PFAS, HPV and obesity are linked to lower male fertility
A review links PFAS chemicals, HPV and obesity to poorer sperm health in men. The chapter, from an Italian andrology group, gathers lab, animal and human studies. Between 30% and 60% of infertile men get no clear diagnosis. The authors suggest these exposures may play a role in many of those cases.
Key Findings
Infertility affects one out of six couples in Western countries. Male factor infertility is implicated in about 50% of cases.
Among infertile men, 30–60% are left without a clear diagnosis.
The authors compared 212 young men from a PFAS-contaminated area of northeast Italy with 171 age-matched controls. Most exposed men had reduced testicular volume, penile length and anogenital distance.
In HPV-infected men, viral clearance of approximately 85.3% was reached after 24 months of follow-up. Fewer anti-sperm antibodies and better sperm motility paralleled the clearance.
Obese men had continuously raised scrotal temperature with less day-to-night variation. Healthy controls showed a pattern that swung between day and night.
Interpretation
The chapter is an expert overview in a clinical andrology textbook. It describes no systematic search and leans on the authors' own studies. Many human findings on PFAS, HPV and obesity are reported as associations. Mechanisms come from cell, animal and lab experiments, such as sperm exposed to PFOA in a dish. The authors note that PFAS research has focused mostly on female fertility. The chapter gives no overall estimate of how many cases of unexplained male infertility these exposures account for.
RRM Context
Restorative reproductive medicine treats unexplained infertility as undiagnosed. The 30–60% of infertile men with no clear diagnosis fits that view. The three exposures give clinicians specific causes to look for in the male partner. The chapter puts male factor at about 50% of cases, which supports evaluating both partners from the start.
Our editorial summary of this paper, not the article's abstract.
Abstract
Male infertility may depend by pre-testicular (for example, hypothalamic or pituitary diseases), testicular, and post-testicular (for example, obstructive pathologies of seminal ducts) causes. However, a large proportion (30–60%) of infertile males does not receive a clear diagnosis. In these cases, generally reported as idiopathic infertility, there is a strong suspicion of genetic factors yet to be discovered. Furthermore, male fertility may be influenced by a host of lifestyle risk factors such as environment, nutrition, exposure to infections, and smoking. Therefore, lifestyle and environment risk factors may have a role in many cases of idiopathic male infertility. In this chapter, we focus our attention on these risk factors, discussing three paradigmatic situations of interference between environment/lifestyle and male fertility, thus providing the pathophysiological basis of their detrimental impact on male fertility: exposure to environmental endocrine disruptors, such as perfluoro-alkyl substances (PFAS); exposure to viruses, such as HPV; effect of nutritional status and obesity.
Grande G et al., 2026·The Journal of clinical endocrinology and metabolism·Free to read
Male factor infertility (MFI) is frequently labelled idiopathic when evaluation relies primarily on semen analysis, potentially overlooking endocrine and pathophysiological mechanisms relevant for targeted management.
To phenotypically define MFI and develop a pathophysiology-based classification aimed at reducing idiopathic infertility following comprehensive evaluation.
Prospective monocentric cohort study conducted at a tertiary referral academic centre.
Eight hundred male partners of infertile couples evaluated between October 2024 and January 2026 after exclusion of isolated female factor infertility.
Prevalence of MFI categories, hormonal patterns across phenotypes, and proportion of idiopathic infertility after comprehensive work-up.
All patients underwent standardized clinical evaluation, hormonal assessment (total testosterone, FSH, LH), testicular ultrasound, and complete semen analysis. Microbiological testing, transrectal ultrasound, and genetic analyses were performed according to guidelines.
Primary spermatogenic failure was the most prevalent category (56.0%), followed by infection/inflammation (22.4%) and hypogonadotropic hypogonadism (8.5%). Idiopathic infertility was identified in only 5.3% of cases. Distinct endocrine profiles were observed, with high-FSH spermatogenic failure representing the dominant phenotype.
Comprehensive phenotyping markedly reduces the proportion of patients classified as having idiopathic infertility and identifies clinically relevant subgroups. This prospective study provides validation of a pathophysiology-based classification and supports a shift toward endocrine-integrated diagnostic strategies in male infertility, with potential implications for targeted management.
Rocca MS et al., 2026·Journal of translational medicine·Free to read
Standard semen analysis has little prognostic value in distinguishing fertile from infertile men. Furthermore, in men with semen parameters within the reference ranges, it cannot distinguish fertile men from infertile men, i.e. partners of couples with idiopathic infertility. Oxidative stress, mitochondrial dysfunction, sperm telomere shortening, and DNA fragmentation have been proposed as contributors to impaired male fertility. However, these biomarkers have not been evaluated as a whole in subjects with normal semen parameters, partners of fertile and infertile couples.
To characterise a multidimensional panel of sperm biomarkers-including sperm telomere length (STL), mitochondrial DNA copy number (mtDNAcn), reactive oxygen species (ROS), lipid peroxidation (LP), sperm chromatin dispersion (SCD), and respiratory control ratio (RCR)-and to identify whether these parameters might discriminate, in men with normal semen parameters, infertile men from fertile controls.
