Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing’s disease in remission and controlled acromegaly

Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing’s disease in remission and controlled acromegaly | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing’s disease in remission and controlled acromegaly Luciana Martel-Duguech, Helena Bascuñana, Víctor Priego Corredor, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6485925/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Jul, 2025 Read the published version in Endocrine → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Patients with controlled Cushing’s disease (CD) and acromegaly (ACRO) often experience persistent musculoskeletal dysfunction and impaired quality of life (QoL) despite biochemical normalization. Although undergoing supervised physical activity is a clear unmet need of pituitary patients, evidence on the effectiveness of individually tailored exercise programs in these populations is scanty . Objective: The aim of this pilot study was to evaluate the effectiveness of a 12-week individually tailored and supervised exercise program on muscle function, bone health, and patient-reported outcomes (PROMs) in patients with biochemically controlled CD and ACRO. Methods: Twenty patients (10 women with CD in remission, 10 men with controlled ACRO) participated in a structured program combining aerobic and resistance exercises, supervised by professional trainers, three times a week over 12 weeks. Outcomes assessed at baseline and post-intervention included, grip strength and physical performance on gait speed, timed up-and-go, chair stand test, muscle structure and quality on ultrasound examination, body composition and bone mineral density (BMD), as measured using dual-x-absorptiometry (DXA), and QoL, as evaluated using disease-specific (CushingQoL, AcroQoL) and generic (SF-12, PANAS, PHQ-9, and GAD-7) questionnaires. Results: After the 12-week intervention, significant improvements were observed in physical performance tests (p<0.05 for all parameters vs. baseline) in both CD and ACRO patients. Ultrasound-measured muscle thickness increased CD patients after completion of the program (p<0.05), while a decreased echogenicity was found in ACRO patients (p<0.05) CD patients demonstrated significant improvements in waist circumference, diastolic blood pressure, lean mass fraction, trunk fat fraction, and femoral BMD (p<0.05). Conclusion: An individually tailored, supervised 12-week exercise intervention significantly enhanced muscle structure and physical performance in patients with controlled CD and ACRO. Physical activity trainers should be included in the multidisciplinary team dedicated to the management of pituitary diseases Cushing’s disease Acromegaly Exercise intervention Muscle quality Bone mineral density Physical performance Quality of life Patient-reported outcomes Individually tailored training Musculoskeletal dysfunction Figures Figure 1 Figure 2 Figure 3 Introduction The management of Cushing’s disease (CD) and acromegaly (ACRO) requires a collaborative and multidisciplinary approach to effectively address the clinical complexity of these conditions and their long-term impact on patient’s wellbeing. Recent guidelines have highlighted that an interdisciplinary team, ideally integrated within a Pituitary Tumor Center of Excellence (PTCOE), should take care of patients with CD and ACRO to ensure optimal care, from early diagnosis to long-term follow-up (Casanueva et al., 2017 ; Fleseriu et al., 2021 ; Giustina et al., 2020 ). Despite such growing awareness, significant challenges remain in clinical practice. After control of hormone excess, the symptomatic burden of both conditions is still elevated and often underrecognized by the clinicians (Andela et al., 2015b ; Kreitschmann-Andermahr et al., 2018 ; Valassi et al., 2022 ). A focus group study conducted in subjects with pituitary adenomas described fatigue and pain as the most bothersome physical complaints of CD and ACRO patients, and also indicated receiving physiotherapy and sport recommendations as important patients’ unmet needs regarding care (Andela et al., 2015a ). A recent study showed that almost half of 320 patients with CD in remission complained of invalidating muscle weakness, though only a small subgroup of them was seen by a physiotherapist and received a targeted treatment (Valassi et al., 2022 ) A high prevalence of fatigue and weakness has also been reported by ACRO patients who showed dissatisfaction with the care received and a clear need for more effective and individually tailored multidisciplinary approaches (Geer et al., 2022 , 2019 ). We have previously described a sustained deterioration of muscle quality, mainly related to intramuscular fatty infiltration, in both CD in remission and controlled ACRO patients, which, in turn, was associated with low performance on several muscle functionality tests (Martel-Duguech et al., 2021b , 2020 ). While muscle dysfunction and sarcopenia have been associated with impaired QoL in CD patients in remission, pain, weakness and clinical arthropathy have been described as important contributors to altered physical functioning, mood disorders and low QoL in ACRO (Cangiano et al., 2022 ; Cellini et al., 2021 ; Johnson et al., 2003 ; Martel-Duguech et al., 2021a ; Miller et al., 2008 ; Wassenaar et al., 2010 ). Evidence suggests that individually tailored exercise interventions, developed and supervised by experts, can improve muscle function, bone health, and QoL in various populations (Liu and Latham, 2009 ; Strasser et al., 2013 ). For instance, in older adults, 12-week resistance training programs have been shown to increase muscle strength, enhance physical function, and improve muscle quality by reducing intramuscular fatty infiltration (Goodpaster et al., 2008a ; Liu and Latham, 2009 ). In postmenopausal women with osteopenia or osteoporosis, high-intensity resistance training over a similar timeframe has been associated with improvements in bone mineral density (BMD) at weight-bearing sites such as the hip and lumbar spine, alongside reductions in fracture risk (Watson et al., 2018 ). Moreover, structured exercise programs in middle-aged and obese individuals have demonstrated significant improvements in body composition, metabolic health, and psychosocial well-being, including reduced symptoms of depression and anxiety (Carraça et al., 2021 ; Strasser et al., 2013 ).To date, few studies evaluated the effects of structured exercise interventions in ACRO patients, demonstrating an improvement in muscle strength, functional capacity, body balance, and QoL ( Lima et al., 2019 Haliloglu et al., 2019 ; Hatipoglu et al., 2014 )). However, these studies included heterogeneous groups with both active and controlled disease, limiting the interpretation of outcomes according to disease status. To the best of our knowledge, no studies have assessed the impact of exercise programs in CD patients thus far The objective of this pilot study is to assess whether a 12-week individually tailored exercise program, under the supervision of professional trainers, effectively improves muscle performance, bone health and patients reported outcomes (PROMs) in patients with biochemically controlled CD and ACRO. In particular, we compared physical and psychological parameters at baseline vs. those assessed after the completion of the exercise program. Subjects and methods Subjects Patients with Cushing’s disease (CD) We studied 10 women with CD in remission. Inclusion criteria were age younger than 65 and duration of remission of at least 3 years. Diagnosis of CS was made after clinical, biochemical, and radiological evaluations, based on internationally agreed guidelines (Nieman LK et al. J Clin Endocrinol Metab. 2008.). All patients had abnormal values on at least two of the following tests: elevated UFC, late-night salivary or serum cortisol, 1 mg overnight dexamethasone suppression test (ODST), or 48-hour 2 mg/day low-dose dexamethasone suppression test (LDDST). Nine patients had CD due to a microadenoma and 1 had a macroadenoma. The median duration of hypercortisolism was 28 (20) months and was defined as the time elapsed from the initial symptoms, as referred by patients, and final diagnosis of CD. Eight patients (80%) received preoperative treatment with steroidogenesis inhibitors to control clinical symptoms of hypercortisolism. All the CD patients underwent transsphenoidal surgery (TSS) a median of 154 (117) months previously, and 2 of them (20%) also received radiotherapy a median of 142 (108) months after unsuccessful surgery (n = 1) or recurrence (n = 1). Mean (± SD) time of remission, defined as the time elapsed from diagnostic confirmation of remission to study entry, was 13 ± 7 years, [median, 13(8); and range, 3 to 204 months]. CD was considered in remission if either adrenal insufficiency was demonstrated (basal morning cortisol < 171 nmol/L [< 6.2µg/dL] and/or undetectable 24-hour free urinary cortisol) or morning cortisol suppression < 50nmol/L (< 1.8µg/dL) after 1 mg dexamethasone overnight was observed. All patients had received hydrocortisone (HC) replacement (between 10 and 20 mg per day) for a median of 19 (21) months after surgery. Median time free from HC replacement was 91 (102) months. At study entry, 1 patient was still taking HC at a stable dose of 20 mg per day and mean duration of treatment was 152 months. At study entry, all the subjects were re-evaluated for possible pituitary insufficiency. One patient had growth hormone deficiency (GHD), who was replaced with recombinant human GH-rhGH- (duration of treatment 127 months). All patients were postmenopausal. Mean (± SD) duration of menopause was 93 ± 56 months. No patients were taking estrogen/progesterone hormone replacement at study entry. No patients developed gonadotropin deficiency after surgery. One patient was hypothyroid on stable dose (112 µg/day) of L-thyroxine replacement (duration of treatment 155 months). Patients with acromegaly (ACRO) We studied 10 male patients with ACRO. As for CD patients, inclusion criteria were age younger than 65 and duration of remission of at least 3 years. All patients were classified as having controlled disease, defined as mean IGF-I concentrations within the specific age-adjusted reference range on at least two measurements over a period of 6 months and random GH concentrations below 1 µg/L at study entry in those patients who were not on GH receptor antagonist treatment (Giustina et al., 2010 ). When there was a discrepancy between GH and IGF-I, we used normalization of IGF-I concentrations as the most reliable criterion to define 'control' (Alexopoulou et al., 2008 ). When the 75 g oral glucose load was performed, GH values at or below 0.4 µg/L were considered as markers of cured disease. All had a GH-secreting pituitary tumor confirmed pathologically. The median duration of the disease was defined as the time elapsed between the onset of symptoms and signs of ACRO (evaluated through photographs and clinical history) and the time when treatment was proven to be effective. The median duration of control was defined as the time between the achievement of normal hormone values and study entry. One patient was on treatment with a somatostatin analog (SSA), duration of treatment from first treatment to study entry was 108 months. One patient was on treatment with cabergoline, duration of treatment 84 months. All had undergone transsphenoidal surgery (TSS) 24 months to 40 years previously (median, 16 years), 1 had undergone postoperative radiotherapy 21 years prior to study entry. No patient had secondary adrenal insufficiency. One patient had secondary hypothyroidism on adequate L-thyroxine replacement therapy (75 mcg/day). Two males had secondary hypogonadism, defined as testosterone levels below 300 ng/dL (10.4 nmol/L)(Bhasin et al., 2010 ); they had been on stable testosterone replacement doses for more than 1 year, and were, therefore, considered eugonadal. All the patients was tested for GH deficiency and only one (13%) was found to be GH-deficient and were treated with a stable replacement dose of rhGH (0.15mg/day) The following exclusion criteria were applied to both patients with CD and ACRO: presence of comorbidities unrelated to CD and ACRO; stroke; cognitive alteration; uncontrolled hypertension; untreated hypothyroidism, adrenal insufficiency or growth hormone deficiency; any significant limitations due to osteoarthropathy, inability to perform functional tests and history of any orthopedic surgery in the previous year. Patients were informed about the study during their follow-up visit at our clinic at the endocrine clinic of the Hospital Sant Pau, Barcelona, Spain. If they agreed to participate, they were asked to sign the consent. The protocol was approved by the Sant Pau Research Ethics Committee. Methods All patients underwent a 12-week, structured, individually tailored program of combined aerobic and resistance exercise (Fig. 1 ), under the supervision of professional trainers (V.P.C., O.G.V., J.V.R., T.C.P.) from the National Institute of Physical Activity of Catalunya (INEFC). Before starting the protocol, patients were instructed by the supervisor on how to perform the exercises, which were adapted, in each session, to patients’ characteristics and personal history of physical activity. Patients then followed a structured exercise program consisting of three sessions per week, each of them being divided into four parts. First, the active warm-up included range of motion exercises focusing on joint mobility for the neck, shoulders, elbows, hips, knees, and ankles. This also included breathing control and stretching muscles/tendons without pain, with two sets of 15–20 seconds per exercise. Second, the strength workout comprised exercises such as chest press, knee extension, shoulder press, knee flexion, shoulder abduction, hip abduction, biceps flexion, hip adduction, triceps extension, and ankle dorsiflexion. Patients performed three sets of 12–15 repetitions for each exercise at an intensity of 5/6 on the Borg Scale, with 15–20 seconds of rest between exercises and 1 minute of rest between sets. The third part was an endurance workout, consisting of walking for a total of 30 minutes, divided into three sets of 10 minutes each. This was also performed at an intensity of 5/6 on the Borg Scale, with 2 minutes of rest between sets. Finally, the cool down involved passive stretching for the neck, shoulders, elbows, hips, knees, and ankles, with one set of 15–20 seconds per exercise. Outcomes We evaluated the following parameters at baseline and within 72 hours after the completion of the exercise program: blood pressure (BP), BMI, waist and neck circumference, physical performance, body composition, muscle US parameters and QoL Physical performance was assessed through the following tests; gait speed (GS), timed up and go (TUG), 30-s chair stand and grip strength, as described elsewhere (Martel-Duguech et al., 2020 ). All tests were