Geographical incidence of testosterone supplementation in total hip and knee arthroplasty.

Introduction: Prescription testosterone usage in the United States declined after 2013 following reports of its association with myocardial infarction and stroke. However, more recently there has been a documented increase in testosterone prescriptions. Recently, testosterone levels have also been hypothesized to increase infection risk in patients undergoing elective shoulder arthroplasty. Furthermore, testosterone may increase the risk of venous thromboembolism. These complications are perioperative concerns for total hip and knee arthroplasties (THA/TKA). Therefore, the purpose of our study is to identify trends in the incidence of testosterone prescriptions in patients who underwent THA/TKA with respect to geographical population data. Methods: We retrospectively reviewed 40,711 primary THAs and 50,893 primary TKAs performed in males between 1/1/2016 and 12/31/2021 using a commercial claims database. Records were reviewed for demographics, geographical location, and supplemental testosterone prescriptions within 1 year prior to surgery. Patient Metropolitan Statistical Area (MSA) was assessed with respect to United States Census Population Data. Results: We identified 91,604 males who underwent primary THA (n = 40,711) or TKA (n = 50,893). For THA/TKA, patients who were younger had a higher likelihood of having a supplemental testosterone prescription (OR = 0.99, 95 % CI [0.99-1.00], p < 0.001). TKA patients (2,507, 4.9 %) had a higher rate of testosterone prescriptions than THA patients overall (1,413, 3.4 %), (OR = 1.44 95 % CI [1.35, 1.54], p < 0.001) as well as within each year.For THA and TKA patients, patients in the Midwest (OR = 1.61, p < 0.001), South (OR = 3.04, p < 0.001), and West (OR = 2.28, p < 0.001) regions all had higher testosterone prescription rates than the Northeast. Patients living in a city (MSA population ≥200,000) were more likely to be prescribed testosterone (OR = 1.20, p = 0.002). Conclusion: Surgeons conducting TKA/THA should be aware that younger patients, those in higher population areas, and those in the Midwest, South, and West regions are more likely to be prescribed testosterone than those in the Northeast.

Selenium Improves Arsenic-Induced Male Reproductive Dysfunction by Regulating H3K14ac Level.

Arsenic exposure has been known to be associated with male reproduction injury. Exploring the antidote of arsenic and ascertaining proper dose of antidote are important for detoxifying the male reproductive toxicity of arsenic. Selenium, which is essential for the male reproduction and spermatogenesis, can alleviate the toxicity of many environmental toxins, such as metals, and fluoride (F). Selenium relieves arsenic-induced reductions in spermatogenesis index and testicular function marker enzymes via promoting the antioxidative ability of rats. Our previous study has found that arsenic can induce male reproductive toxicity by affecting the level of H3K14ac in the testis, so we further investigate whether selenium can antagonize arsenic-induced male reproductive toxicity through the H3K14ac pathway and ascertain the appropriate dose of selenium. The results show that selenium intervention reduces the accumulation of arsenic in rat testis probably attributing to promote the excretion of arsenic from rat, then improves the testis injury induced by arsenic. Selenium intervention enhances sperm quality, testosterone level, and expression of steroidogenic genes by regulating H3K14ac level and expression of its associated enzymes (KAT2A, BAZ2A, and HDAC6), and thus alleviates the male reproductive toxicity of arsenic, and the proper dose of Se for mitigating arsenic male reproductive toxicity is 1 mg/kg.

Short-Term Changes in Bone Metabolism Among Transgender Men Starting Gender-Affirming Hormone Therapy: A Systematic Review and Meta-analysis.

Transgender and gender diverse individuals experience a gender identity that differs from the sex assigned at birth. Some transgender men may request testosterone to induce virilization; however, its impact on bone health remains to be fully elucidated. The objective of this systematic review and meta-analysis was to evaluate the modifications in bone metabolism over a short-term period among transgender men initiating testosterone therapy. A systematic search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library. The articles of interest had to report longitudinal evaluation conducted among transgender men, before starting testosterone and after 12 and 24 months of therapy. The analyzed parameters were BMD, calcium, phosphate, 25OHD, PTH, P1NP, BAP, osteocalcin and CTx. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger's test, and trim-and-fill analysis were used to assess publication bias. Fourteen studies met the inclusion criteria, including 1484 subjects. In absence of heterogeneity, BMD did not significantly change at lumbar spine, hip, femoral neck, and whole-body evaluations. Calcium, phosphate, 25OHD and PTH remained stable over time. Regarding bone turnover markers, only P1NP showed a statistically significant increase after 12 months of T therapy, in absence of heterogeneity (SMD 0.61 mcg/l; 95% CI: 0.40-0.83; p < 0.0001; I2 = 0%, Pforheterogeneity = 0.48). Testosterone therapy among transgender men seems not to disrupt bone health after 12 and 24 months. A statistically significant elevation in P1NP levels after 12 months of therapy may indicate a positive anabolic effect of testosterone in the short-term.

