min and 27.3 vs 12.8%, respectively). These values were as high as those observed during iv administration of hypotonic saline. 4. The iv route was always associated with lower rates of fractional distal chloride reabsorption (70.7 vs 89.1%) regardless of the solute composition and should be recommended when testing the renal diluting ability of patients suspected of Bartter's syndrome.

Comparative study of two tests of renal diluting ability in Bartter's syndrome

1. Different results concerning distal NaCl reabsorption have been reported for patients with Bartter's syndrome in tests of renal diluting ability. We describe clearance studies performed on 3 patients with Bartter's syndrome using different routes for body fluid content expansion: water was given orally and 0.45 NaCl solution intravenously. The impact of fluid composition was evaluated in one patient who additionally underwent a "reverse test": i.e., intravenous 5 glucose in water and an oral load of 0.45 NaCl solution. 2. Urine flow per ml glomerular filtration rate (GFR) reached higher levels when the iv route was used (20.6 +/- 1.8 vs 11.8 +/- 5.7, P < 0.05). Fractional excretion of Na+, Cl- and osmoles increased during NaCl infusion but not during the oral load. Also, distal delivery of solute increased and was greater than that observed in the oral test (21.9 +/- 5.5 vs 11.4 +/- 2.1, P < 0.05). 3. In contrast, fractional distal chloride reabsorption in the iv test reached subnormal values which were lower than in the oral load test (65.0 +/- 11.2 vs 86.8 +/- 11.0, P < 0.05). A positive correlation was observed between distal delivery and Cl- fractional excretion (r = 0.87; P < 0.005). In one patient, the 5 glucose infusion resulted in greater urine flow and distal delivery when compared to distilled water or 0.45 NaCl taken orally (28.1 vs 13.3 ml/min and 27.3 vs 12.8, respectively). These values were as high as those observed during iv administration of hypotonic saline. 4. The iv route was always associated with lower rates of fractional distal chloride reabsorption (70.7 vs 89.1) regardless of the solute composition and should be recommended when testing the renal diluting ability of patients suspected of Bartter's syndrome.

Different effects of pyridostigmine on growth hormone (GH) response to GH-releasing hormone in endogenous and exogenous hypercortisolemic patients.

1. Somatostatin may play a role in the inhibition of growth hormone (GH) response to GH-releasing hormone (GHRH) in hypercortisolism. To examine this hypothesis we studied the effect of pyridostigmine, a cholinergic agonist that decreases hypothalamic somatostatin, on the GH response to GHRH in 8 controls, in 6 patients with endogenous hypercortisolism (3 with Cushing's disease and 3 with adrenal adenomas) and in 8 patients with exogenous hypercortisolism (lupus erythematosus chronically treated with 20-60 mg/day of prednisone). Each subject received GHRH(1-29)NH2,100 micrograms iv twice, preceded by pyridostigmine (120 mg) or placebo, orally. 2. The GH response to GHRH was significantly blunted in all hypercortisolemic patients compared to controls both after placebo (GH peak, 5.8 +/- 1.6 vs 46.2 +/- 15.9 micrograms/l, mean +/- SEM) and after pyridostigmine (15.7 +/- 5.6 vs 77.2 +/- 19.8 micrograms/l). 3. The GH response was absent in endogenous hypercortisolemic patients compared to the exogenous group, both after placebo (2.2 +/- 0.3 vs 8.5 +/- 2.4 micrograms/l) and after pyridostigmine (4.9 +/- 2.5 vs 23.8 +/- 8.7 micrograms/l). The GH release after GHRH/pyridostigmine for the exogenous group was similar to the response of controls treated with GHRH/placebo. 4. These results confirm that the GH response to GHRH is blunted in hypercortisolism, although more pronounced in the endogenous group. Pyridostigmine partially reversed this inhibition in the exogenous group. Therefore, somatostatin may play a role in the inhibition of GHRH-induced GH release in exogenous hypercortisolemic states.

Different effects of pyridostigmine on growth hormone (GH) response to GH-releasing hormone in endogenous and exogenous hypercortisolemic patients

1. Somatostatin may play a role in the inhibition of growth hormone (GH) response to GH-releasing hormone (GHRH) in hypercortisolism. To examine this hypothesis we studied the effect of pyridostigmine, a cholinergic agonist that decreases hypothalamic somatostatin, on the GH response to GHRH in 8 controls, in 6 patients with endogenous hypercortisolism (3 with Cushing's disease and 3 with adrenal adenomas) and in 8 patients with exogenous hypercortisolism (lupus erythematosus chronically treated with 20-60 mg/day of prednisone). Each subject received GHRH(1-29)NH2,100 micrograms iv twice, preceded by pyridostigmine (120 mg) or placebo, orally. 2. The GH response to GHRH was significantly blunted in all hypercortisolemic patients compared to controls both after placebo (GH peak, 5.8 +/- 1.6 vs 46.2 +/- 15.9 micrograms/l, mean +/- SEM) and after pyridostigmine (15.7 +/- 5.6 vs 77.2 +/- 19.8 micrograms/l). 3. The GH response was absent in endogenous hypercortisolemic patients compared to the exogenous group, both after placebo (2.2 +/- 0.3 vs 8.5 +/- 2.4 micrograms/l) and after pyridostigmine (4.9 +/- 2.5 vs 23.8 +/- 8.7 micrograms/l). The GH release after GHRH/pyridostigmine for the exogenous group was similar to the response of controls treated with GHRH/placebo. 4. These results confirm that the GH response to GHRH is blunted in hypercortisolism, although more pronounced in the endogenous group. Pyridostigmine partially reversed this inhibition in the exogenous group. Therefore, somatostatin may play a role in the inhibition of GHRH-induced GH release in exogenous hypercortisolemic states