Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis

__Abstract__ Dopamine is the predominant catecholamine neurotransmitter in the human central nervous system, where it controls a variety of functions including cognition, emotion, locomotor activity, food intake and endocrine regulation. Dopamine also plays multiple roles in the periphery as a modulator of cardiovascular and renal function, gastrointestinal motility and the endocrine system (1). Dopamine exerts its functions via the binding with dopamine receptors (1). Dopamine receptors belong to the family of seven transmembrane domain G protein-coupled receptors and include five different receptor subtypes, named D1-Ds. The members of dopamine receptor family are encoded by genes localized on different chromosome loci, displaying a considerable homology in their protein structure and function. The analysis of dopamine receptor structure and function suggests the existence of two different groups of receptors: D1-like, including D1 and D5 receptors, associated to a stimulatory function, and Dz-like, including Dz, D3 and D4 receptors, associated to an inhibitory function. The D1 and Ds receptors are encoded by intronless genes and share an 80% homology in their transmembrane domains. The Dz receptor shares a 75% homology with the D3 and a 53% homology with the D4 transmembrane domains and all three receptor subtypes are encoded by genes, which are interrupted by introns. The Dz receptor exists in two main variants, called Dzlong and Dzshort, generated by an alternative splicing of an 87 base pairs exon. These two D2 receptor isoforms differ for the presence or absence of a stretch of 29 amino acids in the third cytoplasmic loop in their protein structure. Splicing variants of the D3 receptor encoding nonfunctional proteins have been also identified. The analysis of the D4 receptor reveals the existence of polymorphic variations within the coding sequence, being a 48 base pairs sequence existent as a direct repeat sequence (D4.1), fourfold (D4.4), sevenfold (D4.7) or eleven fold (D4.11) repeat sequence. Therefore, the D4 receptor isoforms differ for the length of the third cytoplasmic loop and have one, four, seven or eleven times the same insert of a stretch of 19 amino acids in their protein structure. The Ds receptor has two related pseudogenes, which share a 95% homology with the gene and encode for truncated non functional forms of the receptor (1). The molecular characteristics of human dopamine receptor family are summarized in Table 1. A schematic representation of the human dopamine receptor is shown in Fig. 1

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

Objective  (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design  Analytical, retrospective. Measurements  GH nadir after oGTT. Subjects  Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80 years) were studied. Results  The GH nadir after glucose load ranged from 0·01 (<assay detection limit) to 0·65 μg/l was higher in women and was inversely correlated with age, BMI, waist circumference, waist/hip, total cholesterol, triglycerides, basal and maximal glucose and basal insulin levels and directly correlated with basal GH levels, IGF-I SDS and HDL-cholesterol (P values ranging 0·004-<0·0001). On multistep regression analysis, the best predictors of nadir GH levels were waist circumference (t = -9·64, P < 0·0001), gender (t = -3·86, P = 0·0001) and age (t = -3·63, P = 0·0003). The results of comparative analysis among subjects grouped according to these variable showed different results in GH nadir in premenopausal women with waist circumference ≤88 cm (97th percentile 0·65 μg/l), in premenopausal women with waist circumference ≤88 cm and in men of any age with waist circumference ≤102 cm (97th percentile 0·33 μg/l) and in subjects of either gender and any age with waist circumference >88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions  The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used

Growth hormone stimulation tests in the differential diagnosis of Parkinson'sdisease

Idiopathic Parkinson's disease (IPD) is a common neurodegenerative disorder whose differential diagnosis from other forms of atypical parkinsonism, for instance multiple system atrophy (MSA) or progressive supranuclear palsy, may be difficult, especially in the early stages. Growth hormone stimulation tests have been recently reported to be useful in the differential diagnosis between IPD and MSA. Both clonidine, an alpha(2)-adrenoceptor agonist, and arginine, an amino acid activating the cholinergic system, have been used to assess growth hormone response in patients with IPD and MSA. This review summarizes the results of several studies and discusses the validity of these tests in the differential diagnosis of parkinsonisms

Is arginine test a reliable tool for differential diagnosis of multiple system atrophy?

Arginine test for differential diagnosis of multiple system atrophy

Complications of Cushing's syndrome: state of the art

Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome

The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC

Smoke, alcohol and drug addiction and male fertility

In recent decades, the decline in human fertility has become increasingly more worrying: while therapeutic interventions might help, they are vexing for the couple and often burdened with high failure rates and costs. Prevention is the most successful approach to fertility disorders in males and females alike. We performed a literature review on three of the most common unhealthy habits - tobacco, alcohol and drug addiction - and their reported effects on male fertility. Tobacco smoking is remarkably common in most first-world countries; despite a progressive decline in the US, recent reports suggest a prevalence of more than 30% in subjects of reproductive age - a disturbing perspective, given the well-known ill-effects on reproductive and sexual function as well as general health. Alcohol consumption is often considered socially acceptable, but its negative effects on gonadal function have been consistently reported in the last 30 years. Several studies have reported a variety of negative effects on male fertility following drug abuse - a worrying phenomenon, as illicit drug consumption is on the rise, most notably in younger subjects. While evidence in these regards is still far from solid, mostly as a result of several confounding factors, it is safe to assume that cessation of tobacco smoking, alcohol consumption and recreational drug addiction might represent the best course of action for any couple trying to achieve pregnancy

Cushing syndrome, metabolic syndrome and inflammation: a suggested way out

Endogenous hypercortisolism is associated with an increased cardiovascular risk. Cushing Syndrome (CS) shares many clinical features with metabolic syndrome, including abdominal obesity, systemic arterial hypertension, insulin resistance, dyslipidemia, and thrombotic diatesis. Moreover, CS represents an interesting pattern of an endocrine disorder associated with chronic lowgrade inflammation which is not blunted by the resolution of hypercortisolism. The proinflammatory state that accompanies the metabolic syndrome may provide a connection between CS, inflammation and metabolic processes, which is highly deleterious for vascular functions. There is evidence that dietary patterns similar to those of the Mediterranean-style diet exert ositive effects on almost all components of the metabolic syndrome and other conditions associated with, including inflammation, insulin resistance, and endothelial dysfunction. Therefore, an intervention strategy based on lifestyle changes may play a role in patients with resolution of hypercortisolism in which the anti-inflammatory effects of cortisol are lost and cytokines levels are increased. In this setting, the Mediterranean healthy dietary pattern may represent an innovative approach in order to improve the disease course and to reduce in the long term the cardiovascular risk of people affected by C

Cardiovascular alterations in adult GH deficiency

There is a growing body of evidence indicating that patients with adult GH deficiency (GHD) are characterized by a cluster of traditional and emerging cardiovascular risk factors and markers, which can significantly increase their cardiovascular morbidity and mortality possibly linked to aberrations in GH status. Patients with adult GHD present multiple different cardiovascular abnormalities. In addition, cardiovascular risk in adult GHD is increased due to altered body composition, abnormal lipid profile, insulin resistance and impaired glucose metabolism. Cardiovascular risk factors can be reversed, at least partially, after GH replacement. However, evidence on the effects of GH replacement on cardiovascular events and mortality is too limited in adult GHD patients. Aim of this review is to provide an at-a-glance overview of the role of the GH/IGF-I on the cardiovascular system and the state of art of the effects of GH replacement on cardiovascular system