Kindness Isn't Just about Being Nice: The Value Proposition of Kindness as Viewed through the Lens of Incivility in the Healthcare Workplace.

The healthcare workplace is a high-stress environment. All stakeholders, including patients and providers, display evidence of that stress. High stress has several effects. Even acutely, stress can negatively affect cognitive function, worsening diagnostic acumen, decision-making, and problem-solving. It decreases helpfulness. As stress increases, it can progress to burnout and more severe mental health consequences, including depression and suicide. One of the consequences (and causes) of stress is incivility. Both patients and staff can manifest these unkind behaviors, which in turn have been shown to cause medical errors. The human cost of errors is enormous, reflected in thousands of lives impacted every year. The economic cost is also enormous, costing at least several billion dollars annually. The warrant for promoting kindness, therefore, is enormous. Kindness creates positive interpersonal connections, which, in turn, buffers stress and fosters resilience. Kindness, therefore, is not just a nice thing to do: it is critically important in the workplace. Ways to promote kindness, including leadership modeling positive behaviors as well as the deterrence of negative behaviors, are essential. A new approach using kindness media is described. It uplifts patients and staff, decreases irritation and stress, and increases happiness, calmness, and feeling connected to others.

Kindness as a Stress Reduction-Health Promotion Intervention: A Review of the Psychobiology of Caring.

Chronic stress is a ubiquitous problem shouldered by many people worldwide. Although the stressors are myriad (eg, loneliness, finances, health, discrimination), the corporal response to them either causes or exacerbates mental and physical illness, including depression, anxiety, and cardiovascular disease. Identifying efficient ways to help people buffer their response and promote resilience and wellness is critical to improving overall health. Positive interpersonal connection is a proven way to promote resilience and happiness. It is associated with decreased mortality and markers of better health. Kindness and caring are prosocial behaviors that build positive interpersonal connections and can uplift both the giver and receiver. Simply seeing kindness and caring activates the neuropsychology of kindness, elevating the viewer and promoting generosity, interpersonal connection, and inclusion. That augmenting positive emotions, enhancing interpersonal connection, and inducing prosocial behavior change are possible through seeing kindness opens the opportunity to bolster resilience in higher stress settings like health care. In a recent study, watching kindness media in a health care setting rapidly increased self-reported feelings of happiness, calm, gratitude, and being inspired. Viewers were significantly more generous. Providing staff and patients with a nonjudgmental lift to enhance caring interactions through kindnesses media can be an important, low-cost adjunct to improving the healthcare environment.

What's Playing in Your Waiting Room? Patient and Provider Stress and the Impact of Waiting Room Media.

Patients enter the healthcare space shouldering a lot of personal stress. Concurrently, health care providers and staff are managing their own personalstressors as well as workplace stressors. As stress can negatively affect the patient-provider experience and cognitive function of both individuals, it is imperative to try to uplift the health care environment for all. Part of the healthcare environmental psychology strategy to reduce stress often includes televisions in waiting rooms, cafeterias, and elsewhere, with the intent to distract the viewer and make waiting easier. Although well-intentioned, many select programming which can induce stress (eg, news). In contrast, as positive media can induce desirable changes in mood, it is possible to use it to decrease stress and uplift viewers, including staff. Positive media includes both nature media, which can relax and calm viewers and kindness media, which uplifts viewers, induces calm, and promotes interpersonal connection and generosity. Careful consideration of waiting room media can affect the patient-provider experience.

Kindness Media Rapidly Inspires Viewers and Increases Happiness, Calm, Gratitude, and Generosity in a Healthcare Setting.