A total of 150 men with semen parameters within the normal ranges were enrolled: 47 male partners of couples with idiopathic infertility and 103 fertile controls. STL and mtDNAcn were quantified by qPCR; ROS were assessed using OxiSperm®II with semiquantitative imaging; LP was measured spectrophotometrically in seminal plasma; SCD was used to determine DNA fragmentation; and mitochondrial function was evaluated by oxygen consumption and RCR. Correlations between biomarkers and semen parameters were analysed using Pearson or Spearman coefficients, and intergroup comparisons were adjusted for age.
Semen parameters did not differ significantly between male partners of fertile and infertile couples. compared to men of fertile couples, men of infertile couples exhibited significantly shorter STL (0.57 ± 0.59 vs 1.21 ± 1.13, p_adj = 0.001) and higher oxidative stress, with both ROS (8300.9 ± 4214.8 vs 6555.3 ± 3394.3, p_adj = 0.027) and LP (88.33 ± 55.50 vs 40.29 ± 46.98, p_adj < 0.001) markedly elevated. mtDNAcn, SCD, and RCR showed no difference between the groups. Across the entire cohort, STL correlated negatively with ROS and LP and positively with RCR. ROS correlated negatively with total sperm count, motility and RCR, and positively with LP. LP displayed the strongest pattern of associations, correlating negatively with concentration, total count, motility, STL and RCR, and positively with age and volume.
Among men with normal semen analysis, partners of couples with idiopathic infertility exhibit a distinct sperm molecular profile characterised by telomere shortening and oxidative imbalance. STL, ROS and LP emerged as age-independent biomarkers associated with infertility status and showed promising discriminatory ability in this cohort, supporting their integration as second-level tests to complement routine semen analysis in cases of normozoospermia.
Besides gonadal involvement (hypogonadism, male factor infertility, and testicular hypotrophy), patients with Klinefelter syndrome (KS) may suffer from several extra-gonadic complications, including neoplastic events.
The aim of this review is to summarize all major clinical evidence dealing with the association between KS and neoplastic diseases and provide practical suggestions for the management of patients with KS regarding neoplastic risk.
This narrative review was conducted through a comprehensive search of the PubMed database, using combinations of the following keywords: "Klinefelter syndrome," "cancer," "neoplasm," "breast cancer," "germ cell tumor," "lymphoma," and "testosterone replacement therapy".
KS is associated with a higher risk of breast cancer and mediastinal germ cell tumors and an apparent higher risk of hematological malignancies, in particular non-Hodgkin lymphoma and leukemia. Evidence on testicular cancer is limited, with no clear increase in risk attributable to KS, while prostate cancer has a lower risk and lower mortality rate.
Given the complexity of the syndrome and the limited available evidence, regular clinical follow-up with targeted investigations when clinically indicated may facilitate early diagnosis and management of associated comorbidities.
De Toni L et al., 2026·Journal of endocrinological investigation·Free full text on PubMed Central
Varicocele is a recognized male factor of infertility. Surgical/microsurgical correction represents a therapeutical option to improve fertility outcomes but predictive parameters for the identification who can actually benefit from varicocele correction are under investigated. Here we aimed to identify baseline predictors of semen outcome improvement after varicocele treatment by scleroembolization approach.
85 patients receiving varicocele treatment by anterograde scleroembolization (ASE, N = 42) or retrograde scleroembolization (RSE, N = 43) were retrospectively recruited. Basal and 6-months follow-up evaluation of semen, hormonal and ultrasound parameters (US) were performed to address the respective effect of varicocele treatment. In addition, basal parameters were assessed as clinical outcome predictors.
Varicocele grade reduction was observed in more than 90% of patients (P < 0.001). Compared to basal, significant increase of sperm concentration (10.0 ± 9.2 × 106cells/mL vs. 23.4 ± 26.9 × 106cells/mL; P < 0.001), total sperm count (TSC 39.0 ± 54.5 × 106cells vs. 70.3 ± 90.6 × 106cells, P < 0.001) and total motile sperm count (TMS, 9.8 ± 12.8 × 106cells vs. 36.7 ± 58.1 × 106cells, P < 0.001), was observed, with no differences between RSE or ASE. All US parameters were also improved (all P < 0.001). Logistic regression analysis of basal semen and ultrasound parameters showed that basal sperm motility and left testis-mean transit time (L-MTT) were associated with TSC and TMS doubling at follow-up. However, Receiver Operating Characteristic curve analysis showed that only basal L-MTT basal sperm was consistently associated with TSC and TMS doubling at follow-up (respectively: AUC = 0.834, CI: 0.747-0.921 and AUC = 0.805, CI: 0.708-0.901; both P < 0.001).
Baseline sperm count and US parameters represent useful clinical descriptors to address those subjects eligible for varicocele correction.
