Exploring the relationship between Hashimoto's thyroiditis and male fertility:A meta-analytic and meta-regression perspective on hormonal and seminal factors

Objective:To explore the relationship between Hashimoto's autoimmune hypothyroidism(HT)and male fertility,focusing on hormonal and seminal factors.Methods:A systematic literature search was conducted across databases such as PubMed,Web of Science,EMBASE,Scopus,Cochrane,and Google Scholar,covering studies published from January 2000 to March 2024.Studies investigating the impact of HT on semen quality parameters and reproductive hormones were included.Pooled effect estimates were calculated using standard mean difference(SMD)and 95%confidence intervals(CI).Results:A total of 8 studies with 8965 participants were included.HT significantly affected semen quality and reproductive hormone levels.Specifically,there was a notable decrease in progressive morphology(SMD=-0.78;95%CI:-1.40 to-0.17;P=0.01)and sperm motility(SMD=-1.151;95%CI:-1.876 to-0.425;P=0.002).In addition,there were no significant changes in reproductive hormones,although there were elevated levels of luteinizing hormone(SMD=0.437;95%CI:0.000 to 0.874;P=0.050)and follicle-stimulating hormone(SMD=0.293;95%CI:-0.171 to 0.758;P=0.216),with a slight impact on testosterone levels(SMD=-1.143;95%CI:-2.487 to 0.200;P=0.095).Conclusions:This systematic review and meta-analysis provides robust evidence of the detrimental effects of HT on semen quality and reproductive hormones,underscoring the necessity for thorough evaluation and management of thyroid function in male infertility assessments.

Integration of omics studies indicates that species-dependent molecular mechanisms govern male fertility

Background Comparative and comprehensive omics studies have recently been conducted to provide a comprehensive understanding of the biological mechanisms underlying infertility.However,because these huge omics datasets often contain irrelevant information,editing strategies for summarizing and filtering the data are necessary prerequisite steps for identifying biomarkers of male fertility.Here,we attempted to integrate omics data from spermatozoa with normal and below-normal fertility from boars and bulls,including transcriptomic,proteomic,and metabolomic data.Pathway enrichment analysis was conducted and visualized using g:Profiler,Cytoscape,EnrichmentMap,and AutoAnnotation to determine fertility-related biological functions according to species.Results In particular,gamete production and protein biogenesis-associated pathways were enriched in bull spermatozoa with below-normal fertility,whereas mitochondrial-associated metabolic pathways were enriched in boar spermatozoa with normal fertility.These results indicate that below-normal fertility may be determined by aberrant regulation of protein synthesis during spermatogenesis,and the modulation of reactive oxygen species generation to maintain capacitation and the acrosome reaction governs boar sperm fertility.Conclusion Overall,this approach demonstrated that distinct molecular pathways drive sperm fertility in mammals in a species-dependent manner.Moreover,we anticipate that searching for species-specific signaling pathways may aid in the discovery of fertility-related biomarkers within large omics datasets.

Preliminary Studies on the Effect of Photoperiod and Temperature on Male Fertility of a Cytoplasmic Male Sterile Line in Wheat

[Objective] The study aimed to reveal the effect of photoperiod and temperature on male fertility of cytoplasmic male sterile line Vtai911289a in wheat and discuss the mechanism of male fertility alteration. [ Method ] The sowing-date tests and designed conditions were conducted during 2003 -2005. [ Result] Fertility of Vtai911289a, could alter under specific photoperiod and temperature conditions. Temperature is one of the main factors influencing male fertility of the male sterile lines. Vtai911289a, showed stable sterility under the condition of the mean of daily temperature at fertility sensitive stage lower than 19℃ and presented partial fertility when the mean of daily temperature at fertility sensitive stage lower than 20 - 22℃. Photoperiod to some extent affects the male fertility of Vtai911289a, long-day condition is helpful for the male fertility of the sterile line. [ Conclusion] The application of photoperiod temperature-sensitive cytoplasmic male sterile line in production has a higher safety than that of temperature sensitive sterile line.