Light pollution: time to consider testicular effects.

Technological advances have led to a modern-day lighting and smartphone revolution, with artificial light exposure at night increasing to levels never before seen in the evolutionary history of living systems on Earth. Light as a pollutant, however, remains largely unrecognized, and the reproductive effects of light pollution are mostly if not entirely unconsidered. This is despite the reproductive system being intricately linked to metabolism and the circadian system, both of which can be disturbed even by low levels of light. Here, we aim to change this perspective by reviewing the physiological and pathophysiological mechanisms by which light exposure alters the intricate hormonal, metabolic and reproductive networks that are relevant to reproductive toxicology. Nascent human studies have recently identified the photoreceptors responsible for the light dose relationship with melatonin suppression and circadian re-entrainment, directly shown the association between the alignment of light-dark cycles with activity-rest cycles on metabolic health and provided proof-of-principle that properly timed blue light-enriched and blue light-depleted delivery can accelerate circadian re-entrainment. With these advances, there is now a need to consider testicular effects of light pollution.

Nandrolone decanoate-induced hypogonadism in male rats: Dose- and time-dependent effects on pituitary and testicular hormonal functions.

Anabolic-androgenic steroids (AASs) impairment of reproduction has been reported. We investigated dose- and time-dependent effects of Nandrolone decanoate (ND) on reproductive system in comparison with Testosterone enanthate (TE). Male Wistar rats were administrated with 1, 3, and 9 mg/kg/weeks ND or 1 and 3 mg/kg/weeks TE for 8 weeks, and testicular phenotype and reproductive hormones were assessed at 4 and 8 weeks post-treatments. AASs × treatment period interaction was significant for gonadosomatic index (GSI), testosterone (T), 17ß-estradiol (E2), and luteinizing hormone (LH). At 4 weeks post-treatment, GSI was decreased in rats treated with 3 mg/kg/weeks ND and T was decreased in all ND-treated groups, while no significant changes in LH levels were observed. At 8 weeks post-treatment, GSI was decreased in rats treated with 1 and 3 mg/kg/weeks ND and with 3 mg/kg/weeks TE, T was decreased in all groups, and E2 and LH were increased and decreased, respectively, in rats treated with 9 mg/kg/weeks ND and with 3 mg/kg/weeks TE. The testes showed histopathological defects in both ND- and TE-treated rats suggesting a delay in seminiferous cycle. This study shows AASs-induced hypogonadism at low-dose that coincided with inhibition of T biosynthesis and disruption of T feedback on pituitary.

Androgen Deficiency, Associations and Survival of Men With Stage 4 and 5 Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Anaemia is a key cause of morbidity in chronic kidney disease (CKD). Androgen deficiency (AD) in males can contribute to anaemia of all causes, including in CKD. We sought to examine the prevalence of AD in men with CKD, the extent to which it contributed to anaemia and whether it was independently associated with long-term survival. METHODS: This cross-sectional observational study was conducted among males aged 18 years and over with CKD stages 4 and 5. The study analysed morning blood samples with regard to their full blood count, urea and electrolytes, albumin, lipids, testosterone (T) and sex hormone binding globulin, with calculation of free testosterone by mass action equation. Mortality data were obtained 15 years later for survival analysis. RESULTS: Among 322 patients with a mean age of 63 years, the overall prevalence of AD was 68.9%. There was a statistically significant negative correlation between erythropoiesis stimulating agent (ESA) dose and testosterone concentrations (Pearson correlation -0.193, p = 0.05). There was a positive correlation between haemoglobin (Hb) and free testosterone level among patients not on ESA therapy (Pearson correlation 0.331, p < 0.001). Kaplan-Meier plots showed p < 0.001 on log-rank analysis, indicating that AD was significantly associated with worse survival. However, in Cox regression analysis, free testosterone was not associated with survival (95% CI for free testosterone 0.997-1.000). CONCLUSIONS: AD is highly prevalent among this population, and increases further with older age and more severe CKD warranting haemodialysis. Association of lower Hb and higher ESA dose with lower T concentration might be causative, which has important pharmaco-economic as well as clinical implications. Lower survival in men with low T, more likely reflects overall poor health rather than causation. A properly constituted randomised controlled study evaluating the effect of native T replacement is warranted in men with CKD and AD.

