Phoenix dactylifera L. pollen versus pentoxifylline on improvement of sperm parameters in idiopathic male infertility: A randomized clinical trial.

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.

A multi-modal approach to investigate Desmodium gangeticum's influence on stress-induced male infertility: In vivo, in vitro, and in silico assessments.

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).

Pathophysiology of obesity-related infertility and its prevention and treatment by potential phytotherapeutics.

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, 3ß-HSD and 17ß-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.

Effect of Medicago sativa seed powder (Plus vitamin E vs. vitamin E alone) on semen analysis in men with idiopathic infertility: A double blind randomized clinical trial.

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 × 106/ml to 48.5 ± 19.1 × 106/ml in M. sativa and from 39.5 ± 23.5 × 106/ml to 41.2 ± 20.9 × 106/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.

Exploring the Potential of Plant Bioactive Compounds against Male Infertility: An In Silico and In Vivo Study.

Infertility is a well-recognized multifactorial problem affecting the majority of people who struggle with infertility issues. In recent times, among infertility cases, the male factor has acquired importance, and now it contributes to approximately half of the infertility cases because of different abnormalities. In the current study, we used natural phytochemicals as potential drug-lead compounds to target different receptor proteins that are involved in the onset of male infertility. A set of 210 plant phytochemicals were docked counter to active site residues of sex hormone-binding globulin, a disintegrin and metalloproteinase 17, and DNase I as receptor proteins. On the basis of binding scores and molecular dynamics simulation, the phytochemicals tricin, quercetin, malvidin, rhamnetin, isorhamnetin, gallic acid, kaempferol, esculin, robinetin, and okanin were found to be the potential drug candidates to treat male infertility. Molecular dynamics simulation showed tricin as a strong inhibitor of all selected receptor proteins because the ligand-protein complexes remained stabilized during the entire simulation time of 100 ns. Further, an in vivo study was designed to evaluate the effect of tricin in male rats with nicotine-induced infertility. It was explored that a high dose of tricin significantly reduced the levels of alanine transaminase, aspartate transaminase, urea, creatinine, cholesterol, triglyceride, and low-density lipoprotein and raised the level of high-density lipoprotein in intoxicated male rats. A high dose of tricin also increased the reproductive hormones (i.e., testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin) and reduced the level of DHEA-SO4. The phytochemical (tricin, 10 mg/kg body weight) also showed significant improvement in the histo-architecture after nicotine intoxication in rats. From the current study, it is concluded that the phytochemical tricin could serve as a potential drug candidate to cure male infertility.

Antioxidant activity of Flemingia praecox and Mucuna pruriens and their implications for male fertility improvement.

Globally, 15-24% couples are unable to conceive naturally and 50% of cases of this problem are due to infertility in males. Of this, about 50% of male infertility problems are developed due to unknown reasons called as idiopathic infertility. It is well established that, reactive oxygen species (ROS) have negative impact on male fertility and are involved in 80% of total idiopathic male infertility cases. Medicinal plants are considered as an alternative approach for mitigating the health problems. The plants with good antioxidant capacity can improve the male infertility symptoms generated by ROS. Such medicinal plants can be used to alleviate the symptoms of male infertility with their diverse phytoconstituents. Mucuna pruriens is a well-accepted herb, with its seeds being used to improve the male fertility in various ways and one of the ways is by eliminating the ROS. In our field survey, another plant, Flemingia praecox, although less known, its roots are used in all problems related to the male fertility by tribal people of the Gadchiroli district of Maharashtra, India. The study was conducted to determine in vitro antioxidant potential of F. praecox and compared the results with the well-established male fertility improving plant M. pruriens with special emphasis on medicinally important roots of F. praecox and seeds of M. pruriens. The objective of the study was investigated by studying their total phenol (TPC) and flavonoid (TFC) content, antioxidant parameters (DPPH, FRAP, ABTS, DMPD, ß-carotene bleaching and TAA) and finally DNA damage protection capacity of the plant extracts was studied. The plant parts used for the medicinal purposes have been investigated along with other major parts (leaves, stem and roots of both the plants) and compared with synthetic antioxidants, BHA, BHT and ascorbic acid. Moreover, the inhibition of two male infertility enzyme markers, PDE5 and arginase by F. praecox root and M. pruriens seed extract was also studied in vitro. The results showed that F. praecox possesses higher antioxidant activity than M. pruriens in the majority of studies as observed in TFC, DPPH, TAA, ABTS and DMPD assays. However, M. pruriens seeds showed best results in TPC, FRAP and DNA damage protection assay. F. praecox root extract also gave better PDE5 inhibition value than M. pruriens seeds. This study will help to establish the authenticity of F. praecox used by tribal people and will encourage its further use in managing the male infertility problems.