Determination of sperm acrosin activity for evaluation of male fertility

Aim: To investigate a simple method for assaying acrosin activity for the evaluation of male fertility. Methods:The acrosin activity of 7.5 × 10~6 sperm without seminal plasma and acrosin activity inhibitors was assayed using N-α-benzoyl-DL-arginine-p-nitroanilide (BAPNA) and detergent (Triton X-100) as substrate. Results: The acrosin ac-tivity of 60 normal fertile men (35 ± 10 μIU/10~6 sperm ) was higher than that of 168 infertile men ( 16 ± 8 μIU/10~6sperm) (P <0.01). It was indicated that there was a significant positive correlation between the acrosin activity andthe sperm motility ( r ≥ 0.6534, P < 0.01) and a significant negative correlation between the sperm malformed rateand the WBC number ( r ≤ -0.5426, P < 0.01). The temperature and time of incubation and the sperm concentrationcould influence the assay results. Conclusion: Acrosin activity is an important index for the evaluation of male fer-tility. The approach developed by the authors is a simple method for the determination of acrosin activity.

Evidence that chronic hypoxia causes reversible impairment on male fertility

Aim： To evaluate the effect of chronic hypoxia on human spermatogenic parameters and their recovery time. Methods： Seminological parameters of six male healthy mountain trekkers were evaluated in normoxia at sea level. After 26 days exposure to altitude （ranging from 2 000 m to 5 600 m, Karakorum Expedition） the same parameters were again evaluated after returning to sea level. These parameters were once again evaluated after 1 month and then again after 6 months. Results： Sperm count was found to be lower immediately after returning to sea level （P = 0.0004） and again after a month （P = 0.0008）. Normal levels were reached after 6 months. Spermatic motility （%） shows no reduction immediately after returning to sea level （P = 0.0583）, whereas after 1 month this reduction was significant （P = 0.0066）. After 6 months there was a recovery to pre-hypoxic exposure values. Abnormal or immature spermatozoa （%） increased immediately after returning to sea level （P = 0.0067） and then again after 1 month （P = 0.0004）. After 6 months there was a complete recovery to initial values. The total number of motile sperm in the ejaculate was found to be lower immediately after returning to sea level （P = 0.0024） and then again after 1 month （P = 0.0021）. After 6 months there was a recovery to pre-hypoxic exposure values. Conclusion： Chronic hypoxia induces a state of oligospermia and the normalization of such seminological parameters at the restoration of previous normoxic conditions after 6 months indicate the influence of oxygen supply in physiological mechanisms of spermatogenesis and male fertility.

Function of seminal vesicles and their role on male fertility

The present review has been designed to update the recent developments on the function of seminal vesicles andtheir role on male fertility. It is indicated that the true corrected fructose level is a simple method for the assessment ofthe seminal vesicular function. Measurement of seminal fructose used universally as a marker of the seminal vesiclefunction is not an appropriate approach due to its inverse relationship with the sperm count. The true corrected fructosedefined as [log. motile sperm concentration] multiplied by [seminal fructose concentration] has been shown to be abetter marker of the seminal vesicle function. Seminal vesicular secretion is important for semen coagulation, sperm motility, and stability of sperm chromatinand suppression of the immune activity in the female reproductive tract. In conclusion, the function of seminal vesicle is important for fertility. Parameters as sperm motility, sperm chro-matin stability, and immuno-protection may be changed in case of its hypofunction. (Asian J Androl 2001 Dec; 3:251 -258)

Pro-oxidative and anti-oxidative imbalance in human semen and its relation with male fertility

Oxidative stress is a common condition suffered by biological systems in aerobic conditions. Human semen also has its own molecular guard against the free radicals created by normal respiratory process or from immune reactions. The equilibrium of the creation and scavenging of free radicals is mandatory in the spermatozoa to fertilize and initiate a full-term pregnancy. The paper is a systematic review of publications that evaluate oxidative stress in semen. The Cochrane Library, Medline (1966-2003), Embase (1988-2003), SciSearch (1981-2003) and the conference papers were searched. When sperm samples from fertile and infertile males were analyzed, some of the mechanisms that determine the oxidative stress level were found to be impaired while others were unaltered. In conclusion, the literature as a whole provides contradictory findings and it is necessary to carry out more work to identify all the enzymatic and non-enzymatic systems involved in oxidative stress in the ejaculate, in order to develop new diagnostic systems and therapeutic strategies for combating detrimental free radical imbalance in the semen.

