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...

Yarrow JF, Conover CF, McCoy SC, Lipinska JA, Santillana CA, Hance JM, Cannady DF, VanPelt TD, Sanchez J, Conrad BP, Pingel JE, Wronski TJ, Borst SE. 17␤-Hydroxyestra-4,9,11-trien-3-one (trenbolone) exhibits tissue selective anabolic activity: effects on muscle, bone, adiposity, hemoglobin, and prostate. Am J Physiol Endocrinol Metab 300: E650 -E660, 2011; First published January 25, 2011; doi:10.1152/ajpendo.00440.2010.-Selective androgen receptor modulators (SARMs) now under development can protect against muscle and bone loss without causing prostate growth or polycythemia. 17␤-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 5␣-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 Յ 0.001) and produced a dose-dependent partial protection against orchiectomy-induced total and trabecular bone mineral density losses (P Ͻ 0.05) and visceral fat accumulation (P Ͻ 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 testosteroneenanthate and high-dose TREN elevated prostate mass by 84 and 68%, respectively (P Ͻ 0.01). In summary, low-dose administration of the non-5␣-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.

Bone may contain an intraskeletal reservoir of sex steroids that is capable of producing biological effects. The purposes of these experiments were to 1) establish and validate methods to extract and measure intraskeletal sex hormones, 2) compare serum and intraskeletal sex hormone abundance, and 3) determine the impact of testosterone-enanthate administration and orchiectomy on intraskeletal sex hormone concentrations. Tibiae from male F344 rats were crushed, suspended in an aqueous buffer, disrupted mechanically and sonically, extracted with organic solvents, dried, and reconstituted in assay buffer appropriate for measurement of testosterone, dihydrotestosterone, and estradiol by immunoassay. Prior to extraction, bone homogenate was spiked with [³H]testosterone, [³H]dihydrotestosterone, or [³H]estradiol, and >80% of each ³H-labeled sex hormone was recovered. Extracted bone samples were also assayed with and without known amounts of unlabeled sex hormones, and >97% of the expected hormone concentrations were measured. Administration of testosterone-enanthate increased intraskeletal testosterone 11-fold and intraskeletal dihydrotestosterone by 82% without altering intraskeletal estradiol (P < 0.01). Conversely, orchiectomy did not alter intraskeletal testosterone or estradiol but increased intraskeletal dihydrotestosterone by 39% (P < 0.05). In intact rats, intraskeletal testosterone and dihydrotestosterone were directionally higher than in serum, whereas intraskeletal estradiol was directionally lower than serum. Serum androgens were positively correlated with intraskeletal androgens (r = 0.74-0.96, P < 0.001); however, neither serum nor intraskeletal androgens nor serum estradiol were correlated with intraskeletal estradiol. We report the validation of a novel method for measuring intraskeletal sex hormones. Our findings demonstrate that the intraskeletal sex steroid reservoirs are modifiable and only partially influenced by circulating sex hormones.

BACKGROUND Over the past 30 years, the demographics, clinical characteristics, and management of trauma patients have changed dramatically. During this same period, the organ donor population has also changed. The interactions between these two demographic shifts have not been examined in a systematic way. We hypothesize that trauma victims continue to be an important source of organs. We set out to systematically examine traumatic donors in an attempt to identify opportunities to increase organ recovery and quality. METHODS In this retrospective analysis, we compared trauma donors (TDs) and non-TDs (NTDs) in the Scientific Registry of Transplant Recipients standard analysis files, a clinical data set collected by the Organ Procurement Transplant Network on all solid organ transplant candidates, donors, and recipients in the United States since 1987. RESULTS Scientific Registry of Transplant Recipients contained data on 191,802 deceased donors. The percentage of TDs decreased from 55.3% in 1987 to 35.8% in 2016 (p < 0.001) primarily due to a steady increase in NTDs. Trauma donors are younger and have fewer comorbidities while the percentage of donors who were public health service high risk or who underwent donation after cardiac death were clinically similar. The TDs produce more organs/donor (3.5 vs. 2.4, p < 0.001), are more likely to yield an extrarenal organ, and exhibit lower (better) Kidney Donor Risk Index scores, a predictor of graft longevity. These better outcomes are maintained after stratifying by age. CONCLUSION Over the past 30 years, the number of NTDs has increased much more than the number of TDs. However, TDs remain a critically important organ donor source, yielding more organs per donor, better quality kidneys, and a higher likelihood of extrarenal organs. Potential causes, such as improved resuscitation protocols, should be examined in the future. LEVEL OF EVIDENCE Retrospective review, level III.

Poorer than expected, living donor liver transplant outcomes are observed after recipient graft artery thrombosis. At grafting, the risk for later thrombosis is high if a dissected hepatic artery is used for standard reconstruction. Surgeon diagnosis of dissection requires nonstandard management with alternative technique in addition to microvascular expertise. Intimal flap repair with standard reconstruction is contingent on basis of a redo anastomosis. It is a suboptimal choice for living donor transplantation. Achieving goal graft arterial perfusion at first revascularization is crucial for superior outcomes. Managing dissection at grafting with nonstandard left gastric artery reconstruction is unreported. Our experience is limited, but this is our preferred alternative technique to standard hepatic artery reconstruction complicated by dissection. Here, we describe our two-case experience with left gastric arterialized grafts for management of dissection. Our living donor graft recipients with alternatively arterialized grafts are now 6- and 2-years posttransplant.