Peptide

Adrenocorticotropic hormone 
Adrenocorticotropic hormone (ACTH) or corticotropin, is a  hormone produced by the anterior pituitary gland in response to biological stress by effecting the increased production and release of corticosteroids(a)

1. Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis
Stress alters brain-gut interactions and could exacerbate intestinal disorders, including irritable bowel syndrome. Alterations in the intestinal microbiota have been associated with irritable bowel syndrome.
In the study to mice that were not exposed to stress were co-housed with mice subjected to WAS to determine the effects of WAS-induced dysbiosis, measured by sequencing bacterial 16S ribosomal RNA. We also assessed the effects of a peroxisome proliferator-activated receptor-γ agonist and probiotics, found that mice expose to stress inhibits NLRP6 and alters the composition of the gut microbiota, leading to intestinal inflammation. These findings might explain the benefits of probiotics for patients with stress-associated gastrointestinal disorders(1).

2. Corticotropin-releasing hormone in depression and post-traumatic stress disorder
Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction.  According to the study by the Cincinnati VAMC, Psychiatry Service, overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis(2).

3. Early-life stress-induced anxiety-related behavior in adult mice 
Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. In the study used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress, indicated that as adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice(3).

4. Stress and Visceral Pain: Focusing on Irritable Bowel Syndrome
Irritable bowel syndrome (IBS) is characterized by chronic recurrent abdominal pain or abdominal discomfort associated with bowel dysfunction. According to the study by the Tohoku University Graduate School of Medicine Sendai, it is also thought to be a disorder of the brain-gut link associated with an exaggerated response to stress. Corticotropin-releasing hormone (CRH), a major mediator of the stress response in the brain-gut axis, is an obvious candidate in the pathophysiology of IBS. Indeed, administration of CRH has been shown to aggravate the visceral sensorimotor response in IBS patients and the administration of peptidergic CRH antagonists seems to alleviate IBS pathophysiology. Serotonin (5-HT) is another likely candidate associated with brain-gut function in IBS since 5-HT3 antagonists, 5-HT4 agonists, and antidepressants were demonstrated to regulate 5-HT neurotransmission in IBS patients. Autonomic nervous system function, the neuroimmune axis, and the brain-gut-microbiota axis show specific profiles in IBS patients(4).

5. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation
Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress.  The study by  Tohoku University Graduate School of Medicine, first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients and administered alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by alphahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing(5).

6. Effect of a corticotropin releasing hormone receptor antagonist on colonic sensory and motor function in patients with IBS.
Corticotropin releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with an exaggerated response to stress. In the study of ten normal healthy subjects and 10 IBS patients, diagnosed according to the Rome II criteria, the tone of the descending colon and intraluminal pressure of the sigmoid colon were measured at baseline, during rectal electrical stimulation (ES), and at recovery after administration of saline and visceral perception after colonic distension or rectal ES was evaluated as threshold values on an ordinate scale. The same measurements were repeated after administration of alphahCRH (10 micro g/kg), found that peripheral administration of alphahCRH improves gastrointestinal motility, visceral perception, and negative mood in response to gut stimulation, without affecting the hypothalamo-pituitary-adrenal axis in IBS patients(6).

7. Impact of corticotropin-releasing hormone on gastrointestinal motility and adrenocorticotropic hormone in normal controls and patients with IBS
Corticotropin-releasing hormone (CRH) plays a key role in modulating intestinal motility in stressed animals. In the study to evaluate the effect of CRH on intestinal motility in humans and to determine whether patients with irritable bowel syndrome (IBS) have an exaggerated response to CRH, showed that
CRH induced motility of the descending colon in both groups (p < 0.001) and induced greater motility indexes in IBS patients than in controls (p < 0.05). CRH produced duodenal phase III motor activity in 80% of the subjects and duodenal dysmotility in 40% of IBS patients. Abdominal symptoms evoked by CRH in IBS patients lasted significantly longer than those in controls (p < 0.05). CRH induced significant increases in plasma ACTH levels in both groups (p < 0.001) and produced significantly higher plasma ACTH levels in IBS patients than in controls (p < 0.001)(7).

