Aging affects reproductive capabilities in males through physiological and behavioral alterations, including endocrine changes and decreased libido. In this study, we investigated the influence of intermittent fasting (IF) on these aging-related declines, using male C57BL/6J mice. Our findings revealed that IF significantly preserved reproductive success in aged mice, not by improving traditional reproductive metrics such as sperm quality or endocrine functions but by enhancing mating behavior. This behavioral improvement was attributed to IF's ability to counter age-dependent increases in serotonergic inhibition, primarily through the decreased supply of the serotonin precursor tryptophan from the periphery to the brain. Our research underscores the potential of dietary interventions like IF in mitigating age-associated declines in male reproductive health and suggests a novel approach to managing conditions related to reduced sexual desire, highlighting the complex interplay between diet, metabolism, and reproductive behavior.

Given the various roles of testosterone in men's health, we conducted a multi-ancestral genetic analysis of total testosterone, free testosterone, SHBG, and hypogonadism in men within the Million Veteran Program (MVP). Here we identified 157 significant testosterone genetic variants, of which 8 have significant ancestry-specific associations. These variants implicate several genes, including SERPINF2, PRPF8, BAIAP2L1, SHBG, PRMT6, and PPIF, related to liver function. Genetic regulators of testosterone have cell type-specific effects in the testes, liver, and adrenal gland and are associated with disease risk. We conducted a meta-analysis amongst ancestry groups to identify 188 variants significantly associated with testosterone, of which 22 are novel associations. We constructed genetic scores for total testosterone, SHBG levels, and hypogonadism and find that men with higher testosterone genetic scores have lower odds of diabetes, hyperlipidemia, gout, and cardiac disorders. These findings provide insight into androgen regulation and identify novel variants for disease risk stratification.

This study aimed to develop a novel adsorbent, Zn2+ -loaded hexanediamine-chitosan (HDA-CS) beads, for the selective removal of human testosterone from plasma. The preparation involved synthesizing chitosan beads, modifying them with hexanediamine to enhance adsorption capacity and subsequently loading them with zinc ions. The effects of the HDA spacer, Zn2+ concentration, and adsorption time on the adsorption percentage for testosterone were systematically investigated through a series of adsorption experiments. Results indicated that the Zn2+ -HDA-CS beads achieved a maximum adsorption capacity of approximately 35% within 90 min. The analysis of plasma concentrations of Zn2+ , albumin, and sex hormone-binding globulin (SHBG) indicated that the adsorption process involved a complex interaction between testosterone-bound SHBG and albumin for Zn2+ binding sites on the beads. Additionally, the adsorbent demonstrated good storage stability and selectivity for testosterone, with minimal impact on total protein content in plasma. These findings highlight the potential of Zn2+ -HDA-CS beads as an effective therapeutic option for managing testosterone levels in clinical settings, particularly in patients undergoing androgen deprivation therapy for prostate cancer.

Renal aging is a physiological process characterized by structural and functional changes in the kidneys. The presence of disorders or pathologies can exacerbate these age-related changes, potentially leading to organ dysfunction. Chronic kidney disease (CKD), a significant global public health issue, is particularly prevalent in the elderly and is often associated with the age-related decline in kidney function. Anemia is one of the most frequent complications of CKD and is also highly prevalent in the elderly. Mild anemia, often multifactorial, is the most common presentation. Understanding the mechanisms driving anemia in this population is crucial to ensure appropriate treatment. The primary etiologies include nutritional deficiency, anemia of unknown cause, and anemia of chronic diseases, including CKD. This review provides an in-depth exploration of the complex pathophysiological mechanisms underlying anemia in elderly patients with CKD.

The androgen receptor (AR) signalling pathway has been intensively studied in the context of prostate cancer, where androgen deprivation therapy is part of the standard of care for metastatic disease. By contrast, fewer studies have investigated the impact and translational potential of targeting AR in other cancer types where it is also expressed and functional. In this Review, we discuss the current understanding of AR in non-prostatic cancer types and summarize ongoing AR-directed clinical trials. While different androgen levels contribute to sexual dimorphism in cancer, targeting the AR system could benefit both sexes and help overcome resistance to targeted therapies. However, a bimodal function of AR signalling, which suppresses stromal changes associated with the early stages of cancer development, also needs to be considered. Future research is necessary to scrutinize cellular and molecular mechanisms of action of AR in cancer cells and the tumour microenvironment, to develop selective modulators of AR activity, and to identify patients with non-prostatic cancer who might benefit from targeting this pathway. AR-directed manipulation of host immune cells may offer a promising therapeutic approach for many types of cancers.

The aims of this cross-sectional study were to (a) assess actigraphy-based sleep parameters (total sample and gender differences), (b) assess differences in morphological parameters and physical function between short- versus normal-sleepers and poor- versus good-sleepers, and (c) assess the possible correlations between sleep variables and morphological and physical function parameters in older subjects.

This study enrolled 42 healthy older participants (60-80 years). Participants completed the following clinical evaluations: (1) whole-body dual-energy X-ray absorptiometry to assess the appendicular skeletal muscle mass index; (2) magnetic resonance imaging acquisition to determine the cross-sectional muscle area of thigh muscles and intermuscular adipose tissue; (3) risk of fall assessment through the mini-Balance Evaluation Systems Test; (4) strength assessment: (a) chair stand test and (b) handgrip strength test; (5) sleep monitoring by actigraphy to assess total sleep time, sleep efficiency, wake after sleep onset, sleep latency, fragmentation index, mobile time, and subjective sleep quality.

31.0% of subjects were short-sleepers (total sleep time < 6 hr), 19.1% were poor-sleepers (sleep efficiency < 85%), and gender differences were detected in mobile time (males: 15.8 ± 6.0 and females: 13.4 ± 6.8; p < .001) and fragmentation index (males: 35.3 ± 14.3 and females: 29.6 ± 14.6; p < .001); no significant differences were observed between groups (short- vs. normal-sleepers and poor- vs. good-sleepers) in morphological and physical function variables; correlation analysis showed that sleep latency negatively correlated with Mini-Balance Evaluation Systems Test (r = -.352; p = .022) and a positive correlation was detected between cross-sectional muscle area and mobile time (r = .349, p = .023).

No differences were observed in morphological and function parameters between good- versus poor-sleepers, those subjects with worse sleep onset latency (i.e., longer time to fall asleep) registered higher for risk of fall. The potential role of sleep in the physiological mechanisms of muscular aging must be explored through cross-sectional cohort studies with a larger population.

