Low growth hormone secretion associated with post-acute sequelae SARS-CoV-2 infection (PASC) neurologic symptoms: A case-control pilot study.

OBJECTIVE: To determine if patients that develop lingering neurologic symptoms of fatigue and "brain fog" after initial recovery from coronavirus disease 2019 (COVID-19) have persistent low growth hormone (GH) secretion as seen in other conditions with similar symptom etiology. DESIGN: In this case-control observational pilot study, patients reporting lingering neurologic post-acute sequelae of SARS-CoV-2 (PASC, n = 10) symptoms at least 6 months after initial infection were compared to patients that recovered from COVID-19 without lingering symptoms (non-PASC, n = 13). We compared basic blood chemistry and select metabolites, lipids, hormones, inflammatory markers, and vitamins between groups. PASC and non-PASC subjects were tested for neurocognition and GH secretion, and given questionnaires to assess symptom severity. PASC subjects were also tested for glucose tolerance and adrenal function. RESULTS: PASC subjects reported significantly worse fatigue, sleep quality, depression, quality of life, and gastrointestinal discomfort compared to non-PASC. Although PASC subjects self-reported poor mental resilience, cognitive testing did not reveal significant differences between groups. Neurologic PASC symptoms were not linked to inflammatory markers or adrenal insufficiency, but were associated with reduced growth hormone secretion. CONCLUSIONS: Neurologic PASC symptoms are associated with gastrointestinal discomfort and persistent disruption of GH secretion following recovery from acute COVID-19. (www. CLINICALTRIALS: gov; NCT04860869).

Proteomic investigation of human skeletal muscle before and after 70 days of head down bed rest with or without exercise and testosterone countermeasures.

INTRODUCTION: Long-term head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-term space flight. Agents such as testosterone, in addition to regular exercise, are effective countermeasures for reducing loss of skeletal muscle mass and function. OBJECTIVE: We investigated the skeletal muscle proteome of healthy men in response to long term HDBR alone (CON) and to HDBR with exercise (PEX) or exercise plus testosterone (TEX) countermeasures. METHOD: Biopsies were performed on the vastus lateralis before (pre) HDBR and on HDBR days 32 (mid) and 64 (post). Extracted proteins from these skeletal muscle biopsies were subjected to 2-dimensional gel electrophoresis (2DE), stained for phosphoproteins (Pro-Q Diamond dye) and total proteins (Sypro Ruby dye). Proteins showing significant fold differences (t-test p ≤ 0.05) in abundance or phosphorylation state at mid or post were identified by mass spectroscopy (MS). RESULTS: From a total of 932 protein spots, 130 spots were identified as potentially altered in terms of total protein or phosphoprotein levels due to HDBR and/or countermeasures, and 59 unique molecules emerged from MS analysis. Top canonical pathways identified through IPA included calcium signaling, actin cytoskeleton signaling, integrin linked kinase (ILK) signaling, and epithelial adherens junction signaling. Data from the pre-HDBR proteome supported the potential for predicting physiological post-HDBR responses such as the individual's potential for loss vs. maintenance of muscle mass and strength. CONCLUSIONS: HDBR resulted in alterations to skeletal muscle abundances and phosphorylation of several structural and metabolic proteins. Inclusion of exercise alone or in combination with testosterone treatment modulated the proteomic responses towards cellular reorganization and hypertrophy, respectively. Finally, the baseline proteome may aid in the development of personalized countermeasures to mitigate health risks in astronauts as related to loss of muscle mass and function.

Efficacy of Testosterone plus NASA Exercise Countermeasures during Head-Down Bed Rest.

