Stephen E. Borst

Tissue selectivity and potential clinical applications of trenbolone (17β-hydroxyestra-4,9,11-trien-3-one): A potent anabolic steroid with reduced androgenic and estrogenic activity

Recently, the development of selective androgen receptor modulators (SARMs) has been suggested as a means of combating the deleterious catabolic effects of hypogonadism, especially in skeletal muscle and bone, without inducing the undesirable androgenic effects (e.g., prostate enlargement and polycythemia) associated with testosterone administration. 17beta-Hydroxyestra-4,9,11-trien-3-one (trenbolone; 17beta-TBOH), a synthetic analog of testosterone, may be capable of inducing SARM-like effects as it binds to androgen receptors (ARs) with approximately three times the affinity of testosterone and has been shown to augment skeletal muscle mass and bone growth and reduce adiposity in a variety of mammalian species. In addition to its direct actions through ARs, 17beta-TBOH may also exert anabolic effects by altering the action of endogenous growth factors or inhibiting the action of glucocorticoids. Compared to testosterone, 17beta-TBOH appears to induce less growth in androgen-sensitive organs which highly express the 5alpha reductase enzyme (e.g., prostate tissue and accessory sex organs). The reduced androgenic effects result from the fact that 17beta-TBOH is metabolized to less potent androgens in vivo; while testosterone undergoes tissue-specific biotransformation to more potent steroids, dihydrotestosterone and 17beta-estradiol, via the 5alpha-reductase and aromatase enzymes, respectively. Thus the metabolism of 17beta-TBOH provides a basis for future research evaluating its safety and efficacy as a means of combating muscle and bone wasting conditions, obesity, and/or androgen insensitivity syndromes in humans, similar to that of other SARMs which are currently in development.

The role of TNF-α in insulin resistance

Insulin resistance is an important component of the metabolic syndrome associated with obesity. Early-stage insulin-resistance and related mild glucose intolerance may be compensated by increased insulin secretion. When combined with impaired insulin secretion, insulin resistance plays an important role in type 2 diabetes (1). Insulin-resistance is also associated with a variety of pathological conditions, including trauma, infection, and cancer. Obesity and type 2 diabetes are the most common metabolic diseases in Western societies, together affecting as much as half of the adult population (2). The prevalence of these conditions is not only high, but continues to increase. We have only recently come to appreciate the role of fat, especially visceral fat, as an endocrine organ. Visceral fat is the source of a number of substances which might play a role in the development of insulin resistance. Among the latter are tumor necrosis factor-α (TNF-α), adiponectin, IL-6, resistin and free fatty acids. This review will discuss the regulation of insulin responses by TNF-α and evidence supporting the hypothesis that over expression of TNF-α plays a role in the pathophysiology of insulin resistance.Insulin resistance is an important component of the metabolic syndrome associated with obesity. Early-stage insulin-resistance and related mild glucose intolerance may be compensated by increased insulin secretion. When combined with impaired insulin secretion, insulin resistance plays an important role in type 2 diabetes (1). Insulin-resistance is also associated with a variety of pathological conditions, including trauma, infection, and cancer. Obesity and type 2 diabetes are the most common metabolic diseases in Western societies, together affecting as much as half of the adult population (2). The prevalence of these conditions is not only high, but continues to increase. We have only recently come to appreciate the role of fat, especially visceral fat, as an endocrine organ. Visceral fat is the source of a number of substances which might play a role in the development of insulin resistance. Among the latter are tumor necrosis factor-α (TNF-α), adiponectin, IL-6, resistin and free fatty acids. This review will discuss the regulation of insulin responses by TNF-α and evidence supporting the hypothesis that over expression of TNF-α plays a role in the pathophysiology of insulin resistance.

Effects of resistance training on insulin-like growth factor-I and IGF binding proteins.

