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Objective: This randomized clinical trial study aims to investigate the effects of antioxidant food supplementation on the total antioxidant capacity of seminal plasma, sperm DNA fragmentation, sperm chromatin quality, and semen parameters., Methods: In this study, a total of 48 subfertile men with moderate physical activity were included. Group 1 was recommended to use the antioxidant supplements, while antioxidant food supplements were not given to Group 2. Total antioxidant capacity, sperm DNA fragmentation, sperm chromatin structure, hormone levels, physical activities, and semen parameters were evaluated before and after treatment. Total antioxidant capacity, sperm DNA fragmentation, and sperm chromatin structure were assessed using ELISA, transferase dUTP nick end labeling, and aniline blue staining, respectively., Results: Sperm DNA fragmentation (p=0.003) and histone/protamine ratio (p<0.001) were significantly decreased in the patients receiving antioxidant treatment. There was no statistical difference in the total antioxidant capacity values of the post-treatment groups., Conclusion: Antioxidant therapy seems to improve sperm DNA fragmentation and histone/protamine ratios in subfertile patients., Clinical Trial Registration Number: NCT06042738.

Previous studies have shown beneficial effects of empagliflozin (Empa), a selective inhibitor of the sodium-glucose cotransporter 2 (SGLT2), on diabetes and cardiovascular outcomes in patients with diabetes. However, whether Empa could ameliorate diabetes mellitus (DM)-induced male spermatogenesis dysfunction remains unclear. Our study aimed to investigate the effect of Empa in the development of DM-induced male spermatogenesis dysfunction and to reveal the molecular mechanisms. DM mice were orally treated with Empa to investigate the effects of Empa on DM-induced male mice spermatogenesis dysfunction. We employed a cardiac-specific C1q/tumor necrosis factor-related protein 9 (CTRP9)-deficient mouse model and a cardiac-specific CTRP9 overexpression mouse model to investigate its role in the protection of Empa against diabetes-induced male subfertility. We found that Empa treatment could improve DM-induced male mice subfertility. Interestingly, we discovered that cardiac-derived CTRP9 was decreased in DM mice and this decrease was prevented by Empa treatment. A CTRP9 blocking antibody or cardiac-specific depletion of CTRP9 abolished the protection of Empa on DM-induced male subfertility. Cardiac-specific CTRP9 overexpression ameliorated DM-induced male subfertility. Mechanistically, we identified that cardiac-derived CTRP9 increased steroidogenesis in mice with diabetes in a PKA-dependent manner. We also provided direct evidence that activation of AMP activated protein kinase α (AMPKα)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signalling pathway by CTRP9 was responsible for the attenuation of ferroptosis in Leydig cells. In conclusions, we supposed that Empa was a potential therapeutic agent against DM-induced male mice spermatogenesis dysfunction., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Reactive oxygen species are secondary messengers in multiple intracellular and tissue reactions, modulate the activity of mitogenic signaling pathways, and are formed predominantly in the course of metabolic activity. Both direct and indirect data on male reproductive dysfunction associated with SARSCoV-2 are described, as well as its possible pathophysiological and immunological explanations., Purpose: of the work: to evaluate the dynamics of lipid peroxidation and antioxidant protection in men after SARS-CoV-2 infection while taking an antioxidant complex., Results: In the observed patients, the components characterizing significant damage to metabolic homeostasis were analyzed in the blood plasma: the state of lipid peroxidation was judged by the level of compounds with double bonds, ketodienes and conjugated trienes, diene conjugates, and TBA-active products in the blood. The intensity of antioxidant defense processes was assessed by the concentrations of -tocopherol and retinol, as well as by the activity of superoxide dismutase. In the prooxidant-antioxidant system, the balance was restored towards antioxidant components in the group of patients after taking the antioxidant complex., Conclusions: the effectiveness of antioxidant correction largely depends on the degree of protection of the structure and function of cell membranes, as a result, the use of this drug is advisable, since it reduces the level of lipid peroxidation and enhances the antioxidant defense of the body.

Purpose: This study evaluated the effectiveness of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) treatments using multiple pharmaceutical agents that could simultaneously preserve or enhance fertility capability., Materials and Methods: This was a single-center-based, randomized controlled study, whereas the final analysis evaluated a total 350 CP/CPPS patients (age range, 28-40 years) and 50 patients were randomly allocated to each therapeutic group, with a 1:1 ratio. The therapeutic groups consist of tadalafil (group 1, 5 mg daily), L-carnitine (group 2, 2 g daily), Serenoa repens extract (group 3, 320 mg daily), group 4 (tadalafil+L-carnitine), group 5 (tadalafil+ S. repens ), group 6 (L-carnitine+ S. repens ), and group 7 (tadalafil+L-carnitine+ S. repens ). The treatment outcomes at 3 months post-therapy were analyzed., Results: At 3 months post-therapy, the mean total sperm motility was significantly improved in all groups. A normal morphology improvement was observed in L-carnitine receiving groups. The mean total score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and the mean International Prostate Symptom Score (IPSS) showed the greatest reduction in intensity in group 7. Logistic regression analyses showed that group 5 and group 7 were significantly associated with improvements in total IPSS and total NIH-CPSI scores at 3 months post-therapy. Group 7 was a significant predictor for improving total sperm motility, leukocytospermia and normal form of sperm., Conclusions: Tadalafil, carnitine, and S. repens combination therapy could be considered a feasible treatment option for CP/CPPS males with subfertility., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association.)

Sperm production depends on proper Sertoli-germ cell interaction, and we hypothesized that receptor activator of nuclear factor κB ligand (RANKL) activity in Sertoli cells may influence spermatogenesis. Treatment with the RANKL inhibitor denosumab, normally used to treat osteoporosis, increased testicular weight, inhibin B, and germ cell proliferation in ex vivo testis cultures and in vivo in a humanized RANKL mouse. The effect on germ cell proliferation was positively associated with baseline serum concentrations of anti-müllerian hormone (AMH). In accordance, denosumab increased germ cell proliferation in ex vivo human testis cultures with low/moderate but not severe impairment of Sertoli cell function. In a placebo-controlled randomized clinical trial, denosumab had no effect on semen quality but increased sperm concentration in a subgroup of infertile men with serum AMH ≥38 pmol/L at baseline. In conclusion, high serum AMH may increase the probability of a beneficial response to denosumab treatment in infertile men, thus suggesting a possible venue for precision medicine in male infertility., Competing Interests: Declaration of interests M.B.J. holds two patents on the use of RANKL inhibitors to treat male infertility and founded the spin-out company XY Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Subfertility is a multifactorial disorder that affects the rabbit production industry. However, subfertility may be treated by using a simple intervention such as vitamin supplementation. Vitamin E and selenium (Se) are potent antioxidants that protect the male reproductive system. The aim of this study is to determine the effects of vitamin E and Se on testicular size, semen quality and freezability, antioxidant activity, testosterone levels, and fertility in subfertile rabbits. Twenty-one New Zealand rabbits were classified as subfertile rabbits based on their semen characteristics and fertility records. The rabbits were randomly allocated into 3 equal groups (G1: control; G2: injected with Vit E 100 IU/head + Se 0.1 mg/kg b.w.; G3: injected with Vit E 200 IU/head + Se 0.2 mg/kg b.w. once weekly for 8 weeks).Once weekly for 8 W, blood samples were collected to measure serum testosterone level and total antioxidant capacity (TAC), and semen samples were collected by artificial vagina to assess the quality of fresh and frozen semen. At the 8th week of the study, 150 multiparous does were artificially inseminated with fresh semen to assess the fertility of rabbits after treatment; 50 does for each group. At the end of the study, rabbits were slaughtered to assess testicular morphometry. Fresh and post-thaw semen quality parameters were significantly (p < 0.05) higher in G3in comparison with G2and G1, respectively. Also, testosterone level was significantly (p < 0.05) increased at the 2nd week in G3in comparison with other groups. Conception and kindling rates were significantly (p < 0.05) higher in does which were inseminated with semen fromG3. In conclusion, injection of vitamin E and selenium at a higher dose (G3) improved the testicular morphology, quality of fresh and post-thaw semen, and most importantly, the fertility of subfertile rabbits., (© 2024. The Author(s).)

