Infertility is a major clinical challenge worldwide, affecting approximately 10% to 15% of couples of reproductive age [1-2]. It is estimated that male factors contribute to around 40% of infertility cases, with compromised semen quality being the primary cause of male infertility [3]. Although numerous studies have identified potential risk factors such as environmental toxins, mumps virus infections, and alcohol consumption that might affect semen quality, the exact underlying causes remain elusive [4]. Recently, research has increasingly explored the relationship between abnormal body mass index (BMI) and semen quality; however, the results have been controversial. For example, Wang et al. [5] reported that an increased BMI was linked with a lower total sperm number and sperm concentration in northern China. Meanwhile, another large-scale study by Ma et al. found that being underweight or overweight were both associated with a decreased total motile sperm count [6]. Lu et al. [7] found that BMI, the Waist–Hip Ratio (WHR), and WC cannot predict male semen quality; however, semen quality was significantly related to levels of Follicular Stimulating Hormone (FSH) and Luteinizing Hormone (LH). Accordingly, the World Health Organization (WHO) categorizes individuals as overweight if their Body Mass Index (BMI) is 25 kg/m² or higher and classifies obesity as a BMI of 30 kg/m² or greater [8]. However, the thresholds for Body Mass Index (BMI) classification vary among different racial and ethnic groups. The BMI criteria mentioned earlier are applicable to non-Asian populations, which include individuals identifying as Hispanic, non-Hispanic white, non-Hispanic black, and other similar racial or ethnic categories. In contrast, the threshold for identifying obesity among Asian populations is a BMI of 27.5 kg/m² or higher [9]. In Iran, the prevalence of overweight and obesity stands at 59.3% [10]. Evidence indicates that overweight and obese men typically exhibit lower sperm counts compared to those with normal weight [11]. Additionally, a high BMI negatively influences various dimensions of male fertility, such as sperm count, motility, morphology, and testosterone levels [12]. However, some studies have suggested that there may be no significant correlation between BMI and semen quality parameters [13]. It is proposed that obesity primarily affects male fertility by reducing testosterone levels and deteriorating semen quality [14]. Importantly, since sperm motility is more closely linked to pregnancy success and fertility rates than sperm concentration, motility issues are frequently observed in obese men, with reported prevalence rates of 39.9% and 24.2% in two separate studies [15]. Conversely, optimizing BMI in obese men has been shown to improve hormone levels, erectile function, and semen quality [16]. Concurrently, the substantial role of oxidative stress (OS) in the emergence of male reproductive disorders has garnered significant research interest in recent years [17]. Maintaining a redox balance is vital for supporting various essential functions of sperm [18]. An imbalance in the production and elimination of Reactive Oxygen Species (ROS) can lead to oxidative damage, adversely affecting sperm quality [18].Spermatozoa are particularly vulnerable to oxidative damage owing to their limited antioxidant defense and the abundance of Polyunsaturated Fatty Acids (PUFAs) in their cell membranes [19]. Under specific pathological conditions, ROS can evolve into highly reactive species that disrupt cellular signaling pathways and inflict considerable damage to critical biomolecules, including nucleic acids, proteins, and lipids [20]. This damaging cascade can compromise membrane integrity, lead to mitochondrial dysfunction, reduce sperm motility, and result in DNA damage and programmed cell death (apoptosis) [21]. Obesity has the potential to induce systemic oxidative stress in the testes and sperm, compromising testosterone synthesis, spermatogenesis, and overall sperm quality [22]. Furthermore, increased adipose tissue levels in the scrotal region have been associated with elevated oxidative stress [23]. This oxidative stress arises from an imbalance between ROS production and the activity of three key anti-ROS enzymes: Superoxide Dismutase (SOD), Catalase (CAT), and Glutathione Peroxidase (GPX). When ROS levels become excessively elevated, cellular damage ensues [24]. Although the mechanisms generating oxidative stress in semen and their roles in male reproduction have only recently started to be elucidated, many questions remain unanswered, presenting ample opportunities for future research. Consequently, the role of free radicals and oxidative stress in fertility and subfertility requires ongoing scientific investigation. The aim of this study was to assess semen attributes in obese versus non-obese men experiencing unexplained infertility at the Royan Institute.

