Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unlike other forms of primary aldosteronism, recent prospective studies have paradoxically revealed that glucocorticoid-remediable aldosteronism (GRA) is usually characterized by normal potassium (K+) levels. To evaluate this paradox we studied 10 GRA subjects and 14 healthy controls in two protocols: 1) the renal K+ excretory response to acute oral administration of 50 mmol K+ chloride and to fludrocortisone, 0.2 mg p.o. q12 h x 4 doses; and 2) the aldosterone response to administration of 50 mmol K+ chloride. The K+ excretion rate (KER) in GRA subjects (n = 6) at baseline (45.6 +/- 8.3 microEq/min), after K+ (134 +/- 34.2 microEq/min), and after fludrocortisone (100 +/- 35.0 microEq/min) was not significantly different than that seen in the control (n = 8) subjects (54.9 +/- 19.0, 154 +/- 35.5, 112 +/- 45.8 microEq/min, respectively). Thus the renal kaliuretic response to K+ ingestion and exogenous mineralocorticoid is normal in GRA. Serum aldosterone increased from 5.0 +/- 3.8 at baseline to a maximum of 13.1 +/- 6.6 ng/dL 60 min after K+ ingestion in control subjects (n = 7), but failed to increase in GRA subjects (n = 14), going from 8.7 +/- 3.8 (baseline) to 8.8 +/- 5.4 ng/dL at 60 min (P = 0.004 vs. control). The blunted aldosterone response to K+ in GRA in association with the sharp diurnal decline in aldosterone in this ACTH-regulated syndrome probably results in a milder degree of hyperaldosteronism compared with other forms of primary aldosteronism, thereby producing volume expansion with minimal renal K+ wasting.
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PMID:Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism. 939 55

X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.
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PMID:Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene. 970 29

Myotonic muscular dystrophy (MMD) is a disease of autosomal dominant inheritance characterized by multisystem disease, including myotonia, muscle-wasting and weakness of all muscular tissues, and endocrine abnormalities attributed to a genetic abnormality causing a defective cAMP-dependent kinase. We have previously reported that MMD patients demonstrate ACTH hypersecretion after endogenous CRH release stimulated by naloxone administration while manifesting a normal cortisol (F) response. Additionally, others have reported a reduced adrenal androgen (AA) response to exogenous ACTH administration in MMD patients. As ACTH stimulates the secretion of both AAs and F, it is possible that the discordant relationship of these hormones in MMD patients results from a defect of adrenocortical ACTH receptor function or postreceptor signaling or subsequent biochemical events. Furthermore, the molecular abnormality seen in MMD patients may suggest that the mechanism underlying the frequently observed discordances in the secretion of glucocorticoids and AAs (e.g. adrenarche, surgical trauma, severe burns, or intermittent glucocorticoid administration) are explainable solely via an alteration in the function of the ACTH receptor or postreceptor signaling. To ascertain whether the responses of F and AAs to endogenous ACTH diverged in this disorder, we prospectively studied the responses of these hormones to naloxone-stimulated CRH release in nine premenopausal women with MMD and seven healthy age and weight-matched control women. After naloxone infusion (125 micrograms/kg, i.v.), blood sampling was performed at baseline (i.e. -5 min) and at 30 and 60 min. In addition to the absolute hormone level at each time, we calculated the net increment (i.e. change) at 30 and 60 min and the area under the curve (AUC) for F, ACTH, dehydroepiandrosterone (DHA), and androstenedione (A4). Consistent with our previous study, MMD patients demonstrated higher ACTH levels at all sampling times except [minud]5 min. AUC analysis revealed the ACTHAUC values were significantly higher in MMD than in control women (457 +/- 346 vs. 157 +/- 123 pmol/min.L; P < 0.03), whereas the FAUC response did not differ between MMD and controls (13860 +/- 3473 vs. 13375 +/- 3465 nmol/min.L; P > 0.5). Despite the greater ACTH secretion, the baseline circulating dehydroepiandrosterone sulfate levels were significantly lower in MMD compared with control women (18 +/- 23 vs. 61 +/- 23 mumol/L; P < 0.002). The serum concentrations of A4 at baseline, 30 min, and 60 min and DHA levels at 30 and 60 min were also significantly lower in MMD vs. control women. Additionally, the A4AUC and DHAAUC values were significantly lower in MMD patients than in controls. Furthermore, the net response of DHA at 60 min to the endogenous ACTH increase was also reduced in MMD patients compared with that in control subjects (2.3 +/- 2.1 vs. 5.6 +/- 2.6 nmol/L; P < 0.02). In conclusion, in addition to ACTH hypersecretion to CRH-mediated stimuli, these data suggest that MMD patients have a defect in the adrenocortical response to ACTH, reflected in normal F and reduced DHA and A4 secretion. Whether this defect is inherent to the disease or simply reflects adaptive changes to chronic disease remains to be demonstrated. However, it is possible that further studies of the response of MMD patients to ACTH may reveal a mechanism that explains the frequently observed dichotomy in the secretion of glucocorticoids and AAs.
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PMID:Androgen response to hypothalamic-pituitary-adrenal stimulation with naloxone in women with myotonic muscular dystrophy. 974 31

Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder of steroid biosynthesis, caused by a molecular defect in the steroidogenic acute regulatory protein (StAR). Patients with CLAH usually manifest severe salt wasting, hypovolemia, enlargement of the adrenal glands and complete female external genitalia irrespective of the gonadal sex. CLAH seems to be more common in Koreans and Japanese than in other ethnic populations, with a preponderance of the mutation of a glutamine to a stop codon at the 258th amino acid residue (Q258X) in the StAR gene. Clinical findings of five unrelated Korean patients with CLAH and their molecular defects in the StAR gene are described, and the gene frequency of the Q258X mutation in the Korean population is investigated. All patients developed hypovolemic shock due to severe salt wasting in the first three months after birth. All were hyperpigmented, and three of five phenotypic females were genetic males. The basal ACTH level was extremely high in all patients with the minimal concentrations of all adrenal and gonadal steroids. The Q258X mutation was identified in 9 out of 10 alleles, indicating that the genetic defect in the StAR gene of Korean patients with CLAH is highly homogeneous probably due to a founder effect. The carrier frequency of the Q258X mutation in the normal Korean population has been estimated as approximately 1 in 250 with the allele frequency of 1 in 500. However, the confidence limits of the gene frequency for the mutant allele are wide (0.5 to 8.0 among 1,000 alleles). This implies that the carrier frequency could be lower, down to 1/1,000, or higher, up to 16/1,000.
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PMID:Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia. 982 24

An unexplained hallmark of prolonged critical illness is the fact that food does not prevent or reverse protein wasting, while fat is paradoxically accrued. This 'wasting syndrome' often persists after the underlying disease has been resolved and thus perpetuates intensive care dependency. Although the crucial role of an intact hypothalamus-pituitary axis for homeostasis during stress is well recognized, the differences between the neuroendocrine changes observed in acute and prolonged critical illness were only recently described. Novel insights in this area are reviewed here. The initial endocrine stress response consists primarily of a peripheral inactivation of anabolic pathways while pituitary activity is essentially amplified or maintained. These responses presumably provide the metabolic substrates and host defense required for survival and to delay anabolism, and thus should be considered as adaptive and beneficial. Persistence of this acute stress response throughout the course of critical illness was hitherto assumed. This assumption has now been invalidated, since a uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH has been observed in protracted critical illness, causing diminished stimulation of several target organs. Impaired pulsatile secretion of anterior pituitary hormones in the chronic phase of critical illness seems to have a hypothalamic rather than a pituitary origin, as administration of relevant releasing factors evoked immediate and pronounced pituitary hormone release. A reduced availability of TRH, one of the endogenous ligands of the GH-releasing peptide (GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay critically ill men, also of GHRH, appear to be involved. This hypothesis was further explored by investigating the effects of continuous i.v. infusion of GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of GH, TSH and PRL was re-amplified by relevant combinations of releasing factors which also substantially increased circulating levels of IGF-I, GH-dependent binding proteins, thyroxine and tri-iodothyronine (T3) while avoiding a rise in reverse T3. Active feedback-inhibition loops prevented overstimulation of target organs and metabolic improvement was noted with the combined infusion of GHRP and TRH. Whether this novel endocrine strategy will also enhance clinical recovery from critical illness remains to be explored.
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PMID:Novel insights into the neuroendocrinology of critical illness. 1087 25

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis size was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.
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PMID:X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients. 1093 Nov 8

