Basal Plasma Adrenocorticotropic Hormone Research Articles

Intact GR dimerization is critical for restraining plasma ACTH levels during chronic psychosocial stress

Male C57BL/6N mice exposed to the chronic subordinate colony housing (CSC; 19 days) paradigm, a preclinically validated model of chronic psychosocial stress, are characterized by unaffected basal morning plasma corticosterone (CORT) concentrations despite adrenal and pituitary hyperplasia and increased adrenocorticotropic hormone (ACTH) plasma concentrations, compared with single-housed control (SHC) mice. However, as CSC mice are still able to show an increased CORT secretion towards novel heterotypic stressors, these effects might reflect an adaptation rather than a functional breakdown of general hypothalamus-pituitary-adrenal (HPA) axis functionality. In the present study we used male mice of a genetically modified mouse line, to investigate whether genetically-driven ACTH overexpression compromises adaptational processes occurring at the level of the adrenals during CSC exposure. Experimental mice carried a point mutation in the DNA binding domain of the glucocorticoid (GC) receptor (GR), attenuating dimerization of GR (GRdim), resulting in a congenially compromised negative feedback inhibition at the level of the pituitary.In line with previous studies, CSC mice in both the wild type (WT; GR+/+) and GRdim group developed adrenal enlargement. Moreover, compared with respective SHC and WT mice, CSC GRdim mice show increased basal morning plasma ACTH and CORT concentrations. Quantitative polymerase chain reaction (qPCR) analysis revealed neither a genotype effect, nor a CSC effect on pituitary mRNA expression of the ACTH precursor proopiomelanocortin (POMC). Finally, CSC increased anxiety-related behavior, active coping and splenocyte in vitro (re)activity in both WT and GRdim mice, while a CSC-induced increase in adrenal lipid vesicles and splenic GC resistance was detectable only in WT mice. Of note, lipopolysaccharide (LPS)-stimulated splenocytes of GRdim mice were resistant to the inhibitory effects of CORT.Together our findings support the hypothesis that pituitary ACTH protein concentration is negatively controlled by GR dimerization under conditions of chronic psychosocial stress, while POMC gene transcription is not dependent on intact GR dimerization under both basal and chronic stress conditions. Finally, our data suggest that adrenal adaptations during chronic psychosocial stress (i.e., ACTH desensitization), aiming at the prevention of prolonged hypercorticism, are protective only to a certain threshold of plasma ACTH levels.

Management of pituitary pars intermedia dysfunction in practice: A clinical audit

In horses/ponies with pituitary pars intermedia dysfunction (PPID), pergolide mesylate treatment, with monitoring of therapeutic response, is recommended by contemporaneous literature and equine endocrinologists. However, it is unknown whether these recommendations are adhered to in private practice. This clinical audit aimed to compare treatment and monitoring of PPID cases in veterinary practice against available recommendations. Case data and basal plasma adrenocorticotropic hormone (ACTH) concentrations from all equids tested for PPID between 2012 and 2016 from a single veterinary practice in the UK were obtained. Records were reviewed and information on treatment and monitoring over the subsequent 2–6 years was extracted and compared with published recommendations. After exclusions, the audit population was 480 animals (median age, 20 years). The most common presenting signs were laminitis and/or historical laminitis (51.2%) and hypertrichosis and/or delayed coat shedding (24.5%). Based on seasonally adjusted reference intervals for basal ACTH concentration, 51.7% (n = 248) of animals were classified as positive, 37.1% (n = 178) as negative and 11.3% (n = 54) as equivocal for PPID. Records were available for 459 animals; of which pergolide treatment was initiated in 78.7% (n = 185/235) of positive cases, 19.2% (n = 10/52) of equivocal cases and 6.4% (n = 11/172) of cases classified as negative. Overall, 87.2% (n = 129/148) of cases commenced treatment as per recommendations. Only 77.7% (n = 160/206) of pergolide-treated animals had documented PPID monitoring and of these, only 48.1% (n = 77/160) had follow-up basal ACTH testing in the first 1–3 months following diagnosis. The findings confirm that management of PPID in veterinary practice fell below contemporaneous recommendations, especially for monitoring.

