George Chrousos

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

Arginine vasopressin (AVP) acts synergistically with corticotropin-releasing hormone (CRH) to stimulate ACTH release from the anterior pituitary. In a previous study of bilateral simultaneous inferior petrosal sinus (IPS) sampling in healthy human subjects, we observed lateralized ACTH secretion, suggesting lateralized secretion of an ACTH-regulating hypothalamic factor. To investigate this possibility, we measured ACTH, CRH, AVP, and oxytocin (OT) levels in the IPS and the peripheral circulation in nine normal volunteers, before and after 1 microgram/kg i.v. bolus ovine CRH (oCRH). At baseline, ACTH, AVP, and OT exhibited a significant (P < 0.05) two to threefold intersinus gradient (ISG), indicating the existence of a dominant petrosal sinus. Endogenous CRH was undetectable in all samples. Despite similar exogenous oCRH levels in both petrosal sinuses, oCRH caused a significant increase (P < 0.001) in the ACTH ISG (15.8 +/- 5.6, mean +/- SEM), suggesting increased responsiveness of one dominant side of the anterior pituitary. This was associated with an ipsilateral CRH-induced AVP release and a significant increase (P < 0.01) in the AVP ISG (8.6 +/- 2.3), suggesting lateralized AVP secretion by the hypothalamus. Furthermore, the increased AVP ISG after oCRH correlated strongly with the ACTH ISG (r = 0.92, P < 0.01). oCRH administration did not affect OT. These findings suggest that there is a dominant petrosal sinus in healthy volunteers that appears to reflect a dominant side of the adenohypophysis, characterized by increased functional activity and/or responsiveness of the pituitary corticotrophs. This may reflect lateralized hypothalamic and/or suprahypothalamic function resulting in CRH-responsive lateralized secretion of AVP from parvocellular and/or magnocellular axons in the median eminence and the posterior pituitary. Although the functional and teleologic significance of these findings remains to be investigated, our data suggest a novel mechanism for CRH-mediated ACTH release, namely CRH-induced release of AVP which then enhances CRH action on the corticotrophs. Furthermore, our data represent the first direct evidence for the concept of brain lateralization with respect to neuroendocrine secretion.

Corticotropin-releasing hormone production by a small cell carcinoma in a patient with ACTH-dependent Cushing’s syndrome

We describe a patient with Cushing’s syndrome and metastatic small cell lung cancer. The plasma ACTH concentrations were markedly elevated (91.6 pmol/L), and the AM Cortisol did not suppress by >50% overnight after administration of 8 mg dexamethasone, both consistent with the ectopic ACTH syndrome. Immunohistochemical studies of a single metastatic tumor specimen, however, demonstrated an absence of ACTH and yet an abundance of corticotropin-releasing hormone (CRH). In addition, radioimmunoassay of the patient’s plasma demonstrated persistently elevated CRH concentrations. The majority of the plasma CRH immunoreactivity exhibited the same chromatographic mobility as synthetic r/h CRH (1–41) on HPLC. Failure to evaluate the tumor tissue for the presence of ACTH and/or CRH would have led to the erroneous conclusion that this patient’s Cushing’s syndrome resulted from paraneoplastic ACTH production. We conclude that immunoassay of plasma for both ACTH and CRH and, perhaps, immunostaining of tumor samples are required to distinguish between the ectopic ACTH and CRH syndromes.

The Hypothalamic-Pituitary- Adrenal Axis in Human Health and Disease

The hypothalamic-pituitary-adrenal (HPA) axis plays a fundamental role in the maintenance of basal and stress-related homeostasis. This neuroendocrine axis consists of three distinct components located in the hypothalamus, the pituitary gland and the adrenal cortex. Glucocorticoids, the end-products of the HPA axis, exert their diverse actions in virtually all tissues through their ubiquitously expressed glucocorticoid receptor. A broad spectrum of pathologic conditions affecting any of the three anatomical parts results in hypo- or hyper-activation of the HPA axis and subsequent clinical manifestations of glucocorticoid deficiency or excess, respectively. Moreover, our ever-increasing understanding of glucocorticoid receptor signaling has allowed us to approach diagnostically and therapeutically these endocrine diseases in a more integrated way. However, the pathophysiology, differential diagnosis and therapy of some of these disorders still remain challenging. In this chapter, we describe the physiologic and endocrine aspects of the HPA axis, and we present the clinical manifestations and therapeutic management of its most common disorders.

