Testosterone has a pivotal role in spermatogenesis, erectile function, libido and expression of secondary sexual characteristics. The prevalence of symptomatic, laboratory-proven testosterone deficiency increases with age and is often treated with testosterone replacement therapy (TRT). Treatment with exogenous androgens suppresses gonadotropin levels, inhibits endogenous testosterone production and drastically reduces intratesticular testosterone, consequently impairing spermatogenesis. Sperm production often slowly resumes after TRT cessation. However, the rate of recovery shows highly variable kinetics that might complicate family planning. Medical therapies (including aromatase inhibitors and selective oestrogen receptor antagonists) and exogenous gonadotropins (including human chorionic gonadotropin and follicle-stimulating hormone) may be used to preserve or restore spermatogenesis in select populations receiving TRT. Exogenous testosterone is contraindicated in men trying to conceive, but new short-acting formulations, including oral testosterone undecanoate and nasal testosterone gel, might incompletely suppress the hypothalamic-pituitary-gonadal axis and partially preserve spermatogenesis.

Sarcopenia is recognized as a complex and multifactorial disorder that includes nutritional deficiency, inactivity, proinflammatory status, hormonal changes, neurological degeneration, and metabolic disturbances. It's pathogenesis is not fully understood. Therefore, identifying specific biomarkers of sarcopenia will help us understand its pathophysiology. The most frequently reported blood-derived biomarkers of sarcopenia are growth factors, neuromuscular junctions, endocrine systems, mitochondrial dysfunction, inflammation-mediated and redox processes, muscle protein turnover, blood metabolomics, and behavior-mediated biomarkers. Here, we address the implications of sarcopenia biomarkers based on our research experience with Korean Frailty and Aging Cohort Study cohort data. It includes free testosterone, myostatin, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF-15), procollagen type III N-terminal peptide (P3NP), creatinine-based biomarkers, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), brain-derived neurotrophic factor (BDNF), metabolites (proline, alanine, tryptophan), and multi-biomarker risk score. We attempted to explain the paradoxical findings of myostatin and FGF-21 levels in relation to sarcopenia. GDF-15 levels were associated with sarcopenia prevalence but not its incidence. Plasma P3NP and BDNF levels may be biomarkers of muscle quality rather than quantity. Lower erythrocyte eicosapentaenoic acid (EPA) and docosahexaenoic acid levels were associated with slow gait speed, and erythrocyte EPA levels were associated with low handgrip strength. We developed a multi-biomarker risk score for sarcopenia and found that its accuracy in diagnosing sarcopenia was higher than that of any single biomarker.

Testosterone has been implicated in mood regulation, yet its role in the development and treatment of depression remains unclear. This study investigated the association between testosterone concentrations and the incidence of depression in older men.

We utilized data from 4 107 men aged 70 years and older who participated in the Aspirin in Reducing Events in the Elderly (ASPREE) and ASPREE-XT studies. Serum total testosterone concentrations were measured at baseline and year 3. Depressive symptoms were assessed annually using the CES-D-10 scale, with incident depression defined as a CES-D-10 score of ≥8. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) for incident depression, adjusted for potential confounders.

During a median follow-up of 8.4 years, 1 449 participants experienced an episode of depression. Baseline total testosterone concentrations were not significantly associated with the risk of incident depression, whether treated as continuous variables (HR 1.00, 95% CI 0.99-1.01) or when categorized into quintiles. Similarly, changes in testosterone concentrations from baseline to year 3 did not predict incident depression (aHR 1.03, 95% CI 0.99-1.08). A subgroup analysis focusing on men with biochemical evidence of hypogonadism also found no association with incident depression.

Our findings do not support an association between testosterone concentrations and the risk of developing depression in older men. These results suggest that testosterone is not an important factor in the pathogenesis of depression in this population. There may still be individual variability in response to testosterone changes and its potential impact on mood disorders.

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 review explores the increasing use of testosterone therapy in aging men, driven by the need to address age-related symptoms like decreased libido, muscle weakness, and anemia. Studies such as the Testosterone Trials and Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men trial show that testosterone therapy can offer benefits in sexual function, physical performance, and bone density, with no significant increase in risks for cardiovascular events or prostate cancer. However, conflicting data suggest that careful, individualized treatment is necessary, especially in older men with existing health conditions.

Testosterone is the classical male anabolic hormone, involved in sexual development, virilisation and regulation of body composition in adult men. Organic disease involving the hypothalamus, pituitary or testes may interfere with endogenous testosterone production. In such men, testosterone treatment effectively ameliorates symptoms and signs of androgen deficiency. However, non-gonadal factors including age, body mass index and medical comorbidities influence circulating testosterone, and older men have on average lower testosterone concentrations compared with younger men. In these men, testosterone treatment would be a pharmacological intervention requiring stringent justification via high-quality evidence from randomised controlled trials (RCTs). Recent RCTs show benefits of testosterone treatment to improve sexual function, anaemia and bone mineral density in older men, and to prevent or revert type 2 diabetes mellitus in men at high risk. Results from a large cardiovascular safety trial in men with or at risk of cardiovascular disease provide important reassurance as to cardiovascular and prostate safety of testosterone treatment. Key questions remain as to whether testosterone's anabolic and other effects can be used safely to counter reductions in lean mass associated with incretin-based weight loss medications in men with obesity, and whether it might prevent disabilities including frailty, osteoporotic fractures and dementia in older men generally. This last question could be answered by a new testosterone RCT, targeting men in the 65-80 years age bracket, which would necessarily be large and of extended duration. A composite endpoint could be used which integrates potential benefits and risks, such as disability-free survival.

Gonadal testosterone stimulates skeletal muscle anabolism and contributes to sexually differentiated adipose distribution through incompletely understood mechanisms. Observations in humans and animal models have indicated a major role for androgen receptor (AR) in mediating sex differences in body composition throughout the lifespan. Traditional surgical, genetic and pharmacological studies have tested systemic actions of circulating androgens, and more recent transgenic approaches have allowed for tests of AR gene function in specific androgen responsive niches contributing to body composition, including: skeletal muscle and surrounding interstitial cells, white and brown adipose, as well as trabecular and cortical bone. Less well understood is how these functions of gonadal androgens interact with exercise. Here, we summarize the understood mechanisms of action of AR and its interactions with exercise, specifically on outcomes of body composition and muscle function, and the global- and tissue-specific role of AR in regulating skeletal muscle, adipose, and bone morphology. Additionally, we describe the known effects of androgen and AR manipulation on female body composition, muscle morphology, and sport performance, while highlighting a need for greater inclusion of female subjects in human and animal muscle physiology and endocrinology research.

