Graziani A et al., 2026·Journal of clinical medicine·Free full text on PubMed Central
Erectile dysfunction (ED) is increasingly recognized as an early manifestation of systemic vascular disease and might represent a window for cardiovascular risk assessment. Dynamic penile colour Doppler ultrasound (PCDU) provides quantitative arterial and venous parameters that could reflect subclinical vascular impairment. We investigated the association between PCDU parameters and estimated cardiovascular risk in men with ED. In this single-center retrospective observational study, 275 men undergoing PCDU for ED were evaluated. Clinical characteristics, biochemical data, and QRISK3 10-year cardiovascular risk scores were collected. Mean peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were analyzed. Correlation analyses, logistic regression using a QRISK3 ≥ 10% threshold, linear regression models, age-stratified analyses, and receiver operating characteristic (ROC) curve analyses were performed. Patients with impaired PSV (<35 cm/s) were older and exhibited higher QRISK3 scores and a greater prevalence of diabetes mellitus and previous cardiovascular events. Mean PSV was inversely correlated with QRISK3 (r = -0.203, p < 0.01) and was associated with higher cardiovascular risk categories in unadjusted logistic regression (β = -0.016, p = 0.048), but not after adjustment for age and diabetes mellitus. ROC analysis showed modest discrimination of increased cardiovascular risk (AUC = 0.60). The addition of PSV to a model including age and diabetes resulted in minimal improvement in discrimination (AUC 0.966 vs. 0.968). Age-stratified analysis demonstrated a significant association between lower PSV and higher cardiovascular risk only in patients ≤60 years. A progressive increase in QRISK3 was observed according to the number of abnormal Doppler parameters (p = 0.013). PCDU parameters reflect the overall cardiovascular risk burden in men with ED. Although not independent predictors beyond traditional risk factors, penile Doppler abnormalities might identify a vascular phenotype associated with higher estimated cardiovascular risk, particularly in younger individuals. These findings support the role of comprehensive vascular assessment in selected patients with ED.
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.
Ferraioli G et al., 2026·Andrology·Free full text on PubMed Central
Classic Klinefelter syndrome (KS) is characterized by one extra X chromosome (47, XXY), leading to hypergonadotropic hypogonadism and higher risk of alterations in glycolipid homeostasis, cardiovascular diseases, and low bone mineral density. Most frequently, KS is diagnosed in adulthood because of infertility.
To investigate the potential association between the age at first visit and the presence of comorbidities in patients with KS.
In this cross-sectional retrospective study, we analyzed the data from 445 patients affected by non-mosaic 47, XXY KS and aged less than 50 years. Anthropometric measurements, biochemical and hormonal tests, semen analysis, scrotal echo-color Doppler, and dual energy X-ray absorptiometry (DXA) were performed on the patients. A subset of patients underwent testicular sperm extraction (TESE).
Age at first visit significantly correlated positively with waist circumference (WC), body mass index (BMI), blood glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, and negatively with total testosterone (TT), calculated free testosterone (cFT), calcium, phosphorus, vitamin D, and lumbar Z-score. Age at the first visit >26 years was associated with higher frequency of increased WC, BMI, and hypercholesterolemia. Among the 199 patients who underwent testicular biopsy, the mean retrieval rate was 36.2% and was higher in the younger group (<26 years).
Early diagnosis and management of KS is important for preventing or reducing comorbidities later in life. In particular, glycemic, lipid, and phospho-calcium metabolism worsen with advancing age at first visit. Furthermore, early management of the patient seems to be associated with a higher probability of recovering spermatozoa through TESE.
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.
Cosci I et al., 2025·Frontiers in pharmacology·Free full text on PubMed Central
Immune checkpoint inhibitors (ICIs), namely, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody Ipilimumab and anti- and programmed cell death 1 (PD-1) monoclonal antibodies Nivolumab, and Pembrolizumab, have improved the treatment outcomes for many other cancer types. However, their impact on fertility remains under-explored.
The possible direct effects of ICIs on human sperm was investigated. Spermatozoa from ten normozoospermic donors were exposed to Ipilimumab, Nivolumab, or Pembrolizumab at concentrations ranging from 1 to 100 ng/mL. Sperm motility was assessed through standard laboratory process. Cell viability and apoptosis markers were evaluated by flow-cytometry using fluorescent Annexin-V probe and Terminal Uridine Nick-End Label (TUNEL) assays. Protein-A-purified therapeutic antibodies (IgG) were also evaluated.