PURPOSE Our goal was to determine the effects resistance training on circulating IGF-I and on two of its major binding proteins, IGFBP-1 and IGFBP-3. Additional goals were to compare the time course of hormonal changes with the time course of strength changes and to determine the effect of training volume on the extent of hormonal changes. METHODS Thirty-one men and women (mean age = 37 +/- 7 yr) completed a 25-wk, 3 d x wk(-1) program in which they performed single-set resistance training (1-SET, N = 11), multiple-set resistance training (3-SET, N = 11), or no exercise (Control, N = 9). Before training, and after 13 and 25 wk of training, blood hormones were analyzed and strength was assessed as the sum of one-repetition maximum (1-RM) for leg extension and chest press exercises. RESULTS During the first 13 wk of resistance training, circulating IGF-I increased by approximately 20% in both the 1-SET and 3-SET groups (P = 0.041). No further increases occurred between 13 and 25 wk. In the 3-SET group, IGFBP-3 decreased 20% between 13 and 25 wk (P = 0.008). Training did not alter IGFBP-1. Increases in 1-RM strength occurred mainly during the first 13 wk of training and were significantly higher with 3-SET training compared to 1-SET. CONCLUSIONS These findings indicate that increased circulating IGF-I may, at least in part, mediate increases in strength that result from resistance training.

Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF)

Brain derived neurotrophic factor (BDNF) is postulated to be an important mediator of exercise-induced neuroprotection. We tested the hypothesis that resistance exercise elevates circulating BDNF. Twenty healthy untrained college-aged males underwent a 5-week traditional or eccentric-enhanced progressive resistance training intervention. Blood was acquired at rest and 1, 30, and 60min following a standardized resistance exercise testing bout performed at baseline and at the completion of the intervention. Serum BDNF responses did not differ between the two groups at any time point during baseline or post-intervention testing; thus, all values were combined into a single cohort for further analysis. Resting BDNF was not altered by the exercise training intervention [23,304+/-1835pg/ml (baseline) vs. 19,433+/-1992pg/ml (post-intervention)]. Following the baseline resistance exercise bout, serum BDNF increased 32% (p<0.05) and was gradually reduced to 41% below resting levels at 60min into recovery (p<0.01). During post-intervention testing, serum BDNF increased 77% in response to the standardized resistance exercise bout (p<0.01) and returned to resting values within 30min. Ultimately, the change in serum BDNF from rest to immediately post-exercise was 98% greater at post-intervention than at baseline (p<0.05). Our study is the first to demonstrate that resistance exercise induces a robust, yet transient, elevation of circulating BDNF and that progressive resistance training augments this response; perhaps demonstrating one mechanism through which exercise influences brain health.

Modulation of GH/IGF-1 axis: Potential strategies to counteract sarcopenia in older adults

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.

Myogenic and proteolytic mRNA expression following blood flow restricted exercise.

Aim:  Resistance exercise performed at low loads (20–30% of maximal strength) with blood flow restriction (BFR) acutely increases protein synthesis and induces hypertrophy when performed chronically. We investigated myogenic and proteolytic mRNA expression 8 h following an acute bout of knee extension exercise.

Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis

BackgroundPotential cardiovascular (CV) risks of testosterone replacement therapy (TRT) are currently a topic of intense interest. However, no studies have addressed CV risk as a function of the route of administration of TRT.MethodsTwo meta-analyses were conducted, one of CV adverse events (AEs) in 35 randomized controlled trials (RCTs) of TRT lasting 12 weeks or more, and one of 32 studies reporting the effect of TRT on serum testosterone and dihydrotestosterone (DHT).ResultsCV risks of TRT: Of 2,313 studies identified, 35 were eligible and included 3,703 mostly older men who experienced 218 CV-related AEs. No significant risk for CV AEs was present when all TRT administration routes were grouped (relative risk (RR) = 1.28, 95% confidence interval (CI): 0.76 to 2.13, P = 0.34). When analyzed separately, oral TRT produced significant CV risk (RR = 2.20, 95% CI: 1.45 to 3.55, P = 0.015), while neither intramuscular (RR = 0.66, 95% CI: 0.28 to 1.56, P = 0.32) nor transdermal (gel or patch) TRT (RR = 1.27, 95% CI: 0.62 to 2.62, P = 0.48) significantly altered CV risk. Serum testosterone/DHT following TRT: Of 419 studies identified, 32 were eligible which included 1,152 men receiving TRT. No significant difference in the elevation of serum testosterone was present between intramuscular or transdermal TRT. However, transdermal TRT elevated serum DHT (5.46-fold, 95% CI: 4.51 to 6.60) to a greater magnitude than intramuscular TRT (2.20-fold, 95% CI: 1.74 to 2.77).ConclusionsOral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies.

Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial

Testosterone acts directly at androgen receptors and also exerts potent actions following 5α-reduction to dihydrotestosterone (DHT). Finasteride (type II 5α-reductase inhibitor) lowers DHT and is used to treat benign prostatic hyperplasia. However, it is unknown whether elevated DHT mediates either beneficial musculoskeletal effects or prostate enlargement resulting from higher-than-replacement doses of testosterone. Our purpose was to determine whether administration of testosterone plus finasteride to older hypogonadal men could produce musculoskeletal benefits without prostate enlargement. Sixty men aged ≥60 yr with a serum testosterone concentration of ≤300 ng/dl or bioavailable testosterone ≤70 ng/dl received 52 wk of treatment with testosterone enanthate (TE; 125 mg/wk) vs. vehicle, paired with finasteride (5 mg/day) vs. placebo using a 2 × 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8-14% (P = 0.015 to <0.001), fat-free mass 4.04 kg (P = 0.032), lumbar spine bone mineral density (BMD) 4.19% (P < 0.001), and total hip BMD 1.96% (P = 0.024) while reducing total body fat -3.87 kg (P < 0.001) and trunk fat -1.88 kg (P = 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P < 0.001). Coadministration of finasteride did not alter any of these effects. Over 12 mo, testosterone also increased prostate volume 11.4 cm(3) (P = 0.0051), an effect that was completely prevented by finasteride (P = 0.0027). We conclude that a higher-than-replacement TE combined with finasteride significantly increases muscle strength and BMD and reduces body fat without causing prostate enlargement. These results demonstrate that elevated DHT mediates testosterone-induced prostate enlargement but is not required for benefits in musculoskeletal or adipose tissue.

Thermoregulation with Age: Role of Thermogenesis and Uncoupling Protein Expression in Brown Adipose Tissue

Abstract To investigate whether attenuation of thermogenesis in interscapular brown adipose tissue (IBAT) may account for the loss of thermoregulation with age, we examined two indices of thermogenesis after two types of cold exposure: one in which the senescent rats maintained homeothermy and the other in which the senescent rats became hypothermic. To this end, we assessed body temperature, guanosine 5′-diphosphate (GDP) binding to the IBAT mitochondrial uncoupling protein (UCP) and the induction of UCP mRNA after both 1-hr and 48-hr mild cold exposures at 8°C and after a more severe, 1-hr cold exposure at 4°C in 3- and 24-month-old F-344 rats. Thermoneutrality was determined to occur at an ambient temperature of 26°C in rats of both ages. In the 1-hr mild cold-exposed rats, there was no significant increase in GDP binding to IBAT UCP. However, after 48 hr of mild cold exposure, there was a 3-fold increase in GDP binding and a 5-fold increase in the expression of UCP mRNA despite no hypothermia in either the young or old rats. During the more severe cold exposure, the senescent rats, but not the young rats, became hypothermic. GDP binding to UCP increased 75% following cold exposure and, surprisingly was the same in young and old rats. UCP transcripts did not increase during the 1-hr cold exposure. These data, coupled with our previous findings of diminished β3-agonist-stimulated IBAT thermogenesis, suggest that (i) IBAT thermogenesis, at least in the senescent rats, may be mediated by other than β3-adrenergic receptors, and (ii) that altered heat dissipation or impaired thermogenesis at some site other than interscapular BAT is responsible for the observed hypothermia. [P.S.E.B.M. 1994, Vol 205]

Effects of Resistance Training on Insulin‐Like Growth Factor and its Binding Proteins in Men and Women Aged 60 to 85

OBJECTIVES: We have reported that resistance training (RT) elevates insulin‐like growth factor (IGF‐I) in healthy young adults. Our goals were to determine whether RT produces a similar effect in the healthy older persons and to determine the effects of low‐ versus high‐intensity RT on hormonal status.