Reduced Serum Testosterone Levels Research Articles

Efficacy of Quercetin and Quercetin Loaded Chitosan Nanoparticles Against Cisplatin-Induced Renal and Testicular Toxicity via Attenuation of Oxidative Stress, Inflammation, and Apoptosis.

Flavonoids, including quercetin, have attracted much attention due to their potential health-promoting effects. The current experiment aims to see whether quercetin (QUE) in nanoparticle form could mitigate testicular and renal toxicity caused by cisplatin (CIS) more effectively than normally formulated QUE. Rats were randomly treated with CIS alone or in combination with QUE or QUE.NPs (Quercetin-loaded chitosan nanoparticles) for 4 weeks. QUE and QUE.NPs were given orally (10 mg/kg, three times a week), while CIS was given intraperitoneally (2 mg/kg, twice a week). Compared to QUE- and CIS + QUE.NP-treated rats, CIS exposure induced anxiety and emotional stress as well as promoted oxidative stress in both testicular and renal tissues. Moreover, CIS reduced serum testosterone levels and diminished testicular IL-10, as well as CIS-induced renal failure, as indicated by hypokalemia, and increased levels of creatinine, urea, sodium, IL-18, and KIM-1. Further, severe histological changes were observed in the testis and kidney of CIS-intoxicated rats. Regarding immunohistochemical staining, CIS significantly upregulated Bax, downregulated Bcl-2, and moderately enhanced PCNA expression. Our findings suggest that both QUE and QUE.NPs modulated emotional disturbance and improved testicular and renal functions via modulation of oxidation, inflammation, and apoptosis. However, QUE.NPs performed better than QUE-treated rats.

Gut microbial 3α‐hydroxysteroid dehydrogenase promotes depression in males via degrading testosterone

AbstractAbnormal gut microbiota is associated with the occurrence of depression, but the specific pathophysiological role of gut microbiota in the pathogenesis of depression is still unknown. We found that the levels of serum steroid hormone testosterone in male patients with depression were lower than in healthy controls. Using testosterone as the only carbon source, the testosterone‐degrading bacteria Arthrobacter koreensis was isolated from fecal of low testosterone male patients with depression. We found that A. koreensis administration in mice led to reduced serum testosterone levels and depression‐like behaviors, which were improved by antibiotic treatment. Using whole genome sequencing, the gene mediating testosterone degradation in A. koreensis was identified and annotated as 3α‐hydroxysteroid dehydrogenase (3α‐HSD). Escherichia coli heterologously expressing 3α‐HSD obtained the capacity to degrade testosterone, causing depression‐like behaviors after gavage to mice. Testosterone supplementation improves depression‐like behavior in mice induced by gavage of Escherichia coli heterologously expressing 3α‐HSD. Finally, the universality of 3α‐HSD in gut of male patients with depression was higher than that of healthy controls. Overall, our results revealed a new pathway that potentially links testosterone degradation by gut microbes harboring 3α‐HSD enzymes to the pathogenesis of depression. Gut microbial 3α‐HSD can induce depression in mice via testosterone degradation. This means that 3α‐HSD expressed by gut bacteria may be a potential target for depression in men.

Histomorphological Changes in Testis of Rats with Prolonged Exposure to Allethrin-Based Mosquito Coil Smoke.

To explore the potential adverse effects of prolonged inhalation of mosquito coil smoke on the testicular histomorphology and serum testosterone levels in rats. An experimental study. Place and Duration of the Study: Department of Anatomy, Army Medical College, National University of Medical Sciences (NUMS), Rawalpindi, Pakistan, from January to December 2020. This study was carried out on 20 male Sprague-Dawley rats, divided into control Group A (n = 10) and experimental Group B (n = 10). Rats in Group B were exposed to mosquito coil smoke (allethrin-based) for 4 hours / day for 12 weeks. After 12 weeks of exposure, serum testosterone levels and testicular morphology (seminiferous tubule diameter, germinal epithelium height, and testicular capsule thickness) were compared between the groups. Rats exposed to mosquito coil smoke showed significantly reduced serum testosterone levels (p <0.001) along with testicular histological disruption in terms of significantly dilated seminiferous tubules (p <0.001), reduced germinal epithelial height (p <0.001), and thickened testicular capsule (p <0.001), as compared to the control group. Prolonged inhalation of allethrin-based mosquito coil smoke reduced serum testosterone levels and caused testicular histological disruption in the exposed group of rats. Allethrin, Germinal epithelium, Mosquito coil, Seminiferous tubules, Testicular capsule, Testosterone, Testis.