Testosterone has been shown to enhance hippocampal neurogenesis through increased cell survival, but which stages of new neuron development are influenced by testosterone remains unclear. Therefore, we tested the effects of sex steroids administered during three different periods after cell division in the dentate gyrus of adult male rats to determine when they influence the survival of new neurons. Adult male rats were bilaterally castrated. After 7 days of recovery, a single injection of bromodeoxyuridine (BrdU) was given on the first day of the experiment (Day 0) to label actively dividing cells. All subjects received five consecutive days of hormone injections during one of three stages of new neuron development (days 1-5, 6-10, or 11-15) after BrdU labeling. Subjects were injected during these time periods with either testosterone propionate (0.250 or 0.500 mg/rat), dihydrotestosterone (0.250 or 0.500 mg/rat), or estradiol benzoate (1.0 or 10 µg/rat). All subjects were euthanized sixteen days later to assess the effects of these hormones on the number of BrdU-labeled cells. The high dose of testosterone caused a significant increase in the number of BrdU-labeled cells in the hippocampus compared to all other groups, with the strongest effect caused by later injections (11-15 days old). In contrast, neither DHT nor estradiol injections had any significant effects on number of BrdU-labeled cells. Fluorescent double-labeling and confocal microscopy reveal that the majority of BrdU-labeled cells were neurons. Our results add to past evidence that testosterone increases neurogenesis, but whether this involves an androgenic or estrogenic pathway remains unclear.

This work aimed to evaluate the effects of the aqueous extract of Vepris afzelii roots on a rat model of hypogonadism. Phytochemical screening and acute toxicity of the extract were performed using different procedures. Hypogonadism was induced orally in adult Wistar rats using cyproterone acetate (30 mg/kg) for ten days. Besides six normal rats (10 ml/kg of distilled water, normal control), 30 hypogonadal rats were subdivided into five groups of six animals each, receiving for 14 days: distilled water (10 ml/kg, hypogonadal control), testosterone (4 mg/kg/3days) and the extract of V. afzelii (100, 200 and 400 mg/kg). Sexual behavior, sperm parameters, testes function and structure were assessed. Compared to the normal controls, significant (p = 0.0000) increases in mount (24 ± 0.94 seconds vs. 1200 ± 00 seconds) and intromission (49.16 ± 10.85 seconds vs. 1200 ± 00 seconds) latencies, and post-ejaculatory interval (381.72 ± 37.55 seconds vs. 1200 ± 00 seconds) were observed in all groups receiving cyproterone acetate on day 0. Total inhibitions of mounts (63.50 ± 8.91 vs. 00 ± 00), intromissions (36.66 ± 3.51 vs. 00 ± 00) (p = 0.0000), ejaculations (2.83 ± 00 vs. 00 ± 00, p = 0.0002) frequencies and mean copulatory interval (627.30 ± 81.80 vs. 00 ± 00, p = 0.0000) were also observed in these groups. Moreover, decreases in daily sperm production (2.65 ± 0.19 vs. 1.17 ± 0.08, p = 0.0498), percentage of sperm mobility (78.64 ± 8.41 vs. 10.12 ± 2.32), serum testosterone level (8.39 ± 0.63 ng/dl vs. 1.68 ± 0.19 ng/dl), diameter of seminiferous tubules (111.97 ± 0.51 µm vs. 94.51 ± 0.57 µm) and height of germinal epithelium (46.58 ± 0.34 µm vs. 33.74 ± 0.66 µm) (p = 0.0000) associated with increases in sperm transit (3.13 ± 0.45 vs. 11.07 ± 1.45, p = 0.0000) were also observed in these groups. Interestingly, compared to hypogonadal control and day 0, the administration of V. afzelii extract induced significant (p = 0.0000) improvements in all these altered parameters with 400 mg/kg being the most active dose. These results, attributed to saponins, flavonoids, polyphenols and triterpenes detected in this plant's extract confirm its traditional usage and could be useful for the management of patients suffering from hypogonadism.

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs. Numerous inputs for a specific tissue are produced by the activity of circadian clocks of other tissues or cell types, generating a form of crosstalk known as clock communication. In mammals, the central clock in the hypothalamus integrates signals from external light-dark cycles to align peripheral clocks elsewhere in the body. This regulation is complemented by a tissue-specific milieu of external, systemic and niche inputs that modulate and cooperate with the cellular circadian clock machinery of a tissue to tailor its functional output. These mechanisms of clock communication decay during ageing, and growing evidence suggests that this decline might drive ageing-related morbidities. Dietary, behavioural and pharmacological interventions may offer the possibility to overcome these changes and in turn improve healthspan.

The decline in testosterone levels among older men remains a subject of debate. While some cross-sectional and longitudinal studies have reported a decrease in testosterone with advancing age, others have not observed this trend. In this study, we aimed to evaluate testosterone levels and identify predictors of low testosterone in an age-stratified cohort of men.

From January 2016 to June 2022, a cohort of men receiving routine care at a primary care center was prospectively analyzed. Participants were stratified into age groups: 45-64 years (middle-aged), 65-74 years (young-old), 75-84 years (middle-old), and ≥85 years (oldest-old). Comprehensive clinical and laboratory assessments were conducted, including waist circumference, glucose levels, triglycerides, HDL cholesterol, and total testosterone. Low testosterone was defined as levels below 300ng/dL. Metabolic syndrome was diagnosed in accordance with established diagnostic criteria.

The study included 3.489 subjects across age groups. Median testosterone levels were similar across all age groups. The prevalence of low testosterone was around 20% in all groups and did not significantly vary with age. Obesity, as indicated by increased waist circumference (WC) >102 cm, was strongly associated with low testosterone. The prevalence of low testosterone increased from 8% in those with WC≤93cm to 44% in those with WC≥110cm.

This study highlights the significant association between low testosterone levels and obesity, reinforcing the importance of addressing comorbidities in testosterone decline.