Single-arm study of testosterone gel replacement therapy and ambulatory blood pressure outcomes in men with hypogonadism.

BACKGROUND AND OBJECTIVE: Studies examining ambulatory blood pressure (BP) response to testosterone replacement therapy are needed owing to inconsistent prior findings across formulations. This study assessed testosterone gel 1.62% and 24-h ambulatory BP. MATERIALS AND METHODS: Single-arm non-inferiority trial (NCT04274894) conducted at 36 US sites enrolled 246 men with hypogonadism (mean age, 57.6 years; mean office systolic/diastolic BP [SBP/DBP], 129.8/79.5 mm Hg) who were treated for 16 weeks with once-daily testosterone gel treatment (starting dose, 40.5 mg/day; min, max dose, 20.25, 81.0 mg/day) to achieve testosterone concentration of 350-750 ng/dL. Main outcome measures included mean change in 24-h average SBP (primary endpoint) and DBP from baseline to week 16. The non-inferiority threshold was a two-sided 95% confidence interval (CI) upper limit <3.0 mm Hg for 24-h average SBP. RESULTS: Increase in mean ± SD serum testosterone concentration to a physiologic level (baseline, 244.4 ± 93.9 ng/dL; week 16, 502.5 ± 394.4 ng/dL) was associated with a 1.9-mm Hg mean change in 24-h average SBP observed in the primary analysis (baseline, 123.5 mm Hg; week 16, 125.4 mm Hg; 95% CI, 0.63-3.13 mm Hg; n = 169). As the upper CI limit modestly exceeded the non-inferiority margin (3 mm Hg), study drug effect on SBP could not be ruled out. Non-inferiority was observed in subgroups without hypertension or diabetes (95% CI, upper limit <3.0 mm Hg) and was not observed in those with hypertension or diabetes. Daytime SBP and DBP changes were larger compared with nighttime. No clear cardiovascular adverse events or new safety signals were identified. DISCUSSION AND CONCLUSIONS: While the effect of testosterone gel 1.62% on 24-h average SBP could not be ruled out based on the study's non-inferiority margin, the clinical relevance of the small-magnitude mean increase of 1.9 mm Hg is anticipated to be minimal considering the results of the TRAVERSE study of testosterone gel 1.62% and major adverse cardiac events. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov identifier: NCT04274894 (registered February 17, 2020).

Effect of deep testosterone reduction on the prognosis of metastatic prostate cancer with high-volume disease.