Background and Objectives: Stress is a ubiquitous aspect of modern life that affects both mental and physical health. Clinical care settings can be particularly stressful for both patients and providers. Kindness and compassion are buffers for the negative effects of stress, likely through strengthening positive interpersonal connection. In previous laboratory-based studies, simply watching kindness media uplifts (elevates) viewers, increases altruism, and promotes connection to others. The objective of the present study is to examine whether kindness media can affect viewers in a real-world, pediatric healthcare setting. Methods: Parents and staff in a pediatric dental clinic were studied. Study days were randomized for viewers to watch either original kindness media or the standard televised children's programming that the clinic shows. Participants scored self-rated pre-media emotions in a survey, watched either media type for 8 min, and then completed the survey. All participants were informed that they would receive a gift card for their participation. After completion of the survey, participants were asked if they wanted to keep the card or donate it to a family in need. Results: Fifty (50) participants completed the study; 28 were parents and 22 were staff. In comparison to viewers of children's programming, participants who watched kindness media had significant increases in feeling happy, calmer, more grateful, and less irritated (p < 0.05), with trends observed in feeling more optimistic and less anxious. Kindness media caused marked increases in viewers' reports of feeling inspired, moved, or touched (p < 0.001). No change was observed in self-reported compassion, although baseline levels were self-rated as very high. People who watched kindness media were also more generous, with 85% donating their honoraria compared to 54% of Standard viewers (p = 0.03). Conclusions: Kindness media can increase positive emotions and promote generosity in a healthcare setting.

Mixed Meal and Intravenous L-Arginine Tests Both Stimulate Incretin Release Across Glucose Tolerance in Man: Lack of Correlation with ß Cell Function.

BACKGROUND: The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion. METHODS: Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and ß cell function were measured before and following each stimulus. RESULTS: Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of ß cell function. CONCLUSIONS/INTERPRETATION: Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/ß cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.

Outpatient versus inpatient mixed meal tolerance and arginine stimulation testing yields comparable measures of variability for assessment of beta cell function.

Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Φtot); and disposition index (DItot = Si* Φtot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX). RESULTS: Baseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort. [Table: see text] In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of ß-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

OBJECTIVE: Standardized, reproducible, and feasible quantification of ß-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. RESEARCH DESIGN AND METHODS: Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. CONCLUSIONS: Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis.

BACKGROUND: Faced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management. The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease. METHODS: We identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab. The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14-16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria. For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression. RESULTS: The classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders. Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression. The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment. In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment. CONCLUSIONS: We were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts. Additional prospective studies are needed to validate and refine the classifier for clinical use.

Arginine is preferred to glucagon for stimulation testing of ß-cell function.

A key aspect of research into the prevention and treatment of type 2 diabetes is the availability of reproducible clinical research methodology to assess ß-cell function. One commonly used method employs nonglycemic secretagogues like arginine (arg) or glucagon (glgn). This study was designed to quantify the insulin response to arg and glgn and determine test repeatability and tolerability. Obese overnight-fasted subjects with normal glucose tolerance were studied on 4 separate days: twice using arg (5 g iv) and twice with glgn (1 mg iv). Pre- and postinfusion samples for plasma glucose, insulin, and C-peptide were acquired. Arg and glgn challenges were repeated in the last 10 min of a 60-min glucose (900 mg/min) infusion. Insulin and C-peptide secretory responses were estimated under baseline fasting glucose conditions (AIRarg and AIRglgn) and hyperglycemic (AIRargMAX AIRglgnMAX) states. Relative repeatability was estimated by intraclass correlation coefficient (ICC). Twenty-three (12 men and 11 women) subjects were studied (age: 42.4 ± 8.3 yr; BMI: 31.4 ± 2.8 kg/m²). Geometric means (95% CI) for baseline-adjusted values AIRarg and AIRglgn were 84 (75-95) and 102 (90-115) µU/ml, respectively. After the glucose infusion, AIRargMAX and AIRglgnMAX were 395 (335-466) and 483 (355-658) µU/ml, respectively. ICC values were >0.90 for AIRarg andAIRargMAX. Glucagon ICCs were 0.83, 0.34, and 0.36, respectively, although the exclusion of one outlier increased the latter two values (to 0.84 and 0.86). Both glgn and arg induced mild adverse events that were transient. Glucagon, but not arginine, induced moderate adverse events due to nausea. Taken together, arginine is preferred to glucagon for assessment of ß-cell function.

Systems diagnostics: anticipating the next generation of diagnostic tests based on mechanistic insight into disease.