Testosterone in Puberty Regulates Emotional Contagion and Consolation via the Vasopressin System in the Anterior Cingulate Cortex of C57BL/6J Mice

Introduction: Empathy is the ability of an individual to present and respond to the emotions of others and is thought to originate from parental behavior. Testosterone could promote aggression and inhibit biparental behavior and vasopressin (AVP) could promote aggression. Given levels of aggression and parental care are closely associated with levels of empathy, we hypothesized that testosterone may influence empathetic behavior via the AVP system. Methods: We examined testosterone levels and tested social, empathic, and anxiety-like behaviors after castration surgery to pubertal mice, and subsequently examined the molecular levels of AVP, V1aR in different brain regions. Finally, pharmacological experiments were used to test the effects on empathic behavior by injecting testosterone in combination with V1aR antagonist. Results: Here, we show that pubertal castration reduced serum testosterone levels, increased empathetic behavior and sociality, and reduced anxiety-like behaviors in male C57 mice. The pubertal castration also reduced AVP and vasopressin receptor (V1aR) protein levels, and AVP mRNA levels in the PVN. It also reduced the number of AVP-positive neurons in the PVN. In addition, pubertal subcutaneous injection of testosterone reduced emotional contagion and consolation of castrated mice, while concomitant injection of V1aR antagonists into the anterior cingulate cortex (ACC) reversed the downregulation of emotional contagion and consolation induced by testosterone. Conclusion: It is suggested that testosterone in puberty regulates empathetic behavior in C57 mice possibly via the AVP system in the ACC. These findings help us to understand the neuroendocrine mechanisms underlying empathetic behavior and provide potential targets for the treatment of psychiatric disorders associated with low empathy.

Depression-related testosterone deficiency is linked to reduced cholesterol levels in Leydig cells of CUMS mice.

Male reproductive problems under psychological stress were widely studied. Using chronically unpredictable mild stress-treated mice, we found that reduced serum testosterone levels were related to the low level of cholesterol in the Leydig cells. Testosterone deficiency in humans can be caused by depressive symptoms; however, the causes of this deficiency are incompletely understood. This study demonstrates that male mice with depression-like symptoms due to chronic unpredictable mild stress (CUMS) show reduced serum testosterone levels and disrupted sexual behaviors. However, the observed testosterone reductions were not caused by apoptosis of Leydig cells. Oil red O staining revealed that lipid droplets were dramatically decreased in Leydig cells, suggesting that defects in cholesterol uptake might be related to testosterone deficiency in depression-like mice. To investigate the potential mechanism, lipid homeostasis was examined by liquid chromatography-tandem mass spectrometry. The results revealed that higher levels of sphingomyelins (SM 8:0;2O/28:1, 18:0;2O/22:2, 33:0;3O, 33:1;2O) were linked to decreased cholesterol levels. Further investigation indicated that testosterone biosynthesis from cholesterol in Leydig cells was impaired by the downregulation of Ldlr, Srb1, Lhr, and P450scc. Elevated levels of interferon signaling-associated pathways in depression-like mice testes may also contribute to decreased testosterone levels. Taken together, these findings provide a novel understanding of male reproductive problems under psychological stress and suggest that cholesterol uptake might be a causal factor in reduced testosterone production in depression-like mice.

Triclosan inhibits testosterone biosynthesis in adult rats via inducing m6A methylation-mediated autophagy

Triclosan is a potent antibacterial compound widely used in everyday products. Whether triclosan affects Leydig cell function in adult male rats remains unknown. In this study, 0, 50, 100, or 200 mg/kg/day triclosan was gavaged to Sprague-Dawley male rats from 56 to 63 days postpartum. Triclosan significantly reduced serum testosterone levels at ≥ 50 mg/kg/day via downregulating the expression of Leydig cell gene Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3 and regulatory transcription factor Nr3c2 at 100–200 mg/kg. Further analysis showed that triclosan markedly increased autophagy as shown by increasing LC3II and BECN1 and decreasing SQSTM1. The mRNA m6A modification analysis revealed that triclosan significantly downregulated Fto expression at 200 mg/kg while upregulating Ythdf1 expression at 100 and 200 mg/kg, leading to methylation of Becn1 mRNA as shown by MeRIP assay. Triclosan significantly inhibited testosterone output in rat R2C Leydig cells at ≥ 5 μM via downregulating Fto and upregulating Ythdf1. SiRNA Ythdf1 knockdown can reverse triclosan-mediated mitophagy in R2C cells, thereby reversing the reduction of testosterone output. In summary, triclosan caused Becn1 m6A methylation by downregulating Fto and upregulating Ythdf1, which accelerated Becn1 translation, thus leading to the occurrence of autophagy and the decrease of testosterone biosynthesis.