The circadian clock regulates physiological and biochemical processes in nearly every species. Sexual and reproductive behaviors are two processes controlled by the circadian timing system. Evidence supporting the importance of proper clock function on fertility comes from several lines of work demonstrating that misalignment of biological rhythms or disrupted function of the body's master clock, such as occurs from repeated shift work or chronic jet lag, negatively impacts reproduction by interfering with both male and female fertility. Along these lines, dysregulation of clock genes leads to impairments in fertility within mammals, and disruption of circadian clock timing negatively impacts sex hormone levels and semen quality in males, and it leads to ovulatory deficiencies in females. Here, we review the current understanding of the circadian modulation of both male and female reproductive hormones-from animal models to humans. Further, we discuss neural circuits within the hypothalamus that may regulate circadian changes in mammalian sexual behavior and reproduction, and we explore how knowledge of such circuits in animal models may help to improve human sexual function, fertility, and reproduction.

Alzheimer's disease is a highly complex and multifactorial neurodegenerative disorder, with age being the most significant risk factor. The incidence of Alzheimer's disease doubles every 5 years after the age of 65. Consequently, one of the major challenges in Alzheimer's disease research is understanding how the brain changes with age. Gaining insights into these changes could help identify individuals who are more prone to developing Alzheimer's disease as they age. Over the past 25 years, studies on brain aging have examined thousands of human brains to explore the neuronal basis of age-related cognitive decline. However, most of these studies have focused on adults over 60, often neglecting the critical menopause transition period. During menopause, women experience a substantial decline in ovarian sex hormone production, with a decrease of about 90% in estrogen levels. Estrogen is known for its neuroprotective effects, and its significant loss during menopause affects various biological systems, including the brain. Importantly, despite known differences in dementia risk between sexes, the impact of biological sex and sex hormones on brain aging and the development of Alzheimer's disease remains underexplored.

The lack of association between serum testosterone levels and symptoms suggestive of hypogonadism is a significant barrier in the determination of late-onset hypogonadism (LOH) in men. This study explored whether testosterone levels increase after morning awakening, likewise the cortisol awakening response (CAR) in the hypothalamic-pituitary-adrenal (HPA) axis, and whether testosterone levels during the post-awakening period are associated with age and symptoms suggestive of late-onset hypogonadism (LOH) in men.

Testosterone and cortisol levels were determined in saliva samples collected immediately upon awakening and 30 and 60 min after awakening, and scores of the Aging Males' Symptoms (AMS) questionnaire were obtained from 225 healthy adult men.

A typical CAR (an increase in cortisol level ≥ 2.5 nmol/L above individual baseline) was observed in 155 participants (the subgroup exhibiting typical CAR). In the subgroup exhibiting CAR, testosterone levels sharply increased during the post-awakening period, showing a significant negative correlation with age, total AMS score, and the scores of 11 items on the somatic, psychological, and sexual AMS subscales. Of these items, three sexual items (AMS items #15-17) were correlated with age. Meanwhile, there was no notable increase in testosterone levels and no significant correlation of testosterone levels with age and AMS score in the subgroup exhibiting no typical CAR (n = 70).

The results indicate that the hypothalamus-pituitary-gonad (HPG) axis responds to morning awakening, and determining testosterone levels during the post-awakening period in men with typical CAR may be useful for assessing HPG axis function and LOH.

There is general consensus that an improper diet negatively impacts health and that nutrition is a primary tool for the prevention of non-communicable diseases. Unfortunately, the importance of studying body composition, which can reveal early predictors of gender-related diseases, is still not well understood in this context. Currently, individuals are still classified as obese based solely on their body mass index, without considering the amount of fat, its distribution, and the quantity of muscle and bone mass. In this regard, the body composition phenotype defined as "osteosarcopenic obesity" affects approximately 6-41 % of postmenopausal women, with prevalence increasing with age due to the hormonal and metabolic changes that occur during this period. This particular phenotype arises from the strong relationship between visceral fat, muscle, bone, and gut microbiota and predispose postmenopausal women to frailty. Frailty is a complex clinical phenomenon with significant care and economic implications for our society. Recent studies suggest that women have a higher prevalence of frailty syndrome and its individual components, such as osteoporosis, fractures and sarcopenia, compared to men. Here, we provide a comprehensive overview of recent advances regarding the impact of gender on body composition and frailty. Furthermore, we reflect on the crucial importance of personalized nutritional interventions, with a focus on reducing visceral fat, increasing protein intake and optimizing vitamin D levels. A review of the scientific literature on this topic highlights the importance of studying body composition for a personalized and gender-specific approach to nutrition and dietetics, in order to identify frailty syndrome early and establish personalized treatments. This new method of researching disease predictors could likely help clarify the controversial results of studies on vitamin D, calcium and proteins, translate into practical wellness promotion across diverse elderly populations.

Blue Zones are regions of the world that have a higher number of individuals who live longer than the expected average. The current paper revisits principles previously identified to be common in Blue Zones and to be contributing to longevity (move naturally, eat wisely, improve resilience to stress, get adequate sleep, keep strong family ties, stimulate strong community support, respect for the planet and having a purpose in life'), compares these to the 6 pillars of Lifestyle Medicine (healthy eating, exercising, avoidance of smoking and other risky substances, stress management, restorative sleep, and forming and maintaining relationships) and reviews new studies investigating the association between behavioral factors and longevity. In addition to the role of behavior, the review also discusses the important role of genetics and emphasizes the importance of conducting further research to understand how behavioral and genetic factors may affect molecular pathways with consequent effects on wellbeing and longevity.

Electro-acoustic stimulation (EAS) combines electric stimulation via a cochlear implant (CI) with residual low-frequency acoustic hearing, with benefits for music appreciation and speech perception in noise. However, many EAS CI users lose residual acoustic hearing, reducing this benefit. The main objectives of this study were to determine whether chronic EAS leads to more hearing loss compared with CI surgery alone in an aged guinea pig model, and to assess the relationship of any hearing loss to histology measures. Conversely, it is also important to understand factors impacting efficacy of electric stimulation. If one contributor to CI-induced hearing loss is damage to the auditory nerve, both acoustic and electric thresholds will be affected. Excitotoxicity from EAS may also affect electric thresholds, while electric stimulation is osteogenic and may increase electrode impedances. Hence, secondary objectives were to assess how electric thresholds are related to the amount of residual hearing loss after CI surgery, and how EAS affects electric thresholds and impedances over time.