Seasonal variation of endogenous adrenocorticotropic hormone concentrations in healthy non-geriatric donkeys in Northern California

Elevated plasma adrenocorticotropic hormone (ACTH) is often used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. The hormone naturally increases in the fall in horses, and donkeys have been found to have higher ACTH concentrations than horses. However, circannual variation of ACTH has not been assessed in donkeys. The objective of the study was to establish seasonal variation of basal plasma ACTH concentrations over the course of a year in clinically healthy, non-geriatric donkeys. It was hypothesized that donkey ACTH concentrations would be higher than those reported in horses without PPID in all seasons, and that, similarly to horses, ACTH concentrations would further increase in the fall months. Twenty-six healthy adult donkeys (10 standards, 16 miniatures), a median (range) of 6 (2–13) years of age, were included. Donkeys were housed at a single location. Serial plasma samples were obtained monthly for 12 months. Plasma ACTH concentrations were determined by immunoassay. Data are presented as median (range), with a P-value < 0.05 considered significant. ACTH concentrations were lowest in the winter and spring [12.8 (5.0–73.6) pg/ml and 12.5 (2.8–62.6) pg/ml, respectively], with an increase in the summer [53.2 (29.7–305.0) pg/ml], and peak in the fall [77.1 (12.4–319.0) pg/ml]. ACTH concentrations were highest in the month of September [122.0 (41.7–319.0) pg/ml]. Donkey ACTH concentrations were higher than equine reference ranges from May through November but showed similar circannual variation with dramatic increases in the fall months. Species-specific reference ranges are necessary for accurate interpretation of endocrinopathy screenings in donkeys.

Sciatic nerve injury rebalances the hypothalamic-pituitary-adrenal axis in rats with persistent changes to their social behaviours.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic–pituitary–adrenal (HPA)‐axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA‐axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA‐axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA‐axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC2R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC2R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double‐labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA‐axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

Basal plasma adrenocorticotrophic hormone concentration for diagnosing pituitary pars intermedia dysfunction in horses: Comparative analysis of two systematic reviews

Basal plasma adrenocorticotrophic hormone concentration for diagnosing pituitary pars intermedia dysfunction in horses: Comparative analysis of two systematic reviews

Pituitary size alteration and adverse effects of radiation therapy performed in 9 dogs with pituitary-dependent hypercortisolism

The purpose of this study was to determine the therapeutic and/or adverse effects of radiation therapy (RT) against pituitary tumors in dogs with pituitary-dependent hypercortisolism, as monitored by frequent post-RT detailed MRI examinations, clinical signs, and changes in hormone concentrations. Nine dogs with an adrenocorticotropic hormone (ACTH)-secreting pituitary mass diagnosed by magnetic resonance imaging (MRI) underwent RT for 4weeks (total of 48Gy in 4-Gy fractions). Pituitary height/brain area (P/B) value, clinical signs, basal plasma ACTH concentrations, serum cortisol concentrations (pre- and post-ACTH stimulation test) and adverse effects of RT were evaluated before and post-RT.The P/B value was significantly lower in all nine dogs post-RT. One dog lacking any neurological signs demonstrated no change in clinical signs pre and post-RT. Out of 8 dogs which exhibited neurological signs pre-RT, half of them demonstrated complete resolution of their signs, whereas the other half showed transient resolution. In all animals with recurrence of neurological signs, pituitary tumor regrowth was not observed; however, MRI revealed moderate to severe pituitary hemorrhage. Late adverse effect (bilateral otitis media) was observed in three of nine dogs post-RT. RT did not induce any significant changes in the dogs' basal plasma ACTH concentration and pre- and post-ACTH serum cortisol concentrations.In conclusion, RT is effective to reduce pituitary size and the mass effect, but does not appear to affect blood hormone concentrations, necessitating additional medical treatment against hypercortisolism. Periodic MRI imaging post-RT enables early detection of adverse effects of RT.

Reduction in basal plasma Adrenocorticotropic hormone (ACTH) and Prolactin during treatment with escitalopram for depression

Reduction in basal plasma Adrenocorticotropic hormone (ACTH) and prolactin during treatment with escitalopram for depression.

Loss of hypothalamic corticotropin-releasing hormone markedly reduces anxiety behaviors in mice.