Spatial memory declines with age, and this decline is associated with decreased testosterone levels. However, the specific role of the androgen receptor in spatial memory performance in both young and aged rats remains largely unexplored. Our study aimed to investigate the effects of chronic androgen receptor blockade on spatial memory performance in young and aged male rats. Young (3 months old) and aged (21 months old) Wistar rats were assigned to one of three experimental groups: control, vehicle-, or flutamide-treated (10 mg/kg SC for 14 days). Spatial memory was evaluated using the Barnes maze (Days 8-14 of flutamide administration). The phases of spatial memory acquisition (4 daily trials/4 days) and retention (1 trial/day, 3 days after acquisition) were evaluated. The results indicated that older animals took longer to find the goal, traveled greater distances, and moved more slowly than their younger counterparts in the Barnes maze, regardless of treatment. During the acquisition phase, flutamide administration delayed learning in both young and aged animals. Specifically, flutamide-treated animals exhibited delayed learning during the assessment of overnight forgetting (trial 1 on each day of the acquisition phase). During the retention phase, an age-related effect was observed in the flutamide-treated groups. These findings suggest that androgen receptor blockade induces cognitive deficits in both young and aged male rats, supporting the modulatory role of endogenous androgens in memory function.

Background/Objectives: Low testosterone levels and low vitamin D status are associated with increased cardiometabolic risk. The purpose of this study was to investigate whether vitamin D status determines the cardiometabolic effects of testosterone replacement therapy. Methods: The study population consisted of three groups of men with late-onset hypogonadism: vitamin D-naive individuals with 25-hydroxyvitamin D levels between 20 and 30 ng/mL (group I), males with 25-hydroxyvitamin D levels between 30 and 60 ng/mL receiving vitamin D supplementation because of previous low vitamin D status (group II), and vitamin D-naïve subjects with 25-hydroxyvitamin D levels between 30 and 60 ng/mL (group III). Circulating levels of total testosterone, 25-hydroxyvitamin D, glucose, insulin, lipids, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen, and urinary albumin-to-creatinine ratio (UACR) were assessed before and six months after intramuscular testosterone administration (250 mg every three weeks). Results: Group I differed from the remaining groups in baseline values of 25-hydroxyvitamin D, hsCRP, homocysteine, fibrinogen, UACR, and the Framingham Risk Score. In all three groups, testosterone injections increased plasma testosterone levels and had a neutral effect on 25-hydroxyvitamin D concentration. In groups II and III, the drug improved insulin sensitivity and reduced LDL cholesterol, uric acid, hsCRP, homocysteine, fibrinogen, and UACR. In group I, the impact of testosterone was limited to a small decrease in HDL cholesterol and hsCRP. Only in groups II and III did testosterone reduce the Framingham Risk Score. There were no differences in the strength of testosterone action between both groups. In groups II and III, the replacement-induced changes in insulin sensitivity, LDL cholesterol, uric acid, hsCRP, homocysteine, fibrinogen, UACR, and the Framingham Risk Score positively correlated with 25-hydroxyvitamin D concentration. Conclusions: The study results suggest that the cardiometabolic effects of exogenous testosterone in men with testosterone deficiency may be determined by vitamin D status.

Age-related testosterone depletion in men is a risk factor for Alzheimer's disease (AD). How testosterone modulates AD risk remains to be fully elucidated, although regulation of tau phosphorylation has been suggested as a contributing protective action. To investigate the relationship between testosterone and tau phosphorylation, we first evaluated the effect of androgen status on tau phosphorylation in 3xTg-AD mice. Depletion of endogenous androgens via gonadectomy resulted in increased tau phosphorylation that was prevented by acute testosterone treatment. Parallel alterations in the phosphorylation of both glycogen synthase kinase 3β (GSK3β) and protein kinase B (Akt) suggest possible components of the underlying signaling pathway. To further explore mechanism, primary cultured neurons were treated with a physiological concentration of testosterone or its active metabolite dihydrotestosterone (DHT). Results showed that testosterone and DHT induced significant decreases in phosphorylated tau and significant increases in phosphorylation of Akt and GSK3β. Pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K) effectively inhibited androgen-induced increases in Akt and GSK3β phosphorylation, and decreases in tau phosphorylation. In addition, androgen receptor (AR) knock-down by small interfering RNA prevented androgen-induced changes in the phosphorylation of Akt, GSK3β and tau, suggesting an AR-dependent mechanism. Additional experiments demonstrated androgen-induced changes in Akt, GSK3β and tau phosphorylation in AR-expressing PC12 cells but not in AR-negative PC12 cells. Together, these results suggest an AR-dependent pathway involving PI3K-Akt-GSK3β signaling through which androgens can reduce tau phosphorylation. These findings identify an additional protective mechanism of androgens that can improve neural health and inhibit development of AD.

The average current life expectancy entails that women will spend over one-third of their lives in menopause. Follicle-stimulating hormone (FSH) levels in women begin to increase roughly six years before the final menstrual period, reaching a menopausal plateau that is nearly 14 times the level of FSH observed in men, a profound sex-specific difference. A promising new body of work examines whether these age-associated increases in FSH contribute to multiple menopause-related conditions, including psychiatric morbidities. This paper highlights research advances showing the potential role of FSH and its underlying mechanisms in mental health conditions for women in menopause and makes the call for more research.

Traumatic brain injuries (TBIs) are conditions affecting brain function caused by blunt or penetrating forces to the head. Symptoms may include confusion, impaired consciousness, coma, seizures, and focal or sensory neurological motor injuries.

This study evaluated sex hormone profiles and their predictive role in returning consciousness after severe traumatic brain injury.

We included 120 patients with TBIs and collected comprehensive information about each patient, including the cause of the trauma, age, gender, Glasgow Coma Scale (GCS) score, Injury Severity Score (ISS), and neuroradiological imaging data. The ISS was used to assess the severity of the trauma. At the same time, the lowest GCS score was recorded either before sedation and intubation in the emergency room or by emergency medical services personnel. For female participants, samples were collected during the luteal phase of the menstrual cycle (days 18 to 23).

The mean age of male patients was 33.40 years, ranging from 23 to 45 years, while female patients had an average age of 34.25 years, ranging from 25 to 48 years. The primary cause of injury for both genders was motor vehicle accidents. In male patients, testosterone levels were significantly higher in those classified as responsive (RC) compared to those non-responsive (NRC), with levels of 2.56 ± 0.47 ng/mL versus 0.81 ± 0.41 ng/mL (p = 0.003). A cut-off point of 1.885 ng/mL for testosterone levels in males was established, achieving a sensitivity and specificity of 86.7% and 86.7%, respectively. In female patients, progesterone levels were elevated in those who regained consciousness, measuring 1.80 ± 0.31 ng/mL compared to 0.62 ± 0.31 ng/mL (p = 0.012). A cut-off point of 1.335 ng/mL for progesterone levels in females was determined, with a sensitivity and specificity of 93.3% and 86.7%, respectively.

