Karen L. Herbst

Testosterone action on skeletal muscle.

Purpose of reviewTo highlight recent data demonstrating direct anabolic effects of androgens on the mammalian skeletal muscle and review the mechanisms by which testosterone regulates body composition. Recent findingsTestosterone increases lean body mass and decreases fat mass in young men; the magnitude of the changes induced by testosterone in lean and fat mass are correlated with testosterone dose and the prevalent testosterone concentrations. Older men are as responsive to the anabolic effects of testosterone on the muscle as young men, but have increased frequency of adverse events with higher testosterone doses. This reciprocal change in lean and fat mass induced by androgens is best explained by the hypothesis that androgens promote the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibit adipogenesis through an androgen receptor mediated pathway. Resident muscle satellite cells increase in number with testosterone administration forming myoblasts leading to greater numbers of myonuclei in larger myofibers. Testosterone administration is associated with increased size of motor neurons. The roles of 5-α reduction and aromatization of testosterone into dihydrotestosterone and estradiol, respectively, in mediating testosterone effects on body composition are poorly understood. SummaryTestosterone induces skeletal muscle hypertrophy by multiple mechanisms, including its effects in modulating the commitment of pluripotent mesenchymal cells. These changes in skeletal muscle lead to improved muscle strength and leg power; however, further studies are needed to determine the effects of testosterone on physical function and health-related outcomes in sarcopenia associated with aging and chronic illness.

Desogestrel plus testosterone effectively suppresses spermatogenesis but also causes modest weight gain and high-density lipoprotein suppression

OBJECTIVE To test the hypothesis that oral desogestrel (DSG) plus testosterone would uniformly and rapidly suppress sperm concentrations in young men as effectively as levonorgestrel (LNG) plus testosterone and cause less high-density lipoprotein (HDL) suppression and weight gain. DESIGN Single-blind, randomized trial. SETTING VA Puget Sound and University of Washington, Seattle, Washington. PATIENT(S) Twenty-four healthy young men, aged 20-49. INTERVENTION(S) Subjects were randomized to three groups of men who were administered 6 months of therapy with oral DSG plus im testosterone enanthate: 150 microg of DSG plus 50 mg of testosterone (DSG 150-T 50), 150 microg of DSG plus 100 mg of testosterone (DSG 150-T 100) or 300 microg of DSG plus 100 mg of testosterone (DSG 300-T 100). We compared these three groups to two groups of historical controls of 100 mg of im testosterone alone or 150 microg of oral LNG plus 100 mg of im testosterone (LNG 125-T 100 group) enrolled in similar studies. MAIN OUTCOME MEASURE(S) Suppression of sperm counts to severe oligoazoospermia (sperm counts <1 x 10(6)/mL) and azoospermia, weight gain, and serum high-density cholesterol (HDL) suppression. RESULT(S) Azoospermia was achieved in all eight men receiving DSG 150-T 100 and seven of the eight men in the DSG 300-T 100 group. DSG 150 or 300 plus T 100 suppressed spermatogenesis as effectively as LNG 125-T 100 and more effectively than DSG 50-T 100 or testosterone alone. All groups tended to gain weight compared with their baseline, but the weight gain was greatest (and statistically significant) in the DSG 150-T 100, DSG 300-T 100, and LNG 125-T 100 groups. Serum HDL levels were modestly suppressed in all groups, and this effect was greatest in the DSG 300-T 100 and LNG 125-T 100 groups. CONCLUSION(S) The combination of DSG plus testosterone is a very effective regimen for suppression of spermatogenesis and has acceptably low side effects.

Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr null mice

OBJECTIVE Insulin-resistant states, such as obesity and type 2 diabetes, contribute substantially to accelerated atherogenesis. Null mutations of myostatin (Mstn) are associated with increased muscle mass and decreased fat mass. In this study, we determined whether Mstn disruption could prevent the development of insulin resistance, proatherogenic dyslipidemia, and atherogenesis. RESEARCH DESIGN AND METHODS C57BL/6 Ldlr−/− mice were cross-bred with C57BL/6 Mstn−/− mice for >10 generations to generate Mstn−/−/Ldlr−/− double-knockout mice. The effects of high-fat/high-cholesterol diet on body composition, plasma lipids, systemic and tissue-specific insulin sensitivity, hepatic steatosis, as well as aortic atheromatous lesion were characterized in Mstn−/−/Ldlr−/− mice in comparison with control Mstn+/+/Ldlr−/− mice. RESULTS Compared with Mstn+/+/Ldlr−/− controls, Mstn−/−/ Ldlr−/− mice were resistant to diet-induced obesity, and had greatly improved insulin sensitivity, as indicated by 42% higher glucose infusion rate and 90% greater muscle [3H]-2-deoxyglucose uptake during hyperinsulinemic-euglycemic clamp. Mstn−/−/Ldlr−/− mice were protected against diet-induced hepatic steatosis and had 56% higher rate of hepatic fatty acid β-oxidation than controls. Mstn−/−/Ldlr−/− mice also had 36% lower VLDL secretion rate and were protected against diet-induced dyslipidemia, as indicated by 30–60% lower VLDL and LDL cholesterol, free fatty acids, and triglycerides. Magnetic resonance angiography and en face analyses demonstrated 41% reduction in aortic atheromatous lesions in Ldlr−/− mice with Mstn deletion. CONCLUSIONS Inactivation of Mstn protects against the development of insulin resistance, proatherogenic dyslipidemia, and aortic atherogenesis in Ldlr−/− mice. Myostatin may be a useful target for drug development for prevention and treatment of obesity and its associated type 2 diabetes and atherosclerosis.