8. Placental Corticotropin-Releasing Hormone Mediates the Association Between Prenatal Social Support and Postpartum Depression


In the study to test whether prenatal social support predicted depressive symptoms at 8 weeks postpartum in a multiethnic sample of 210 women and whether the stress hormone placental corticotropin-releasing hormone (pCRH), measured at 19, 29, and 37 weeks' gestation, mediated this relationship, found that prenatal family support predicted significantly fewer depressive symptoms postpartum and more gradual increases in pCRH from 29 to 37 weeks' gestation. Furthermore, steeper increases in pCRH during this same period predicted more depressive symptoms postpartum. Finally, these changes in pCRH in late pregnancy mediated the relationship between prenatal family support and postpartum depressive symptoms. These results suggest that social and biological risk factors for postpartum depressive symptoms are intertwined and move us closer to an integrated biopsychosocial understanding of postpartum depression(8).

9. Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy
Corticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. In the study of a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples was collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay and each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record, found that maternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length(9).

10. Predicting risk of preterm delivery by second-trimester measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations
In the study to  to evaluate the ability of these biochemical tests and a clinical risk factor score to prospectively discriminate pregnancies at high risk for preterm delivery with a sample of eight hundred sixty women were studied prospectively from the early second trimester until delivery found that the combination of measurement of maternal plasma corticotropin-releasing hormone and alpha-fetoprotein concentrations in the second trimester with risk factor scoring provides a more accurate indicator of the risk of preterm delivery than does risk factor scoring alone. This method of risk assessment may therefore be of use in targeting prevention strategies(10).

























11. Central deficiency of corticotropin-releasing hormone receptor type 1 (CRH-R1) abolishes effects of CRH on NREM but not on REM sleep in mice
Corticotropin-releasing hormone (CRH) is the major activator of the hypothalamic-pituitary-adrenocortical (HPA) system and orchestrates the neuroendocrine, autonomous as well as behavioral responses to stress. In the study to investigate in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity, found that CRH has a major impact on wake and NREMS regulation which is predominantly mediated through central CRH-R1. Peripheral actions of CRH, i.e., elevated HPA activity, may interfere with its central effects on REMS but not on NREMS suppression(11).

12. Deficiency of corticotropin-releasing hormone type-2 receptor alters sleep responses to bacterial lipopolysaccharide in mice
In the study to investigate whether CRH-R2 interferes with sleep responses to immune challeng and to examine effects of bacterial lipopolysaccharide (LPS) on sleep in CRH-R2 deficient (KO) mice. CRH-R2 KO mice and control littermates (CL) were implanted with electrodes for recording electroencephalogram (EEG) and electromyogram, indicated that after recovery, LPS was applied by intraperitoneal injection at doses of 0.1, 1.0, or 10 μg at dark onset. In response to LPS injection NREMS of both genotypes was enhanced in a dose-dependent manner. However, CRH-R2 KO mice showed a larger increase, in particular after 10 μg of LPS compared to CL mice. During postinjection, reduced delta power for NREMS was detected in both genotypes after each dose, but the highest dose evoked a marked elevation of EEG activity in a limited frequency band (4 Hz). However, the EEG power of lower frequencies (1-2 Hz) increased more in CRH-R2 KO than in CL mice(12).

13. Corticotropin-releasing hormone exerts direct effects on neuronal progenitor cells: implications for neuroprotection
In the study to investiage the involvement process of corticotrophin-releasing hormone (CRH) or factor as the major mediator of adaptive response to stressors, found that  CRH could reverse the damaging effects of glucocorticoid on neural stem/progenitor cells (NS/PCs), while its genetic deficiency results in compromised proliferation and enhanced apoptosis during neurogenesis. Analyses in fetal and adult mouse brain revealed significant expression of CRH receptors in proliferating neuronal progenitors. Furthermore, by using primary cultures of NS/PCs, we characterized the molecular mechanisms and identified CRH receptor-1 as the receptor mediating the neuroprotective effects of CRH. Finally, we demonstrate the expression of CRH receptors in human fetal brain from early gestational age, in areas of active neuronal proliferation. These observations raise the intriguing possibility for CRH-mediated pharmacological applications in diseases characterized by altered neuronal homeostasis, including depression, dementia, neurodegenerative diseases, brain traumas and obesity(13).

14. Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior
In the study to investigate whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice, showed that Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior(14).

15.. Corticotropin-releasing hormone deficiency is associated with reduced local inflammation in a mouse model of experimental colitis
CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. AQccording to the study by Division of Endocrinology, Children's Hospital, Boston, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism(15).

16. Cell-type specific deletion of GABA(A)α1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction
Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. In the study used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO] resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus, showed that normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes(16).