A long-standing paradigm posits that hypothalamic corticotropin-releasing hormone (CRH) regulates neuroendocrine functions such as adrenal glucocorticoid release, while extra-hypothalamic CRH plays a key role in stressor-triggered behaviors. Here we report that hypothalamus-specific Crh knockout mice (Sim1CrhKO mice, created by crossing Crhflox with Sim1Cre mice) have absent Crh mRNA and peptide mainly in the paraventricular nucleus of the hypothalamus (PVH) but preserved Crh expression in other brain regions including amygdala and cerebral cortex. As expected, Sim1CrhKO mice exhibit adrenal atrophy as well as decreased basal, diurnal and stressor-stimulated plasma corticosterone secretion and basal plasma ACTH, but surprisingly, have a profound anxiolytic phenotype when evaluated using multiple stressors including open field, elevated plus maze, holeboard, light-dark box, and novel object recognition task. Restoring plasma corticosterone did not reverse the anxiolytic phenotype of Sim1CrhKO mice. Crh-Cre driver mice revealed that PVHCrh fibers project abundantly to cingulate cortex and the nucleus accumbens shell, and moderately to medial amygdala, locus coeruleus, and solitary tract, consistent with the existence of PVHCrh-dependent behavioral pathways. Although previous, nonselective attenuation of CRH production or action, genetically in mice and pharmacologically in humans, respectively, has not produced the anticipated anxiolytic effects, our data show that targeted interference specifically with hypothalamic Crh expression results in anxiolysis. Our data identify neurons that express both Sim1 and Crh as a cellular entry point into the study of CRH-mediated, anxiety-like behaviors and their therapeutic attenuation.

From Appearance of Adrenal Autoantibodies to Clinical Symptoms of Addison's Disease: Natural History.

Recent progress in the immunopathology field has greatly improved our understanding of the natural history of autoimmune diseases, particularly of Addison's disease. Addison's disease is known to be a chronic illness characterized by adrenocortical gland insufficiency that develops following a long and mainly asymptomatic period, characterized by the presence of circulating autoantibodies directed to adrenal cortex antigens. In this chapter we describe the groups of subjects at risk of developing Addison's disease, together with the diagnostic tests considered the most appropriate for evaluating adrenal function: determination of basal plasma adrenocorticotropic hormone (ACTH) levels, plasma renin activity, plasma aldosterone and cortisol levels, and cortisol levels after intravenous stimulation with ACTH (ACTH test). The employment of specific clinical, immunological and functional criteria in the subjects with autoantibodies to the adrenal cortex allows identifying those at risk of developing overt disease. The independent risk factors for the progression to adrenal failure have also been identified and they contribute to different risks of developing clinical Addison's disease. Based on the risk level, the subjects should be monitored over time to observe early signs of adrenal dysfunction, and start substitutive treatment as soon as possible. For patients presenting with high risk, prevention strategies and trials might be available.

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma presented as Cushing syndrome and complicated by invasive aspergillosis

Adrenocorticotropic hormone (ACTH)-producing pheochromocytoma has been rarely reported, whereas only a few cases of Cushing syndrome accompanied by opportunistic infections have been reported. We experienced a patient with pheochromocytoma with ectopic Cushing syndrome complicated by invasive aspergillosis. A 35-year-old woman presented with typical Cushingoid features. Her basal plasma cortisol, ACTH, and 24-hour urine free cortisol levels were significantly high, and 24-hour urine metanephrine and catecholamine levels were slightly elevated. The endogeneous cortisol secretion was not suppressed by either low- or high-dose dexamethasone. Abdominal computed tomography (CT) revealed a heterogeneous enhancing mass measuring approximately 2.5 cm in size in the left adrenal gland. No definitive mass lesion was observed on sellar magnetic resonance imaging. On fluorine-18 fluorodeoxyglucose positron emission tomography/CT, a hypermetabolic nodule was observed in the left upper lung. Thus, we performed a percu- taneous needle biopsy, which revealed inflammation, not malignancy. Thereafter, we performed a laparo- scopic left adrenalectomy, and its pathologic finding was a pheochromocytoma with positive immunohisto- staining for ACTH. After surgery, the biochemistry was normalized, but the clinical course was fatal despite intensive care because of the invasive aspergillosis that included the lungs, retina, and central nervous system.

Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress

The melanocortin 4 receptor (MC4R), well-known for its role in the regulation of energy balance, is widely expressed in stress-regulatory brain regions, including the paraventricular nucleus of the hypothalamus (PVH) and the medial amygdala (MeA). In agreement with this, MC4R has been implicated in hypothalamic-pituitary-adrenocortical axis (HPA) regulation. The present work investigated the role of chronic Mc4r function to modulate basal HPA axis tone and to facilitate acute HPA responses to psychological stress, using a novel rat model with Mc4r loss-of-function. In this study, adult male rats were placed into 3 groups (n=15/group) according to genotype [wild-type (WT); heterozygous mutant (HET); and homozygous mutant (HOM)]. Basal (pre-stress) plasma adrenocorticotropic hormone (ACTH) and corticosterone were measured in the AM and PM, and the HPA axis response to restraint was assessed in the AM. Rats were perfused at 2h after restraint to assess the effect of loss of MC4R on stress-induced c-Fos immunolabeling in stress-regulatory brain regions. We find that basal (non-stress) AM and PM plasma ACTH and corticosterone showed a normal diurnal rhythm that was not altered according to genotype. Consistent with this, adrenal and thymus weights were unaffected by genotype. However, the plasma ACTH and corticosterone responses to restraint were significantly reduced by loss of MC4R function. Likewise, stress-induced c-Fos immunolabeling in both PVH and MeA was significantly reduced by loss of Mc4r function. These results support the hypothesis that endogenous MC4R signaling contributes to the HPA axis response to stress. Because MC4R plays a critical role in the regulation of energy balance, the present work suggests that it may also serve as an important communication link between brain metabolic and stress systems.

Ectopic Acth-Secreting Syndrome: A Single-Center Experience

ObjectiveEctopic adrenocorticotropic hormone (ACTH)-secreting syndrome (EAS) is a rare cause of ACTH-dependent endogenous hypercortisolism. The objective of this study was to analyze clinical, biochemical, and imaging characteristics; management strategies; and outcomes of EAS patients. MethodWe screened the records (1993-2012) of ACTH-dependent endogenous hypercortisolism cases managed at a tertiary care center. ResultsOf the 218 patients, 17 were diagnosed with EAS. The median 8:00 AM serum cortisol was 36 μg/dL (11.4-82.7 μg/dL), and the median basal plasma ACTH was 156 pg/mL (53.5-468 pg/mL). Notably, ACTH levels below 100 pg/mL were found in 4 patients. Suspicious microadenoma was found on magnetic resonance imaging (MRI) of the pituitary in 5 patients, and all of them underwent transsphenoidal surgery (TSS). Inferior petrosal sinus sampling (IPSS) was performed in 8 patients, and the results were suggestive of a peripheral source in all 8. Computed tomography (CT) localized the lesion in 15/17 patients. In 2 patients with negative CTs, gallium DOTATATE positron emission tomography (PET) scans localized the lesion. Despite difficulties localizing bronchial carcinoids, the cure rate was high (72%). In contrast, thymic carcinoids were easily localized but had poor outcomes. ConclusionEAS cannot be ruled out on the basis of marginally elevated ACTH. In cases with an equivocal MRI pituitary finding, prior IPSS can help avoid unnecessary TSS. CT is a useful modality for localization of an ectopic source. Functional imaging may help in cases where anatomical imaging fails. (Endocr Pract. 2013;19:1007-1014)

Longitudinal Evaluation of the Hypothalamic-Pituitary-Testicular Function in 8 Boys with Adrenal Hypoplasia Congenita (AHC) Due to NR0B1 Mutations