We can conclude that sex hormone levels in the acute phase of TBIs can vary between males and females. Notably, serum testosterone levels in males and progesterone levels in females with TBIs are significant prognostic factors for assessing the likelihood of regaining consciousness after such injuries. These findings underscore the importance of considering sex hormone profiles in TBI recovery prognosis.

We aimed to depict the age-specific distribution of total Testosterone (tT) levels among young men presenting to a single academic centre with uro-andrological complaints. Overall, tT levels from 2593 men aged 20-44 years were analyzed. Men were grouped into 'infertile men' and 'men with sexual dysfunction (SD)' according to their primary complaints. Data was also collected from 71 same-ethnicity age-comparable fertile controls. Linear regression fitted the relationship between tT and increasing age. Distribution of tT was determined for each 5-year age-group, both for the overall population and the subgroups. tT quantiles were reported for each sample sub-group and age-group. Of 2664 men, 1913 (71.81%) were classified as infertile, 680 (25.52%) with SD and 71 as fertile men (2.67%), respectively. tT levels depicted a reduction of 0.14 nmol/L per year between 20 and 44 years of age (p < 0.001) within the overall study population. Significant reduction was also observed for the population stratified by urological complaints (all p < 0.05). This is the first study to describe tT levels as a function of baseline clinical status in a large same-ethnicity cohort of young men, uniformly assessed using a standardized laboratory method.

Few longitudinal studies have described the prevalence and development of biochemical hypogonadism in aging testicular cancer survivors (TCSs) in comparison to men from the general population (control subjects).

Serum total and free testosterone (Ttotal, Tfree) were measured in 593 TCSs median11 and 27 years after TC diagnosis (Survey-First; Survey-Last). Post-treatment adverse health outcomes (AHOs) were recorded. The results were compared to those in 578 control subjects. Treatment was stratified as surgery alone, radiotherapy alone, or platinum-based chemotherapy. Biochemical hypogonadism was defined as Ttotal <8 nmol/l, or as Ttotal <12 nmol/l and Tfree <225 pmol/l. We used multivariable logistic regression analysis to explore associations with age and treatment intensity. Statistical significance was set at p <0.05.

Between the first and last survey the prevalence of biochemical hypogonadism increased from 12% to 41% in the TSC group and from 5% to 11% in the control group. Three decades after diagnosis, the probability of biochemical hypogonadism was significantly correlated with increasing age and greater treatment intensity. The combined age- and treatment- related probability of hypogonadism was more than threefold higher in the TCS group than in the control group. At the last survey, fewer eugonadal than hypogonadal TCS men reported at least one AHO attributable to androgen deficiency (54% vs 72%; p <0.001). Limitations include the availability of only one blood sample per survey wave.

For aging TCSs, the probability of biochemical hypogonadism depends on age and prior treatment intensity and is threefold higher than for control subjects at 30 yr after diagnosis. As late hypogonadism is associated with AHO incidence, the development of hypogonadism should be monitored via regular blood tests during TCS follow-up.

Depending on the treatment they received, older survivors of testicular cancer (TC) are at persistent risk of lower testosterone levels. Our study revealed low testosterone in 40% of TC survivors older than 60 years compared to 10% of similarly aged men from the general population. Low testosterone is associated with chronic conditions such as diabetes, fatigue, and/or erectile dysfunction. Testosterone should be regularly monitored during follow-up for TC survivors.

Background/Objectives: The aim of this study was to investigate the relationship between age, the severity of erectile dysfunction (ED), and the various hormones that may influence erectile function. Methods: A multicenter cross-sectional study was conducted between January 2015 and December 2023. The study assessed age, sexual function using the IIEF-15 questionnaire, and the levels of total testosterone (TT), free testosterone (FT), FSH, LH, estradiol, prolactin (PRL), and SHBG. Results: A total of 411 patients were included in the study. The mean age of the patients was 63.19 years. The vast majority (91.73%) exhibited some degree of ED. The severity of ED increases with age, ranging from 56.26 years for patients without ED to 73.12 years for those with severe ED. A statistically significant negative correlation was observed between IIEF and age, while a positive correlation was observed between IIEF and serum levels of TT and FT (p < 0.05). Age was significantly correlated with all evaluated hormones (p < 0.01), except estradiol and prolactin. Total testosterone levels progressively decreased with the increase in the severity of erectile dysfunction, from a median of 7.05 ng/mL in patients with normal erectile function to 3.56 ng/mL in those with severe symptoms, remaining above the normal minimum threshold across all groups, whereas free testosterone (FT) levels also declined progressively. All erectile dysfunction groups had median FT levels below the normal minimum threshold. FSH, LH, and SHBG showed an increase with each progressive severity of erectile dysfunction. The multivariate linear regression revealed that IIEF scores are significantly associated with age, TT, and FT levels, while FSH did not present a statistically significant association in this model. Conclusions: Age shows a significant statistical correlation with both the severity of erectile dysfunction and the levels of total testosterone, free testosterone, LH, FSH, and SHBG. Total and free testosterone levels are significantly associated with the severity of erectile dysfunction, with free testosterone median values remaining above the normal minimum threshold in all patients with erectile dysfunction. Therefore, free testosterone should be considered a routine test, alongside total testosterone. In contrast, LH, estradiol, SHBG, and prolactin do not demonstrate any statistical correlation with erectile dysfunction and should not be recommended as routine investigations.

Spermatogenesis is finely regulated by histone methylation, which is crucial for regulating gene expression and chromatin remodeling. Functional studies have demonstrated that the histone lysine methyltransferases (KMTs) SETD1B, CFP1, SETDB1, G9A, and SETD2 play pivotal roles in spermatogenesis through establishing the key histone methylation marks, H3K4me3, H3K9me2, H3K9me3, and H3K36me3, respectively. This study aimed to evaluate the spatiotemporal expression of these KMTs and methylation marks as well as senescence-associated β-galactosidase (β-GAL), transcriptional activity, and apoptosis rates in mouse testes during biological aging. In accordance with these purposes, the following groups of Balb/C mice were created: young (1- and 2-week-old), prepubertal (3- and 4-week-old), pubertal (5- and 6-week-old), postpubertal (16-, 18-, and 20-week-old), and aged (48-, 50-, and 52-week-old). The β-GAL staining gradually increased from the young to the aged groups (P < 0.01). The SETD1B, G9A, SETDB1, and SETD2 protein levels increased in spermatogonia, early and pachytene spermatocytes, and Sertoli cells of the aged group (P < 0.05). In contrast, CFP1 protein level decreased in spermatogonia, pachytene spermatocytes, round spermatids, and Sertoli cells towards the older ages (P < 0.05). Moreover, H3K4me3, H3K9me2, H3K9me3, and H3K36me3 levels increased in the aged group (P < 0.05). There was also a significant reduction in apoptosis rates in seminiferous tubules of the pubertal, postpubertal, and aged groups (P < 0.01). Consequently, accumulation of histone methylation marks due to increased expression of KMTs in spermatogenic and Sertoli cells during testicular aging may alter chromatin reprogramming and gene expression, contributing to age-related fertility loss.