Mouse models in male fertility research

Limited knowledge of the genetic causes of male infertility has resulted in few treatment and targeted therapeutic options. Although the ideal approach to identify infertility causing mutations is to conduct studies in the human population, this approach has progressed slowly due to the limitations described herein. Given the complexity of male fertility, the entire process cannot be modeled in vitro. As such, animal models, in particular mouse models, provide a valuable alternative for gene identification and experimentation. Since the introduction of molecular biology and recent advances in animal model production, there has been a substantial acceleration in the identification and characterization of genes associated with many diseases, including infertility. Three major types of mouse models are commonly used in biomedical research, including knockoutJknockin/gene-trapped, transgenic and chemical-induced point mutant mice. Using these mouse models, over 400 genes essential for male fertility have been revealed. It has, however, been estimated that thousands of genes are involved in the regulation of the complex process of male fertility, as many such genes remain to be characterized. The current review is by no means a comprehensive list of these mouse models, rather it contains examples of how mouse models have advanced our knowledge of post-natal germ cell development and male fertility regulation.

Proteomics of spermatogenesis： from protein lists to understanding the regulation of male fertility and infertility

Proteomic technologies have undergone significant development in recent years, which has led to extensive advances in protein research. Currently, proteomic approaches have been applied to many scientific areas, including basic research, various disease and malignant tumour diagnostics, biomarker discovery and other therapeutic applications. In addition, proteomics-driven research articles examining reproductive biology and medicine are becoming increasingly common. The key challenge for this field is to move from lists of identified proteins to obtaining biological information regarding protein function. The present article reviews the available scientific literature related to spermatogenesis. In addition, this study uses two-dimensional electrophoresis mass spectrometry （2DE-MS） and liquid chromatography （LC）-MS to construct a series of proteome profiles describing spermatogenesis. This large-scale identification of proteins provides a rich resource for elucidating the mechanisms underlying male fertility and infertility.

Genome-wide analyses on transcription factors and their potential microRNA regulators involved in maize male fertility

Anther development is a programmed biological process crucial to plant male reproduction. Genomewide analyses on the functions of transcriptional factor(TF) genes and their microRNA(miRNA) regulators contributing to anther development have not been comprehensively performed in maize. Here, using published RNA-Seq and small RNA-Seq(sRNA-Seq) data from maize anthers at ten developmental stages in three genic male-sterility(GMS) mutants(ocl4, mac1, and ms23) and wild type W23, as well as newly sequenced maize anther transcriptomes of ms7-6007 and lob30 GMS mutants and their WT lines, we analyzed and found 1079 stage-differentially expressed(stage-DE) TF genes that can be grouped into six(premeiotic, meiotic, postmeiotic, premeiotic-meiotic, premeiotic-postmeiotic, and meiotic-postmeiotic clusters) expression clusters. Functional enrichment combined with cytological and physiological analyses revealed specific functions of genes in each expression cluster. In addition, 118 stage-DE miRNAs and99 miRNA-TF gene pairs were identified in maize anthers. Further analyses revealed the regulatory roles of zma-miR319 and zma-miR159 as well as ZmMs7 and ZmLOB30 on ZmGAMYB expression. Moreover,ZmGAMYB and its paralog ZmGAMYB-2 were demonstrated as novel maize GMS genes by CRISPR/Cas9 knockout analysis. These results extend our understanding on the functions of miRNA-TF gene regulatory pairs and GMS TF genes contributing to male fertility in plants.

Drug treatment of male fertility disorders

Drug treatment remains an active domain in the therapy of male fertility disorders. Although there are only a fewconditions that allow causal treatment, rational approaches are possible in many cases. Best results are obtained in casesrequiring an anti-inflammatory treatment and in patients with an impaired sperm transport. High-dosage administrationof FSH is a promising new development, aimed particularly at improving the disturbed sperm structures. A careful di-agnostic work-up with elucidation of the underlying disease is essential to achieve a successful therapy.

Cytological study on haploid male fertility in maize

Doubled haploid(DH)breeding technology,which relies on haploid genome doubling,is widely used in commercial maize breeding.Spontaneous haploid genome doubling(SHGD),a more simplified and straightforward method,is gaining popularity among maize breeders.However,the cytological mechanism of SHGD remains unclear.This study crossed inbred lines RL36 and RL7,which have differing SHGD abilities,with inducer line YHI-1 to obtain haploid kernels.The meiotic processes of pollen mother cells(PMCs)in the haploid plants were compared with diploid controls.The results suggested that three main pathways,the early doubling of haploid PMCs,the first meiotic metaphase chromosomal segregation distortion,and anomaly of the second meiosis,are responsible for SHGD.Furthermore,flow cytometry analysis of ploidy levels in leaves and PMCs from haploids and diploid controls revealed that somatic cell chromosome doubling and germ cell chromosome doubling are independent processes.These findings provide a foundation for further studies on the underlying mechanism of SHGD,aiding the application of DH technology in maize breeding practices.