17. A novel role of peripheral corticotropin-releasing hormone (CRH) on dermal fibroblasts
In the study to to assess the effects of endogenous CRH in the biology of mouse and human skin fibroblasts, the primary cell type involved in wound healing, showed that  expression of CRH and its receptors in primary fibroblasts, and we demonstrate the functionality of fibroblast CRH receptors by induction of cAMP. Fibroblasts genetically deficient in Crh (Crh-/-) had higher proliferation and migration rates and compromised production of IL-6 and TGF-β1 compared to the wildtype (Crh+/+) cells. Human primary cultures of foreskin fibroblasts exposed to the CRF(1) antagonist antalarmin recapitulated the findings in the Crh-/- cells, exhibiting altered proliferative and migratory behavior and suppressed production of IL-6(17).

18. Isolated adrenocorticotropic hormone deficiency presenting with hypercalcemia in a patient on long-term hemodialysis
There is a report of a report on a 44-year-old female hemodialysis (HD) patient who presented with hypercalcemia secondary to isolated adrenocorticotropic hormone (ACTH) deficiency. She had been suffering from nausea and abdominal pain caused by recurrent esophageal ulcer. Blood calcium (Ca) adjusted for serum albumin concentration was increased to 14.9 mg/dL (3.72 mmol/L) concurrently with fever and hypotension. Serum intact parathyroid hormone (PTH)-related peptide was not elevated, but serum intact PTH and 1,25-(OH)2 vitamin D3 were decreased to 31 pg/mL (ng/L) and 8.1 pg/mL (2.6 pmol/L), respectively. This case suggested that secondary adrenal insufficiency caused by isolated ACTH deficiency could be an occult cause of severe hypercalcemia in HD subjects(18).

19. May primary empty sella turcica be a cause of isolated ACTH deficiency
Isolated ACTH deficiency is an uncommon cause of secondary adrenocortical insufficiency and accompaniment with primary empty sella has been reported in several case. There is a report of a case of isolated ACTH deficiency associated with empty sella. A sixty-two year old woman was admitted to our endocrine clinic with complaints of weakness, fatigue, weight loss, nausea, vomiting, and lack of appetite for about one month. Physical examination indicated orthostatic hypotension and epigastric tenderness. Although cranial and abdominal computerized tomography images were evaluated as normal, cranial magnetic resonance imaging of the pituitary gland revealed 'primary empty sella turcica'. Replacement therapy with methylprednisolon resulted in the improvement of hypoglycemia, hyponatremia and clinical symptoms. Based on these results, the patient was diagnosed as isolated ACTH deficiency and was scheduled for follow up by our outpatient clinic(19).

20. The cause of syndrome of inappropriate ADH secretion" (SIADH)
According to the centre hospitalier régional universitaire de Lille, the causes of SIADH are classic: neoplastic (notably small-cell lung cancer), iatrogenic (particularly psychoactive drugs, chemotherapy), lung and cerebral. Some causes have been recently described: familial hyponatraemia via X-linked recessive disease caused by an activating mutation of the vasopressin 2 receptor; and corticotropin insufficiency related to drug interference between some inhaled glucocorticoids and cytochrome p450 inhibitors, such as the antiretroviral drugs and itraconazole, etc. SIADH in marathon runners exposes them to a risk of hypotonic encephalopathy with fatal cerebral oedema. SIADH treatment is based on water restriction and demeclocycline. V2 receptor antagonists are still not marketed in France. These aquaretics seem effective clinically and biologically, without demonstrated improvement to date of mortality in eu- and hypervolaemic hyponatraemia. Obviously treatment of a corticotropic deficit, even subtle, should not be overlooked, as well as the introduction of fludrocortisone in isolated hypoaldosteronism and discontinuation of iatrogenic drugs(20).

21. Severe Hypoglycemia due to Isolated ACTH Deficiency in Children
Isolated ACTH deficiency causes life-threatening severe hypoglycemia. There is a report of a patient had undetectable plasma ACTH repeatedly and cortisol 0 mcg/dl before and after ACTH 1-24 stimulation. There was no evidence of other pituitary hormone deficiency. Glucocorticoid replacement therapy resulted in resolution of all symptoms and normalization of blood glucose. Previously published data on isolated ACTH deficiency in children is summarized. Review of the literature showed that the prevalence of this condition could be underestimated in the neonatal period and in Prader-Willi syndrome. Isolated ACTH deficiency occurs in older children as well as in neonates(21).