Positive Effects of the Nutraceutical Association of Lycopene and Selenium in Experimental Varicocele.

Many natural substances commonly found in healthy diets have been studied for their potential to reduce male infertility associated with varicocele. A positive role of selenium (Se) or lycopene alone was demonstrated in experimental varicocele, while no data are available on their association. One group of male Sprague-Dawley rats was sham operated and daily treated with Se (3 mg/kg, i.p.), lycopene (1 mg/kg, i.p.), or their association. A second group underwent surgery to induce varicocele. Sham and half of the varicocele animals were sacrificed after twenty-eight days, while the residual animals were treated for one more month and then sacrificed. In varicocele animals, testosterone levels and testes weight were reduced, Hypoxia Inducible Factor-1α (HIF-1α) expression was absent in the tubules and increased in Leydig cells, caspare-3 was increased, seminiferous epithelium showed evident structural changes, and many apoptotic germ cells were demonstrated with TUNEL assay. The treatment with lycopene or Se alone significantly increased testis weight and testosterone levels, reduced apoptosis and caspase-3 expression, improved the tubular organization, decreased HIF-1α positivity of Leydig cells, and restored its tubular positivity. Lycopene or Se association showed a better influence on all biochemical and morphological parameters. Therefore, the nutraceutical association of lycopene plus Se might be considered a possible therapeutic tool, together with surgery, in the treatment of male infertility. However, long-term experimental and clinical studies are necessary to evaluate sperm quantity and quality.

[Treatment of infertility in men with pathospermia associated with oxidative stress].

INTRODUCTION: Oxidative stress considered to be the main cause of male infertility. Surgical treatment of varicocele and elimination of the inflammatory process in the male accessory glands can help reduce the level of oxidative stress, however, in most cases, antioxidant therapy is additionally prescribed. Currently, much attention is paid to regulatory peptides as a component of antioxidant therapy due to their antioxidant, anti-inflammatory and immunomodulatory properties. AIM: To evaluate the efficiency of a complex of antimicrobial peptides and cytokines Superlymph for the treatment of male infertility associated with oxidative stress. MATERIALS AND METHODS: A total of 30 patients with elevated levels of reactive oxygen species were recruited in the open, prospective, multicenter study. Ejaculate analysis (WHO-2010), MAR-test, sperm DNA damage testing and reactive oxygen species measurement were performed. All patients received Superlymph 25 IU/day for 60 days. Antibiotics and vitamin D were also prescribed if indicated. In addition, 12 patients took dietary supplements with antioxidant action. Laboratory tests were repeated after the completion of treatment. RESULTS: Superlymph therapy led to an improvement in standard semen parameters as well as decrease in sperm DNA fragmentation and oxidative stress. At the end of treatment, a significant increase in the sperm concentration was observed (46.8 [30; 87] vs. 62 [43-89], p=0.002). After treatment, there was also an increase in the median of sperm cells with normal morphology (3 [1; 7] vs. 4.5 [2; 9], p=0.002). The median sperm DNA fragmentation was lower compared to baseline, but this difference did not reach significant level (19 [14; 26] vs. 15 [10.5; 19.5], p=0.06). A significant decrease in the level of oxidative stress both in patients who took Superlymph as monotherapy (43 [27; 51] vs. 33 [22; 44], p=0.005), and as part of combination therapy with other antioxidants (31 [22; 54] vs. 21 [12; 36], p=0.009) was also observed. CONCLUSION: Superlymph contributes to the improvement of standard ejaculate parameters as well as decrease in the level of sperm DNA fragmentation and oxidative stress.

