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.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Genetic variability within the follicle-stimulating hormone (FSH)-related genes might contribute to phenotypic heterogeneity in patients with Klinefelter syndrome (KS), yet its clinical impact on sperm retrieval remains unclear.
To investigate the association between FSHB c.211 G > T and FSHR polymorphisms (c.2039 A > G and c.29 G > A) and hormonal parameters, as well as their potential role in predicting sperm retrieval rate (SRR) in patients with KS undergoing testicular sperm extraction (TESE).
A retrospective cohort of patients with KS was analyzed. Only subjects not receiving testosterone replacement therapy were included (n = 417). Hormonal, anthropometric, and clinical variables were compared across genotypes using nonparametric tests. Additive genetic models were applied to evaluate allele-dose effects. Multivariable logistic regression was performed to identify independent predictors of SRR. Predictive performance of clinical and combined clinical-genetic models was assessed using ROC curve analysis.
FSHB and FSHR genes polymorphisms were associated with variations in serum FSH concentrations, confirming a modulatory role of the FSH-related genes. In additive modeling, the FSHR c.29 G > A polymorphism emerged as an independent predictor of SRR (adjusted OR: 0.29; 95% CI, 0.09-0.97), whereas FSHB c.211 G > T showed a nonsignificant trend. The inclusion of genetic variants modestly improved predictive accuracy compared with clinical variables alone, as demonstrated by ROC analysis.
Genetic variants within the genes involved in FSH action might contribute incremental information for the prediction of sperm retrieval in patients with KS. While the overall predictive gain remains moderate, additive genetic modeling highlights a potential allele-dose effect of FSHR c.29 G > A on reproductive outcome, supporting a role for integrated clinical-genetic assessment in this population, although external validation remains required.
Klinefelter syndrome (KS) is characterized by marked phenotypic heterogeneity that might be influenced by genetic modifiers, including androgen receptor (AR) repeat length (CAGn and GGCn). The clinical relevance of these repeat lengths in patients with KS before testosterone replacement therapy (TRT) remains unclear.
To investigate the association between AR repeat length and anthropometric, hormonal, metabolic, and reproductive parameters in a well-characterized cohort of untreated adult patients with KS.
In this cross-sectional single-center study, 214 men with classical 47, XXY karyotype were evaluated prior to TRT. Clinical, biochemical, and reproductive parameters were analyzed according to AR CAGn and GGCn repeat length. Nonparametric tests, multivariable linear and logistic regression models, and interaction terms between CAGn and GGCn were tested. Standardized beta coefficients were used to compare the relative contribution of AR repeat length with major clinical determinants.
In unadjusted analyses, CAG repeat length was associated with estradiol concentrations, whereas GGC repeat length showed associations with hematocrit, platelet count, and total cholesterol. However, most associations were characterized by small effect sizes and did not persist after multivariable adjustment for possible confounders (age, BMI, and total testosterone levels). Moreover, AR repeat length was not associated with sperm retrieval rate. Standardized beta analyses demonstrated that testosterone levels, BMI, and age accounted for the largest proportion of phenotypic variability, whereas CAGn and GGCn repeat length had minimal roles.
In untreated patients with KS, AR repeat length (CAGn and GGCn) appears to have a limited clinical impact compared with classical endocrine and metabolic determinants. These findings suggest that phenotypic variability in KS might be primarily driven by chromosomal aneuploidy and primary testicular dysfunction rather than AR repeat length.
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.