22. ACTH deficiency suspected as depression with severe appetite loss
There is a report of a patient showed severe appetite loss and vomiting in May of the year X. His business had started to experience difficulty two months earlier. A medical workup of the digestive system and a brain MRI revealed no abnormality. Subsequently, the patient was referred for a psychiatric examination with suspected depression in August. Psychiatric pharmacotherapy improved his appetite only temporarily, and he was admitted as a psychiatric inpatient. A more thorough evaluation led to a diagnosis of isolated ACTH deficiency on the basis of abnormally low levels of ACTH and cortisol. The patient's symptoms improved with hydrocortisone supplementation. CASE II: A factory worker in his late fifties started to experience appetite loss, nausea/ vomiting, and decreased energy in May of the year Y, without any apparent cause. Medical evaluations by a family physician, a digestive system specialist, and a neurologist, including a brain CT, were unremarkable. Depression was suspected and the patient was referred to the authors' psychiatric clinic in July of the same year. Upon examination, the patient presented with depressive symptoms such as a depressed mood, decreased energy, middle insomnia, and loss of interest. Blood tests and a hormonal workup revealed abnormally low ACTH and cortisol levels. The patient was admitted as an inpatient of the endocrinology department, and a diagnosis of isolated ACTH deficiency was made. Hydrocortisone supplementation improved his symptoms. In both cases, anti-pituitary antibody was negative and there were no findings of an empty sella or swelling of the pituitary gland. Therefore, isolated ACTH deficiency was a more likely diagnosis than lymphocytic adenohypophysitis. It is important to diagnose this condition as early as possible since it is treatable with hydrocortisone supplementation with a favorable prognosis. Screening for ACTH and cortisol levels should be considered when symptoms of suspected depression include severe general fatigue and appetite loss with vomiting(22).

23. Elderly case of isolated ACTH deficiency presenting with depression and digestive symptoms
There is a report of a 76-year-old man first referred to his local hospital at the beginning of August 2005 with nausea and vomiting, and admitted on August 15 with progressive fatigue of unknown etiology. Gastrointestinal examination was performed, but no obvious abnormalities were detected in the upper or lower digestive tract. Hematology tests also revealed no abnormalities, except for slight eosinophilia. He developed depression and was given an antidepressant agent. After suffering from hyponatremia and disorientation, he was subsequently admitted to our hospital on August 28. At that time, serum adrenocorticotropic hormone (ACTH) and cortisol levels were low, while both the ACTH and corticotrophin-releasing hormone (CRH) stress tests showed no response. Other stress tests revealed normal responses, so he was given a diagnosis isolated ACTH deficiency and received corticosteroid therapy(23).































24. May hydrocortisone cause adrenocorticotropic hormone (ACTH) deficiency





 There is a report of a case of ACTH deficiency. A 75-year-old man complained of anoxia, nausea and vomiting. Three years ago, he had an attack of loss of consciousness. On admission, his serum sodium level was down to 119.6 mEq.l-1. Plasma osmolality was low and urinary osmolality was high without edema, and he was diagnosed as having SIADH. After CRH test, rapid ACTH test and continuous ACTH test, he was diagnosed as having ACTH deficiency, and he was treated with steroids. One year later, he received urethrotomy due to urethrostenosis under spinal anesthesia with no trouble. In the next year, he was scheduled for sigmoidectomy due to sigmoid colon cancer under general anesthesia combined with epidural anesthesia. In the morning of his operation, he took hydrocortisone 10 mg per os. During operation, hydrocortisone 300 mg was given intravenously divided for three times. Plasma ACTH and aldosterone levels were below normal ranges, but serum cortisol was above the normal range. His operation was finished without troubles. Regarding this case, we discussed steroid therapy during anesthesia and operation(24).

25. Testicular adrenal rest "tumor" or Leydig cell tumor
There is a report of a case of mass-forming TART and we discuss the clinical, radiological, and morphological features as well as the major differential diagnosis of this rare lesion. Testicular adrenal rest tumors (TARTs) are an important complication of CAH, which probably develop from ectopic remnants of intra-testicular adrenal tissue stimulated by Adrenocorticotropic hormone (ACTH) hypersecretion. These lesions are typically located within the rete testis and are bilateral, synchronous, nodular and multiple. TART usually, but not always, responses to suppressive medical therapy. TART leads to testicular structural damage, spermatogenesis disorders, infertility and most importantly, mass-forming lesions that could be mistaken for Leydig cell tumor (LCT). The later has a significantly different behavior with up to 10% of being malignant. Nowadays, due to advances in diagnosing and treating CAH, mass-forming TART is rarely encountered(25).