Sample Preparation

This cross-sectional study was conducted at the Royan Institute University Hospital, targeting men seeking infertility services between April 2017 and March 2019. A total of 280 patients presenting infertility symptoms were evaluated, with participants classified into three BMI categories: 75 non-obese (BMI < 25 kg/m²), 75 overweight (BMI 25-29 kg/m²), and 75 obese (BMI ≥ 30 kg/m²). Weight and height of each participant were accurately measured using professional, calibrated devices. The BMI was then calculated using the formula:

As per the World Health Organization's guidelines from 2016, these measurements were taken on the same day as the semen collection, with weight measured using a digital scale with a 180 kg capacity. Written informed consent for participation was obtained from all subjects, and the study received approval from the Research Ethics Committee of the Royan Institute. The study engaged male partners of infertile couples who were visiting the Andrology laboratory for semen analysis scheduling. Participants, aged between 20 and 50 years, were briefed about the study's objectives before being invited to partake. Each participant completed a questionnaire that gathered personal information including ethnicity, lifestyle choices, period of abstinence, occupation, medical history, highest educational level attained, reproductive history, genetic risk factors, and lifestyle habits like alcohol consumption and smoking. Men with chronic illnesses such as diabetes, kidney disease, chronic liver conditions, epilepsy, chronic inflammatory bowel disease, atherosclerosis, vascular diseases, hypertension, genital disorders, testicular torsion, genitourinary anomalies, past testicular surgeries, azoospermia, leukocytospermia, or those on medications known to adversely affect fertility, including steroid users, were excluded from the study. Factors such as smoking, alcohol use, and exposure to chemicals, hookah smoking, testicular surgeries, and the duration of infertility were taken into account during participant evaluation.

Semen Analysis

Semen samples were obtained from participants using sterile containers through masturbation, following a sexual abstinence period of 2 to 5 days. The samples were maintained at 37°C for 30 minutes to allow liquefaction. Analysis of the semen adhered to the World Health Organization (WHO) guidelines established in 2010, and all samples were evaluated within one hour of collection. The assessment employed both Computer-Assisted Semen Analysis (CASA) and traditional manual methods tailored to the specific sample characteristics. Parameters recorded for each sample included sperm count, pH, semen volume, motility percentages, sperm concentration, and the proportion of morphologically normal sperm, with morphology assessed via Papanicolaou staining [25].

Measurement of Reactive Oxygen Species (ROS)

The ROS levels in all 280 semen samples were measured between 10 and 30 minutes post-ejaculation, as ROS levels diminish over time. ROS quantification was conducted using luminol, which emits chemiluminescence upon oxidation in the presence of ROS. A sperm count was performed for each sample, including both negative and positive controls. Negative controls consisted of 195 μl of phosphate-buffered saline (PBS) combined with 5 μl of a 5 mM luminol working solution, while positive controls included 175 μl of PBS, 20 μl of 30% hydrogen peroxide (H?O?), and 5 μl of the luminol working solution. To measure ROS, 5 μl of the luminol working solution was added to 195 μl of liquefied whole semen, and the mixture was gently agitated. The resulting ROS levels were adjusted for sperm concentration and reported as relative light units per second per million sperm (RLU/sec/10^6 sperm) [26].

Sperm Plasma Membrane Lipid Peroxidation

Lipid peroxidation of the sperm plasma membrane was assessed by determining the concentration of malondialdehyde (MDA) through the Thiobarbituric Acid (TBA) method, based on the approach described by Buege and Aust, with slight modifications. The TBA-TCA reagent, comprising 15% w/v TCA, 0.375% w/v TBA, and 0.25N HCl, was mixed with the sperm suspension in a 2:1 ratio. This mixture was incubated in a boiling water bath for one hour, followed by a cooling period in an ice bath for ten minutes. Subsequently, the suspension was centrifuged at 1500 g for ten minutes, and the supernatant was collected for absorbance measurement at 535 nm. The MDA concentration was calculated using a specific absorbance coefficient of 1.56 × 10^5 mol/cm³. Ultimately, sperm membrane Lipid Peroxidation (LPO) was expressed as nmol of MDA generated per 10^6 spermatozoa [27].

Total Antioxidant Capacity (TAC) Measurement

The Total Antioxidant Capacity (TAC) was evaluated using a colorimetric method with a specific total antioxidant assay kit sourced from MBL (Germany). The measurements were taken using a Microplate Reader (Synergy^™ H4 Hybrid Multi-Mode Microplate Reader, BioTek^®, USA) and expressed in nanomoles per microliter of semen (nmol/μl). To prepare the samples for analysis, frozen seminal plasma was thawed by submerging vials in a water bath maintained at 37°C for 20 minutes. Following the manufacturer's protocol, the antioxidant capacity of the thawed samples was assessed promptly [25].