Establishment of a male fertility prediction model with sperm RNA markers in pigs as a translational animal model

Background:Male infertility is an important issue that causes low production in the animal industry.To solve the male fertility crisis in the animal industry,the prediction of sperm quality is the most important step.Sperm RNA is the potential marker for male fertility prediction.We hypothesized that the expression of functional genes related to fertilization will be the best target for male fertility prediction markers.To investigate optimum male fertility prediction marker,we compared target genes expression level and a wide range of field data acquired from artificial insemination of boar semen.Results:Among the genes related to acrosomal vesicle exocytosis and sperm–oocyte fusion,equatorin(EQTN),zona pellucida sperm-binding protein 4(ZP4),and sperm acrosome membrane-associated protein 3 exhibited high accuracy(70%,90%,and 70%,respectively)as markers to evaluate male fertility.Combinations of EQTN-ZP4,ZP4-protein unc-13 homolog B,and ZP4-regulating synaptic membrane exocytosis protein 1(RIMS1)showed the highest prediction value,and all these markers are involved in the acrosome reaction.Conclusion:The EQTN-ZP4 model was efficient in clustering the high-fertility group and may be useful for selection of animal that has superior fertility in the livestock industry.Compared to the EQTN-ZP4 model,the ZP4-RIMS1 model was more efficient in clustering the low-fertility group and may be useful in the diagnosis of male infertility in humans and other animals.The appointed translational animal model and established biomarker combination can be widely used in various scientific fields such as biomedical science.

Pyruvate kinase M in germ cells is essential for sperm motility and male fertility but not spermatogenesis

Male germ cells employ specific metabolic pathways throughout their developmental stages.In a previous study,we discovered heightened expression of pyruvate kinase M(PKM),a pivotal glycolytic enzyme,in spermatogonia and spermatids.To gain deeper insights into PKM's roles in spermatogenesis,sperm function,and male fertility,we engineered a conditional-knockout mouse model(Pkm-vkO mice)to selectively disrupt the Pkm gene within germ cells.Despite maintaining regular testicular histology and sperm morphology,the male Pkm-vko mice were infertility,characterized by significant impairments in sperm motility and adenosine triphosphate(ATP)generation.In addition,Pkm-null spermatozoa exhibited similar deficits in protein tyrosine phosphorylation linked to capacitation,as well as compromised performance in in vitro fertilization experiments.To conclude,PKM's presence is not obligatory for the entirety of spermatogenesis in male germ cells;however,it emerges as a critical factor influencing sperm motility and overall male fertility.

Pro-fertility effect of Ficus carica fruit extract in streptozotocin-induced male rats

Objective:To explore the impact of Ficus carica fruit aqueous extract on fertility parameters in streptozotocin(STZ)-induced male rats.Methods:Twenty-four male Sprague-Dawley rats were divided into four different groups.All groups except a normal control group were induced with 50 mg/kg of streptozotocin(STZ)intravenously to induce diabetes.A positive control group was treated with an antidiabetic drug,metformin(500 mg/kg)whereas a negative control group remained untreated throughout the experiment.Meanwhile,another diabetic rat group received treatment with 400 mg/kg of aqueous Ficus carica fruit extract.Rats in the treatment group were administered Ficus carica fruit aqueous extract daily through forcefeeding via oral gavage for a 21-day period.Assessments included the sperm quality(count,motility and morphology),histology of the testes,serum testosterone and fasting blood glucose(FBG)level.Results:The FBG level of the Ficus carica-treated rats exhibited a significant decrease compared to the negative control group(P<0.05).Sperm quality analysis also indicated that the aqueous Ficus carica extract had significant positive effects on sperm count and motility(P<0.05).The histology of the testes in Ficus caricatreated rats revealed an improved cell arrangement in the germinal cell layer.Furthermore,serum testosterone level showed an increment in the Ficus carica treatment group in comparison to the negative control group.Conclusions:Our findings provide compelling evidence for the profertility and anti-hyperglycemic properties of aqueous Ficus carica fruit extract in diabetic-induced male rats.

The PIWI-specific insertion module helps load longer piRNAs for translational activation essential for male fertility

PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.