Melatonin is a pineal hormone that regulates testicular activity (i.e., steroidogenesis and spermatogenesis) through two complementary mechanisms, indirect effects exerted via the hypothalamic-adenohypophyseal axis and direct actions that take place on the different cell populations of the male gonad. The effects of increased age on the testis and the general mechanisms involved in testicular pathology leading to infertility are still only poorly understood. However, there is growing evidence that link testicular aging and idiopathic male infertility to local inflammatory and oxidative stress events. Because literature data strongly indicate that melatonin exhibits anti-inflammatory and anti-oxidant properties, this review focuses on the potential benefits exerted by this indoleamine at testicular level in male reproductive fertility and aging. Taking into account that the effects of melatonin supplementation on testicular function are currently being investigated, the overview covers not only promising prospects but also many questions concerning the future therapeutic value of this indoleamine as an anti-aging drug as well as in the management of cases of male infertility for which there are no medical treatments currently available., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hydrogen sulfide (H 2 S) is an endogenously produced signaling molecule that belongs to the group of gasotransmitters along with nitric oxide (NO) and carbon monoxide (CO). H 2 S plays a pivotal role in male reproductive processes. It is produced in various tissues and cells of the male reproductive system, including testicular tissue, Leydig and Sertoli cells, epididymis, seminal plasma, prostate, penile tissues, and sperm cells. This review aims to summarize the knowledge about the presence and effects of H 2 S in male reproductive tissues and outline possible therapeutic strategies in pathological conditions related to male fertility, e. g. spermatogenetic disorders and erectile dysfunction (ED). For instance, H 2 S supports spermatogenesis by maintaining the integrity of the blood-testicular barrier (BTB), stimulating testosterone production, and providing cytoprotective effects. In spermatozoa, H 2 S modulates sperm motility, promotes sperm maturation, capacitation, and acrosome reaction, and has significant cytoprotective effects. Given its vasorelaxant effects, it supports the erection of penile tissue. These findings suggest the importance and therapeutic potential of H 2 S in male reproduction, paving the way for further research and potential clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pilsova, Pilsova, Zelenkova, Klusackova, Chmelikova, Postlerova and Sedmikova.)

Herbal products with antioxidant properties have gained attention for their potential impact on male reproductive health. One such botanical, Ceratonia siliqua (commonly known as carob), has been empirically used by infertile men in Iran and Turkey. Carob, a pod-bearing tree native to the Mediterranean, exhibits promising therapeutic potential for various aspects of male reproductive health. Carob consumption may positively affect sperm count, motility, and morphology in infertile men. The proposed mechanisms involve antioxidant activity, improved blood flow, and enhanced energy production within sperm. Carob's richness in antioxidants like polyphenols and flavonoids might counteract oxidative stress, a major contributor to sperm dysfunction. Carob may influence male sex hormones by potentially stimulating testosterone production and inhibiting estrogen conversion. While carob demonstrates promise as a natural supplement for male fertility, more robust research is necessary to solidify its therapeutic role. This exploration could pave the way for the development of novel dietary or nutraceutical interventions to address male infertility. While preliminary research suggests positive effects on sperm health and potential hormonal influence, robust clinical trials are needed to solidify carob's therapeutic efficacy. This exploration paves the way for future research on carob as a natural supplement and potentially opens doors for novel dietary or nutraceutical interventions to address male infertility., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Infertility is a major reproductive health problem. Approximately 50% of all documented cases of infertility are attributable to male factors, such as poor testicular function and semen quality. The recent significant global decline in sperm counts has serious implications for male fertility, but the armamentarium for improving testicular function and semen quality is limited. Natural products have a wide range of activities and are a major source of drugs for disease prevention and treatment. To provide ideas and a theoretical basis for the research and development of therapeutic drugs for male infertility, this review summarizes natural products (mostly monomers) that have been shown to improve testicular function and semen quality and their possible mechanisms of action. These natural products primarily improve testicular function and semen quality via antioxidant, antiapoptotic, and anti-inflammatory effects, in addition to increasing serum testosterone and reducing DNA damage in spermatozoa and testicular cells. Prospects for the application of natural products in the treatment of male infertility are discussed., (© 2024 American Society of Andrology and European Academy of Andrology.)