Societal demand for faster and more accurate assignment of treatments is based in both patient care needs and in health economics. From a patient care standpoint, there needs to be a transformation from the empiric method of therapeutic decision making to avoid unwanted side effects from inefficacious treatments. For health economics, the delay in effective therapy and expenditures for ineffective therapies add to the burden of care. To accomplish this transformation, we need to modify our current method of classifying disease from a phenotypic description to one that incorporates the different molecular drivers that created the observed phenotype. To do so, a deeper, systems-based understanding of these disease drivers is required, which will yield a new generation of diagnostic tests, or systems diagnostics.

Company Profile: Selventa, Inc.

Selventa, Inc. (MA, USA) is a biomarker discovery company that enables personalized healthcare. Originally founded as Genstruct, Inc., Selventa has undergone significant evolution from a technology-based service provider to an active partner in the development of diagnostic tests, functioning as a molecular dashboard of disease activity using a unique platform. As part of that evolution, approximately 2 years ago the company was rebranded as Selventa to reflect its new identity and mission. The contributions to biomedical research by Selventa are based on in silico, reverse-engineering methods to determine biological causality. That is, given a set of in vitro or in vivo biological observations, which biological mechanisms can explain the measured results? Facilitated by a large and carefully curated knowledge base, these in silico methods generated new insights into the mechanisms driving a disease. As Selventa's methods would enable biomarker discovery and be directly applicable to generating novel diagnostics, the scientists at Selventa have focused on the development of predictive biomarkers of response in autoimmune and oncologic diseases. Selventa is presently building a portfolio of independent, as well as partnered, biomarker projects with the intention to create diagnostic tests that predict response to therapy.

Early patient stratification and predictive biomarkers in drug discovery and development: a case study of ulcerative colitis anti-TNF therapy.

The current drug discovery paradigm is long, costly, and prone to failure. For projects in early development, lack of efficacy in Phase II is a major contributor to the overall failure rate. Efficacy failures often occur from one of two major reasons: either the investigational agent did not achieve the required pharmacology or the mechanism targeted by the investigational agent did not significantly contribute to the disease in the tested patient population. The latter scenario can arise due to insufficient study power stemming from patient heterogeneity. If the subset of disease patients driven by the mechanism that is likely to respond to the drug can be identified and selected before enrollment begins, efficacy and response rates should improve. This will not only augment drug approval percentages, but will also minimize the number of patients at risk of side effects in the face of a suboptimal response to treatment. Here we describe a systems biology approach using molecular profiling data from patients at baseline for the development of predictive biomarker content to identify potential responders to a molecular targeted therapy before the drug is tested in humans. A case study is presented where a classifier to predict response to a TNF targeted therapy for ulcerative colitis is developed a priori and verified against a test set of patients where clinical outcomes are known. This approach will promote the tandem development of drugs with predictive response, patient selection biomarkers.

Atherosclerosis drug development in jeopardy: the need for predictive biomarkers of treatment response.

The limited predictability of phase II biomarkers for atherosclerosis outcomes in phase III studies stands in contrast to the number and varied types of biomarkers--soluble, imaging, and functional--that have been used in a diverse array of trials. Although collectively abundant, these biomarker data exist in a fragmented state. Most biomarkers are studied one at a time, only measure a specific aspect of atherosclerosis, are not integrated in a substantive way, and compete with one another for validation; in the end, progress is slow. The proposed solution from the Atherosclerosis Working Group, a committee of experts from academia, the pharmaceutical industry, government, and the nonprofit sector and managed by the Foundation for the National Institutes of Health Biomarkers Consortium, is to integrate these different measures into an in silico model of atherosclerosis. Through integration of diverse biomarker measurements and outcomes in silico, we may be able to improve trial design as well as the predictive power of short-term markers for longer-term outcomes.

Do technical and commercial biases contribute to the pharmaceutical industry's productivity problems? An analysis of how reordering priorities can improve productivity.

Of the many issues that contribute to the pharmaceutical industry's productivity problems, biases in the drug discovery and development (DDD) process should be included on the list. The dominant bias pervading the early DDD process is the requirement to identify and develop a commercializable molecule, long before the importance of the target in human disease is understood. That requirement filters out many potentially valuable projects. By changing the emphasis from identifying a commercializable molecule to using molecular tools to test the relevance of the mechanism in humans, the projected number of proofs of concept and subsequent launches could increase up to fivefold. Because this tool paradigm requires resources, one consideration is to form a consortium to share the burden, benefiting both the industry and patients in need.