OBJECTIVE: This study aims to investigate the correlation between serum testosterone levels after one month of treatment and prognosis in patients with high-volume disease metastatic prostate cancer (mPCa) who are undergoing combined androgen blockade therapy (CAB). METHODS: The clinical data of 199 patients with high-volume disease mPCa, diagnosed through biopsy pathology and imaging, were retrospectively analyzed from January 2010 to October 2022 in the Department of Urology at the First Affiliated Hospital of Xinjiang Medical University. Among these patients, 111 cases had a deep reduction in serum testosterone (< 0.7 nmol/l) after one month of treatment, while 88 cases did not achieve a deep reduction (≥ 0.7 nmol/l). The study utilized the Kaplan-Meier method to plot survival curves and employed the multifactor COX regression model to analyze independent risk factors. The risk factors with a significance level of P < 0.05 in the multivariate analysis were included in the nomogram prediction model. The accuracy of the model was assessed using the ROC curve and the calibration curve, while the net benefit for patients was evaluated through the decision curve analysis (DCA). RESULTS: The group that achieved deep testosterone reduction(DTR) had a higher proportion of PSA < 0.2 ng/ml and a greater PSA decline rate after six months of treatment (P < 0.05). The group that achieved DTR and the group that did not achieve DTR had a progression to castration resistant prostate cancer(CRPC) time of 17.93 ± 6.68 months and 13.43 ± 6.12 months, respectively (P < 0.001). The median progression-free survival time for the 2 groups were 18 months and 12 months, respectively (P < 0.001). The median overall survival times were 57 months and 32 months, respectively (P < 0.001). The median progression-free survival times were 18, 15, and 10 months for the group that achieved DTR within 1 month, the group that achieved DTR beyond 1 month but within 1 year, and the group that did not achieve DTR within 1 year, respectively (P < 0.001), and the median survival times were 57, 45, and 26 months, respectively (P < 0.001). COX multivariate analysis revealed that a testosterone level of ≥ 0.7 nmol/l at 1 month of treatment is an independent risk factor for the progression to CRPC and prognosis in patients with high-volume disease mPCa (P < 0.05). The risk of death in patients with a testosterone level of ≥ 0.7 nmol/l at 1 month of treatment was 2.087 times higher than that of patients with a level of < 0.7 nmol/l (P < 0.05). A nomogram prediction model was developed using independent risk factors, with the area under the ROC curve (AUC) for progression-free survival (PFS) at 12, 15, 18, and 21 months being 0.788, 0.772, 0.760, and 0.739, respectively. For 3 and 5 years, the AUCs for overall survival (OS) were 0.691 and 0.624. The calibration curve demonstrated good consistency between the model's predicted values and the actual outcomes. CONCLUSION: Patients with high-volume disease mPCa who receive CAB treatment may experience extended progression-free survival and overall survival if their serum testosterone levels are below 0.7 nmol/l after one month of treatment. The longer it takes to achieve DTR, the worse the patient's prognosis may be. The nomogram prediction model developed in this study demonstrates good predictive ability in assessing the progression and prognosis of high-volume disease mPCa.

Association between serum cotinine and total testosterone in adult males based on NHANES 2011-2016.

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 (ß: 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.

Role of Gonadal Steroid Hormones in the Eye: Therapeutic Implications.

Gonadal steroid hormones are critical regulatory substances involved in various developmental and physiological processes from fetal development through adulthood. These hormones, derived from cholesterol, are synthesized primarily by the gonads, adrenal cortex, and placenta. The synthesis of these hormones involves a series of enzymatic steps starting in the mitochondria and includes enzymes such as cytochrome P450 and aromatase. Beyond their genomic actions, which involve altering gene transcription over hours, gonadal steroids also exhibit rapid, nongenomic effects through receptors located on the cell membrane. Additionally, recent research has highlighted the role of these hormones in the central nervous system (CNS). However, the interactions between gonadal steroid hormones and the retina have received limited attention, though it has been suggested that they may play a protective role in retinal diseases. This review explores the synthesis of gonadal hormones, their mechanisms of action, and their potential implications in various retinal and optic nerve diseases, such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), or retinitis pigmentosa (RP), discussing both protective and risk factors associated with hormone levels and their therapeutic potential.

High SHBG and Low Bioavailable Testosterone are Strongly Causally Associated with Increased Forearm Fracture Risk in Women: An MR Study Leveraging Novel Female-Specific Data.

The effects of androgens on women's bone health are not fully understood. Mendelian randomization (MR) studies using sex-combined data suggest that sex hormone-binding globulin (SHBG) and bioavailable testosterone (BioT) causally affect bone traits. Given significant sex differences in hormone regulation and effects, female-specific MR studies are necessary. In the current study, we explored the causal relationships of SHBG, BioT, and total testosterone (TT) with forearm fracture (FAFx) risk in women using two-sample MR analyses. We utilized a unique female-specific FAFx outcome dataset from three European biobanks (UFO, HUNT, Estonian Biobank) comprising 111,351 women and 8823 FAFx cases, along with female-specific genetic instruments of SHBG, BioT, and TT identified in the UK Biobank. We also assessed bone mineral density (BMD) at the forearm (FA), femoral neck (FN), and lumbar spine (LS) using female-specific GWAS data from the GEFOS consortium. High SHBG (odds ratio per standard deviation increase (OR/SD): 1.53, 95% confidence intervals (CIs): 1.34-1.75), low BioT (OR/SD: 0.77, 0.71-0.84) and low TT (OR/SD 0.90, 0.83-0.98) were causally associated with increased FAFx risk. BioT was positively, and SHBG inversely, causally associated with especially FA-BMD, but also LS-BMD and FN-BMD, while TT was only significantly positively associated with FA-BMD and LS-BMD. We propose that endogenous androgens and SHBG are important for women's bone health at distal trabecular-rich bone sites such as the distal forearm and may serve as predictors for FAFx risk.