Graziani A et al., 2026·Andrology·Free full text on PubMed Central
Male factor infertility (MFI) is involved in half of the cases of couple infertility. The follicle-stimulating hormone (FSH) therapy is considered efficient to improve semen parameters and pregnancy rate in patients with idiopathic MFI, following the lesson learned from hypogonadotropic hypogonadism. However, while in patients with hypogonadotropic hypogonadism FSH therapy, in combination with human chorionic gonadotropin (hCG), is a well-established treatment, in patients with MFI the effects of the FSH therapy are variable and unpredictable. The FSH therapy in MFI should be a personalized treatment, tailored on the characteristics of the male patient and the couple. The pivotal aspect is the accurate identification of patients who might benefit from such treatment (responders) from those who might not (nonresponders). To date, selection of patients to be treated is based on history, physical examination, semen analysis, and hormonal assessment. However, these parameters cannot adequately identify a priori responder patients. Furthermore, tailored management should include pharmacological adaptation (dosage and duration of the therapy), as happens during ovarian hyperstimulation in assisted reproductive technologies. In a fully personalized therapy, pharmacogenetic factors must be considered. In this paper, we describe the evidence dealing with the pharmacogenetics of the FSH therapy in MFI, presenting the physiological and physiopathological basis and the pharmacogenetics studies dealing with effects of polymorphisms in the beta-subunit of FSH (FSHB) and the FSH receptor (FSHR) gene. According to the evidence so far available, genetic evaluation of FSHB and FSHR is recommended only for research purposes, since the data are not conclusive and even contrasting. Furthermore, the evidence so far is derived from quite small studies with different endpoints considered and relatively few cases. Better studies that consider the combined effect of several FSHB and FSHR gene polymorphisms, together with clinical, biochemical, seminal and testicular cytology, are necessary to develop an algorithm that might predict the response to the FSH treatment.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Graziani A et al., 2024·Human reproduction (Oxford, England)
Genetic causes account for 10-15% of male factor infertility, making the genetic investigation an essential and useful tool, mainly in azoospermic and severely oligozoospermic men. In these patients, the most frequent findings are chromosomal abnormalities and Y chromosome long arm microdeletions, which cause a primary severe spermatogenic impairment with classically increased levels of FSH. On the other hand, polymorphisms in the FSH receptor (FSHR) and FSH beta chain (FSHB) genes have been associated with different FSH plasma levels, due to variations in the receptor sensitivity (FSHR) or in the production of FSH from the pituitary gland (FSHB). Here, we describe an unusual patient with a combined genetic alteration (classic AZFc deletion of the Y chromosome and TT homozygosity for the -211G>T polymorphism in the FSHB gene (rs10835638)), presenting with cryptozoospermia, severe hypospermatogenesis, and normal LH and testosterone plasma concentrations, but low FSH levels. The patient partially benefitted from treatment with FSH (150 IU three times/week for 6 months) which allowed him to cryopreserve enough motile spermatozoa to be used for intracytoplasmic sperm injection. According to our knowledge, this is the first report of an infertile man with AZFc microdeletion with low FSH plasma concentrations related to homozygosity for the -211G>T polymorphism in the FSHB gene.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Graziani A et al., 2024·Genes·Free full text on PubMed Central
Several genes are implicated in spermatogenesis and fertility regulation, and these genes are presently being analysed in clinical practice due to their involvement in male factor infertility (MFI). However, there are still few genetic analyses that are currently recommended for use in clinical practice. In this manuscript, we reviewed the genetic causes of qualitative sperm defects. We distinguished between alterations causing reduced sperm motility (asthenozoospermia) and alterations causing changes in the typical morphology of sperm (teratozoospermia). In detail, the genetic causes of reduced sperm motility may be found in the alteration of genes associated with sperm mitochondrial DNA, mitochondrial proteins, ion transport and channels, and flagellar proteins. On the other hand, the genetic causes of changes in typical sperm morphology are related to conditions with a strong genetic basis, such as macrozoospermia, globozoospermia, and acephalic spermatozoa syndrome. We tried to distinguish alterations approved for routine clinical application from those still unsupported by adequate clinical studies. The most important aspect of the study was related to the correct identification of subjects to be tested and the correct application of genetic tests based on clear clinical data. The correct application of available genetic tests in a scenario where reduced sperm motility and changes in sperm morphology have been observed enables the delivery of a defined diagnosis and plays an important role in clinical decision-making. Finally, clarifying the genetic causes of MFI might, in future, contribute to reducing the proportion of so-called idiopathic MFI, which might indeed be defined as a subtype of MFI whose cause has not yet been revealed.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Rocca MS et al., 2023·The Journal of clinical endocrinology and metabolism
Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity.