The protective effect of Ozone on the mice testicular damage induced by methotrexate.

Methotrexate (MTX) is widely administered for the treatment of various cancers. However, MTX induces male reproductive toxicity. In the current study, the effect of ozone therapy (OT) on reducing the toxic effects of MTX in the mouse testicles has been investigated. Twenty-four mice were divided into four groups: control, OT (4 mg/kg ozone), MTX (20 mg/kg), and MTX + OT. Testosterone levels, histological changes, and oxidative stress biomarkers were assessed to evaluate the protective effects of OT. The results demonstrated that MTX disrupted germinal epithelium, reduced serum testosterone levels, and enhanced oxidative stress in testicular tissue. However, treatment with OT attenuated these adverse effects. OT effectively restored the levels of antioxidant enzymes, such as catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD). OT reduced lipid peroxidation, as indicated by decreased malondialdehyde (MDA) levels. OT preserved normal spermatogenesis, improved morphometric parameters, and reduced histological changes by MTX. Moreover, OT effectively restored testosterone levels. OT protects against MTX-induced testicular damage by suppressing oxidative stress.

EFFECT OF AFLATOXIN B1 ON THE HAEMATOLOGY, TESTES, AND LUNGS OF ADULT MALE RATS: A PHYSIOLOGICAL AND HISTOLOGICAL STUDY

Background: Aflatoxins are food-contaminating metabolites that can intoxicate and damage multiple organs. This study compared the effects of aflatoxin powder (AFB) and aflatoxin liquid (AFS) administrations on the testes and lungs of rats and elaborated their potential activity mechanisms.Methods: Fifteen rats were equally divided into 3 groups. The AFB and AFS groups were orally administered with aflatoxin B1 powder (0.5 mg/kg) and aflatoxin B1 liquid (0.5 mg/kg) for 21 days. The control group was fed on a basal pellet diet and water. The body weights of the rats were measured at the beginning of the trial and on the 7th, 14th, and 21st days. Blood samples were withdrawn at the end of the experiments and examined for complete blood count (CBC) [red blood cells (RBCs), hemoglobin content, mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), white blood cells (WBCs), and platelet, neutrophil, monocyte, lymphocyte, basophil, and eosinophil counts]. The levels of oxidative stress biomarkers, e.g. malonaldehyde (MDA) and nitric oxide (NO), and serum testosterone were determined. Testes and lungs were examined under a light microscope to assess the aflatoxin B1-induced histopathological changes.Results: The weight gain and its percentages were significantly high in the AFS group than AFB group (P &lt;0.050). Neutrophil, lymphocyte, monocyte, and basophil counts were also significantly increased in AFB and AFS groups in comparison to the controls. A significant increase in eosinophil count was noted in the AFB group as compared to controls whereas lymphocyte count remained significantly high in the AFS group than AFB group. Testosterone serum levels significantly decreased in both groups (AFB and AFS) as compared to the control group. MDA and NO serum levels were also significantly high in the AFS group than the AFB group whereas the levels of both groups (AFB and AFS) were higher than in controls. Histological examinations of the testes revealed severe testicular damage, loss of the spermatogenesis process, necrosis, degeneration, shrinkage, and atrophy of seminiferous tubules in both AFB and AFS groups. Histological observations of the lungs depicted large numbers of inflammatory cells, mast cell infiltration, dilated alveolar sacs with exudates, and marked hemorrhages in both groups (AFB and AFS). The histological damages of the testes and lungs were more prominent in the AFS group than AFB group.Conclusion: The results demonstrated elevated oxidative stress markers and reduced serum testosterone levels in AFB and AFS-treated rats. Both studied organs (testes and lung) were severely damaged with more obvious changes in AFS treated group than in AFB treated group.

