Growth hormone deficiency in treated acromegaly and active Cushing's syndrome

Growth hormone deficiency (GHD) in adults is characterized by reduced quality of life and physical fitness, skeletal fragility, increased weight and cardiovascular risk. It may be found in (over-) treated acromegaly as well as in active Cushing's syndrome. Hypopituitarism may develop in patients after definitive treatment of acromegaly, although the exact prevalence of GHD in this population is still uncertain because of limited awareness, and scarce and conflicting data so far available. Because GHD associated with acromegaly and Cushing's syndrome may yield adverse consequences on similar target systems, the final outcomes of some complications of both acromegaly and Cushing's syndrome may be further affected by the occurrence of GHD. It is still largely unknown, however, whether GHD in patients with post-acromegaly or active Cushing's syndrome (e.g. pharmacologic glucocorticoid treatment) may benefit from GH replacement. We review the diagnostic, clinical and therapeutic aspects of GHD in adults treated for acromegaly and in those with active Cushing's syndrome.

Introduction

Growth hormone deficiency (GHD) may be caused by organic factors generally in association with other pituitary hormone deficiencies in patients with pituitary macroadenomas or supra-sellar tumors, pituitary stalk lesions, after pituitary neurosurgery or radiotherapy. It may also be functional in disease states in which hypothalamic dysregulation of GH secretion may occur, such as hypoadrenalism (Giustina effect), as well as hypercortisolism and hypogonadism [1].

GHD of the adult is now recognized as a well-defined clinical condition, characterized by reduced quality of life and physical fitness, skeletal fragility, adiposity and increased cardiovascular risk [2].

Acromegaly is a chronic disease characterized by excess secretion of GH, generally caused by a pituitary macro-adenoma (in about 70% of cases), which results in elevated circulating levels of GH and insulin-like growth factor (IGF)-1 [3]. Acromegaly is associated with reduced life expectancy from comorbidities related to GH hypersecretion, such as cardiovascular, respiratory, metabolic and neoplastic complications [4], [5].

Treatment of acromegaly should be ideally directed towards the restoration of physiological GH secretion, which is achieved when the tumor is removed, such that the response of GH to dynamic stimuli and its integrated daily secretion are normalized. Several patients with acromegaly receiving treatment, however, do not achieve complete normalization of GH secretion [6], whereas others may develop organic hypopituitarism and GH deficiency (GHD) as a results of overtreatment of acromegaly.

On the other hand, it is well known that glucocorticoid excess, independently of its origin (ACTH-dependent and ACTH-independent hypercortisolism, chronic pharmacologic glucocorticoid treatment) may cause systemic complications, such as diabetes mellitus, arterial hypertension, coronary artery disease, congestive heart failure and fragility fractures [7]. Exposure to glucocorticoid excess leads to functional suppression of GH secretion.

Complications of GHD, either organic or functional, may be clinically relevant in patients with a history of acromegaly or active Cushing's syndrome, who are, per se, at an increased risk of developing cardiovascular, metabolic and skeletal complications [8]. It is largely unknown, however, whether patients with GHD related to acromegaly overtreatment or glucocorticoid excess may benefit from GH replacement [9], [10], [11], ∗[12].