Chronic tyrosine kinase inhibitor (TKI) use in metastatic renal cell carcinoma (mRCC): can this lead to the adverse effect of hypogonadism?

Background: Patients with metastatic renal cell carcinoma (mRCC) are commonly treated with tyrosine kinase inhibitors (TKIs). An adverse effect frequently suffered by patients is lethargy, which often leads to dose reduction or drug cessation. We aimed to assess whether hypogonadism is related to treatment with TKIs.

Methods: We prospectively assessed gonadal function in 41 consecutive males with mRCC treated with TKIs. Demographic, clinical, and biochemical variables were collected, and statistical analyses performed to assess correlation and survival. Data Capture for each patient was perfomred at the time of entry in the study.

Results: There was a 77% incidence of hypogonadism in this cohort. Assessment of testosterone level and time on TKI treatment revealed a correlation with linear regression R² of 0.24 and regression coefficient of ?0.003 (p = 0.019). Odds ratio for hypogonadism at >30 months on TKIs was 12.1 (p = 0.011). Odds ratios above and below this value showed a confirmatory trend, suggesting that this may be a chronic adverse effect.

Conclusions: Our findings provide an important and robust hypothesis for a prospective clinical trial to be performed.

Expert Opinion: Given the present data, patients who have symptoms suggestive of hypogonadism must have an assessment of gonadal function and be treated.     

Seasonal changes in neuronal turnover in a forebrain nucleus in adult songbirds

Neuronal death and replacement, or neuronal turnover, in the adult brain are one of many fundamental processes of neural plasticity. The adult avian song control circuit provides an excellent model for exploring mature neuronal death and replacement by new neurons. In the song control nucleus, HVC of adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelli) nearly 68,000 neurons are added each breeding season and die during the subsequent nonbreeding season. To accommodate large seasonal differences in HVC neuron number, the balance between neuronal addition and death in HVC must differ between seasons. To determine whether maintenance of new HVC neurons changes within and between breeding and nonbreeding conditions, we pulse-labeled two different cohorts of new HVC neurons under both conditions and quantified their maintenance. We show that the maintenance of new HVC neurons, as well as new nonneuronal cells, was higher at the onset of breeding conditions than at the onset of nonbreeding conditions. Once a steady-state HVC volume and neuronal number were attained in either breeding or nonbreeding conditions, neuronal and nonneuronal maintenance were similarly low. We found that new neuronal number correlated with a new nonneuronal number within each cohort of new neurons. Together, these data suggest that sex steroids promote the survival of an initial population of new neurons and nonneuronal cells entering HVC. However, once HVC is fully grown or regressed, neuronal and nonneuronal cell turnover is regulated by a common mechanism likely independent of direct sex steroid signaling.     

Do men with normal testosterone–oestradiol ratios benefit from letrozole for the treatment of male infertility?

Research question

Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone–oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone–oestradiol ratio?

Aqueous and ethanol extracts of Dracaena arborea (Wild) Link (Dracaenaceae) alleviate reproductive complications of diabetes mellitus in rats

Reproductive dysfunction is one of the most prevalent diabetes complications. Draceana arborea is known to enhance sexual function in diabetic rats, but the underlying mechanisms have not been thoroughly elucidated. This study examined the effects of D. arborea on some reproductive complications of diabetes in rats. Aqueous and ethanol (500 and 100 mg/kg respectively) extracts of D. arborea, Sildenafil citrate (1.44 mg/kg), trimethylamine‐N‐oxide (TMAO, 20 mg/kg) and distilled water (10 ml/kg) were orally administered for 28 days to streptozotocin‐induced diabetic rats. Glycaemia, body and reproductive organ masses, fertility parameters, total proteins, antioxidant enzymes activities, serum and testicular testosterone and the histology of the testes and epididymis were determined. Results revealed significant decreases in body and absolute and relative masses of testes, epididymis, seminal vesicles, prostate and vas deferens, fertility parameters, epididymal and testicular total proteins, serum and testicular testosterone levels as well as antioxidant enzymes activities. Interestingly, while having minor anti‐hyperglycaemic effects, these abnormalities associated with testicular and epididymal alterations were alleviated by D. arborea especially the aqueous extract (500 mg/kg). These outcomes provided evidence of the androgenic properties of D. arborea in diabetic rats, which could be useful for a better management of sexual dysfunctions in diabetic patients.     