Increased food intake and energy expenditure following administration of olanzapine to healthy men.

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 +/- 2.2 kg/m(2), respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-alpha (TNF-alpha) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.

Potential implications of matrix metalloproteinase-9 in assessment and treatment of coronary artery disease.

BACKGROUND: Matrix metalloproteinase (MMP)-9, a member of the MMP superfamily is consistently implicated in the pathophysiology of atherosclerosis and plaque rupture, the most common mechanism responsible for acute coronary syndrome (ACS). AIM: To summarize the role of MMP-9 in atherosclerosis and its potential implications in assessment and treatment of coronary artery disease (CAD). METHODS: We reviewed the PubMed database for relevant data regarding the role of MMP-9 in the pathophysiology of atherosclerosis. In the light of these data, we postulate potential implications of MMP-9 in the management and treatment of CAD. RESULTS AND CONCLUSIONS: Existing data strongly support the role of MMP-9 in plaque destabilization and rupture. Based on the current knowledge, MMP-9 can potentially serve as a diagnostic biomarker in ACS and a prognostic biomarker in ACS and chronic CAD patients. MMP-9 is reduced by therapies that are associated with favourable outcome in atherosclerosis and thus may serve as a surrogate biomarker of treatment efficacy. However, large morbidity and mortality trials are still required to confirm that MMP-9 reduction is associated with improved outcome independent of the traditional risk factors (i.e. low-density lipoprotein cholesterol). Given its role in plaque rupture, inhibition of MMP-9 may promote plaque stabilization and consequently reduce cardiovascular events. Yet, the efficacy and safety of MMPs inhibitors should be first studied in preclinical models of atherosclerosis.

Non-traditional biomarkers of atherosclerosis in stable and unstable coronary artery disease, do they differ?

BACKGROUND: Biomarkers of atherosclerosis are emerging as a potential tool for assessment of coronary artery disease (CAD) patients. As acute coronary syndrome (ACS), and stable CAD are distinguished in their pathophysiology it is conceivable that they are also characterized by different biomarkers of atherosclerosis. METHODS: We systematically reviewed the literature for clinical studies of several non-traditional biomarkers of atherosclerosis reflecting various pathophysiological processes, namely macrophage-activity, oxidative-stress, tissue remodeling, and thrombosis in ACS and stable CAD to determine whether circulating biomarkers are differently expressed/predict outcome in these two clinical conditions. RESULTS: Macrophage-activity (monocyte chemoattractant protein-1, neopterin), tissue-remodeling (matrix metalloproteinase-9) and thrombosis (tissue-factor) related biomarkers were consistently elevated in ACS compared to stable CAD, in accordance with the pathophysiological role of these mediators in plaque rupture, characterizing ACS. Thus, these biomarkers may be applicable for diagnosis of ACS. Additionally, neopterin was consistently shown to predict outcome in both stable and ACS patients and myeloperoxidase was strongly shown to predict outcome in ACS, implying for their potential role in risk stratification of these patients. CONCLUSIONS: As ACS and stable CAD are characterized by different pathophysiological processes, it appears that the biomarkers that are associated with them are differently expressed in these two clinical conditions

The regulation of body and skeletal muscle protein metabolism by hormones and amino acids.

For many decades, it has been recognized that insulin, growth hormone, glucocorticoids, insulin-like growth factor 1, thyroid hormones, and other hormones regulate body protein metabolism. It has been more recently recognized, but not understood, that humor factors present in states of acute and chronic inflammation could have a strong impact on protein turnover. Most recently, the role of amino acids, acting as signaling molecules, has become increasingly clarified. In aggregate, these factors (together with neuromuscular activity) determine the balance of body protein mass. We will review some of these data, particularly focusing on amino acids, insulin, and the growth hormone axis and their actions in muscle and how these relate to whole-body protein metabolism.