BackgroundBoys carrying mutations in the NR0B1 gene develop adrenal hypoplasia congenita (AHC) and impaired sexual development due to the combination of hypogonadotropic hypogonadism (HH) and primary defects in spermatogenesis.MethodsWe analysed the evolution of hypothalamic-pituitary-testicular function of 8 boys with AHC due to NR0B1 mutations. Our objective was to characterize and monitor the progressive deterioration of this function.ResultsThe first symptoms appeared in the neonatal period (n = 5) or between 6 months and 8.7 years (n = 3). Basal plasma adrenocorticotrophic hormone (ACTH) concentrations increased in all boys, whilst cortisol levels decreased in one case. The natremia was equal or below 134 mmol/L and kaliemia was over 5 mmol/L. All had increased plasma renin. In 3 of 4 patients diagnosed in the neonatal period and evaluated during the first year, the basal plasma gonadotropins concentrations, and their response to gonadotropin releasing hormone (GnRH) test (n = 2), and those of testosterone were normal. The plasma inhibin B levels were normal in the first year of life. With the exception of two cases these concentrations decreased to below the normal for age. Anti-Müllerian hormone concentrations were normal for age in all except one case, which had low concentrations before the initiation of testosterone treatment. In 3 of the 8 cases the gene was deleted and the remaining 5 cases carried frameshift mutations that are predicted to introduce a downstream nonsense mutation resulting in a truncated protein.ConclusionsThe decreases in testosterone and inhibin B levels indicated a progressive loss of testicular function in boys carrying NR0B1 mutations. These non-invasive examinations can help to estimate the age of the testicular degradation and cryopreservation of semen may be considered in these cases as investigational procedure with the aim of restoring fertility.

The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

AimTo elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity.MethodsPlasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine.ResultsDiazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity.ConclusionThe results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity.

Prevalence, risk factors and clinical signs predictive for equine pituitary pars intermedia dysfunction in aged horses

Equine pituitary pars intermedia dysfunction (PPID) is an ageing-related neurodegenerative disorder. The prevalence and risk factors for PPID using seasonally adjusted basal adrenocorticotropic hormone (ACTH) concentrations in aged horses have not been previously reported. To determine the prevalence, risk factors and clinical signs predictive for PPID in a population of horses aged ≥ 15 years in Queensland, Australia. Owner-reported data was obtained using a postal questionnaire distributed to an equestrian group. A subgroup of surveyed owners were visited and a veterinary physical examination performed on all horses aged ≥ 15 years. Blood samples were analysed for basal plasma alpha melanocyte-stimulating hormone (α-MSH) and ACTH concentrations, routine haematology and selected biochemistry. Aged horses with elevations above seasonally adjusted cut-off values for basal plasma ACTH were considered positive for PPID. Positive horses were compared with their aged counterparts to determine risk factors and clinical signs associated with PPID. Pituitary pars intermedia dysfunction was prevalent in aged horses (21.2%) despite owners infrequently reporting it as a known or diagnosed disease or disorder. Numerous clinical or historical signs were associated with an increased risk of PPID in the univariable model, but only age (odds ratio (OR) 1.18; 95% confidence interval (CI) 1.11-1.25, P<0.001) and owner-reported history of hirsutism (OR 7.80; 95% CI 3.67-16.57, P<0.001) remained in the final multivariable model. There were no routine haematological or biochemical variables supportive of a diagnosis of PPID. Pituitary pars intermedia dysfunction occurs commonly in aged horses despite under-recognition by owners. The increased risk of PPID with age supports that this is an ageing associated condition. Aged horses with clinical or historical signs consistent with PPID, especially owner-reported hirsutism (delayed shedding and/or long hair coat), should be tested and appropriate treatment instituted.

Evaluation of basal plasma α‐melanocyte‐stimulating hormone and adrenocorticotrophic hormone concentrations for the diagnosis of pituitary pars intermedia dysfunction from a population of aged horses

The sensitivity and specificity of basal plasma α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotrophic hormone (ACTH) for the diagnosis of pituitary pars intermedia dysfunction (PPID) has not been evaluated in a population-based study. To evaluate basal plasma α-MSH and ACTH concentrations for the diagnosis of PPID in a population of horses aged ≥ 15 years. Owner-reported data were obtained using a postal questionnaire distributed to an equestrian group. A subgroup of surveyed owners was visited and veterinary examination performed on horses aged ≥ 15 years. Blood samples were analysed for plasma α-MSH and ACTH concentrations. Seasonally adjusted cut-off values for α-MSH and ACTH concentrations for the diagnosis of PPID were obtained using Youden index values against a clinical gold standard diagnosis (hirsutism plus 3 or more clinical signs of PPID). α-melanocyte-stimulating hormone and ACTH were highly correlated with each other and with clinical and historical indicators of PPID. The increase in both α-MSH and ACTH with increasing numbers of clinical signs in affected horses supports a spectrum of disease. Both variables were affected by season, with derived cut-off values being higher in autumn compared with other seasons. Sensitivity and specificity were moderate and good in nonautumn seasons (59 and 93%, respectively) for α-MSH using a cut-off of 52.0 pmol/l. Sensitivity and specificity were good in nonautumn seasons (80 and 83%, respectively) for ACTH using a cut-off of 29.7 pg/ml. For both α-MSH and ACTH, sensitivity and specificity were close to 100% for samples obtained during the autumn period. Basal plasma α-MSH and ACTH had moderate-to-good sensitivity and specificity for the diagnosis of PPID, which improved substantially during the autumn period, suggesting this may be the ideal time to test. Further studies to develop seasonally adjusted reference intervals for different geographical locations are warranted.