Chronic pain, pain that lasts beyond three months, is a common finding in the elderly. It is often due to musculoskeletal conditions but can be precipitated by other factors as well. While physiological systems decline with aging, chronic pain is influenced by changes in hormone profiles as men and women enter into andropause and menopause, respectively. Research on gonadal hormones is limited, especially when it comes to their relationship with chronic pain. Women tend to experience less pain with aging compared to their premenopausal years, and this is partially explained by the fact that estrogen enhances pain sensitivity and its decline during menopause decreases it. However, hormone replacement therapy (HRT) seems to increase pain tolerance post-menopause. There is some evidence that testosterone plays a protective factor in pain perception. Men on the other hand, have higher pain tolerance as testosterone is considered to be a protective factor. With aging and decreasing testosterone, older men tend to be less tolerant to pain. This paper explores how hormonal changes with aging impact pain perception in both men and women, highlighting several pain conditions influenced by hormones. Although research remains limited, the potential of HRT as a treatment for common pain conditions is examined.

This study aimed to assess the efficacy and safety of Fufang Xuanju capsule in males with late-onset hypogonadism (LOH) complaining of sexual dysfunction during 3 months period. We identified the patients through questionnaires and laboratory examinations. Patients in the treatment group (n = 57) and placebo group (n = 50) received Fufang Xuanju capsules (3.78 g) or placebo capsules daily for 3 months, respectively. After treatment, the plasma total testosterone of both groups sustained, however, libido and erectile dysfunction in patients of the treatment group but not placebo group were significantly improved, measured by elevated scores of International Index of Erectile Function-5. The overall efficacy rate of Fufang Xuanju capsule for LOH was 71.9%. The most striking clinical effects were observed in patients exhibiting mild and moderate erectile dysfunction. No severe adverse effects were observed during the period of study. The remaining parameters such as total prostate-specific antigen, prostate volume and uroflow rate remained stable. Fufang Xuanju capsule proves to be an effective and safe treatment in a short time to alleviate symptoms of sexual dysfunction in LOH patients, especially in those exhibiting mild and moderate erectile dysfunction. Little effect on the level of total testosterone makes it well suitable for LOH patients which have contraindications of testosterone replacement therapy.

One third of the multiple sclerosis (MS) population consists of peri- or postmenopausal women. Many symptoms of menopause overlap those of MS. Some studies show increased speed of disability progression after menopause, while others indicate an unaltered trajectory.

Determine the association between menopause and MS disease course.

Cohort study with clinical data collected prospectively. Self-reported age of menopause, smoking and parity collected retrospectively.

We included 559 peri-/postmenopausal women and 386 similarly aged men. There was no significant difference in EDSS progression (slope coef 0.03, 0.02-0.08, p = 0.208) or annual relapse rate (ARR) (0.10, 0.29-0.10, p = 0.324) in the 5 years before and after menopause. Women's EDSS progressed slower than men's after menopause (coef -0.02, 95% CI -0.04 to -0.002, p = 0.032), but there was no difference in ARR [coef. -0.01, 95% CI -0.04 to -0.01, p = 0.262]. Women who reached menopause before MS onset had shorter time to diagnosis than women who reached menopause after onset (3.1 years (3.1) vs. 7.4 years (8.1), p < 0.001). Women who reached menopause before diagnosis had an even longer time to diagnosis (8.8 (9.3) vs. 5.5 (6.3), p < 0.001).

There were no significant differences in EDSS progression or ARR before and after menopause. In fact, men progressed faster than women, suggesting there is no negative impact of menopause on disease progression, as measured by EDSS and relapses.

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.

Due to its important role in fertility, reproductive endocrine function has been subject to natural selection in all organisms including human males. Moreover, reproductive endocrine function is subject to change as males age. Indeed, the biology of aging is also subject to natural selection. As males age, hormone function such as variation in testosterone can change as the result of general somatic degradation. However these changes are not universal and can differ between human male populations depending on lifestyle and ecological context. The degree to which this variation is adaptive remains an open question but recent evolutionary anthropology research has provided some clarity. While knowledge of evolutionary approaches has limitations, the benefits of understanding the origins and comparative context of reproductive endocrine function in older human males are significant. This paper discusses our present comprehension of reproductive endocrinology and aging in human males, with a focus on human diversity across varied lifestyles, ecologies, and environments. In addition, comparative great ape research is examined. Current research challenges and future directions related to the importance of evolutionary biology and human diversity for understanding human male aging are discussed.

The peripheral stress response, consisting of the autonomic nervous system (ANS) and hypothalamic pituitary adrenal-axis (HPA-axis), functions to maintain homeostasis in response to stressors. Cervical spine manual therapy has been shown to differentially modulate the stress response in healthy populations. No study has investigated whether cervical spine mobilizations can differentially modulate the stress response in individuals with persistent post-concussion symptoms (PPCS), a population characterized by a dysfunctional stress response.

A randomized, controlled, parallel design trial was performed to investigate whether upper or lower cervical spine mobilization can differentially modulate components of the stress response in individuals with PPCS. The outcomes were salivary cortisol (sCOR) concentration (primary) and the HRV metric, rMSSD, measured with a smartphone application (secondary). Nineteen males diagnosed with PPCS, aged 19-35, were included. Participants were randomly assigned into either intervention group, upper (n = 10) or lower (n = 9) cervical spine mobilization. Each outcome was collected at different time points, pre- and post-intervention. Statistical analyses were performed using the Friedman's Two-Way ANOVA, Mann-Whitney U test, and Wilcoxon Signed Rank Test.

There was a statistically significant within-group reduction in sCOR concentration 30 minutes following lower cervical spine mobilizations and statistically significant within-group increase in rMSSD 30 minutes following upper cervical spine mobilizations.

The results of this trial provide preliminary evidence for cervical spine mobilizations to differentially modulate components of the stress response at specific time points. Understanding the mechanisms of the effect of cervical spine mobilizations on the stress response provides a novel rationale for selecting cervical spine mobilizations to rehabilitate individuals with PPCS.

