Metabolic Syndrome Consequent to Endocrine Disorders. Группа авторов

Direct effect of IGF-1 on stimulation of NO synthesis in the endothelial cells was demonstrated. Increased levels of asymmetrical dimethyl arginine, an endogenous inhibitor of endothelial NO synthase involved in the pathogenesis of endothelial dysfunction, have also been reported in these patients, as well as, reduction during GHRT along with improved endothelial function [59, 60]. Higher levels of pregnancy-associated plasma protein A were found in GHD patients compared to controls [47]. Pregnancy-associated plasma protein A is proposed as a marker of increased atherothrombotic risk, which is highly expressed in eroded and ruptured atherosclerotic plaques in acute coronary syndrome and ischemic stroke. It is produced by smooth muscle cells in the arterial wall.

Higher prevalence of atheromatous plaque in common carotid artery, in asymptomatic GHD patients, and improvement during short-term GHRT, of increased carotid media thickness was also demonstrated [61].

A number of different markers of vascular and endothelial dysfunction are reportedly altered in GHD patients including changes in fibrinolytic system, soluble adhesion molecules, and inflammatory cardio-vascular markers [62–71].

C-reactive protein (CRP) is a marker of inflammation and an independent cardiovascular risk factor. Elevated CRP levels are associated with negative cardiovascular prognosis and can predict development of type 2 diabetes, hypertension, and MetS. Both lean and obese subjects with GHD have an approximately 4- to 5-fold increase in CRP suggesting a pro-inflammatory state linked directly to GHD [70, 71]. GHRT reduced CRP levels in adults with GHD, which was not affected by the changes in the body composition or endothelial function [70, 71]. Similar effects have been shown for fibrinogen, interleukin-6, and tumor necrosis factor alpha levels in GHD patients [65, 70, 71].

GHD is characterized by impaired fibrinolysis due to increase in major fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which downregulates fibrinolysis by rapid inhibition of tissue plasminogen activator (t-PA). PAI-1 is produced in endothelial cells and adipocytes under influence of complex genetic and metabolic factors. It has been shown that elevated level of PAI-1 is associated with increased risk of thromboembolic disorders. On the other hand, t-PA, the main activator of plasminogen, is predominantly produced in endothelial cells and rapidly inactivated by PAI-1 after release in blood. Increased levels of PAI-1 activity and t-PA antigen in adult patients with GHD significantly decreased during 2 years of GHRT [66, 67]. Several authors linked abnormalities of fibrinolytic parameters to metabolic changes which accompany GHD state. Positive correlation between PAI-1 and t-PA levels on one side and insulin concentration and triglyceride level were reported [68, 69]. This is in accordance with fact that low density lipoproteins increase PAI-1 activity by influence on regulatory elements within PAI-1 gene promoter region. During 12 months of GHRT fibrinolytic capacity returned to normal values although triglyceride levels, insulin, and insulin sensitivity did not change significantly, suggesting a direct impact of GH on endothelial cells and their ability to release pro-fibrinolytic components especially t-PA [69].

      Available data support the evidence of beneficial direct GHRT effects on vasculature, endothelial function, proinflammatory molecules, adhesion markers, and fibrinolytic function in adult GHD patients with hypopituitarism. Data regarding autonomic nervous system dysfunction are scarce. Reported reduction and normalization of cardiovascular mortality rates and death from myocardial infarction further support these findings [14].

      Cardiac Function and Morphology

Achievement of peak cardiac mass remains under the influence of GH in young adulthood and adolescence. Direct and indirect GH action via IGF-1 causes increased synthesis of myosin light chain-2 and troponin I, leading to cardiac cell growth. IGF-1 is also known to increase intra-cellular calcium and calcium sensitivity, leading to increased cardiac contractility [72]. GHD causes myocardial hypokinesis with loss of normal response to exercise [73, 74]. In adults with childhhood-onset GHD cardiac mass is significantly reduced. Previous echo studies in younger patients, receiving higher doses of GH have clearly demonstrated increase in left ventricular mass within one year of GHRT [75–77]. Recently this was demonstrated in the middle-aged GHD patients using magnetic resonance imaging [76, 78]. Study in older GHD patients demonstrated no difference suggesting that other factors than GH, such as BP, have a more significant effect on cardiac mass in older individuals.

      Anabolic effects of GHRT on LV mass seem to be short-lasting (1–2 years of GHRT) and disappear soon after discontinuation of treatment or return to normal after 2 years of long-term (10 years) GHRT. However, decrease in diastolic BP and improvement of diastolic filling seem to persist during long-term (7 years) GHRT [32].

      MetS and Fatty Liver Disease in Patients with GHD and Hypopituitarism

      Recently, several reports have suggested that hepatic impairment and hepatic steatosis may be particularly related to MetS in GHD. Non-alcoholic fatty liver disease (NAFLD) can be diagnosed using imaging techniques while diagnosis of non-alcoholic steato-hepatitis (NASH) is based on histological finding obtained by liver biopsy. NASH is progressive disease characterized by steatosis, inflammatory infiltration, hepatocyte injury, and fibrosis, which can lead to hepatic cirrhosis [3, 81].

Visceral adiposity with insulin resistance and lipid accumulation within hepatocytes, increased oxidative stress, cytokine induction, and inflammation are important for the pathogenesis of the fatty liver disease. Several other factors including (older) age, race, (male) gender, BMI (obesity, especially visceral), and diabetes are known to affect individual susceptibility to NAFLD. Visceral obesity with associated insulin resistance, which are predominant in patients with adult GHD, may play a role in the development of NAFLD irrespective of the BMI value. Direct effects of GH/IGF-1 axis on hepatic metabolism are also important. In mice, GH receptor deletion or post-receptor JAK2 or STAT5 deletion in the hepatocytes results in steatosis and impaired lipid metabolism, while exogenous IGF-1, in the animal model of liver cirrhosis, reduces fibrosis [82–85].