Ulcerative colitis is a public health issue with a rising worldwide incidence. It has been found that current medications for treating UC may cause varying degrees of damage to male fertility. Our previous study demonstrated that cyanidin-3-O-glucoside (C3G) treatment could effectively restore reproductive damage in a mouse model of DSS induced colitis. However, the underlying mechanism of C3G alleviates UC induced male reproductive disorders remain scarce. The aim of this study is to discover the molecular mechanisms of C3G on the amelioration of UC stimulated reproductive disorders. The targeted genes toward UC-induced reproductive injury upon C3G treatments were explored by transcriptomic analysis. Hematological analysis, histopathological examination, and real time transcription-polymerase chain reaction (RT-PCR) analysis were applied for conjoined identification. Results showed that C3G may effectively target for reducing pro-inflammatory cytokine IL-6 in testis through cytokine-cytokine receptor interaction pathway. Transcriptome sequencing found that a series of genetic pathways involved in the protective effects of C3G on male reproduction were identified by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Further results presented that C3G could effectively restore mRNA expression levels of Ly6a and Col1a1, closely linked with UC induced male reproductive damage pathways. Sufficient results implied that Ly6a and Col1a1 may be treated as the promising therapeutic targets for the mechanism of C3G in treating UC induced reproductive impairment. C3G administration might be an effective dietary supplementation strategy for male reproduction improvement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Male infertility is identified by the inability of a man to successfully impregnate his fertile female partner, even following a year of regular unprotected sexual intercourse. About half of all infertility cases are attributed to what is known as "male factor" infertility. The escalating prevalence of male infertility in the contemporary era across the globe can be largely attributed to environmental pollution, which is the common etiological factor due to the ubiquitous presence of the environmental contaminants. Bisphenol A is recognized as an endocrine-disrupting chemical that has adverse effects on both male and female reproductive systems. On the other hand, numerous studies have demonstrated that Panax ginseng possessed the potential to improve male infertility parameters; promote spermatogenesis, recover the quality and motility of sperm and enhance testicular functions as it acted as a natural androgen supplement. The objective of this review is to offer a summary of the findings obtained from the current research data on the insult of bisphenol A (BPA) on male infertility and its supposed mode of action, as well as shed light on the potent ameliorative role of Panax ginseng extract, with a special focus on the mechanism behind its action. This review delivers a clear understanding of BPA mechanism of action on male infertility and the presumed risks deriving from its exposure. Also, this review provides evidence for the functional role of Panax ginseng extract in restoring male fertility., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Cadmium (Cd) is an environmental pollutant known as endocrine disruptor . Cd has been reported to induce perturbations of the testicular functions and the subsequent decline of the male fertility of both animals and humans. Chlorella vulgaris (ChV) a species of green microalga has been reported to have multiple beneficial activities such as anti-inflammatory, antioxidant, and antiapoptotic effects. Thus, this work was conducted to declare the benefits of Chlorella vulgaris (ChV) (500 mg/kg doses) against cadmium chloride CdCl 2 (2 mg/kg doses) toxicity on the main and accessory reproductive organs' weight, structure, and function of male rats. Briefly, 40 adult male rats in 4 groups (n = 10) were used as follows; control, ChV, CdCl2, and CdCl2+ChV. (i) The 1st group was kept as control fed on pellet chow and water ad libitum. (ii) The second group is Chlorella vulgaris (ChV) group fed with C. vulgaris alga for 10 days (500 mg/kg BW). (iii) The third group was administrated CdCl 2 (2mg/kg BW) via subcutaneous injection (S/C) daily for 10 days. (iv) The fourth group administered both CdCl 2 and ChV with the abovementioned doses daily for successive 10 days. Our observations declared that cadmium exhibited an adverse influence on the testes and prostate gland architecture indicated by seminiferous tubule destruction, testicular edema, degeneration of Leydig cells, and prostate acini damage. All together affect the epididymal semen quality and quantity including sperm viability, motility, and count. Interestingly, ChV could restore the testicular architecture and spermatozoa regeneration accompanied by semen quality improvement and increased reproductive hormones including testosterone. On the other side, ChV suppresses reactive oxygen species (ROS) formation via enhancement the antioxidant-related genes in the testicular tissue including SOD, CAT, GSH, and MDA and maintaining spermatocyte survival via suppression of apoptotic related genes including caspase3 and activating steroidogenic related genes including StAR and HSD17β3 in the cadmium-treated testes. In this study, ChV could enhance male fertility under normal or stressful conditions and ameliorate the adverse effects of hazardous heavy metals that are widely distributed in our environment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ethnopharmacological Relevance: Phoenix dactylifera L. pollen is the male reproductive dust of palm flowers known as a natural product that is considered a strong stimulant of sexual potency and fertility in Iranian traditional medicine (ITM). In this regard, no evidence-based medications are empirically prescribed to treat IMI. However, applying traditional medicine for the treatment of male infertility has attracted more attention in recent years., Aim of the Study: Phoenix dactylifera L. pollen was compared with pentoxifylline (PTX) to evaluate its efficacy on sperm parameters., Materials and Methods: During this parallel randomized controlled trial, 80 adult men with asthenozoospermia, oligozoospermia, or teratozoospermia (age 20-35 years) were enrolled. In two separate groups of participants with a 1:1 ratio, participants received either 6 g of Phoenix dactylifera L. pollen powder daily or 400 mg of PTX tablets daily for 90 days. We measured the sperm parameters as well as the serum sex hormones in the sample. ANCOVA and t-tests were used to compare groups., Results: There was no significant difference between the study groups in terms of baseline characteristics or demographic characteristics. According to the results, participants who took Phoenix dactylifera L. pollen powder had significantly improved sperm concentration (p = 0.016), morphology (p = 0.029), sperm counts (p = 0.012), progressive motility (p = 0.016), total motility (p = 0.018), and reduced immotile sperms (p = 0.014) compared to those who took PTX., Conclusions: In light of these results, Phoenix dactylifera L. pollen is recommended as a treatment factor for ameliorating IMI by enhancing sperm functional capacity and semen parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Placebo influence on such objective indicators, as sperm quality and infertility, has not been studied previously, but some studies report that placebo may distort even objective outcomes. The aim of current study is to assess the placebo effect on fertility in patients suffering from sperm abnormalities and/or infertility., Evidence Acquisition: We conducted a search of two databases (Scopus and MEDLINE) and identified placebo-controlled clinical trials which focused on sperm abnormalities and/or male infertility treatment. Primary outcomes included changes in semen parameters (volume, total count, sperm concentration in semen, progressive motility, morphology (normal cells)). Secondary outcomes included DNA fragmentation and change in pregnancy rate., Evidence Synthesis: Seventy-seven articles published from 1983 to 2022 were included. Statistically significant changes were observed for the following values: total sperm count, mean change 0.16 (95% CI 0.05, 0.26); P=0.004, I 2 =75.1%; and progressive motility, mean change 0.13 (95% CI 0.02, 0.24); P=0.026, I 2 =84.9%. In contrast, placebo did not affect sperm concentration, sperm volume, sperm morphology or DNA fragmentation index. The publication bias for all the values measured with Egger's test and funnel plots was low., Conclusions: The current meta-analysis indicated a statistically significant increase of total sperm count and progressive motility in the placebo group. In contrast, placebo did not affect sperm concentration, sperm volume, sperm morphology and DNA fragmentation index. These findings should be considered while planning or analyzing placebo-controlled clinical trials.

Background: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy., Objective: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis., Methods: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI)., Results: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78-3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23-4.62), tamoxifen (SMD - 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD - 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44-2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo., Conclusion: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men., Prospero: CRD42023430179., (© 2024. The Author(s).)

Background: The global prevalence of infertility is 9%, with male factors potentially accounting for 40% to 60% of cases. Conventional treatments can be ineffective, invasive, costly, and linked to adverse effects and high risks. Previous studies have shown that, Chinese herbal medicine (CHM) can regulate the hypothalamus-pituitary-testis axis, improve sperm abnormalities and quality, mitigate oxidative stress, and decrease DNA fragmentation index (DFI). Yet, the evidence backing the use of Chinese herbal medicine (CHM) for treating male factor infertility lacks conviction due to study design limitations, and there remains a scarcity of studies on the live birth rate following CHM treatment for male factor infertility. Here, we describe the rationale and design of a randomized waitlist-controlled trial to evaluate the effect of CHM on the live birth rate among males with infertility., Methods: This study is a single-center, randomized, waitlist-controlled study. A total of 250 couples diagnosed with male factor infertility will be enrolled in this study and then randomly allocated into two groups in a 1:1 ratio. Male participants in CHM group (treatment group) will receive CHM once a day for 3 months. Male participants in the waitlist group (control group) will not receive any treatment for 3 months. After 3 months, participants in both groups need to be followed up for another 12 months. The primary outcome will be the live birth rate; secondary outcomes include semen quality parameters, DFI and pregnancy related outcomes. Safety will also be assessed., Discussion: The purpose of this trial is to explore the effects and safety of CHM on the live birth rate among couples dealing with male factor infertility. The outcome of this trial may provide a viable treatment option for male factor infertility., Trial Registration: Chinese Clinical Trial Registry: ChiCTR2200064416. Registered on 7 October 2022, https://www.chictr.org.cn., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wen, Xu, Zou, Wang, Xing, Chen, Zhu, Chen, Tan, Zhang, Pan, Chen, Wang and Wu.)

Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility., (© 2024. The Author(s).)

Objective: Human choriogonadotrophin (hCG) treatment of gonadotrophin-deficient infertile men uses hCG of urinary (uhCG) or recombinant (rhCG) origin, but these treatments have not been compared nor are there studies defining rhCG dosing in men., Design: hCG products were studied in randomized cross-over single-dose studies of standard (Study 1, 1500 IU and 62.5 µg, respectively) or high (Study 2, 5000 IU and 250 µg) dose and a multi-dose population pharmacology study of hCG use., Participants: Eight (Study 1) and seven (Study 2) volunteers in cross-over and 52 gonadotrophin-deficient men in the multi-dose study MEASUREMENTS: In cross-over studies, serum testosterone (T), dihydrotestosterone (DHT) and estradiol by liquid chromatography-mass spectrometry (LCMS) and serum hCG, LH, FSH, SHBG and T (observational study) by immunoassays., Results: After standard and high-dose injection, serum hCG and testosterone responses had similar timing and peak concentrations except for a mildly lower early (<48 h) serum testosterone with uhCG. In the multi-dosing study, both hCGs had similar pharmacokinetics (pooled half-life 5.8 days, p < .001), while serum testosterone concentrations were stable after injection and did not differ between hCG products. Bench testing verified that 20% of pens from 4/10 individuals were used inappropriately., Conclusions: Although hCG pharmacokinetics are not formally bioequivalent, the similar pharmacodynamic effects on serum testosterone indicate that at the doses tested both hCGs provide comparable clinical effects. The starting dose of rhCG for treating gonadotrophin-deficient men should be 62.5 µg (6 clicks) of the rhCG pen., (© 2024 Commonwealth of Australia. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched., Methods: Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells., Results: A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by busulfan. Moreover, OCA intervention reduced busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy., Conclusions: This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility., (© 2024. The Author(s).)

