Growth hormone replacement normalizes impaired fibrinolysis: New insights into endothelial dysfunction in patients with hypopituitarism and growth hormone deficiency

Miljić, Dragana; Miljić, Predrag; Doknic, Mirjana; Pekić, Sandra; Stojanović, Marko; Cvijović, Goran; Micić, Dragan; Popović, Vera

doi:10.1016/j.ghir.2013.08.005

Cited by 16 publications

(16 citation statements)

References 41 publications

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“…Since the beginning of 1990s, several retrospective studies have demonstrated the relationship between hypopituitarism and the increase of cardiovascular risk, especially in women, with the increase of mortality associated with cardiovascular disease, specifically been confirmed also in a recent work by Miljic et al [64]. Even the activity of protein S, which is decreased in GHD patients, is normalized by the therapy [65].…”

Section: C Mortality and Cardiovascular Events In Adult Ghdmentioning

confidence: 79%

Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]

et al. 2015

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Abstract. Adult growth hormone deficiency (GHD) is a well defined clinical condition, which is characterized by abnormal body composition, impaired physical activity and decreased quality of life. In addition, in recent years, growing interest has been shown towards cardiovascular risks in adult patients affected by GHD. In this regard, GHD is widely known to be associated with increased mortality, likely due to the increase of risk factors, such as central obesity, impaired lipid and glucose profiles and other less-known risk factors, such as inflammatory cytokines, endothelial dysfunction and oxidative stress. However, very few papers have recently discussed this topic. In this review, the aim is to clarify this issue by discussing evidence regarding the effects of adult GHD on metabolic and cardiovascular profiles.

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Section: C Mortality and Cardiovascular Events In Adult Ghdmentioning

confidence: 79%

Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]

et al. 2015

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“…We previously demonstrated that adults with GH deficiency have decreased tPA activity, along with a defective fibrinolytic response to venous occlusion . Miljic et al also reported an improvement in stimulated endothelial tPA release following venous occlusion after 1 year of GH replacement aimed to normalize IGF‐1 in GH‐deficient adults. We demonstrated that GH mediates tPA activity levels through the GHR in women, as the addition of GHR blockade suppressed tPA activity before and during stimulated GH secretion.…”

Section: Discussionmentioning

confidence: 91%

“…In healthy patients, acute systemic and intra‐arterial GH infusion increases GH without affecting IGF‐1, and increases endothelium‐dependent vasodilator function . Patients with GH deficiency demonstrate altered fibrinolytic balance, characterized by elevated plasminogen activator inhibitor‐1 (PAI‐1) antigen levels and lower tissue plasminogen activator (tPA) activity, which resolves with GH replacement therapy . IGF‐1 also exerts many favorable endothelial effects via the IGF‐1 receptor, including enhanced endothelium‐dependent vasodilation, anti‐inflammatory effects, and maintenance of vascular integrity via activated endothelial progenitor cells .…”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase‐4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women

Wilson

Brown

Nian

et al. 2018

JAHA

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BackgroundDiminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH‐releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase‐4. We tested the hypothesis that dipeptidyl peptidase‐4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity.Methods and ResultsHealthy adults participated in a 2‐part double‐blind, randomized, placebo‐controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)– (n=5), nitric oxide– (n=7), or glucagon‐like peptide‐1 receptor– (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin–like growth factor‐1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin–like growth factor‐1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (r s=−0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon‐like peptide‐1 receptor blockade affected vasodilation or tPA.ConclusionsSitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin–like growth factor‐1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR‐independent mechanism.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.

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“…GH deficient adults have abnormal lipoprotein profiles (Cuneo et al 1993), impaired cardiac function (Cuocolo et al 1996), and impaired insulin tolerance (Johansson et al 1995), which can be improved by GH treatment. In GH deficient patients, GH replacement has a favorable effect on endothelial t-PA release and fibrinolysis capacity, likely to account for their decreased vascular complications (Miljic et al 2013). In patients with adult-onset GH deficiency in response to pituitary irradiation, higher cardiovascular risk at baseline was reversed by 10-years of GH replacement (Elbornsson et al 2013).…”

Section: Childhood-vs Adult-onset Gh/igf-1 Deficiencymentioning

confidence: 99%

Growth hormone, insulin-like growth factor-1 and the aging brain

Ashpole

Sanders

Hodges

et al. 2015

Experimental Gerontology

179

126

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Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and mental function are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH/IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan.

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Growth hormone replacement normalizes impaired fibrinolysis: New insights into endothelial dysfunction in patients with hypopituitarism and growth hormone deficiency

Cited by 16 publications

References 41 publications

Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]

Impact of adult growth hormone deficiency on metabolic profile and cardiovascular risk [Review]

Dipeptidyl Peptidase‐4 Inhibition Potentiates Stimulated Growth Hormone Secretion and Vasodilation in Women

Growth hormone, insulin-like growth factor-1 and the aging brain

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