Efficacy of coenzyme Q10 supplementation for male infertility with high sperm DNA fragmentation index: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Infertility is a focal issue in public health and affects human reproduction and survival. Notably, an increasing number of studies in recent decades have found that sperm DNA integrity plays a critical role in the development of healthy embryos. Among the multiple pathogenic factors of sperm DNA fragmentation, oxidative stress has proven to be predominant. Coenzyme Q10 supplementation, which has been used for the treatment of male infertility, has shown good clinical efficacy due to its oxidation resistance, but its efficacy as measured by the sperm DNA fragmentation index remains controversial. To address this issue, we will perform a systematic review and meta-analysis to evaluate the efficacy of coenzyme Q10 for male infertility patients with a high sperm DNA fragmentation index. METHODS AND ANALYSIS: The PubMed, Embase, Cochrane Central Register of Studies and Web of Science databases will be comprehensively searched from inception to 31 December 2022 to identify relevant studies published in the English language using appropriate search strategies. The search terms will be derived from the following concepts: sperm DNA fragmentation, coenzyme Q10 and randomised controlled trials. Two review stages, that is, title and abstract screening and full-text screening, will be performed by two reviewers. The risk of bias, publication bias and evidence grade of the included studies will be assessed using a standardised protocol. Data will be used to calculate effect sizes. Heterogeneity among the studies will be evaluated graphically. Subgroup analysis and sensitivity analysis will be performed if necessary to validate the results. ETHICS AND DISSEMINATION: No ethical approval will be needed, as there will be no participants in this study. We will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to disseminate the findings through publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42022293340.

Effectiveness of non-pharmaceutical intervention on sperm quality: a systematic review and network meta-analysis.

Infertility affects about 10% of the world's population and has been recognized by the WHO as a global public health problem. The aim of this network meta-analysis was to investigate the efficacy of non-pharmaceutical interventions on sperm quality. All randomized clinical trials (RCTs) from the PubMed, MEDLINE, Embase, China national knowledge infrastructure (CNKI), Wanfang database, and Cochrane Library databases evaluating the effectiveness of non-pharmaceutical interventions on semen parameters using network meta-analyses. Results of the ω-3 fatty acid, lycopene, acupuncture, and vitamin suggested evident advantages in improving sperm concentration (MD, 9.93 (95% CI, 7.21 to 12.65)), (MD, 8.79 (95% CI, 2.67 to 14.91)), (MD, 5.40 (95% CI, 2.32 to 8.49)) and (MD, 3.82 (95% CI, 0.70 to 6.94) respectively). Acupuncture has a significant advantage over placebo in improving sperm total motility (MD, 17.81 (95% CI, 10.32 to 25.29)), and the effect of lycopene was obviously greater than that of placebo (MD, 19.91 (95% CI, 2.99 to 36.83)). Lycopene, Coenzyme Q10 (CoQ10), acupuncture, ω-3 fatty acid, and vitamin suggested significant advantages in improving sperm forward motility (MD, 8.64 (95% CI, 1.15 to 16.13), MD, 5.28 (95% CI, 2.70 to 7.86), MD, 3.95 (95% CI, 3.23 to 4.67), MD, 3.50 (95% CI, 2.21 to 4.79)) and (MD, 2.38 (95% CI, 0.96 to 3.80) respectively). This review establishes that non-pharmaceutical interventions, particularly acupuncture, exercise, lycopene, ω-3 fatty acids, CoQ10, zinc, vitamins, selenium, carnitine, or foods rich in these supplements, profitably improve sperm quality that may be used to treat male infertility.

Effectiveness of Nutritional Therapies in Male Factor Infertility Treatment: A Systematic Review and Network Meta-analysis.

