Publications

Adaptation of the Mineralocorticoid Target Tissues to the High Circulating Cortisol and Progesterone Plasma Levels in the Squirrel Monkey^*

Many New World primate species have elevated circulating free plasma cortisol concentrations, target tissue resistance to cortisol, and no evidence of sodium retention. A representative New World primate, the squirrel monkey (Saimiri sciureus), has plasma cortisol concentrations above those necessary to cause complete suppression of the renin-angiotensinaldosterone axis in an Old World primate, the cynomolgus monkey (Macaca fascicularis). Despite this, the arterial blood pressure as well as the plasma sodium, potassium, and bicarbonate levels of the squirrel monkey are similar to those of the cynomolgus monkey, and its plasma aldosterone concentrations are approximately 2-fold higher. These findings suggest that cortisol has minimal sodium-retaining effects in this species. Renal cytosol aldosterone receptor concentrations are about 2- to 3-fold lower in the squirrel monkey than in the cynomolgus, whereas the receptor affinities for [3H] aldosterone are similar in the two monkeys. Higher concentrations of cortisol are needed to displace [3H]aldosterone from the mineralocorticoid receptor in the squirrrel monkey than from the renal receptor in the cynomolgus [apparent equilibrium dissociation constant (K1) = 7.8 × 10−7vs. 2.9 × 10−8 M, respectively]. In addition, in contrast to man and presumably other Old World primates, plasma aldosterone concentrations in the female squirrel monkey do not increase during the reproductive cycle or pregnancy when progesterone concentrations are 10- to 20-fold higher than those of the male or the reproductively quiescent female. This suggests that progesterone is a poor aldosterone antagonist in this species. We conclude that a low concentration of mineralocorticoid receptors in New World Primates is compensated for by higher aldosterone levels, with a concomitant increase in receptor occupancy. The salt-retaining potency of cortisol is low, presumably because of a decrease in the affinity of the aldosterone receptor for glucocorticoids in New World primates. (Endocrinology115: 25–32, 1984)

Endocrinologic and Psychologic Evaluation of 21-Hydroxylase Deficiency Carriers and Matched Normal Subjects: Evidence for Physical and/or Psychologic Vulnerability to Stress

Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 ± 3.4 vs. 42.7 ± 6.4 μg/d, P = 0.03) and higher peak ACTH (75.7 ± 8.1 vs. 54.2 ± 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 ± 28.1 vs. 107.1 ± 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

Behavioral, Adrenal, and Sympathetic Responses to Long-Term Administration of an Oral Corticotropin-Releasing Hormone Receptor Antagonist in a Primate Stress Paradigm

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4–6 kg) male rhesus monkeys received AA (20 mg/kg·d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P < 0.005, NE; P < 0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P < 0.05, NE; P < 0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stressrelated disorders.

Sociotropy, Autonomy, Stress, and Depression in Gushing Syndrome

Cognitive theory ascribes nonendogenous depression to latent dysfunctional beliefs activated by stressors impinging upon core values (e.g., rejection for a sociotropic person). To address ambiguities in past tests of the theory, this study measured personality (Sociotropy-Autonomy Scale) and recent stressors (Life Experience Survey and Hassles Scale) among 14 Cushing syndrome patients and 12 controls. Patients scored nonsignificantly higher in sociotropy, and sociotropy correlated positively with depression among patients. Because depression in Cushing syndrome presumably results from biological dysfunction rather than from the interaction of personality and relevant stressors, these results imply that sociotropy may be a consequence of depression as opposed to a contributory cause. There was no congruence between personality and types of stressors reported, which suggest that mood-dependent recall does not account for past evidence of congruence.

Apoplexy of a Silent Pituitary Adenoma as the Only Presentation of a Novel<i>AIP</i>Mutation in a Greek Family with Familial Isolated Pituitary Adenoma

The ARCHYTAS Intelligent Decision-Support System for the Protection of Monumental Structures

No abstract is provided for this article.

Stress and Endocrine Physiology

Effects of short- and long-duration hypothyroidism on function of the rat hypothalamic-pituitary-adrenal axis.