The protective effect of crocin against testicular toxicity induced by ionizing radiation via AKT/FOXO pathway.

Crocin, a pharmacologically active component of Crocus sativus L. (saffron), has been informed to be beneficial in the treatment of stress-related oxidative impairment. In the present study, we examined the protective role of crocin against testicular damage induced by radiation (acute and fractionated) and the alteration of the AKT/FOXO signaling pathway. Male Wister albino rats were exposed to acute dose of 6 Gy and a fractionated dose of gamma radiation (2 Gy every 2 days up to 6 Gy total doses). Rats were pretreated intraperitoneally with crocin in a dose of 50 mg/kg for seven consecutive days prior to exposure to irradiation at a level of 6 Gy and during the fractionated irradiation of rats. Control groups were run concurrently. Ionizing radiation caused changes in the level of oxidative stress biomarkers manifested as elevation of thiobarbituric acid reactive substance, total nitrate/nitrite and reactive oxygen species (ROS) associated with a decrease in catalase as well as in the level of inflammatory parameters (decrease in expression of Nrf2 which was related to a significant increase in expression of NF-κB p65). Irradiation produced cellular damage characterized by an increase in serum lactate dehydrogenase. These findings were aligned with increased expression of the forkhead box O-1 (FOXO-1) and activation of protein kinase B (AKT) pathway. Irradiation of rats led to reduction in serum testosterone level and testicular weights. Pretreatment with the indicated dose of crocin shielded against the changes in all the evaluated parameters. Administration of crocin can be introduced as a novel preclinical approach for regulation of testicular damage induced by radiation; via controlling the ongoing oxidative stress and inflammatory reaction as well as activation FOXO/AKT signaling pathway.

A mixture of glyphosate and 2,4-D herbicides enhances the deleterious reproductive outcomes induced by Western diet in obese male mice.

The consumption of Western diet (WD) - enriched in fats and sugars - is associated with overweight, obesity and male reproductive disorders. In addition to WD intake, crops and dairy products display residues of herbicides, including glyphosate and 2,4-D that are widely applied worldwide. The concomitant exposure to WD and herbicides - mimicking contemporary scenarios - is not fully investigated. Thus, we evaluated the effects of glyphosate and 2,4-D, alone or in mixture, on WD-induced alterations in the male genital system. Male C57BL6J mice were submitted to WD (chow containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose) for 6 months. Concomitantly to WD, the animals received glyphosate (0.05, 5, or 50 mg/kg/day), 2,4-D (0.02, 2 or 20 mg/kg/day) or their mixture (0, 05 + 0.02, 5 + 2, or 50 + 20 mg/kg/day) by intragastrical administration (5×/week). Doses were based on Acceptable Daily Intake (ADIs) or No Observed Adverse Effect Level (NOAEL) values. Herbicide exposure did not alter the WD-induced obesity, hypercholesterolemia and hyperglycemia. WD induced sperm cell abnormalities, reduced the number, volume and area of Leydig cells, enhanced the frequency of epididymal abnormalities, decreased the proliferation in both germinal and epididymal epithelia, and reduced the number of androgen receptor (AR) positive epididymal cells. Remarkably, the herbicide mixtures promoted such WD-induced effects: increased the frequency of sperm cell and epididymal abnormalities (absence of sperm, cytoplasmic vacuoles, and clear cell hypertrophy) (5 + 2 and 50 + 20 doses); decreased Leydig cell nuclei volume and area (5 + 2 and 50 + 20 doses), reduced epididymal cell proliferation (all mixtures), and AR expression (50 + 20 dose). In addition, herbicide mixtures reduced serum testosterone levels (5 + 2 and 50 + 20 doses). Our findings indicate that the mixture of glyphosate and 2,4-D herbicides, mimicking environmentally relevant scenarios, promotes WD-induced changes in the male genital system.