performed under the supervision of a physical medicine specialist (HB). Body composition was assessed using dual-energy X-ray absorptiometry (DXA) (Hologic Discovery W, Software Apex Version 13.4), following standardized protocols. Measurements included appendicular skeletal muscle mass (ASM), calculated as the sum of lean mass from both arms and legs (excluding bone mass) and adjusted for height squared (ASM/height²), as well as total fat mass and trunk fat mass, reported in both kilograms and as percentages of body mass. Lean mass was also measured and expressed as a percentage of body weight. Bone health parameters included BMD at the lumbar spine and femoral neck, with corresponding T-scores used to classify bone status relative to a young healthy reference population. These measurements were performed pre- and post-intervention to evaluate changes in body composition and bone health. In the ACRO group, the post-exercise assessment of body composition and BMD using DXA could not be completed due to logistical challenges in scheduling the examinations during the COVID-19 pandemic. Although another DXA was performed in these patients more than 1 year after the completion of the program, we decided to not compare these data with those obtained at baseline (pre-exercise), due to the fact that such a large time frame could interfere with a reliable assessment of the exercise effects on body composition. In the CD group, both pre- and post-exercise DXA assessments could be completed and, therefore, body composition parameters at both time points could be compared, as shown in Table 1 . We obtained transverse US images of the rectus femoris (Philips Affiniti 70; The Netherlands) and assessed muscle thickness (cm), volume (ml) and muscle quality at the middle and distal third of rectus femoris (RF) and vastus intermedius (VI) on both sides. Muscle quality was measured as muscle intensity using the Heckmatt’s rating scale (Heckmatt et al., 1982 ); Grade 1: Normal muscle structure and echogenicity. Grade 2: Increased muscle grayscale level with still a distinct bone echo. Grade 3: Marked increased grayscale level of the muscle with diminished bone echo. Grade 4: Very strongly increased grayscale level with a total loss of bone echo. Quality of life (QoL) was assessed using the following questionnaires: CushingQoL is a disease-specific qustionnaire consisting of 12 items that cover seven concepts referring to problems relevant to CS patients. Items are scored on a 5-point Likert scale, resulting in a score of 12 (worst) to 60 (best) which is standardised to a scale of 0-100. Higher scores indicate more favourable HRQoL (Webb et al., 2008 ) AcroQoL (Acromegaly Quality of Life Questionnaire) is a specific tool designed to assess QoL in patients with ACRO consisting of 22 items and is divided into two main domains, physical and psychological dimensions; the latter is further subdivided into two further subdimensions, appearance and personal relations. Each item in the questionnaire is rated on a 5-point Likert scale, where patients indicate the frequency or how much they agree or disagree with each statement based on their experiences. Each item is scored from 1 to 5, with higher scores indicating better QoL. Global scores and those for each dimension are summed and then transformed into a scale from 0 to 100, where 100 represents the best possible QoL and 0 represents the worst (Badia et al., 2004 ) The SF-12 is a self-reported outcome measure assessing the impact of health on an individual’s everyday life. SF-12 evaluates the following eight domains: 1) Limitations in physical activity because of health problems. 2) Limitations of social activities because of physical or emotional problems. 3) Limitations in usual role activities because of physical health problems. 4) Bodily pain. 5) General mental health (psychological distress and well-being). 6) Limitations in usual role activities because of emotional problems. 7) Vitality (energy and fatigue). 8) General health perceptions. Patients complete a 12-question survey, and the responses are then scored by a clinician. The SF-12 generates two summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS), each ranging from 0 to 100. Higher scores indicate better health status and fewer limitations, with scores closer to 100 reflecting minimal impairment. Lower scores suggest greater health-related limitations and poorer QoL (Ware et al., 1996 ) The Positive and Negative Affect Schedule (PANAS) is a scale consisting of words that describe feelings and emotions, with separate scales measuring positive affect (PA) and negative affect (NA). Respondents rate each emotion on a scale from 1 (very slightly or not at all) to 5 (extremely), based on how much they have felt that way during a specified time frame. The PA and NA scores are calculated by summing the ratings for their respective items. Higher PA scores indicate higher levels of positive emotions and engagement, while higher NA scores reflect greater levels of distress and negative emotions.(Watson et al., 1988 ) The Patient Health Questionnaire-9 (PHQ-9) is a multipurpose instrument used for screening, diagnosing, monitoring, and measuring the severity of depression. It assesses nine domains: 1) Little interest or pleasure in doing things. 2) Feeling down, depressed, or hopeless. 3) Trouble falling asleep, staying asleep, or sleeping too much. 4) Feeling tired or having little energy. 5) Poor appetite or overeating. 6) Feeling bad about yourself or that you are a failure or have let yourself or your family down. 7) Trouble concentrating on things, such as reading the newspaper or watching television. 8) Moving or speaking so slowly that other people have noticed. 9) Thoughts of being better off dead or self-harm. Each domain is scored from 0 (not at all) to 3 (nearly every day), with the total score ranging from 0 to 27. Scores of 5, 10, 15, and 20 represent thresholds for mild, moderate, moderately severe, and severe depression, respectively.(Kroenke et al., 2001 ) The Generalized Anxiety Disorder Questionnaire (GAD-7) is a self-administered questionnaire used as a screening tool and severity measure for generalized anxiety disorder (GAD). Patients are required to respond to seven questions about symptoms: 1) Feeling nervous, anxious, or on edge. 2) Not being able to stop or control worrying. 3) Worrying too much about different things. 4) Trouble relaxing. 5) Being so restless that it’s hard to sit still. 6) Being easily annoyed or irritable. 7) Feeling afraid as if something awful might happen. Each question is scored from 0 (not at all) to 3 (nearly every day), yielding a total score ranging from 0 to 21. Scores of 5, 10, and 15 represent mild, moderate, and severe anxiety, respectively (Spitzer et al., 2006 ). Statistical analysis For statistical analysis, GraphPad Prism® version 9 (Graph-Pad Software, San Diego, Calif., USA) was used. Continuous data are presented as mean ± SD, while categorical variables are presented as absolute/relative frequencies. We performed statistical comparisons of quantitative data with Student’s t test or ANOVA. When the two variables compared were not normally distributed, we used the Mann-Whitney U test. To evaluate the effectiveness of the exercise program, we performed a statistical analysis using a paired Student's t-test. This test was chosen to compare the pre- and post-exercise data for each patient, allowing us to assess the changes within the same individuals over the course of the study. All statistical tests were two sided with p values of < 0.05 considered significant. Results General characteristics and body composition General metabolic characteristics and body composition of patients with CD at baseline and post-exercise evaluation are shown in Table 1. Table 1. Clinical Features and Body Composition in Patients with Cushing’s Disease Pre- and Post-Exercise Program Pre exercice evaluation Post exercice evaluation p value General Features : BMI, mean±SD 35.5±1.3 31.3±6 0.322 SBP (mmHg), mean±SD 144±21 132±14 0.242 DBP (mmHg), mean±SD 86±10 76±8 0.0483 Heart rate (bpm), mean±SD 85±16 76±16 0.399 Waist circumference (cm), mean±SD 107±13 103±13 0.041 Hip circumference (cm), mean±SD 107±14 113±15 0.501 Neck circumference (cm), mean±SD 37±3 35±2 0.324 Body composition Body Mass (cm 3 ), mean±SD 73280±14463 66454±120005 0.211 Fat Mass (cm 3 ), mean ±SD 33312±9559 29207±8799 0.475 Fat Mass (%), mean±SD 45.4±5 43.9±8 0.182 Lean Mass (cm 3 ), mean±SD 34818±4989 36038±3469 0.398 Lean Mass (%), mean±SD 47.5±6 54.1±6 0.006 Trunk Fat (cm 3 ), mean±SD 18494±4326 16729±5192 0.427 Trunk fat (%), mean±SD 47.8±5 43±8 0.042 Bone features T-score: Lumbar, mean±SD -0.8±2.2 -1.3±1.9 0.771 Femoral, mean±SD -1.8±0.6 -0.8±1.2 0.04 BMD (gr/cm 3 ) Lumbar, mean±SD 0.9±0.2 0.8±0.2 0.299 Femoral, mean±SD 0.6±0.1 1.1±0.1 0.003 TBS, mean±SD 1.2±0.1 1.1±0.1 0.574 Data are presented as mean ± standard deviation (SD). Abbreviations: BMI, Body Mass Index; SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; BPM, Beats Per Minute; BMD, Bone Mineral Density; TBS, Trabecular Bone Score. The mean waist circumference was significantly lower on post exercise evaluation as compared with baseline (103±13 vs. 107±13 cm; p=0.041). The mean diastolic blood pressure (DBP) was significantly lower on post exercise evaluation as compared with baseline (86±10 vs. 76±8 mmHg; p=0.048). The mean lean mass fraction was significantly higher on post-exercise evaluation as compared with baseline (54.1% vs. 47.5%; p=0.006). The mean trunk fat fraction was significantly lower on post-exercise evaluation as compared with baseline (43% vs. 48%; p = 0.040). Mean femoral T-score was significantly higher on post-exercise evaluation as compared with baseline (-0.8±1.2 vs. -1.8±0.6; p=0.04). Mean femoral BMD was significantly higher on the post-exercise evaluation as compared with baseline (1.1±0.1 vs. 0.6±0.1 gr/cm 3 ; p=0.030). General metabolic characteristics of patients with ACRO at baseline and post-exercise evaluation are shown in Table 2. Table 2. Clinical Features in Patients with Controlled Acromegaly Pre- and Post-Exercise Program Pre exercice evaluation post exercice evaluation p value General Features : BMI, mean±SD 28.2±2.4 27.5±2.8 0.663 SBP (mmHg), mean±SD 147.8±28.5 129±14.8 0.690 DBP (mmHg), mean±SD 89±8.7 80.2±8 0.182 Heart rate (bpm), mean±SD 67.6±3 61.8±10.8 0.156 Waist circumference (cm), mean±SD 102.5±4.6 98.6±4.7 0.158 Hip circumference (cm), mean±SD 120±43.2 106.9±9.9 0.449 Neck circumference (cm), mean±SD 40.7±1 39.4±1.2 0.059 Data are presented as mean ± standard deviation (SD). Abbreviations: BMI, Body Mass Index; SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; BPM, Beats Per Minute. No significant differences in these parameters were found between the two phases (p=n.s.) Pre- and post-exercise muscle functionality Patients with CD performed better on post-exercise evaluation as compared with baseline on the GS test (0.99±0.19 vs. 1.2±0.2; p<0.001), TUG test (7.5±1 vs. 6.4±0.9; p=0.0024) and 30-sec chair stand (11.9±2.4 vs. 25.6±5.1; p=0.006) (Figure 2). Patients with ACRO performed better on post-exercise evaluation as compared with baseline on GS (1.2±0.2 vs. 1.5±0.2; p=0.003), TUG (5.9±0.9 vs. 5.2±0.9; p=0.036), and 30-sec chair stand (20.1±6.01 vs. 27.1±8.1; p=0.011) (Figure 3). Pre- and post-exercise muscle ultrasound parameters In CD patients, rectus femoralis was significantly thicker on post-exercise evaluation at the middle and distal third in the right lower limb (middle 1.5±0.3 cm vs. 2.1±0.2 cm; p = 0.036, distal third 0.8±0.1cm vs. 1.2±0.1 cm; p=0.001) and at the left lower limb (middle 1.4±0.3 cm vs. 1.6±0.2 cm; p = 0.045, distal third 0.9±0.1 cm vs. 1.2±0.2 cm; p=0.004), as compared with baseline In patients with CD, vastus intermedius was significantly thicker on the post-exercise evaluation at the middle and distal third of the right lower limb (middle 1.2±0.2 cm vs. 1.5±0.3 cm; p = 0.032, distal third 0.8±0.1 cm vs. 1.3±0.2 cm; p<0.001), as compared with baseline. Vastus intermedius was significantly thicker at the distal third in the left Table 3. Ultrasound Muscle Parameters in Patients with Cushing’s Disease Pre- and Post-Exercise Program Pre exercice evaluation post exercice evaluation p value Right lower limb: Rectus femoralis 1/2 (cm), mean±SD 1.5±0.3 2.1±0.2 0.036 Rectus femoralis 1/2 (ml), mean±SD 1.9±1.1 3.7±1.2 0.051 Vastus intermedius 1/2 (cm), mean±SD 1.2±0.2 1.5±0.3 0.032 Vastus intermedius 1/2 (ml), mean±SD 1±0.7 1.7±0.6 0.045 Rectus femoralis 1/3 (cm), mean±SD 0.8±0.1 1.2±0.1 0.001 Rectus femoralis 1/3 (ml), mean±SD 0.3±0.1 0.8±0.1 <0.001 Vastus intermedius 1/3 (cm), mea±SD 0.8±0.3 1.3±0.2 <0.001 Vastus intermedius 1/3 (ml), mean±SD 0.4±0.2 0.8±0.5 <0.001 Left lower limb: Rectus femoralis 1/2 (cm), mean±SD 1.4±0.3 1.6±0.2 0.045 Rectus femoralis 1/2 (ml), mean±SD 1.8±1.4 2.3±0.9 0.053 Vastus intermedius 1/2 (cm), mean±SD 1.3±0.3 1.6±0.3 0.157 Vastus intermedius 1/2 (ml), mean±SD 1.5±1.1 2.4±1.1 0.189 Rectus femoralis 1/3 (cm), mean±SD 0.9±0.1 1.2±0.2 0.004 Rectus femoralis 1/3 (ml), mean±SD 0.4±0.2 1.1±0.6 0.008 Vastus intermedius 1/3 (cm), mean+±D 1±0.2 1.3±0.3 0.001 Vastus intermedius 1/3 (ml), mean±SD 0.6±0.5 1.3±0.9 0.001 Heckmatt scale RF 1/2 , mean±SD 2.3±0.7 2.1±0.3 0.562 Heckmatt scale RF 1/3 inf., mean±SD 2±0.5 2.3±0.5 0.239 Normal US Evaluation, number (%) 0 (0) 1 (10) 1 lower limb (1±0.2 cm vs. 1.3±0.3 cm; p=0.001) (Table 3), as compared with baseline. In patients with ACRO, the Heckmatt scale score at the rectus femoralis on post-exercise evaluation was significantly lower (middle 1.83±0.4 vs 1.14±0.3, p = 0.035; distal third 2±0.0 vs. 1.14±0.4; p = 0.008), as compared with baseline, indicating an improvement of muscle quality (Table 4). Data are presented as mean ± standard deviation (SD). Comparison of ordinal data (Heckmatt scale) was performed using the Mann-Whitney U test. Abbreviations: RF, Rectus Femoris Table 4. Ultrasound Muscle Parameters in Patients with Controlled Acromegaly Pre- and Post-Exercise Program Pre exercice evaluation post exercice evaluation p value Right lower limb: Rectus femoralis 1/2 (cm), mean±SD 1.8±0.5 2.1±0.5 0.354 Rectus femoralis 1/2 (ml), mean±SD 4±2.9 5.8±3.7 0.368 Vastus intermedius 1/2 (cm), mean±SD 1.6±0.4 1.7±0.5 0.711 Vastus intermedius 1/2 (ml), mean±SD 2.5±1.4 3.5±2.0 0.344 Rectus femoralis 1/3 (cm), mean±SD 0.8±0.1 1.2±0.1 0.529 Rectus femoralis 1/3 (ml), mean±SD 1.5±0.4 1.3±0.3 0.152 Vastus intermedius 1/3 (cm), mea±SD 3.8±4.2 1.3±0.7 0.372 Vastus intermedius 1/3 (ml), mean±SD 1.2±0.3 1.5±0.4 0.178 Left lower limb: Rectus femoralis 1/2 (cm), mean±SD 1.9±0.4 1.9±.2 0.697 Rectus femoralis 1/2 (ml), mean±SD 3.9±2.3 4.2±1.5 0.824 Vastus intermedius 1/2 (cm), mean±SD 1.7±0.2 1.7±0.4 0.667 Vastus intermedius 1/2 (ml), mean±SD 2.9±0.9 3±1.4 0.852 Rectus femoralis 1/3 (cm), mean±SD 1.5±0.3 1.4±0.3 0.483 Rectus femoralis 1/3 (ml), mean±SD 2±1.3 1.5±0.9 0.464 Vastus intermedius 1/3 (cm), mean+±D 1.4±0.3 1.3±0.4 0.552 Vastus intermedius 1/3 (ml), mean±SD 1.7±0.8 1.5±0.9 0.575 