BACKGROUND: Nutritional therapies are effective alternative treatments for male infertility or subfertility. These are cost-effective and easily implementable, unlike other advanced invasive treatments. Even moderate improvements in sperm quality could improve spontaneous pregnancy. OBJECTIVE: We aimed to compare the effectiveness of all nutritional therapies in male infertility/subfertility treatment and ranked their efficacy based on type and etiology. We intend to aid clinicians with an evidence-based approach to affordable and safer initial infertility treatment for those who mainly do not wish to have other advanced invasive treatments or could not afford or have access to them. METHODS: We included 69 studies with 94 individual study arms identified from bibliographic databases and registries. We included studies in adult men with proven infertility or subfertility that investigated nutritional or dietary supplement therapies compared with control or placebo and at least reported on a sperm parameter. We undertook a network meta-analysis and performed a pairwise meta-analysis on all sperm parameter outcomes and meta-regression. No language or date restriction was imposed. A systematic article search was concluded on August 29, 2022. RESULTS: Our network meta-analysis is the first to compare all dietary interventions in a single analysis, sub-grouped by intervention type and type of infertility. L-Carnitine with micronutrients, antioxidants, and several traditional herbal supplements showed statistically and clinically significant improvement in sperm quality. Meta-regression identified that improvement in the sperm count, motility and morphology translated into increased pregnancy rates (p < 0.001; p < 0.001; p < 0.002, respectively). In particular, L-carnitine with micronutrient therapy (risk ratio [RR]: 3.60, 95% CI 1.86, 6.98, p = 0.0002), followed by zinc (RR 5.39, 95% CI 1.26, 23.04, p = 0.02), significantly improved pregnancy rates. Men with oligozoospermia (RR 4.89), followed by oligoasthenozoospermia (RR 4.20) and asthenoteratozoospermia (RR 3.53), showed a significant increase in pregnancy rates. CONCLUSION: We ranked nutritional therapies for their ability to improve sperm quality in men with infertility. Nutritional therapies, particularly L-carnitine alone or combined with micronutrients, significantly improved sperm parameters and pregnancy rates even under severe conditions. We believe these affordable solutions may be valuable for people without access to or who do not wish to undergo more invasive and costly fertility treatments.

Wuzi Yanzong prescription from Traditional Chinese Medicine for male infertility: a narrative review.

Wuzi Yanzong prescription (WYP), as a classical prescription for male infertility with kidney essence deficiency, is composed of Gouqizi (), Tusizi (), Wuweizi (), Fupenzi () and Cheqianzi (). It has been used for hundreds of years in the treatment of male infertility, known as "the first prescription of ancient and modern seeds", with convincing clinical evidence. At present, more than 100 chemical compounds have been isolated from WYP, including polysaccharide, fatty acids, flavonoids, phenylpropanoids, organic acids, alkaloids, terpenoids, etc. Pharmacological and clinical studies show that WYP has an obvious effect on reproductive system diseases, especially male infertility, which has a very wide application prospect. It also has effects on the nervous system, inhibiting liver injury, lowering blood sugar and blood lipid, anti-aging, improving immunity, resisting hypoxia and fatigue effects. This study reviewed the chemical constituents, quality control, pharmacology, and clinical application of WYP. There is no doubt about the clinical value of WYP, but its quality control system is not perfect, pharmacological mechanism is not fully explained, and clinical applications need to be reevaluated. Therefore, the follow-up researches should proceed from the theory of Traditional Chinese Medicine (TCM) and clinical applications, further explain the theoretical connotation, reveal the mechanism of action, and provide the basis for the secondary development of classic famous prescriptions. In addition, WYP is mostly used in combination with western medicines besides being used alone. Whether it can improve the efficacy and reduce side effects will also be a meaningful research direction in the future.

The Effect of Selenium Therapy on Semen Parameters, Antioxidant Capacity, and Sperm DNA Fragmentation in Men with Idiopathic Oligoasthenoteratospermia.