26. Isolated ACTH deficiency: a heterogeneous disorder
Isolated adrenocorticotropin (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency. The clinical manifestations of isolated ACTH deficiency are variable, nonspecific and similar to those seen in adrenocortical insufficiency of any cause. The diagnosis of isolated ACTH deficiency due to intrinsic pituitary disease is made unequivocally when all the following criteria are met: 1) low basal urinary 17-hydroxycorticosteroid (17-OHCS) levels with or without low basal plasma cortisol, 2) low or normal basal plasma ACTH, 3) stimulation of cortisol, 17-OHCS or both during prolonged ACTH administration, 4) lack of 17-OHCS elevation in response to metyrapone and 5) normal secretory indices of other pituitary hormones. Isolated ACTH deficiency secondary to suprapituitary (e.g., hypothalamic) dysfunction is also based upon the above criteria, but, in addition, is associated with stimulation of cortisol and ACTH secretion following vasopressin administration(26).

27. Isolated ACTH deficiency
Isolated ACTH is a rare cause of secondary adrenocortical insufficiency. The diagnosis is made by the demonstration of low cortisol production with low plasma ACTH, absent adrenal responses to stimulation for pituitary or hypothalamus with intact adrenal response to exogenous ACTH, and normal secretory indices of other pituitary hormones. We conclude that the diagnosis of this condition may be difficult due to the varied clinical presentation and etiologies, according to the study by the University of Alcalá de Henares(27).

28. Chronic adrenal failure secondary to an isolated deficiency of ACTH
Chronic adrenal failure due to hypothalamic-hypophyseal disorders is rarely encountered. This can be due to hormonal deficiencies generally related to the presence of a brain tumor or an infiltrating process and sometimes to an isolated deficiency of ACTH. There is a report of  two patients with adrenal failure with low basal cortisol levels and a poor response to short cortisol stimulation test with ACTH. Long cortisol stimulation test with ACTH was normal and ACTH was not stimulated with corticotropin releasing factor. However, other specific dynamic pituitary hormonal tests were normal. The uncommon clinical presentation of the disease, such as severe hypoglycemic crisis and fever of unknown origin (FUO), is underscored(28).

29. Thyroid dysfunction in isolated adrenocorticotropic hormone (ACTH) deficiency
There is a report of a 56-year-old woman, developed somnolence and hypoglycemia due to isolated ACTH deficiency. She also had the features of hypothyroidism, namely mounding phenomenon, muscle rigidity, increased plasma myogenic enzymes and cold intolerance. Both free T3 and free T4 were decreased, and basal as well as TRH-stimulated TSH levels were abnormally high. Plasma thyroglobulin was increased and no anti-thyroid antibodies were detected. All thyroid related physical and biochemical abnormalities disappeared after hydrocortisone replacement. A review of the literature on 103 cases disclosed that more than half the cases with isolated ACTH deficiency had a high plasma level of TSH, basal and/or TRH-induced, while the antithyroid antibodies were reported to be positive in only 13 cases. In more than 70% of such cases, the abnormality in the pituitary-thyroid axis was transient and was reversed by glucocorticoid replacement. Our case and cases in the literature indicate that the interference of thyroid hormone synthesis and/or secretion by glucocorticoid deficiency per se is the major cause of thyroid dysfunction rather than associated autoimmune thyroid disease(29).

30. Musculoskeletal symptoms and neurological investigations in adrenocortical insufficiency
There is a report of a case of a 61-year-old man with isolated adrenocorticotropic hormone deficiency who presented with musculoskeletal symptoms, including flexion contractures. We performed three neurological investigations: nerve conduction studies, electromyography, and muscle biopsy analysis. From the literature review, we found that (a) analysis of muscle biopsy is the most sensitive technique, followed by electromyography and then nerve conduction studies; and (b) the longer the duration of the musculoskeletal symptoms, the greater the incidence of abnormal findings with all three techniques(30).

31. Behçet disease with isolated ACTH deficiency
There is report of a case of a patient with longstanding Behçet disease, with neurological symptoms predominantly, who became hospitalized for adrenal insufficiency, caused by isolated deficiency of corticotropin (DAACTH). DAACTH is a typical characteristic of hypophysitis, reported in association with many autoimmune diseases. Nevertheless, hypothalamic-pituitary injury in Behçet disease is exceptional. We review the literature and possible mechanisms of this association until now not reported(31).

