Changes in Sperm Parameters with Time in Men with Normal and Abnormal Baseline Semen Analysis.

The association between paternal age and sperm quality in the population level has been previously studied. Only limited data exists regarding the intra-personal variations in semen parameters among fertile and infertile men over time. We aimed to assess trends over time in semen parameters among men with normal and abnormal baseline sperm parameters and investigate potential risk factors for sperm quality deterioration. This retrospective cohort study was conducted at a university-affiliated medical center in vitro fertilization (IVF) unit. Patients with at least two semen analyses (SA) performed > 1 year apart, with the last SA done between 2017 and 2021, were included. The study consisted of two main analyses-comparison of intra-patient's sperm parameters changes in men with normal and abnormal baseline SA (BSA) and analysis of risk factors for developing abnormal semen parameters over time in men who had normal BSA parameters. This study included a total of 902 men assessed for infertility with normal and abnormal BSA. The average time interval between tests was 1015 days (range 366-7709 days). Among individuals with normal BSA, there was a mild decline in most parameters-concentration (- 6.53 M/ml), motility (- 7.74%), and total motile count (TMC) (- 21.80 M) (p < 0.05 for all parameters). In contrast, a slight improvement in most parameters, except for concentration, was noted in men with abnormal BSA-volume (+ 0.21 ml), motility (+ 8.72%), and TMC (+ 14.38 M) (p < 0.05 for all parameters). Focusing on men with normal BSA, 33.5% of individuals developed abnormality in one or more of their sperm parameters over time, within a mean time of 1013 ± 661 days. We also found that only time between tests emerged as an independent prognostic factor for the development of abnormal SA later. Interestingly, sperm deterioration in participants in their third, fourth, and fifth decades of life with normal initial semen analysis was similar. Our study provides evidence of a decline in semen quality over time in individuals with normal BSA, in contrast to men with abnormal BSA. Longer time intervals between tests independently increase the risk of sperm abnormalities.

Identification and selection of healthy spermatozoa in heterozygous carriers of the Phe508del-variant of the CFTR-gene in assisted reproduction.

The pathogenic variant Phe508del of the CFTR-gene is the most frequent cause of cystic fibrosis (CF). Whereas male CF-patients are infertile due to bilateral agenesis of the efferent ducts, the fertility status of male heterozygous carriers is uncertain. We aimed at demonstrating the involvement of the CFTR-ion channel during sperm capacitation and to potentially select variant-free spermatozoa in heterozygous carriers of the CFTR-variant using flow cytometry (FC). Using FC and sorting, single cell polymerase chain reaction, immuno-fluorescent staining an experimental study was performed on nine fertile semen donors and three heterozygous infertile men carrying the Phe508del gene variant. Chemical inhibition of CFTR interfered with sperm capacitation. Most viable spermatozoa of heterozygous carriers of the Phe508del variant of the CFTR-gene show immune-fluorescent CFTR. Sperm capacitation in Phe508del carriers was similar to that in healthy semen donors. Distribution of the Phe508del allele in trio data of CF-affected families corresponded to the expected recessive inheritance pattern. Infertility in Phe508del heterozygous men is unlikely to be caused by the pathogenic variant although some contribution cannot be excluded. Normal sperm capacitation in carriers of pathogenic variants of the Phe508del-gene may in part explain the high prevalence of a potentially lethal recessive disorder.

Human INHBB Gene Variant (c.1079T>C:p.Met360Thr) Alters Testis Germ Cell Content, but Does Not Impact Fertility in Mice.

Testicular-derived inhibin B (α/ß B dimers) acts in an endocrine manner to suppress pituitary production of follicle-stimulating hormone (FSH), by blocking the actions of activins (ß A/B/ß A/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (ß B-subunit of inhibin B and activin B) in a man suffering from infertility (azoospermia). In this study, we aimed to test the causality of the p.Met360Thr variant in INHBB and testis function. Here, we used CRISPR/Cas9 technology to generate InhbbM364T/M364T mice, where mouse INHBB p.Met364 corresponds with human p.Met360. Surprisingly, we found that the testes of male InhbbM364T/M364T mutant mice were significantly larger compared with those of aged-matched wildtype littermates at 12 and 24 weeks of age. This was attributed to a significant increase in Sertoli cell and round spermatid number and, consequently, seminiferous tubule area in InhbbM364T/M364T males compared to wildtype males. Despite this testis phenotype, male InhbbM364T/M364T mutant mice retained normal fertility. Serum hormone analyses, however, indicated that the InhbbM364T variant resulted in reduced circulating levels of activin B but did not affect FSH production. We also examined the effect of this p.Met360Thr and an additional INHBB variant (c.314C>T: p.Thr105Met) found in another infertile man on inhibin B and activin B in vitro biosynthesis. We found that both INHBB variants resulted in a significant disruption to activin B in vitro biosynthesis. Together, this analysis supports that INHBB variants that limit activin B production have consequences for testis composition in males.