Replacement with sex steroids in hypopituitary men and women: implications for gender differences in morbidities and mortality.

Hypopituitarism is a heterogenous disorder characterised by a deficiency in one or more anterior pituitary hormones. There are marked sex disparities in the morbidity and mortality experienced by patients with hypopituitarism. In women with hypopituitarism, the prevalence of many cardiovascular risk factors, myocardial infarction, stroke and mortality are significantly elevated compared to the general population, however in men, they approach that of the general population. The hypothalamic-pituitary-gonadal axis (HPG) is the most sexually dimorphic pituitary hormone axis. Gonadotropin deficiency is caused by a deficiency of either hypothalamic gonadotropin-releasing hormone (GnRH) or pituitary gonadotropins, namely follicle-stimulating hormone (FSH) and luteinising hormone (LH). HPG axis dysfunction results in oestrogen and testosterone deficiency in women and men, respectively. Replacement of deficient sex hormones is the mainstay of treatment in individuals not seeking fertility. Oestrogen and testosterone replacement in women and men, respectively, have numerous beneficial health impacts. These benefits include improved body composition, enhanced insulin sensitivity, improved atherogenic lipid profiles and increased bone mineral density. Oestrogen replacement in women also reduces the risk of developing type 2 diabetes mellitus. When women and men are considered together, untreated gonadotropin deficiency is independently associated with an increased mortality risk. However, treatment with sex hormone replacement reduces the mortality risk comparable to those with an intact gonadal axis. The reasons for the sex disparities in mortality remain poorly understood. Potential explanations include the reversal of women's natural survival advantage over men, premature loss of oestrogen's cardioprotective effect, less aggressive cardiovascular risk factor modification and inadequate oestrogen replacement in women with gonadotropin deficiency. Regrettably, historical inertia and unfounded concerns about the safety of oestrogen replacement in women of reproductive age have impeded the treatment of gonadotropin deficiency.

Multiple stressors disrupt sex hormones and fitness outcomes: effects of hypoxia and turbidity on an African cichlid fish.

Freshwater organisms face a complex array of environmental stressors that can negatively affect endocrine function and subsequent fitness outcomes. Hypoxia and turbidity are two environmental stressors that are increasing due to human activities that could lead to endocrine disruption and reduced reproductive output. Our research addresses how hypoxia and elevated turbidity affect traits related to reproductive success, specifically sex hormone concentrations, investment in reproductive tissues and body size. We used wild fish from two populations (a river and a swamp) of an African cichlid, Pseudocrenilabrus multicolor, to produce offspring that were reared in a full factorial split brood rearing experiment (hypoxic/normoxic × clear/turbid). River and swamp populations represent divergent habitat types with respect to the stressors of interest, being well-oxygenated but turbid or hypoxic and clear, respectively. Overall, we found evidence for plastic responses to both stressors. Specifically, we found that there was an interactive effect of oxygen and turbidity on testosterone in males from both populations. Additionally, males of both populations reared under hypoxic conditions were significantly smaller in both mass and standard length than those raised under normoxic conditions and invested less in reproductive tissues (quantified as gonadosomatic index). Hypoxia and turbidity are experienced naturally by this species, and these environmental stressors did not affect the number of eggs laid by females when experienced in the absence of another stressor (i.e. normoxic/turbid or hypoxic/clear). However, there was an interactive effect of hypoxia and turbidity, as females reared and maintained under this treatment combination laid fewer eggs. This research underscores the importance of considering the possibility of stressor interactions when determining how anthropogenic stressors affect fitness outcomes.

Efficacy of Type III Thyroplasty in Vocal Masculinization in Trans Men: A Retrospective Observational Study.