The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males.
A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses.
We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic.
This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.
Rocca MS et al., 2021·Genes·Free full text on PubMed Central
Telomeres are considered to be an internal biological clock, and their progressive shortening has been associated with the risk of age-related diseases and reproductive alterations. Over recent years, an increasing number of studies have focused on the association between telomere length and fertility, identifying sperm telomere length (STL) as a novel biomarker of male fertility. Although typically considered to be repeated DNA sequences, telomeres have recently been shown to also include a long non-coding RNA (lncRNA) known as TERRA (telomeric repeat-containing RNAs). Interestingly, males with idiopathic infertility show reduced testicular TERRA expression, suggesting a link between TERRA and male fertility. The aim of this study was to investigate the role of seminal TERRA expression in embryo quality. To this end, STL and TERRA expression were quantified by Real Time qPCR in the semen of 35 men who underwent assisted reproductive technologies (ART) and 30 fertile men. We found that TERRA expression in semen and STL was reduced in patients that underwent ART (both p < 0.001). Interestingly, TERRA and STL expressions were positively correlated (p = 0.010), and TERRA expression was positively associated with embryo quality (p < 0.001). These preliminary findings suggest a role for TERRA in the maintenance of sperm telomere integrity during gametogenesis, and for the first time, TERRA expression was found as a predictive factor for embryo quality in the setting of assisted reproduction.
Rocca MS et al., 2020·Molecular genetics & genomic medicine·Free full text on PubMed Central
The androgen receptor (AR) is a nuclear receptor, encoded by the AR gene on the X chromosome. Within the first exon of the AR gene, two short tandem repeats (STR), CAG and GGC, are a source of polymorphism in the population. Therefore, high-throughput methods for screening AR, such as next-generation sequencing (NGS), are sought after; however, data generated by NGS are limited by the availability of bioinformatics tools. Here, we evaluated the accuracy of the bioinformatics tool HipSTR in detecting and quantify CAG repeats within the AR gene.
The AR gene of 228 infertile men was sequenced using NGSgene panel. Data generated were analyzed with HipSTR to detect CAG repeats. The accuracy was compared with the results obtained with Sanger.
We found that HipSTR was more accurate than Sanger in genotyping normal karyotype men (46,XY), however, it was more likely to misidentify homozygote genotypes in men with Klinefelter syndrome (47,XXY).
Our findings show that the bioinformatics tool HipSTR is 100% accurate in detecting and assessing AR CAG repeats in infertile men (46,XY) as well as in men with low-level mosaicism.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
Rocca MS et al., 2020·Journal of assisted reproduction and genetics·Free full text on PubMed Central
To develop and assess a novel custom next-generation sequencing (NGS) panel for male infertility genetic diagnosis.
A total of 241 subjects with diagnosis of idiopathic infertility ranging from azoospermia to normozoospermia were sequenced by a custom NGS panel including AR, FSHB, FSHR, KLHL10, NR5A1, NANOS1, SEPT12, SYCP3, TEX11 genes. Variants with minor allele frequency < 1% were confirmed by Sanger sequencing.
Nineteen missense variants were detected in 23 subjects with abnormal sperm count, whilst no variants were identified in normozoospermic men. Of identified variants, we prioritized variants classified as pathogenic and of uncertain significance (VUS) (63.1%, 12/19). No missense variants were found in males with normal seminal parameters (0/67). Therefore, the prevalence of variants was significantly higher in patients with spermatogenic impairment (16/174 vs 0/67, p = 0.007).
This study confirms the utility to apply NGS panel for infertility diagnosis in order to find new genetic variants potentially linked to male infertility with much higher accuracy than standard tests suggested by guidelines. Indeed, based on biological significance, prevalence in the general population and clinical data of patients, it is plausible that identified variants in this study might be linked to quantitative spermatogenic impairment, although further studies are needed.