Sperm Chromatin Structure Assay (SCSA)

The Sperm Chromatin Structure Assay (SCSA) is a flow cytometry-based technique employed to measure the susceptibility of sperm DNA to acid-induced denaturation in situ. For the assay, frozen semen samples were rapidly liquefied in a water bath at 37°C, follow by dilution to achieve a concentration of 1-2 × 10^6 sperm per milliliter. A 200 μl aliquot of this suspension was then mixed with 200 μl of an acid-detergent solution and incubated for 30 seconds. Subsequently, 900 μl of acridine orange (AO) staining solution was added (sourced from Sigma-Aldrich, St. Louis, MO, USA), before the sample was analyzed using flow cytometry. In each analysis, a total of 10,000 events were recorded at a flow rate approximating 200 cells per second. The DNA fragmentation index (DFI), indicating the extent of sperm DNA damage, was determined by assessing the ratio of red fluorescence to total fluorescence. The DFI values were subsequently analyzed using FlowJo software, providing quantitative insights into sperm chromatin integrity and DNA health [25].

Statistical Analysis

Data analysis was conducted using the SPSS statistical software package version 22 (SPSS, Chicago, IL, USA). The results are presented as mean ± Standard Deviation (SD). The normality of the data distribution was assessed utilizing the Kolmogorov-Smirnov (K-S) test. The independent sample t-test or the Mann-Whitney U test was employed for comparisons between two groups, depending on the appropriateness based on data characteristics. Furthermore, Pearson’s correlation coefficient test was utilized to evaluate the relationships among various factors under investigation. A p-value of less than 0.05 was deemed statistically significant, indicating a meaningful difference or correlation within the study context.

Demographic characteristics of the Participants

The results of the demographic analysis of the examined groups are presented in Table-1. It was observed that only the age and Body Mass Index (BMI) (P<0.001) and Duration infertility variables showed significant differences among the groups (P<0.05). In contrast, the variables related to smoking consumption, alcohol intake, and surgical history were not found to be statistically significant (P>0.05). This suggests that age and BMI may play a more crucial role in differentiating the groups compared to the other variables analyzed.

Table 1: Demographic characteristics.

Semen Analysis Results in Infertile Groups

The results of the study indicated a significant reduction in both sperm count (p=0.016) and total sperm count (p=0.021) in the infertile obese group when compared to the control group and the infertile overweight group (P<0.05). Furthermore, the categories of total sperm motility (p=0.00) and slowly progressive sperm (p=0.00) and A+B progressive (p=0.001) sperm and normal morphology(p=0.00) showed a decrease in the infertile obese group relative to the control group, while an increase was observed in these categories when compared to the infertile overweight group. Conversely, the parameter of non-motile sperm (p=0.009) and teratozoospermia index (p=0.00) exhibited a significant increase in the infertile obese group compared to both the control group and the overweight infertile group. However, no significant changes were noted in the categories of non-progressive sperm and rapidly progressive sperm (p>0.05), as presented in Table-2. These findings suggest that obesity may have a detrimental impact on sperm quality, particularly in terms of sperm count, mobility, and progression, which could have implications for fertility outcomes in affected individuals.

Table 2: Semen Analysis Results.

Assessment of Oxidative Stress Indicators in Infertile Groups

The analysis of oxidative stress indicators among the various infertile groups is presented in Table-3. It was observed that only the Total Antioxidant Capacity (TAC) in the infertile obese group exhibited a significant reduction when compared to both the control group and the overweight infertile group (p=0.00). In contrast, no significant changes were detected in other indicators, including Reactive Oxygen Species (ROS), Lipid Peroxidation (LPO), and DNA Fragmentation Index (DFI). These findings suggest that while the Total Antioxidant Capacity is notably impaired in obese infertile individuals, other oxidative stress markers may not differ significantly in this context.

Table 3: Oxidative Stress Indicators Analysis Results.

ROS: Reactive oxygen species; TAC: Total antioxidant capacity; LPO: Lipid peroxidation; DFI: DNA Fragmentation Index.