32. Isolated ACTH deficiency and primary thyroid insufficiency in an atopic patient: hypophysitis
There is a report of 6 years after surgery for epidermoid lung cancer, a 58-year-old man presented with atopic dermatitis and a high level of IgE, primary hypothyroidism of autoimmune origin, slight hyperprolactinemia and adrenal insufficiency of pituitary origin. ACTH levels were low and unresponsive to CRH. There was no deficiency of the other pituitary hormones and the MRI of the pituitary was normal. The other instances of autoimmune thyroiditis associated with ACTH deficiency are reviewed. The etiology of the deficiency is discussed in the context of a possible hypophysitis(32).

33. Isolated ACTH deficiency associated with Hashimoto disease
Isolated ACTH deficiency is a rare cause of secondary adrenocortical insufficiency. The diagnosis is made by the demonstration of low cortisol production with low plasma ACTH, absent adrenal responses to stimulation for pituitary or hypothalamus with intact adrenal response to exogenous ACTH, and normal secretory indices of other pituitary hormones. Although the pathogenesis of isolated ACTH deficiency is uncertain in most cases, autoimmune process is intimately involved as suggested by the histological evidence of lymphocytic hypophysitis and frequent observation of circulating antipituitary antibodies. In isolated ACTH deficiency, there have been occasional associations with Hashimoto disease which is characterized by the presence of a autoimmune mechanism, according to the study by the Osaka City University Medical School(33).

34. Isolated adrenocorticotropin deficiency and flexion contractures syndrome
There is a report of  a 73-year-old man with isolated adrenocorticotropic hormone deficiency and "flexion contractures" syndrome along with a review of the relevant literature. The patient initially presented anorexia, vomiting, arthralgias, malaise, and weight loss, which progressively deteriorated during the subsequent 6 months. He was admitted to the hospital with fever, confusion, severe cachexia, sinus tachycardia, low blood pressure, hyponatremia, and inability to stand or walk due to severe flexion contractures of the lower extremities (from hips to knees). The flexion contractures were not resolved by physiotherapy or diazepam administration. Due to his life-threatening condition the patient was empirically submitted to glucocorticoid replacement therapy and a remarkable relief from all the above symptoms was observed. A subsequent thorough endocrine investigation suggested the diagnosis of isolated ACTH deficiency (IAD) of unknown pathogenetic mechanism(34).

35. Flexion contractures of the legs as the initial manifestation of adrenocortical insufficiency
There is a report of a 51-year-old woman presented with flexion contractures of the legs. Physical examination showed decreased passive movements of the bilateral hip and knee joints without muscle spasms or neurological abnormalities. Laboratory evaluation showed no response of ACTH or plasma cortisol to stimulation with CRH or insulin. Diagnosis of isolated adrenocorticotropic hormone deficiency was made. The patient was started on prednisolone 5 mg daily, and flexion contractures of the legs rapidly disappeared. Although the musculoskeletal manifestation of this patient is similar to that of stiff-person syndrome, flexion contracture of the legs associated with adrenocortical insufficiency seems to be a separate disease entity from stiff-person syndrome(35).

36. Mental deterioration and hypertension: uncommon manifestation of corticotropin insufficiency and functional carboxymethyl oxidase block




There is a report of a a new case of muscle contractures associated with adrenocortical deficiency. Outstanding features were the diffusion of the contractures, rhabdomyolysis and an encephalopathy which disappeared with hormonal therapy. Endocrinological investigations revealed a functional carboxymethyl oxidase type II defect which could, in part, explain our patient's neuromuscular symptoms(36).

37. Acquired corticotropin insufficiency in adults
There is a report of two new cases of isolated corticotropin deficiency, associated with TSH deficiency in one of the two patient. The diagnostic was made difficult because the symptoms were mainly psychiatric. Low plasmatic cortisol and ACTH level were found, with low T3, T4 and TSH in the second patient. The TSH did not respond to the stimulation by TRH. The cerebral tomodensitometry and magnetic resonance imaging focused on the sella turcica were normal, eliminated a tumor and showed an empty sella turcica. The patients have to be followed-up because an isolated deficiency may further complete to panhypopituitarism(37).

38. Dementia with contractures' as presenting signs of secondary adrenocortical insufficiency
There is a report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed(38).