Obesity May Impairs Mice Testicular Structure by STAT3/CYP19A1/Testosterone

Obesity is an increasing serious global public health issue and a risk factor for male infertility. Aromatase expression level is elevated in obese men, and this high level is as-sociated with diminished serum testosterone levels. We explored the underlying mechanism of infertility in obese men. Genome-wide association study datasets were used to predict the causal relationship between obesity and male infertility. An obese male mouse model was generated by feeding mice a high-fat diet while control model was generated by feeding mice a normal chow diet. Serum indicators including free fatty acids, insulin, Follicle-stimulating hormone, and testosterone were measured using ELISA, and impaired fertility in mice was demonstrated using immunohistochemistry. The expression levels of STAT3 and CYP19A1 were measured by RT-qPCR and western blotting, respectively. Simultaneous bioinformatics analysis of publicly available data was performed using the R programming language and JASPAR database. Obesity might lead to male infertility from a genomic perspective. Obese mice displayed reduced serum testosterone and follicle stimulating hormone levels along with structural abnormalities, ectopic lipid deposition, and chronic inflammation in the testes. Upregulation of STAT3/CYP19A1 expression in obese mice was linked to reduced serum testosterone levels and impaired fertility. Our observation may support the hypothesis that since the elevation of STAT3 expression in obesity, the promoted expressed CYP19A1 could increase a shift from testosterone to estrogens. The persistently elevated level of estrogen will further stimulate STAT3, which may constitute a positive feedback loop. These findings provide new insights into the mechanisms of obesity-mediated male fertility impairment.

Leydig cell development in pubertal male rats is blocked by perfluorotetradecanoic acid through decreasing AMPK-mTOR-autophagy pathway

Perfluorotetradecanoic acid (PFTeDA) is a type of perfluoroalkyl acid that has been linked to various health effects in animals and humans. The study aimed to investigate the potential impact of PFTeDA exposure on Leydig cell development in rats during puberty. Understanding the effects of PFTeDA on Leydig cells is crucial as these cells play a significant role in male reproductive function. Male Sprague-Dawley rats were gavaged with PFTeDA at doses of 0, 1, 5, and 10 mg/kg/day from postnatal day 35–56. The serum hormone levels were measured and testicular transcriptome changes were analyzed by RNA-seq and verified by qPCR, and the levels of steroidogenesis-related proteins and energy regulators were measured. PFTeDA significantly reduced serum testosterone levels while slightly increasing LH levels. RNA-seq and qPCR analysis showed that genes responsive to oxidative phosphorylation (Naufa1 and Ndufs6) and steroidogenesis (Ldlr, Star, Cyp11a1) were markedly downregulated at ≥ 5 mg/kg, while those related to ferroptosis (Alox15) and cell senescence (Map2k3 and RT1-CE3) were significantly upregulated. PFTeDA markedly reduced SIRT1 (silent information regulator 1) /PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) and AMPKA (AMP activated kinase A), LC3B and Beclin1 (biomarkers for autophagy) levels while increasing phosphorylated mTOR. In vitro treatment of PFTeDA at 5 μM significantly reduced androgen output of Leydig cells from 35-day-old male rats while ferrostatin 1 (10 μM) reversed PFTeDA-mediated inhibition. In conclusion, the inhibitory effects of PFTeDA on pubertal rat Leydig cell development are possibly regulated by inducing ferroptosis thereby downregulating SIRT1/AMPKA/ autophagy pathways, eventually resulting in reduced steroidogenesis.

Melatonin Ameliorates Cyclophosphamide-Induced Spermatogenesis Disorder by Reducing Pyroptosis

As a chemotherapeutic drug, cyclophosphamide (CP) has a negative impact on male fertility due to its reproductive toxicity. Melatonin (Mel) promotes the male reproductive system and increases testosterone synthesis. This study is aimed at exploring the molecular mechanism of Mel as a protector of male fertility against CP-induced cytotoxicity. A CP toxicity model was established in adult ICR male mice by intraperitoneal injection of 100 mg/kg CP every other day for a week. Protective effects of Mel on the testis from CP-induced damage were evaluated using four groups of ICR male mice that received intraperitoneal injections of normal saline, 100 mg/kg CP, 10 mg/kg Mel, or the same dosage of CP and Mel, respectively. Testis morphology was observed by hematoxylin and eosin (HE) staining. Sperm quality parameters were evaluated, and sperm function was studied by in vitro fertilization (IVF). Proliferation, meiosis, and pyroptosis markers were examined by western blot. Results showed that CP treatment induced testis toxicity in a time-dependent manner with the most severe damage to the testis at two weeks post CP treatment. CP-treated mice showed reduced testicular weight and impaired spermatogenesis by downregulating PCNA and SYCP3, reduced serum testosterone levels, decreased sperm counts and motility, increased seminiferous tubule vacuolization, and oxidative damage to spermatogenic cells. All these effects, apart from testicular weight, could be ameliorated by Mel administration. The IVF experiment revealed that CP treatment reduced the rates of sperm fertilization and blastocyst development, which were also enhanced by Mel. Mel-treated mice also showed increased expression of proliferation-associated protein PCNA and meiosis-associated proteins REC8, STRA8, and SYCP3, which were all reduced by CP. Furthermore, Mel inhibited the pyroptosis of spermatogenic cells by reducing GSDMD and IL18 expression. In conclusion, this study indicated that Mel might protect the testis from CP-induced DNA damage to germ cells through the alleviation of pyroptosis.

