Marco Ghezzi
University of Padua
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Featured researches published by Marco Ghezzi.
Fertility and Sterility | 2015
Alberto Ferlin; Maria Santa Rocca; Cinzia Vinanzi; Marco Ghezzi; Andrea Di Nisio; Carlo Foresta
OBJECTIVE 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. DESIGN Retrospective cross-sectional cohort study and functional analysis of mutant proteins. SETTING 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.
The Journal of Sexual Medicine | 2012
Daniela Zuccarello; Marco Ghezzi; Manuel Pengo; Monica Forzan; Anna Chiara Frigo; Alberto Ferlin; Carlo Foresta
INTRODUCTION Premature ejaculation (PE) is defined as the inability of men to control ejaculation and it is the most prevalent male sexual dysfunction. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic (5-hydroxytryptamine [5-HT]) system. A genetic etiology of PE in humans was stated accounting for around 30%. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT or serotonin transporter [SERT]), the major regulator of serotonergic neurotransmission, have been linked with the pathogenesis of PE and associated with the clinical response to therapy with contrasting results. AIM In order to establish a possible pathogenetic link between PE and SLC6A4 polymorphisms, we analyzed the 5-HTT-linked polymorphic region (5-HTTLPR), rs25531, and STin2 polymorphisms in 121 patients affected by lifelong and acquired PE. METHODS Polymerase chain reaction (PCR)-based technology followed by restriction fragment length polymorphism (RFLP) analysis. MAIN OUTCOME MEASURES Intravaginal ejaculatory latency time was measured by stopwatch in order to diagnose PE, and the results of the SLC6A4 polymorphisms analysis in PE patients was compared with the control group. RESULTS Genotype frequencies for 5-HTTLPR, rs25531, and STin2 for both patients and controls showed no significant deviation from Hardy-Weinberg equilibrium. No statistically significant differences were found in the frequency of SLC6A4 gene polymorphisms in PE patients vs. controls, or in lifelong PE patients vs. controls, or acquired PE patients vs. controls, or lifelong PE vs. acquired PE patients. The obtained data were contrasting with three out of four previously published reports. CONCLUSIONS The present results indicate that no difference exists in SLC6A4 polymorphisms frequency between PE patients and controls. A comparison with the previously published reports on this field is reported.
The Journal of Clinical Endocrinology and Metabolism | 2016
Luca De Toni; Andrea Di Nisio; Elena Speltra; Maria Santa Rocca; Marco Ghezzi; Daniela Zuccarello; Nunzio Turiaco; Alberto Ferlin; Carlo Foresta
CONTEXT 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. OBJECTIVE 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. METHODS 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. RESULTS 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. CONCLUSION 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.
Fertility and Sterility | 2016
Andrea Garolla; Bruno Engl; Damiano Pizzol; Marco Ghezzi; Alessandro Bertoldo; Alberto Bottacin; Marco Noventa; Carlo Foresta
OBJECTIVE To evaluate the reproductive outcome of infertile couples undergoing assisted reproduction techniques (ART) with or without human papillomavirus (HPV) semen infection. DESIGN Cross-sectional clinical study. SETTING Units of andrology, reproductive medicine, and gynecology. PATIENT(S) A total of 226 infertile couples. INTERVENTION(S) Male partners were evaluated by means of fluorescence in situ hybridization (FISH) for HPV on semen. After a diagnostic period, female partners underwent intrauterine insemination (IUI) or intracytoplasmic sperm injection (ICSI). MAIN OUTCOME MEASURE(S) Seminal parameters and FISH analysis for HPV in sperm head. Spontaneous or assisted pregnancies, live births, and miscarriages were recorded. Statistical analysis included unpaired Student t test and chi-square test. RESULT(S) Fifty-four male partners (23.9%) had HPV semen infection confined to sperm, confined to exfoliated cells, or in both cells. During the diagnostic period, noninfected couples showed spontaneous pregnancies. IUI and ICSI treatments were performed in, respectively, 60 and 98 noninfected and in 21 and 33 infected couples, with 38.4% and 14.2% cumulative pregnancy rates, respectively. The follow-up of pregnancies showed a higher miscarriage rate in infected couples (62.5% vs. 16.7%). Ongoing pregnancies of the latter group were characterized by HPV infection confined to exfoliated cells. CONCLUSION(S) A reduction in natural and assisted cumulative pregnancy rate and an increase in miscarriage rate are related to the presence of HPV at sperm level. Although the exact mechanism by which sperm infection is able to impair fertility remains unclear, this aspect is worthy of further investigations. If confirmed, these results could change the clinical and diagnostic approach to infertile couples.
