Rehabilitation Program in Patients With Acromegaly
Rehabilitation Program in Patients With Acromegaly
Acromegaly is chronic, systemic and highly disabling disease. People with Acromegaly show a
 significant reduction in peripheral muscle strength associated with a loss resistance and
 lethargy. They tend the fatigue more easily when compared to individuals without the disease,
 which involves exercise intolerance and disability resulting in a quality of life impaired.
 Acromegaly have important functional limitations that adversely affect the performance in the
 activities of day-to-day and contribute to the worsening of the disease. Based on previous
 studies, the investigators believe that acromegaly participants with would have benefit from
 a treatment protocol facing physical performance and improved quality of life. Main
 Objective: To evaluate the effect of home rehabilitation on quality of life of participants
 with acromegaly. Methods: In this study of longitudinal intervention, they will undergo a
 rehabilitation program lasting three months, three times a week lasting 60 minutes each
 session. The protocol will be the assessment of Acromegaly Quality of Life Questionnaire
 (AcroQol) questionnaire, functional assessment by the walk test of six minutes (6MWT),
 peripheral muscle strength and assessment of joint integrity, fatigue will be measured by the
 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire that
 evaluates the fatigue in the chronic participants. The assessment will be in 3 different
 moment (month 0, month 2 month 3). The treatment protocol will consist of warm-up and
 cool-down, strengthening exercise and muscular endurance, aerobic training, and balance
 training and proprioception. Prospects: The participants with acromegaly will benefited
 significantly after undergoing a physical therapy rehabilitation protocol the following
 parameters: Resistance and muscle strength, pain conditions and disorders skeletal muscle,
 improvement in activities of daily living and consequent better quality of life.
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.
Inclusion Criteria:

 -  Patients with acromegaly, of both sexes, older than 18 and younger than 65 years,
 either with active or controlled disease.

 -  Patients who present clinical stability and who are eligible for the treatment
 protocol (patients with hormone deficiency will continue on replacement therapy -
 SILVA et al., 2013).

 -  Signature of the Informed Consent Term (TCLE).

 Exclusion Criteria:

 -  Patients with inability to perform the 6MWT, according to ATS criteria.

 -  Patients who have cognitive impairment by mini mental state examination (MEEN).

 -  Abandonment of treatment during the application of the protocol.

 -  Uncontrolled hypertension (> 180/100 mmHg with medication use).

 -  Use of psychotropic drugs.

 -  Any significant limitations due to osteoarthropathy.

 -  History of surgery in the previous year with exercise restriction. Não Untreated
 hypothyroidism or hypocortisolism (HUBBLE et al., 2014).

 -  IPAQ with very active classification.