Genetics and Immunology · Reproductive Genetics
Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C
Cryptorchidism is the most frequent congenital birth defect in male children and represents an important risk factor for infertility and testicular cancer. Major regulators of testicular descent are the hormones insulin-like factor 3 (INSL3) and testosterone, and disruption of these pathways might cause cryptorchidism.
To determine the frequency of genetic alterations in cryptorchidism.
Case-control study in 2 departments of pediatric surgery in Italy between January 2003 and March 2005.
Six hundred male infants with cryptorchidism. Boys were followed up for 2 to 3 years (through January 2008) and orchidopexy was performed in those who were persistently cryptorchid. We analyzed 300 noncryptorchid male children aged 1 to 4 years as controls.
Karyotype anomalies and INSL3, INSL3 receptor, and androgen receptor gene mutations.
The frequency of genetic alterations in boys with cryptorchidism was low (17/600 [2.8%; 95% confidence interval {CI}, 1.7%-4.5%]) and was significantly higher in participants with persistent cryptorchidism (16/303 [5.3%; 95% CI, 3.0%-8.4%]; P = .001) and those with bilateral cryptorchidism (10/120 [8.3%; 95% CI, 4.1%-14.8%]; P = .001) than in controls (1/300 [0.3%; 95% CI, 0.1%-0.8%]). Boys with persistent cryptorchidism had a 17-fold greater odds of having a genetic alteration (odds ratio, 16.7; 95% CI, 2.2-126.5). The most common genetic findings in those with cryptorchidism were 8 cases of Klinefelter syndrome and 5 cases of mutations in the INSL3 receptor gene. Genetic alterations were not found in boys with low birth weight or low gestational age, who had frequent spontaneous descent of the testes.
In a small percentage of the study population, there was a statistically significant association between bilateral and persistent cryptorchidism and genetic alterations, including Klinefelter syndrome and INSL3 receptor gene mutations.
Mazzilli R et al., 2026 · Journal of endocrinological investigation
Male factor could contribute, alone or in combination with female factor, to the inability to conceive in a couple in more than half of cases. The effect of male factor infertility (MFI) on embryological assisted reproductive technology (ART) outcomes remains an ongoing discussion. to evaluate the impact of MFI on embryo aneuploidy rates, to better understand the role and possible indication for Preimplantation genetic testing for aneuploidies (PGT-A), considering the role of sperm characteristics, paternal age, sperm DNA fragmentation and sperm aneuploidies. this narrative review included all available articles, published up to January 2026. Available evidence, often based on heterogeneous and old-fashioned methodologies, suggests that MFI may impair embryonic development, particularly in terms of fertilization rate and blastulation rate, more than embryo euploidy; however, a comprehensive evaluation of MFI should be integrated into clinical practice in the context of couple infertility, to also optimize the efficiency and outcomes of ART. Promising results emerged from sperm DNA fragmentation as a tool to predict embryo euploidy, but further investigations involving larger sample sizes and improved standardization are required.
Graziani A et al., 2026 · Andrology · Free to read
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.
Scala A et al., 2026 · Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · Free full text on PubMed Central
In transgender adults, reference-gender choice alters Z-scores and fracture-risk estimates. Z-scores differ by 0.4-0.6 SD, with male references identifying more individuals with low BMD for age, especially in those assigned male at birth. Dual-reference reporting is advisable until further evidence becomes available. Transgender individuals, especially those assigned male at birth (AMAB), exhibit lower bone mineral density (BMD) compared with the cisgender population. Interpretation of densitometric data is challenging, as the choice of reference gender can significantly influence Z-scores and fracture risk scores. This study aims to evaluate the impact of the gender reference database (male or female) on the assessment of BMD and fracture risk in transgender adults prior to gender-affirming hormone therapy (GAHT). We conducted a cross-sectional analysis of 249 transgender individuals (153 assigned female at birth - AFAB and 96 AMAB) aged 18-43 years, recruited in the Hospitals of Padua and Brescia (Italy). Z-scores were calculated using both male and female reference databases and FRAX scores were computed using both gender inputs. Associations with anthropometric, biochemical, and hormonal parameters were explored. Z-scores differed systematically depending on the reference gender, with mean ΔZ ranging 0.4-0.6 SD across skeletal sites. Switching reference databases frequently led to reclassification of BMD status. AMAB individuals showed a higher prevalence of low BMD for age, particularly when assessed against male references (27.1%), whereas AFAB participants generally maintained normal BMD. However, FRAX scores remained low. BMI and 25-OH vitamin D levels were independent predictors of BMD and Z-scores in AMAB individuals. The choice of reference gender significantly influences densitometric interpretation in young transgender adults. Until further evidence becomes available, calculating Z-scores using both male and female reference databases is advisable. Early preventive interventions remain essential to preserve bone health.
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.
