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.

17ß-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate.

Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17ß-Hydroxyestra-4,9,11-trien-3-one (trenbolone), a potent testosterone analog, may have SARM-like actions because, unlike testosterone, trenbolone does not undergo tissue-specific 5α-reduction to form more potent androgens. We tested the hypothesis that trenbolone-enanthate (TREN) might prevent orchiectomy-induced losses in muscle and bone and visceral fat accumulation without increasing prostate mass or resulting in adverse hemoglobin elevations. Male F344 rats aged 3 mo underwent orchiectomy or remained intact and were administered graded doses of TREN, supraphysiological testosterone-enanthate, or vehicle for 29 days. In both intact and orchiectomized animals, all TREN doses and supraphysiological testosterone-enanthate augmented androgen-sensitive levator ani/bulbocavernosus muscle mass by 35-40% above shams (P ≤ 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (P < 0.05) and visceral fat accumulation (P < 0.05). The lowest doses of TREN successfully maintained prostate mass and hemoglobin concentrations at sham levels in both intact and orchiectomized animals, whereas supraphysiological testosterone-enanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively (P < 0.01). In summary, low-dose administration of the non-5α-reducible androgen TREN maintains prostate mass and hemoglobin concentrations near the level of shams while producing potent myotrophic actions in skeletal muscle and partial protection against orchiectomy-induced bone loss and visceral fat accumulation. Our findings indicate that TREN has advantages over supraphysiological testosterone and supports the need for future preclinical studies examining the viability of TREN as an option for androgen replacement therapy.

Comparison of standard versus reconstruction proximal interlocking screw configurations for antegrade intramedullary nail fixation of femoral shaft fractures.

BACKGROUND: The standard proximal interlocking screw (SS) configuration for antegrade intramedullary nail (IMN) fixation of femoral shaft fractures is lateral to medial or from the greater to less trochanter. Some authors argue for the routine use of the reconstruction screw (RS) configuration (oriented up the femoral neck) instead to prevent femoral neck complications. The purpose of this study was to compare a matched cohort of patients receiving these screw configurations and subsequent complications. METHODS: A retrospective review of two urban level-one trauma centers identified adults with isolated femoral shaft fractures undergoing antegrade IMN. Patients with RS and SS configurations were matched 1:1 by age, sex, fracture location, and AO classification in order to compare complications. RESULTS: 130 patients with femoral shaft fractures were identified. SS and RS configurations were used in 83 (64%) and 47 (36%) patients. 30 patients from each group were able to be matched for analysis. The RS and SS group did not differ in age, fracture location, AO classification, operative time, or number of distal interlocking screws. The RS group had fewer open fractures and were more likely to have two proximal screws. There were 7 complications, including 5 nonunions and 2 delayed unions, with no detectable difference between RS vs. SS groups (10% vs 13%, Proportional difference -3%, 95% confidence interval (CI) -30 to 14%, p = 0.1). There were no femoral neck complications in the entire cohort of 130 patients. On multivariate analysis none of the variables analyzed were independently associated with the development of complications. CONCLUSIONS: In this matched cohort of patients with femoral shaft fractures undergoing antegrade IMN fixation, RS and SS configurations were associated with a similar number of complications and no femoral neck complications. The SS configuration remains the standard for antegrade IMN femoral shaft fixation. LEVEL OF EVIDENCE: Level III, Retrospective cohort study.

High Prevalence of Low Serum Biologically Active Testosterone in Older Male Veterans.

OBJECTIVES: Assess the prevalence of hypogonadism in older male Veterans by comparing direct measurements of total testosterone (T) and bioavailable testosterone (BioT) versus indirect BioT values derived from existing and newly developed regression analyses. DESIGN: Cohort study. SETTING: Malcom Randall VA Medical Center, Gainesville, FL. PARTICIPANTS: Community-dwelling male Veterans aged 60 and older (n = 203). MEASUREMENTS: Total T, BioT, albumin, sex hormone-binding globulin (SHBG), and body mass index were evaluated. Blood values were assessed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and clinical or commercially available immunoassays to compare accuracy among assessment techniques. Existing and newly developed multiple regression analyses were evaluated to assess accuracy in predicting BioT. RESULTS: Total T was 13.80 ± 6.25 nmol/L (398 ± 180 ng/dL) and was low (≤10.4 nmol/L or ≤300 ng/dL) in 34% of participants. SHBG was 58 ± 35 nmol/L and elevated (≥62 nmol/L) in 36% of participants. BioT was 1.94 ± 0.97 nmol/L (56 ± 28 ng/dL), with 72% of participants below the clinical cutoff (≤2.43 nmol/L or ≤70 ng/dL). Albumin was within the normal clinical range. Total T and BioT measured via immunoassay and LC-MS/MS were moderately to highly correlated, with no differences between assessment methods. Several existing predictive equations overestimated BioT by 74% to 166% within our cohort (P < .001). A newly developed regression model that included total T, SHBG, albumin, and age more accurately predicted BioT, with values correlated (r = 0.508, P < .001) and comparable to LC-MS/MS. CONCLUSION: In our cohort, the prevalence of low total T was higher and low BioT was markedly higher than reported in the general age-matched population, indicating a greater incidence of hypogonadism in older male Veterans. In addition, existing empiric formulae, derived from other populations produced BioT values that were considerably greater than those directly measured, whereas our newly developed regression analysis provides improved predictive capabilities for older male Veterans.

Transcriptional regulation of myotrophic actions by testosterone and trenbolone on androgen-responsive muscle.

Androgens regulate body composition and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. Recently, we demonstrated that trenbolone (a potent synthetic testosterone analogue that is not a substrate for 5-alpha reductase or for aromatase) induces myotrophic effects in skeletal muscle without causing prostate enlargement, which is in contrast to the known prostate enlarging effects of testosterone. These previous results suggest that the 5α-reduction of testosterone is not required for myotrophic action. We now report differential gene expression in response to testosterone versus trenbolone in the highly androgen-sensitive levator ani/bulbocavernosus (LABC) muscle complex of the adult rat after 6weeks of orchiectomy (ORX), using real time PCR. The ORX-induced expression of atrogenes (Muscle RING-finger protein-1 [MuRF1] and atrogin-1) was suppressed by both androgens, with trenbolone producing a greater suppression of atrogin-1 mRNA compared to testosterone. Both androgens elevated expression of anabolic genes (insulin-like growth factor-1 and mechano-growth factor) after ORX. ORX-induced increases in expression of glucocorticoid receptor (GR) mRNA were suppressed by trenbolone treatment, but not testosterone. In ORX animals, testosterone promoted WNT1-inducible-signaling pathway protein 2 (WISP-2) gene expression while trenbolone did not. Testosterone and trenbolone equally enhanced muscle regeneration as shown by increases in LABC mass and in protein expression of embryonic myosin by western blotting. In addition, testosterone increased WISP-2 protein levels. Together, these findings identify specific mechanisms by which testosterone and trenbolone may regulate skeletal muscle maintenance and growth.