Rehabilitation Program in Patients With Acromegaly

Acromegaly is a rare, chronic, disabling disease of endocrine origin that causes several debilitating systemic dysfunctions due to the excessive production of growth hormone (GH) and insulin-like growth factor I (IGF-I) (Gadelha et al., 2017).

In 98% of cases, the disease is caused by a sporadic somatotropinoma. Sporadic somatotropinomas are tumors of monoclonal origin; a mutation that activates the alpha subunit of stimulatory G protein (sgp) is the most common genetic alteration, and it is found in approximately 40% of participants. Somatrotopinomas can be macro- (≥1 cm) or microadenomas (<1 cm); purely GH-secreting (60% of cases), mixed (GH, prolactin, thyroid-stimulating hormone and/or corticotrophin) and occasionally pituitary carcinomas (fewer than 20 published cases); and, even more rarely, hypothalamic neoplasms secreting growth hormone-releasing hormone (GHRH), which stimulates the pituitary gland's production of GH. However, there may occasionally be secondary causes or ectopic sources of GHRH. Typical secondary sources include malignant neoplasms of the adrenals, lungs and pancreas; more rarely, GHRH is secreted by neuroendocrine tumors of the gastrointestinal tract, such as gastrinomas and insulinomas. GH-secreting ectopic tumors (pancreatic islet tumor and non-Hodgkin's lymphoma) occur very rarely (Chanson and Salenave, 2008; Chanson et al., 2009).

In a smaller percentage of cases (5%), the disease may have a familial nature, such as multiple endocrine neoplasia syndromes type 1 and type 4, Carney complex, and familial isolated pituitary adenoma (FIPA), including its subtype, isolated familial somatotropinoma (IFS) (Gadelha et al., 2017; Marques et al., 2017). There are anecdotal reports of the disease being caused by an overdose of GH during treatment for children who do not produce this hormone and in athletes who use GH as a drug to improve muscle performance (Macintyre 1987; Karges et al. 2004).

Chronic exposure to GH and IGF-I has multisystemic repercussions, with changes in metabolic parameters, body composition, cardiac function, pulmonary function, muscle function and exercise capacity, among other effects (Dantas et al., 2013; Hatipoglu et al., 2014; Volschan et al., 2017). IGF-I is produced primarily by the liver (which is responsible for ≈75% of circulating IGF-I) in response to elevated GH levels and, to a lesser extent, to endocrine stimulation of insulin in the liver (Aguirre et al., 2016). Additionally, IGF-I provides an inhibitory feedback signal for GH secretion in the hypothalamus, stimulating the production of somatostatin in the pituitary (Ohlsson et al., 2009). IGF-I is also produced locally in various body tissues, including cartilaginous cells (Aguirre et al., 2016). The availability of IGF-I is tightly regulated by insulin-like growth factor binding proteins (IGFBPs) (Rajpathak et al., 2009). Elevated levels of IGF-I affect several pathways of metabolism, including (1) competition with insulin for the insulin receptor, resulting in diabetes mellitus; (2) general somatic hypertrophy (e.g., macroglossia, acromegalic heart, large kidneys and bulky skeletal muscles); and (3) binding to insulin-like growth factor-1 receptor (IGF-1R), which is a tyrosine kinase receptor that causes the phosphorylation and activation of various intracellular signaling pathways, including the activation of the AKT pathway, which results in the growth and proliferation of somatic cells (Cruzat et al., 2008; Aguirre et al., 2016; Adigun and Mesfin, 2017).

Many of the clinical manifestations of acromegaly are common to other, more prevalent diseases, and diagnosis is often delayed by approximately 8 to 10 years after the onset of the first signs and symptoms (Brue and Castinetti, 2016). Adult participants with acromegaly have the characteristic features of forehead protrusion, nose and lip augmentation, nasolabial sulcus accentuation, prognathism, and enlarged hands and feet (Adigun and Mesfin, 2017). Acromegaly can lead to visceromegaly, hypertension, arrhythmias, cardiomyopathy, diabetes mellitus, ventilatory dysfunction, sleep apnea, osteoarthritis and compressive neuropathies (Colaco et al., 2004; Pivonello et al., 2017). These participants may also present with general fatigue, headache, visual changes, hyperhidrosis, acanthosis nigricans, hypopituitarism, hyperprolactinemia, nephrocalcinosis and an increased incidence of colon and thyroid cancer (Table 1) (Colao et al., 2004). The clinical diagnosis is confirmed biochemically by an elevated IGF-I level for age and a nadir serum GH concentration higher than 1.0 μg/L following an oral glucose tolerance test (Katznelson et al., 2014). The assessment of tumor volume and extent is based on imaging studies using magnetic resonance imaging or computed tomography of the sella turcica (Melmed et al., 2005). The goals of treatment are to correct (or prevent) tumor compression by excision, reduce GH and IGF-I levels to normal, control symptoms, improve quality of life and reduce mortality (Cordido et al., 2013, Leopoldo et al., 2017). Transsphenoidal surgery is the treatment of choice, with exceptions for participants who have a clinical contraindication or who refuse the procedure or in cases of almost entirely unresectable tumors (e.g., those with an epicenter within the cavernous sinus) (Katznelson et al., 2014). When surgery fails to correct GH/IGF-I hypersecretion, adjuvant drug treatment is indicated. At present, there are three classes of drugs available for the treatment of acromegaly: somatostatin receptor ligands, dopaminergic agonists, and GH receptor antagonists (Giustina et al., 2014, Katznelson et al., 2014). Radiation therapy is currently proposed as a third-line treatment (Chanson et al., 2009; Leopoldo et al., 2017). The prognosis of acromegaly has improved in recent years. However, even when participants are cured or their disease is well controlled, sequelae often remain (Leopoldo et al., 2017).