Background: Worldwide, infertility affects about 15% of reproductive-age couples. In many cases, infertility can't be treated, however new treatment options with promising value have been involved in recent clinical trials. The aim of this clinical trial was to evaluate the impacts of adding coenzyme Q10 (CoQ10) to letrozole on the results of spermiogram and sex hormone tests in men diagnosed with idiopathic oligoasthenoteratozoospermia (iOAT) syndrome, which is a type of male defective spermatogenesis of unknown etiology. Methods: This randomized, open-label, parallel two-arm interventional study included 67 adult male patients aged 18-60 years with a confirmed diagnosis of iOAT syndrome recruited from The High Institute for Infertility Diagnosis & Assisted Reproduction Technologies/Nahrain University. Patients were randomly separated into two groups, Group A included 29 patients treated with letrozole 2.5 mg tablet orally twice a week, Group B included 38 patients treated with a combination of letrozole 2.5 mg tablet orally twice a week plus CoQ10 400 mg per day. Both groups completed treatment for three months. Semen samples, serum follicle-stimulating hormone (FSH), estradiol (E 2 ), and testosterone (T) were analyzed at day one, and at the end of month one, two and three. Results: Both groups showed that sperm concentration, normal morphology, total sperm count and motility, serum testosterone and FSH levels, and T/E 2 ratio were significantly increased, while estradiol levels significantly decreased after three months of treatment. Seminal fluid volume changed significantly in group A only. In comparing between the two groups, all measured parameters, apart from sperm motility and FSH level, demonstrated a significant difference after three months of treatment, while sperm volume reached significant value after only two months of therapy. Conclusions: CoQ10 as adjuvant treatment to letrozole effectively improved most of the tested sperm parameters in Iraqi men with iOAT. Registration: ClinicalTrials.gov ( NCT05847257, May 6, 2023)., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Fadhil EB et al.)

Objective: Idiopathic male infertility is common, yet there is no approved treatment. This study aimed to understand practice patterns towards empirical medical therapy (EMT) for idiopathic male infertility in Australia and New Zealand (NZ)., Design: Clinical members of the Endocrine Society of Australia, Fertility Society of Australia & NZ, and Urological Society of Australia & NZ were invited to complete a survey. Questions included demographics, EMT practice habits, and thoughts regarding infertility case scenarios. Unadjusted group differences between specialists, those with and without additional training in male infertility, and frequency of managing it were evaluated., Results: Overall, 147 of 2340 members participated (6.3%); majority were endocrinologists and gynaecologists. Participants were experienced; 35% had completed additional training in male infertility and 36.2% reported they frequently manage male infertility. Gynaecologists were more likely to manage male infertility and attend education courses than endocrinologists and urologists. Beliefs about the effect of EMT on sperm concentration and pregnancy did not differ between speciality types. Many respondents considered all patient scenarios suitable for EMT. Of medications, hCG and clomiphene were selected most. Two respondents indicated they would use testosterone to treat male infertility., Conclusions: This study demonstrates common use of EMT in Australia and NZ for idiopathic male infertility. The breadth of responses reflects a lack of consensus within the current literature, highlighting the need for further research to clarify their role in the management of idiopathic male infertility., (© 2024 John Wiley & Sons Ltd.)

Objective: To verify, based on a systematic literature review, the effects of the main analgesics on male fertility., Data Sources: The studies were analyzed from the PubMed, SciELO and LILACS databases., Study Selection: The articles selected for the present review included: cohort studies; cross-sectional studies, clinical trials; complete studies; studies with animal models that addressed the proposed theme and that were published within the stipulated period from March 1, 2013, to March 31, 2023, in English, Portuguese and Spanish. These would later have to go through inclusion stages such as framing the type of study and exclusion criteria., Data Collection: Author's name, year of publication, study population, number of patients, analgesic, administration time, dose, and effect., Conclusions: There are in vitro and in vivo studies that link paracetamol and ibuprofen to endocrine and seminal changes that are harmful to male fertility. However, more clinical research is needed to determine the doses and timing of administration that affect fertility. The effects of aspirin on male fertility are still unclear due to the lack of studies and consistent methodologies. There is not enough research on dipyrone and its relationship with male fertility, requiring more studies in this area.

Infertility is a widespread global issue that affects approximately 15% of sexually active and active couples, which contributes to about 50% of cases. Currently, the condition remains prevalent and often inadequately treated. This systematic review aims to evaluate existing studies investigating the effects of probiotic supplementation in men. A comprehensive search was conducted across major databases, including PubMed, Cochrane, Science Direct, and Scielo, using relevant keywords such as 'probiotic' OR 'Lactobacillus' OR 'Bifidobacterium' AND 'Male infertility' OR 'male fertility' OR 'sperm quality' OR 'sperm motility' OR 'oligoasthenoteratozoospermia' and their Portuguese equivalents. Four randomized clinical studies met the inclusion criteria, focusing on men diagnosed with idiopathic male infertility (oligozoospermia, teratozoospermia, and asthenozoospermia). The findings revealed that probiotic administration exhibited promising antioxidant properties by combating reactive oxygen species (ROS), consequently protecting sperm DNA from damage that correlates with declining sperm quality. Significant improvements were observed across all sperm parameters, with notable enhancement in motility. Consequently, probiotic supplementation emerges as a potential therapeutic alternative for men diagnosed with idiopathic infertility, demonstrating positive effects on sperm quality.

Testosterone boosters are heavily marketed on social media and marketplaces to men with claims to significantly increase testosterone. Lax industry regulation has allowed sales of supplements to thrive in the absence of verification of their purported benefits. Our primary objective was to systematically review all data published in the last two decades on testosterone boosters and determine their efficacy. Our outcome of interest was total testosterone increase versus placebo in four different populations: male athletes, men with late-onset hypogonadism infertile men and healthy men. Following search and screening, 52 studies were included in our review, relating to 27 proposed testosterone boosters: 10 studies of cholecalciferol; 5 zinc/magnesium; 4 Tribulus terrestris and creatine; 3 Eurycoma longifolia and Withania somnifera; 2 betaine, D-aspartic acid, Lepidium meyenii and isoflavones; while the remainder were single reports. Our findings indicate that most fail to increase total testosterone. The exceptions were β-hydroxy β-methylbutyrate and betaine, which can be considered effective for male athletes. Eurycoma longifolia, a blend of Punica granatum fruit rind and Theobroma cacao seed extracts (Tesnor ™ ) and purified Shilajit extract (PrimaVie ™ ) can be considered possibly effective for men with late-onset hypogonadism; Eurycoma longifolia and Withania somnifera possibly effective for healthy men; and a non-hormonal aromatase inhibitor (Novadex XT ™ ) possibly effective for male athletes., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Oxidative stress and disruption of energy metabolism in the reproductive system, especially sperm, play a significant role in diabetes-related infertility. Zataria multiflora Boissis (ZMB), a medicinal plant containing various bioactive compounds, may have efficacy in treating metabolic diseases and reproductive disorders. Therefore, the aim of this study was to investigate the effects of different doses of ZMB extract on diabetes-induced reproductive dysfunction by assessing oxidative damage and the gene expression of insulin receptor substrate (IRS) and pyruvate kinase (PK) in male rats' sperm., Methods: Sixty adult male Wistar rats were randomly divided into six groups; control (C), diabetes (D), and diabetic animals treated with glibenclamide (G, 50 mg/kg) and thyme extract (T100, T200, and T400). Diabetes was induced by intraperitoneal injection of Streptozotocin (STZ) (50 mg/kg). Insulin, glucose, oxidative and pro-inflammatory markers in the serum, and gene expressions of IRS, and PK were measured in the stored sperms in the epididymis. Changes in the process of spermatogenesis were assessed through the histological evaluation of the testis. Gas chromatography-mass spectrometry (GC-MS) was used to analyze the quantity and quality of thyme extract., Key Findings: The study results indicated that body weight, food intake, and sperm parameters significantly improved in a dose-dependent manner in the T200 group compared to the other groups. Additionally, in the same group, pro-inflammatory biomarkers, DNA fragmentation, and MDA levels decreased, while the levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzymes in the stored epididymal sperm significantly improved compared to the other groups. The expression of IRS and PK, along with the mean counts of spermatogenesis cell lines (especially Sertoli cells), significantly increased in the T200 group., Summary: In conclusion, thymol appears to alleviate diabetes-induced reproductive dysfunction by inhibiting oxidative damage, improving the metabolic state, and upregulating the expression of IRS and PK genes in the sperm of male rats., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study aims to investigate the current evidence regarding the impact of oral antioxidant supplementation on semen parameters of infertile men., Materials and Methods: We conducted a systematic search of PubMed, and Cochrane electronic databases, adhering to modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The focus was on studies exploring the effects of antioxidant therapy on infertile men, with an examination of antioxidants in terms of types, doses, rationale for use, and their impact on semen parameters measures., Results: A total of 18 studies that met the inclusion criteria were included in this study. Out of these, 14 studies reported a significantly positive influence of antioxidant therapy on basic semen parameters and advanced sperm function. These comprised 11 randomized clinical trials and 7 prospective studies. Commonly utilized antioxidants included Vitamin E, Vitamin C, carnitines, co-enzyme Q10, N-acetyl cysteine, zinc, selenium, folic acid, and lycopene., Conclusions: Overall, antioxidants generally demonstrate a favorable effect on semen parameters of infertile men. However, further research is necessary to pinpoint the optimal antioxidant regimen that can be applied safely and effectively in clinical practice.