39. Isolated acquired ACTH deficiency and primary hypothyroidism
Idiopathic isolated ACTH deficiency, congenital or acquired, is rare. It may be found in association with primary hypothyroidism. There is a report of four cases of acquired idiopathic isolated ACTH deficiency illustrating its importance and variable presentation. All cases had a structurally normal pituitary gland and persistently normal residual pituitary function. Three cases had co-existing primary hypothyroidism. We discuss the protean presentation of this rare but important condition, its treatment, associations, and possible aetiologies(39).

40. Early-onset severe obesity with ACTH deficiency and red hair in a boy
There is a report of a  patient of 2.8 years old male who is extremely obese and severe hyperphagic from birth. He had seizures attacks and apnea from the second week of his life. He has red hair and serum cortisol and ACTH levels are very low. We examined our patient as a hypocortisolism due to ACTH deficiency and central hypothyrodism. After the corticosteroid replacement therapy hair color changed to brown. We performed molecular genetic analysis at the Institue for Experimental Pediatric Endocrinology laboratory in Berlin, Germany by Krude H. and found compound heterozygous mutations. As a result the case is diagnosed as POMC deficiency(40).

Sources
(a) http://en.wikipedia.org/wiki/Adrenocorticotropic_hormone
(1) http://www.ncbi.nlm.nih.gov/pubmed/23470617
(2) http://www.ncbi.nlm.nih.gov/pubmed/11337099
(3) http://www.ncbi.nlm.nih.gov/pubmed/22672268
(4) http://www.ncbi.nlm.nih.gov/pubmed/24021863
(5) http://www.ncbi.nlm.nih.gov/pubmed/17238026
(6) http://www.ncbi.nlm.nih.gov/pubmed/15194643
(7) http://www.ncbi.nlm.nih.gov/pubmed/9691924
(8) http://www.ncbi.nlm.nih.gov/pubmed/23997996
(9) http://www.ncbi.nlm.nih.gov/pubmed/9790402
(10) http://www.ncbi.nlm.nih.gov/pubmed/10411821
(11) http://www.ncbi.nlm.nih.gov/pubmed/20394311
(12) http://www.ncbi.nlm.nih.gov/pubmed/21704697
(13) http://www.ncbi.nlm.nih.gov/pubmed/23380766
(14) http://www.ncbi.nlm.nih.gov/pubmed/23106615
(15) http://www.ncbi.nlm.nih.gov/pubmed/18403481
(16) http://www.ncbi.nlm.nih.gov/pubmed/22992651
(17) http://www.ncbi.nlm.nih.gov/pubmed/21765902
(18) http://www.ncbi.nlm.nih.gov/pubmed/12900850
(19) http://www.ncbi.nlm.nih.gov/pubmed/18063931
(20) http://www.ncbi.nlm.nih.gov/pubmed/22119069
(21) http://www.ncbi.nlm.nih.gov/pubmed/21760815
(22) http://www.ncbi.nlm.nih.gov/pubmed/21226246
(23) http://www.ncbi.nlm.nih.gov/pubmed/17337864
(24) http://www.ncbi.nlm.nih.gov/pubmed/12134656
(25) http://www.ncbi.nlm.nih.gov/pubmed/23984262
(26) http://www.ncbi.nlm.nih.gov/pubmed/6276646
(27) http://www.ncbi.nlm.nih.gov/pubmed/9568810
(28) http://www.ncbi.nlm.nih.gov/pubmed/2547231
(29) http://www.ncbi.nlm.nih.gov/pubmed/7920902
(30) http://www.ncbi.nlm.nih.gov/pubmed/21116065
(31) http://www.ncbi.nlm.nih.gov/pubmed/20096211
(32) http://www.ncbi.nlm.nih.gov/pubmed/8209203
(33) http://www.ncbi.nlm.nih.gov/pubmed/8254946
(34) http://www.ncbi.nlm.nih.gov/pubmed/19121993
(35) http://www.ncbi.nlm.nih.gov/pubmed/12924497
(36) http://www.ncbi.nlm.nih.gov/pubmed/8059160
(37) http://www.ncbi.nlm.nih.gov/pubmed/8191076
(38) http://www.ncbi.nlm.nih.gov/pubmed/3709003
(39) http://www.ncbi.nlm.nih.gov/pubmed/19110973
(40) http://www.ncbi.nlm.nih.gov/pubmed/23431750