Population aging is a global phenomenon driving research focus toward preventing and managing age-related disorders. Functional hypogonadism (FH) has been defined as the combination of low testosterone levels, typically serum total testosterone below 300-350 ng/dL, together with manifestations of hypogonadism, in the absence of an intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis. It is usually seen in middle-aged or elderly males as a product of aging and multimorbidity. This age-related decline in testosterone levels has been associated with numerous adverse outcomes. Testosterone therapy (TTh) is the mainstay of treatment for organic hypogonadism with an identifiable intrinsic pathology of the HPT axis. Current guidelines generally make weak recommendations for TTh in patients with FH, mostly in the presence of sexual dysfunction. Concerns about long-term safety have historically limited TTh use in middle-aged and elderly males with FH. However, recent randomized controlled trials and meta-analyses have demonstrated safe long-term outcomes regarding prostatic and cardiovascular health, together with decreases in all-cause mortality and improvements in various domains, including sexual function, body composition, physical strength, bone density, and hematopoiesis. Furthermore, there are numerous insightful studies suggesting additional benefits of TTh, for instance in cardio-renal-metabolic conditions. Specifically, future trials should investigate the role of TTh in improving symptoms and prognosis in various clinical contexts, including sarcopenia, frailty, dyslipidemia, arterial hypertension, diabetes mellitus, fracture risk, heart failure, stable angina, chronic kidney disease, mood disorders, and cognitive dysfunction.

The definition and diagnosis of functional hypogonadism (FH) remains challenging due to the nonspecific nature of symptoms and the inconsistency in normal testosterone thresholds. We conducted this single-center cross-sectional study on medical records of men aged 18 and above undergoing annual health check-ups to evaluate the correlation of age and metabolic components with testosterone. A total of 5,374 healthy men were included in the analysis. Total testosterone levels peaked at 18 years and gradually declined to age 40, followed by a mild increase. Based on the American Urology Association guideline, age-specific cutoffs for low testosterone were 14.61 nmol/l, 12.74 nmol/l, 12.70 nmol/l, and 13.98 nmol/l for those under 30, 30-40, 40-50, and over 50 years old respectively. Triglyceride - Glucose index showed a consistent negative correlation with testosterone across all age groups. In conclusion, testosterone levels demonstrated an age-related decline in early adulthood but a potential increase thereafter among healthy Vietnamese men. Metabolic components, rather than aging, had a consistent negative correlation with testosterone. Age-specific cutoffs for low testosterone may improve the detection of functional hypogonadism.

Sociodemographic, lifestyle, and medical variables influence total testosterone (T) and sex hormone-binding globulin (SHBG) concentrations. The relationship between these factors and "free" T remains unclear. We examined 21 sociodemographic, lifestyle, and medical predictors influencing calculated free T (cFT) in community-dwelling men across ages.

This is a cross-sectional analysis in 20 631 participants in the Androgens in Men Study.

Individual participant data (IPD) were provided by 9 cohorts. Total T was determined using mass spectrometry, SHBG using immunoassays, and cFT using the Vermeulen formula. Associations were analyzed using 2-stage random effects IPD meta-analyses.

Cohort median ages ranged from 40 to 76 years and median cFT concentrations from 174.3 to 422.8 pmol/L. In men aged 17-99 years, there was a linear inverse association of cFT with age (-57.2 pmol/L [95% confidence interval, -69.4, -44.9] per 1 SD increase in age). Calculated free T increased with increasing baseline body mass index (BMI) among men with BMI < 23.6 kg/m2, but decreased among men with BMI > 23.6 kg/m2 (-24.7 pmol/L [-29.1, -20.3] per 1 SD increase in the 25.4-29.6 kg/m2 BMI range). Calculated free T was lower in younger men, who were married or in a de facto relationship (-18.4 pmol/L [-27.6, -9.3]) and in men who formerly smoked (-5.7 pmol/L [-8.9, -2.6]), were in poor general health (-14.0 pmol/L [-20.1, -7.8]), and had diabetes (-19.6 pmol/L [-23.0, -16.3]), cardiovascular disease (-5.8 pmol/L [-8.3, -3.2]), or cancer (-19.2 pmol/L [-24.4, -14.1]).

Calculated free T was most prominently associated with age and BMI. The linear, inverse association with age, nonlinear association with BMI, and presence of diabetes, cancer, and sociodemographic factors should be considered when interpreting cFT values.

Hormones are chemical messengers that regulate a wide range of physiological processes including metabolism, development, growth, reproduction and mood. The concentration of hormones that orchestrate the numerous bodily functions is very low (1 nM or less). Efforts have been made to develop highly sensitive tools to detect them. This review represents a critical comparison between different types of nanoparticle-based electrochemical biosensors for the detection of various hormones, namely cortisol, sex hormones (estradiol, progesterone, testosterone), insulin, thyroid-stimulating hormone (TSH) and growth hormone (GH). The electrochemical biosensors investigated for each hormone are first divided on the basis of the biological fluid tested for their detection, and successively on the basis of the electrochemical transducer utilized in the device (voltammetric or impedimetric). Focus is placed on the nanoparticles employed and the successive electrode modification developed in order to improve detection sensitivity and specificity and biosensor stability. Limit of detection (LOD), linear range, reproducibility and possibility of regeneration for continuous reuse are also investigated and compared. The review also addresses the recent trends in the development of wearable biosensors and point-of-care testing for hormone detection in clinical diagnostics useful for endocrinology research, and the future perspectives regarding the integration of nanomaterials, microfluidics, near field communication (NFC) technology and portable devices.

The relationship between smoking and testosterone levels in adult males remains a topic of ongoing debate. Serum cotinine is considered a reliable marker of both smoking intensity and exposure to tobacco smoke. Therefore, we aim to examine the association between serum cotinine levels and total testosterone concentrations in adult males using data from the U.S. National Health and Nutrition Examination Survey (NHANES) database. Our study assessed the relationship between serum cotinine and total testosterone using weighted linear regression models and subgroup analysis. A fully adjusted model with smooth curve fitting was employed to investigate the potential nonlinear association between serum cotinine and total testosterone. Threshold effects were analyzed to identify the inflection point between serum cotinine and total testosterone. Indeed, a total of 7797 participants were included in our study. After adjusting for potential confounding variables, the findings indicate a positive association between serum cotinine levels and total testosterone levels (β: 0.05, 95%CI: 0.02, 0.09). Furthermore, applying smoothed curve fitting analysis and threshold effects, an inflection point was detected at a serum cotinine level of 487 ng/ml. Above this threshold, total testosterone levels declined with increasing serum cotinine levels. In conclusion, the findings of our study suggest a positive association between elevated serum cotinine levels and total testosterone levels in adult men. However, it is essential to note that this association may be reversed at excessively high serum cotinine concentrations.

