in 2,589 adult patients with hypopituitarism and GHD showed that approximately 71% of patients had elevated total and low-density lipoprotein (LDL) cholesterol levels, 49% were below desired target value for HDL cholesterol, while 55% had higher triglycerides [29]. Obesity was prominent (32% had a BMI >30) [26]. Waist circumference was above the target value in 46% and BP elevated in 26% of patients [26]. Statistically significant reductions in total cholesterol, waist-to-hip ratio, and fat tissue by dual X-ray absorptiometry, with a corresponding increase in lean body mass, were observed after 1 and 2 years of GH replacement [26].
The study from the USA analyzed prevalence of the MetS in elderly adult, predominantly male hypopituitary patients (n = 141, mean age 66 years) [3]. The study was controlled for obesity to see if endocrine deficiency per se is associated with metabolic consequences. Hypopituitary patients exhibited significantly higher prevalence of hypertension (88 vs. 78%), hypertriglyceridemia (80 vs. 70%), and MetS (90 vs. 71%) [3]. Results of this study suggested that hypopituitarism per se is associated with MetS independent of BMI.
More recent study on the prevalence of MetS in patients with hypopituitarism from KIMS database (Pfizer International Metabolic Database) reported rates of 43.1% [5]. MetS prevalence was related to age, BMI, waist circumference, GHD duration, and etiology of hypopituitarism [5]. Highest prevalence was reported in patients with craniopharyngeomas 45.9%, pituitary adenomas 44.7%, and idiopathic/congenital GHD 42.4% [5]. Prevalence of diabetes mellitus, cardiovascular, and cerebrovascular morbidity was higher in the MetS group and increased significantly with the escalating number of components of the MetS [5].
Study which followed 98 GHD patients on long-term GH replacement therapy (GHRT), for at least 10 years, demonstrated ongoing beneficial effects of the GHRT on lipid profile in the presence of increase in anthropometric parameters such as BMI, waist circumference, and systolic BP [7]. As a consequence, prevalence of the MetS increased significantly after 10 years of GHRT [7]. It was concluded that the increase in MetS prevalence, from 32.7 to 46.9% after 5 years of GHRT and to 57.1% after 10 years of GHRT, was higher than expected as a consequence of aging alone [7].
In contrast to the previous study, in Nordinet International outcome study, 36% of patients, with data on the MetS at baseline, fulfilled the criteria for MetS, while 40% fulfilled those criteria at 4 years of GH replacement, suggesting no significant change in the prevalence of MetS during treatment with GH [16].
Impact of GHD and GHRT on Components of MetS in Patients with Hypopituitarism
Patients with adult GHD exhibit a well-defined clinical phenotype including reduced lean body mass, muscle strength and exercise capacity, excess abdominal fat mass with insulin resistance and dyslipidemia, decreased bone mineral density, decreased energy, and quality of life. Adverse cardiometabolic profile and increased prevalence of MetS in GHD are typically characterized by clustering of risk factors including increased accumulation of visceral adipose tissue, insulin resistance, dyslipidemia with increased total cholesterol, LDL cholesterol, triglycerides, and decreased HDL cholesterol. GHD in adults is also associated with impaired endothelial function and fibrinolysis, increased adhesion and inflammatory markers, as well as some distinctive changes in cardiac function and morphology [27–79].
Pathogenesis of MetS in hypopituitary patients with GHD is depicted in Figure 1.
Isolated GHD (IGHD) provides the ideal model to characterize the influence of GHD per se without the confounding interferences from other pituitary hormone deficiencies or their treatment. The prevalence of IGHD is less than 10%. These patients may reflect those in whom a pituitary insult is evolving from a known or idiopathic cause [80, 81]. The study which compared patients with IGHD (n = 274) and MPHD (n = 2,594) from KIMS data base was unable to detect differences in serum lipid levels, glucose metabolism, fracture rate, and quality of life between the 2 groups of patients [80]. It has been shown that IGHD and MPHD patients have not only similar baseline clinical presentation and prevalence of MetS, but respond equally well to 2 years of GHRT [80]. Similar prevalence of MetS in hypopituitary patients with MPHD (43.1%) and IGHD (42.4%) was also confirmed in the recent study from KIMS database [5].
Dyslipidemia in GHD and Responses to GHRT
Adults with GHD have unfavorable lipid profiles characterized by increased total and LDL cholesterol and triglycerides, while decreased HDL was observed only in women [27]. GHRT significantly improves lipid profiles in these patients [27–33]. Significant decrease in total and LDL cholesterol and increase in HDL cholesterol during short- (1–2 years) and long-term (5–15 years) GHRT were reported [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