OBJECTIVE: This observational study aims to evaluate the efficacy of type III thyroplasty (TP3) in achieving vocal masculinization in transgender men who have not obtained satisfactory results from testosterone therapy alone. Specifically, it aims to determine the change in the fundamental frequency (F0) of the voice before and after surgery and compare the results with previous studies. STUDY DESIGN: A retrospective observational study. METHODS: Transgender men who were dissatisfied with their voice after at least 12months of testosterone therapy and underwent TP3 from January 2019 to January 2024 were evaluated. Acoustic voice analysis was performed before and 6months after surgery to measure changes in the fundamental frequency (F0) of the voice. RESULTS: Thirteen transgender men, aged 20 to 54, were included. The mean preoperative F0 was 156 Hz, which significantly decreased to a mean postoperative F0 of 108.77 Hz, with a mean difference of 47.23 Hz (P-value <0.001). One patient developed subcutaneous emphysema postoperatively, which was managed successfully. No other significant complications were reported. CONCLUSIONS: TP3 is an effective and safe surgical intervention for vocal masculinization in transgender men who do not achieve satisfactory results with testosterone therapy alone. This study, the largest series of TP3 cases in transgender men to date, underscores the importance and efficacy of this technique. Further research with larger sample sizes and longer follow-up periods is needed to confirm these findings and establish robust clinical protocols.

Molecular characteristics and regulatory role of insulin-like growth factor 1 gene in testicular Leydig cells of Tibetan sheep.

This study aimed to analyze the molecular characteristics of insulin-like growth factor 1 (IGF1) gene in the testes of Tibetan sheep and its role in the testosterone synthesis and cell development. First, we cloned IGF1 gene for bioinformatics analysis, and the primary Leydig cells (LCs) of Tibetan sheep were isolated to explore its effect on the proliferation, apoptosis and function of LCs. Finally, the specific regulatory mechanism of IGF1 on LCs was analyzed by transcriptome sequencing. Results showed that overexpression of IGF1 increased the proliferation rate and decreased apoptosis of LCs. In addition, overexpression of IGF1 altered expression of genes related to testosterone synthesis and transformation and significantly increased amount of the final product testosterone. Mechanistically, IGF1 stimulated the expression of the proliferating cell nuclear antigen and IGF1R and promoted the proliferation of LCs via the PI3K/Akt signaling pathway. Collectively, what should be clear from the results reported here is that IGF1 might play roles in the proliferation or differentiation and testosterone synthesis of LCs. These findings add to our understanding on the regulation of testosterone synthesis in sheep and other mammals.

Low protein uptake during peripuberty impairs the testis, epididymis, and spermatozoa in pubertal and adult Wistar rats.

Protein malnutrition during critical periods poses significant risks to reproductive health. Thus, this study aims to evaluate the immediate and delayed effects of a 30-day low-protein diet on the postnatal development of the male reproductive system. For so, male rats were fed a protein-deficient diet from postnatal day 30-60, followed by evaluations of testis, epididymis, and spermatozoa both at the end of the diet and after a 60-day recovery period. Testicular and epididymal weight was lowered in pubertal animals. Several histological alterations were found in the testis, such as acidophilic cells and vacuoles in the seminiferous epithelium, and sperm production was compromised. In the epididymis, the luminal compartment was diminished, and the stroma was enlarged both in the caput and cauda; in the cauda, the epithelial compartment was enlarged; the transit time of spermatozoa through this organ was diminished. Testosterone production was lowered. Spermatozoa's motility, mitochondrial activation, and acrosomal integrity were impaired, and several alterations in morphology were observed. After the recovery period, testicular and epididymal weight was restored. Tissue remodulation was observed in the epididymis, but the spermatozoa's transit time in this organ was not altered. Sperm and testosterone production, spermatozoa motility, mitochondrial activation, and acrosomal integrity were also restored. However, testicular histological alterations and spermatic morphological abnormalities were maintained in protein-restricted animals. Protein restriction during peripuberty impairs the reproductive maturation of pubertal Wistar rats, impairing testicular and epididymal function, with lasting effects even after dietary correction.

Independent effects of testosterone, estradiol, and sex chromosomes on gene expression in immune cells of trans- and cisgender individuals.

The origins of sex differences in human disease are elusive, in part because of difficulties in separating the effects of sex hormones and sex chromosomes. To separate these variables, we examined gene expression in four groups of trans- or cisgender individuals: XX individuals treated with exogenous testosterone (n=21), XY treated with exogenous estradiol (n=13), untreated XX (n=20), and untreated XY (n=15). We performed single-cell RNA-sequencing of 358,426 peripheral blood mononuclear cells. Across the autosomes, 8 genes responded with a significant change in expression to testosterone, 34 to estradiol, and 32 to sex chromosome complement with no overlap between the groups. No sex-chromosomal genes responded significantly to testosterone or estradiol, but X-linked genes responded to sex chromosome complement in a remarkably stable manner across cell types. Through leveraging a four-state study design, we successfully separated the independent actions of testosterone, estradiol, and sex chromosome complement on genome-wide gene expression in humans.