Two groups of guinea pigs, aged 9 to 21 months, were implanted with a CI in the left ear. Preoperatively, the animals had a range of hearing losses, as expected for an aged cohort. At 4 weeks after surgery, the EAS group (n = 5) received chronic EAS for 8 hours a day, 5 days a week, for 20 weeks via a tether system that allowed for free movement during stimulation. The nonstimulated group (NS; n = 6) received no EAS over the same timeframe. Auditory brainstem responses (ABRs) and electrically evoked ABRs (EABRs) were recorded at 3 to 4 week intervals to assess changes in acoustic and electric thresholds over time. At 24 weeks after surgery, cochlear tissue was harvested for histological evaluation, only analyzing animals without electrode extrusions (n = 4 per ear).

Cochlear implantation led to an immediate worsening of ABR thresholds peaking between 3 and 5 weeks after surgery and then recovering and stabilizing by 5 and 8 weeks. Significantly greater ABR threshold shifts were seen in the implanted ears compared with contralateral, non-implanted control ears after surgery. After EAS and termination, no significant additional ABR threshold shifts were seen in the EAS group compared with the NS group. A surprising finding was that NS animals had significantly greater recovery in EABR thresholds over time, with decreases (improvements) of -51.8 ± 33.0 and -39.0 ± 37.3 c.u. at 12 and 24 weeks, respectively, compared with EAS animals with EABR threshold increases (worsening) of +1.0 ± 25.6 and 12.8 ± 44.3 c.u. at 12 and 24 weeks. Impedance changes over time did not differ significantly between groups. After exclusion of cases with electrode extrusion or significant trauma, no significant correlations were seen between ABR and EABR thresholds, or between ABR thresholds with histology measures of inner/outer hair cell counts, synaptic ribbon counts, stria vascularis capillary diameters, or spiral ganglion cell density.

The findings do not indicate that EAS significantly disrupts acoustic hearing, although the small sample size limits this interpretation. No evidence of associations between hair cell, synaptic ribbon, spiral ganglion cell, or stria vascularis with hearing loss after cochlear implantation was seen when surgical trauma is minimized. In cases of major trauma, both acoustic thresholds and electric thresholds were elevated, which may explain why CI-only outcomes are often better when trauma and hearing loss are minimized. Surprisingly, chronic EAS (or electric stimulation alone) may negatively impact electric thresholds, possibly by prevention of recovery of the auditory nerve after CI surgery. More research is needed to confirm the potentially negative impact of chronic EAS on electric threshold recovery.

The role of different biological variables including biological sex, age, and sex hormones in Human immunodeficiency virus (HIV) cure approaches is not well understood. The γc-cytokine IL-15 is a clinically relevant cytokine that promotes immune activation and mediates HIV reactivation from latency. In this work, we examined the interplay that biological sex, age, and sex hormones 17β-estradiol, progesterone, and testosterone may have on the biological activity of IL-15. We found that IL-15-mediated CD4+ T cell activation was higher in female donors than in male donors. This difference was abrogated at high 17β-estradiol concentration. Additionally, there was a positive correlation between age and both IL-15-mediated CD8+ T cell activation and IFN-γ production. In a primary cell model of latency, biological sex, age, or sex hormones did not influence the ability of IL-15 to reactivate latent HIV. Finally, 17β-estradiol did not consistently affect reactivation of translation-competent reservoirs in CD4+ T cells from people living with HIV who are antiretroviral therapy (ART) suppressed. Our study has found that biological sex and age, but not sex hormones, may influence some of the biological activities of IL-15. Understanding how different biological variables may affect HIV cure therapies will help us evaluate current and future clinical trials aimed toward HIV cure in diverse populations.

Observational studies have found associations between sex hormones and metabolic syndrome(Mets), but the causal relationships remains unclear. This study utilizes univariable and multivariable Mendelian randomization (MR) to elucidate the associations between sex hormones (including sex hormone-binding globulin(SHBG), estradiol(E2), testosterone(T)) and Mets and its subtypes (including waist circumference(WC), fasting blood glucose(FBG), high blood pressure(HBP), high-density lipoprotein(HDL-C), triglycerides(TG)).

We utilized summary data from large-scale genome-wide association studies. Univariable Mendelian randomization (UMVMR) analysis was primarily conducted using the inverse variance weighted method (IVW), with secondary analyses employing the weighted median, MR-Egger regression, simple mode method, and weighted mode method. Subsequently, multivariable Mendelian randomization (MVMR) was employed to assess the causal relationships between SHBG, T, E2, and MetS and its components: WC, FPG, HBP, HDL-C, and TG. Sensitivity analyses were conducted to assess result reliability.

Genetically predicted SHBG was significantly negatively associated with MetS (UMVMR: β=-0.72; 95% CI = 0.41 to 0.57; P = 1.28e-17; MVMR: β=-0.60; 95% CI=-0.83 to -0.38; P < 0.001). Positive causal relationships were observed between SHBG and WC(MVMR: β = 0.10; 95% CI = 0.03 to 0.17; P = 0.01) and HDL-C (MVMR: β = 0.41; 95% CI = 0.21 to 0.60; P < 0.001), while negative causal relationships were found between SHBG and HBP (MVMR: β=-0.02; 95% CI=-0.04 to -0.00; P = 0.02), TG (MVMR: β=-0.48; 95% CI=-0.70 to -0.26; P < 0.001). Genetically predicted E2 exhibited a negative association with TG (MVMR: β=-1.49; 95% CI=-2.48 to -0.50; P = 0.003). Genetically predicted T was negatively associated with TG (MVMR: β=-0.36; 95% CI=-0.71 to -0.00; P = 0.049) and WC (MVMR: β=-0.13; 95% CI=-0.24 to -0.02; P = 0.02), with inconsistent sensitivity analyses. Additionally, No other causal associations were found.

Our study indicates that SHBG is a protective factor for MetS, potentially delaying its onset and progression through improvements in HBP and TG. Furthermore, T and E2 may improve TG levels, with T also reducing WC levels. Importantly, our study provides new insights for the prevention and treatment of MetS.

The objective was to determine the effects of older age on hearing preservation after cochlear implantation (CI), and whether steroids improve hearing preservation in older animals. We hypothesized greater hearing preservation would be observed in (1) young animals compared to older animals and (2) older animals receiving steroids compared to no steroids. The secondary objective was to assess levels of fibrosis utilizing optical coherence tomography (OCT).