Heckmatt scale RF 1/2, mean±SD 1.83±0.4 1.14±0.3 0.035 Heckmatt scale RF 1/3 inf., mean±SD 2±0.0 1.14±0.4 0.008 Normal US Evaluation, number (%) 1(10) 6 (60) Data are presented as mean ± standard deviation (SD). Comparison of ordinal data (Heckmatt scale) was performed using the Mann-Whitney U test. Abbreviations: RF, Rectus Femoris Pre- and post-exercise PROMs No significant changes of PROMs measures were observed after the exercise intervention as compared with baseline in both CD and ACRO patients (p=n.s.). Discussion In this study, we have demonstrated that a 12-week individually tailored physical activity program significantly improved both structural and functional muscle parameters in patients with CD in long-term remission and in patients with controlled ACRO. These findings emphasize the therapeutic potential of exercise as a crucial component of multidisciplinary care for addressing residual musculoskeletal impairment in these populations. A significant improvement in physical performance was observed, as evidenced by better results on GS, TUG, and the 30-second chair stand test. These functional gains reflect enhanced mobility, balance, and muscle strength in both groups. Muscle ultrasound revealed distinct structural adaptations between CD and ACRO patients. In CD, a greater muscle thickness in the rectus femoris and vastus intermedius suggested an increase in lean muscle mass, whereas in ACRO, reduced muscle echogenicity indicated an improvement in muscle quality, likely due to decreased intramuscular fatty infiltration. These distinct responses underscore the complexity of the mechanisms underlying muscle dysfunction in CS and ACRO, shaped by their unique pathophysiological profiles (Khaleeli et al., 1984 , 1983 ) Despite the recognized burden of musculoskeletal dysfunction in CD and ACRO, our study addresses an important unmet need. Current clinical management often overlooks muscle dysfunction, with limited access to targeted rehabilitation/exercise interventions (Geer et al., 2022 , 2019 ; Valassi et al., 2022 ). A multidisciplinary approach, incorporating exercise programs supervised by physiotherapists, could address these gaps and improve patient satisfaction. Integrating such interventions into Pituitary Tumor Centers of Excellence (PTCOEs) should be prioritized to deliver comprehensive care tailored to these patients' characteristics. Muscle dysfunction in CD is primarily driven by glucocorticoid-induced myopathy, characterized by the atrophy of fast-twitch muscle fibers due to proteolysis and reduced protein synthesis. Fatigue and impaired muscle function frequently persist even after remission, linked to increased intramuscular fatty infiltration, which correlates with balance, strength, and mobility impairments (Martel-Duguech et al., 2020 ). In ACRO, prolonged exposure to excess GH and IGF-1 leads to persistent musculoskeletal complications, including muscle pain and arthropathy that limit physical functioning. Patients with long-term controlled ACRO often display significant fatty infiltration within thigh muscles, which has been independently associated with reduced performance on the TUG test, a key assessment of mobility, balance, and walking ability (Martel-Duguech et al., 2021b ). Importantly, this association is observed regardless of muscle area or joint symptoms, which are common and debilitating features in ACRO (Martel-Duguech et al., 2021b ). Our findings suggest that while exercise effectively improves muscle function in both groups, the structural adaptations may differ. The observed benefits of our combined aerobic and resistance exercise protocol can be attributed to several mechanisms previously documented in other populations, including molecular, metabolic, structural, neural, and inflammatory adaptations (Carraça et al., 2021 ; Goodman, 2014 ; Gundersen, 2011 ; Liu and Latham, 2009 ; Strasser et al., 2013 ). At the molecular level, resistance exercise stimulates mTOR pathway, promoting protein synthesis and muscle hypertrophy, while inhibiting proteolytic activity through the ubiquitin-proteasome system (Goodman, 2014 ; Gundersen, 2011 ). Additionally, myokines released during exercise, such as irisin and brain-derived neurotrophic factor (BDNF), play critical roles in muscle repair and metabolic regulation (Severinsen and Pedersen, 2020 ; Zunner et al., 2022 ). Structurally, the increase in muscle thickness observed in CD patients likely reflects hypertrophic adaptations driven by resistance training, which predominantly targets type II muscle fibers (Toigo and Boutellier, 2006 ). In ACRO patients, the reduction in muscle echogenicity observed on ultrasound may represent decreased intramuscular fatty infiltration, a finding supported by evidence that exercise enhances lipid metabolism and mitochondrial function (Goodpaster et al., 2008b ). Neural adaptations also contribute significantly, particularly in the early phases of training, through enhanced motor unit recruitment, firing rate, and intermuscular coordination, which improve muscle function and strength even before structural changes occur (Gabriel et al., 2006 ). Metabolic adaptations to exercise, including increased mitochondrial biogenesis and improved oxidative capacity, likely contribute to sustained amelioration of muscle endurance and performance (Hong et al., 2022 ). Furthermore, the anti-inflammatory effects of exercise, characterized by reductions in circulating pro-inflammatory cytokines such as TNF-α and IL-6, may facilitate muscle repair and improve quality (Pedersen and Febbraio, 2008 ). Exercise also improves insulin sensitivity by enhancing glucose uptake in skeletal muscle through increased translocation of GLUT-4 transporters to the cell membrane and promoting mitochondrial biogenesis, thereby reducing insulin resistance and supporting metabolic health (Holloszy, 2005 ). Previous prospective studies have demonstrated the positive effects of exercise programs on patients with ACRO, particularly in improving functional capacity, balance, and QoL. For instance, Lima et al. showed that a 12-week therapist-oriented home rehabilitation program significantly improved muscle function, body balance, and health-related QoL in 17 patients with ACRO, of whom 12 were controlled and 5 had active disease (Lima et al., 2019 ). Haliloglu et al. demonstrated enhanced physical performance, dynamic balance and body-self-perception after a 3-month,group-based exercise program involving 11 patients (7 controlled, 4 active), although their approach lacked individual tailoring and did not specifically address muscle composition or sarcopenia-related parameters (Haliloglu et al., 2019 ; Hatipoglu et al., 2015 , 2014 ). In contrast, our study’s strength lies in its structured, progressive, and individually tailored approach to exercise, which focused on improving muscle quality, strength, balance and daily function, and BMD. Unlike the previously mentioned studies, our intervention involved direct supervision by professional trainers, individually tailored exercise intensity, established progression planning, and it used validated tools to assess muscle outcomes. Furthermore, our program duration of 3 months aligns closely with evidence-based recommendations for achieving meaningful musculoskeletal adaptations (Borde et al., 2015 ). In particular, a unique aspect of our study was the integration of validated tools recommended by the European Working Group on Sarcopenia in Older People (EWGSOP) to assess muscle performance and quality (Cruz-Jentoft et al., 2019). Specifically, we used functional performance tests like the TUG, GS, HGS and 30-second chair-to-stand, alongside ultrasound to measure rectus femoris thickness and echointensity. These tools provided a comprehensive evaluation of sarcopenia-related parameters, bridging a gap between clinical assessments and muscle features . Resistance training programs were associated with significant improvements in muscle function, body composition, BMD and QoL across diverse populations, including cancer survivors, patients with chronic kidney disease (CKD), older adults, middle-aged individuals, post-bariatric surgery patients, individuals with growth hormone deficiency (GHD), and postmenopausal women (Amer et al., 2018 ; Cheema et al., 2014 ; Coelho et al., 2002 ; Guadalupe-Grau et al., 2009 ; Liu and Latham, 2009 ; Stegen et al., 2011 ; Straight et al., 2016 ; Strasser et al., 2013 ; Watson et al., 2018 ). In middle-aged and older adults, progressive resistance training was effective in enhancing physical function, reducing disability, and increasing lower-extremity power, which is crucial for mobility and fall prevention (Liu and Latham, 2009 ; Straight et al., 2016 ). Similarly, in post-bariatric surgery patients, resistance training has proven effective in mitigating lean muscle mass loss, improving body composition, and enhancing functional capacity during the post-operative period (Stegen et al., 2011 ; Woodlief et al., 2015 ). In individuals with GHD, resistance training has been shown to significantly improve muscle function, even in the absence of recombinant growth hormone therapy (Amer et al., 2018 ; Coelho et al., 2002 ). Additionally, resistance training lasting from 8 to 12 months demonstrated a positive impact on bone health by improving BMD and reducing fracture risk in several populations, including older adults and postmenopausal women with osteopenia/osteoporosis (Watson et al., 2018 ) This effect is especially relevant for individuals with a history of chronic corticosteroid use, as studies have shown that resistance training ranging from 6 to 12 months can mitigate corticosteroid-induced bone loss (Kast et al., 2022 ; Mitchell et al., 2003 ). For instance, resistance training for 6 months has been shown to prevent vertebral osteoporosis in lung transplant recipients on glucocorticoid therapy and improve BMD in key fracture-prone sites such as the lumbar spine and proximal femur (Kast et al., 2022 ; Mitchell et al., 2003 ). Interestingly, our study did not observe significant changes in QoL parameters in patients with CD or ACRO following the 12-week exercise intervention. This outcome may reflect the relatively short duration of the program or the multifactorial nature of QoL in these populations (Webb et al., 2008 , 2006 ). Indeed, the disease-specific questionnaires (AcroQoL and CushingQoL) used, were originally validated over a 6-month follow-up period, suggesting that shorter durations such that in our study, might not adequately capture subtle or incremental changes in QoL (Webb et al., 2008 , 2006 ) Longer interventions of resistance training, lasting from 6 to 12 months, were associated with significant QoL improvement in cancer survivors and older adults (Liu and Latham, 2009 ; Strasser et al., 2013 ). Moreover, in obese subjects, 12-week exercise interventions improved general physical functioning and psychosocial well-being, though the positive effects on QoL, especially in terms of psychological dimensions, were more pronounced after longer periods of intervention(Carraça et al., 2021 ). The limited time frame of 12 weeks in our study may have been insufficient to detect measurable improvements in QoL for patients with CD and ACRO, whose QoL is influenced by persistent musculoskeletal, psychological, and disease-specific factors. It should be highlighted that other studies have shown that QoL improvements in patients with pituitary diseases, including CD and ACRO, can be challenging to achieve. For instance, Albarel et al. offered an individualized education program to patients with pituitary diseases and described significant improvements in physical and psychological limitation scores of the SF-36 QoL questionnaire at the end of the program, with these benefits persisting at follow-up (Albarel et al., 2020 ). However, other QoL dimensions, such as mental health, showed transient deterioration before returning to baseline levels, reflecting the multifactorial pathogenesis of QoL deterioration in this population, which is thought to require alonglasting and multidisciplinary management. Similarly, Andela et al. demonstrated improvements in self-efficacy and vitality following a self-management 8-weeks program in patients with pituitary diseases, although no significant changes in broader QoL or mental health parameters were observed, (Andela et al., 2017 ). Collectively, these findings emphasize the need for comprehensive, tailored, and possibly longer-term interventions that address sustained QoL improvements in CD and ACRO. Our study has several limitations, including the relatively short intervention duration, lack of a control group, small sample size, and the choice to only include either female or male individuals in each disease group. These pitfalls might have affected the statistical power of the analysis, thus preventing us from detecting changes in some parameters. Moreover, we did not assess the concentrations in blood of any potential mediators of the beneficial effects of exercise on the outcomes included and this is a clear limitation. Future studies should include larger, sex-balanced cohorts to disentangle the interplay between gender, disease-specific pathophysiology, and exercise-mediated adaptations. This approach will provide a more comprehensive understanding of how to optimize exercise prescriptions for diverse patient populations. In conclusion, our findings highlight the importance of an individually tailored exercise program in improving muscle function and physical performance in CD and ACRO patients. Beyond achieving biochemical control, a multidisciplinary approach, incorporating physiotherapy, is essential to address residual musculoskeletal dysfunction and improve overall functional capacity. Future studies should explore longer-duration interventions and their impact on disease-specific QoL outcomes. Declarations The authors declare no conflicts of interest. Funding Declaration This study was supported by the Instituto de Salud Carlos III, grant number FIS PI 21/0123, and co-funded by the European Regional Development Fund (FEDER). Author Contribution L.M.D. and E.V. conceived and designed the study. L.M.D., H.B., V.P.C., O.G.V., J.V.R., and T.C.P. performed data collection and conducted the intervention. H.B. supervised and performed the functional assessments. L.M.D. performed statistical analyses. L.M.D. and E.V. interpreted the data and wrote the main manuscript text. S.M.W. provided critical intellectual input and revised the manuscript. All authors reviewed and approved the final manuscript. 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Progressive resistance strength training for improving physical function in older adults. Cochrane database Syst. Rev. 2009. https://doi.org/10.1002/14651858.CD002759.PUB2 Martel-Duguech, L., Alonso-Jiménez, A., Bascuñana, H., Díaz-Manera, J., Llauger, J., Nuñez-Peralta, C., Biagetti, B., Montesinos, P., Webb, S.M., Valassi, E., 2020. Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing’s Syndrome. J. Clin. Endocrinol. Metab. 