Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency

Abstract

Objective: GH replacement therapy (GHRT) in adult-onset GH deficiency (AOGHD) reduces carotid intima-media thickness (IMT) and increases myocardial mass, with improvement of systolic and diastolic function. These observations have reinforced the use of GHRT on AOGHD. Conversely, we have previously reported that in adults with lifetime congenital and severe isolated GH deficiency (IGHD) due to a mutation in GHRH receptor gene (GHRHR), a 6-month treatment with depot GH increased carotid IMT, caused the development of atherosclerotic plaques, and an increase in left ventricular mass index (LVMI), posterior wall, and septal thickness and ejection fraction. Such effects persisted 12 months after treatment (12-month washout -12mo). Methods: We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout -60mo). Results: Carotid IMT reduced significantly from 12 to 60mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60mo, remaining higher than pretherapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60mo, but absolute posterior wall increased from 12 to 60mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60mo in comparison with 12mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60mo compared with both 12mo and baseline. Conclusions: In adults with lifetime congenital IGHD, the increase in carotid IMT elicited by GHRT was transitory and returned to baseline 5 years after therapy discontinuation. Despite this, the number of subjects with plaques remained stable at 60mo and higher than at baseline. 166 977-982 European Journal of Endocrinology

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

“…Despite the only modest increase in the levels of IGF-I, GHRT improved lipid profile and body composition, and increased all the parameters related to LV mass, but also increased significantly carotid IMT, and induced the development of carotid atherosclerotic plaques (75). Fortunately, we saw arrrest of the atherosclerosis progression after five years from the interruption of treatment (76). These observations should be considered before starting GHRT in adults with previously untreated congenital GHD.…”

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”

Should patients with adult GH deficiency receive GH replacement?

“…Lipid profile and body composition improved, but carotid intimal thickness increased and carotid atherosclerotic plaques developed within 6 months of treatment, with a 52-fold higher likelihood to have a carotid atherosclerotic plaque by 12 months even after discontinuation of GH therapy. Five years after cessation of GH therapy, intima-media thickness returned to normal, but the number of atherosclerotic plaques did not change (161). Some findings in that model may not be directly applicable to AO-GHD.…”

Fasting levels of growth hormone are associated with carotid intima media thickness but are not affected by fluvastatin treatment

“…al investigated the bulb IMT in female GH-deficient patients and did not find any significant difference when compared with healthy controls [ 25 ]. GH replacement therapy has in some studies shown beneficial effects on the bulb IMT in individuals with adult-onset GHD [ 23 , 26 , 27 ], but negative effects in congenital GHD [ 28 ]. Thus, data from GHD-patients are conflicting and if anything indicates a negative association between GH and bulb IMT, but data from acromegaly patients support our finding with the association being positive.…”