Risk of health status worsening in primary infertile men: A prospective 10-year follow-up study.

BACKGROUND: A severe male infertility factor has been associated with both lower health status and increased mortality in infertile men. OBJECTIVES: To investigate reproductive factors associated with health status impairment in infertile men over a 10-year time frame since the first clinical evaluation. MATERIALS AND METHODS: Data from 899 infertile men were analysed at baseline between 2003 and 2010. Health-significant comorbidities were scored with the Charlson Comorbidity Index. Patients were followed up yearly recording any worsening in their health status until 2019. Cox regression models were used to estimate hazard ratios and 95% confidence intervals of Charlson Comorbidity Index score increase. RESULTS: At a median follow-up of 136 months (Interquartile range: 121, 156), 85 men (9.5%) depicted an increase of their baseline Charlson Comorbidity Index score of at least one point. The most frequent reason for Charlson Comorbidity Index upgrade was cancer (34%), cardiovascular diseases (29%) and diabetes mellitus (22%). Compared to patients without a Charlson Comorbidity Index increase, patients with a Charlson Comorbidity Index increase presented with higher body mass index and follicle-stimulating hormone values, a higher rate of baseline Charlson Comorbidity Index ≥ 1 (all p < 0.01) and a greater proportion of non-obstructive azoospermia (p < 0.001). In the Cox regression model, the patient's BMI (p < 0.001), baseline Charlson Comorbidity Index ≥ 1 (p < 0.01) and azoospermia status (p = 0.001) were found to be independently associated with Charlson Comorbidity Index increases. CONCLUSIONS: Almost 10% of men presenting for primary infertility had a decrease of the overall health status already in the relatively short 10-year time frame after the first presentation. Non-obstructive azoospermic men showed the worst health status impairment and should be strictly followed-up regardless of their fertility status.

Oncofertility Information Available for Recently Approved Novel Non Cytotoxic and Immunotherapy Oncology Drugs.

We reviewed the available animal and human reproductive function studies of recently approved noncytotoxic oncology drugs. We reviewed the oncofertility information in the prescribing information for the US Food and Drug Administration (FDA)-approved products and/or the product information and consumer medicine information for Therapeutic Goods Administration (TGA)-approved drugs of 32 novel oncology drugs approved between 2014 and 2018 in the United States and/or Australia supplemented by a literature review for additional reproductive effects. No human studies were available on the reproductive effects of all 32 drugs. A systematic literature review of animal reproductive toxicity studies provided only very limited data with nine drugs displaying impaired male fertility, three impaired female fertility, and nine producing impaired fertility in both male and female animals. Two drugs in the study are reported to have no demonstrable impact on fertility in animal reproductive toxicity studies and nine are reported to have unknown effects on fertility. Of the 32 newly listed drugs, only 4 had recommendations regarding potential human fertility risks and accordingly advised clinicians about fertility preservation procedures for patients. The lack of human data and limited animal reproductive toxicity data raises concerns about the potential impact of these novel oncology drugs on human fertility and reproductive function. Consequently, adequate oncofertility recommendations, including for fertility preservation procedures, counselling for psychological or cost implications, and future prognosis for fertility are hindered by this paucity of relevant data. More data on human reproductive effects of novel oncology drugs is urgently required to facilitate effective use of the growing array of oncofertility care options available.

Environmental and occupational pesticide exposure and human sperm parameters: A Navigation Guide review.