Spermatozoa had high PD-1 (>99%) and negligible CTLA-4 expression. Exposure to ICIs, was associated with a concentration-dependent impairment of sperm motility, noticeable for Pembrolizumab and Ipilimumab since 10 ng/mL, and for Nivolumab since 100 ng/mL. However, no significant effect on cell apoptosis or viability was shown. Purified IgG from ICIs maintained the adverse effect on cell motility without affecting viability.
ICIs, specifically Pembrolizumab, Nivolumab, and Ipilimumab, adversely affect human sperm motility in vitro. Further research is required to understand the underlying mechanisms and clinical implications.
Petre GC et al., 2025·Nutrients·Free full text on PubMed Central
Background/Objectives: Male infertility is multifactorial, involving genetic, environmental, lifestyle, and medical factors. Recent research has underscored the influence of lifestyle choices, such as dietary habits, smoking, alcohol abuse, and metabolic disturbances, on sperm quality. In this context, nutrition plays a pivotal role: adherence to a healthy diet like the Mediterranean Diet (MD), which emphasizes seasonal, fresh, and whole foods, has been linked to improved sperm performance. Conversely, a high intake of ultra-processed foods (UPFs), characterized by additives, high levels of sugars, fats, and salt, and a nutrient-poor profile, may impair sperm quality. Based on data supporting the reproductive health benefits of the MD, this observational cross-sectional study aimed at evaluating the possible relationship between MD adherence, assessed using the 14-point a priori Mediterranean Diet Adherence Screener (MEDAS) and intake of ultra-processed foods (UPFs), based on the NOVA classification, and sperm quality in 358 individuals (mean age 34.6 ± 9.3 years) who spontaneously referred to our center of reproductive medicine. Semen analyses were performed according to the WHO 2021 criteria. Hormonal profiles (FSH, LH, testosterone, SHBG, bioavailable testosterone, and calculated free testosterone) were also determined. MD adherence score was significantly and positively correlated with semen parameters, whilst negatively correlated with FSH and LH levels. In contrast, UPF intake was correlated with poor semen parameters, whilst no association was observed with hormonal levels. Multivariate analyses confirmed these associations and showed the independency from age and BMI. Notably, among men with FSH levels < 8 IU/mL, higher quartiles of UPF intake had lower markers of sperm quality, particularly for viability and typical morphology. Differently, high MD adherence scores were associated with high quality sperm parameters even when FSH levels were >8 IU/mL. This study provides evidence that the adherence to MD, and conversely reduced intake of ultra-processed foods, is associates with a better semen profile. These findings suggest the possible role of dietary interventions as a modifiable factor in the management of male infertility.
Petre GC et al., 2023·Nutrients·Free full text on PubMed Central
Infertility, affecting 15 to 25% of couples in the most developed countries, is recognized by the World Health Organization as a public health issue at a global level. Different causes are acknowledged to reduce fertility in both sexes. In particular, about 40-50% of cases recognize a male factor. Dietary habits and lifestyle are acknowledged to influence sperm quality and are therefore important modifiable factors in male reproductive health. Conditions such as overweight/obesity, impaired glucose metabolism and determinants of metabolic syndrome, together with unhealthy lifestyle behavior, i.e., smoking cigarettes and physical inactivity, are suggested to have a negative impact on male fertility. While individual elements and characteristics of the Western diet and habits are considered risk factors for male infertility, the Mediterranean diet (MD) seems to promote reproductive potential for improving sperm quality. It is also interesting to note that previous observational studies reported a positive correlation between the consumption of the single food classes of the MD pattern (i.e., vegetables and fruits, poultry, fish and seafood, whole grains, low-fat dairy products) and the quality of several sperm parameters. To evaluate the relationship between sperm parameters and MD adherence, we performed a cross-sectional study on the seminal data of 300 males (mean age 34.6 ± 9.1 years) who spontaneously referred to our center of reproductive medicine. The evaluation of adherence to MD was performed with a validated 14-point Mediterranean Diet Adherence Screener (MEDAS) questionnaire. Our findings showed that sperm parameters such as sperm count, motility, viability and normal morphology are significantly and positively correlated with MEDAS, independently of BMI and age. In addition, the application of an ROC curve on MEDAS value vs. seminal alterations identified 6.25 as the score threshold value below which altered sperm parameters were more likely to occur [AUC = 0.096 (CI: 0.059-0.133; p < 0.00)]. Therefore, adhering to the MD with at least a MEDAS score of 6.26 increases the probability of normozoospermia. Moreover, subjects who had a MEDAS value lower than 6.25 had an Odds Ratio of 6.28 (CI = 3.967-9.945) for having at least one altered sperm parameter compared to those who were more adherent to the MD. In conclusion, our findings show that a higher adherence to the MD is associated with better semen parameters, in particular in relation to sperm count, sperm concentration, typical sperm morphology, and sperm progressive motility.