The study aimed to determine the in-vitro effect of metformin on total antioxidant capacity (TAC) of seminal samples of infertile male subjects. It was conducted from January to June 2022 on forty-four seminal plasma samples collected from male infertile patients, age ranging from 18 to 55 years. All 44 semen samples were treated as three distinct groups: (i) a control group (ii) a study group subjected to oxidative stress (OS) induction and (iii) a test group exposed to OS induction and subsequent treatment with metformin. OS was introduced by using commercially available 100μM hydrogen peroxide (H 2 O 2 ) and incubated for twenty-four hours at 37 º C. After that 1 ml of 100 mmol/l concentration of commercially available Metformin (PHR 1331, CAS: 461-58-5) was administered to test group samples for additional 24h at 37 º C. Low levels of TAC were observed after OS induction in comparison to the control group (p=0.01). In test samples (after treatment with Metformin), a positive correlation of TAC with sperm count, normal sperm morphology and sperm motility were observed however, results were not significant. The antioxidant effect of Metformin was shown to improve the antioxidant capacity of OS induced samples and their sperm parameters in seminal plasma of infertile male subjects.

The incidence of male infertility has been increasing year by year, and one of the major causes is testicular spermatogenic epithelial injury, which affects the spermatogenic function of the testis. Ferroptosis is a novel mode of cell death and plays an important role in testicular cell injury. Some traditional Chinese medicines can intervene in the progression of testicular injury by regulating the ferroptosis pathway in testicular spermatogenic epithelia. This paper focuses on the effect of traditional Chinese drugs in regulating the ferroptosis pathway in testicular cells, and summarizes the advances in the studies of traditional Chinese medicines in the treatment of testicular spermatogenic epithelial injury, aiming to provide a theoretical basis for the selection of relevant medicines and their clinical application.

Oxidative stress is one of the main mechanisms responsible for male infertility. Various conditions such as varicocele, obesity, advanced age, and lifestyle can lead to an increase in reactive oxygen species, causing an oxidative imbalance in the reproductive environment. Spermatozoa are sensitive to reactive oxygen species and require energy to carry out their main function of fertilizing the egg. Excessive reactive oxygen species can affect sperm metabolism, leading to immobility, impaired acrosome reaction, and cell death, thereby impairing reproductive success. This double-blind randomized study evaluated the effect of supplementation with L-carnitine, acetyl-L-carnitine, vitamins, and other nutrients on semen quality in 104 infertile patients with or without varicocele, while also investigating the impact of factors such as obesity and advanced age on treatment. Sperm concentration significantly increased in the supplemented group compared to the placebo group ( P = 0.0186). Total sperm count also significantly increased in the supplemented group ( P = 0.0117), as did sperm motility ( P = 0.0120). The treatment had a positive effect on patients up to 35 years of age in terms of sperm concentration ( P = 0.0352), while a body mass index (BMI) above 25 kg m -2 had a negative effect on sperm concentration ( P = 0.0110). Results were not showing a net benefit in stratifying patients in accordance with their BMI since sperm quality increase was not affected by this parameter. In conclusion, antioxidant supplementation may be beneficial for infertile patients and has a more positive effect on younger patients with a normal weight., (Copyright © 2024 Copyright: © The Author(s)(2024).)

Significance: Radiotherapy, which employs ionizing radiation to destroy or prevent the multiplication of tumor cells, has been increasingly used in the treatment of neoplastic diseases, especially cancers. However, radiation collaterally leads to prolonged periods of sperm count suppression, presumably due to impaired spermatogenesis by depleting the germ cell pool, which has long-term side effects for male reproduction. Recent Advances: Studies of antioxidant compounds as a potential strategy for male fertility preservation have been performed mainly from animal models, aiming to prevent and restore the male germinal tissue and its function, particularly against the oxidative stress effects of radiation. Evidence in preclinical and clinical trials has shown that inhibitors of the renin-angiotensin system and other drugs, such as statins and metformin, are candidates for ameliorating radiation-induced damage to several tissues, including the testis and prostate. Critical Issues: Research for developing an ideal radioprotective agent is challenging due to toxicity in the normal tissue, tumor radioresistance, cellular response to radiation, costs, regulation, and timeline development. Moreover, male radioprotection experiments in humans, mainly clinical trials, are scarce and use few individuals. This scenario is reflected in the slow progress of innovation in the radioprotection field. Future Directions: Expanding human studies to provide clues on the efficacy and safety of radioprotective compounds in the human reproductive system is necessary. Drug repurposing, frequently used in clinical practice, can be a way to shorten the development pipeline for innovative approaches for radioprotection or radiomitigation of the repercussions of radiotherapy in the male reproductive system.