105, 2039–2049. https://doi.org/10.1210/clinem/dgz329 Martel-Duguech, L., Alonso-Jimenez, A., Bascuñana, H., Díaz-Manera, J., Llauger, J., Nuñez-Peralta, C., Montesinos, P., Webb, S.M., Valassi, E., 2021a. Prevalence of sarcopenia after remission of hypercortisolism and its impact on HRQoL. Clin. Endocrinol. (Oxf). 95, 735–743. https://doi.org/10.1111/CEN.14568 Martel-Duguech, L., Alonso-Pérez, J., Bascuñana, H., Díaz-Manera, J., Llauger, J., Nuñez-Peralta, C., Montesinos, P., M Webb, S., Valassi, E., 2021b. Intramuscular fatty infiltration and physical function in controlled acromegaly. Eur. J. Endocrinol. 185, 167–177. https://doi.org/10.1530/EJE-21-0209 Miller, A., Doll, H., David, J., Wass, J., 2008. Impact of musculoskeletal disease on quality of life in long-standing acromegaly. Eur. J. Endocrinol. 158, 587–593. https://doi.org/10.1530/EJE-07-0838 Mitchell, M.J., Baz, M.A., Fulton, M.N., Lisor, C.F., Braith, R.W., 2003. Resistance training prevents vertebral osteoporosis in lung transplant recipients. Transplantation 76, 557–562. https://doi.org/10.1097/01.TP.0000076471.25132.52 Pedersen, B.K., Febbraio, M.A., 2008. Muscle as an endocrine organ: Focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406. https://doi.org/10.1152/PHYSREV.90100.2007/ASSET /IMAGES/LARGE/Z9J0040824860006.JPEG Severinsen, M.C.K., Pedersen, B.K., 2020. Muscle–Organ Crosstalk: The Emerging Roles of Myokines. Endocr. Rev. 41, 594–609. https://doi.org/10.1210/ENDREV/BNAA016 Spitzer, R.L., Kroenke, K., Williams, J.B.W., Löwe, B., 2006. A Brief Measure for Assessing Generalized Anxiety Disorder: The GAD-7. Arch. Intern. Med. 166, 1092–1097. https://doi.org/10.1001/ARCHINTE.166.10.1092 Stegen, S., Derave, W., Calders, P., Van Laethem, C., Pattyn, P., 2011. Physical fitness in morbidly obese patients: effect of gastric bypass surgery and exercise training. Obes. Surg. 21, 61–70. https://doi.org/10.1007/S11695-009-0045-Y Straight, C.R., Lindheimer, J.B., Brady, A.O., Dishman, R.K., Evans, E.M., 2016. Effects of Resistance Training on Lower-Extremity Muscle Power in Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Sports Med. 46, 353–364. https://doi.org/10.1007/S40279-015-0418-4 Strasser, B., Steindorf, K., Wiskemann, J., Ulrich, C.M., 2013. Impact of resistance training in cancer survivors: a meta-analysis. Med. Sci. Sports Exerc. 45, 2080–2090. https://doi.org/10.1249/MSS.0B013E31829A3B63 Toigo, M., Boutellier, U., 2006. New fundamental resistance exercise determinants of molecular and cellular muscle adaptations. Eur. J. Appl. Physiol. 97, 643–663. https://doi.org/10.1007/S00421-006-0238-1 Valassi, E., Chiodini, I., Feelders, R.A., Andela, C.D., Abou-Hanna, M., Idres, S., Tabarin, A., 2022. Unmet needs in Cushing’s syndrome: the patients’ perspective. Endocr. Connect. 11. https://doi.org/10.1530/EC-22-0027 Ware, J.E., Kosinski, M., Keller, S.D., 1996. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med. Care 34, 220–233. https://doi.org/10.1097/00005650-199603000-00003 Wassenaar, M.J.E., Biermasz, N.R., Kloppenburg, M., Klaauw, A.A. va. der, Tiemensma, J., Smit, J.W.A., Pereira, A.M., Roelfsema, F., Kroon, H.M., Romijn, J.A., 2010. Clinical osteoarthritis predicts physical and psychological QoL in acromegaly patients. Growth Horm. IGF Res. 20, 226–233. https://doi.org/10.1016/J.GHIR.2010.02.003 Watson, D., Clark, L.A., Tellegen, A., 1988. Development and Validation of Brief Measures of Positive and Negative Affect: The PANAS Scales. J. Pers. Soc. Psychol. 54, 1063–1070. https://doi.org/10.1037/0022-3514.54.6.1063 Watson, S.L., Weeks, B.K., Weis, L.J., Harding, A.T., Horan, S.A., Beck, B.R., 2018. High-Intensity Resistance and Impact Training Improves Bone Mineral Density and Physical Function in Postmenopausal Women With Osteopenia and Osteoporosis: The LIFTMOR Randomized Controlled Trial. J. Bone Miner. Res. 33, 211–220. https://doi.org/10.1002/JBMR.3284 Webb, S.M., Badia, X., Baarahona, M.J., Colao, A., Strasburger, C.J., Tabarin, A., van Aken, M.O., Pivonello, R., Stalla, G., Lamberts, S.W.J., Glusman, J.E., 2008. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur. J. Endocrinol. 158, 623–630. https://doi.org/10.1530/EJE-07-0762 Webb, S.M., Badia, X., Surinach, N.L., Astorga, R., Benito, P., Catalá, M., Gaztambide, S., Gilabert, M., Gómez, J.M., Halperin, I., Lucas, A., Lucas-Morante, T., Moreno, B., de Pablos, P., Páramo, C., Picó, A., Roset, M., Torres, E., Varela, C., 2006. Validity and clinical applicability of the acromegaly quality of life questionnaire, AcroQoL: a 6-month prospective study. Eur. J. Endocrinol. 155, 269–277. https://doi.org/10.1530/EJE.1.02214 Woodlief, T.L., Carnero, E.A., Standley, R.A., Distefano, G., Anthony, S.J., Dubis, G.S., Jakicic, J.M., Houmard, J.A., Coen, P.M., Goodpaster, B.H., 2015. Dose response of exercise training following roux-en-Y gastric bypass surgery: A randomized trial. Obesity (Silver Spring). 23, 2454–2461. https://doi.org/10.1002/OBY.21332 Zunner, B.E.M., Wachsmuth, N.B., Eckstein, M.L., Scherl, L., Schierbauer, J.R., Haupt, S., Stumpf, C., Reusch, L., Moser, O., 2022. Myokines and Resistance Training: A Narrative Review. Int. J. Mol. Sci. 2022, Vol. 23, Page 3501 23, 3501. https://doi.org/10.3390/IJMS23073501 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 10 Jul, 2025 Read the published version in Endocrine → Version 1 posted Editorial decision: Revision requested 19 May, 2025 Reviews received at journal 18 May, 2025 Reviews received at journal 12 May, 2025 Reviewers agreed at journal 29 Apr, 2025 Reviewers agreed at journal 28 Apr, 2025 Reviewers invited by journal 28 Apr, 2025 Editor assigned by journal 24 Apr, 2025 Submission checks completed at journal 24 Apr, 2025 First submitted to journal 19 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6485925","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":449637349,"identity":"62185cb5-7592-473c-9e50-b5cdda11fa42","order_by":0,"name":"Luciana Martel-Duguech","email":"","orcid":"","institution":"Hospital S Pau, Institut de Recerca Sant Pau (IIB-Sant Pau)","correspondingAuthor":false,"prefix":"","firstName":"Luciana","middleName":"","lastName":"Martel-Duguech","suffix":""},{"id":449637351,"identity":"8b24c80b-7da6-4b3d-9e6b-4d6e2f26f3e6","order_by":1,"name":"Helena Bascuñana","email":"","orcid":"","institution":"Hospital Sant Pau","correspondingAuthor":false,"prefix":"","firstName":"Helena","middleName":"","lastName":"Bascuñana","suffix":""},{"id":449637354,"identity":"9b0c7d9b-169a-4592-9bbb-d5b1602a2e3a","order_by":2,"name":"Víctor Priego Corredor","email":"","orcid":"","institution":"Instituto Nacional de Educación Física de Cataluña (INEFC)","correspondingAuthor":false,"prefix":"","firstName":"Víctor","middleName":"Priego","lastName":"Corredor","suffix":""},{"id":449637356,"identity":"84e406c6-0e8d-4a96-b20d-acc08fcc8c6e","order_by":3,"name":"Oriol González-Viñuela","email":"","orcid":"","institution":"Instituto Nacional de Educación Física de Cataluña (INEFC)","correspondingAuthor":false,"prefix":"","firstName":"Oriol","middleName":"","lastName":"González-Viñuela","suffix":""},{"id":449637357,"identity":"f2d7cf36-2516-477d-932e-f6ede2b8e8a1","order_by":4,"name":"Judith Vinyals Ribé","email":"","orcid":"","institution":"Instituto Nacional de Educación Física de Cataluña (INEFC)","correspondingAuthor":false,"prefix":"","firstName":"Judith","middleName":"Vinyals","lastName":"Ribé","suffix":""},{"id":449637358,"identity":"c9e8a1d6-a4aa-4b68-b76a-fcb578fd6c3a","order_by":5,"name":"Toni Caparrós Pons","email":"","orcid":"","institution":"Instituto Nacional de Educación Física de Cataluña (INEFC)","correspondingAuthor":false,"prefix":"","firstName":"Toni","middleName":"Caparrós","lastName":"Pons","suffix":""},{"id":449637359,"identity":"dd3518b9-8a79-451f-95ec-2d02d851b3ab","order_by":6,"name":"Susan M Webb","email":"","orcid":"","institution":"Hospital S Pau, Institut de Recerca Sant Pau (IIB-Sant Pau)","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"M","lastName":"Webb","suffix":""},{"id":449637360,"identity":"5e2cab09-bc2d-4aff-93f5-7a897ff4ff16","order_by":7,"name":"Elena Valassi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYHACxgNAgoefmRQ9YC2SzQyMDSAeD7FaGAwOEKuFXyL5wYEff+pkjI+zX39cwGAnb09Ii+SMNIODvW2HecwO8xQ2z2BINuwhpMXgzAGDA7wNB0BaEpt5GA4wEtRif+b4h4N//tTxGDdDtNgTtoW9x+AwDxszjwEz+0GQlkSCWiSO9xQclgX6ReIwD+PsGQbJyT0HCGjhb2bf+PDNnzp7/v7jDz4XVNjZtjcQsgYBgG5jMCBeOQiwPyApzYyCUTAKRsHIAQDg6z77kyUmnwAAAABJRU5ErkJggg==","orcid":"","institution":"Germans Trias i Pujol Hospital and Research Institute","correspondingAuthor":true,"prefix":"","firstName":"Elena","middleName":"","lastName":"Valassi","suffix":""}],"badges":[],"createdAt":"2025-04-19 16:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6485925/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6485925/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12020-025-04331-7","type":"published","date":"2025-07-10T15:58:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82143827,"identity":"de48c936-2204-4cef-a1eb-699c2be997bd","added_by":"auto","created_at":"2025-05-07 06:43:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23166,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of the 12-week individually tailored exercise intervention protocol\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6485925/v1/a3e1d5e1124aa9ba906bfad5.png"},{"id":82141633,"identity":"3cb7da07-47f8-46fa-82a2-b7d724aacdc6","added_by":"auto","created_at":"2025-05-07 06:35:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":28515,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMuscle Performance in Patients with Cushing's Disease Before and After Exercise Intervention. \u003c/strong\u003eThe left side of each panel shows individual patient results for gait speed (m/sec), timed up-and-go test (sec), and 30-second chair-to-stand test (repetitions) measured before (Pre) and after (Post) a supervised exercise program. Lines connect paired data from each patient. The right side of each panel displays the mean difference (Post minus Pre) across all patients with 95% confidence intervals. Statistical significance was defined as p \u0026lt; 0.05\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6485925/v1/23d4358dbb7dada8d3f9ab92.png"},{"id":82141634,"identity":"7befb490-77b5-4785-9239-dbcd84ef6529","added_by":"auto","created_at":"2025-05-07 06:35:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25465,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMuscle Performance in ACRO patients Before and After Exercise Intervention. \u003c/strong\u003eThe left side of each panel shows individual patient results for gait speed (m/sec), timed up-and-go test (sec), and 30-second chair-to-stand test (repetitions) measured before (Pre) and after (Post) a supervised exercise program. Lines connect paired data from each patient. The right side of each panel displays the mean difference (Post minus Pre) across all patients with 95% confidence intervals. Statistical significance was defined as p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6485925/v1/a7a33b4d03b453071ab039d9.png"},{"id":86699452,"identity":"d6041cdd-479e-4157-b77f-1f5e05bb747f","added_by":"auto","created_at":"2025-07-14 16:09:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1123450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6485925/v1/7a0da4b7-67bd-465e-acbf-6123318fea54.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing’s disease in remission and controlled acromegaly","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe management of Cushing\u0026rsquo;s disease (CD) and acromegaly (ACRO) requires a collaborative and multidisciplinary approach to effectively address the clinical complexity of these conditions and their long-term impact on patient\u0026rsquo;s wellbeing. Recent guidelines have highlighted that an interdisciplinary team, ideally integrated within a Pituitary Tumor Center of Excellence (PTCOE), should take care of patients with CD and ACRO to ensure optimal care, from early diagnosis to long-term follow-up (Casanueva et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Fleseriu et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Giustina et al., \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Despite such growing awareness, significant challenges remain in clinical practice. After control of hormone excess, the symptomatic burden of both conditions is still elevated and often underrecognized by the clinicians (Andela et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2015b\u003c/span\u003e; Kreitschmann-Andermahr et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Valassi et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). A focus group study conducted in subjects with pituitary adenomas described fatigue and pain as the most bothersome physical complaints of CD and ACRO patients, and also indicated receiving physiotherapy and sport recommendations as important patients\u0026rsquo; unmet needs regarding care (Andela et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2015a\u003c/span\u003e). A recent study showed that almost half of 320 patients with CD in remission complained of invalidating muscle weakness, though only a small subgroup of them was seen by a physiotherapist and received a targeted treatment (Valassi et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA high prevalence of fatigue and weakness has also been reported by ACRO patients who showed dissatisfaction with the care received and a clear need for more effective and individually tailored multidisciplinary approaches (Geer et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe have previously described a sustained deterioration of muscle quality, mainly related to intramuscular fatty infiltration, in both CD in remission and controlled ACRO patients, which, in turn, was associated with low performance on several muscle functionality tests (Martel-Duguech et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2021b\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). While muscle dysfunction and sarcopenia have been associated with impaired QoL in CD patients in remission, pain, weakness and clinical arthropathy have been described as important contributors to altered physical functioning, mood disorders and low QoL in ACRO (Cangiano et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Cellini et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Johnson et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Martel-Duguech et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021a\u003c/span\u003e; Miller et al., \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Wassenaar et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEvidence suggests that individually tailored exercise interventions, developed and supervised by experts, can improve muscle function, bone health, and QoL in various populations (Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Strasser et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). For instance, in older adults, 12-week resistance training programs have been shown to increase muscle strength, enhance physical function, and improve muscle quality by reducing intramuscular fatty infiltration (Goodpaster et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2008a\u003c/span\u003e; Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). In postmenopausal women with osteopenia or osteoporosis, high-intensity resistance training over a similar timeframe has been associated with improvements in bone mineral density (BMD) at weight-bearing sites such as the hip and lumbar spine, alongside reductions in fracture risk (Watson et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Moreover, structured exercise programs in middle-aged and obese individuals have demonstrated significant improvements in body composition, metabolic health, and psychosocial well-being, including reduced symptoms of depression and anxiety (Carra\u0026ccedil;a et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Strasser et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).To date, few studies evaluated the effects of structured exercise interventions in ACRO patients, demonstrating an improvement in muscle strength, functional capacity, body balance, and QoL ( Lima et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2019\u003c/span\u003e Haliloglu et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hatipoglu et al., \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2014\u003c/span\u003e)). However, these studies included heterogeneous groups with both active and controlled disease, limiting the interpretation of outcomes according to disease status. To the best of our knowledge, no studies have assessed the impact of exercise programs in CD patients thus far\u003c/p\u003e \u003cp\u003eThe objective of this pilot study is to assess whether a 12-week individually tailored exercise program, under the supervision of professional trainers, effectively improves muscle performance, bone health and patients reported outcomes (PROMs) in patients with biochemically controlled CD and ACRO. In particular, we compared physical and psychological parameters at baseline vs. those assessed after the completion of the exercise program.