Preface

In early pubertal boys, testosterone and LH are associated with improved anti-oxidation during an aerobic exercise bout

Salt intake in mineralocorticoid receptor antagonist-treated primary aldosteronism: foe or ally?

Inverse association of leptin levels with renal cell carcinoma: Results from a case-control study

A data mining and semantic analysis reveals novel insights into the genetic characteristics of the glucocorticoid receptor interactome

The availability of single nucleotide polymorphisms (SNPs) that have been identified in a given gene and have been related to several diseases provides the opportunity to study complex biological pathways and can assist researchers in better associating genes and disease‑linked terms in the areas of genetics, genomics and epigenetics. The study of the glucocorticoid receptor (GR) interactome through SNP observations in 'key‑player' genes will provide researcher with the opportunity to draw the 'genomic grammar' of the complex biological mechanisms associated with GR function and will open new horizons in biology, medicine, pharmacology and even extend to personalized medicine. The GR interactome is extensive, and is involved in several physiological and pathological processes of the organism. Glucocorticoids are the final product of the hypothalamic‑pituitary‑adrenal axis and an inextricable part of the stress system. These hormones are implicated in various critical systems and processes for the human organism, such as the immune system, development, metabolism and several others. GR is the protein that mediates their actions and is involved in several interactions with specific genes and proteins. In the present study, in order to unravel new beneficial knowledge on genetic targets regarding the GR interactome, a data mining and semantic pipeline was performed using the available literature. More specifically, through bioinformatics tools and methods, the most relevant SNPs and genes connected to the GR interactome were extracted. Subsequently, the outcome SNPs were filtered, annotated, classified and evaluated in order to create the 'genomic grammar' and identify the related disease with the interactome of GR. Genomic background and heredity play a significant role in the GR interactome. A more in‑depth understanding of the biological pathways and complex actions of the GR may lead to the design and development of more effective treatments for inflammatory and autoimmune diseases, as well as cancers.

A TMEM63A Nonsense Heterozygous Variant Linked to Infantile Transient Hypomyelinating Leukodystrophy Type 19?

Infantile onset transient hypomyelination (IOTH) is a rare form of leukodystrophy that is associated with transient motor impairment and delayed central nervous system myelination. Here, we report a case of a new mutation in the transmembrane protein 63A (TMEM63A) gene identified using Whole-Exome Sequencing (WES) in an 8.5-year-old boy with clinical symptoms similar to IOTH. The patient exhibited a mild developmental delay, including hypotonia and delayed motor milestones, as well as some notable phenotypic characteristics, such as macrocephaly and macrosomia. Despite the absence of early neuroimaging, genetic testing revealed a paternally inherited variant in TMEM63A (NM_14698.3:c.220A&gt;T;p:(Arg74*)), potentially linked to infantile transient hypomyelinating leukodystrophy type 19. Our findings in this study and the patient’s favorable clinical course underscore the potential for successful myelination even with delayed initiation and may contribute to a better understanding of the genotype–phenotype correlation in IOTH, emphasizing the importance of genetic analysis in unresolved developmental delay cases and providing critical insights for accurate diagnosis, prognosis and potential therapeutic strategies in rare leukodystrophies.

Vector and Scalar IMs in Structural Response Estimation and Risk Assessment: Part II – Building Demand Assessment

Corticotropin releasing hormone: relevance to normal physiology and to the pathophysiology and differential diagnosis of hypercortisolism and adrenal insufficiency.