Experimental Animal Study.

Laboratory.

Three groups of guinea pigs: young (YCI; 8.5 ± 0.5 weeks; n = 10), old (OCI; 19.1 ± 1.0 months; n = 9) and old + steroids (OCI+S; 19.1 ± 1.0 months; n = 9) underwent CI. The OCI+S group received a steroid taper over 7 days starting 2 days before surgery to 4 days after. Auditory brainstem response (ABR) measurements were performed preoperatively and postoperatively. OCT imaging was performed to assess cochleae for extent of fibrotic tissue growth in the scala tympani.

The YCI group had significantly better hearing preservation as measured by smaller increases in ABR thresholds [mean shift: 2.79 ± 0.66] compared to the OCI group [mean shift = 12.44 ± 5.6]. The OCI+S group had significantly better hearing preservation [2.66 ± 1.50] compared to the OCI group. No significant differences was seen in fibrosis across groups.

Young animals and older animals that received steroids had better hearing after CI than older animals not given steroids, but hearing preservation was not correlated with the level of fibrosis assessed using OCT. This work is the first to investigate differences in hearing preservation by age in an animal model, and supports the protective effects of steroids on hearing preservation in older individuals.

Currently, in pork auctions in Korea, only carcass weight and backfat thickness provide information on meat quantity, while the production volume of primal cuts and fat contents remains largely unknown. This study aims to predict the production of primal cuts in pigs and investigate how these carcass traits affect pricing. Using the VCS2000, the production of shoulder blade, loin, belly, shoulder picnic, and ham was measured for gilts (17,257 pigs) and barrows (16,365 pigs) of LYD (Landrace × Yorkshire × Duroc) pigs. Single and multiple regression analysis were conducted to analyze the relationship between the primal cuts and carcass weight. The study also examined the correlation between each primal cut, backfat thickness (1st thoracic vertebra backfat thickness, grading backfat thickness, and Multi-brached muscle middle backfat thickness), pork belly fat percentage, total fat yield, and auction price. A multiple regression analysis was conducted between the carcass traits that showed a high correlation and the auction price. After conducting a single regression analysis on the primal cuts of gilt and barrow, all coefficients of determination (R2) were 0.77 or higher. In the multiple regression analysis, the R2 value was 0.98 or higher. The correlation coefficient between the carcass weights and the auction price exceeded 0.70, while the correlation coefficients between the primal cuts and the auction prices were above 0.65. In terms of fat content, the backfat thickness of gilt exhibited a correlation coefficient of 0.70, and all other items had a correlation coefficient of 0.47 or higher. The correlation coefficients between the Forequarter, Middle, and Hindquarter and the auction price were 0.62 or higher. The R2 values of the multiple regression analysis between carcass traits and auction price were 0.5 or higher for gilts and 0.4 or higher for barrows. The regression equations between carcass weight and primal cuts derived in this study exhibited high determination coefficients, suggesting that they could serve as reliable means to predict primal cut production from pig carcasses. Elucidating the correlation between primal cuts, fat contents and auction prices can provide economic indicators for pork and assist in guiding the direction of pig farming.

Purpose: The aim of this study was to investigate and compare the levels of luteinizing hormone (LH), testosterone (T), estradiol (ES), sex hormone-binding globulin (SHBG), and insulin-like growth factor 1 (IGF-1) in master sprint (MS) and master endurance (ME) athletes. Additionally, the possible associations between these hormones, body composition, and lipid profile with athletic performance (% of performance in relation to the current world record) were analyzed. Materials and Methods: The participants were all men: (i) 34 MS (51.0 ± 6.8 years); and (ii) 32 ME (51.7 ± 9.4 years). Student's t-tests for independent samples were performed to compare all variables between groups. Results: MS had a significantly higher (p = .008) average IGF-1 (154.78 ± 29.85 ng/mL) when compared to ME (129.92 ± 25.48 ng/mL). Performance was significantly correlated with IGF-1 (r = 0.424). The MS group had a moderately lower body fat than ME athletes (MS 12.54 ± 4.07 vs. ME 14.60 ± 4.12; p = .078; d = 0.503). Conclusions: Thus, strength/power training exercise/sport seems to be more beneficial for obtaining a higher IGF-1 compared to aerobic/distance exercise/sport. In addition, LH, T, ES, and SHBG were similar between the two groups of athletes and were comparable to the reference values of younger adults.

Previous work has demonstrated a deficiency in urology resident education when it comes to andrology and male infertility. We analyzed the top 100 most frequently cited and influential articles published on testosterone deficiency and its associated therapy, allowing trainees and clinicians to review and understand the characteristics of impactful literature for self-directed learning purposes.

The ISI Web of Knowledge database was used to find articles on testosterone deficiency, hypogonadism, and replacement therapies. Relevant, peer-reviewed, English articles were included. Article details, including title, citation count, publication year, and more, were gathered. Articles were classified based on content (e.g. clinical outcomes, anatomy, and trends) using defined criteria.

The top 300 most cited were reviewed with 100 included. The most cited article had 774 citations, averaging 234 in the top 100. Publication years had peaks in 2003-2004 and 2006-2007. The US led in publications (56), followed by England (16), Germany (14), and Italy (13). Common affiliations included US Department of Veteran Affairs, Veterans Health Administration, RIC Research Education Clinical Center, and University of California System. Articles were categorized as LOE 2 (47), LOE 1 (22), and LOE 5 (21). Articles focused on clinical outcomes (71.7%), anatomy/biomechanics/physiology (14.1%), clinical guidelines (8.1%), and screening (4%). The "Journal of Clinical Endocrinology & Metabolism" published 26 of the top 100 cited articles.

This analysis highlights influential articles regarding testosterone deficiency and management. The discussed articles have significant clinical and therapeutic implications for the practicing urologist which may bolster deficits in current resident education.