The impact of maternal overnutrition and obesity on hypothalamic-pituitary-adrenal axis response of offspring to stress

We evaluated the effect of maternal obesity before and throughout gestation on offspring hypothalamic-pituitary-adrenal axis function. Multiparous Rambouillet by Columbia crossbred ewes were fed either 100% of National Research Council (NRC) recommendations (control, C) or 150% of NRC recommendations (obese, OB) from 60 d before mating until lambing. Ten lambs born to OB ewes (five males and five females), and eight lambs born to C ewes (three male and five female) were studied. From delivery to weaning lambs were maintained with their mothers, who were all fed 100% NRC recommendations. After weaning, all lambs were group housed and fed the same diet to meet NRC requirements. At 19 mo of age lambs were placed in individual pens and fed a pelletized diet to meet maintenance requirements. Jugular vein catheters were placed and 2 d later lambs received an intravenous (i.v.) adrenocorticotropic hormone (ACTH) challenge followed by an i.v. corticotropin-releasing hormone (CRH)/arginine vasopressin (AVP) challenge 1 d later. Thirty d later offspring were again catheterized and placed into metabolism crates for 2 d before receiving an isolation stress test. ACTH and cortisol responses to the isolation stress test and CRH/AVP challenge and cortisol responses to ACTH challenge were determined. Cortisol was quantified via radioimmunoassay and ACTH was quantified using an Immulite 1000; both were analyzed using repeated measures using the MIXED procedure of SAS. Offspring from OB ewes had elevated basal plasma ACTH and cortisol compared with C offspring before all three challenges (P < 0.05). Offspring from OB mothers tended (P = 0.06) to have a greater ACTH response after an i.v. CRH/AVP injection than offspring from C mothers (12,340 ± 1,430 vs 8,170 ± 1,570 area under the curve, respectively). Cortisol response to the CRH/AVP and ACTH challenges was not influenced by maternal nutrition (P = 0.46) and averaged 4.77 ± 0.2 μg/dL and 1.94 ± 0.01 μg/dL, respectively. The ACTH response following the isolation stress test was also similar (P = 0.82) for OB and C offspring (147 ± 20 pg/mL), and cortisol response during the isolation stress test was similar between C and OB offspring (P = 0.64, 5.25 ± 0.3 μg/dL). These findings suggest that maternal obesity before and during gestation does not affect stress responses by the offspring, but has an impact on hypothalamic-pituitary-adrenal sensitivity. The lack of differences in cortisol release under the influence of difference concentrations of ACTH during the CRH/AVP challenge could indicate adrenal dysfunction in OB offspring.

Clinical, Biological and Genetic Analysis of 8 Cases of Congenital Isolated Adrenocorticotrophic Hormone (ACTH) Deficiency