Gonadal hormones differentially regulate sex‐specific stress effects on glia in the medial prefrontal cortex

Women are more susceptible to various stress‐linked psychopathologies, including depression. Dysfunction of the medial prefrontal cortex (mPFC) has been implicated in depression, and studies indicate sex differences in stress effects on mPFC structure and function. For example, chronic stress induces dendritic atrophy in the mPFC in male rats, yet dendritic growth in females. Recent findings suggest glial pathways toward depression. Glia are highly responsive to neuronal activity and function as critical regulators of synaptic plasticity. Preclinical models demonstrate stress‐induced microglial activation in mPFC in males, yet deactivation in females. By contrast, stress reduces astrocyte complexity in mPFC in male rats, whereas the effects in females are unknown. Glia possess receptors for most gonadal hormones and gonadal hormones are known to modulate neuronal activity. Thus, gonadal hormones represent a potential mechanism underlying sex differences in glia, as well as divergent stress effects. Therefore, we examined the role of gonadal hormones in sex‐specific stress effects on neuronal activity (ie FosB/ ΔFosB induction) and glia in the mPFC. The findings obtained indicate greater microglial activation in mPFC in females and a greater astrocyte area in males. Basal astrocyte morphology is modulated by androgens, whereas androgens or oestrogens dampen the microglial state in males. Astrocyte morphology is associated with neuronal activity in both sexes, regardless of hormonal condition. Chronic stress induced astrocytic atrophy in males, yet hypertrophy in females, with gonadal hormones partly regulating this difference. Stress effects on microglia are oestradiol‐dependent in females. Taken together, these data suggest sex‐specific, gonadal hormone‐dependent stress effects on astrocytes and microglia in the mPFC.     

Endogenous testosterone determines metformin action on prolactin levels in hyperprolactinaemic men: A pilot study

Metformin was found to reduce elevated prolactin levels in women but not in men. The current study was aimed at investigating whether endogenous testosterone determines the impact of metformin on lactotroph function in men. This prospective case‐control study included 28 men with recently diagnosed type 2 diabetes mellitus and mild or moderate hyperprolactinaemia, 14 of whom had low testosterone levels, while in the remaining 14 ones' testosterone levels were within the reference range. All participants received metformin (2.55‐3 g daily) for the following 4 months. Circulating levels of glucose, insulin, prolactin, testosterone, oestradiol, gonadotropins, sex hormone‐binding globulin adrenocorticotropic hormone, insulin‐like growth factor‐1, thyrotropin and free thyroid hormones were measured at the beginning and at the end of the study. Although metformin reduced plasma glucose levels and improved insulin sensitivity in both groups, this effect was stronger in participants with low testosterone levels. Only in patients with abnormally low testosterone levels, the drug decreased prolactin levels. This effect, which was accompanied by an increase in luteinizing hormone levels, was inversely correlated with baseline testosterone and calculated free testosterone levels, and positively with treatment‐induced improvement in insulin sensitivity. In both treatment groups, metformin produced a neutral effect on plasma levels of the remaining hormones. The obtained results suggest that endogenous testosterone may attenuate the impact of metformin on lactotropic cells.     

Anxious to see you: Neuroendocrine mechanisms of social vigilance and anxiety during adolescence

Social vigilance is a behavioral strategy commonly used in adverse or changing social environments. In animals, a combination of avoidance and vigilance allows an individual to evade potentially dangerous confrontations while monitoring the social environment to identify favorable changes. However, prolonged use of this behavioral strategy in humans is associated with increased risk of anxiety disorders, a major burden for human health. Elucidating the mechanisms of social vigilance in animals could provide important clues for new treatment strategies for social anxiety. Importantly, during adolescence the prevalence of social anxiety increases significantly. We hypothesize that many of the actions typically characterized as anxiety behaviors begin to emerge during this time as strategies for navigating more complex social structures. Here, we consider how the social environment and the pubertal transition shape neural circuits that modulate social vigilance, focusing on the bed nucleus of the stria terminalis and prefrontal cortex. The emergence of gonadal hormone secretion during adolescence has important effects on the function and structure of these circuits, and may play a role in the emergence of a notable sex difference in anxiety rates across adolescence. However, the significance of these changes in the context of anxiety is still uncertain, as not enough studies are sufficiently powered to evaluate sex as a biological variable. We conclude that greater integration between human and animal models will aid the development of more effective strategies for treating social anxiety.     

Monitoring testosterone levels in testosterone-treated men

Dose adjustment with transdermal testosterone preparations should recognize the variability of serum total testosterone levels between applications and over the course of 24?h. Dose adjustments are also made difficult by between-laboratory assay variability. Low SHBG with obesity and diabetes lowers the total testosterone level, and free or bioavailable testosterone may prove to be a better choice for monitoring the progress and dosing of testosterone-treated men with adult onset hypogonadism.