The testosterone undecanoate oil solution is the most widely used injection of testosterone for long-acting effects on the market, whereas the formulation carries the potential risk of causing pulmonary vascular embolism, inflammation, and pain at the injection site. Therefore, a sustained-released long-acting injection of testosterone with strong security is urgently exploited. Herein, a poorly water-soluble testosterone-cholesterol prodrug (TST-Chol) was synthesized by esterification. The water solubility of TST-Chol was decreased by 644 folds in comparison to that of testosterone (TST). Moreover, suspensions of TST and TST-Chol were prepared and analyzed in vitro, utilizing three distinct particle sizes: small-sized nanocrystals (SNCs) measuring 300 nm, medium-sized microcrystals (MMCs) measuring 12 μm, and large-sized microcrystals (LMCs) measuring 20 μm. The findings from the in vitro release study indicated that the sustained release of the drug was significantly influenced by the solubility and particle sizes of the suspension. Notably, the suspensions with low water solubility and larger particle sizes exhibited a more desirable sustained-release effect in vitro. Furthermore, the study on pharmacokinetics exhibited that TST-Chol SNCs produced a sustained TST plasma concentration in vivo for up to 40 days and no obvious pathological changes in lung tissue were found. Our study indicated that solubility and particle sizes of suspensions had made a difference in pharmacokinetics and provided a valuable reference for the advancement of long-acting injections.

Aim: The aim of the present study was to investigate the expansion and prevalence of anabolic steroid use by examining the divergent effects between health and drug abuse and to create more awareness around the harmful consequences of these drugs when administered at abusive levels. Methods: A focused and concise literature search was conducted, and 101 high-quality articles were included in the review. Results: The findings underscore the adverse health risks of steroid abuse, emphasizing the stark contrast between health and drug abuse. Conclusions: While steroids and other performance-enhancing drugs can yield muscle growth, strength and even fat loss, abusing these substances can lead to adverse health outcomes. Furthermore, within the fitness subculture, particularly in the realm of bodybuilding, steroid abuse fosters an atmosphere of cheating and deception, frequently downplaying or ignoring the negative and sometimes deadly consequences it brings.

Benign prostatic hyperplasia (BPH), as a clinical entity that affects many people, has always been in the forefront of interest among researchers, pharmaceutical companies, and physicians. Patients with BPH exhibit a diverse range of symptoms, while current treatment options can occasionally cause adverse events. All the aforementioned have led to an increased demand for more effective treatment options.

This review summarizes the outcomes of new medications used in a pre-clinical and clinical setting for the management of male lower urinary tract symptoms (LUTS)/BPH and provides information about ongoing trials and future directions in the management of this condition. More specifically, sheds light upon drug categories, such as reductase‑adrenoceptor antagonists, drugs interfering with the nitric oxide (NO)/cyclic guanosine monophosphate (GMP) signaling pathway, onabotulinumtoxinA, vitamin D3 (calcitriol) analogues, selective cannabinoid (CB) receptor agonists, talaporfin sodium, inhibitor of transforming growth factor beta 1 (TGF-β1), drugs targeting the hormonal control of the prostate, phytotherapy, and many more.

Clinical trials are being conducted on a number of new medications that may emerge as effective therapeutic alternatives in the coming years.

Low testosterone (T), common in aging men, associates with cardiovascular disease. We investigated whether follicle-stimulating hormone (FSH), which is affected by T, modulates the cardiovascular effects associated with low T or castration. FSHβ-/-:low-density lipoprotein receptor (LDLR)-/- mice, untreated or castrated (orchiectomy, gonadotropin-releasing hormone agonist or antagonist), demonstrated significantly less atherogenesis compared with similarly treated LDLR-/- mice, but not following FSH delivery. Smaller plaque burden in LDLR-/- mice receiving gonadotropin-releasing hormone antagonists vs agonists were nullified in FSHβ-/-:LDLR-/- mice. Atherosclerotic and necrotic plaque size and macrophage infiltration correlated with serum FSH/T. In patients with prostate cancer, FSH/T following androgen-deprivation therapy initiation predicted cardiovascular events. FSH facilitates cardiovascular disease when T is low or eliminated.

Bisphenol A (BPA) is an environmentally dispersed chemical associated with tumor development. Phytochemicals such as indole-3-carbinol (I3C) and genistein (GEN) have chemoprotective effects on tumor cells. Thus, this study aimed to evaluate the prostatic morphological aspects of rats exposed to BPA, GEN, and I3C during the perinatal period and submitted to hormonal stimulus in adulthood. Blood was collected to obtain hormone concentrations. Slides stained with hematoxylin & eosin, and picrosirius were subjected to fractal, stereological, morphometric, and collagen quantification analysis. I3C decreased the plasma dihydrotestosterone levels, and both phytochemicals increased the plasma estrogen levels. Unlike phytochemicals, BPA did not alter any of the parameters evaluated. GEN reduced the epithelial height, while I3C increased the fractal dimension and stromal collagen. Although BPA did not alter the prostate morphology, the phytochemicals provided beneficial effects for the prostate histological organization in adult animals subjected to hormonal stimulus.

Aging is accompanied by a decreased DNA repair capacity, which might contribute to age-associated functional decline in multiple tissues. Disruption in hormone signaling, associated with reproductive organ dysfunction, is an early event of age-related tissue degeneration, but whether it impacts DNA repair in nonreproductive organs remains elusive. Using skin fibroblasts derived from healthy donors with a broad age range, we show here that the downregulation of expression of XRCC4, a factor involved in nonhomologous end-joining (NHEJ) repair, which is the dominant pathway to repair somatic double-strand breaks, is mediated through transcriptional mechanisms. We show that the androgen receptor (AR), whose expression is also reduced during aging, directly binds to and enhances the activity of the XRCC4 promoter, facilitating XRCC4 transcription and thus stabilizing the genome. We also demonstrate that dihydrotestosterone (DHT), a powerful AR agonist, restores XRCC4 expression and stabilizes the genome in different models of cellular aging. Moreover, DHT treatment reverses senescence-associated phenotypes, opening a potential avenue to aging interventions in the future.

Sarcopenia is a crucial factor in assessing the nutritional status of chronic liver disease patients and predicting their prognosis and survival. The serum ammonia level is closely associated with sarcopenia regarding ammonia, a key regulator in the liver-muscle axis. In addition, various changes in energy metabolism and hormones are also involved in sarcopenia. The psoas muscle area can represent the overall skeletal muscle mass in liver disease patients. Therefore, measuring the psoas muscle area with computed tomography or magnetic resonance imaging is considered an objective and reliable method for assessing muscle mass. Providing sufficient calorie and protein intake is crucial for preventing and treating sarcopenia. In addition, engaging in appropriate exercise and addressing concurrent hormonal and metabolic changes can be helpful.

Although several studies have examined the association between estradiol and human aggression, a consistent understanding of their correlation has yet to be established. This study aimed to investigate this relationship comprehensively.