Physical and psychological stress has an inverse relation with male libido and sperm quality. The present study investigates the potential fertility-enhancing properties of Desmodium gangeticum (DG) root extracts in male Wister rats subjected to immobilization-induced stress (SIMB). DG roots were extracted using n-hexane (HEDG), chloroform (CEDG), and water (AEDG). In the pilot study, aphrodisiac protentional was investigated at two doses (125 and 250 mg kg -1 ) of each extract. In the main study, the HEDG and AEDG at 125 and 250 mg kg -1 were challenged for the stress by immobilization (SIMB), for 6 h daily over 28 days. Parameters assessed included aphrodisiac effects, gonadosomatic index (GSI), semen quality, sperm quantity, fructose content, serum hormonal levels, testicular oxidative stress, and testicular histopathology. Additional in silico studies, including the lipid solubility index, molecular docking, molecular dynamics, and SymMap studies were conducted for validation. HEDG demonstrated significant aphrodisiac activity, improved - GSI, sperm quality and quantity, and fructose content, serum testosterone levels, histological changes induced by SIMB in the testes. Swiss ADME studies indicated Gangetin (a pterocarpan) had a high brain permeation index (4.81), a superior docking score (-8.22), and higher glide energy (-42.60), compared with tadalafil (-7.17). The 'Lig fit Prot' plot in molecular dynamics simulations revealed a strong alignment between Gangetin and phosphodiesterase type 5 (PDE5). HEDG exerts aphrodisiac effects by increasing blood testosterone levels and affecting PDE5 activity. The protective effects on spermatozoa-related parameters and testicular histological changes are attributed to the antioxidant and anti-inflammatory properties, of pterocarpan (gangetin)., Competing Interests: Declaration of Competing Interest The authors affirm that they do not possess any identifiable financial conflicts or personal associations that might have affected the integrity of the research presented in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Different parts of the alfalfa plant (Medicago sativa L.), especially its seeds, have been introduced as a semen quality enhancer in the folk medicine of different regions of Iran as well as in the traditional Persian medicine (PM) books. The seeds of this plant are also used in many combined medicines to treat male infertility in PM., Aim of the Study: This study was designed to investigate the effect of M. sativa seed powder plus vitamin E vs. vitamin E alone on semen analysis of men with idiopathic infertility., Materials and Methods: In this randomized clinical trial, 60 participants were randomly divided into two groups and then received M. sativa seed powder (6 g daily) or placebo for three months, as add-on to vitamin E (100 U). Results of semen analysis (sperm total count, motility, and morphology as well as semen volume) of these two groups and their changes were compared before and after treatment as the primary outcome. The number of pregnancies after one month and probable side effects were also assessed., Results: After 12 weeks, sperm total count changed from 36.2 ± 21.8 × 10 6 /ml to 48.5 ± 19.1 × 10 6 /ml in M. sativa and from 39.5 ± 23.5 × 10 6 /ml to 41.2 ± 20.9 × 10 6 /ml in placebo, percentage of normal morphology changed from 1.8 ± 0.8% to 2.6 ± 1.2 % in M. sativa and from 2.0 ± 0.9% to 2.6 ± 1.2% in placebo and percentage of motile sperm changed from 36.5 ± 11.8 % to 39.7 ± 12.0% in M. sativa and from 39.3 ± 10.1 % to 38.1 ± 12.1% in placebo. The improvements in M. sativa group are significantly better than placebo group (P = 0.00, 0.01 and 0.04, respectively). However, semen volume decreased in both groups, but its changes were not significant. The number of pregnancies was four in the intervention and zero in placebo group. One case with abdominal bloating and one with respiratory allergy withdrew from the intervention group. No other adverse effect was reported., Conclusions: In this study, significant improvement was detected in sperm parameters (except semen volume) of men with idiopathic infertility in M. sativa plus vitamin E group in compare to vitamin E alone after 12 weeks. These findings suggest that the M. sativa, as a complementary therapy, may have a beneficial effect on semen quality. More clinical trials with larger sample size are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This single-center real-life study was conducted to evaluate the most effective combination of nutraceuticals and the most appropriate indications for the treatment of male infertile patients., Methods: Infertile patients aged 20-55 years were treated with a combination of antioxidants (Androlen ® ; Enfarma, Misterbianco, Catania, Italy) (group A), with Androlen ® (Enfarma) and a mixture of fibrinolytic molecules (Lenidase ® , Enfarma) (group B), or Androlen ® (Enfarma) and other molecules different from those used for the patients of the group B (group C). Patients were also subdivided according to the presence of varicocele, mild testicular hypotrophy, idiopathic infertility, and chronic male accessory gland infection., Results: Forty-three patients were enrolled. In the overall analysis, only progressive motility significantly improved after therapy. Subgroup analysis showed a significant increase in progressive motility, total motile sperm count (TMSC), and in the percentage of alive spermatozoa after treatment in the group A. Progressive motility improved significantly in patients with varicocele, while the TMSC in patients with varicocele and those with idiopathic infertility. The percentage of alive spermatozoa increased in patients with testicular hypotrophy., Conclusions: Treatment with antioxidants increased progressive sperm motility, especially in patients with varicocele or idiopathic infertility.

For several years, fertility disorders have been on the increase worldwide. These disorders affect both sexes, but are more pronounced in men; and in half of cases the etiology is unknown. The role of drugs in male infertility has been little studied to date. Most of the available data comes from experimental animal studies, with all their limitations. With the exception of a few drugs, such as certain anticancer agents, human data are rare. This article describes the mainly drugs known to have deleterious effects on male fertility, the mechanisms leading to these effects and methods used to assess the risk of drug-induced male infertility. It underlines the need for further work in experimental research, clinical trials and post-marketing surveillance to improve our knowledge of drugs that induce male infertility. Although these adverse effects are not life-threatening, they can have a significant impact on patients' lives., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Bisphenol A (BPA) is a prevalent endocrine disruptor found in natural environments. Exposure to BPA has been associated with male infertility. The natural phytochemical icariin (ICA) has demonstrated significant promise for the treatment of male infertility. However, its effectiveness is limited due to its low bioavailability, poor water solubility, and insufficient targeting abilities. Herein, novel nanoparticles are generated from the natural silk fibroin, which are used to load ICA. The efficient drug delivery system (ICA-SNPs) result in significantly focused drug distribution to spermatogonium, enhancing the anti-infertility properties of ICA, and can effectively mitigate spermatogenesis dysfunction induced by BPA, control serum sex hormone levels, and enhance testicular ultrastructure. Additionally, the ICA-SNPs restore spermatogenesis dysfunction primarily via the hormone biosynthesis, spermatogonium meiosis process, and glycerophospholipid metabolism., (© 2023 Wiley-VCH GmbH.)

Ethnopharmacological Relevance: Studies have found that the causes of male infertility are complex, and spermatogenic dysfunction accounts for 30%-65% of male infertility causes, which is the main cause of male infertility. Asperosaponin VI (ASVI) is a saponin extracted from the traditional Chinese herb Dipsacus asperoides C.Y.Cheng & T.M.Ai. However, the precise protective impact and underlying mechanism of ASVI in the therapy of spermatogenic dysfunction remain unknown., Aim of the Study: To investigate the impact of ASVI on the spermatogenic dysfunction induced by cytoxan (CTX) in mice, as well as explore any potential mechanisms., Materials and Methods: Potential ASVI targets were screened using the Pharmapper and Uniprot databases, while genes related to spermatogenic dysfunction were collected from the GeneCards database. The String and Cytoscape databases were then used for PPI analysis for the common targets of ASVI and spermatogenic dysfunction. Meanwhile, the Metascape database was used for KEGG and GO analysis. In vivo experiments, spermatogenic dysfunction was induced in male mice by intraperitoneal administration of CTX (80 mg/kg). To demonstrate the possible protective effects of ASVI on reproductive organs, CTX-induced spermatogenic dysfunction mice with different dosages of ASVI (0.8, 4, 20 mg/kg per day) treatment were collected and gonad weight was detected. The testis and epididymis were detected again by H&E. To assess the impact of ASVI on fertility in male mice, we analyzed sperm quality, serum hormones, sexual behavior, and fertility. The mechanism was investigated using WB, IF, IHC, and Co-IP technology., Results: The ASVI exhibited interactions with 239 associated targets. Furthermore, 1555 targets associated with spermatogenic dysfunction were predicted, and further PPI analysis identified 6 key targets. Among them, the EGFR gene exhibited the highest degree of connection and was at the core of the network. Based on the GO and KEGG enrichment analysis, ASVI may affect spermatogenic dysfunction through the EGFR pathway. In vivo experiments, ASVI significantly improved CTX-induced damage to male fertility and reproductive organs, increasing sperm quality. At the same time, ASVI can resist CTX-induced testicular cell damage by increasing p-EGFR, p-ERK, PCNA, and p-Rb in the testis and by promoting the interaction of CyclinD1 with CDK4. In addition, ASVI can also regulate sex hormone disorders and protect male fertility., Conclusions: ASVI improves CTX-induced spermatogenesis dysfunction by activating the EGFR signaling pathway and regulating sex hormone homeostasis, which may be a new potential protective agent for male spermatogenic dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic-pituitary-gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.