Global sperm counts have declined in recent decades, coinciding with the proliferation of endocrine-disrupting chemicals, of which pesticides are some of the most common. Previous systematic reviews of epidemiologic studies published between 1991 through 2013 have reported associations between environmental and occupational pesticide exposure and reduced sperm quality, particularly associations with reduced sperm concentration. This systematic review used the Navigation Guide to critically evaluate the current body of evidence examining sperm quality and pesticide exposure in epidemiological studies. PubMed, Scopus, and Web of Science databases were searched for all English-language articles published after September 2012 until August 2021. Original observational studies that assessed human sperm quality parameters, defined as concentration, motility, morphology, and DNA integrity, and individual-level pesticide exposure were included. The risk of bias for each included study and the strength of evidence were evaluated using the Navigation Guide protocol. Nineteen studies assessing environmental or occupational pesticide exposure and sperm parameters were included. Eighteen studies were cross-sectional studies and one prospective cohort; sample sizes ranged from 42 to 2122 men from 14 different countries. Fifteen (79 %) studies found at least one significant association between pesticide exposure and reduced sperm quality. The overall risk of bias across studies was classified as low to moderate. The quality of evidence was determined to be moderate based on systematic evaluation criteria. There were consistent adverse associations between pesticide exposure and sperm motility (63 % of studies) and DNA integrity (80 % of studies). For sperm concentration and morphology, 42 % and 36 % of studies found significant negative associations, respectively. The strength of the body of evidence overall was rated as having sufficient evidence of toxicity. Regarding specific sperm endpoints, there was sufficient evidence that pesticides are toxic for sperm motility and DNA integrity; limited evidence of toxicity for sperm concentration; and inadequate evidence of toxicity for sperm morphology. The studies reviewed here showed consistent associations between pesticide exposure and diminished sperm parameters, particularly sperm motility and sperm DNA integrity. These findings are largely consistent with results of previous reviews, which have found significant negative associations between pesticide exposure and sperm quality in 13 of 20 (65 %) studies published between 1991 and 2008, and in 14 of 17 (82 %) studies published between 2008 and 2012. After thirty years of mounting evidence, actions are needed to reduce pesticide risks to testicular function and male fertility.

Impact of cilia-related genes on mitochondrial dynamics during Drosophila spermatogenesis.

Spermatogenesis is a dynamic process of cellular differentiation that generates the mature spermatozoa required for reproduction. Errors that arise during this process can lead to sterility due to low sperm counts and malformed or immotile sperm. While it is estimated that 1 out of 7 human couples encounter infertility, the underlying cause of male infertility can only be identified in 50% of cases. Here, we describe and examine the genetic requirements for missing minor mitochondria (mmm), sterile affecting ciliogenesis (sac), and testes of unusual size (tous), three previously uncharacterized genes in Drosophila that are predicted to be components of the flagellar axoneme. Using Drosophila, we demonstrate that these genes are essential for male fertility and that loss of mmm, sac, or tous results in complete immotility of the sperm flagellum. Cytological examination uncovered additional roles for sac and tous during cytokinesis and transmission electron microscopy of developing spermatids in mmm, sac, and tous mutant animals revealed defects associated with mitochondria and the accessory microtubules required for the proper elongation of the mitochondria and flagella during ciliogenesis. This study highlights the complex interactions of cilia-related proteins within the cell body and advances our understanding of male infertility by uncovering novel mitochondrial defects during spermatogenesis.

Adverse effects of antiepileptic drugs on hormones of the hypothalamic-pituitary-gonadal axis in males: A review.

The HPG axis is critical in the maintenance of spermatogenesis and sexual function in males. The GnRH-releasing neurons of the hypothalamus are the axis's main hierarchical element. These neurons make connections with different areas of the brain to regulate the release of GnRH. Neurotransmitters have a critical in the connections between these neurons. So, neurotransmitters can inhibit or stimulate the release of GnRH by affecting GnRH-releasing neurons. In neurological disorders, neurotransmitter's activities inevitably change; therefore, these changes can affect the HPG axis via affecting GnRH-releasing neurons, just like in epilepsy. Many investigations have attracted attention to be decreased fertility potential in males with epilepsy. It has been stated that changes in the HPG axis hormone levels have been found in these patients. Moreover, it has also been observed that sperm quality decreased in patients. It has been emphasized that a decrease in sperm quality may be related to both epilepsy and AEDs. It has been shown that AEDs caused decreased sperm quality by impairing the HPG axis, so they act like endocrine-disrupting chemicals. AEDs can affect fertility and cause additive adverse effects in terms of sperm quality together with epilepsy. Therefore, it is crucial to investigate the adverse reproductive effects of AEDs, which are frequently used during reproductive ages, and determine the role of the HPG axis on potential reproductive pathologies.