We systematically searched five English databases (PubMed, Web of Science, EMBASE, Cochrane Library, and CINAHL) from their inception to June 5, 2023. Two authors independently screened publications and extracted data based on predefined inclusion and exclusion criteria. Statistical analyses were performed using Review Manager 5.4, and a random-effects model was used to pool the data.

We identified 14 eligible studies comprising data from 1820 participants that met the inclusion criteria. This meta-analysis indicated a positive correlation between estradiol and human aggression, albeit a weak one. The pooled Fisher z value was 0.16 (95% confidence interval = 0.05-0.26; I2 = 73%, p <.00001). Furthermore, we found that participants' sex and age, the measures of aggression, and the literature quality might be sources of heterogeneity.

Human aggression exhibited a weak positive correlation with estradiol concentration, whereas this relationship was influenced by participants' sex and age, the measure of aggression used, and the quality assessment of the literature. Gaining a better understanding of the association between estradiol and aggression could aid in the identification of populations prone to aggression.

Male fertility declines with age. The mevalonate pathway, through which cholesterol and nonsteroidal isoprenoids are synthesized, plays key role in metabolic processes and is an essential pathway for cholesterol production and protein prenylation. Male reproductive aging is accompanied by dramatic changes in the metabolic microenvironment of the testis. Since the mevalonate pathway has an important role in spermatogenesis, we attempted to explore the association between male reproductive aging and the mevalonate pathway to explain the mechanism of male reproductive aging. Alterations in the mevalonate pathway may affect male reproductive aging by decreasing cholesterol synthesis and altering testis protein prenylation. Decreased cholesterol levels affect cholesterol modification, testosterone production, and remodeling of germ cell membranes. Aging-related metabolic disorders also affect the metabolic coupling between somatic cells and spermatogenic cells, leading to male fertility decline. Therefore, we hypothesized that alterations in the mevalonate pathway represent one of the metabolic causes of reproductive aging.

Healthy aging is an important concern in an aging society. Although the causal relationship between hypogonadism and erectile dysfunction in elderly men remains unclear, many physicians have achieved positive results after implementing exogenous testosterone supplementation therapy in patients with normal or slightly low blood testosterone. The purpose of this study was to conduct a systematic review and meta-analysis on whether testosterone replacement therapy (TRT) could improve sexual function in the elderly, as reported recently.

As a comprehensive literature search was performed to find articles published in PubMed, Embase, and Cochrane databases by January 2022. The search used keywords of 'aged', 'male', 'sexual behavior', and 'testosterone'. Randomized controlled trials (RCTs) were finally selected. As the main effect variable, results of a questionnaire on sexual function were analyzed and the effects of TRT were compared to those of placebo control.

Five RCT studies were included in this meta-analysis. The overall improvement by mean difference of sexual function for testosterone supplementation was 0.082 (95% CI: -0.049 to 0.213). In subgroup analysis, only intramuscular injection of 1,000 mg testosterone significantly improved sexual function of the elderly (0.229, 95% CI: 0.112 to 0.347). There was no significant difference in sexual function according to testosterone dose in meta-ANOVA (p=0.957). The difference was not statistically significant either in the meta-regression test (p=0.310). Egger's regression coefficient test did not indicate a publication bias (p=0.132).

Although our overall effect size (that is, sexual function effect of TRT) did not show a significant improvement, the direction of improvement in erection and motivation was clearly shown. The injection formulation resulted in a significant sexual function improvement. Since only a few RCTs were included in the analysis, more well-designed prospective studies are needed to have a definite conclusion.

This study aimed to investigate the effects of sex hormone imbalance on rat prostatic inflammation and fibrosis and identify the key molecules involved.

Castrated Sprague-Dawley (SD) rats were treated with a constant dose of oestradiol (E2) and different doses of dihydrotestosterone (DHT) to achieve different oestrogen/androgen ratios. After 8 weeks, serum E2 and DHT concentrations, relative seminal vesicle weights, histopathological changes and inflammation were measured, collagen fiber content and oestrogen receptor (ER) and androgen receptor (AR) expression were detected, mRNA sequencing and bioinformatics analysis were performed to identify differentially expressed genes (DEGs).

The severity of inflammation in the rat dorsolateral prostate (DLP) was higher, collagen fibre content and ER expression in the rat DLP and prostatic urethra were increased and AR expression in the rat DLP was decreased in the 1:1 E2/DHT-treated group than that in the 1:10 E2/DHT-treated group. RNA-seq analysis identified 487 DEGs, and striking increases in the expression of mRNAs encoding collagen, collagen synthesis and degradation enzymes, growth factors and binding proteins, cytokines and chemokines, and cell-surface molecules were confirmed in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group. mRNA expression of secreted phosphoprotein 1 (Spp1) and protein expression of osteopontin (OPN, encoded by Spp1) were increased in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group, and Spp1 expression correlated positively with Mmp7, Cxcl6 and Igfn1 expression.

The imbalance in the oestrogen/androgen ratio may affect rat prostatic inflammation and fibrosis, and OPN might be involved in this process.

Endocrine disrupting chemicals (EDCs) such as phthalates, found in our daily environment, are nowadays suggested to be associated with adverse outcomes. Prenatal exposure was found associated with neurodevelopmental complications such as behavioral difficulties in school age children.

To explore the association between intrauterine exposure to phthalates and emotional/behavioral development of 24 months old toddlers.

Women were recruited at 11-18 weeks of gestation and provided spot urine samples, analyzed for phthalate metabolites (DEHP, DiNP, MBzBP). Offspring were examined at 24 months of age, using standard maternal report, regarding developmental and behavioral problems (CBCL, ASQ-3, HOME questionnaires) (N = 158). To explore the associations between metabolite levels and developmental outcomes, multivariate GLM analysis (General Linear Model) was used according to tertiles and developmental scores on each developmental outcome.

Associations of Di-(2-ethylhexyl) phthalate (DEHP) maternal exposure with behavioral-developmental outcomes were found only in boys. Compared with boys with lower DEHP maternal exposure, boys with high DEHP maternal exposure had lower developmental score in personal social abilities in the ASQ-3 questionnaire (50.68 + 8.06 and 44.14 + 11.02, high and low DEHP, respectively, p = 0.03), and more internalizing problems (for example, emotionally reactive score in high and low DEHP: 53.77 + 7.41 and 50.50 + 1.19, respectively, p = 0.029; anxious or depressed score: 53.38 + 5.01 and 50.75 + 1.34, respectively, p = 0.009; and somatic complaints scores 64.03 + 10.1 and 55.84 + 7.84, respectively, p = 0.003), and externalizing problems (49.28 + 8.59 and 43.33 + 9.11, respectively, p = 0.039). No differences were found in the development and behavior problems between high and low DEHP maternal exposure level in girls.