Organic male hypogonadism due to irreversible hypothalamic-pituitary-testicular (HPT) pathology is easily diagnosed and treated with testosterone-replacement therapy. However, controversy surrounds the global practice of prescribing testosterone to symptomatic men with low testosterone and non-gonadal factors reducing health status, such as obesity, type 2 diabetes, and ageing (ie, functional hypogonadism), but without identifiable HPT axis pathology. Health optimisation remains the gold-standard management strategy. Nevertheless, in the last decade large clinical trials and an individual patient data meta-analysis of smaller clinical trials confirmed that testosterone therapy induces modest, yet statistically significant, improvements in sexual function without increasing short-term to medium-term cardiovascular or prostate cancer risks in men with functional hypogonadism. Although testosterone improves bone mineral density and insulin sensitivity in these men, trials from the last decade suggest insufficient evidence to determine the safety and effectiveness of use of this hormone for the prevention of fractures or type 2 diabetes. This Review discusses the pathogenesis and diagnosis of male hypogonadism and appraises the evidence underpinning the management of this condition.

Background: Long-term use of supraphysiologic doses of anabolic-androgenic steroids (AAS) has been associated with impaired visuospatial memory in young men but little is known about its cognitive effects in middle-aged men.Objectives: We compared cognition in middle-aged men with histories of long-term AAS use and age-matched non-users.Methods: We administered cognitive tests from the CANTAB battery to 76 weightlifters aged 37-60 years (mean [SD] 48.5 [6.5] years), of whom 51 reported at least 2 years of cumulative AAS use and 25 reported no AAS exposure.Results: We found no significant AAS user versus non-user group differences on visuospatial, verbal memory, emotional recognition, or executive function tasks (corrected p's ≥ .00089; effect sizes ≤ .5).Conclusions: Our null visuospatial task findings contrast with our prior younger cohort study (mean age 37.1 [7.1] years), in which we found impaired visuospatial task performance in people who use AAS, and with other reports of cognitive impairments in younger men use AAS. Men who use AAS may develop early visuospatial memory deficits that stabilize by middle age while middle-aged non-users' performance may "catch up" due to normal age-related visuospatial declines. Similar effects could contribute to our null findings on other tasks. Between-study cohort substance use differences or environmental factor differences that modify cognition, such as study geographical location and time of year, also could contribute to our discordant findings. Since young adult male AAS users experience increased mortality from unnatural causes, improving our understanding of AAS cognitive effects in this age group is important.

This study sets out to investigate the potential effect of males' testosterone level on speech production and speech perception. Regarding speech production, we investigate intra- and inter-individual variation in mean fundamental frequency (fo) and formant frequencies and highlight the potential interacting effect of another hormone, i.e. cortisol. In addition, we investigate the influence of different speech materials on the relationship between testosterone and speech production. Regarding speech perception, we investigate the potential effect of individual differences in males' testosterone level on ratings of attractiveness of female voices. In the production study, data is gathered from 30 healthy adult males ranging from 19 to 27 years (mean age: 22.4, SD: 2.2) who recorded their voices and provided saliva samples at 9 am, 12 noon and 3 pm on a single day. Speech material consists of sustained vowels, counting, read speech and a free description of pictures. Biological measures comprise speakers' height, grip strength, and hormone levels (testosterone and cortisol). In the perception study, participants were asked to rate the attractiveness of female voice stimuli (sentence stimulus, same-speaker pairs) that were manipulated in three steps regarding mean fo and formant frequencies. Regarding speech production, our results show that testosterone affected mean fo (but not formants) both within and between speakers. This relationship was weakened in speakers with high cortisol levels and depended on the speech material. Regarding speech perception, we found female stimuli with higher mean fo and formants to be rated as sounding more attractive than stimuli with lower mean fo and formants. Moreover, listeners with low testosterone showed an increased sensitivity to vocal cues of female attractiveness. While our results of the production study support earlier findings of a relationship between testosterone and mean fo in males (which is mediated by cortisol), they also highlight the relevance of the speech material: The effect of testosterone was strongest in sustained vowels, potentially due to a strengthened effect of hormones on physiologically strongly influenced tasks such as sustained vowels in contrast to more free speech tasks such as a picture description. The perception study is the first to show an effect of males' testosterone level on female attractiveness ratings using voice stimuli.

In this study, we aimed to perform a network meta-analysis (NMA) to investigate the effects of different testosterone replacement therapy (TRT) administration routes on lower urinary tract symptoms (LUTS) in aging men with late-onset hypogonadism (LOH).

A systematic search of PubMed, Embase, The Cochrane Library, CNKI, WanFang Data, and VIP was conducted to identify randomized controlled trials (RCTs) reporting data on International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) level, or prostate volume. NMA was performed, and subgroup analysis was conducted to assess the impact of TRT duration on outcomes.

A total of 21 RCTs involving 2453 participants were included. For pairwise meta-analysis, p values for TRT delivered by transdermal, intramuscular, and oral routes were as follows: IPSS: 0.93, 0.20, and 0.76; PSA level: 0.20, 0.27, and 0.98; prostate volume: 0.18, 0.04, and 0.16. There were no significant differences in IPSS, PSA level, or prostate volume between TRT routes. In subgroup analysis, long-term intramuscular TRT significantly decreased IPSS (p = 0.03), short-term transdermal TRT increased PSA levels (p < 0.001), and short-term intramuscular TRT increased the prostate volume (p = 0.04). Other forms of TRT showed no significant change in IPSS, PSA level, and prostate volume compared with the placebo. Indirect comparison of the three administration routes demonstrated no significant differences in IPSS, PSA level, and prostate volume. Nevertheless, surface under the cumulative ranking curve analysis indicated that intramuscular TRT had an 83% probability of being the best method for decreasing IPSS.

The results demonstrate that TRT does not worsen LUTS regardless of the administration route. Intramuscular TRT may be the preferred treatment for aging men with LOH and LUTS. Intramuscular TRT may be the preferred treatment for men with LOH and LUTS. Further research is warranted to validate these findings and optimize TRT management strategies.