Zańko A et al., 2022·International journal of environmental research and public health·Free full text on PubMed Central
Infertility is a problem that affects millions of couples around the world. It is known as a disease of couples, not individuals, which makes diagnosis difficult and treatment unclear. Male infertility can have many causes, from mechanical ones to abnormal spermatogenesis or spermiogenesis. Semen quality is determined by a number of factors, including those dependent on men themselves, with the number of infertile men growing every year. These include, e.g., diet, physical activity, sleep quality, stress, among many others. As these factors co-exist with insulin resistance, which is a disease closely related to lifestyle, it has been singled out in the study due to its role in affecting semen quality. In order to examine connections between lifestyle, insulin resistance, and semen quality, a review of literature published from 1989 to 2020 in the following databases PubMed/Medline, EMBASE (Elsevier), Scopus, Web of Science, and Google Scholar was performed. Hence, semen quality, environment, and insulin resistance are interrelated, thus it is difficult to indicate which aspect is the cause and which is the effect in a particular relationship and the nature of possible correlations. Since the influence of lifestyle on semen quality has been extensively studied, it is recommended that more thorough research be done on the relationship between insulin resistance and semen quality, comparing the semen quality of men with and without insulin resistance.
Ku CW et al., 2025·BMJ open·Free full text on PubMed Central
Despite the global prevalence of low fertility rates, male contributions to fertility and reproductive health outcomes have been understudied. This study aims to investigate the male contribution to fertility and explore the underlying biological mechanisms. Specifically, we aim to (1) identify male factors associated with successful pregnancy, (2) develop a fertility index incorporating modifiable factors for both males and females to predict pregnancy rate and (3) explore the relationship of male modifiable factors with semen parameters and molecular characteristics. We will conduct an unmatched case-control study involving 240 couples with impaired male fertility (cases) and 240 couples with normal male fertility (controls). Between July 2024 and June 2026, we will recruit 480 eligible couples from KK Women's and Children's Hospital, Singapore. Male and female participants will complete questionnaires on sociodemographics, general health and lifestyle factors, and their anthropometry and body fat composition will be measured. Blood and semen samples from the male participants will be collected for biochemical, molecular and semen analyses. Predictive male factors will be identified using the least absolute shrinkage and selection operator method, accounting for female factors. We will construct a logistic regression model incorporating both male and female factors to derive a fertility index, which will be evaluated using cross-validation on subsets of the study population. Multivariable linear regression will be used to explore relationships between male modifiable exposures and semen parameters. The study protocol has received approval from the Centralised Institutional Review Board of SingHealth (2024/2120), Singapore. Participants will provide written informed consent. Study results will be disseminated through conferences and peer-reviewed scientific journals. NCT06293235.
Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse. It affects about 15% of all couples in the United States and at least 180 million couples worldwide. Male infertility is defined by the World Health Organization (WHO) as the inability of a male to make a fertile female pregnant for a minimum of at least 1 year of regular unprotected intercourse. The male is solely responsible for about 20% of cases and is a contributing factor in another 30% to 40% of all infertility cases. As male and female causes often co-exist, it is essential that both partners are investigated for infertility and managed together. Overall, the male factor substantially contributes to about 50% of all cases of infertility. There are several reasons for male fertility, including both reversible and irreversible conditions. Other factors can influence each partner, including age, medications, surgical history, exposure to environmental toxins, genetic problems, and systemic diseases. The key purpose for evaluating a male for infertility is to identify his contributing factors, offer treatment for those that are reversible, determine if he is a candidate for assisted reproductive techniques (ART), and provide counseling for irreversible and untreatable conditions. Up to 6% of men evaluated for male infertility will be found to have more serious underlying pathology, such as cancer. This is an additional reason to do a comprehensive evaluation of the male partners of infertile couples so that any significant, underlying medical conditions can be identified and treated.
Assidi M, 2022·Cells·Free full text on PubMed Central
Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. Present-day clinicians rely primarily on standard semen analysis to diagnose male reproductive potential and develop treatment strategies. To address sperm quality assessment bias and enhance analysis accuracy, the World Health Organization (WHO) has recommended standardized sperm testing; however, conventional diagnostic and therapeutic options for male infertility, including physical examination and semen standard analysis, remain ineffective in relieving the associated social burden. Instead, assisted reproductive techniques are becoming the primary therapeutic approach. In the post-genomic era, multiomics technologies that deeply interrogate the genome, transcriptome, proteome, and/or the epigenome, even at single-cell level, besides the breakthroughs in robotic surgery, stem cell therapy, and big data, offer promises towards solving semen quality deterioration and male factor infertility. This review highlights the complex etiology of male infertility, especially the roles of lifestyle and environmental factors, and discusses advanced technologies/methodologies used in characterizing its pathophysiology. A comprehensive combination of these innovative approaches in a global and multi-centric setting and fulfilling the suitable ethical consent could ensure optimal reproductive and developmental outcomes. These combinatorial approaches should allow for the development of diagnostic markers, molecular stratification classes, and personalized treatment strategies. Since lifestyle choices and environmental factors influence male fertility, their integration in any comprehensive approach is required for safe, proactive, cost-effective, and noninvasive precision male infertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream.
Male Fertility › Male Factor Causes › Lifestyle and Environment · Lifestyle and Environment › Environmental Exposures › Persistent Organic Pollutants
DOI 10.1007/978-3-031-11701-5_12 10.1007/978-3-031-11701-5_12 Grande et al. 2022, Grande 2022
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