Maternal DEHP metabolite concentrations measured in first trimester urine was associated with children's emotional/behavioral developmental problems in 24-months old boys, supporting accumulating evidence of DEHP as a potentially harming chemical and call for environmental attention.

Ageing is a natural process with physiological changes in different body parts and has been associated with decreased reproductive capacity. Factors such as imbalance in the antioxidant defence system, vascular diseases, diabetes mellitus, accessory reproductive glands infection, obesity as well as buildup of toxic substances play a role in age-related male reproductive malfunction. Age is inversely proportional to volume of semen, sperm count, sperm progressive motility, sperm viability, normal sperm morphology. The observed negative correlation between ageing and semen indices contributes to male infertility and reproductive decline. Normal levels of ROS, plays crucial role in facilitating sperm function, such as capacitation, hyper-activation, acrosome reaction as well as sperm-oocyte fusion; however, a substantial elevation in the endogenous level of ROS, especially in reproductive tissues, usually instigates destruction of sperm cells and heightened male infertility. Contrarily, antioxidants, such as vitamins C and E, beta-carotene, and micronutrients like zinc and folate, have been found by researchers to facilitate normal semen quality and male reproductive function. Furthermore, the role of hormonal imbalance as a result of the compromised hypothalamic-pituitary-gonadal axis, Sertoli and Leydig cells disorder, and nitric oxide-medicated erectile dysfunction during ageing cannot be undermined.

The dietary acid load (DAL) is a novel marker of overall diet quality, which has been associated with overweight, type 2 diabetes and altered glucocorticoid secretion. A potential association with sex hormones is thus not inconceivable. We investigated whether DAL was associated with serum total testosterone concentrations of men in the National Health and Nutrition Examination Survey. The DAL scores, including the potential renal acid load (PRAL) and net endogenous acid production (NEAP), were estimated and compared between participants with low and normal testosterone levels. The investigated sample encompassed n = 377 males with a mean age of 49.50 years. Approximately 73% of the sample were of Non-Hispanic White origin. None of the examined DAL scores showed significant associations with serum testosterone levels. We observed no significant differences in the crude DAL scores between individuals with low testosterone levels and individuals with normal testosterone levels. Multivariate regression models adjusting for covariates confirmed the lack of associations between the PRAL and serum testosterone. Our results are of particular importance for those individuals who wish to lower their DAL in light of the presumable health effects of a more alkaline diet. Our data suggest that diet modifications toward a lower intake of animal protein and refined grains (which consecutively translates into a lower DAL) may not negatively affect men's testosterone levels.

Testosterone deficiency (TD) is an increasingly common problem with significant health implications, but its diagnosis and management can be challenging. A multi-disciplinary panel from BSSM reviewed the available literature on TD and provide evidence-based statements for clinical practice. Evidence was derived from Medline, EMBASE and Cochrane searches on hypogonadism, testosterone therapy (T Therapy) and cardiovascular safety from May 2017 to September 2022. This revealed 1,714 articles, including 52 clinical trials and 32 placebo-controlled randomised controlled trials. A total of twenty-five statements are provided, relating to five key areas: screening, diagnosis, initiating T Therapy, benefits and risks of T Therapy, and follow-up. Seven statements are supported by level 1 evidence, eight by level 2, five by level 3, and five by level 4. Recent studies have demonstrated that low levels of testosterone in men are associated with increased risk of incident type 2 diabetes mellitus, worse outcomes in chronic kidney disease and COVID 19 infection with increased all-cause mortality, along with significant quality of life implications. These guidelines should help practitioners to effectively diagnose and manage primary and age-related TD.

The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology.

There is a bidirectional interaction between circulating testosterone and blood glucose levels. We aim to investigate the testosterone levels in men with early-onset type 2 diabetes (T2DM).

A total of 153 drug naive men with T2DM were enrolled in the study. Early- (n = 63) and late-onset (n = 90) T2DM was classified according to age 40 years old. Clinical characteristics and plasma for biochemical criterions were collected. Gonadal hormones were measured using chemiluminescent immunometric assay. The concentrations of 3β- and 17β-HSD were determined using ELISA.

Compared with men with late-onset T2DM, those with early-onset T2DM had lower serum total testosterone (TT), sex hormone-binding globulin (SHBG), and FSH, but higher dehydroepiandrosterone sulfate (DHEA-S) level (p < 0.05). The mediating effect analysis showed that the decreased TT levels in patients with early-onset T2DM were associated with the higher HbA1c, BMI, and triglyceride in these patients (both p < 0.05). The early-onset of T2DM directly correlated with increased DHEA-S (both p < 0.01). The 3β-HSD concentration in the early-onset T2DM group was lower than that in the late-onset T2DM group (11.07 ± 3.05 vs. 12.40 ± 2.72 pg/mL, p = 0.048) and was positively correlated with fasting C-peptide, while negatively correlated with HbA1c and fasting glucagon (p all < 0.05).

Patients with early-onset T2DM showed inhibition of conversion from DHEA to testosterone, which may attribute to the low level of 3β-HSD and high blood glucose in these patients.

Prostate cancer (PCa) is considered one of the most important medical problems in the male population, with a very high incidence after the age of 65. Frailty represents one of the most critical issues facing healthcare due to its inherent relationship with poor healthcare outcomes. The physical phenotype of frailty syndrome based on Fried criteria has been associated with poor outcomes, morbidity, and premature mortality. To date, there are few studies that have analyzed frailty syndrome in patients with localized and advanced (mPCa) disease under androgen-deprivation therapy.

Our goal was to assess whether there are differences in frailty criteria between mPCa and localized PCa. We also evaluated the role of other geriatric variables such as depressive and insomnia symptoms, which are frequently reported in cancer patients.

In this cross-sectional study, frailty syndrome was evaluated in both groups, as well as its possible relationship with cognitive functions, depressive and insomnia symptoms, and other clinical variables related to PCa and its treatment. Frailty was defined on Fried's criteria: low lean mass, weakness, self-reported exhaustion, low activity level, and slow walking speed; prefrailty was defined as having one or two of those criteria and frailty as having three or more, depressive symptoms were defined by the Yesavage scale, cognitive functions with the Mini-Mental examination test, and insomnia symptoms by the Athens scale and self-reported health status.