PFAS Exposure is Associated with a Lower Spermatic Quality in an Arctic Seabird.

Several studies have reported an increasing occurrence of poly- and perfluorinated alkyl substances (PFASs) in Arctic wildlife tissues, raising concerns due to their resistance to degradation. While some research has explored PFAS's physiological effects on birds, their impact on reproductive functions, particularly sperm quality, remains underexplored. This study aims to assess (1) potential association between PFAS concentrations in blood and sperm quality in black-legged kittiwakes (Rissa tridactyla), focusing on the percentage of abnormal spermatozoa, sperm velocity, percentage of sperm motility, and morphology; and (2) examine the association of plasma levels of testosterone, corticosterone, and luteinizing hormone with both PFAS concentrations and sperm quality parameters to assess possible endocrine disrupting pathways. Our findings reveal a positive correlation between the concentration of longer-chain perfluoroalkyl carboxylates (PFCA; C11-C14) in blood and the percentage of abnormal sperm in kittiwakes. Additionally, we observed that two other PFAS (i.e., PFOSlin and PFNA), distinct from those associated with sperm abnormalities, were positively correlated with the stress hormone corticosterone. These findings emphasize the potentially harmful substance-specific effects of long-chain PFCAs on seabirds and the need for further research into the impact of pollutants on sperm quality as a potential additional detrimental effect on birds.

Optimal Restoration of Spermatogenesis following Testosterone Therapy using hCG and FSH.

OBJECTIVE: To study improvements in spermatogenesis in men with a history of testosterone therapy using a novel fertility treatment regimen. DESIGN: A single-center retrospective cohort analysis. SUBJECTS: Seventy-seven men with previous testosterone use seeking fertility treatment from January 2020 to March 2024. EXPOSURE: A treatment regimen of 3000IU human Chorionic Gonadotropin (hCG) and 75IU Follicle Stimulating Hormone (FSH) three times a week was utilized. MAIN OUTCOME MEASURES: The primary outcome measured was change in sperm concentration during hCG/FSH therapy. The secondary outcome measured was whether concurrent testosterone therapy during hCG/FSH therapy affected recovery of spermatogenesis. RESULTS: Within the entire cohort (n=77), 74% of men demonstrated improvements in their sperm concentrations. There was not a significant difference in recovery of sperm concentration in men who stayed on testosterone therapy during hCG/FSH reboot (No testosterone therapy [n=50], 74% improved vs. Concurrent testosterone therapy [n=27], 74% improved). CONCLUSION: We report optimal recovery of spermatogenesis with hCG/FSH therapy in infertile men with a history of testosterone use. Concurrent testosterone therapy does not impede hCG/FSH-mediated spermatogenic recovery.

Activation of aryl hydrocarbon receptor protein promotes testosterone synthesis to alleviate abnormal spermatogenesis caused by cholestasis.

In this study, we have investigated potential roles of cholestasis played in spermatogenesis in the cholestatic animal model generated by giving the mice DDC diet. The data showed that cholestasis jeopardized the testicular structure and function by downregulating the expressions of genes related to the androgen's synthesis. Mechanistically, the cholestasis disturbers the liver's tryptophan metabolism and its metabolites. These tryptophan metabolites including serotonin, 5-Hydroxyindoleacetic acid, 4-(2-Aminophenyl)-2,4-dioxobutanoic acid and Quinoline-4,8-diol were significantly reduced in the cholestatic mice model compared to their controlled counterparts. These tryptophan metabolites are the endogenous ligands of AHR and their levels are positively correlated to the expressions of genes related to the androgen's synthesis and AHR. Notably, supplementation of AHR ligand ITE promoted the expression of genes related to the testosterone synthesis and alleviated abnormal spermatogenesis. In addition, the bacteria that disturbed the tryptophan metabolism in cholestatic mice were identified by 16S rDNA sequencing and Spearman correlation analysis. Briefly, we have identified a cholestasis associated gut microbiota-testis axis. This axis is responsible for the cholestasis induced abnormal spermatogenesis and male reproductive dysfunction. Breaking vicious cycle of this axis may be a suitable strategy to prevent and treat the cholestasis associated male infertility.