INTRODUCTION: Prolonged confinement to head-down bed rest (HDBR) results in musculoskeletal losses similar to those observed during long-duration space flight. Exercise countermeasures by themselves have not completely prevented the deleterious losses in muscle mass or function in HDBR or space flight. PURPOSE: The objective was to investigate the safety and efficacy of intermittent, low-dose testosterone treatment in conjunction with NASA exercise (SPRINT) countermeasures during 70 d of 6° HDBR. METHODS: Healthy men (35 ± 8 yr) were randomized into one of three groups that remained inactive (CON) or performed exercise 6 d·wk in addition to receiving either placebo (PEX) or testosterone treatment (TEX, 100 mg·wk). Testosterone/placebo injections were administered once a week for 2 wk, followed by 2 wk off and so on, during HDBR. RESULTS: Total, leg, and trunk lean body mass (LBM) consistently decreased in CON, increased in TEX, and had little or no changes in PEX. Total, leg, and trunk fat mass consistently increased in CON and PEX and decreased in TEX. Leg strength decreased in CON, whereas PEX and TEX were protected against loss in strength. Changes in leg LBM correlated positively with changes in leg muscle strength. CONCLUSIONS: Addition of a testosterone countermeasure enhanced the preventative actions of exercise against body composition changes during long-term HDBR in healthy eugonadal men. This is the first report to demonstrate that cycled, low-dose testosterone treatment increases LBM under conditions of strict exercise control. These results are clinically relevant to the development of safe and effective therapies against muscle atrophy during long-term bed rest, aging, and disease where loss of muscle mass and strength is a risk. The potential space flight applications of such countermeasure combinations deserve further investigations.

A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women.

BACKGROUND: Cancer cachexia negatively impacts cancer-related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment. METHODS: A randomized, double-blind, placebo-controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival. RESULTS: A total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0-7%) whereas those receiving placebo lost 3.3% (95% CI, -7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups. CONCLUSIONS: In patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo.

Functional Changes after Recombinant Human Growth Hormone Replacement in Patients with Chronic Traumatic Brain Injury and Abnormal Growth Hormone Secretion.

We explored the effects of recombinant human growth hormone (rhGH) replacement on physical and cognitive functioning in subjects with a moderate-to-severe traumatic brain injury (TBI) with abnormal growth hormone (GH) secretion. Fifteen individuals who sustained a TBI at least 12 months prior to study enrollment were identified as having abnormal GH secretion by glucagon stimulation testing (maximum GH response less than 8 ng/mL). Peak cardiorespiratory capacity, body composition, and muscle force testing were assessed at baseline and one year after rhGH replacement. Additionally, standardized neuropsychological tests that assess memory, processing speed, and cognitive flexibility, as well as self-report inventories related to depression and fatigue, were administered at baseline and 1 year after rhGH replacement. Comparison tests were performed with proper post hoc analyses. All analyses were carried out at α < 0.05. Peak O2 consumption, peak oxygen pulse (estimate of cardiac stroke volume), and peak ventilation all significantly increased (p < 0.05). Maximal isometric and isokinetic force production were not altered. Skeletal muscle fatigue did not change but the perceptual rating of fatigue was reduced by ∼25% (p = 0.06). Cognitive performance did not change significantly over time, whereas self-reported symptoms related to depression and fatigue significantly improved. The observed changes suggest that rhGH replacement has a positive impact on cardiorespiratory fitness and a positive impact on perceptual fatigue in survivors of TBI with altered GH secretion.

A randomized pilot study of monthly cycled testosterone replacement or continuous testosterone replacement versus placebo in older men.

CONTEXT: Cycling androgens has been reported by athletes to improve physical performance by enhancing muscle mass and strength, a paradigm that has not been studied, and may have clinical value in older men being treated with testosterone. OBJECTIVE: We investigated the efficacy of a monthly cycled testosterone regimen that uses half the testosterone dose as the current standard of care continuous therapy on body composition and muscle strength in older men. DESIGN, SETTING, AND PATIENTS: Twenty-four community-dwelling older men 70 ± 2 yr of age with total testosterone levels below 500 ng/dl were randomized at the Institute for Translational Sciences-Clinical Research Center into a 5-month double-blind placebo-controlled trial. INTERVENTION: Subjects were dosed weekly for 5 months, receiving continuous testosterone (TE, n = 8; 100 mg testosterone enanthate, im injection), monthly cycled testosterone (MO, n = 8; alternating months of testosterone and placebo), or placebo (PL, n = 8). MAIN OUTCOME MEASURES: Main outcomes included body composition by dual-energy x-ray absorptiometry and upper and lower body muscle strength. Secondary outcomes included body weight, serum hormones, and mixed-muscle protein fractional synthesis rate (FSR). RESULTS: Total lean body mass was increased and percent fat was reduced after 5 months in TE and MO (P < 0.05). Upper body muscle strength increased in TE, and lower body muscle strength increased in TE and MO (P < 0.05). FSR increased in TE and MO (P < 0.05) but not in PL. CONCLUSIONS: Cycled testosterone improved body composition and increased muscle strength compared with placebo and increased FSR similarly to continuous testosterone.

