Medical Treatment of Acromegaly: Comorbidities and Their Reversibility by Somatostatin Analogs

Abstract

Relief of symptoms can be achieved following surgery for growth hormone (GH)-secreting adenomas, as well as after pharmacological therapy with somatostatin analogs. Recently, long-acting somatostatin analog depot formulations, octreotide LAR and lanreotide SR have become available. Somatostatin analogs control GH/insulin-like growth factor (IGF)-1 excess, induce tumor shrinkage in a high proportion of patients, improve symptoms of acromegaly with relatively limited side effects and are successfully administered in patients not suitable for surgery. Furthermore, preoperative somatostatin analogs have been suggested to improve outcome for tumors with limited invasiveness, while surgical tumor debulking in cases that are, at least partially, somatostatin resistant, increases the achievement of normal IGF-1 levels by postoperative somatostatin analog treatment. Effective control of hypertension, as well as diabetes, is mandatory in order to reduce the increased vascular morbidity/mortality. Control of GH/IGF-1 excess generally improves glucose metabolism. Somatostatin analogs improve insulin sensitivity, exerting, however, a concomitant direct inhibitory effect on insulin secretion, with a net balance leaning towards a deterioration in glucose homeostasis. As a result, oral insulin secretagogues (and/or insulin) should probably be preferred to insulin sensitizers in acromegalic patients developing diabetes while on somatostatin analogs. Nevertheless, glucose tolerance remains normal in most of the nondiabetic acromegalic patients, while diabetic acromegalic patients on insulin are at risk for hypoglycemia during initiation of somatostatin analog therapy. Although successful management of acromegaly has been associated with improvement in morphological and functional parameters of cardiomyopathy, limited and conflicting information is available regarding the effect on blood pressure control. Contradictory results have also been reported regarding sleep hypopnea or apnea in treated acromegalic patients. As acromegalic skeletal abnormalities are rather irreversible, apneic episodes may persist after normalization of hormonal levels. Aggressive therapy, including surgery, pharmacological treatment and, in some cases, pituitary irradiation, aiming at normalization of IGF-1 levels, is required for arthropathy management. Some improvement in pain, crepitus and range of motion has been observed after treatment with somatostatin analogs. Information on the impact of disease control, either by surgery or somatostatin analog treatment, on gonadal function is limited. Finally, the link between the hormonal/biochemical and the psychiatric/psychological features of acromegaly, as well as a potential basis for positive effects of somatostatin analog therapy remain unclear.

Sleep apnoea syndrome is highly prevalent in acromegaly and only partially reversible after biochemical control of the disease

“…Since the obstructive component of SAS was predominant, it can be assumed that the irreversible craniofacial deformations occurring in the previous active phase may account for the persistence of the apnoeic episodes after biochemical control, as already shown by some authors (5,15,19,26). This hypothesis could also explain why, in our experience, the duration of disease remission among the subgroup of controlled acromegalic patients does not correlate with the presence of SAS.…”

“…Rosenow et al (14) found a relative high frequency of SAS in patients with treated acromegaly, at least of 21%, with a positive correlation with GH/IGF1 levels, age as well as neck and index-finger circumference as measures of soft tissue hypertrophy. Some studies showed significant improvement or cure of SAS after adenomectomy (18,(21)(22)(23), while others found persisting nocturnal breathing abnormalities (24) or sleep apnoea in patients previously treated with pituitary surgery (4) or only slight to moderate improvement despite normalized or decreased hormonal levels (25) probably due to the irreversible changes of the craniofacial region and upper respiratory tract (5,15,19,26). Finally, there are many reports of relief of SAS during treatment with s.c. or long acting release (LAR) octreotide (16,20,26,27), although SAS can persist after normalization of hormonal levels (26,28).…”

Influence of disease control with pegvisomant on sleep apnoea and tongue volume in patients with active acromegaly

“…Some studies showed significant improvement or cure after adenomectomy (37,38), while others found persisting nocturnal breathing abnormalities (39) in patients previously treated with pituitary surgery (25) or only slight to moderate improvement despite normalized or decreased hormonal levels (40) probably due to the irreversible changes of the craniofacial region and upper respiratory tract (14,28,32). Finally, there are many reports of relief during treatment with s.c. or long-acting release octreotide (17,29,41), although the sleep apnoea can persist after GH/IGF1 normalization (17,41).…”

Sleep apnea syndrome in acromegalic patients: Can morphological evaluation guide us to optimize treatment?

“…For instance, some studies showed significant improvement after pituitary surgery [7] or somatostatin analogues [8,9], while others observed that SAS persisted after recovery of acromegaly in a relatively high percentage of patients, despite a potential association with IGF-I levels and disease duration [1]. In their longitudinal study, Castellani et al noted how active acromegalic patients who achieved biochemical control, regardless of how they did so (surgery, radiotherapy and/or medical therapy), experienced improvement of their sleep disorder.…”