Agaristi Lamprokostopoulou

Stress, the Stress System and the Role of Glucocorticoids

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases.

Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance.

Primary Generalized Glucocorticoid Resistance is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene (NR3C1). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Primary Generalized Glucocorticoid Resistance, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When the condition is suspected, we recommend sequencing analysis of the NR3C1 gene as well as of other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next-generation sequencing will undoubtedly uncover novel hGR partners or cofactors.

Transient generalized glucocorticoid hypersensitivity.

Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo‐activation of the hypothalamic–pituitary–adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated.

The effect of intrauterine growth on leukocyte telomere length at birth

Abstract Objective: Telomeres are specialized nucleoprotein structures located at the ends of chromosomes, which play a crucial role in genomic stability. Telomere shortening has been proposed as a biomarker for the onset of age-related diseases. This study aimed to determine whether restricted or increased intrauterine growth affects leukocyte telomere length (LTL) at birth. Materials and methods: One hundred sixty-five (n = 165) full-term neonates participated in the study. Fetuses were classified as intrauterine growth restriction (IUGR, n = 21), large-for-gestational-age (LGA, n = 15), or appropriate-for-gestational-age (AGA, n = 129), based on customized birth-weight standards. Mixed arteriovenous cord blood samples were collected for isolation of leukocyte DNA. The LTL was measured using multiplex monochrome quantitative real-time PCR and telomeric restriction fragments through Southern blot analysis (terminal restriction fragment [TRF]). Results: Despite differences among groups in birth weight, length and head circumference, LTL did not differ among AGA (6.78 ± 0.58), IUGR (10.54 ± 1.80), and LGA (11.95 ± 2.42) neonates (p = .098). Cord blood IGF-1 and IGFBP-3 concentrations were higher in the LGA group. LTL positively correlated with birth length (r = 0.176, p = .032). Conclusions: Intrauterine growth does not seem to affect LTL at birth. Further studies, comprising a larger sample size of IUGR, LGA, and AGA neonates, are required to determine whether growth at birth influences LTL.

Primary Generalized Glucocorticoid Resistance or Chrousos Syndrome: Allostasis Through a Mutated Glucocorticoid Receptor

Primary generalized glucocorticoid resistance or Chrousos syndrome is a rare familial or sporadic condition, which affects almost all organs and is characterized by partial target tissue insensitivity to glucocorticoids. Patients with this condition may be asymptomatic or may present with clinical manifestations of mineralocorticoid and/or androgen excess. The molecular basis of Chrousos syndrome has been associated with point mutations, insertions or deletions in the NR3C1 gene that expresses the human glucocorticoid receptor, a member of the steroid receptor family of the nuclear receptor superfamily of transcription factors. We and others have systematically investigated the molecular mechanisms of action of the mutant glucocorticoid receptors causing Chrousos syndrome by applying standard methods of molecular and structural biology. In this chapter, we discuss the clinical manifestations, pathophysiology, molecular pathogenesis, diagnostic approach, and therapeutic management of Chrousos syndrome.

Recent Advances in the Molecular Mechanisms Causing Primary Generalized Glucocorticoid Resistance or Chrousos Syndrome

Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare condition characterized by generalized, partial, target tissue insensitivity to glucocorticoids owing to inactivating mutations, insertions or deletions in the human glucocorticoid receptor (hGR) gene ( NR3C1 ). Recent advances in molecular and structural biology have enabled us to elucidate the molecular mechanisms of action of the mutant receptors, and to understand how certain conformational alterations of the defective hGRs result in generalized glucocorticoid resistance. Furthermore, our ever-increasing understanding of the molecular mechanisms of glucocorticoid action indicates that the glucocorticoid signaling pathway is a stochastic system that plays a fundamental role in maintaining both basal and stress-related homeostasis. In this review, we summarize the clinical manifestations and molecular pathogenesis of Chrousos syndrome, we present our recent findings from the functional characterization of three novel heterozygous point mutations in the NR3C1 gene, and we discuss the diagnostic approach and therapeutic management of the condition. When Chrousos syndrome is suspected, we recommend sequencing analysis of the NR3C1 gene, as well as other genes encoding proteins involved in the glucocorticoid signal transduction. The tremendous progress of next generation sequencing will undoubtedly uncover novel hGR partners or cofactors.