Rare adipose disorders (RADs) masquerading as obesity

Rare adipose disorders (RADs) including multiple symmetric lipomatosis (MSL), lipedema and Dercums disease (DD) may be misdiagnosed as obesity. Lifestyle changes, such as reduced caloric intake and increased physical activity are standard care for obesity. Although lifestyle changes and bariatric surgery work effectively for the obesity component of RADs, these treatments do not routinely reduce the abnormal subcutaneous adipose tissue (SAT) of RADs. RAD SAT likely results from the growth of a brown stem cell population with secondary lymphatic dysfunction in MSL, or by primary vascular and lymphatic dysfunction in lipedema and DD. People with RADs do not lose SAT from caloric limitation and increased energy expenditure alone. In order to improve recognition of RADs apart from obesity, the diagnostic criteria, histology and pathophysiology of RADs are presented and contrasted to familial partial lipodystrophies, acquired partial lipodystrophies and obesity with which they may be confused. Treatment recommendations focus on evidence-based data and include lymphatic decongestive therapy, medications and supplements that support loss of RAD SAT. Associated RAD conditions including depression, anxiety and pain will improve as healthcare providers learn to identify and adopt alternative treatment regimens for the abnormal SAT component of RADs. Effective dietary and exercise regimens are needed in RAD populations to improve quality of life and construct advanced treatment regimens for future generations.

Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIV-associated weight loss

Testosterone increases fat-free mass (FFM) in men infected with human immunodeficiency virus (HIV), but its effects on muscle performance, physical function, mood, and quality of life are poorly understood. Sixty-one HIV-infected men with weight loss were randomized to receive weekly intramuscular injections of 300 mg of testosterone enanthate or placebo for 16 wk. The primary outcome of interest was physical function (walking speed, stair-climbing power, and load-carrying ability). Secondary outcome measures included body weight and composition, muscle performance, sexual function, mood, and quality of life. Serum nadir free and total testosterone levels increased (+188.0 +/- 29.6 and +720 +/- 86 ng/dl) in the testosterone, but not placebo, group. Testosterone administration was associated with increased FFM (2.8 +/- 0.5 kg), which was significantly greater than in the placebo group (P < 0.0001). Leg press strength increased significantly in testosterone-treated (P = 0.027), but not placebo-treated, men; the difference between groups was not significant. Other measures of muscle performance and physical function did not change significantly in either group. Men receiving testosterone demonstrated significantly greater improvements in mental health and quality-of-life scores than those receiving placebo and improvements in fatigue/energy and mood scores that were not significantly different from those receiving placebo. Sexual function scores did not change in either group. In HIV-infected men with weight loss, a supraphysiological dose of testosterone significantly increased FFM but did not improve self-reported or performance-based measures of physical function. Improvements in mood, fatigue, and quality-of-life measures in the testosterone group, although clinically important, need further confirmation.

The 2011–2016 Transdisciplinary Research on Energetics and Cancer (TREC) Initiative: Rationale and Design

PurposeRecognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.MethodsThe National Cancer Institute developed an innovative concept to establish a center grant mechanism in nutrition, energetics, and physical activity, referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011–2016 TREC Collaborative Network and the 15 research projects being conducted at the centers.ResultsFour academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes three animal studies, three cohort studies, four randomized clinical trials, one cross-sectional study, and two modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.ConclusionThe NIH Science of Team Science group will evaluate the value added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk of cancer as well as cancer survivors.