Growth hormone axis in patients with chronic kidney disease

Kidneys play an essential role in the metabolism of the majority of hormones. Chronic kidney disease (CKD) causes endocrine disturbances, which develop already at the early stages, but become more prominent as renal failure progresses. Alterations in the homeostasis of calcium, phosphorus, vitamin D, and parathyroid hormone are the most common endocrine disorders observed in these patients and they have been extensively described in the literature. However, a variety of other primary or secondary endocrinopathies are also present in these patients, including growth hormone (GH) axis derangement. Data from the NAPRTCS (North American Pediatric Renal Trials and Collaborative Studies) database revealed that 36.9% of children with chronic kidney disease present with severe growth impairment (height below the third percentile). Growth retardation is more pronounced in younger patients and even more severe in male subjects [1–3]. The growth retardation seen in patients with chronic kidney disease is also associated with increased morbidity and mortality. It has been demonstrated that each standard deviation decrease in height among pediatric patients who are on dialysis or after transplantation contributes to an increase in mortality by 14% [4]. The mechanisms leading to growth retardation in patients with CKD are thought to be multifactorial. Undernutrition with inadequate protein and calorie intake, water and electrolyte losses, vitamin D deficiency with secondary hyperparathyroidism and renal osteodystrophy, anemia, metabolic acidosis, as well as long-term therapy with glucocorticoids seem to be the main contributory factors [5–7]. However, even with optimal medical and nutritional therapy, children with CKD cannot approach normal height without growth hormone supplementation therapy [1]. This fact highlights the importance of detection of changes in the GH and insulin-like growth factor (IGF-1) axis to assess the growth failure. Decreased appetite, which is often present in patients with CKD, is associated with decreased levels of ghrelin, a GH secretagogue and a potent orexigenic factor that stimulates feeding by interaction with hypothalamic nuclei [8]. However, GH levels are usually normal or even elevated in these patients [9, 10], suggesting that CKD is mainly a state of GH resistance and not GH deficiency. A number of factors leading to GH resistance have been proposed, and they include: (1) reduced GH receptors numbers in target tissues, (2) post-receptor defects in GH signaling [Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling], and (3) reduced levels of free IGF-1 [5]. GH binding to the growth hormone receptor (GHR) results in its dimerization and the auto-phosphorylation of the tyrosine kinase JAK, which then stimulates phosphorylation of STAT proteins. These phosphorylated proteins translocate into the nucleus and activate certain GH-regulated genes. In uremia, the density of GHR is low, while the JAK/STAT pathway is impaired, probably through suppression by cytokine signaling (SOCS) proteins [11–13]. GH actions are mostly mediated by IGF-1, which is mainly produced in the liver and acts as an anabolic hormone after binding to the IGF-1 receptor (IGF-1R) [14]. Only 1% of IGF-1 normally circulates in a free bioactive form, the rest being bound to IGF-binding proteins (IGFBPs) which can either potentiate (IGFBP3, IGFBP5) or inhibit (IGFBP1, IGFBP2, IGFBP4) its action. In patients with CKD, increased levels of inhibitory IGFBPs have been shown to be associated with the degree of renal dysfunction [15]. Levels of IGFBP3, which is the most * Andromachi Vryonidou mahi_vr@hotmail.com

Early life stress and trauma: developmental neuroendocrine aspects of prolonged stress system dysregulation

Experience of early life stress (ELS) and trauma is highly prevalent in the general population and has a high public health impact, as it can trigger a health-related risk cascade and lead to impaired homeostatic balance and elevated cacostatic load even decades later. The prolonged neuropsychobiological impact of ELS can, thus, be conceptualized as a common developmental risk factor for disease associated with increased physical and mental morbidity in later life. ELS during critical periods of brain development with elevated neuroplasticity could exert a programming effect on particular neuronal networks related to the stress response and lead to enduring neuroendocrine alterations, i.e., hyper- or hypoactivation of the stress system, associated with adult hypothalamic-pituitary-adrenal axis and glucocorticoid signaling dysregulation. This paper reviews the pathophysiology of the human stress response and provides evidence from human research on the most acknowledged stress axis-related neuroendocrine pathways exerting the enduring adverse effects of ELS and mediating the cumulative long-term risk of disease vulnerability in adulthood.

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.