Pappalardo C et al., 2023·Frontiers in cell and developmental biology·Free full text on PubMed Central
Environmental pollutants are claimed to be major factors involved in the progressive decline of the fertility rate worldwide. Exposure to the heavy metal Cadmium (Cd) has been associated with reproductive toxicity due to its ionic mimicry. However, the possible direct accumulation of Cd in human sperm cells has been poorly investigated. In this study, we aimed to clarify the possible direct effect of Cd exposure on sperm function through the analysis of its cell accumulation. Semen samples from 30 male subjects residing in high environmental impact areas and adhering to the "Exposoma e Plurifocalità nella Prevenzione Oncologica" campaign for testis cancer prevention were compared with semen samples from 15 males residing in low exposure areas. Semen levels and cell Cd content were quantified by inductively coupled plasma (ICP) spectroscopy. Cell Cd distribution was assessed by scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS). The impact of Cd on sperm function was evaluated by the in vitro exposure to the heavy metal, whilst possible scavenging approaches/agents were assessed. In addition to higher values of semen Cd, exposed subjects showed a reduction in total motile sperm fraction compared to not-exposed controls (59.6% ± 13.6% vs. 66.3% ± 7.3%, p = 0.037). Semen Cd levels were also significantly correlated with SEM-EDS signals of Cd detected on the head and neck of sperm (respectively p = 0.738, p < 0.001 and ρ = 0.465, p < 0.001). A total of 2 h of in vitro exposure to 0.5 μM Cd was associated with a significant reduction of sperm progressive motility. Scavenging approaches with either hypo-osmotic swelling or 10 μM reduced glutathione were ineffective in blunting cell Cd and restoring motility. The reduction of exposure levels appears to be the main approach to reducing the reproductive issues associated with Cd.
Garolla A et al., 2021·Andrology·Free full text on PubMed Central
Scrotal color Doppler ultrasonography and transrectal ultrasonography provide crucial information about the clinical status of testes and male accessory glands.
To analyze the impact of ultrasound in the evaluation of infertile males.
A total of 1120 records from infertile men were retrospectively evaluated (from January 2016 up to June 2020). Data on physical examination, semen analysis, sperm culture, scrotal color Doppler ultrasonography and transrectal ultrasonography, as well as sex hormones were analyzed. Among them, 238 reports from oligozoospermic/azoospermic infertile patients (P) fulfilling the inclusion criteria were considered for data analysis. Patients were subdivided into two groups according to follicle-stimulating hormone (FSH) values (Pa with FSH < 8 U/L and Pb with FSH ≥ 8 U/L). Sixty-three fertile volunteers (mean ± SD years) were enrolled as controls (C).
A higher prevalence of ultrasound abnormalities was recorded in P compared to C. Pb group had significantly lower bitesticular volume compared to Pa and C. Pa had a higher prevalence of transrectal ultrasonography abnormalities than Pb (69.9% vs. 38.4%), whereas Pb had a higher prevalence of abnormalities at scrotal color Doppler ultrasonography (60.0% vs. 28.3%, both p < 0.01). Bitesticular volume was inversely proportional to the number of altered seminal parameters and able to predict gonadotropin levels. A bitesticular volume <17 cc was associated with a higher risk of azoospermia (odds ratio = 1.799). Intratesticular vascularization was inversely correlated with gonadotropin levels and directly correlated with sperm count. A higher prevalence of prostate and seminal vesicle alterations was detected in patients and in Pa group, when compared with Pb group.
Ultrasound abnormalities are correlated with seminal parameters and may guide the clinician in the diagnostic workflow of male infertility, suggesting spermatogenesis impairment or genital tract obstructions.