Multidrug antiretroviral regimes in HIV-infected patients may have side effects. The most frequent side effects are changes in fat metabolism and distribution. We describe a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth and fat loss in the lower limbs, which occurs in approximately 10% of HIV-infected women treated with combined antiretroviral therapy. To elucidate the metabolic, endocrine, and immunologic consequences of the observed disturbance, we measured serum lipids, glucose, C-peptide, ACTH, plasma, urinary cortisol, and cytokines IL-2, IFN gamma, Il-4, IL-10, Il-12, and TNF alpha in 36 patients with FR and in a control group without FR. There were no significant differences in hormonal and metabolic laboratory testing between the two groups. Immunology studies showed that in vitro production of TNF alpha and IL-10 was lower and IL-12 production higher in SR patients. Whether or not such immune alterations may be reponsible or be caused by fat redistribution remains to be explained. One year after the follow up, 50% of the patients treated with triple therapy developed lipodystrophy, characterized by weight loss, face-wasting, and hyperglycemia; the remaining 50% remained unchanged. In 13 patients the 3TC withdrawal was followed by improvements of the syndrome in 50% and of lipodystrophy in about 25%. These data suggest that the FR syndrome is frequent in patients treated with 3TC and that it is associated with characteristic changes in the cytokine production.
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PMID:Fat redistribution in HIV-infected patients. A new hormonal-immune disorder? 1126 26

Adrenal nodules have been described in patients with 21-hydroxylase deficiency (21OHD). These nodules are usually considered to be ACTH-dependent, as is the commonly seen diffuse cortical hyperplasia. We evaluated the presence and behavior of adrenal nodules in patients with 21OHD. Based upon hormonal status and treatment compliance, the patients were classified into three categories: poor, regular and good control. Out of the 26 patients, eight had the non-classic, four salt-wasting and 14 simple virilizing forms. All patients underwent initial adrenal morphological studies, either by CT or MRI. Those with nodules were reevaluated after 12 months of adequate replacement therapy. Nodules were found in four of eight untreated patients and two of three patients with poor hormonal control, but not in the 15 patients with regular or good control. Adrenal nodules in these six patients demonstrated a considerable size reduction and even disappearance after adequate replacement therapy, showing that these nodules were ACTH-dependent. Thus, six out of 26 patients with 21OHD presented adrenal nodules, which were more frequent in the untreated or poorly-controlled patients, and all regressed in size after adequate therapy.
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PMID:Adrenal nodules in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: regression after adequate hormonal control. 1132 75

Cognition in patients with CAH has not been as well studied as other aspects of psychologic function. Nevertheless, it is possible to make some conclusions and to offer a number of hypotheses for further study (Table 1). First, patients with CAH do not seem to have an overall intellectual advantage as a direct consequence of the disease. The high IQs reported in some groups of patients with CAH are also reported in their siblings and probably reflect sampling bias. Second, it is possible that, on average, patients with salt-wasting CAH have lower overall ability than patients with the simple-virilizing form, but both groups are well within the normal range, and there is considerable variability among both groups. Third, the evidence to date does not confirm that patients with CAH are more likely to have diagnosable learning disabilities when compared with their unaffected relatives, but this issue has not been well studied with the appropriate psychoeducational assessments. It is unlikely that patients with CAH are at substantially increased risk for frank learning disabilities, but they may be likely to have problems in specific areas. Fourth, females with CAH seem to have enhanced spatial ability as a result of exposure to high levels of androgens early in development. The neural substrate of this advantage is unknown but a subject of active research. It is unclear whether when compared with their unaffected siblings, females with CAH are better in other abilities that are typically performed best by males or worse in abilities typically performed best by females. Fifth, it is likely that patients with CAH have other cognitive changes as a consequence of disease characteristics (besides androgens) and of the treatment of the disease. Some evidence suggests that patients with CAH are more likely to have white-matter brain changes produced by the disease and its treatment. This has not been well studied but should be because of the potential clinical implications. It is reasonable to hypothesize that there will be cognitive changes that reflect effects of undertreatment (e.g., ACTH effects on attention) and other changes that reflect effects of overtreatment (e.g., glucocorticoid effects on memory). Some of these effects may be transient, reflecting acute brain changes, whereas others may become chronic as a result of permanent brain changes with repeated exposure. There is need for continuing study of cognition in patients with CAH. Such studies will provide basic information about hormonal effects on cognition and the neural mechanisms that mediate those effects. They will also provide important clinical information to guide psychologic and medical treatment of patients.
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PMID:Cognitive function in congenital adrenal hyperplasia. 1134 35

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.
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PMID:Transient pseudohypoaldosteronism with complex malformation of internal genitalia. A case report. 1135 9


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