Serum IGF-1 concentrations in a sample of patients with traumatic brain injury as a diagnostic marker of growth hormone secretory response to glucagon stimulation testing.

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in adults is established through growth hormone (GH) stimulation testing, which is often complex, expensive, time-consuming and may be associated with adverse side effects. The decision to perform GH provocative testing is influenced by clinical findings, medical history and biochemical evidence. We report in this study our experience using the glucagon stimulation test (GST) in assessing GHD in adult patients with traumatic brain injury (TBI) as it relates to baseline serum insulin-like growth factor-1 (IGF-1) concentrations. DESIGN: A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal IGF-1 cut-off for diagnosis of GHD at different potential diagnostic GST cut-off values (<3, <5, & <10 µg/l). PATIENTS: One hundred and thirty-eight patients (98 men and 40 women) with a documented history of moderate to severe TBI were assessed for GHD using serum IGF-1 concentrations and the GST. MEASUREMENTS: IGF-1 values were compared with peak GH values obtained following the GST. RESULTS: An IGF-1 cut-off value of 175 µg/l minimized the misclassification of GHD patients and GH-sufficient patients and provided a sensitivity of 83% and specificity of 40%, as well as a negative predictive power of 90% considering a criterion for peak GH response of <3 µg/l. CONCLUSIONS: Our current findings are consistent with previous work assessing peak GH response using the insulin tolerance test (ITT) in a non-TBI sample, suggesting that diagnostic accuracy may be optimized if the GST is used when obtained serum IGF-1 concentrations are below 175 µg/l. While the decision to perform provocative testing to assess GHD in adult patients should be based on the clinician's clinical impression, the findings from this retrospective study can provide useful clinical information and serve as a guide.

Aerobic capacity and growth hormone deficiency after traumatic brain injury.

CONTEXT: GH deficiency occurs in approximately 20% of all individuals who suffer from a moderate to severe traumatic brain injury. OBJECTIVE: This study determined whether GH deficiency secondary to traumatic brain injury had an effect on aerobic capacity. DESIGN: Subjects were screened for GH deficiency by the glucagon stimulation test and performed a maximal treadmill exercise test. SETTING: Patients were studied in the postacute recovery phase after traumatic brain injury. PARTICIPANTS: Thirty-five individuals were studied. Groups were formed as follows: normal GH axis, greater than 8 ng/ml response (n = 12); insufficient, GH 3-8 ng/ml response (n = 11); and deficient, less than 3 ng/ml response (n = 12). INTERVENTION: There was no intervention. MAIN OUTCOME MEASURE: Aerobic capacity was assessed by measuring expired gases during a graded treadmill exercise test. One-way and two-way ANOVAs were carried out on all peak and submaximal cardiorespiratory variables, respectively. Appropriate post hoc comparisons followed as necessary. RESULTS: Significantly higher peak oxygen consumption was found in traumatic brain injury subjects with GH normal vs. GH insufficient and deficient [26.4 +/- 6.9, 20.8 +/- 4.6, and 19.7 +/- 5.0, respectively (P < 0.05)]. Submaximal oxygen consumption was significantly higher in the GH normal group. All other variables were statistically similar. CONCLUSIONS: This study shows that individuals with traumatic brain injury with normal GH secretion have below normal aerobic capacity and those patients who have GH insufficiency/deficiency are further deconditioned. Studies of GH replacement in these subjects should be conducted to assess whether GH therapy can improve cardiorespiratory fitness and prevent secondary disability.