Vitagliano A et al., 2021·Nutrients·Free full text on PubMed Central
Infertility is the condition of about 15% of couples that cannot get a conception after one year of unprotected sexual intercourse. In females, the reduced reproductive capacity underlies the most varied causes. Dietary supplements (DS) might be used to improve the pregnancy rate and a wide range of DS are proposed today to support female fertility. Although many authors demonstrated the positive effect of some of these products, the real efficacy of this approach is still debated. In order to evaluate the potential efficacy of DS for female infertility, we analysed the products marketed in Italy, using an original approach. A review of literature was performed to evaluate the effect of nutraceuticals on various female reproductive outcomes and to detect the minimal effective daily dose (mED) able to improve at least one of these. Thereafter, we conceived a formula to classify the expected efficacy of each DS. Each DS was scored and included into three classes of expected efficacy: higher, lower, and none. Ten out of 24 supplements (41.7%) resulted in the higher and 8 (34.3%) in the lower efficacy group, the remaining 6 DS (25.0%) were expected to have no efficacy. DS marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence of efficacy. These findings raise serious doubt about the potential effectiveness of most commercial DS for female infertility.
Garolla A et al., 2021·Frontiers in endocrinology·Free full text on PubMed Central
Dietary supplements (DS) for male infertility marketed in Italy were evaluated for composition, concentration of ingredients, and recommended daily dose. A systematic review of literature identified ingredients potentially effective on sperm parameters and their minimal effective daily dose (mED).
This study was conducted in order to critically evaluate the composition and efficacy of DS marketed in Italy.
DESIGN This was a systematic review of randomized controlled trials.
A formula allowed us to classify the expected efficacy of each DS, based on composition. Each DS was scored and included into three classes of expected efficacy: high, low, and none.
Among 24 supplements, 3 (12.5%) fall in high, 9 (37.5%) in lower, and 12 (50.0%) in no expected efficacy class. DS composition showed 36 substances, 18 with no literature on male fertility and 18 showing positive effect on sperm parameters, thus considered potentially active ingredients (PAI). All DS were mixtures of ingredients, containing from 2 to 17 different substances. Fifteen supplements (65.2%) contained at least 1 ingredient without evidence of efficacy and 21 formulations had PAI dosed below mED. Some PAI were associated to the improvement of specific sperm parameters.
DS were usually blends of many substances that are frequently employed at negligible dose or without any evidence of efficacy on male reproduction. Some ingredients have been demonstrated to be effective on specific sperm parameters by RCTs. We report a list of ingredients with potential efficacy on specific sperm parameters, aimed to allow a tailored use of DS.
The market of DS for male infertility offers products with potential efficacy in the improvement of sperm parameters but also many with uncertain effects. Based on current scientific literature, our study can help in the choice of DS that are more likely to be effective on specific sperm alterations, so providing the best supplementation for each patient.
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.
Flesia L et al., 2020·Sexual medicine·Free full text on PubMed Central
Young adult males are more likely to demonstrate health-risk behaviors than other individuals. The use of specific data about health-risk behaviors within this population might be important to promote effective preventive psychosocial and educational programs and interventions.
To provide a detailed description of health-related lifestyles, substance-related behaviors, and sexual habits that can negatively affect fertility, sexual sphere, and health in a large sample of Italian young adult males.
A sample comprising 2,170 males aged 18-21 years, attending the last year of high school, was administered an online questionnaire made up of 39 multiple-choice questions. The questionnaire explored health-related lifestyles, substance-related behaviors, and sexuality and sexual habits. Descriptive analyses were conducted.
The outcome measures included data about health-related lifestyles, substance-related behaviors, and sexuality and sexual habits reported by Italian young adult males.
Health-related lifestyles: 92.9% of the sample reported practicing some physical activity during the week. 90.3% declared a Mediterranean diet and 8.1% a hyperproteic diet. Substance-related behaviors: 33.8% of the sample reported having smoked tobacco at least once in their lives; among them, 71% reported current daily smoking. 40.2% declared drinking alcohol from 5 to 7 days in a week. 32.9% of the sample reported currently using a substance. Sexuality and sexual habits: 97.1% of the sample self-defined themselves as heterosexual. 73.3% of participants rated their knowledge about sexuality as "excellent/good," 58.7% about sexually transmitted infections. Only 4.8% reported having had a seminal liquid examination. Half of the sample (52.2%) declared having had sexual intercourses, in the largest proportion protected sex. 14.7% of the sample reported having at least one sexual dysfunction. 88.6% of participants reported having used pornography, 18.7% every day.