Idiopathic male infertility (IMI) remains challenging as the etiology of semen abnormalities is still unidentified. Sperm DNA fragmentation (SDF) has been suggested as a potential mechanism. Oral antioxidants including selenium have been tried for IMI with variable results. This study was undertaken to explore the effect of selenium therapy on semen parameters, antioxidant capacity, and SDF in infertile patients with idiopathic oligoasthenoteratospermia (OAT). Sixty-five infertile men with idiopathic OAT and fifty fertile controls were included in this prospective clinical study. Patients received selenium (200 µg/day) orally for 6 months. Seminal fluid parameters (WHO 5th criteria), total antioxidant capacity (TAC), catalase (CAT), and seminal SDF levels were assessed for all participants at the start of the study and after 6 months. Sperm concentration (P < 0.001), progressive motility (P < 0.001), and total motility (P < 0.01) significantly increased in patients after selenium therapy. Seminal TAC and CAT increased in patients post-therapy as compared to baseline values (P < 0.01). SDF levels significantly decreased (P < 0.001) in patients following selenium treatment in comparison to baseline values. SDF levels also correlated negatively with sperm progressive motility (r = - 0.44, P = 0.003) and total motility (r = - 0.48, P = 0.001). In conclusion, selenium therapy (200 µg/day) for 6 months increases sperm concentration, motility, seminal antioxidant capacity, and reduces SDF in patients with idiopathic OAT. Thus, selenium could be a promising therapy for men with IMI and may boost their fertility and fertility treatment outcomes.

Therapeutic potential of rutin in male infertility: A mini review.

Male infertility has become a problem worldwide, and recent research has emphasized the development of more effective therapy options. Among natural compounds, rutin has been widely studied for its potential to treat dysfunction related to male infertility, including a reduction in sperm quality, spermatogenesis disruption and structural disruption in the testis. A thorough review of scientific literature published in several databases, including Google Scholar, PubMed/MEDLINE and Scopus, was used to synthesize the present state of research on the role of rutin in male reproductive health. Rutin has been shown to possess antiapoptotic, antioxidant and anti-inflammatory activities, among others, which are crucial in the management of male infertility. Numerous investigations have shown that rutin protects against male infertility and have explored the underlying mechanisms involved. The present review, therefore, assesses the therapeutic mechanisms involved in male infertility treatment using rutin. Rutin was able to mitigate the induced oxidative stress, apoptosis, inflammation, and related physiological processes that can cause testicular dysfunction. Please cite this article as: Rotimi DE, Elebiyo TC, Ojo OA. Therapeutic potential of rutin in male infertility: A mini review. J Integr Med. 2023; 21(2): 130-135.

Carob extract induces spermatogenesis in an infertile mouse model via upregulation of Prm1, Plzf, Bcl-6b, Dazl, Ngn3, Stra8, and Smc1b.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnopharmacological studies for drug discovery from natural compounds play an important role for developing current therapeutical platforms. Plants are a group of natural sources which have been served as the basis in the treatment of many diseases for centuries. In this regard, Ceratonia siliqua (carob) is one of the herbal medicine which is traditionally used for male infertility treatments. But so far the main mechanisms for effects of carob are unknown. Here, we intend to investigate the ability of carob extract to induce spermatogenesis in an azoospermia mouse model and determine the mechanisms that underlie its function. AIM OF THE STUDY: This is a pre-clinical animal model study to evaluate the effect of carob extract in spermatogenesis recovery. METHODS: We established an infertile mouse model with the intent to examine the ability of carob extract as a potential herbal medicine for restoration of male fertility. Sperm parameters, as well as gene expression dynamics and levels of spermatogenesis hormones, were evaluated 35 days after carob administration. RESULTS: Significant enhanced sperm parameters (P < 0.05) showed that the carob extract could induce spermatogenesis in the infertile mouse model. Our data suggested an anti-apototic and inducer role in the expressions of cell cycle regulating genes. Carob extract improved the spermatogenesis niche by considerable affecting Sertoli and Leydig cells (P < 0.05). The carob-treated mice were fertile and contributed to healthy offspring that matured. Our data confirmed that this extract triggered the hormonal system, the spermatogenesis-related gene expression network, and signaling pathways to induce and promote sperm production with notable level (P < 0.05). We found that the aqueous extract consisted of a polar and mainly well water-soluble substance. Carob extract might upregulate spermatogenesis hormones via its amino acid components, which were detected in the extract by liquid chromatography-mass spectrometry (LC-MS). CONCLUSION: Our results strongly suggest that carob extract might be a promising future treatment option for male infertility. This finding could pave the way for clinical trials in infertile men. This is the first study that has provided reliable, strong pre-clinical evidence for carob extract as an effective candidate for fertility recovery in cancer-related azoospermia.