 Analysis of the Relationship between Sperm Parameters and Oxidative Stress Indices

The calculation of standardized regression coefficients utilized to determine the direction and strength of relationships between sperm parameters and antioxidant levels is presented in Table-4. Among the variables analyzed, Body Mass Index (BMI) and semen volume demonstrated significant correlations with alterations in Reactive Oxygen Species (ROS) levels. Additionally, BMI was significantly associated with changes in Total Antioxidant Capacity (TAC), while variations in Lipid Peroxidation (LPO) levels were correlated with sperm parameters such as Normal Morphology and defects in the neck and mid-piece of sperm. Furthermore, changes in the DNA Fragmentation Index (DFI) exhibited a significant relationship with the parameters of slowly progressive sperm (class B) and the total number of abnormal sperm. These findings underscore the intricate relationships between obesity-related parameters and oxidative stress markers, as well as their implications on sperm quality.

Table 4: Result of relationship between sperm parameters and oxidative stress indices.

*Indicating the significant direction and intensity between sperm parameters and antioxidant index levels (p<0.05).

Obesity has emerged as a significant public health concern over the past few decades, primarily due to its association with various metabolic disorders and chronic diseases [28]. Beyond these well-documented implications, recent empirical studies have begun to illuminate the relationship between obesity and reproductive health, particularly its detrimental impact on male fertility [29]. The demographic analysis of the examined groups underscored significant differences in age and Body Mass Index (BMI) (P<0.001), as well as the duration of infertility (P<0.05), supporting findings from prior studies that emphasize the critical role these factors play in male infertility. Specifically, a study conducted by Kozopas et al [30], demonstrated that advanced age and elevated BMI are linked to poorer semen quality and reduced fertility potential. These findings are consistent with those reported by MacDonald et al [31], where BMI was highlighted as a significant predictor of infertility outcomes, thus affirming the notion that age and BMI are pivotal in differentiating among infertile populations. In contrast, variables such as smoking consumption, alcohol intake, and surgical history did not show significant statistical differences (P>0.05), which aligns with research conducted by Agarwal et al [32]. Their study indicated that while lifestyle factors do influence sperm health, the direct correlation may vary and is sometimes overshadowed by other demographic variables like age and BMI. The study findings indicate a significant reduction in both sperm count (p=0.016) and total sperm count (p=0.021) among the infertile obese group when juxtaposed against the control group and the infertile overweight cohort. This distinction highlights not only a quantitative deficiency in sperm production within the obese population but also raises concerns regarding the potential mechanisms underpinning this decline. The relationship between obesity and hormonal alterations is well-documented, with adiposity leading to changes in testosterone levels and an increase in estrogen, which can adversely affect spermatogenesis [33]. The findings of this study align with previous research that highlights the detrimental effects of obesity on male reproductive health. For instance, a study by Palmer et al [34], emphasized that obesity negatively impacts spermatogenesis, leading to decreased sperm production. Additionally, Donerta? et al [35], corroborated that higher Body Mass Index (BMI) is consistently linked to poorer sperm parameters, including reduced sperm concentration and motility. Some authors even suggest greater clinical implications of the total sperm count in relation to the sperm concentration [36].

The observed decline in sperm count among the infertile obese group is further compounded by significant impairments in sperm motility and morphology. Specifically, this study found that parameters such as slowly progressive sperm, A+B progressive sperm, and normal morphology were notably reduced in comparison to the control group. These findings echo those of a study by Wang et al. [37], which reported similar declines in motility and morphological integrity among obese men. Moreover, a comprehensive review by Ribeiro et al. highlighted the impact of obesity-related factors, such as oxidative stress and hormonal imbalance, on sperm function. The meta-analysis suggests that compromised sperm motility is a common consequence of increased body mass index, reinforcing the need to address obesity as a modifiable risk factor in male infertility [38].