\u003c/p\u003e"},{"header":"Subjects and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003ePatients with Cushing\u0026rsquo;s disease (CD)\u003c/h2\u003e \u003cp\u003eWe studied 10 women with CD in remission. Inclusion criteria were age younger than 65 and duration of remission of at least 3 years. Diagnosis of CS was made after clinical, biochemical, and radiological evaluations, based on internationally agreed guidelines (Nieman LK et al. J Clin Endocrinol Metab. 2008.). All patients had abnormal values on at least two of the following tests: elevated UFC, late-night salivary or serum cortisol, 1 mg overnight dexamethasone suppression test (ODST), or 48-hour 2 mg/day low-dose dexamethasone suppression test (LDDST). Nine patients had CD due to a microadenoma and 1 had a macroadenoma. The median duration of hypercortisolism was 28 (20) months and was defined as the time elapsed from the initial symptoms, as referred by patients, and final diagnosis of CD.\u003c/p\u003e \u003cp\u003eEight patients (80%) received preoperative treatment with steroidogenesis inhibitors to control clinical symptoms of hypercortisolism. All the CD patients underwent transsphenoidal surgery (TSS) a median of 154 (117) months previously, and 2 of them (20%) also received radiotherapy a median of 142 (108) months after unsuccessful surgery (n\u0026thinsp;=\u0026thinsp;1) or recurrence (n\u0026thinsp;=\u0026thinsp;1). Mean (\u0026plusmn;\u0026thinsp;SD) time of remission, defined as the time elapsed from diagnostic confirmation of remission to study entry, was 13\u0026thinsp;\u0026plusmn;\u0026thinsp;7 years, [median, 13(8); and range, 3 to 204 months]. CD was considered in remission if either adrenal insufficiency was demonstrated (basal morning cortisol\u0026thinsp;\u0026lt;\u0026thinsp;171 nmol/L [\u0026lt;\u0026thinsp;6.2\u0026micro;g/dL] and/or undetectable 24-hour free urinary cortisol) or morning cortisol suppression\u0026thinsp;\u0026lt;\u0026thinsp;50nmol/L (\u0026lt;\u0026thinsp;1.8\u0026micro;g/dL) after 1 mg dexamethasone overnight was observed. All patients had received hydrocortisone (HC) replacement (between 10 and 20 mg per day) for a median of 19 (21) months after surgery. Median time free from HC replacement was 91 (102) months. At study entry, 1 patient was still taking HC at a stable dose of 20 mg per day and mean duration of treatment was 152 months. At study entry, all the subjects were re-evaluated for possible pituitary insufficiency. One patient had growth hormone deficiency (GHD), who was replaced with recombinant human GH-rhGH- (duration of treatment 127 months). All patients were postmenopausal. Mean (\u0026plusmn;\u0026thinsp;SD) duration of menopause was 93\u0026thinsp;\u0026plusmn;\u0026thinsp;56 months. No patients were taking estrogen/progesterone hormone replacement at study entry. No patients developed gonadotropin deficiency after surgery. One patient was hypothyroid on stable dose (112 \u0026micro;g/day) of L-thyroxine replacement (duration of treatment 155 months).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003ePatients with acromegaly (ACRO)\u003c/h3\u003e\n\u003cp\u003eWe studied 10 male patients with ACRO. As for CD patients, inclusion criteria were age younger than 65 and duration of remission of at least 3 years. All patients were classified as having controlled disease, defined as mean IGF-I concentrations within the specific age-adjusted reference range on at least two measurements over a period of 6 months and random GH concentrations below 1 \u0026micro;g/L at study entry in those patients who were not on GH receptor antagonist treatment (Giustina et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). When there was a discrepancy between GH and IGF-I, we used normalization of IGF-I concentrations as the most reliable criterion to define 'control' (Alexopoulou et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). When the 75 g oral glucose load was performed, GH values at or below 0.4 \u0026micro;g/L were considered as markers of cured disease.\u003c/p\u003e \u003cp\u003eAll had a GH-secreting pituitary tumor confirmed pathologically. The median duration of the disease was defined as the time elapsed between the onset of symptoms and signs of ACRO (evaluated through photographs and clinical history) and the time when treatment was proven to be effective. The median duration of control was defined as the time between the achievement of normal hormone values and study entry.\u003c/p\u003e \u003cp\u003eOne patient was on treatment with a somatostatin analog (SSA), duration of treatment from first treatment to study entry was 108 months.\u003c/p\u003e \u003cp\u003eOne patient was on treatment with cabergoline, duration of treatment 84 months. All had undergone transsphenoidal surgery (TSS) 24 months to 40 years previously (median, 16 years), 1 had undergone postoperative radiotherapy 21 years prior to study entry.\u003c/p\u003e \u003cp\u003eNo patient had secondary adrenal insufficiency. One patient had secondary hypothyroidism on adequate L-thyroxine replacement therapy (75 mcg/day). Two males had secondary hypogonadism, defined as testosterone levels below 300 ng/dL (10.4 nmol/L)(Bhasin et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2010\u003c/span\u003e); they had been on stable testosterone replacement doses for more than 1 year, and were, therefore, considered eugonadal.\u003c/p\u003e \u003cp\u003eAll the patients was tested for GH deficiency and only one (13%) was found to be GH-deficient and were treated with a stable replacement dose of rhGH (0.15mg/day)\u003c/p\u003e \u003cp\u003eThe following exclusion criteria were applied to both patients with CD and ACRO: presence of comorbidities unrelated to CD and ACRO; stroke; cognitive alteration; uncontrolled hypertension; untreated hypothyroidism, adrenal insufficiency or growth hormone deficiency; any significant limitations due to osteoarthropathy, inability to perform functional tests and history of any orthopedic surgery in the previous year.\u003c/p\u003e \u003cp\u003ePatients were informed about the study during their follow-up visit at our clinic at the endocrine clinic of the Hospital Sant Pau, Barcelona, Spain. If they agreed to participate, they were asked to sign the consent. The protocol was approved by the Sant Pau Research Ethics Committee.\u003c/p\u003e\n\u003ch3\u003eMethods\u003c/h3\u003e\n\u003cp\u003eAll patients underwent a 12-week, structured, individually tailored program of combined aerobic and resistance exercise (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), under the supervision of professional trainers (V.P.C., O.G.V., J.V.R., T.C.P.) from the National Institute of Physical Activity of Catalunya (INEFC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBefore starting the protocol, patients were instructed by the supervisor on how to perform the exercises, which were adapted, in each session, to patients\u0026rsquo; characteristics and personal history of physical activity. Patients then followed a structured exercise program consisting of three sessions per week, each of them being divided into four parts. First, the active warm-up included range of motion exercises focusing on joint mobility for the neck, shoulders, elbows, hips, knees, and ankles. This also included breathing control and stretching muscles/tendons without pain, with two sets of 15\u0026ndash;20 seconds per exercise. Second, the strength workout comprised exercises such as chest press, knee extension, shoulder press, knee flexion, shoulder abduction, hip abduction, biceps flexion, hip adduction, triceps extension, and ankle dorsiflexion. Patients performed three sets of 12\u0026ndash;15 repetitions for each exercise at an intensity of 5/6 on the Borg Scale, with 15\u0026ndash;20 seconds of rest between exercises and 1 minute of rest between sets. The third part was an endurance workout, consisting of walking for a total of 30 minutes, divided into three sets of 10 minutes each. This was also performed at an intensity of 5/6 on the Borg Scale, with 2 minutes of rest between sets.\u003c/p\u003e \u003cp\u003eFinally, the cool down involved passive stretching for the neck, shoulders, elbows, hips, knees, and ankles, with one set of 15\u0026ndash;20 seconds per exercise.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eWe evaluated the following parameters at baseline and within 72 hours after the completion of the exercise program: blood pressure (BP), BMI, waist and neck circumference, physical performance, body composition, muscle US parameters and QoL\u003c/p\u003e \u003cp\u003ePhysical performance was assessed through the following tests; gait speed (GS), timed up and go (TUG), 30-s chair stand and grip strength, as described elsewhere (Martel-Duguech et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). All tests were performed under the supervision of a physical medicine specialist (HB). Body composition was assessed using dual-energy X-ray absorptiometry (DXA) (Hologic Discovery W, Software Apex Version 13.4), following standardized protocols. Measurements included appendicular skeletal muscle mass (ASM), calculated as the sum of lean mass from both arms and legs (excluding bone mass) and adjusted for height squared (ASM/height\u0026sup2;), as well as total fat mass and trunk fat mass, reported in both kilograms and as percentages of body mass. Lean mass was also measured and expressed as a percentage of body weight. Bone health parameters included BMD at the lumbar spine and femoral neck, with corresponding T-scores used to classify bone status relative to a young healthy reference population. These measurements were performed pre- and post-intervention to evaluate changes in body composition and bone health. In the ACRO group, the post-exercise assessment of body composition and BMD using DXA could not be completed due to logistical challenges in scheduling the examinations during the COVID-19 pandemic. Although another DXA was performed in these patients more than 1 year after the completion of the program, we decided to not compare these data with those obtained at baseline (pre-exercise), due to the fact that such a large time frame could interfere with a reliable assessment of the exercise effects on body composition. In the CD group, both pre- and post-exercise DXA assessments could be completed and, therefore, body composition parameters at both time points could be compared, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We obtained transverse US images of the rectus femoris (Philips Affiniti 70; The Netherlands) and assessed muscle thickness (cm), volume (ml) and muscle quality at the middle and distal third of rectus femoris (RF) and vastus intermedius (VI) on both sides. Muscle quality was measured as muscle intensity using the Heckmatt\u0026rsquo;s rating scale (Heckmatt et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e1982\u003c/span\u003e); Grade 1: Normal muscle structure and echogenicity. Grade 2: Increased muscle grayscale level with still a distinct bone echo. Grade 3: Marked increased grayscale level of the muscle with diminished bone echo. Grade 4: Very strongly increased grayscale level with a total loss of bone echo.\u003c/p\u003e \u003cp\u003eQuality of life (QoL) was assessed using the following questionnaires:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e CushingQoL is a disease-specific qustionnaire consisting of 12 items that cover seven concepts referring to problems relevant to CS patients. Items are scored on a 5-point Likert scale, resulting in a score of 12 (worst) to 60 (best) which is standardised to a scale of 0-100. Higher scores indicate more favourable HRQoL (Webb et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2008\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAcroQoL (Acromegaly Quality of Life Questionnaire) is a specific tool designed to assess QoL in patients with ACRO consisting of 22 items and is divided into two main domains, physical and psychological dimensions; the latter is further subdivided into two further subdimensions, appearance and personal relations. Each item in the questionnaire is rated on a 5-point Likert scale, where patients indicate the frequency or how much they agree or disagree with each statement based on their experiences. Each item is scored from 1 to 5, with higher scores indicating better QoL. Global scores and those for each dimension are summed and then transformed into a scale from 0 to 100, where 100 represents the best possible QoL and 0 represents the worst (Badia et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2004\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe SF-12 is a self-reported outcome measure assessing the impact of health on an individual\u0026rsquo;s everyday life. SF-12 evaluates the following eight domains: 1) Limitations in physical activity because of health problems. 