[Exploring the mechanisms of Jujing pill on varicocele-associated male infertility via network pharmacology and molecular docking technology].

OBJECTIVE: To investigate the potential mechanism of treating varicocele-associated male infertility with Jujing pill using network pharmacology and molecular docking technology. METHODS: The TCMSP and BATMAN databases were used to search for the Chinese medicine components of the Jujing pill and obtain the corresponding targets. The databases GeneCards, DISGENET, OMIM, and HPO were searched for 'varicocele' and 'male infertility' to identify the potential targets of varicocele-associated male infertility. Wayne diagrams were drawn using the jvenn tool to determine the intersection targets of the Chinese medicine targets and disease targets. The intersecting targets were further analyzed to identify the components and Chinese medicine corresponding to them. A Chinese medicine-active ingredient-target network map was constructed in Cytoscape 3.8.2. The protein-protein interaction (PPI) network of the intersecting targets was constructed using the STRING platform. The intersecting targets were imported into the DAVID database for GO enrichment analysis and KEGG-based pathway enrichment analysis. The KEGG database was used to select the most relevant pathway to the topic, and a KEGG pathway map was constructed using the mapper tool. The top 15 pathways with FDR values and their related targets and components were used to draw a core ingredient-target-pathway map. Finally, molecular docking was performed to verify the protein receptors and small molecule ligands of the core genes, and the results were visualized using AutoDock and PyMol software. RESULTS: A total of 207 ingredients and 1103 predicted targets of Jujing pill were screened. Additionally, 285 targets of varicocele were also identified. By using a Venn diagram, 86 common targets were obtained. The analysis of Gene Ontology (GO) results revealed significant enrichment in various biological processes (BP) such as positive regulation of gene expression, positive regulation of transcription, positive and negative regulation of apoptotic processes, response to hypoxia, response to estradiol, and positive regulation of nitric oxide biosynthesis processes. Furthermore, significant enrichment in cellular components (CC) was observed in macromolecules, cytoplasm, nucleus, and phosphatidylinositol 3-kinase complex. In terms of molecular function (MF), enrichment was found in enzyme binding, identical protein binding, transcriptional co-activator binding, and others. KEGG analysis demonstrated enrichment in pathways related to cancer, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, FoxO signaling pathway, and more. Molecular docking results indicated that the core ingredients exhibited a strong binding capacity with the key targets. Conclusion： The effective active ingredients of Jujing pill exert their therapeutic effects on varicocele-associated male infertility through multiple targets and pathways. These findings provide a theoretical basis for future cell and animal experiments to verify the mechanism of action of Jujing pill in treating varicocele-associated male infertility.

Effects of alpha-lipoic acid on sperm quality in patients with varicocele-related male infertility: study protocol for a randomized controlled clinical trial.

BACKGROUND: Varicocele is a high incidence and is considered to be the most common and correctable cause of male infertility. Oxidative stress (OS) plays a central role in the pathogenesis of varicocele-related male infertility. In addition to varicocelectomy, antioxidant supplementation seems to be an effective scheme for the treatment of varicocele-related male infertility, but it is still controversial. The purpose of this study is to determine the effects of alpha-lipoic acid (ALA) supplementation on sperm quality in patients with varicocele-related male infertility. METHODS: In this randomized controlled clinical trial, we will randomize 80 patients with varicocele-related male infertility from Guilin People's Hospital. The non-surgical observation group (n = 20) will receive ALA, the non-surgical control group (n = 20) will receive vitamin E, the surgical observation group (n = 20) will receive ALA after the operation, and the surgical control group (n = 20) will receive vitamin E after the operation. The course of treatment will be 3 months. The results will compare the changes in semen parameters, sex hormones, testicular volume, sperm DNA fragment index (DFI), seminal plasma malondialdehyde (MDA), and total antioxidant capacity (TAC) between the groups at baseline and after 3 months of antioxidant supplementation. DISCUSSION: Whether it is necessary to use antioxidants in varicocele-related male infertility, how potent antioxidants should be used, postoperative application or non-surgical independent application still needs to be explored. This study attempts to compare the effects of two antioxidants (ALA and vitamin E) on sperm quality in patients with varicocele-related male infertility (surgical or non-surgical) and attempted to answer the above questions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100054958. Registered on 29 December 2021.

