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Query: UMLS:C0015672 (fatigue)
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Hereditary primary adrenal insufficiency syndromes due to ACTH resistance include hereditary glucocorticoid deficiency (HGD) and Allgrove's syndrome (AS). Patients with both conditions present in childhood with failure to thrive, weakness, and fatigue or adrenal crisis; patients with AS in addition have alacrima and achalasia (triple A syndrome). We studied four kindreds with HGD and four kindreds with AS for abnormalities of the ACTH receptor (ACTHR) gene. The ACTHR coding sequence in all AS kindreds and two HGD kindreds was normal. Analysis of the ACTHR gene of the proband in one of the HGD kindreds showed him to be homozygous for the previously described G221T transition causing a Ser74Ile substitution of the protein, which has been shown to inactivate the ACTHR in signal transduction. The proband in another HGD kindred was found to be a compound heterozygote with the G221T transition in one allele and a novel C818A transition in the other allele of ACTHR. The C818A transition caused the substitution of the highly conserved Pro273 by His in the receptor protein. In vitro expression of the mutated ACTHR in mouse melanoma M3 cells showed that at a medium ACTH concentration of 3 nM, cells transfected with the wild-type ACTHR produced twofold and threefold, respectively, of the amount of intracellular cAMP when compared to cells transfected with the ACTHR carrying the Pro273His and the Ser74Ile mutation, respectively, confirming that HGD in this kindred is caused by loss-of-function mutations of the ACTHR. These results showed that the genetic cause of the ACTH-resistant syndromes is heterogeneous.
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PMID:Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency. 975 16

A 33 year-old Japanese woman complained of generalized fatigue, recurrent infections and gradual weight loss 1 year after her first delivery. During delivery, no excessive bleeding or change in blood pressure was noted. On endocrinologic examination 2 years after delivery, she was found to have severe adrenal insufficiency and hypothyroidism. Pituitary function tests revealed impaired responses of ACTH, PRL and gonadotropins, and normal response of GH. TSH response to TRH was delayed but not exaggerated. Cranial magnetic resonance imaging showed an empty sella. The adrenal glands were responsive to extrinsic ACTH, and adequately accumulated 123I-aldosterol. Antipituitary and antithyroid autoantibodies were detected in her serum. She was diagnosed with partial hypopituitarism associated with empty sella syndrome. Approximately 2 months after administration of cortisone acetate 25 mg/ day her general condition was noticeably improved, with normalization of thyroid function and improvement of gonadotropin responses to GnRH. This case suggests that a physiologic dose of glucocorticoid is necessary to maintain not only thyroid function but also some of the remaining pituitary functions in patients with empty sella syndrome manifesting hypopituitarism.
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PMID:Reversible hypothyroidism in empty sella syndrome: a case report. 979 Feb 74

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.
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PMID:Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. 979 75

Pseudo-hypoaldosteronism (PHA) is due to mineralocorticoid resistance and manifests as hyponatremia and hyperkalemia with increased plasma aldosterone levels. It may be familial or secondary to abnormal renal sodium handling. We report the case of a 54-year-old woman with multifocal cancer of the colon, who developed PHA after subtotal colectomy, ileal resection and jejunostomy. She was treated with 6 g of salt daily to prevent dehydration, which she stopped herself because of reduced fecal losses. One month later she was admitted with signs of acute adrenal failure, i.e. fatigue, severe nausea, blood pressure of 80/60 mmHg, extracellular dehydration, hyponatremia (118 mmol/l); hyperkalemia (7.6 mmol/l), increased blood urea nitrogen (BUN) (200 mg/dl) and creatininemia (2.5 mg/dl), and decreased plasma bicarbonates level (HCO3-: 16 mmol/l; N: 27-30). However, the plasma cortisol was high (66 microg/100 ml at 10:00 h; N: 8-15) and the ACTH was normal (13 pg/ml, N: 10-60); there was a marked increase in plasma renin activity (>37 ng/ml/h; N supine <3), active renin (869 pg/ml; N supine: 1.120), aldosterone (>2000 pg/ml; N supine <150) and plasma AVP (20 pmol/l; N: 0.5-2.5). The plasma ANH level was 38 pmol/l (N supine: 5-25). A urinary steroidogram resulted in highly elevated tetrahydrocortisol (THF: 13.3 mg/24h; N: 1.4+/-0.8) with no increase in tetrahydrocortisone (THE: 3.16 mg/24h; N: 2.7+/-2.0) excretion, and with low THE/THF (0.24; N: 1.87+/-0.36) and alpha THF/THF (0.35; N: 0.92+/-0.42) ratios. The number of mineralocorticoid receptors in mononuclear leukocytes was in the lower normal range for age, while the number of glucocorticoid receptors was reduced. Small-bowel resection in ileostomized patients causes excessive fecal sodium losses and results in chronic sodium depletion with contraction of the plasma volume and severe secondary hyperaldosteronism. Nevertheless, this hyperaldosteronism may be associated with hyponatremia and hyperkalemia suggesting PHA related to the major importance of the colon for the absorption of sodium. In conclusion, this case report emphasizes 1) the possibility of a syndrome of acquired PHA with severe hyperkalemia after resection of the ileum and colon responding to oral salt supplementation; 2) the major increase in AVP and the small increase in ANH; 3) the strong increase in urinary THF with low THE/THF and alpha THF/THF ratios; 4) the normal number of lymphocytic mineralocorticoid receptors outside the acute episode.
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PMID:Transient pseudo-hypoaldosteronism following resection of the ileum: normal level of lymphocytic aldosterone receptors outside the acute phase. 1019 79