Actualización sobre COVID-19 e histofisiología del sistema reproductor masculino / Update on COVID-19 and histophysiology of the male reproductive system

RESUMEN: La reciente pandemia de la COVID-19 ha sacudido a la sociedad teniendo una importante repercusión en el campo de la salud y de la investigación. Dada su relevancia, se han llevado a cabo estudios sobre los efectos del SARS-CoV-2 en la fisiología humana. En concreto, sobre la posible presencia y transmisión del virus a través del sistema reproductor masculino y su posible efecto en el éxito reproductivo. Conocer si la presencia del virus altera los órganos responsables del desarrollo y maduración de las células de la serie espermatogénica podría revelarnos su implicación en la calidad seminal. Por ello, nos planteamos esta revisión, con el fin de analizar las principales evidencias científicas sobre los efectos del SARS-CoV-2 en la histofisiología del sistema reproductor masculino y sobre la capacidad fecundante de los espermatozoides.

SUMMARY: The recent COVID-19 pandemic has shaken up society, having a significant impact on the field of health and research. Given its relevance, studies have been performed on the effects of SARS-CoV-2 on human physiology. In particular, the possible presence and transmission of the virus through the male reproductive system could affect reproductive success. Knowing if the presence of the virus disrupts the organs responsible for the development and maturation of the cell lines involved in spermatogenesis could reveal its implications in sperm quality. For that reason, we proposed this review, in order to analyze the main scientific evidence on the effects of SARS-CoV-2 on the histophysiology of the male reproductive system and sperm fertilizing capacity.

Androgens in SARS-CoV-2 coronavirus infections.

Recent molecular biology findings have shown that for the penetration of the SARS-CoV-2 coronavirus into host cells, a key role is played by protease serine 2, the activity of which is dependent on androgens. The important role of androgens is also evidenced by clinical observations that men in some age categories are infected by this novel coronavirus up to two times more frequently than women. In addition, men with androgenic alopecia tend to have more serious clinical courses, while men with androgen deprivation as a result of prostate cancer treatments tend to have milder courses. This is in line with the fact that preadolescent children are only rarely sickened with serious forms of SARS-CoV-2 infections. Even though these observations may be explained by other factors, many authors have hypothesized that lowered androgen levels and blocking their activity using anti-androgen medication may moderate the course of the viral infection in intermediately- to critically-affected cases. Clearly, it would be important for androgen deprivation to block not just gonadal androgens, but also adrenal androgens. On the other hand, low androgen levels are considered to be a risk factor for the course of SARS-CoV-2 infections, either because low androgen levels have a general effect on anabolic-catabolic equilibrium and energy metabolism, or because of the ability of testosterone to modify the immune system. It is not yet clear if infection with this novel coronavirus might induce hypogonadism, leading to undesirable side effects on male fertility.

Glucose Metabolism Disorder Induces Spermatogenic Dysfunction in Northern Pig-Tailed Macaques (Macaca leonina) With Long-Term SIVmac239 Infection.

Although spermatogenic dysfunction is widely found in patients with human immunodeficiency virus (HIV), the underlying reasons remain unclear. Thus far, potential hypotheses involving viral reservoirs, testicular inflammation, hormone imbalance, and cachexia show inconsistent correlation with spermatogenic dysfunction. Here, northern pig-tailed macaques (NPMs) exhibited marked spermatogenic dysfunction after long-term infection with simian immunodeficiency virus (SIVmac239), with significant decreases in Johnsen scores, differentiated spermatogonial stem cells, and testicular proliferating cells. The above hypotheses were also evaluated. Results showed no differences between SIV- and SIV+ NPMs, except for an increase in follicle stimulating hormone (FSH) during SIV infection, which had no direct effect on the testes. However, long-term SIVmac239 infection undermined pancreatic islet ß cell function, partly represented by significant reductions in cellular counts and autophagy levels. Pancreatic islet ß cell dysfunction led to glucose metabolism disorder at the whole-body level, which inhibited lactate production by Sertoli cells in testicular tissue. As lactate is the main energy substrate for developing germ cells, its decrease was strongly correlated with spermatogenic dysfunction. Therefore, glucose metabolism disorder appears to be a primary cause of spermatogenic dysfunction in NPMs with long-term SIVmac239 infection.

Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation.

Background: Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system. Results: The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB). Conclusions: The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Obesity and reproduction: a committee opinion.

The purpose of this American Society for Reproductive Medicine Practice Committee report is to provide clinicians with principles and strategies for the evaluation and treatment of couples with infertility associated with obesity. This revised document replaces the Practice Committee document titled "Obesity and reproduction: an educational bulletin" last published in 2015 (Fertil Steril 2015;104:1116-26).

The level of secondary messengers and the redox state of NAD+/NADH are associated with sperm quality in infertility.

In order to explore the interrelation of Calcium, cAMP, and redox state of pyridine nucleotides in seminal plasma and ejaculate quality in cases of idiopathic infertility we conducted an evaluation of 170 infertile males and 46 fertile males aged 20-43 years. Sperm analysis was undertaken according to WHO protocol. The content of Calcium in the seminal plasma was detected using optical emission spectrometry, cAMP levels were determined via enzymatic immunoassay. The redox state of pyridine nucleotides was evaluated from the ratio of pyruvate to lactate, determined via enzymatic method. Our results show a decrease in Calcium, cAMP, pyruvate and the oxidation-reduction potential of pyridine nucleotides in the seminal plasma of infertile males with pathospermia. This corresponds to anaerobic inversion of oxidative conversions and metabolism inadaptation. Such processes are often seen in inflammatory and autoimmune conditions. cAMP levels reliably correlated with the number of progressively mobile sperm cells, but not with the number of their pathological forms. A positive correlation between the concentration of cAMP and calcium was discovered as well. Pathospermia was characterized by the positive relation between the value of the NAD+/NADH coefficient and the spermatozoa concentration that was not present in fertile donors. Our study shows distinct changes in the concentration of secondary messengers and redox state of pyridine nucleotides in the seminal fluid that can act as molecular predictors for the development of idiopathic infertility.

Iatrogenic male infertility: medical and surgical treatments that impair male fertility.

Many medical and surgical treatments result in impaired male fertility. Sometimes impairments are permanent, while other times they may be reversible. Clinicians who treat urologic and nonurologic problems, as well as those of us who treat male and female infertility should understand what treatments affect which aspects of reproduction and what options for management are available. Conditions for which treatment may impair fertility range from benign prostatic hyperplasia to cancer to behavioral health issues. This month's Views and Reviews summarizes these conditions, the mechanisms of fertility impairment as well as preemptive and posttreatment approaches for management.

The role of benign prostatic hyperplasia treatments in ejaculatory dysfunction.

Ejaculatory dysfunction is not only psychologically distressing but can become a significant obstacle for men who wish to conceive. Dysfunction comes in the form of anejaculation, reduced ejaculation, retrograde ejaculation, painful ejaculation, or premature ejaculation. Most treatments for lower urinary tract symptoms related to benign prostatic hyperplasia, which commonly occurs in aging men, carry significant risks of absent, reduced, or retrograde ejaculation. This review focuses on such risks that accompany both the medical and surgical management of lower urinary tract symptoms/benign prostatic hyperplasia and how these risks impact male fertility.

Medical therapies causing iatrogenic male infertility.

Primum non nocere. As physicians, our goal is to treat illnesses and alleviate suffering; however, in doing so, we can generate new problems in a game of medical whack-a-mole. For some patients, certain consequences or side effects are tolerable, while others may believe they have no alternative. For a male patient with infertility, a thorough history is imperative to elucidate whether the patient has been or is currently being exposed to medications that will harm libido, spermatogenesis, ejaculation, or the hypothalamic-pituitary-testosterone axis. This article will review the most common medications causing iatrogenic male infertility as well as options to minimize or even reverse their impact.

Iatrogenic effects of radical cancer surgery on male fertility.