Testosterone with Dutasteride, but Not Anastrazole, Improves Insulin Sensitivity in Young Obese Men: A Randomized Controlled Trial

INTRODUCTION Testosterone (T) administration to men increases T, estradiol (E2), dihydrotestosterone (DHT), and fat-free mass (FFM), and decreases fat mass (FM) but does not consistently improve insulin sensitivity (IS). AIM The aim of this study was to examine the effects of T administration in obese, nondiabetic men on body composition and IS, and to determine if inhibition (i) of metabolism of T to E2 with anastrazole or to DHT with dutasteride alters these effects. METHODS This was a 98-day randomized, double-blind, parallel group, placebo-controlled trial of 57 men, 24-51 year, free T in the lower 25% of normal range (<0.33 nmol/L), body mass index ≥ 30.0 kg/m(2). Subjects were randomized to one of four groups: (i) placebo: gel, pills, and injection; (ii) T/DHT/iE2: T gel, anastrazole, and acyline (gonadotropin releasing-hormone antagonist to suppress endogenous T); (iii) T/iDHT/E2: T gel, dutasteride, and acyline; (iv) T/DHT/E2: T gel, placebo pills, and acyline. MAIN OUTCOME MEASURES Main outcome measures are insulin sensitivity as percent change (%Δ) in glucose disposal rates (GDR) from a two-step euglycemic clamp (GDR1 and 2), and %FM and %FFM by dual X-ray absorptiometry scan. RESULTS Insulin Sensitivity: %Δ GDR1 differed across groups (P = 0.02, anova) and was significantly higher in the dutasteride (T/iDHT/E2) compared with the placebo and T gel (T/DHT/E2) groups. %ΔGDR2 was higher in the dutasteride (T/iDHT/E2) compared with the anastrazole (T/DHT/iE2) group. Body Composition: T gel alone (T/DHT/E2) or with dutasteride (T/iDHT/E2) significantly increased %FFM (P < 0.05) and decreased %FM (P < 0.05). There was no change in %FFM or %FM after placebo or anastrazole (T/DHT/iE2). CONCLUSIONS The combination of T plus dutasteride improved body composition and IS while T alone improved body composition but not IS, suggesting that when T is administered to men, reduction to DHT attenuates the beneficial effects of aromatization to E2 on IS but not body composition.

An abnormal lymphatic phenotype is associated with subcutaneous adipose tissue deposits in Dercum’s disease

Investigational, near‐infrared fluorescence (NIRF) lymphatic imaging was used to assess lymphatic architecture and contractile function in participants diagnosed with Dercums disease, a rare, poorly understood disorder characterized by painful lipomas in subcutaneous adipose tissues.

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

BackgroundObesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs), for 6 months in rodent models restores insulin receptor function and insulin sensitivity.MethodsThis 12-week double-blind, randomized, placebo (PL)-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI), doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2). The study included non-DM2 controls (n = 15), and DM2 subjects randomized to PL (n = 13) or doxycycline 100 mg twice daily (MMPI; n = 11). All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment.ResultsThere was a significant decrease in inflammatory markers C-reactive protein (P < 0.05) and myeloperoxidase (P = 0.01) in the MMPI but not PL group. The MMPI also significantly increased skeletal muscle activated/total insulin signaling mediators: 3’phosphoinositide kinase-1 (PDK1) (p < 0.03), protein kinase B (PKB/Akt) (p < 0.004), and glycogen synthase kinase 3ß (GSK3ß) (p < 0.03).ConclusionsThis study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes.Trial RegistrationClinicaltrials.gov NCT01375491

Lipomatosis-associated inflammation and excess collagen may contribute to lower relative resting energy expenditure in women with adiposis dolorosa.

Background:Adiposis dolorosa (AD) is a syndrome of obese and non-obese individuals whose hallmark is lipomatosis: unencapsulated painful fatty masses in subcutaneous fat. Lipomatosis may contain excess collagen and multi-nucleated giant (MNG) cells. Case reports suggest metabolic defects in AD.Objectives:(1) To determine whether women with AD have altered relative resting energy expenditure (REE per total body mass) compared with controls; and (2) to quantitate lipomatosis-associated collagen, MNGs and tissue and blood cytokines that may influence REE.Methods:A total of 10 women with AD were compared with age, body mass index, fat and weight-matched control women. Adipose tissue was obtained from five women with AD and five controls and evaluated for collagen and macrophages/MNGs. Fat mass and fat-free mass were identified by dual X-ray absorptiometry. REE was by determined indirect calorimetry and related to mass. Adipokines and cytokines were evaluated in blood and tissue.Results:Relative REE (REE per total body mass) was lower in women with AD compared with controls (P=0.007). Only lipomatosis (group) and total body mass were significant predictors of REE in forward stepwise regression (P<0.0001). Adipose interleukin (IL)-6 levels were elevated (P=0.03) and connective tissue was increased fourfold in lipomatosis compared with control tissue (P <0.0001). There was no difference in adipose tissue macrophages between groups; 30% of women with AD had MNG cells. Anti-inflammatory IL-13 levels were elevated (P=0.03), and cytokines important in the recruitment of monocytes, Fraktalkine (P=0.04) and macrophage inflammatory protein-1β (P=0.009), were significantly lower in the blood of women with AD compared with controls.Conclusions:The lower relative REE in women with AD compared with controls was associated with increased connective (non-metabolic) tissue in the lipomatosis, and inflammation, although underlying metabolic defects may be important as well. Understanding the pathophysiology and metabolism of lipomatosis in AD may contribute to a better understanding of metabolism in non-lipomatosis obesity.