No inclusive or satisfactory biomedical explanation for chronic fatigue syndrome (CFS) has as yet been forwarded. Recent research suggests that a dysregulated hypothalamic-pituitary-adrenal axis (HPA) may be contributory, and in particular that there may be diminished forward drive and adrenal under-stimulation. In this preliminary study we wished to examine a cohort of CFS patients in whom evidence for such hypofunctioning was found. Our aim was to establish whether these patients had altered adrenal gland size. Patients were recruited from a fatigue clinic. Those who fulfilled the Centre for Disease Control and Prevention (CDC) criteria underwent a 1 microgram adrenocorticotropin (ACTH) stimulation test, a test of adrenal gland functioning. Eight subjects (five females, three males) with a subnormal response to this test underwent a computer tomography (CT) adrenal gland assessment. Measurements were compared with those from a group of 55 healthy subjects. The right and left adrenal gland bodies were reduced by over 50% in the CFS subjects indicative of significant adrenal atrophy in a group of CFS patients with abnormal endocrine parameters. This is the first study to use imaging methods to measure adrenal gland size in CFS. It is a limitation of this study that a selected CFS sample was employed. A future larger study would optimally employ an unselected cohort of CFS patients. This study has implications not only for the elucidation of CFS pathophysiology, but also for possible therapeutic strategies.
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PMID:Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. 1045 10

The effects of training and over-training on plasma cortisol and beta-endorphin (betaEP) concentrations at rest and after standardised exercise tests and the cortisol responses to adrenocorticotropin (ACTH) administration were investigated in standardbred horses. Twelve horses were divided randomly into control and over-trained (OT) groups after 17 weeks slow- and moderate-intensity treadmill training. The standardised treadmill exercise test consisted of 2 min at velocities corresponding to 30, 50, 70 and 100% of maximum O2 consumption. Over-training, defined as a significant decrease in body weight and treadmill run-time-to-fatigue in an incremental velocity test, occurred in the OT group after 32 weeks of training exercise. Peak cortisol concentrations after exercise decreased significantly in the OT group from 320+/-15.6 at week 8 to 245+/-17.0 nmol l(-1) at week 32, and mean cortisol concentrations over a 120-min period after exercise decreased from 258+/-11.7 to 192+/-16.6 nmol l(-1) (P<0.05). Mean and total cortisol and betaEP concentrations in resting horses were not significantly different after over-training. Peak cortisol concentrations after adrenocorticotropin (ACTH) administration were not significantly different in the over-trained group. Dysfunction of the hypothalamo-pituitary-adrenocortical axis occurs in over-trained horses, but this adaptation is not associated with a change in the adrenocortical responsiveness to ACTH.
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PMID:Plasma cortisol and beta-endorphin concentrations in trained and over-trained standardbred racehorses. 1065 Sep 95

We report a case of a seventy-year-old woman with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by Rathke's cleft cyst. She experienced nausea, vomiting, diarrhea, and headache and disturbance of consciousness induced by hyponatremia at a serum sodium level of 100 mEq/l. In spite of severe hyponatremia, urinary sodium excretion was not suppressed and serum osmolality (270 mOsm/kg) was lower than urine osmolality (304 mOsm/kg), and arginine vasopressin (AVP) remained within normal range. SIADH was diagnosed because she was free from other diseases known to cause hyponatremia such as dehydration, cardiac dysfunction, liver dysfunction, renal dysfunction, hypothyroidism, and adrenal insufficiency. Cranial computed tomographic (CT) scan and cranial magnetic resonance (MR) imaging showed a cystic lesion of approximately 2 cm in diameter in the pituitary gland. These images suggested that the cystic lesion was a Rathke's cleft cyst, which was the cause of SIADH. Water restriction therapy normalized her serum sodium concentration and improved her symptoms. After one year, she suffered from general fatigue, appetite loss, fever, and body weight loss (5 kg/2 months). She had neither hypotension nor hypoglycemia, but her serum sodium level was low and serum cortisol, ACTH, and urine free cortisol were very low. Therefore, secondary adrenal insufficiency was suspected and diagnosed by stimulation tests. After start of hydrocortisone replacement therapy (10 mg/day), her symptoms disappeared. In conclusion, Rathke's cleft cyst should be kept in mind as a potential cause in a patient with SIADH, hypopituitarism, and/or adrenal insufficiency.
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PMID:Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and adrenal insufficiency induced by rathke's cleft cyst: a case report. 1107 19