Testosterone's biological functions are extensive, influencing reproductive and systemic health. It plays a vital role in sexual functions, muscle protein synthesis, bone metabolism, fat distribution, and cardiovascular health. The hormone also affects mood, cognitive function, and erythropoiesis, underscoring its importance in both physical and mental health. Testosterone deficiency, or male male hypogonadism, is increasingly recognized as a significant health issue affecting various bodily systems, also in the context of chronic kidney disease (CKD). Recent research indicates a complex interplay between testosterone levels and renal health, suggesting that male male hypogonadism may both impact and be impacted by CKD. The latter is characterized by a gradual loss of kidney function, affects millions globally and is often associated with diabetes mellitus, arterial hypertension, and autoimmune diseases. Men with CKD frequently experience lower testosterone levels, which can exacerbate muscle wasting, reduce quality of life, and increase cardiovascular risk. Overall, low testosterone levels in CKD patients are associated with increased morbidity and mortality. Several mechanisms explain the relationship between CKD and testosterone deficiency. The uremic environment in CKD disrupts the hypothalamic-pituitary-gonadal axis, impairing hormone production. Nutritional deficiencies and chronic inflammation common in CKD patients further suppress gonadal function. The consequences of low testosterone in CKD are profound, with studies suggesting that testosterone replacement therapy (TRT) might improve clinical outcomes, though the long-term effects and causal relationships remain under investigation. The potential benefits of TRT in CKD patients might be significant. TRT can enhance muscle mass and strength, address anemia by stimulating erythropoiesis, improve bone density, and possibly offer cardiovascular benefits by improving body composition and insulin sensitivity. General symptoms of male hypogonadism, such as deteriorated psychological, sexual and physical wellbeing, can be improved by TRT. However, these benefits must be weighed against potential risks. TRT may exacerbate fluid retention, arterial hypertension, or exacerbate existing heart failure, particularly in CKD patients with pre-existing cardiovascular comorbidities. Additionally, concerns about the progression of renal disease via several testosterone affected pathways involving renal tubular integrity exist, highlighting the need for careful patient selection and monitoring. Understanding this relationship is crucial for developing comprehensive treatment strategies that address both renal and endocrine dysfunctions, highlighting the need for integrated patient care, which means good collaboration between subspecialists like nephrologists, endocrinologists, urologists and primary care providers, aiming to improve outcomes and quality of life while mitigating adverse effects.

The incidence of low serum testosterone has been increasing in men of all ages across a period which also corresponds to an increasing prevalence of kidney stones. Currently, the relationship between testosterone and kidney stones is unclear. Using the TriNetX Research Network, we performed a retrospective cohort study to evaluate the risk of developing an initial kidney stone in men based on their total testosterone level. Men aged ≥18 were divided into a low testosterone (<300 ng/dL) and normal testosterone (≥ 300 ng/dL) cohort. Men were excluded if they had a history of a kidney stone encounter diagnosis before testosterone measurement and a history of testosterone therapy prescription at any point. Propensity score matching was employed with an absolute standardized mean difference of less than 0.1 used as an indicator of successful matching. Our main outcome of interest was risk of developing an initial kidney stone in men aged ≥18 and within age-based subgroups. In men 18 and older, low testosterone was associated with a higher risk of one or more kidney stone encounter diagnoses (HR 1.12, 95% CI [1.09-1.15]). When stratified by age, no significant association between low testosterone and kidney stone encounter diagnoses was seen in men aged 18-24 (HR 1.09, 95% CI [0.85-1.39]). The highest risk was observed in men with low testosterone aged 34-44 (HR 1.29, 95% CI [1.17-1.38]). In this study, low serum testosterone was associated with an increased risk of initial kidney stone diagnosis in adult men without testosterone therapy prescriptions at any point in their life. Stratifying by age, the increased risk appears to begin in men aged 25, with the highest observed risk in men aged 33-44.

Biological sex is an important modifier of physiology and influences pathobiology in many diseases. While heart disease is the number one cause of death worldwide in both men and women, sex differences exist at the organ and cellular scales, affecting clinical presentation, diagnosis, and treatment. In this Review, we highlight baseline sex differences in cardiac structure, function, and cellular signaling and discuss the contribution of sex hormones and chromosomes to these characteristics. The heart is a remarkably plastic organ and rapidly responds to physiological and pathological cues by modifying form and function. The nature and extent of cardiac remodeling in response to these stimuli are often dependent on biological sex. We discuss organ- and molecular-level sex differences in adaptive physiological remodeling and pathological cardiac remodeling from pressure and volume overload, ischemia, and genetic heart disease. Finally, we offer a perspective on key future directions for research into cardiac sex differences.

To investigate longitudinal changes in SHBG and free testosterone (free T) levels among Black middle-aged African men, with and without coexistent HIV, and explore associations with incident dysglycaemia and measures of glucose metabolism.

This longitudinal study enrolled 407 Black South African middle-aged men, comprising primarily 322 men living without HIV (MLWOH) and 85 men living with HIV (MLWH), with normal fasting glucose at enrollment. Follow-up assessments were conducted after 3.1 ± 1.5 years.

At baseline and follow-up, SHBG, albumin, and total testosterone were measured and free T was calculated. An oral glucose tolerance test at follow-up determined dysglycaemia (impaired fasting glucose, impaired glucose tolerance, type 2 diabetes) and glucose metabolism parameters including insulin sensitivity (Matsuda index), insulin resistance (homeostasis model assessment of insulin resistance), and beta(β)-cell function (disposition index). The primary analysis focussed on MLWOH, with a subanalysis on MLWH to explore whether associations in MLWOH differed from MLWH.

The prevalence of dysglycaemia at follow-up was 17% (n = 55) in MLWOH. Higher baseline SHBG was associated with a lower risk of incident dysglycaemia (odds ratio 0.966; 95% confidence interval 0.945-0.987) and positively associated with insulin sensitivity (β = 0.124, P < .001) and β-cell function (β = 0.194, P = .001) at follow-up. Free T did not predict dysglycaemia. In MLWH, dysglycaemia prevalence at follow-up was 12% (n = 10). Neither baseline SHBG nor free T were associated with incident dysglycaemia and glucose metabolism parameters in MLWH.

SHBG levels predict the development of dysglycaemia in middle-aged African men but do not exhibit the same predictive value in MLWH.

Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain.

This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations.

We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality.

We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (β=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (β=-0.127), showed an indirect effect on infertility mediated by SUA (β=-0.0187; 95% CI, -0.041 to -0.003; P=0.046).

Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.