Thermal biofeedback and lower extremity blood flow in adults with diabetes: is neuropathy a limiting factor?

Thermal biofeedback may be a useful adjunctive technique for enhancing cutaneous blood flow in patients with lower-extremity vascular complications of diabetes. However, autonomic, sensory, and/or motor neuropathies may impair vasomotion and limit the ability to alter blood flow and achieve significant foot warming with thermal biofeedback. We examined nerve function associated with four common types of diabetic neuropathy (sympathetic-autonomic, vagal-autonomic, sensory, and motor), hypothesizing that both sympathetic-autonomic and sensory neuropathies would limit the acquisition of biofeedback-mediated foot warming. Twenty-four participants with diabetes mellitus (19 with type II and 5 with type I) received a nerve conduction study and neurological evaluation of the upper and lower extremities. Hand temperature, foot temperature, and electrodermal gradient at the toes were monitored across six thermal biofeedback sessions. Participants were able to significantly raise p < .01) foot temperatures across sessions, an average of 2.2 degrees F. Consistent with our hypotheses, 41% of the variance in foot warming was explained by lower-extremity sympathetic-autonomic and sensory nerve function tests. This study demonstrated that a general diabetic population, including patients with mild-to-moderate neuropathy, can increase skin perfusion with thermal biofeedback. As hypothesized, lower-extremity sympathetic-autonomic and sensory neuropathies interfered with foot warming.

Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men.

We examined the effects of GH and/or testosterone (T) administration on body composition, performance, mood, sexual function, bone turnover, and muscle-gene expression in healthy older men. Ten men [mean (SEM) age, 68 (2.5) yr; height, 171.5 (2.4) cm; and weight, 80 (3.0) kg] completed each of the following 1-month, double-blind interventions after a baseline (B) study in randomized order with an intervening 3-month washout: transdermal T patch (5.0 mg/daily); recombinant human GH (6.25 micro g/kg sc daily); and combined hormones (GHT). ANOVA with repeated measures was used to evaluate interventional effects. Integrated serum GH concentrations [mean (SEM)] were elevated comparably by GH and GHT: [B = 363 (55), GH = 1107 (120), T = 459 (131), and GHT = 1189 (46) micro g/liter.min; P < 0.0001]. Serum IGF-I concentrations also increased commensurately after GH and GHT: [B = 168 (14), GH = 285 (16), T = 192 (25), and GHT = 294 (25) micro g/liter; P < 0.0001]. GHT administration increased total estradiol: [B = 110 (20), GH = 106 (13), T = 129 (13), and GHT = 153 (17) pmol/liter; P < 0.02], and both T and GHT elevated free T: [B = 12 (2.1), GH = 11 (1.5), T = 22 (2.8), and GHT = 24 (2.5) pg/ml; P < 0.0001]. No significant changes occurred in strength, flexibility, percentage body fat, or sexual function and mood. However, fat-free mass increased under combined GHT exposure: [B = 55 (1.3), GH = 56 (1.1), T = 55 (1.5), GHT = 57 (1.7) kg; P < 0.03]. Balance improved in response to GH intervention (P < 0.05), as did 30-m walk time during T and GHT interventions [B = 6.6 (0.3), GH = 6.2 (0.7), T = 5.9 (0.3), GHT = 5.5 (0.3) sec; P = 0.04] and stair climb time for all three interventions [B = 32.2 (1.4), GH = 29.8 (1.2), T = 30.5 (1.4), and GHT = 29.9 (1.2) sec (P = 0.0034), wherein the effects of GH, T, and GHT were different from that of B]. Muscle IGF-I gene expression increased by 1.9-fold during GH administration and by 2.3-fold during GHT administration (P < 0.05, compared with B). Myostatin and androgen receptor gene expression were not affected. Serum osteocalcin increased in response to the GH and GHT interventions: [B = 4.8 (0.52), GH = 5.7 (0.54), T = 4.7 (0.33), and GHT = 5.5 (0.39); P <0.009]. There were no significant adverse events during 30 patient-months of intervention. We conclude that 1 month of GH and/or T administration improves certain measures of balance and physical performance in older men and increases muscle IGF-I gene expression.