The prevalence of prefrailty/frailty was slightly higher in mPCa compared to localized PCa (81.5% versus 72.3%, respectively), however by analyzing each of the frailty criteria, two of them were significantly reduced in mPCa compared to localized PCa patients, e.g., gait speed (p = 0.001) and muscle strength (p = 0.04). The reduced gait speed and muscle strength in mPCa were not due to the increased age in mPCa group, or to an increase in comorbidities or shorter time under androgen-deprivation therapy. The symptoms of insomnia were significantly higher in mPCa patients compared to those with localized PCa (p < 0.05) whereas cognitive functions or depressive symptoms were not significantly different between the two groups.

Patients with mPCa under androgen-deprivation therapy display higher alterations in gait speed and muscular strength and insomnia symptoms, thus interventions should be aimed to reduce these alterations in order to limit adverse outcomes related to them and to improve quality of life in these patients.

For the development and maintenance of neuron networks in the brain, epigenetic mechanisms are necessary, as indicated by recent findings. This includes some of the high-order brain processes, such as behavior and cognitive functions. Epigenetic mechanisms could influence the pathophysiology or etiology of some neuronal diseases, altering disease susceptibility and therapy responses. Recent studies support epigenetic dysfunctions in neurodegenerative and psychiatric conditions, such as Alzheimer's disease (AD). These dysfunctions in epigenetic mechanisms also play crucial roles in the transgenerational effects of the environment on the brain and subsequently in the inheritance of pathologies. The possible role of gonadal steroids in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, has become the subject of a growing body of research over the last 20 years. Recent scientific findings suggest that epigenetic changes, driven by estrogen and androgens, play a vital role in brain functioning. Therefore, exploring the role of estrogen and androgen-based epigenetic changes in the brain is critical for the deeper understanding of AD. This review highlights the epigenetic modifications caused by these two gonadal steroids and the possible therapeutic strategies for AD.

How do capacitation ability, measured by Cap-Score™, and traditional semen analysis measures (volume, concentration, motility) change with age in men questioning their fertility (MQF)?

Cap-Score and semen analysis measures were obtained from MQF (n = 2652; multicentric design: 35 reproductive endocrinologist prescribers, n = 16 clinics). Morphology was not included due to differences among clinics. A Mann-Whitney test was used to compare Cap-Scores between MQF and men with known recent paternity (n = 76). The following age groups were constructed for MQF: 20-24, 25-29, 30-34, 35-39, 40-44, 45-49 and 50+. Associations between semen analysis, Cap-Score and age groups were evaluated using mixed-model analysis of variance to identify possible influence of Cap-Score collection kit type (n = 763 collected at home; n = 1889 collected at clinics).

MQF had reduced capacitation ability (mean ± SE; 29.25 ± 0.15 versus 35.34 ± 0.88; P < 0.001). No change in Cap-Score (P = 0.916) or concentration (P = 0.926) was detected with age group. In contrast, both volume (P = 0.008) and % motility (P < 0.001) declined with age.

Men presenting because of difficulties in generating pregnancy showed equivalent reductions in capacitation ability regardless of age. In contrast, motility and volume declined with age. These data suggest that capacitation ability is a more sensitive indicator of male fertility across age groups than traditional semen analysis and should not be reserved for older men. Importantly, these data do not address whether sperm fertilizing ability declines in the general population as men age. Instead, they indicate that if men are having difficulty conceiving, no matter what their age, then defects in sperm fertilizing ability are equally likely to be the cause.

Sarcopenia, a condition of low muscle mass, quality, and strength, is commonly found in patients with chronic liver disease (CLD) and is associated with adverse clinical outcomes including reduction in quality of life, increased mortality, and complications. A major contributor to sarcopenia in CLD is the imbalance in muscle protein turnover wherein changes in various metabolic factors such as hyperammonemia, amino acid deprivation, hormonal imbalance, gut dysbiosis, insulin resistance, chronic inflammation, etc. have important roles. In particular, hyperammonemia is a key mediator of the liver-gut axis and is known to contribute to sarcopenia by various mechanisms including increased expression of myostatin, increased phosphorylation of eukaryotic initiation factor 2a, cataplerosis of α-ketoglutarate, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy-mediated proteolysis. Skeletal muscle is a major organ of insulin-induced glucose metabolism, and sarcopenia is closely linked to insulin resistance and metabolic syndrome. Patients with liver cirrhosis are in a hypermetabolic state that is associated with catabolism and depletion of amino acids, particularly branched-chain amino acids. Sarcopenia can have significant implications for nonalcoholic fatty liver disease, the most common form of CLD worldwide, because of the close link between metabolic syndrome and sarcopenia. This review discusses the potential metabolic derangement as a cause or effect of sarcopenia in CLD, as well as interorgan crosstalk, which that might help identifying a novel therapeutic strategies.

Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression.

To make the diagnosis of hypogonadism in an ageing man, in absence of rare organic cause often referred to as functional or late onset hypogonadism (LOH), he should present with a clinical syndrome suggestive of androgen deficiency and have consistently low serum testosterone (T) levels. This does not differ from the diagnosis of any other form of hypogonadism. Particular to LOH diagnostic are uncertainties surrounding this entity: signs and symptoms of androgen deficiency (including sexual symptoms) are nonspecific in older men; clinical significance of only moderately low T levels is uncertain; comorbidity plays a substantial role with potential for reversibility; the place of T therapy in these men is debatable. This context demands for a pragmatic, but appropriately conservative approach to diagnosis. Evaluation should be stepwise with clinical evaluation, if suggestive for androgen deficiency, followed by measurement of a fasting morning serum T, if unequivocally low to be confirmed in a separate morning sample by a second low T or, if initial T borderline low or in presence of factors known to affect SHBG, by a low calculated free T level. All other (free) T results make hypogonadism an unlikely cause of the patient's symptoms. In the absence of consensus cut-off levels for total and free T in the published clinical guidelines for diagnosis of hypogonadism, it seems appropriate in the context of LOH to use stringent criteria indicating a convincingly low serum T. The approach to the diagnosis of LOH is not fundamentally different from that of other forms of hypogonadism but should put extra weight on prioritizing the shunning of overdiagnosis above the risk of underdiagnosis.