Purpose: A variety of pathologic conditions may increase oxidative stress in semen resulting in structural modifications to spermozoa's plasma membrane that interfere with sperm motility, morphology, and count. Antioxidants are currently being marketed to treat male infertility. In semen, antioxidants may decrease oxidative stress and potentially improve sperm parameters. In this narrative, mini-review we evaluated the effectiveness of antioxidants in infertility., Methods: This mini-review of the current literature has been carried out through searching of the PubMed and Google scholar databases., Results and Conclusions: The literature review suggests that there is evidence that oral antioxidants such as selenium, carnitine, zinc, coenzymeQ10, vitamins E and C, etc. alone or in combinations, improve sperm count, motility, morphology as well as pregnancy rates in infertile men with idiopathic oligoasthenospermia. Unfortunately, most of these studies are poorly designed, limited by sample size, varying in dosage, differing in primary end points, and most notably lacking live birth data. Importantly, large randomized, well-designed, placebo-controlled trials are needed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Nearly, 40% of the causes of male infertility remain idiopathic. The only suggested treatment in idiopathic oligo- and/or asthenozoospermia in normogonadotropic patients is the FSH. In the current clinical practice, efficacy is exclusively assessable through semen analysis after 3 months of treatment. No molecular markers of treatment efficacy are appliable in clinical practice. The aim of the present work is to evaluate the combination of extracellular signal regulated kinase (ERK) 1 and 2 and prolactin inducible peptide (PIP) as potential markers of idiopathic infertility and FSH treatment efficacy., Methods: Western blot and confocal microscopy were performed to analyze the modulation of PIP and ERK1/2 in idiopathic infertile patients (IIP) sperm cells. Taking advantage of mass spectrometry analysis, we identified these proteins unequivocally in sperm cells., Results:  We demonstrated a significant decrease of both PIP protein and of ERK1/2 levels in spermatozoa obtained from IIP in comparison to healthy fertile patients (HFP). Conversely, we reported a significant increase of these markers comparing infertile patients before and after 3 months of FSH treatment. Importantly, this correlated with an increase in total number of sperm and sperm motility after FSH treatment. Finally, we identified of PIP and ERK2 proteins in sperm samples by proteomic analysis., Conclusions: The combined evaluation of ERK1/2 and PIP proteins might represent a useful molecular marker to tailor FSH treatment in the management of male normogonadotropic idiopathic infertility., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Obesity is a complex multifactorial disease in which the accumulation of excess body fat has adverse health effects, as it can increase the risk of several problems, including infertility, in both men and women. Obesity and infertility have risen together in recent years. Against this background, the present review aims to highlight the impact of obesity on infertility and the underlying pathophysiology of obesity-related infertility (ORI) in men and women, and to provide readers with knowledge of current trends in the effective development of phytotherapeutics for its treatment., Methods: We thoroughly searched in PubMed, MEDLINE, Scopus, EMBASE, and Google Scholar to find all relevant papers on ORI and the therapeutic effects of phytotherapeutics on ORI in men and women., Results: The extensive search of the available literature revealed that obesity affects reproductive function through several complex mechanisms such as hyperlipidaemia, hyperinsulinaemia, hyperandrogenism, increased body mass index, disruption of the hormonal milieu, systemic inflammation, oxidative stress, alterations in epigenetics and dysbiosis. On the other hand, several studies reported that phytotherapeutics has a broad therapeutic spectrum of action by improving sex hormone homeostasis, ovarian dysfunction, menstrual cycle and inhibiting ovarian hyperplasia, as well as down-regulating ovarian apoptosis, inflammation and oxidative stress, and controlling metabolic dysfunction in obese women. Male infertility is also addressed by phytotherapeutics by suppressing lipogenesis, increasing testosterone, 3β-HSD and 17β-HSD levels, improving sperm parameters and attenuating testicular dyslipidaemia, oxidative stress, inflammation and germ cell apoptosis., Conclusions: In the present review, we discussed the effects of obesity on reproductive dysfunction in men and women and the underlying pathophysiology of ORI. In addition, the therapeutic effect of phytotherapeutics against ORI was highlighted., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Male infertility is one of the most common complications of diabetes mellitus (DM). Dapagliflozin is widely used to manage the type II DM. This study aimed to assess the dapagliflozin's effects on the spermatogenesis by administering either dapagliflozin (Dapa) or vehicle (db) to male db/db mice, and using littermate male db/m mice as the control (Con). We further performed the integrative analyses of the cecal shotgun metagenomics, cecal/plasmatic/testicular metabolomics, and testicular proteomics. We found that dapagliflozin treatment significantly alleviated the diabetes-induced spermatogenic dysfunction by improving sperm quality, including the sperm concentration and sperm motility. The overall microbial composition was reshaped in Dapa mice and 13 species (such as Lachnospiraceae bacterium 3-1) were regarded as potential beneficial bacteria. Metabolites exhibited modified profiles, in which adenosine, cAMP, and 2'-deoxyinosine being notably altered in the cecum, plasma, and testis, respectively. Testicular protein expression patterns were similar between the Dapa and Con mice. In vivo results indicated that when compared with db group, dapagliflozin treatment alleviated apoptosis and oxidative stress in testis tissues by down-regulating 2'-deoxyinosine. This was further validated by in vitro experiments using GC-2 cells. Our findings support the potential use of dapagliflozin to prevent the diabetes-induced impaired sperm quality and to treat diabetic male infertility., (© 2024. The Author(s).)

Background: Infertility is an inability to conceive after a reasonable period of time (12 months) without the use of contraception or due to a person's incapacity to procreate, whether independently or with a spouse. Problems with the production and maturation of sperm are the most common causes of male infertility additionally; the motility is the major functional character that determines the fertilizing ability of spermatozoa. Therefore the goal of this study is to get better certain sperm function parameters in vitro of asthenozoospermic patient., Objective: The World Health Organization (WHO) and many studies considered the infertility as a disease and so many couples complaining from unsuccessful assisted reproductive technologies (ART) procedures to overcome their problem. The goal of this study is to improve certain sperm function feature in vitro of asthenozoospermic semen patients by using combination of motility inducing namely; Maca, L-carnitine and Pentoxifylline that enhance the medium to improve certain sperm characters that might be utilized for ART centers., Methodology: Semen aliquots were collected from ninety patients with asthenozoospermia who participated in present study, the volume of semen samples with normal ejaculate when was ranged between 1.4-6ml and can be measured by using a measure pipette or conical graduated tube; Inclusion criteria was Asthenozoospermia, oligozoospermia and teratozoospermia men, Infertile idiopathic men also, fertile normozoospermic men. While Exclusion criteria was Azoospermic men, Alcoholic, Patients under treatment with antibiotics and men with Varicocele.The samples split into two equal groups at random. Using Ham's F12 medium, one portion served as the control group, and the other was the treatment group, which was mixing by combining the following ingredients, Maca powder extracts (Lepidium meyenii) (M) 1 mg/ml, 0.5 mg/ml of L-Carnitine (LC), and 10 mg/ml of Pentoxifylline (PTX). The data were analyzed using Statistical Package for Social Sciences (SPSS) version 23.0. The descriptive statistics including frequency, range, mean and standard error, Data from treated and control groups were expressed as mean ± SEM and to compare value between experimental and control groups using Students t-test. Layering approach is used to investigate sperm parameters before and after in vitro activation., Results: The information showed a very large (p< 0.001) increase in active sperm motility grade A, percentage of progressive motility with significant increase in morphologically normal sperm (MNS) with decreased in DNA fragmentation index after activation by layering technique with novel combination medium compared to Hams F12 medium and before activation., Conclusion: The present work stated that novel combination medium (LC, maca and PXT) have potential effects to improve sperm characters in male infertility factors and suggested to be used for sperm preparation and activation in ART programs.

