Effect of Testosterone Supplementation With and Without a Dual 5α-Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Testosterone Production

Bhasin, Shalender; Travison, Thomas G.; Storer, Thomas W.; Lakshman, Kishore M.; Kaushik, Manas; Mazer, Norman A.; Ngyuen, Ahn Hoa; Davda, Maithili N.; Jara, Hernán; Aakil, Adam; Anderson, Stephan W.; Knapp, Philip E.; Hanka, Samson; Mohammed, Nurahmed; Daou, Pierre; Miciek, Renee; Ulloor, Jagadish; Zhang, Anqi; Brooks, Brad; Orwoll, Katie; Hede-Brierley, Leife; Eder, Richard; Elmi, Ayan; Bhasin, Geeta; Collins, Lauren F; Singh, Ravinder J.; Basaria, Shehzad

doi:10.1001/jama.2012.227

Cited by 138 publications

(89 citation statements)

References 53 publications

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“…However, this combination of TE plus finasteride failed to improve lower-extremity maximal strength over 3 yr (33). Others have reported that dutasteride (2.5 mg/day) does not limit the dosedependent TE-induced improvements in lean mass or muscle function in younger eugonadal men who were administered a GnRH agonist to suppress endogenous testosterone, although dutasteride did not prevent TE-induced prostate enlargement in this study (11). As such, questions remain regarding the safety and efficacy of concomitant testosterone and steroid 5␣-reductase inhibitors.…”

mentioning

confidence: 53%

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

Borst

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Conover

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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SC, Cannady DF 2nd, Shuster JJ. Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial. Am J Physiol Endocrinol Metab 306: E433-E442, 2014. First published December 10, 2013; doi:10.1152/ajpendo.00592.2013.-Testosterone acts directly at androgen receptors and also exerts potent actions following 5␣-reduction to dihydrotestosterone (DHT). Finasteride (type II 5␣-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 Ն60 yr with a serum testosterone concentration of Յ300 ng/dl or bioavailable testosterone Յ70 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 ϫ 2 factorial design. Over the course of 12 mo, TE increased upper and lower body muscle strength by 8 -14% (P ϭ 0.015 to Ͻ0.001), fat-free mass 4.04 kg (P ϭ 0.032), lumbar spine bone mineral density (BMD) 4.19% (P Ͻ 0.001), and total hip BMD 1.96% (P ϭ 0.024) while reducing total body fat Ϫ3.87 kg (P Ͻ 0.001) and trunk fat Ϫ1.88 kg (P ϭ 0.0051). In the first 3 mo, testosterone increased hematocrit 4.13% (P Ͻ 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 ϭ 0.0051), an effect that was completely prevented by finasteride (P ϭ 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. testosterone; hypogonadal; prostate enlargement SOME STUDIES OF TESTOSTERONE TREATMENT in older, hypogonadal men report substantial increases in muscle strength and bone mineral density (BMD) (12, 21), whereas others report only modest improvements (31, 41). Studies documenting substantial effects typically employed intramuscular (im) doses of Ն100 mg/wk im injection of long-acting testosterone esters (12, 21). In contrast, lower doses of testosterone that result from transdermal patch or gel administration produce only modest myotrophic effects (31, 32, 41). Meta-analysis data indicate that im testosterone produces a 4% increase in lumbar spine BMD, while transdermal testosterone has no effect (39). Unfortunately, higher doses of testosterone also increase the risk of adverse events, including three that have been confirmed by meta-analysis: polycythemia, a small reduction in HDL-cholesterol, and increased inci...