Female fecundity is finely regulated by hormonal signaling, representing a potential target for endocrine-disrupting chemicals. Among the chemicals of most concern are the perfluoroalkyl substances (PFAS), widely used in consumer goods, that are associated with adverse effects on reproductive health. In this context, the endometrium clearly represents an important fertility determining factor. The aim of this study was to investigate PFAS interference on hormonal endometrial regulation. This study was performed within a screening protocol to evaluate reproductive health in high schools. We studied a cohort of 146 exposed females aged 18-21 from the Veneto region in Italy, one of the four areas worldwide heavily polluted with PFAS, and 1080 non-exposed controls. In experiments on Ishikawa cells included UV-Vis spectroscopy, microarray analysis and qPCR. We report a significant dysregulation of the genetic cascade leading to embryo implantation and endometrial receptivity. The most differentially-expressed genes upon PFOA coincubation were ITGB8, KLF5, WNT11, SULT1E1, ALPPL2 and G0S2 (all p < 0.01). By qPCR, we confirmed an antagonistic effect of PFOA on all these genes, which was reversed at higher progesterone levels. Molecular interference of PFOA on progesterone was confirmed by an increase in the intensity of absorption spectra at 250 nm in a dose-dependent manner, but not in the presence of β-estradiol. Age at menarche (+164 days, p = 0.006) and the frequency of girls with irregular periods (29.5% vs 21.5%, p = 0.022) were significantly higher in the exposed group. Our results are indicative of endocrine-disrupting activity of PFAS on progesterone-mediated endometrial function.
To study the functional properties of six novel missense mutations of the NR5A1 gene encoding the steroidogenic factor 1 (SF-1) identified in six patients with 46,XY disorders of sex development (DSD) and to describe their relative phenotype-genotype relationship.
Genetic and functional studies.
University department.
PATIENT(S): Six 46,XY DSD patients.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Sanger sequencing and multiplex ligation-dependent probe amplification analysis to identify the mutations or deletions/duplications of the NR5A1 gene. Functional studies by transactivation assays to predict the impact of mutations on molecular function.
RESULT(S): NR5A1 exons sequencing identified in six 46,XY DSD patients six novel mutations: p.T40R, p.T47C, p.G328W, p.A351E, p.R427W, and p.Q460R. Five missense variants were heterozygous, and one was homozygous (p.R427W). Functional analysis revealed a significant loss of DNA-binding and transactivation ability for all variants, except for p.Q460R, which showed a modest reduced activity compared with that of the wild-type protein. Phenotypes associated with these mutations varied from males with spontaneous puberty, substantial T production, and possible fertility, to females with and without müllerian structures and primary amenorrhea.
CONCLUSION(S): We describe six novel mutations in NR5A1 gene and showed that they might affect protein structure, therefore compromising seriously the SF-1 role in regulating gonadal development. Clinically, we suggest that NR5A1 analysis should be performed whenever atypical sex organs are evidenced or there is an abnormal sexual development, to have proper diagnosis and better management of patients.
De Toni L et al., 2016·The Journal of clinical endocrinology and metabolism
The G protein-coupled receptor GPRC6A is an emerging effector with multiple endocrine roles, including stimulation of T production from the testis. Recently, two men with an inactivating mutation (F464Y) of GPRC6A have been identified, and they showed primary testicular failure and deranged spermatogenesis. Furthermore, one of them also reported cryptorchidism at birth. In addition, a polymorphism (rs2274911, Pro91Ser) in GPRC6A is associated with prostate cancer, a typical androgen-sensitive cancer.
To study the possible association between rs2274911 polymorphism and male fertility and/or cryptorchidism. Design, Patients, Settings: A total of 611 subjects, including 343 infertile patients, 197 normozoospermic controls, and 71 cryptorchid newborns, were retrospectively selected.
Sequencing analysis for rs2274911 polymorphism and F464Y mutation, and serum levels of FSH, LH, and T were assessed. In vitro functional studies for rs2274911 and F464Y were also performed.