Objective: To analyze the main active components and potential molecular mechanism of Yishen Tongluo Prescription (YTP) in the treatment of male infertility based on network pharmacological technology., Methods: We searched and sorted the main active components of YTP and their individual potential targets in the databases of Systematic Pharmacology of Traditional Chinese Medicine (TCM) and Bioinformatics Analysis Tool of the Molecular Mechanism of TCM, and screened the targets related to male infertility diseases in the databases of Genecards, DisGeNET and OMIM. We made a Venn diagram by intersecting the predicted targets of YTP and those of male infertility diseases, constructed visualized networks for the association of the intersection targets and protein-protein interaction (PPI) using the Cytoscape software and STRING platform respectively, and conducted gene ontology (GO) and KEGG enrichment analyses using the DAVID database and R language "Cluster Profiler" software package respectively., Results: A total of 99 active components, 250 targets of YTP, 4 397 targets of male infertility and 127 common targets were identified. GO analysis revealed that the biological processes of the common targets mainly included transcriptional regulation of RNA polymerase promoter Ⅱ, regulation of gene expressions, regulation of apoptosis, responses to estrogen, and cell responses to hypoxia. KEGG analysis showed significant enrichment of the common targets in the estrogen signaling pathway, cell apoptosis pathway, AGE-RAGE signaling pathway in diabetic complications, and TNF signaling pathway., Conclusion: Through network pharmacology, we identified the main active components of YTP and its multi-target and multi-pathway mechanism in the treatment of male infertility, which has paved the ground for animal and cell experiments in verifying the action mechanism of YTP on male infertility.

Background and objective -Obesity is a prevalent health concern that notably impairs male fertility through hormonal disruptions and other pathophysiological alterations. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can significantly reduce weight. This narrative review synthesizes the existing literature discussing the impact of glucagon-like peptide-GLP-1 RAs on the male reproductive system, particularly on the hypothalamic-pituitary-gonadal axis and spermatogenesis, highlighting their potential impact on male fertility. Material and methods -PubMed database was used for the retrieval of English-language articles published up to November 2023. This non-systematic literature review predominantly concentrates on both pre-clinical and clinical studies pertaining to GLP-1 RAs, specifically exploring their impact on male reproductive hormones and sperm parameters. Results -GLP-1 receptors have been identified within the male reproductive system according to the existing literature. While the exact mechanisms are not well understood, they appear to be involved in glucose homeostasis and energy metabolism, both vital processes in spermatogenesis. Multiple clinical trials have demonstrated the efficacy of GLP-1 RAs for promoting weight loss. Recent studies show that the use of GLP-1 RAs in obese males may enhance sperm metabolism, motility, and insulin secretion in vitro, along with positive effects on the human Sertoli cells. Recent clinical trials discussed in this review demonstrate weight loss associated with GLP-1 RAs is correlated with improvements in sperm count, concentration, and motility. However, the direct impact of GLP-1 RAs on male reproductive hormones remains unclear, necessitating further research to confirm their potential role in treating male infertility. Conclusions -This narrative review summarizes the existing literature discussing the potential impact of GLP-1 RA on the male reproductive system, emphasizing their potential therapeutic role in addressing idiopathic infertility in obese men. Despite numerous studies exploring the influence of GLP-1 and GLP-1 RAs on reproductive hormones, testicular function, and spermatogenesis, further clinical trials are crucial to validate initial evidence. Longer follow-up periods are essential to address uncertainties regarding the long-term repercussions and outcomes of GLP-1 RA use. While this holds true, the current literature suggests that GLP-1RAs show promise as a potential therapeutic approach for improving sperm parameters in obese men.

Introduction: Infertility is a global problem, affecting more than 15% of sexually active couples worldwide. The frequency of the male factor reaches 40-50% and continues to increase. Fertility problems with unknown causes are referred as idiopathic., Aim: To evaluate the possibility of using the Androdoz antioxidant complex in men with infertility., Materials and Methods: A retrospective analysis of the medical records of 32 infertile men aged 21 to 45 years (average of 27.8 +/- 6.7 years) with pathospermia was carried out. Antioxidant complex Androdoz was prescribed 2 capsules bid with meals according to the package insert for up to 3 months. The results were assessed after 3 and 12 months (follow-up period) from the start of therapy. In addition to ejaculate analysis, all patients underwent digital rectal examination, transrectal ultrasound of the prostate and ultrasound of the scrotum, microscopic examination of ejaculate and expressed prostate secretions, and PCR-based assay of urethral swab (Androflor). The zinc concentration in seminal plasma, as well as the total antioxidant capacity of sperm, was also evaluated. Damage to sperm chromosomes was characterized by DNA fragmentation using an assessment of sperm chromatin dispersion., Results: Based on the results of a comparative analysis of ejaculate, it was revealed that taking Androdoz complex not only had a positive effect on sperm motility and viability, but also led to a decrease in the percentage of sperm with DNA fragmentation to a level of less than 15%, and significantly increased the total antioxidant capacity of the ejaculate., Conclusions: The use of Androdoz antioxidant complex in men with reproductive disorders improves the qualitative and quantitative markers of the sperm analysis and the morphological state of the male reproductive system, and allows to replenish the lack of vitamins. The most important effect of Androdoz complex appears after 3 months.

Aim: To compare the effects of cytokine and antibacterial therapy on semen parameters and additional functional tests in patients with infertility due to male accessory gland infections (MAGI) who are preparing for assisted reproductive technologies (ART)., Materials and Methods: A randomized, prospective, controlled clinical trial without blinding was carried out. A total of 60 men from infertile couples with MAGI who were preparing to ART was included in the study. In the main group (n=30) patients received Superlymph, 1 suppository of 25 units, 2 times a day for 20 days. In the control group (n=30), the antibacterial drug Doxycycline 100 mg 2 times a day for 28 days was given. After the end of therapy on day 33+/-3, a repeated sperm analysis, MAR test, a test for reactive oxygen species in the ejaculate and sperm DNA fragmentation, and bacteriological examination of sperm was performed. In addition, a survey for adverse events was carried out. The significance of differences in initial and final parameters and differences between groups was assessed using the Students t-test, Wilcoxon test and Mann-Whitney U-test depending on the data distribution. The Shapiro-Wilk test was done to investigate the normality of data distribution. Fisher's exact test was used to compare categorical variables., Results: The final analysis included data from 53 patients (n=28 in the main group and n=25 in the control group). In both groups, a significant decrease in the level of free oxygen radicals in the ejaculate was noted (p=0.031), which was more pronounced in the main group. There were no differences in other semen parameters. Eradication of the microorganism according to bacteriological examination occurred in 57.1% of patients in the main group and in 88% of those in the control group (p=0.016). In patients receiving monotherapy with Superlymph, there was a significant decrease in the sperm DNA fragmentation index and the concentration of leukocytes in the ejaculate. In patients receiving antibacterial therapy, there was a significant increase in ejaculate volume, a decrease in the proportion of IgG-associated sperm and leukocyte concentration., Conclusion: Many issues of diagnosis and treatment of MAGI have not been thoroughly studied and are poorly standardized. Considering the problems of increasing antibiotic resistance, alternative treatment options are needed. Cytokine therapy (the drug Superlymph) is an effective alternative method of monotherapy for male infertility due to MAGI and is optimal for quickly preparing a couple for ART protocol, given its positive effect on oxidative stress and the index of sperm DNA fragmentation. The prospect of combination therapy with antibiotics and Superlymph seems promising.