href="#ulink_59e6286f-8635-5e08-92f0-d06ceb09685a">28–31]. GHRT may also lower triglycerides although in meta-analysis, including 37 trials, positive effect of GHRT was confirmed only on total and LDL cholesterol [32]. The effect on triglycerides was neutral [32].
Small dense LDL, which may be an independent cardiovascular risk factor, is also common in GHD patients, but GHRT did not affect size of LDL particles [34–36]. Oxidative stress plays an important role in pathogenesis of atherosclerosis mediated by lipid peroxidation in particular of LDL. Oxidative stress is increased in GHD and improves with GHRT [37]. Increase in oxidated LDL was also observed and short-term GHRT was able to reduce lipid peroxidation in GHD [38, 39]. Finally, additive effect of combined statin and GH replacement treatment was observed in these patients [40].
Fig. 1. Pathogenesis of metabolic syndrome (MetS) and its components in patients with hypopituitarism and growth hormone deficiency. Used with permission from Lancet Oncology, reference number 4177570097030 [104].
Glucose Metabolism and Insulin Resistance in GHD and Responses to GHRT
Insulin resistance in adult GHD is attributed to increased visceral fat mass, which is a known risk factor for type 2 diabetes mellitus [41]. Effects of GHRT on glucose metabolism are biphasic leading initially to deterioration of already altered glucose metabolism (due to lipolysis, free fatty acids release, and decline in the peripheral utilization of glucose), with an improvement during the long-term low-dose GHRT due to decreasing visceral fat mass, improved insulin-like growth factor-1 (IGF-1) effects, decrease in adipokines, and proinflammatory molecules associated with insulin resistance, for example, tumor necrosis factor alpha, and increase of those associated with insulin sensitivity, for example, adiponectin [42–47].
Interestingly, GHRT did not affect the risk of diabetes in patients with normal BMI [49]. Age and BMI were predictive factors for diabetes during long-term GHRT [16]. Increase in fasting glucose and significant improvement in hemoglobin A1c (HbA1c) were noted [16]. HbA1c improved in patients with impaired glucose tolerance during GHRT [16]. Although some safety surveillance studies reported that prevalence (around 10%) and incidence of diabetes during 2–5 years of GHRT was not increased compared to the reference population [16, 6], mildly increased prevalence of diabetes mellitus (9.3%) in 6,050 hypopituitary patients with adult onset GHD before GHRT was found versus the expected (8.2%) [48]. Family history of diabetes mellitus, increasing age, BMI, and waist circumference were associated with increased prevalence of diabetes in hypopituitary patients [58]. Women presented with significantly higher prevalence than men [48]. Two etiologies associated with an increased diabetes prevalence were craniopharyngeoma and idiopathic GHD [48]. In another study of 5,143 hypopituitary patients, 10.2% developed diabetes after median period of 1.7 years (range 0.02–10.3) of GHRT [6]. Patients with childhood onset, previous Cushing’s disease and acromegaly were excluded from the study [6]. Patients who developed diabetes mellitus were significantly older and had more components of the MetS such as higher BMI, waist circumference, triglyceride concentrations, systolic and diastolic BP, and lower HDL-cholesterol concentrations [6]. Although the observed versus the expected ratio for diabetes incidence increased in the younger patients, it decreased with the advancing age [6]. Neither age at GHRT start, nor number of additional pituitary deficiencies, nor family history of diabetes had an impact on development of diabetes [6]. Data over period of 6 years showed increase of 0.7 mg/dL/year in fasting plasma glucose concentrations and 0.036%/year in HbA1c, which were statistically significant [6].
Advancing age, BMI, family history of diabetes, female sex, etiology of hypopituitarism (diagnosis of craniopharyngioma, pituitary adenoma, IGHD), and increasing number of components of MetS have been identified as relevant risk factors for diabetes in various studies reported so far [6, 16, 48, 49]. Data regarding the prevalence of diabetes mellitus in GH treated versus untreated patients with adult-onset of hypopituitarism are still lacking as well as prospective randomized controlled trials with life style and/or pharmacological interventions aiming to decrease visceral obesity and insulin resistance in these patients.
Changes in Body Composition: Visceral Obesity in GHD and Response to GHRT
GH exerts anabolic actions on muscle and bone with marked lipolytic effect in fat tissue. The impaired body composition in GHD results in a prevalent central fat distribution due to visceral fat accumulation contributing to an increased cardiometabolic risk. Approximately 7% higher fat mass was demonstrated in GHD patients compared with age-, sex-, and height-adjusted predicted values [50]. It has been shown that adult GHD patients with the same BMI (of 23) had higher waist circumference and visceral fat compared to controls [51].
Long-term GHRT effectively improves body composition in GHD patients. GHRT produces a gradual increase in lean body mass by 2–5 kg and reduction in fat mass by approximately 4–6 kg of visceral fat [52]. The gain in lean body mass is maintained for at least 10 years of GHRT in both men and women [52]. Improvement in body composition reflects reduction in insulin resistance with beneficial effect on vascular risk profile in these patients [52].
Hypertension,