Conversely, the study highlighted a significant increase in non-motile sperm and the teratozoospermia index within the infertile obese group when compared to both control and overweight groups. The elevation of the teratozoospermia index, which assesses the proportion of morphologically abnormal sperm, raises alarm regarding the overall viability of sperm in this subgroup [39]. Teratozoospermia is linked to reduce fertility potential, and its prevalence among obese individuals may indicate considerable challenges in conceiving [40]. The implications of these findings suggest a multi-faceted approach to addressing male infertility that is rooted not only in lifestyle changes but also in a nuanced understanding of the interplay between body mass index (BMI) and reproductive health [40]. The significant reduction in Total Antioxidant Capacity (TAC) observed in the infertile obese group (p=0.00) underscores the adverse effects of obesity on antioxidant defense mechanisms. This finding is consistent with earlier research indicating that obesity can lead to oxidative stress, severely compromising the body’s ability to neutralize free radicals. A study by Guan et al. (2024) reported similar results, showing that obese individuals had diminished TAC, suggesting an increased vulnerability to oxidative damage [41]. In a population-based study, Chrysohoou et al [42], reported an inverse relationship between visceral fat and Total Antioxidant Capacity (TAC). This correlation was found to be more pronounced when considering waist circumference compared to Body Mass Index (BMI) [42]. Furthermore, the lack of significant changes in other oxidative stress indicators, such as Reactive Oxygen Species (ROS), Lipid Peroxidation (LPO), and DNA Fragmentation Index (DFI), contrasts with findings from Jing et al. (2023), who posited that obesity generally elevates markers of oxidative stress [43]. However, this variance may indicate a complex relationship where TAC and specific oxidative stress markers do not uniformly respond to obesity, highlighting the need for more nuanced research [43]. Among the analyzed variables, Body Mass Index (BMI) and semen volume exhibited significant correlations with alterations in Reactive Oxygen Species (ROS) levels. This relationship underscores the impact of obesity on oxidative stress, highlighting how increased adiposity may elevate ROS production, leading to compromised sperm parameters [44]. Additionally, BMI was significantly associated with changes in Total Antioxidant Capacity (TAC). This finding suggests that as BMI increases, the body’s ability to neutralize oxidative stress diminishes, potentially exacerbating fertility issues. Variations in Lipid Peroxidation (LPO) levels were found to correlate with sperm parameters, such as Normal Morphology and defects in the neck and mid-piece of sperm. These insights reinforce the notion that lipid peroxidation, a hallmark of oxidative stress, can adversely affect sperm structure and function, leading to decreased fertility potential [45]. Furthermore, the changes in the DNA Fragmentation Index (DFI) demonstrated a significant relationship with the parameters of slowly progressive sperm (class B) and the total number of abnormal sperm. This indicates that higher oxidative stress levels may be linked to increased DNA fragmentation, which can severely impair sperm viability and fertilization capabilities [46]. These findings collectively highlight the intricate relationships between obesity-related parameters and oxidative stress markers, emphasizing their implications for sperm quality and male fertility.

The results of this study provide compelling evidence that Body Mass Index (BMI) and age significantly influence male fertility, particularly in the context of obesity. Notably, BMI demonstrated strong correlations with alterations in reactive oxygen species (ROS) levels, as well as changes in Total Antioxidant Capacity (TAC), indicating that higher BMI is linked to increased oxidative stress. Importantly, the infertile obese group exhibited a significant reduction in TAC compared to both the control and overweight infertile groups, highlighting the detrimental impact of obesity on antioxidant defenses. Moreover, significant reductions in sperm count, total sperm motility, and normal morphology were observed in the infertile obese group relative to controls, with a notable increase in parameters such as non-motile sperm and teratozoospermia index. These findings suggest a clear deterioration in sperm quality associated with obesity, which may negatively affect fertility outcomes. Additionally, while other oxidative stress markers such as Lipid Peroxidation (LPO) and DNA Fragmentation Index (DFI) did not show significant changes, the apparent impairment of TAC emphasizes the nuanced relationship between oxidative stress and fertility. The lack of statistical significance for smoking, alcohol intake, and surgical history further supports the hypothesis that age and BMI are primary factors affecting male fertility in this population. The findings suggest that obesity detrimentally affects sperm quality and may have critical implications for fertility outcomes, highlighting the need for further research into the mechanisms involved.

Innovation

The innovation of this study lies in its comprehensive approach to examining the impact of Body Mass Index (BMI) and age on male fertility, particularly in obese individuals. Unlike previous studies that often focused solely on one aspect of oxidative stress, this research reveals a strong correlation between BMI and key fertility markers, including reactive oxygen species (ROS) and Total Antioxidant Capacity (TAC). The significant reduction in TAC specifically in the infertile obese group provides new insights into the detrimental effects of obesity on antioxidant defenses, suggesting that this impairment may be a crucial factor in diminished sperm quality. Furthermore, the study emphasizes the relevance of age and BMI over other lifestyle factors like smoking and alcohol intake, which have been frequently addressed in prior literature. This highlights a potential shift in focus for future research and interventions aimed at improving fertility outcomes for obese individuals.

Abbreviations

Acknowledgments

We would like to thank Royan Institute University Hospital and Islamic Azad University.

Conflict of Interests

The authors declare that there is no conflict of interest.

Ethical Approval

This study has been approved by the Ethics Committee Royan Institute.

Funding

This research received no external funding.

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