UDP-glucose epimerase 1,moonlighting as a transcriptional activator,is essential for tapetum degradation and male fertility in rice

Multiple enzymes perform moonlighting functions distinct from their main roles.UDP-glucose epimerases(UGEs),a subclass of isomerases,catalyze the interconversion of UDP-glucose(UDP-Glc)and UDP-galactose(UDP-Gal).We identified a rice male-sterile mutant,osuge1,with delayed tapetum degradation and abortive pollen.The mutant osuge1 protein lacked UDP-glucose epimerase activity,resulting in higher UDP-Gal content and lower UDP-Glc levels in the osuge1 mutant compared with the wild type.Interestingly,we discovered that OsUGE1 participates in the TIP2/bHLH142–TDR–EAT1/DTD transcriptional regulatory cascade involved in tapetum degradation,in which TIP2 and TDR regulate the expression of OsUGE1 while OsUGE1 regulates the expression of EAT1.In addition,we found that OsUGE1 regulates the expression of its own gene by directly binding to an E-box element in the OsUGE1 promoter.Collectively,our results indicate that OsUGE1 not only functions as a UDP-glucose epimerase but also moonlights as a transcriptional activator to promote tapetum degradation,revealing a novel regulatory mechanism of rice reproductive development.

Fertility outcomes following bariatric surgery

Obesity impacts human health in more than one way.The influence of obesity on human reproduction and fertility has been extensively examined.Bariatric surgery(BS)has been used as an effective tool to achieve long-term weight loss in both sexes.BS improves hormonal profiling,increasing the odds of spontaneous pregnancy and success rates following assisted reproductive techniques in infertile females.For obese males,BS does improve sexual function and hormonal profile;however,conflicting reports discuss reduced sperm parameters following BS.Although the benefits of BS in the fertility field are acknowledged,many areas call for further research,like choosing the safest surgical techniques,determining the optimal timing to get pregnant,and resolving the uncertainty of sperm parameters.

Amino acid substitutions of GLY98, LEU245 and GLU543 in COIl distinctively affect jasmonate-regulated male fertility in Arabidopsis

Jasmonate （JA） regulates various plant defense and developmental processes. The F-box protein CORONATINE INSENSITIVE 1 （COIl） perceives JA signals to mediate diverse plant responses including male fertility, root growth, antho- cyanin accumulation, and defense against abiotic and biotic stresses. In this study, we carried out genetic, physiological and biochemical analysis on a series of coil mutant alleles, and found that different amino acid mutations in COIl distinctively af- fect JA-regulated male fertility in Arabidopsis. All the JA responses are disrupted by the COIl mutations W467＂ in coil-l, Q343＂ （coil-6）, G369E （coil-4）, G98D （coil-5）, G155E （coil-7）, D452A （coil-9） and L490A （coil-10）, though the coil-5 mutant （COIlG98D） contains adequate COIl protein （~60% of wild-type）. Interestingly, the low basal level of COIlE543K in the coil-8 mutant （-10% of wild-type COIl level） is sufficient for maintaining male fertility （-50% of wild-type fertility）; the coil-2 mutant with low level of COIlLz45F （-10% of wild-type） is male sterile under normal growth condition （22℃） but male fertile （~80% of wild-type fertility） at low temperature （16℃）; however, both coil-2 and coil-8 are defective in the other JA responses （root growth, anthocyanin accumulation, and plant response to the pathogen Pst DC3000 infection）.

Diagnostic tools in male infertility--the question of sperm dysfunction

Sperm dysfunction is the single most common cause of infertility, yet what is remarkable is that, there is no drug a man can take or add to his spermatozoa in vitroto improve fertility. One reason for the lack of progress in this area is that our understanding of the cellular and molecular workings of the mature spermatazoon is limited. However, over the last few years there has been considerable progress in our knowledge base and in addressing new methods to diagnose sperm dysfunction. We review the current state of the field and provide insights for further development. We conclude that： （i） there is little to be gained from more studies identifying/categorizing various populations of men using a basic semen assessment, where an effort is required in making sure the analysis is performed in an appropriate high quality way; （ii） technological development is likely to bring the reality of sperm function testing closer to implementation into the clinical pathways. In doing this, these assays must be robust, cheap （or more appropriately termed cost effective）, easy to use and clinically useful; and （iii） clinical necessity, e.g., the need to identify the highest quality spermatozoon for injection is driving basic research forward. This is an exciting time to be an andrologist and, likely, a fruitful one.