Homozygous subjects for the risk allele A of rs2274911 had a 4.60-fold increased risk of oligozoospermia and 3.52-fold increased risk of cryptorchidism. A significant trend for increased levels of LH in the GA and AA genotypes, compared with GG homozygotes, was detected in men with azoospermia/cryptozoospermia (P for trend = .027), further supporting an association with primary testicular failure. The mutation F464Y was found in one cryptorchid child (one in 71; 1.41%). Functional studies showed that the A allele of rs2274911 and the F464Y substitution were associated with lower exposition of the receptor on the cell membrane and a reduced downstream phosphorylation of ERK1/2 with respect to wild type.
Our results suggest that GPRC6A inactivation or sub-function contributes to reduced exposure to androgens, leading to cryptorchidism during fetal life and/or low sperm production in adulthood.
Rocca MS et al., 2016·Human reproduction (Oxford, England)
Could sperm telomere length (STL) represent a novel parameter and biomarker of sperm quality?
STL is associated with standard semen quality parameters and, more importantly, it is significantly associated with levels of DNA fragmentation and sperm protamination.
Telomeres are fundamental for genome integrity. Recent studies have demonstrated that STL increases with age and men with oligozoospermia have shorter sperm telomeres than normozoospermic men.
STUDY DESIGN, SIZE, Cohort study conducted from September 2014 to June 2015 on 100 subjects with normal standard semen parameters.
PARTICIPANTS/MATERIALS, SETTING, STL was measured indirectly by quantitative polymerase chain reaction using telomere/single-copy gene ratio, sperm DNA fragmentation by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and protamination by aniline blue staining. Data were analyzed for determining the relationships between STL, standard semen parameters and DNA fragmentation and protamination.
MAIN Among standard semen parameters, STL was positively associated with progressive motility (P = 0.004) and vitality (P = 0.007). STL was significantly and negatively associated with sperm DNA fragmentation (P = 0.001) and significantly and positively associated with protamination (P = 0.002). The role of chance was limited and the findings have biological relevance and a pathophysiological explanation.
LIMITATIONS, For the present study, we deliberately selected only men with normozoospermia to better analyze whether STL might represent a biomarker of sperm quality beyond traditional sperm parameters. Additional studies in proven fertile men with normal sperm parameters are needed.
The measurement of STL is a simple and rapid method that offers further information about the quality of sperm. The results of this study demonstrate that STL could be considered as an additional sperm parameter and opens new perspectives in the evaluation of the infertile male. Additional studies will clarify the significance of this parameter also as a prognostic biomarker in assisted reproduction.
No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.
To study the role of NR5A1 in cryptorchidism and male factor infertility. Mutations in NR5A1 have been initially associated with primary adrenal insufficiency and 46,XY gonadal dysgenesis and more recently with less severe phenotypes, including preliminary descriptions in severe forms of male factor infertility. Far less clear is the possible involvement of NR5A1 mutations in cryptorchidism.
Retrospective cross-sectional cohort study and functional analysis of mutant proteins.
University department.
PATIENT(S): Nine hundred fifty-nine subjects, including children with cryptorchidism and adults with different semen phenotypes associated or not associated with a history of cryptorchidism.
INTERVENTION(S): None.
MAIN OUTCOME MEASURE(S): Mutation screening of NR5A1 by sequencing all exons. Functional analysis of mutant proteins by transactivation assays of CYP11A1 and CYP17A1 promoters.
RESULT(S): We identified seven undescribed and one previously described missense mutation in subjects with severe spermatogenic impairment, without (4/236, 1.7%) and with (3/85, 3.5%) a history of cryptorchidism. Newborns with cryptorchidism carry NR5A1 mutations at low frequency (0.7%), whereas no mutations were found in milder forms of infertility and normozoospermia, irrespective of the presence of cryptorchidism. The mutant proteins showed impaired transactivation of gonadal promoters. A single nucleotide polymorphism (rs1110061; c.437 G→C; p.Gly146Ala) was also associated with more severe forms of spermatogenic impairment with cryptorchidism.
CONCLUSION(S): This study, combined with what is already known about NR5A1-associated phenotypes, suggests considering mutations in this gene as a novel genetic cause of more severe forms of male factor infertility, especially when associated with a history of cryptorchidism.