2) Limitations of social activities because of physical or emotional problems. 3) Limitations in usual role activities because of physical health problems. 4) Bodily pain. 5) General mental health (psychological distress and well-being). 6) Limitations in usual role activities because of emotional problems. 7) Vitality (energy and fatigue). 8) General health perceptions. Patients complete a 12-question survey, and the responses are then scored by a clinician. The SF-12 generates two summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS), each ranging from 0 to 100. Higher scores indicate better health status and fewer limitations, with scores closer to 100 reflecting minimal impairment. Lower scores suggest greater health-related limitations and poorer QoL (Ware et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e1996\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe Positive and Negative Affect Schedule (PANAS) is a scale consisting of words that describe feelings and emotions, with separate scales measuring positive affect (PA) and negative affect (NA). Respondents rate each emotion on a scale from 1 (very slightly or not at all) to 5 (extremely), based on how much they have felt that way during a specified time frame. The PA and NA scores are calculated by summing the ratings for their respective items. Higher PA scores indicate higher levels of positive emotions and engagement, while higher NA scores reflect greater levels of distress and negative emotions.(Watson et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e1988\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe Patient Health Questionnaire-9 (PHQ-9) is a multipurpose instrument used for screening, diagnosing, monitoring, and measuring the severity of depression. It assesses nine domains: 1) Little interest or pleasure in doing things. 2) Feeling down, depressed, or hopeless. 3) Trouble falling asleep, staying asleep, or sleeping too much. 4) Feeling tired or having little energy. 5) Poor appetite or overeating. 6) Feeling bad about yourself or that you are a failure or have let yourself or your family down. 7) Trouble concentrating on things, such as reading the newspaper or watching television. 8) Moving or speaking so slowly that other people have noticed. 9) Thoughts of being better off dead or self-harm. Each domain is scored from 0 (not at all) to 3 (nearly every day), with the total score ranging from 0 to 27. Scores of 5, 10, 15, and 20 represent thresholds for mild, moderate, moderately severe, and severe depression, respectively.(Kroenke et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2001\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe Generalized Anxiety Disorder Questionnaire (GAD-7) is a self-administered questionnaire used as a screening tool and severity measure for generalized anxiety disorder (GAD). Patients are required to respond to seven questions about symptoms: 1) Feeling nervous, anxious, or on edge. 2) Not being able to stop or control worrying. 3) Worrying too much about different things. 4) Trouble relaxing. 5) Being so restless that it\u0026rsquo;s hard to sit still. 6) Being easily annoyed or irritable. 7) Feeling afraid as if something awful might happen. Each question is scored from 0 (not at all) to 3 (nearly every day), yielding a total score ranging from 0 to 21. Scores of 5, 10, and 15 represent mild, moderate, and severe anxiety, respectively (Spitzer et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2006\u003c/span\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eFor statistical analysis, GraphPad Prism\u0026reg; version 9 (Graph-Pad Software, San Diego, Calif., USA) was used. Continuous data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, while categorical variables are presented as absolute/relative frequencies. We performed statistical comparisons of quantitative data with Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test or ANOVA. When the two variables compared were not normally distributed, we used the Mann-Whitney U test. To evaluate the effectiveness of the exercise program, we performed a statistical analysis using a paired Student's t-test. This test was chosen to compare the pre- and post-exercise data for each patient, allowing us to assess the changes within the same individuals over the course of the study. All statistical tests were two sided with p values of \u0026lt;\u0026thinsp;0.05 considered significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eGeneral characteristics and body composition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGeneral metabolic characteristics and body composition of patients with CD at baseline and post-exercise evaluation are shown in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Clinical Features and Body Composition in Patients with Cushing\u0026rsquo;s Disease Pre- and Post-Exercise Program\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"601\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGeneral Features\u0026nbsp;:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eBMI, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e35.5\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e31.3\u0026plusmn;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eSBP (mmHg), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e144\u0026plusmn;21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e132\u0026plusmn;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eDBP (mmHg), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e86\u0026plusmn;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e76\u0026plusmn;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.0483\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eHeart rate (bpm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e85\u0026plusmn;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e76\u0026plusmn;16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eWaist circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e107\u0026plusmn;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e103\u0026plusmn;13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eHip circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e107\u0026plusmn;14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e113\u0026plusmn;15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.501\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eNeck circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e37\u0026plusmn;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e35\u0026plusmn;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.324\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBody composition\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eBody Mass (cm\u003csup\u003e3\u003c/sup\u003e), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e73280\u0026plusmn;14463\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e66454\u0026plusmn;120005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.211\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eFat Mass (cm\u003csup\u003e\u0026nbsp;3\u003c/sup\u003e), mean\u0026nbsp;\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e33312\u0026plusmn;9559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e29207\u0026plusmn;8799\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.475\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eFat Mass (%), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e45.4\u0026plusmn;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e43.9\u0026plusmn;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eLean Mass (cm\u003csup\u003e3\u003c/sup\u003e), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e34818\u0026plusmn;4989\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e36038\u0026plusmn;3469\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.398\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eLean Mass (%), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e47.5\u0026plusmn;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e54.1\u0026plusmn;6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eTrunk Fat (cm\u003csup\u003e3\u003c/sup\u003e), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e18494\u0026plusmn;4326\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e16729\u0026plusmn;5192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eTrunk fat (%), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e47.8\u0026plusmn;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e43\u0026plusmn;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBone features\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eT-score:\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eLumbar, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-0.8\u0026plusmn;2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e-1.3\u0026plusmn;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.771\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eFemoral, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e-1.8\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e-0.8\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eBMD (gr/cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eLumbar, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e0.9\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.299\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eFemoral, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e0.6\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e1.1\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 221px;\"\u003e\n \u003cp\u003eTBS, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 165px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 121px;\"\u003e\n \u003cp\u003e1.1\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.574\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;Data are presented as mean \u0026plusmn; standard deviation (SD). Abbreviations: BMI, Body Mass Index; SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; BPM, Beats Per Minute; BMD, Bone Mineral Density; TBS, Trabecular Bone Score.\u003c/p\u003e\n\u003cp\u003eThe mean waist circumference was significantly lower on post exercise evaluation as compared with baseline (103\u0026plusmn;13 vs. 107\u0026plusmn;13 cm; p=0.041). The mean diastolic blood pressure (DBP) was significantly lower on \u0026nbsp; post exercise evaluation as compared with baseline (86\u0026plusmn;10 vs. 76\u0026plusmn;8 mmHg; p=0.048). The mean lean mass fraction was significantly higher on post-exercise evaluation as compared with baseline (54.1% vs. 47.5%; p=0.006). The mean trunk fat fraction was significantly lower on \u0026nbsp;post-exercise evaluation as compared with baseline (43% vs. 48%; p = 0.040). Mean femoral T-score was significantly higher on \u0026nbsp;post-exercise evaluation as compared with baseline (-0.8\u0026plusmn;1.2 vs. -1.8\u0026plusmn;0.6; p=0.04). Mean femoral BMD was significantly higher on the post-exercise evaluation as compared with baseline (1.1\u0026plusmn;0.1 vs. 0.6\u0026plusmn;0.1 gr/cm\u003csup\u003e3\u003c/sup\u003e; p=0.030).\u003c/p\u003e\n\u003cp\u003eGeneral metabolic characteristics of patients with ACRO at baseline and post-exercise evaluation are shown in Table 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Clinical Features in Patients with Controlled Acromegaly Pre- and Post-Exercise Program\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"651\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epost exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGeneral Features\u0026nbsp;:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eBMI, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e28.2\u0026plusmn;2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e27.5\u0026plusmn;2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.663\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eSBP (mmHg), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e147.8\u0026plusmn;28.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e129\u0026plusmn;14.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.690\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eDBP (mmHg), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e89\u0026plusmn;8.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e80.2\u0026plusmn;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eHeart rate (bpm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e67.6\u0026plusmn;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e61.8\u0026plusmn;10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.156\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eWaist circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e102.5\u0026plusmn;4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e98.6\u0026plusmn;4.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eHip circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e120\u0026plusmn;43.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e106.9\u0026plusmn;9.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.449\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eNeck circumference (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 111px;\"\u003e\n \u003cp\u003e40.7\u0026plusmn;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 183px;\"\u003e\n \u003cp\u003e39.4\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are presented as mean \u0026plusmn; standard deviation (SD). Abbreviations: BMI, Body Mass Index; SBP, Systolic Blood Pressure; DBP, Diastolic Blood Pressure; BPM, Beats Per Minute.\u003c/p\u003e\n\u003cp\u003eNo significant differences in these parameters were found between the two phases (p=n.s.