There are innumerable functional limitations that negatively affect the ability of participants with acromegaly to perform activities of daily living (ADLs) and contribute to the deterioration of their health-related quality of life (HRQoL). The dysfunctions that occur in acromegaly mainly involve the bones, joints and muscles, and these structures are affected in almost all cases (Lopes et al., 2014; Lopes et al., 2014; Mazziotti et al., 2018). In participants with acromegaly, progressive damage to the articular and musculoskeletal systems occurs, causing temporomandibular joint dysfunction, hypertrophic arthropathy, chrondrocalcinosis, limitations of joint mobility, genu varum, acroparesthesias, carpal tunnel syndrome, thoracic spine kyphoscoliosis, intermittent claudication (lumbar spinal stenosis) and proximal myopathy (Colao et al., 2004; Chanson and Salenave, 2008; Pivonello et al., 2017). Acromegaly is associated with significant alterations in both peripheral muscle strength and endurance; these participants have reduced muscle strength despite the marked muscular hypertrophy described in previous skeletal muscle biopsy studies (Nagulesparen et al., 1976; Guedes da Silva et al., 2013; Lopes et al., 2015). Acromegalic arthropathy affects both axial and peripheral sites; the knee is the joint most often involved, followed by the shoulder, hip, ankle, elbow and hand joints (Colao et al., 2004; Scacchi and Cavagnini, 2006). Consequently, joint pain had been described in up to 90% of acromegalic participants and negatively impacts their HRQoL (Crespo et al., 2017).

In acromegaly, arthropathy progresses inexorably in advanced stages and unpredictably in smaller ways; it is not influenced by successful treatment of the disease, except in the case of diffuse joint symptoms and some pain sites (Chanson and Salenave, 2008; Chanson et al., 2009). In terms of skeletal muscle, two recent studies showed a paradoxical reduction in muscle mass and an increase in proximal muscle fatigue in participants who achieved biochemical control of acromegaly (Bredella et al., 2017; Füchtbauer et al., 2017). However, to our knowledge, no controlled trial has investigated the effects of successful treatment of the disease on muscle function, as determined by measures of skeletal muscle performance. Given the advances in the treatment of acromegaly, it seems appropriate to assess the impact of these costly interventions on physical performance and functional abilities in participants with different degrees of GH/IGF-I control. Despite the important functional limitations resulting from the involvement of the osteomyoarticular system, rehabilitation programs are currently recommended for this population.

In recent years, HRQoL has been considered as an important factor in the clinical management of acromegaly (Crespo et al., 2017). In these for this patient population, HRQoL is impaired even after clinical treatment and the normalization of the target biochemical values, i.e., GH and IGF-I, which suggests that new therapeutic approaches should be sought to improve functionality (Geraedts et al., 2017, Kyriakakis et al., 2017, Webb et al., 2017). Several investigators have hypothesized the possible benefits of ADL rehabilitation for this group of people, tracing the profile of changes that occur in this population throughout life and identifying the most important points and the main deficiencies and discomforts reported. However, only two studies have objectively evaluated the contributions of regular physical exercise to the physical and cardiovascular performance of acromegalic participants with the aim of characterizing the importance of physical activity in cases of physical and emotional impairments (Hatipoglu et al., 2014; Hatipoglu et al., 2015). Despite these studies, data on physical performance in acromegaly are limited, and physiotherapeutic approaches to such dysfunctions and with their impacts on participants well-being are still poorly established (Dantas et al., 2013, Guedes da Silva et al., 2013, Lopes et al., 2015). The investigators believe that individuals with acromegaly may benefit from a protocol of physiotherapeutic treatment directed towards controlling functional limitations.