No abstract

Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose-response trial. Participants were young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose-dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm (0.394, 0.850) for psoas; 1.789 cm (1.317, 2.261) for paraspinal muscles, 2.530 cm (1.627, 3.434) for total abdominal muscles, 0.455 cm (0.233, 0.678) for obturator internus, and 0.082 cm (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on-treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction.

Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified neuroblastomas cells are treated with all-trans retinoic acid (ATRA), histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1, HIC1 and SOX4 expression. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, resulting in downregulation of MYCN expression, while upregulating a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.

Context Animal data shows that testosterone administration increases the volume of some parenchymal organs. However, the effects of exogenous testosterone on solid abdominal organs in humans remain unknown. Objective To evaluate the effects of testosterone administration on the volume of liver, spleen and kidneys in a dose-response trial. Participants Young healthy men aged 18 to 50 years participating in the 5α-Reductase (5aR) Trial. Interventions All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone secretion and weekly injections of 50, 125, 300 or 600 mg of testosterone enanthate, and were randomized to receive either 2.5 mg dutasteride (5 α-reductase inhibitor) or placebo daily for 20 weeks. Liver, spleen and kidney volumes were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. Outcomes The dose-effect of testosterone on changes in the volume of parenchymal organs was evaluated by linear regression model. The association between changes in total testosterone (TT) levels and changes in organ volumes were assessed. Results Testosterone administration increased liver volume dose-dependently (17.4 cm3 per 100 mg of weekly testosterone enanthate; p=0.031); the increase in liver volume was positively associated with changes in TT levels (R2=0.08, p=0.024). A dose-dependent, but non-significant, increase in kidney volumes was also seen. Inclusion of dutasteride use into the models showed an independent association of randomization to dutasteride group with liver volume increase. Conclusion Testosterone administration increased the liver volume in a dose-dependent manner. The potential changes in parenchymal organs should be considered when interpreting apparent changes in lean mass in response to anabolic interventions.