Androgen Deprivation Therapy in Current Clinical Practice: Challenges and Future Perspective

Androgen deprivation therapy (ADT) has been used for many years for treating advanced prostate cancer (PCa) and remains the backbone of treatment. Luteinising hormone-releasing hormone (LHRH) receptor agonists are the most widely used ADT drugs. However, newer options, including gonadotropin releasing hormone (GnRH) receptor antagonists such as degarelix and relugolix, may be clinically more beneficial for some patients. GnRH antagonists reduce serum testosterone levels more rapidly than LHRH agonists, without an initial testosterone surge or subsequent microsurges. This article summarises a symposium delivered on 11th March 2023 at the 38th European Association of Urology (EAU) Annual Congress in Milan, Italy, where speakers from three different disciplines described challenges and future perspectives for ADT in current clinical practice. Kurt Miller, Urologist, Charité University Hospital, Berlin, Germany, described the evolution of ADT in the treatment of PCa, from early reports of the benefits of surgical castration to the recent development of oral treatment for chemical castration. Miller explained the acceleration in progress in ADT research over recent years, with the development of novel drugs, drug sequences, and combinations, which have transformed outcomes in PCa. Alberto Bossi, Radiation Oncologist, Amethyst Group, Institut Gustav Roussy (IGR), Paris, France, next described current challenges with ADT management, including outstanding questions about the personalisation of ADT. Finally, Patrick Davey, Consultant Cardiologist, Northampton General Hospital, UK, spoke about ways to maintain a healthy heart on hormone treatment, and noted that cardiovascular safety is a major challenge in the use of ADT. The meeting was chaired by Heather Payne, Consultant Clinical Oncologist, University College Hospital, London, UK, who introduced the speakers and co-ordinated a question-and-answer session at the end of the symposium.

Long COVID and risk of erectile dysfunction in recovered patients from mild to moderate COVID-19

Patients with coronavirus disease 2019 (COVID-19) were shown to have reduced serum testosterone levels compared to healthy individuals. Low testosterone levels are linked with the development of erectile dysfunction (ED). In this case-controlled study, 20 healthy controls and 39 patients with ED 3 months after recovering from mild-to-moderate COVID-19 pneumonia were studied. The patients ranged in age from 31 to 47 years. To identify early and late COVID-19 infections, real-time polymerase-chain reaction (RT-PCR) and COVID-19 antibody testing were done. The levels of luteinizing hormone (LH), follicular stimulating hormone (FSH), total testosterone (TT), free testosterone (FT), free androgenic index (FAI), and sex hormone-binding globulin (SHBG) were measured. The sexual health inventory for patients (SHIM) score was used to measure the erectile function of the patients and controls. When compared to the controls, the TT serum level in long COVID-19 (LC) patients with ED was low (p = 0.01). In contrast to controls, FT and FAI were both lower in LC patients with ED. (p = 0.001). FSH serum levels did not significantly differ (p = 0.07), but in ED patients, LH serum levels were elevated. SHIM scores were associated with low TT (p = 0.30), FT (p = 0.09), and high LH (p = 0.76) in LC patients with ED. Male patients with decreased serum levels of LH and testosterone may have hypothalamic-pituitary–gonadal axis dysfunction, which could lead to the development of LC-induced ED. Therefore, an in-depth research is necessary to confirm the causal link between COVID-19 and ED in LC patients.

Remote limb ischemic postconditioning attenuates myocardial dysfunction induced by testicular torsion/detorsion in rats.