CRH is a 41 amino acid peptide first isolated from ovine and subsequently from rat and human hypothalami. We have conducted a series of clinical studies with oCRH and hCRH in volunteers and patients with various disorders of hypothalamic-pituitary-adrenal function. In volunteers, it was demonstrated that hCRH administration produced ACTH and cortisol responses which closely mimic naturalistically occurring secretory episodes. This data, as well as the demonstration that pulsatile hCRH can reestablish normal ACTH and cortisol secretion in patients with hypothalamic CRH deficiency, strongly argue that CRH is of physiological relevance to the human pituitary-adrenal axis. However, since the ACTH response to an insulin tolerance test is greater than the maximal ACTH response to CRH, other factors such as vasopressin may be relevant to stress-induced ACTH secretion in man. Following the demonstration that CRH seems to be of physiological relevance to human subjects, a CRH stimulation test was developed based on pharmacokinetic and dose response studies with oCRH and hCRH. Based on these data, which revealed that oCRH functions as a long-acting analogue of hCRH, and the demonstration that hormonal responses to CRH are greatest in the evening, patient groups with abnormalities of the hypothalamic-pituitary-adrenal axis were tested with intravenous oCRH with a dose of 1 micrograms/kg given at 2000 hours. This CRH stimulation test has proved helpful in clarifying the pathophysiology of hypercortisolism in a variety of psychiatric disorders characterized by this endocrine abnormality. Thus, blunted ACTH responses in hypercortisolemic patients with depression, anorexia nervosa, and panic anxiety disorder indicate normality of the pituitary corticotroph in these patient subgroups. These data, along with the finding that a continuous infusion of CRH to normal volunteers, reproduces the pattern and magnitude of hypercortisolism in depression and anorexia nervosa, suggest that the hypercortisolism in these disorders represents a defect at or above the hypothalamus resulting in the hypersecretion of CRH. This hypothesis is particularly intriguing in light of the demonstration that CRH administration to experimental animals produces many of the physiological and behavioral responses classically associated with depression and anorexia nervosa, including hypercortisolism, hypothalamic hypogonadism, and decreases in libido and appetite. The CRH stimulation test has also helped to resolve one of the oldest endocrinological dilemmas, namely whether the hypercortisolism of depression and Cushing's disease share a common or dissimilar pathophysiological basis.(ABSTRACT TRUNCATED AT 400 WORDS)

Multi-level conditional spectrum-based record selection for IDA

Incremental dynamic analysis (IDA) is widespread to evaluate the seismic response of structures. It employs one records set scaled to multiple intensity levels (IMLs) to estimate the structural response distribution. However, the dominating earthquake scenarios differ with the intensity, and a single set introduces bias that increases with scaling. The response is, however, better estimated using multiple stripe analysis (MSA) by selecting multiple hazard consistent record sets at different IMLs via, for example, conditional spectrum (CS) method. Still, IDA remains a popular tool, and would benefit from a single “good” set that would be more amenable to scaling with minimal bias. We explore alternatives of a “multi-level” CS (CSML) scheme, whereby the seismic properties of multiple IMLs are combined to derive a single set. Combined with advanced IMs, CSML provides a viable trade-off between the more accurate and complex method of CS–MSA versus the conceptually and practically simpler IDA.

Association of fructose consumption with prevalence of functional gastrointestinal disorders manifestations: results from Hellenic National Nutrition and Health Survey (HNNHS)

The study aimed to assess the total prevalence of functional gastrointestinal disorders (FGID), and separately, irritable bowel syndrome (IBS) among adults and to determine their potential association with fructose consumption. Data from the Hellenic National Nutrition and Health Survey were included (3798 adults; 58·9 % females). Information regarding FGID symptomatology was assessed using self-reported physician diagnosis questionnaires the reliability of which were screened using the ROME III, in a sample of the population. Fructose intake was estimated from 24 h recalls, and the MedDiet score was used to assess adherence to the Mediterranean diet. The prevalence of FGID symptomatology was 20·2 %, while 8·2 % had IBS (representing 40·2 % of total FGID). The likelihood of FGID was 28 % higher (95 %CI: 1·03-1·6) and of IBS 49 % (95 %CI: 1·08-2·05) in individuals with higher fructose intake than with lower intake (3rd tertile compared with 1st). When area of residence was accounted for, individuals residing in the Greek islands had a significantly lower probability of FGID and IBS compared with those residing in Mainland and the main Metropolitan areas, with Islanders also achieving a higher MedDiet score and lower added sugar intake, comparatively to inhabitants of the main metropolitan areas. FGID and IBS symptomatology was most prominent among individuals with higher fructose consumption, and this was most conspicuous in areas with a lower Mediterranean diet adherence, suggesting that the dietary source of fructose rather than total fructose should be examined in relation to FGID.