BackgroundCongenital isolated adrenocorticotrophic hormone (ACTH) deficiency may be rare, but it could be an underestimated cause of neonatal death. Our objective was to shorten the time between first symptoms and diagnosis.MethodsThis single-centre retrospective case-cohort study was carried out on eight consecutive patients.ResultsTwo had the neonatal form and 6 the late onset form. Six were admitted to an intensive care unit at least once for seizures with hypoglycemia, major hypothermia, fever, and/or collapsus. The 2 neonatal cases presented with hypoglycemia and in a state of “apparent death” at birth or hypothermia (29°C) at 6 days. All 6 late onset cases had also been admitted to an emergency department 1–3 times, but had left hospital incorrectly diagnosed. Their first symptoms were noted at 3–12.3 years, and they were diagnosed at 3.3–14.4 years. All had hypoglycemia, and 4 had had seizures. The presenting symptoms were vomiting and/or abdominal pain, asthenia, irritability, difficulty with physical activities, and anorexia. The school performance of 4 deteriorated. Two underwent psychotherapy and treatment for depression, which was stopped when Hydrocortisone® replacement therapy began.The plasma concentrations in spontaneous hypoglycemia were: ACTH<5 to 17.1 pg/mL, with concomitant cortisol <3.5 to 37 ng/mL. The plasma dehydroepiandrosterone sulfate (DHAS) concentrations were low in the 7 evaluated. The coding sequence of TPIT was normal in all.ConclusionSeveral unexplained symptoms in a child, mainly gastro-intestinal symptoms and seizures due to hypoglycemia, may indicate ACTH deficiency. A low or normal basal plasma ACTH despite concomitant low cortisol at 8 a.m. and/or in spontaneous hypoglycemia, associated with low DHAS, in a patient not given corticosteroids is highly suggestive of ACTH deficiency. The isolated character of ACTH deficiency must be confirmed by determining the other hypothalamic-pituitary functions, and Hydrocortisone® replacement therapy initiated in emergency.

Nitric oxide inhibits ACTH-induced cortisol production in near-term, long-term hypoxic ovine fetal adrenocortical cells.

We previously reported that in the sheep fetus, long-term hypoxia (LTH) resulted in elevated basal plasma adrenocorticotropic hormone (ACTH(1- 39)) whereas the cortisol levels were not different from normoxic controls. We also showed that LTH enhances endothelial nitric oxide synthase (eNOS) expression in the fetal adrenal. This study was designed to determine the effect of NO on cortisol production in adrenocortical cells from LTH fetal sheep. Ewes were maintained at high altitude (3820 m) from ∼40 days' gestation (dG) to near term. Between 138 and 141 dG, fetal adrenal glands were collected from LTH and age-matched normoxic control fetuses. Adrenal cortical cells were pretreated with sodium nitroprusside (SNP), nitro-L-arginine methyl ester (L-NAME), L-arginine, or diethyleneamine NO (DETA-NO) and then challenged with 10 nmol/L ACTH. Cortisol responses were compared after 1 hour. Adrenocorticotropic hormone -induced cortisol secretion was significantly higher in LTH versus control (P < .01). Enhancement of NO with L-arginine resulted in a significant reduction of ACTH-mediated cortisol production in the LTH group. DETA-NO also caused a significant decrease in ACTH-mediated cortisol production (P < .05). Inhibition of NOS with L-NAME significantly increased cortisol production in the LTH group (P < .05 compared to ACTH alone), whereas the effect on the control group was not significant. Nitric oxide synthase activity was significantly higher in the LTH group compared to control, but this difference was eliminated following ACTH treatment. These data indicate that LTH enhances adrenal cortical sensitivity to the inhibitory effects of NO on cortisol production. Nitric oxide may, therefore, play an important role in regulating ACTH-induced cortisol production in the LTH fetal adrenal.

Expression of pituitary glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase 1 in obese diabetic rats

Diabetic rat model was induced by high fat diet combined with streptozotocin (STZ). After the model was established, blood samples were taken from jugular veins to examine plasma adrenocorticotropic hormone (ACTH) and corticosterone, and hypothalamus and pituitary were removed for real-time PCR. There were no significant differences in basal plasma ACTH and corticosterone level among control, obese, and obese diabetic rats (P=0.07). The corticosterone rhythm in obese and obese diabetic rats was impaired. Hypothalamus glucocorticoid receptors (GR) mRNA expressions yielded similar results in the groups, but 11β-HSD1 mRNA expression in obese diabetic rats was up-regulated ( vs control rats, P<0.05 ). The expressions of GR and 11β-HSD1 in pituitary of obese diabetic and obese rats were significantly down-regulated (both P<0.05). In the obese diabetic rats, the impaired glucocorticoid negative feedback was partly due to down-regulation of 11 β-HSD1 and GR expressions in pituitary. Key words: Diabetes mellitus, type 2; Pituitary; Negative feedback; 11β-hydroxysteroid dehydrogenase type 1; Glucocorticoid receptors