Oxidative Stress and Male Infertility: Role of Herbal Drugs.

Infertility is a universal health problem affecting 15% of couples, out of which 20-30% cases are due to male infertility. The leading causes of male infertility include hormonal defects, physical reasons, sexual problems, hazardous environment, stressful lifestyle, genetic factors, epigenetic factors, and oxidative stress. Various physiological functions involve reactive oxygen species (ROS) and nitrogen species at appropriate levels for proper smooth functioning. ROS control critical reproductive processes such as capacitation, acrosomal reaction, hyperactivation, egg penetration, and sperm head decondensation. The excessive free radicals or imbalance between ROS and endogenous antioxidant enzymes damages sperm membrane by inducing lipid peroxidation causing mitochondrial dysfunction and DNA damage that eventually lead to male infertility. Numerous synthetic products are available in the market to treat infertility problems, largely ending in side effects and repressing symptoms. Ayurveda contains a particular group of Rasayana herbs, called vajikarana, that deals with nourishment and stimulation of sexual tissues, improves male reproductive vitality, and deals with oxidative stress via antioxidant mechanism. The present study aims to describe oxidative stress and the role of herbal drugs in treating male infertility.

Exploring the pharmacological mechanism of Shengjing capsule on male infertility by a network pharmacology approach.

BACKGROUND: Shengjing capsule (SJC) is a traditional Chinese medicine (TCM) and has gained widespread clinical application for the treatment of male infertility (MI). However, the pharmacological mechanism of SJC against MI remains vague to date. METHOD: The active ingredients of SJC and their targets were identified from the database, and MI-related genes were retrieved from several databases. Protein-protein interaction (PPI) data were obtained to construct the PPI networks. The candidate targets of SJC against MI were identified through topological analysis of the PPI network. Functional enrichment analysis of candidate targets was performed, and the key target genes were identified from the gene-pathway network. RESULTS: We identified 154 active ingredients and 314 human targets of SJC, as well as 564 MI-related genes. Eight pharmacological network diagrams illustrating the interactions among herbs, active ingredients, targets, and pathways, were constructed. The four dominating network maps included a compound-target network of SJC, a compound-anti-MI targets network, a candidate targets PPI network, a pathway-gene network, and a drug-key compounds-hub targets-pathways network. Systematic analysis indicated that the targets of SJC in the treatment of MI mainly involved RPS6, MAPK1, MAPK3, MDM2, and DDX5. Pathway enrichment analysis showed that SJC had the potential to impact multiple biological pathways, such as cancer-related pathways, viral/bacterial infection-related pathways, and signal transduction-related pathways. CONCLUSION: Our results preliminarily revealed the pharmacological basis and molecular mechanism SJC in treating MI, but further experimental research is required to verify these findings.

Coenzyme Q10 and Melatonin for the Treatment of Male Infertility: A Narrative Review.

BACKGROUND: Lifestyle and environmental factors can negatively impact fertility by means of oxidative stress. In this context, antioxidant supplementation therapy has gained much interest in recent years, and different molecules, alone or in combination, have been studied. OBJECTIVE: The purpose of the present review is to investigate the evidence regarding the efficacy of coenzyme Q10 (CoQ10) and melatonin on male infertility. METHODS: A literature search using PUBMED database from 2000 to October 2022 was performed to explore the role of CoQ10 and melatonin on male reproductive function. CONCLUSIONS: The analysis involved a narrative synthesis. CoQ10, alone or in combination, appears to reduce testicular oxidative stress and sperm DNA fragmentation and to improve sperm parameters; particularly sperm motility. Moreover, CoQ10 treatment is associated with higher pregnancy rates, both naturally and through assisted reproductive technology (ART). Larger studies are needed to precisely determine its clinical efficacy. Melatonin is a known antioxidant and preclinical studies have shown its ability to modulate reproductive function through hormonal and immune system regulation and sperm cell proliferation. Regardless, clinical studies are necessary to assess its potential in male infertility.