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre- and post-exercise muscle functionality\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with CD performed better on post-exercise evaluation as compared with baseline on the GS test (0.99\u0026plusmn;0.19 vs. 1.2\u0026plusmn;0.2; p\u0026lt;0.001), TUG test (7.5\u0026plusmn;1 vs. 6.4\u0026plusmn;0.9; p=0.0024) and 30-sec chair stand (11.9\u0026plusmn;2.4 vs. 25.6\u0026plusmn;5.1; p=0.006) (Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with ACRO performed better on post-exercise evaluation as compared with baseline on GS (1.2\u0026plusmn;0.2 vs. 1.5\u0026plusmn;0.2; p=0.003), TUG (5.9\u0026plusmn;0.9 vs. 5.2\u0026plusmn;0.9; p=0.036), and 30-sec chair stand (20.1\u0026plusmn;6.01 vs. 27.1\u0026plusmn;8.1; p=0.011) (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre- and post-exercise muscle ultrasound parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn CD patients, rectus femoralis was significantly thicker on \u0026nbsp;post-exercise evaluation at the middle and distal third in the right lower limb (middle 1.5\u0026plusmn;0.3 cm vs. 2.1\u0026plusmn;0.2 cm; p = 0.036, distal third 0.8\u0026plusmn;0.1cm vs. 1.2\u0026plusmn;0.1 cm; p=0.001) and at the left lower limb (middle 1.4\u0026plusmn;0.3 cm vs. 1.6\u0026plusmn;0.2 cm; p = 0.045, distal third 0.9\u0026plusmn;0.1 cm vs. 1.2\u0026plusmn;0.2 cm; p=0.004), as compared with baseline\u003c/p\u003e\n\u003cp\u003eIn patients with CD, vastus intermedius was significantly thicker on the post-exercise evaluation at the middle and distal third of \u0026nbsp;the right lower limb (middle 1.2\u0026plusmn;0.2 cm vs. 1.5\u0026plusmn;0.3 cm; p = 0.032, distal third 0.8\u0026plusmn;0.1 cm vs. 1.3\u0026plusmn;0.2 cm; p\u0026lt;0.001), as compared with baseline. Vastus intermedius was significantly thicker at the distal third in the left\u003c/p\u003e\n\u003cp\u003eTable 3. Ultrasound Muscle Parameters in Patients with Cushing\u0026rsquo;s Disease Pre- and Post-Exercise Program\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"650\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epost exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRight lower limb:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2.1\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.9\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e3.7\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.7\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.3\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (cm), mea\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.4\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeft lower limb:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.8\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2.3\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.157\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2.4\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.189\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.9\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.4\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.1\u0026plusmn;0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (cm), mean+\u0026plusmn;D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e1\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0.6\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHeckmatt scale RF 1/2 , mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e2.3\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2.1\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.562\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eHeckmatt scale \u0026nbsp;RF 1/3 inf., mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e2\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e2.3\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 245px;\"\u003e\n \u003cp\u003eNormal US Evaluation, number (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 124px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 158px;\"\u003e\n \u003cp\u003e1 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003elower limb (1\u0026plusmn;0.2\u0026nbsp;cm vs. 1.3\u0026plusmn;0.3\u0026nbsp;cm; p=0.001) (Table 3), as compared with baseline.\u003c/p\u003e\n\u003cp\u003eIn patients with ACRO, the Heckmatt scale score at the rectus femoralis on post-exercise evaluation was significantly lower (middle 1.83\u0026plusmn;0.4 vs 1.14\u0026plusmn;0.3, p = 0.035; distal third 2\u0026plusmn;0.0 vs. 1.14\u0026plusmn;0.4; p = 0.008), as compared with baseline, indicating an improvement of muscle quality (Table 4).\u003c/p\u003e\n\u003cp\u003eData are presented as mean \u0026plusmn; standard deviation (SD). Comparison of ordinal data (Heckmatt scale) was performed using the Mann-Whitney U test. Abbreviations: RF, Rectus Femoris\u003c/p\u003e\n\u003cp\u003eTable 4. Ultrasound Muscle Parameters in Patients with Controlled Acromegaly Pre- and Post-Exercise Program\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"626\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epost exercice evaluation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRight lower limb:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.8\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e2.1\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.354\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e4\u0026plusmn;2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e5.8\u0026plusmn;3.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.6\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.7\u0026plusmn;0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.711\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e2.5\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e3.5\u0026plusmn;2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.344\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e0.8\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.529\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (cm), mea\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e3.8\u0026plusmn;4.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.372\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.2\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.178\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLeft lower limb:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.9\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.9\u0026plusmn;.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.697\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e3.9\u0026plusmn;2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e4.2\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.824\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.7\u0026plusmn;0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.7\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/2 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e2.9\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e3\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.852\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (cm), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.483\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eRectus femoralis 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e2\u0026plusmn;1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.464\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (cm), mean+\u0026plusmn;D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.4\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.3\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eVastus intermedius 1/3 (ml), mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.7\u0026plusmn;0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.5\u0026plusmn;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.575\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eHeckmatt scale RF 1/2, mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1.83\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.14\u0026plusmn;0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eHeckmatt scale RF 1/3 inf., mean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e2\u0026plusmn;0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e1.14\u0026plusmn;0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 269px;\"\u003e\n \u003cp\u003eNormal US Evaluation, number (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 107px;\"\u003e\n \u003cp\u003e1(10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 128px;\"\u003e\n \u003cp\u003e6 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 123px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are presented as mean \u0026plusmn; standard deviation (SD). Comparison of ordinal data (Heckmatt scale) was performed using the Mann-Whitney U test. \u003cem\u003eAbbreviations:\u003c/em\u003e RF, Rectus Femoris\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePre- and post-exercise PROMs\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant changes of PROMs measures were observed after the exercise intervention as compared with baseline in both CD and ACRO patients (p=n.s.).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we have demonstrated that a 12-week individually tailored physical activity program significantly improved both structural and functional muscle parameters in patients with CD in long-term remission and in patients with controlled ACRO. These findings emphasize the therapeutic potential of exercise as a crucial component of multidisciplinary care for addressing residual musculoskeletal impairment in these populations.\u003c/p\u003e \u003cp\u003eA significant improvement in physical performance was observed, as evidenced by better results on GS, TUG, and the 30-second chair stand test. These functional gains reflect enhanced mobility, balance, and muscle strength in both groups. Muscle ultrasound revealed distinct structural adaptations between CD and ACRO patients. In CD, a greater muscle thickness in the rectus femoris and vastus intermedius suggested an increase in lean muscle mass, whereas in ACRO, reduced muscle echogenicity indicated an improvement in muscle quality, likely due to decreased intramuscular fatty infiltration. These distinct responses underscore the complexity of the mechanisms underlying muscle dysfunction in CS and ACRO, shaped by their unique pathophysiological profiles (Khaleeli et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e1984\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1983\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eDespite the recognized burden of musculoskeletal dysfunction in CD and ACRO, our study addresses an important unmet need. Current clinical management often overlooks muscle dysfunction, with limited access to targeted rehabilitation/exercise interventions (Geer et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Valassi et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). A multidisciplinary approach, incorporating exercise programs supervised by physiotherapists, could address these gaps and improve patient satisfaction. Integrating such interventions into Pituitary Tumor Centers of Excellence (PTCOEs) should be prioritized to deliver comprehensive care tailored to these patients' characteristics.\u003c/p\u003e \u003cp\u003eMuscle dysfunction in CD is primarily driven by glucocorticoid-induced myopathy, characterized by the atrophy of fast-twitch muscle fibers due to proteolysis and reduced protein synthesis. Fatigue and impaired muscle function frequently persist even after remission, linked to increased intramuscular fatty infiltration, which correlates with balance, strength, and mobility impairments (Martel-Duguech et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In ACRO, prolonged exposure to excess GH and IGF-1 leads to persistent musculoskeletal complications, including muscle pain and arthropathy that limit physical functioning. Patients with long-term controlled ACRO often display significant fatty infiltration within thigh muscles, which has been independently associated with reduced performance on the TUG test, a key assessment of mobility, balance, and walking ability (Martel-Duguech et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2021b\u003c/span\u003e). Importantly, this association is observed regardless of muscle area or joint symptoms, which are common and debilitating features in ACRO (Martel-Duguech et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2021b\u003c/span\u003e). Our findings suggest that while exercise effectively improves muscle function in both groups, the structural adaptations may differ.\u003c/p\u003e \u003cp\u003eThe observed benefits of our combined aerobic and resistance exercise protocol can be attributed to several mechanisms previously documented in other populations, including molecular, metabolic, structural, neural, and inflammatory adaptations (Carra\u0026ccedil;a et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Goodman, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Gundersen, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Strasser et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). At the molecular level, resistance exercise stimulates mTOR pathway, promoting protein synthesis and muscle hypertrophy, while inhibiting proteolytic activity through the ubiquitin-proteasome system (Goodman, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Gundersen, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Additionally, myokines released during exercise, such as irisin and brain-derived neurotrophic factor (BDNF), play critical roles in muscle repair and metabolic regulation (Severinsen and Pedersen, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Zunner et al., \u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Structurally, the increase in muscle thickness observed in CD patients likely reflects hypertrophic adaptations driven by resistance training, which predominantly targets type II muscle fibers (Toigo and Boutellier, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). In ACRO patients, the reduction in muscle echogenicity observed on ultrasound may represent decreased intramuscular fatty infiltration, a finding supported by evidence that exercise enhances lipid metabolism and mitochondrial function (Goodpaster et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2008b\u003c/span\u003e). Neural adaptations also contribute significantly, particularly in the early phases of training, through enhanced motor unit recruitment, firing rate, and intermuscular coordination, which improve muscle function and strength even before structural changes occur (Gabriel et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Metabolic adaptations to exercise, including increased mitochondrial biogenesis and improved oxidative capacity, likely contribute to sustained amelioration of muscle endurance and performance (Hong et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Furthermore, the anti-inflammatory effects of exercise, characterized by reductions in circulating pro-inflammatory cytokines such as TNF-α and IL-6, may facilitate muscle repair and improve quality (Pedersen and Febbraio, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Exercise also improves insulin sensitivity by enhancing glucose uptake in skeletal muscle through increased translocation of GLUT-4 transporters to the cell membrane and promoting mitochondrial biogenesis, thereby reducing insulin resistance and supporting metabolic health (Holloszy, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2005\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious prospective studies have demonstrated the positive effects of exercise programs on patients with ACRO, particularly in improving functional capacity, balance, and QoL. For instance, Lima et al. showed that a 12-week therapist-oriented home rehabilitation program significantly improved muscle function, body balance, and health-related QoL in 17 patients with ACRO, of whom 12 were controlled and 5 had active disease (Lima et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Haliloglu et al. demonstrated enhanced physical performance, dynamic balance and body-self-perception after a 3-month,group-based exercise program involving 11 patients (7 controlled, 4 active), although their approach lacked individual tailoring and did not specifically address muscle composition or sarcopenia-related parameters (Haliloglu et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Hatipoglu et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2015\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn contrast, our study\u0026rsquo;s strength lies in its structured, progressive, and individually tailored approach to exercise, which focused on improving muscle quality, strength, balance and daily function, and BMD. Unlike the previously mentioned studies, our intervention involved direct supervision by professional trainers, individually tailored exercise intensity, established progression planning, and it used validated tools to assess muscle outcomes. Furthermore, our program duration of 3 months aligns closely with evidence-based recommendations for achieving meaningful musculoskeletal adaptations (Borde et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn particular, a unique aspect of our study was the integration of validated tools recommended by the European Working Group on Sarcopenia in Older People (EWGSOP) to assess muscle performance and quality (Cruz-Jentoft et al., 2019). Specifically, we used functional performance tests like the TUG, GS, HGS and 30-second chair-to-stand, alongside ultrasound to measure rectus femoris thickness and echointensity. These tools provided a comprehensive evaluation of sarcopenia-related parameters, bridging a gap between clinical assessments and muscle features .