Effects of Physiologic Growth Hormone Administration on Cardiovascular Risk in Subjects With Growth Hormone Deficiency Following Cure of Acromegaly

The aim of the study is to evaluate the effects of physiologic growth hormone (GH) replacement on cardiovascular risk markers, cardiac autonomic function, arterial distensibility, body composition, and quality of life in men and women with GH deficiency following treatment of acromegaly. We hypothesize that this population will represent a newly identified group of patients for whom GH replacement will be of benefit.

Treatment modalities in acromegaly include transsphenoidal surgery and radiation therapy, which can both result in hypopituitarism. A significant subset of cured acromegalics therefore develop pituitary hormone deficiencies. Although replacement of adrenal, thyroid and gonadal hormones is routine practice, clinicians do not replace GH in this subgroup, even in profoundly GH deficient subjects, as there are no randomized studies proving benefit in this population. With the accumulation of evidence on the beneficial effects of GH replacement, this therapy is becoming standard of care in all subjects with GH deficiency (GHD), except in this acromegaly subgroup where GH has been traditionally withheld. The GHD syndrome is manifested by an increase in cardiovascular risk, which is potentially reversible with GH therapy. Cardiovascular disease is the leading cause of death in acromegalics. Although cure of acromegaly is associated with a reduction in mortality attributable to GH excess, GHD may be a contributing factor to cardiovascular morbidity and mortality in this group of patients, as it is in patients with other pituitary tumors. It is therefore crucial to determine how cured acromegalics with hypopituitarism are affected by the GHD syndrome, and it is essential to study how this particular population responds to GH therapy. Because these patients typically have large macroadenomas and are treated with surgery and radiation therapy, long-term management of hypopituitarism is critical. As with all endocrine disorders, the goal of therapy is normal hormone replacement, not taking patients from a state of hormone excess to one of permanent hormone deficiency.

Cardiovascular status in acromegaly

Acromegaly is associated with a 2-3 fold increase in mortality compared to the general population. GH excess has been recognized to have multiple effects on the heart and cardiovascular system. GH excess affects cardiovascular health indirectly by increasing the prevalence of cardiovascular risk factors including hypertension, insulin resistance/type 2 diabetes, and dyslipidemia. In addition, endothelial dysfunction is more prevalent in acromegaly than in normal controls. Impaired endothelium-dependent vasodilatation with exaggerated sympathetic-mediated vasoconstrictor response has been recently described in acromegalic patients. Although flow-mediated dilatation has been shown to improve in cured acromegalics, it has not been shown to return to normal. Reports on the prevalence of increased carotid intima-media thickness (IMT) are conflicting. Some studies have documented an increase in IMT in active acromegaly and some have not.

A specific acromegaly-related cardiomyopathy -- independent of hypertension, diabetes and dyslipidemia -- has been extensively described. Impairment in ejection fraction after physical activity is observed in up to 73% of patients, which may lead to exercise intolerance in some of them.