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confidence: 53%

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

Borst

Yarrow

Conover

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Although the effect of exercise has not been fully elucidated in humans, this study suggests that increased skeletal muscle sex steroid hormone levels may be involved in the improvement of patients with insulin resistance and hyperglycemia. The administration of 5α-reductase inhibitor with testosterone supplementation for healthy human did not affect alterations of diabetic risk factors such as fasting glucose and hemoglobin A1c (HbA1c) levels in the previous study [25]. Therefore, 5α-reductase inhibitor administration for normal health individuals might not influence diabetic risk factors.…”

Section: Discussionmentioning

confidence: 80%

The Exercise-Induced Improvement in hyperglycemia is Mediated by DHT Produced in the Skeletal Muscle of Zucker Diabetic Fatty Rats

Sato¹

2012

J Diabetes Metab

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The ability of exercise to improve hyperglycemia by enhancing glucose metabolism in the skeletal muscle of type 2 diabetic patients is well established. We reported sex steroid hormones can be locally synthesized in skeletal muscle and decrease fasting blood glucose levels in obese rats. Here, we determined whether exercise-induced production of sex steroid hormones in skeletal muscle could directly reverse hyperglycemia in the Zucker diabetic fatty rat model using osmotic mini pump.Thirty Zucker diabetic fatty rats were randomly assigned to the following groups: control, exercise, or exercise with continuous infusion of 5α-reductase inhibitor.The results indicated 6 weeks of exercise significantly reduced serum insulin and fasting glucose levels compared to control group. Dehydroepiandrosterone, 5α-dehydrotestosterone, and 5α-reductase levels were all significantly higher in skeletal muscle of the exercise group. Moreover, exercise increased glucose transporter-4 translocation with a concomitant upregulation of phosphorylated phosphoinositide 3-kinase, protein kinase B and C-ζ/λ. Furthermore, significant correlations were observed between fasting glucose and muscular DHT levels. Interestingly, the observed exercise-induced improvements in serum insulin and fasting glucose levels were all suppressed by administration of 5α-reductase inhibitor.These results indicated the exercise-induced improvements in glucose metabolism signaling and glucose levels may be directly attributed to the increased levels of sex steroid hormones within skeletal muscles.

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“…62 A recent study observed increased human erythropoiesis as a result of the acceleration of the conversion of dehydroepiandrosterone sulphate (DHEAS) to testosterone by activation of 3-beta-hydroxysteroid dehydrogenase 2 (3beta-HSD2) and/or 17beta-HSD3, resulting in high serum testosterone levels and high Hb levels. 63 The conversion of testosterone to dihydrotestosterone 64 or to oestradiol 65 is not essential for the mediation of its effects on erythropoiesis.…”

Section: Testosterone and Erythropoiesismentioning

confidence: 99%

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

Gonzales

2013

Asian J Androl

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Populations living at high altitudes (HAs), particularly in the Peruvian Andes, are characterized by a mixture of subjects with erythrocytosis (16 g dl 21 ,haemoglobin (Hb)f21 g dl 21 ) and others with excessive erythrocytosis (EE) (Hb.21 g dl 21 ). Elevated haemoglobin values (EE) are associated with chronic mountain sickness, a condition reflecting the lack of adaptation to HA. According to current data, native men from regions of HA are not adequately adapted to live at such altitudes if they have elevated serum testosterone levels. This seems to be due to an increased conversion of dehydroepiandrosterone sulphate (DHEAS) to testosterone. Men with erythrocytosis at HAs show higher serum androstenedione levels and a lower testosterone/androstenedione ratio than men with EE, suggesting reduced 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activity. Lower 17beta-HSD activity via D4-steroid production in men with erythrocytosis at HA may protect against elevated serum testosterone levels, thus preventing EE. The higher conversion of DHEAS to testosterone in subjects with EE indicates increased 17beta-HSD activity via the D5-pathway. Currently, there are various situations in which people live (human biodiversity) with low or high haemoglobin levels at HA. Antiquity could be an important adaptation component for life at HA, and testosterone seems to participate in this process.

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Effect of Testosterone Supplementation With and Without a Dual 5α-Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Testosterone Production

Cited by 138 publications

References 53 publications

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

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

The Exercise-Induced Improvement in hyperglycemia is Mediated by DHT Produced in the Skeletal Muscle of Zucker Diabetic Fatty Rats

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

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