\u003c/p\u003e \u003cp\u003eResistance training programs were associated with significant improvements in muscle function, body composition, BMD and QoL across diverse populations, including cancer survivors, patients with chronic kidney disease (CKD), older adults, middle-aged individuals, post-bariatric surgery patients, individuals with growth hormone deficiency (GHD), and postmenopausal women (Amer et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Cheema et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Coelho et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Guadalupe-Grau et al., \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Stegen et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Straight et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Strasser et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Watson et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). In middle-aged and older adults, progressive resistance training was effective in enhancing physical function, reducing disability, and increasing lower-extremity power, which is crucial for mobility and fall prevention (Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Straight et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Similarly, in post-bariatric surgery patients, resistance training has proven effective in mitigating lean muscle mass loss, improving body composition, and enhancing functional capacity during the post-operative period (Stegen et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2011\u003c/span\u003e; Woodlief et al., \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In individuals with GHD, resistance training has been shown to significantly improve muscle function, even in the absence of recombinant growth hormone therapy (Amer et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Coelho et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). Additionally, resistance training lasting from 8 to 12 months demonstrated a positive impact on bone health by improving BMD and reducing fracture risk in several populations, including older adults and postmenopausal women with osteopenia/osteoporosis (Watson et al., \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) This effect is especially relevant for individuals with a history of chronic corticosteroid use, as studies have shown that resistance training ranging from 6 to 12 months can mitigate corticosteroid-induced bone loss (Kast et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mitchell et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). For instance, resistance training for 6 months has been shown to prevent vertebral osteoporosis in lung transplant recipients on glucocorticoid therapy and improve BMD in key fracture-prone sites such as the lumbar spine and proximal femur (Kast et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2022\u003c/span\u003e; Mitchell et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2003\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInterestingly, our study did not observe significant changes in QoL parameters in patients with CD or ACRO following the 12-week exercise intervention. This outcome may reflect the relatively short duration of the program or the multifactorial nature of QoL in these populations (Webb et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). Indeed, the disease-specific questionnaires (AcroQoL and CushingQoL) used, were originally validated over a 6-month follow-up period, suggesting that shorter durations such that in our study, might not adequately capture subtle or incremental changes in QoL (Webb et al., \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2008\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2006\u003c/span\u003e) Longer interventions of resistance training, lasting from 6 to 12 months, were associated with significant QoL improvement in cancer survivors and older adults (Liu and Latham, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Strasser et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Moreover, in obese subjects, 12-week exercise interventions improved general physical functioning and psychosocial well-being, though the positive effects on QoL, especially in terms of psychological dimensions, were more pronounced after longer periods of intervention(Carra\u0026ccedil;a et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The limited time frame of 12 weeks in our study may have been insufficient to detect measurable improvements in QoL for patients with CD and ACRO, whose QoL is influenced by persistent musculoskeletal, psychological, and disease-specific factors. It should be highlighted that other studies have shown that QoL improvements in patients with pituitary diseases, including CD and ACRO, can be challenging to achieve. For instance, Albarel et al. offered an individualized education program to patients with pituitary diseases and described significant improvements in physical and psychological limitation scores of the SF-36 QoL questionnaire at the end of the program, with these benefits persisting at follow-up (Albarel et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, other QoL dimensions, such as mental health, showed transient deterioration before returning to baseline levels, reflecting the multifactorial pathogenesis of QoL deterioration in this population, which is thought to require alonglasting and multidisciplinary management. Similarly, Andela et al. demonstrated improvements in self-efficacy and vitality following a self-management 8-weeks program in patients with pituitary diseases, although no significant changes in broader QoL or mental health parameters were observed, (Andela et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Collectively, these findings emphasize the need for comprehensive, tailored, and possibly longer-term interventions that address sustained QoL improvements in CD and ACRO.\u003c/p\u003e \u003cp\u003eOur study has several limitations, including the relatively short intervention duration, lack of a control group, small sample size, and the choice to only include either female or male individuals in each disease group. These pitfalls might have affected the statistical power of the analysis, thus preventing us from detecting changes in some parameters. Moreover, we did not assess the concentrations in blood of any potential mediators of the beneficial effects of exercise on the outcomes included and this is a clear limitation. Future studies should include larger, sex-balanced cohorts to disentangle the interplay between gender, disease-specific pathophysiology, and exercise-mediated adaptations. This approach will provide a more comprehensive understanding of how to optimize exercise prescriptions for diverse patient populations.\u003c/p\u003e \u003cp\u003eIn conclusion, our findings highlight the importance of an individually tailored exercise program in improving muscle function and physical performance in CD and ACRO patients. Beyond achieving biochemical control, a multidisciplinary approach, incorporating physiotherapy, is essential to address residual musculoskeletal dysfunction and improve overall functional capacity. Future studies should explore longer-duration interventions and their impact on disease-specific QoL outcomes.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e \u003ch2\u003eFunding Declaration\u003c/h2\u003e \u003cp\u003e\u003cb\u003e\u003c/b\u003eThis study was supported by the Instituto de Salud Carlos III, grant number FIS PI 21/0123, and co-funded by the European Regional Development Fund (FEDER).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.M.D. and E.V. conceived and designed the study. L.M.D., H.B., V.P.C., O.G.V., J.V.R., and T.C.P. performed data collection and conducted the intervention. H.B. supervised and performed the functional assessments. L.M.D. performed statistical analyses. L.M.D. and E.V. interpreted the data and wrote the main manuscript text. S.M.W. provided critical intellectual input and revised the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to sincerely thank all the patients who generously participated in this study for their dedication, effort, and commitment throughout the intervention. Their involvement was crucial in making this research possible\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlbarel, F., Pellegrini, I., Rahabi, H., Baccou, C., Gonin, L., Rochette, C., Vermalle, M., Cuny, T., Castinetti, F., Brue, T., 2020. Evaluation of an individualized education program in pituitary diseases: a pilot study. Eur. J. 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Sci. 2022, Vol. 23, Page 3501 23, 3501. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/IJMS23073501\u003c/span\u003e\u003cspan address=\"10.3390/IJMS23073501\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cushing’s disease, Acromegaly, Exercise intervention, Muscle quality, Bone mineral density, Physical performance, Quality of life, Patient-reported outcomes, Individually tailored training, Musculoskeletal dysfunction","lastPublishedDoi":"10.21203/rs.3.rs-6485925/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6485925/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Patients with controlled Cushing’s disease (CD) and acromegaly (ACRO) often experience persistent musculoskeletal dysfunction and impaired quality of life (QoL) despite biochemical normalization.\u003c/p\u003e\n\u003cp\u003eAlthough undergoing supervised physical activity is a clear unmet need of pituitary patients, evidence on the effectiveness of individually tailored exercise programs in these populations is scanty .\u003c/p\u003e\n\u003cp\u003eObjective: The aim of this pilot study was to evaluate the effectiveness of a 12-week individually tailored and supervised exercise program on muscle function, bone health, and patient-reported outcomes (PROMs) in patients with biochemically controlled CD and ACRO.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Twenty patients (10 women with CD in remission, 10 men with controlled ACRO) participated in a structured program combining aerobic and resistance exercises, supervised by professional trainers, three times a week over 12 weeks. Outcomes assessed at baseline and post-intervention included, grip strength and physical performance on gait speed, timed up-and-go, chair stand test, muscle structure and quality on ultrasound examination, body composition and bone mineral density (BMD), as measured using dual-x-absorptiometry (DXA), and QoL, as evaluated using disease-specific (CushingQoL, AcroQoL) and generic (SF-12, PANAS, PHQ-9, and GAD-7) questionnaires.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e After the 12-week intervention, significant improvements were observed in physical performance tests (p\u0026lt;0.05 for all parameters vs. baseline) in both CD and ACRO patients. Ultrasound-measured muscle thickness increased CD patients after completion of the program (p\u0026lt;0.05), while a decreased echogenicity was found in \u0026nbsp;ACRO patients (p\u0026lt;0.05) CD patients demonstrated significant improvements in waist circumference, diastolic blood pressure, lean mass fraction, trunk fat fraction, and femoral BMD (p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e An individually tailored, supervised 12-week exercise intervention significantly enhanced muscle structure and physical performance in patients with controlled CD and ACRO. Physical activity trainers should be included in the multidisciplinary team dedicated to the management of pituitary diseases\u003c/p\u003e","manuscriptTitle":"Benefits of a 12 weeks-individually tailored physical activity program in patients with Cushing’s disease in remission and controlled acromegaly","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:35:07","doi":"10.21203/rs.3.rs-6485925/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-19T15:01:54+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-18T07:26:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-12T15:30:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53714516481152690954779728077214459613","date":"2025-04-29T10:44:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196171158758278153484047124745035436051","date":"2025-04-28T18:13:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-28T16:30:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-25T01:54:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-25T01:52:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"Endocrine","date":"2025-04-19T16:46:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"endocrine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"endo","sideBox":"Learn more about [Endocrine](https://www.springer.com/journal/12020)","snPcode":"12020","submissionUrl":"https://submission.nature.com/new-submission/12020/3","title":"Endocrine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7a975a48-d0dc-4f09-9305-c7d3f724d8f4","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:04:28+00:00","versionOfRecord":{"articleIdentity":"rs-6485925","link":"https://doi.org/10.1007/s12020-025-04331-7","journal":{"identity":"endocrine","isVorOnly":false,"title":"Endocrine"},"publishedOn":"2025-07-10 15:58:00","publishedOnDateReadable":"July 10th, 2025"},"versionCreatedAt":"2025-05-07 06:35:07","video":"","vorDoi":"10.1007/s12020-025-04331-7","vorDoiUrl":"https://doi.org/10.1007/s12020-025-04331-7","workflowStages":[]},"version":"v1","identity":"rs-6485925","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6485925","identity":"rs-6485925","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}