Torsion of the spermatic cord is a urological emergency that must be treated immediately with surgery, yet detorsion of the testis can cause testicular tissue damage because of ischemia‒reperfusion (I/R) injury. I/R injury is a complex pathophysiological process that may affect the functions of distant organs. Here, we examined whether testicular torsion/detorsion causes myocardial dysfunction. We next investigated the potential beneficial effect and underlying mechanisms of remote ischemic postconditioning (RIPost) on cardiac function after testicular torsion/detorsion. Male Sprague Dawley rats were assigned to three different sets of experimental groups. Testicular I/R was induced by rotating the right testis to 1080 degrees clockwise for 3 hours followed by 3 h of detorsion. RIPost was induced at the onset of testicular detorsion by four cycles of 5-min bilateral femoral artery occlusion with 5-min reperfusion. Cardiac function was determined postdetorsion, and the cardioprotective effect of RIPost was examined. Testicular torsion/detorsion-treated rats had reduced serum testosterone levels, impaired systemic hemodynamics, elevated systemic inflammatory responses and increased serum levels of LDH, CK-MB, α-HBDH and cTnI. Healthy rats transfused with testicular torsion/detorsion-treated plasma presented impaired cardiac function. However, RIPost attenuated remote heart dysfunction induced by testicular torsion/detorsion. Furthermore, RIPost enhanced the phosphorylation of ventricular STAT-3, which is a key component of the SAFE signaling pathways. Inhibition of STAT-3 with Ag490 abolished the RIPost-induced cardioprotection and STAT-3 phosphorylation. Testicular torsion followed by detorsion resulted in impairment of cardiac function. RIPost effectively attenuates this remote cardiac dysfunction. RIPost-induced protective effects may be mediated by the STAT-3 signaling pathway.

Melatonin therapy reverses lead exposure-induced testicular damage in rats despite the lack of effect on serum testosterone levels.

Lead (Pb) exposure induces testicular damage and infertility. The aim of this study was to analyze and compare the therapeutic effects of antioxidants or vitamin D and calcium, which have previously been shown to reduce the toxic effects of Pb co-exposure, in rats. Rats were exposed to Pb for 28 days and subsequently treated with antioxidant (melatonin, silymarin), vitamin D and calcium (VitDCa) or a combination (melatonin or silymarin with VitDCa) for 28 days. Control groups included untreated rats (no Pb exposure or therapy), rats exposed only to melatonin or silymarin and rats exposed to Pb without post exposure therapy. Pb exposure induced testicular damage, increased blood lead level (BLL) and reduced serum testosterone level (STL). Rats exposed to Pb and left untreated for 28 days showed persistent pathological testicular alterations. The two treatments that were most effective in reversing pathological testis damage and restoring spermatogenesis were melatonin and silymarin. However, silymarin and melatonin treatment resulted in significantly different serum testosterone levels in rats. Whereas melatonin therapy reduced serum testosterone to levels lower than those in control rats, silymarin increased serum testosterone to levels higher than those in controls. Our pathological analysis of testes revealed that melatonin promoted spermatogenesis and regression of Pb exposure-induced degenerative changes, despite the associated reduction in serum testosterone levels. This result suggests that circulating testosterone may not have an important role in spermatogenesis. Collectively, our results suggest that melatonin and silymarin are effective therapies against the toxic effects Pb exposure in the male reproductive system.

Bone morphogenetic protein 4 inhibits rat stem/progenitor Leydig cell development and regeneration via SMAD-dependent and SMAD-independent signaling