Several neuroendocrine studies have suggested hypoactivation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. One possible determinant of this neuroendocrine abnormality, as well as the primary symptom of fatigue, is reduced hypothalamic secretion of corticotropin-releasing hormone (CRH). Because CRH and vasopressin secreted from the hypothalamus act synergistically at the pituitary to activate ACTH secretion, the ACTH response to peripheral infusion of vasopressin can provide an indirect measure of hypothalamic CRH secretion. We measured the ACTH and cortisol response to a one hour infusion of arginine vasopressin in 19 patients with chronic fatigue syndrome and 19 age and sex matched healthy volunteers. Patients with chronic fatigue syndrome had a reduced ACTH response to the vasopressin infusion and a more rapid cortisol response to the infusion. These results provide further evidence of reduced hypothalamic CRH secretion in patients with chronic fatigue syndrome.
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PMID:Abnormalities in response to vasopressin infusion in chronic fatigue syndrome. 1108 63

Night shift work has often been associated with increasing degree and frequency of various psychologic complaints. The study examined whether psychologic states after night work are related to adaptive alterations of the cardiovascular and neuroendocrine systems. We studied 18 healthy nurses (age 29+/-2 years) engaged in a modified rapid shift rotation system (day work, 8:15-17:15; evening work, 16:00-22:00; night work, 21:30-8:30). Blood pressure, heart rate, RR interval variability (L/H and HF power spectrum for sympathetic and vagal activities), and physical activity were measured using a multibiomedical recorder for 24 h from the start of work during the night and day shifts. Plasma ACTH and cortisol concentrations were measured at the end of each shift and at 8:30 AM on a day of rest. Each subject's psychologic state was assessed using a validated questionnaire. Among the parameters measured, scores for confusion, depression, anger-hostility, fatigue and tension-anxiety were highest, and scores for vigor lowest, after a night shift. Systolic blood pressure and heart rate during work were lower during night shift than during day shift (119+/-2 vs. 123+/-1 mmHg, p<0.05 and 75+/-1 vs. 84+/-2 bpm, p<0.001, respectively). Both parameters were lower still (p<0.005 and p<0.05) when measured outside of the hospital under waking conditions following a night shift than following a day shift, even though the levels of physical activity were similar. The HF power spectrum of RR interval variability was greater not only during work (24.2+/-2.1 vs. 18.5+/-1.8 ms, p<0.005) but also during the awake period (29.1+/-2.5 vs. 24.4+/-2.6 ms, p<0.005) after the night shift compared with the day shift. Plasma ACTH and cortisol concentrations were lower after night work than in the day of rest (7.3+/-1.2 vs. 11.5+/-2.3 pg/ml, p<0.1 and 11.1+/-1.1 vs. 14.4+/-1.1 mg/dl, p< 0.05). Systolic and diastolic blood pressures during night shift work and the subsequent awake period correlated positively with scores for vigor and negatively with scores for confusion (p<0.05). Plasma ACTH and cortisol concentrations did not correlate with any psychologic scores. We conclude that psychologic disturbances after night work were associated with altered cardiovascular and endocrine responses in healthy nurses. Some of the psychologic complaints may be attributable to lower waking blood pressure.
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PMID:Influence of night shift work on psychologic state and cardiovascular and neuroendocrine responses in healthy nurses. 1121 26

alpha, beta, gamma-MSH and ACTH are derived from the same precursor, POMC(proopiomelanocortin), and are classified as melanocortin. alpha-MSH plays an important role in the regulation of appetite and energy expenditure via central melanocortin receptor, melanocortin 4 receptor(MC4R), which is expressed mainly in hypothalamus. alpha-MSH or its analogue shows inhibitory effect on appetite and inversely MC4R antagonist stimulates appetite. MC4R knock-out mice has adult-onset obesity and decreased energy expenditure. POMC gene expression in hypothalamus is partially regulated by leptin. Agouti-related peptide(AgRP), a homologue of agouti peptide and antagonist of MC3R and MC4R, is expressed in human brain and may act as a inhibitor of alpha-MSH. From the genetical aspect, the region near POMC gene, 2p23, is one of the susceptibility loci of human obesity. POMC gene mutations are found in two families, where mutations in both alleles cause human obesity, red hair, adrenal dysfunction, due to alpha-MSH and ACTH deficiencies. In morbidity obese patients, heterozygous MC4R gene mutations are found among 4% of them. These results suggest the importance of melanocortin and its receptors on appetite regulation in human.
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PMID:[Regulation of appetite by melanocortin and its receptors]. 1126 89


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