Marin P et al., 2001 · Journal of endocrinological investigation
Cryptorchidism is the most frequent congenital anomaly of the urogenital tract in the male, but its etiology is for the most part unknown. Evidence suggests that a possible genetic cause may be involved. Animal models support this hypothesis, and in particular INSL3 (Leydig insulin-like 3 hormone) has been proposed as putative gene for cryptorchidism, since male mice mutant for Insl3 exhibit bilateral abdominal cryptorchidism due to alteration of gubernaculum development. In this study, we analyzed whether mutations in INSL3 could be associated with human cryptorchidism. Heteroduplex analysis and sequencing of both exons of INSL3 in 65 ex-cryptorchid patients and a group of control subjects allowed us to find four nucleotide changes in the sequence of exon I. These mutations are all single base substitutions from G to A at position 27, 96, 126 and 178. Only the 178G-->A substitution changes codon 60 from alanine to threonine (A60T). All mutations were found in comparable distribution in ex-cryptorchid patients and non-cryptorchid men. Therefore, all mutations represent neutral polymorphisms not associated with phenotype. This study confirms previous observations and demonstrates a novel polymorphism in the INSL3 gene. In contrast to that described for the mutant mouse, these data indicate that mutations of INSL3 do not seem to represent a frequent cause of cryptorchidism.
Foresta C et al., 1999 · The Journal of clinical endocrinology and metabolism
To clarify whether cryptorchidism might be the expression of an intrinsic congenital testicular abnormality, we investigated the frequency of Y chromosome long arm (Yq) microdeletions in unilateral excryptorchid subjects manifesting an important bilateral testiculopathy. Microdeletion analysis of Yq was performed by polymerase chain reaction in the following 40 unilateral excryptorchid patients with azoospermia or severe oligozoospermia due to a bilateral severe testiculopathy (Sertoli cell-only syndrome or severe hypospermatogenesis); 20 unilateral excryptorchid men with moderate oligozoospermia and a normal testicular cytological picture in the contralateral testis; 110 patients affected by idiopathic severe primary testiculopathies; 20 patients affected by idiopathic moderate testiculopathy; and, as controls, 50 patients affected by known causes of testiculopathy and 100 fertile men. Eleven of 40 (27.5%) unilateral excryptorchid patients affected by bilateral testiculopathy and 28 of 110 (25.4%) patients affected by idiopathic severe primary testiculopathy showed Yq microdeletions, whereas no microdeletions were found in all the other subjects, nor in male relatives of patients with deletions. Microdeletions were located in different parts of Yq, including known regions involved in spermatogenesis (DAZ and RBM, AZFa, b, and c) and other loci still poorly defined. No difference in localization of deletions was evident between cryptorchid and idiopathic patients. Microdeletions in Yq may be responsible for severe bilateral testicular damage that could be phenotypically expressed by unilateral cryptorchidism, as well as by idiopathic infertility.
Ferlin A et al., 2015 · Fertility and sterility
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.
Foresta C et al., 1999 · Annali italiani di medicina interna : organo ufficiale della Societa italiana di medicina interna
We investigated the possible role of Y chromosome microdeletions in regions previously shown to be important for male germ cell development in unilateral ex-cryptorchid subjects manifesting important bilateral testiculopathy, in order to clarify whether cryptorchidism could be the expression of an intrinsic congenital testicular abnormality. Microdeletion analysis of the Y chromosome long arm was performed by polymerase chain reaction and confirmed by Southern blot in 40 selected unilateral ex-cryptorchid patients with azoospermia or severe oligozoospermia sustained by severe bilateral testiculopathy (Sertoli cell-only syndrome and severe hypospermatogenesis, respectively), 20 unilateral ex-cryptorchid men with moderate oligozoospermia and normal function of the descended testis, 110 patients affected by severe idiopathic primary testiculopathies, 20 patients affected by moderate idiopathic testiculopathy and, as controls, 50 patients affected by known causes of testiculopathy and 50 fertile controls. Eleven out of the 40 (27.5%) unilateral ex-cryptorchid patients affected by bilateral testiculopathy and 28 out of 110 (25.4%) patients affected by severe idiopathic primary testiculopathy showed microdeletions in the Y chromosome long arm, while all other subjects were normal. Male relatives of patients with deletions were also normal. Microdeletions were distributed in different regions of the Y chromosome long arm, including known regions involved in spermatogenesis (DAZ and RBM genes, AZFa, b and c regions) and other still poorly defined loci. No difference in localization of deletions was evident between ex-cryptorchid and idiopathic patients. Microdeletions in the Y chromosome may be responsible for bilateral severe testicular damage: the clinical consequence, other than idiopathic azoospermia and severe oligozoospermia, may also be unilateral cryptorchidism, probably due to altered testicular responses to mechanisms regulating testicular descent.