Iatrogenic causes of male infertility can include medications, chemotherapy, radiation, and surgery. In this review, we discuss commonly performed urologic cancer surgeries and nonurologic surgeries that harbor a high risk of iatrogenic infertility. These include radical prostatectomy, radical cystectomy, retroperitoneal lymph node dissection, pelvic colon surgery, and anterior spine surgery. In addition, we review the anatomy and surgical strategies that help to reduce the risks of infertility. With an increase in life expectancy and improvements in fertility preservation, it is important to properly counsel patients about the risks of infertility and provide options for fertility preservation before surgery.

Z-scores for comparative analyses of spermatogonial numbers throughout human development.

OBJECTIVE: To normalize age-dependent effects on standardized measures of spermatogonial quantity such as the number of spermatogonia per tubular cross-section (S/T) or fertility index. DESIGN: Published quantitative histologic data on human spermatogonial numbers were used to create Z-scores for reference means and tested on archived testicular tissue samples. SETTING: Retrospective cohort study. PATIENT(S): The sample cohort comprised testicular samples from 24 boys with cancer diagnosis and 10 with Klinefelter syndrome, as part of the fertility preservation programs NORDFERTIL and Androprotect, as well as archived histologic samples from 35 prepubertal boys with acute lymphoblastic leukemia and 20 testicular biobank samples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Z-score values for S/T and fertility index on the basis of morphology and germ cell-specific markers (MAGEA4 and/or DDX4) were calculated, and the impact of cancer therapy exposure and genetic disorders on Z-score values was evaluated. RESULT(S): The Z-scores for S/T values in the nontreated samples (-2.08 ± 2.20, n = 28) and samples treated with nonalkylating agents (-1.90 ± 2.60, n = 25) were comparable within ±3 standard deviations of the reference mean value but differed significantly from samples exposed to alkylating agents (-12.14 ± 9.20, n = 22) and from patients with Klinefelter syndrome (-11.56 ± 4.89, n = 8). The Z-scores for S/T were correlated with increasing cumulative exposure to alkylating agents (r = -0.7020). CONCLUSION(S): The Z-score values for S/T allow for the quantification of genetic and cancer treatment-related effects on testicular tissue stored for fertility preservation, facilitating their use for patient counseling.

Effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation rates in infertile men with clinical varicocele: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect of varicocelectomy on sperm deoxyribonucleic acid fragmentation (SDF) rates in infertile men with clinical varicocele. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Infertile men with clinical varicocele subjected to varicocelectomy. INTERVENTION(S): Systematic search using PubMed/Medline, EMBASE, Cochrane's central database, Scielo, and Google Scholar to identify relevant studies published from inception until January 2021. We included studies comparing SDF rates before and after varicocelectomy in infertile men with clinical varicocele. MAIN OUTCOME MEASURE(S): The primary outcome was the difference between the SDF rates before and after varicocelectomy. A meta-analysis of weighted data using random-effects models was performed. Results were reported as weighted mean differences (WMD) with 95% confidence intervals (CIs). Subgroup analyses were performed on the basis of the SDF assay, varicocelectomy technique, preoperative SDF levels, varicocele grade, follow-up time, and study design. RESULT(S): Nineteen studies involving 1,070 patients provided SDF data. Varicocelectomy was associated with reduced postoperative SDF rates (WMD -7.23%; 95% CI: -8.86 to -5.59; I2 = 91%). The treatment effect size was moderate (Cohen's d = 0.68; 95% CI: 0.77 to 0.60). The pooled results were consistent for studies using sperm chromatin structure assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling, sperm chromatin dispersion test, and microsurgical varicocele repair. Subgroup analyses showed that the treatment effect was more pronounced in men with elevated vs. normal preoperative SDF levels, but the impact of varicocele grade remained equivocal. Meta-regression analysis demonstrated that SDF decreased after varicocelectomy as a function of preoperative SDF levels (coefficient: 0.23; 95% CI: 0.07 to 0.39). CONCLUSION(S): We concluded that pooled results from studies including infertile men with clinical varicocele indicated that varicocelectomy reduced the SDF rates. The treatment effect was greater in men with elevated (vs. normal) preoperative SDF levels. Further research is required to determine the full clinical implications of SDF reduction for these men.