Bone morphogenetic protein 4 (BMP4) is an important member of the transforming growth factor-β superfamily. BMP4 is expressed in the Leydig cell lineage. We hypothesized that BMP4 might regulate the development of stem/progenitor Leydig cells. The BMP4 receptors, BMPR1A, BMPR1B, and BMPR2 were found to be expressed in progenitor Leydig cells of prepubertal testis and isolated cells. BMP4 at 1 and 10 ng/mL significantly reduced androgen production and down-regulated steroidogenesis-related gene and protein expression possibly by activating the SMAD signaling pathway (increasing SMAD1/5 phosphorylation and SMAD4) at 24 h treatment. BMP4 at 0.1 ng/mL and higher concentrations markedly reduced the EdU labeling index of CD90+ stem Leydig cells after 24 h treatment and significantly reduced the number of EdU+ stem Leydig cells on the surface of seminiferous tubules after 7 days of culture. BMP4 at 0.01 ng/mL and higher concentrations significantly blocked the differentiation of stem Leydig cells into adult cells, as shown by the reduction of testosterone secretion and the downregulation of Lhcgr, Scarb1, Cyp11a1, Hsd11b1, and Insl3 and their function after 3D seminiferous tubule culture for 3 weeks, and this effect was reversed by co-treatment with the BMP4 antagonists noggin and doxomorphine. In addition, BMP4 also blocked stem Leydig cell differentiation through SMAD-independent signaling pathways (ERK1/2 and AMPK). Ethanedimethane sulfonate (EDS) single injection can result in reduction of testosterone, restoration can happen post treatment. In an in vivo model of Leydig cell regeneration following EDS treatment, intratesticular injection of BMP4 from day 14 to day 28 post-elimination significantly reduced serum testosterone levels and down-regulated the expression of Scarb1, Star, Hsd11b1, and Insl3 and its proteins, possibly through SMAD-dependent and SMAD-independent (ERK1/2 and AMPK) signaling pathways. In conclusion, BMP4 is expressed in cells of the Leydig cell lineage and blocks entry of stem/progenitor Leydig cells into adult Leydig cells through SMAD-dependent and SMAD-independent signaling pathways.

In utero di-(2-ethylhexyl) phthalate-induced testicular dysgenesis syndrome in male newborn rats is rescued by taxifolin through reducing oxidative stress

Testicular dysgenesis syndrome in male neonates manifests as cryptorchidism and hypospadias, which can be mimicked by in utero phthalate exposure. However, the underlying phthalate mediated mechanism and therapeutic effects of taxifolin remain unclear. Di-(2-ethylhexyl) phthalate (DEHP) is the most abundantly used phthalate and can induce testicular dysgenesis syndrome in male rats. To explore the mechanism of DEHP mediated effects and develop a therapeutic drug, the natural phytomedicine taxifolin was used. Pregnant Sprague-Dawley female rats were daily gavaged with 750 mg/kg/d DEHP or 10 or 20 mg/kg/d taxifolin alone or in combination from gestational day 14 to 21, and male pup's fetal Leydig cell function, testicular MDA, and antioxidants were examined. DEHP significantly reduced serum testosterone levels of male pups, down-regulated the expression of SCARB1, CYP11A1, HSD3B1, HSD17B3, and INSL3, reduced the cell size of fetal Leydig cells, decreased the levels of antioxidant and related signals (SOD2 and CAT, SIRT1, and PGC1α), induced abnormal aggregation of fetal Leydig cells, and stimulated formation of multinucleated gonocytes and MDA levels. Taxifolin alone (10 and 20 mg/kg/d) did not affect these parameters. However, taxifolin significantly rescued DEHP-induced alterations. DEHP exposure in utero can induce testicular dysgenesis syndrome by altering the oxidative balance and SIRT1/PGC1α levels, and taxifolin is an ideal phytomedicine to prevent phthalate induced testicular dysgenesis syndrome.

Eugenol reduces serum testosterone levels and sperm viability in adult Wistar rats

Eugenol is the main constituent of clove extract. It is a remarkably versatile molecule incorporated as a functional ingredient in several food products and widely applied in the pharmaceutical industry. Men consume natural products enriched with eugenol for treating sexual disorders and using as aphrodisiacs. Nevertheless, there is no information about the impact of eugenol intake on the reproductive parameters of healthy males. Therefore, we provided 10, 20, and 40 mg kg-1 pure eugenol to adult Wistar rats for 60 days. Testis, epididymis, and spermatozoa were analyzed under microscopic, biochemical, and functional approaches. This phenolic compound did not alter testicular and epididymal biometry and microscopy. However, 20 and 40 mg kg-1 eugenol reduced serum testosterone levels. The highest dose altered lactate and glucose concentrations in the epididymis. All the eugenol concentrations diminished CAT activity and MDA levels in the testis and increased FRAP and CAT activity in the epididymis. Epididymal sperm from rats receiving 10, 20, and 40 mg kg-1 eugenol presented high Ca2+ ATPase activity and low motility. In conclusion, eugenol at low and high doses negatively impacted the competence of epididymal sperm and modified oxidative parameters in male organs, with no influence on their microscopy.