The present study highlighted the need to empower the number and efficacy of preventive interventions to promote health-related behaviors among Italian young male population. Flesia L, Cavalieri F, Angelini S, et al. Health-Related Lifestyles, Substance-Related Behaviors, and Sexual Habits Among Italian Young Adult Males: An Epidemiologic Study. Sex Med 2020;8:361-369.
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.
Male Endocrine and Genetic Factors · Genetic Causes of Male Infertility
To investigate whether sperm recovery is related to clinical features, hormone parameters and testosterone replacement therapy (TRT) in patients with Klinefelter syndrome (KS).
This study provides three interesting insights: (i) the probability to retrieve sperm is not related to testicular volume; (ii) TRT does not affect sperm retrieval rate (SRR); and (iii) reduced levels of LH and FSH represent a negative predictor of sperm retrieval in patients with TRT.
Classical KS shows a karyotype with one extra X chromosome in all of somatic cells and clinical manifestations characterized by hypergonadotropic hypogonadism and infertility.
STUDY DESIGN, We performed a retrospective cohort study. Data from 111 consecutive KS azoospermic patients undergoing testicular sperm extraction (TESE) were collected from 2005 to 2016.
PARTICIPANTS/MATERIALS, Data on anthropometric parameters, reproductive hormones and testicular volumes were collected. SRR was related to clinical characteristics and compared between TRT and untreated patients.
MAIN A total of 38 patients (34.2%) had successful sperm recovery. The comparison of clinical characteristics did not differ between patients with and without sperm recovery. Sperm retrieval was successful also in subjects with smaller testes. The comparison of SRR in patients with or without TRT was not different (33.3% vs 34.6%). In TRT group, LH and FSH levels were significantly lower in subjects with no sperm retrieval (P values, respectively, <.05 and <.001).
LIMITATIONS Well-designed controlled studies are necessary to confirm these data aimed to set the best therapeutic approach for fertility management in hypogonadal patients with nonmosaic KS.
Age at TESE, anthropometric measures, testis volume, sex hormones levels and semen parameters are not predictive parameters of SRR. Among TRT patients, reduced gonadotropin is related to failure in sperm retrieval.
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.
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.
Ferlin A et al., 2015·Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
This manuscript describes the role of low vitamin D in bone metabolism of Klinefelter subjects. Low vitamin D is frequent in this condition and seems to be more important than testosterone in inducing low bone mineral density (BMD) and osteoporosis. Supplementation with vitamin D restores BMD after 2 years of treatment, whereas testosterone alone seems to be ineffective.
Decreased bone mineral density (BMD) in Klinefelter syndrome (KS) is frequent, and it has been traditionally related to low testosterone (T) levels. However, low BMD can be observed also in patients with normal T levels and T replacement therapy does not necessarily increase bone mass in these patients. Nothing is known about vitamin D levels and supplementation in KS. In this study, we determine vitamin D status and bone mass in KS subjects and compare the efficacy of T therapy and vitamin D supplementation on BMD.
A total of 127 non-mosaic KS patients and 60 age-matched male controls were evaluated with reproductive hormones, 25-hydroxyvitamin D, PTH, and bone densitometry by dual-energy X-ray absorptiometry (DEXA). Patients with hypogonadism and/or 25-hydroxyvitamin D deficiency were treated with T-gel 2% and/or calcifediol and re-evaluated after 24 months of treatment.
25-hydroxyvitamin D levels were significantly lower in KS patients with respect to controls, and they had significantly lower lumbar and femoral BMD. The percentage of osteopenia/osteoporosis in subjects with 25-hydroxyvitamin D deficiency was higher with respect to subjects with normal 25-hydroxyvitamin D and was not related to the presence/absence of low T levels. Subjects treated with calcifediol or T + calcifediol had a significant increase in lumbar BMD after treatment. No difference was found in T-treated group.
These data highlight that low 25-hydroxyvitamin D levels seem to have a more critical role than low T levels in inducing low BMD in KS subjects. Furthermore, vitamin D supplementation seems to be more effective than T replacement therapy alone in increasing BMD.