Frontiers in Endocrinology | 2012
Andrea Garolla; Damiano Pizzol; Alessandro Bertoldo; Marco Ghezzi; Umberto Carraro; Alberto Ferlin; Carlo Foresta
Testicular cancer represents the more frequent solid tumor affecting males aged 15–35 years. In the last decades, its incidence showed a progressive increased probably due to genetic and environmental factors. Despite exposure to some viruses such as HIV, HCV, EBV, and HPV is frequently related to cancer development, there are no studies aimed to evaluate the possible implication of viral infections in the pathogenesis of testicular cancer. In this study, we analyzed sperm parameters and prevalence of HPV on sperm in 155 testicular cancer patients at diagnosis (T−1), after orchiectomy (T0) and after 12 months from surgery or from the end of adjuvant treatments (T12). All patients showed a significantly higher prevalence of semen infection than controls (9.5% and 2.4% respectively,) and altered sperm parameters both at T−1 and T0. Considering sperm parameters, at T−1 we observed a reduction of progressive motility, and after orchiectomy patients showed a reduction of sperm concentration and count and a further worsening of motility. Thereafter, patients were assigned to three groups on the basis of medical option after surgery: S = surveillance, R = radiotherapy, and C = chemotherapy +/− radiotherapy. At T12, untreated patients had an improvement of sperm parameters while R group and even more C group had a strong decrease of sperm number (p < 0.01 both vs. T0 and S group). Moreover, patients who received radio and/or chemotherapy had a very high prevalence of HPV semen infection (S = 7.7%, R = 30.8%, and C = 61.5%). In conclusion, patients with testicular cancer had frequently altered sperm parameters and higher prevalence of HPV semen infection that were worsened after radio and chemotherapy. Because HPV infection is a risk factor for cancer development and it may further reduce fertility, we suggest screening for HPV in testicular cancer patients at diagnosis and particularly after adjuvant treatments.
Endocrine | 2017
Andrea Garolla; Marco Ghezzi; Ilaria Cosci; Barbara Sartini; Alberto Bottacin; Bruno Engl; Andrea Di Nisio; Carlo Foresta
The purpose of this study is to evaluate whether follicle-stimulating hormone treatment improves sperm DNA parameters and pregnancy outcome in infertile male candidates to in-vitro fertilization.Observational study in 166 infertile male partners of couples undergoing in-vitro fertilization. Eighty-four patients were receiving follicle-stimulating hormone treatment (cases) and 82 refused treatment (controls). Semen parameters, sexual hormones, and sperm nucleus (fluorescence in-situ hybridization, acridine orange, TUNEL, and γH2AX) were evaluated at baseline (T0) and after 3 months (T1), when all subjects underwent assisted reproduction techniques. Statistical analysis was performed by analysis of variance.Compared to baseline, cases showed significant improvements in seminal parameters and DNA fragmentation indexes after follicle-stimulating hormone therapy (all P < 0.05), whereas no changes were observed in controls. Within cases, follicle-stimulating hormone treatment allowed to perform intrauterine insemination in 35 patients with a pregnancy rate of 23.2 %. Intracytoplasmic sperm injection was performed in all controls and in 49 patients from cases, with pregnancy rates of 23.2 and 40.8 %, respectively (P < 0.05). After 3 months (T0 vs. T1) of follicle-stimulating hormone therapy, cases with positive outcome had reduced DNA fragmentation index and lower double strand breaks (P < 0.05 and P < 0.001 vs. negative outcome, respectively).In this observational study, we showed that follicle-stimulating hormone treatment improves sperm DNA fragmentation, which in turn leads to increased pregnancy rates in infertile males undergoing in-vitro fertilization. In particular, double strand breaks (measured with γH2AX test) emerged as the most sensible parameter to follicle-stimulating hormone treatment in predicting reproductive outcome.
Frontiers in Pharmacology | 2016
Marco Ghezzi; Massimiliano Berretta; Alberto Bottacin; Pierfrancesco Palego; Barbara Sartini; Ilaria Cosci; Livio Finos; Riccardo Selice; Carlo Foresta; Andrea Garolla
Young males have testicular germ cells tumors (TGCT) as the most common malignancy and its incidence is increasing in several countries. Besides unilateral orchiectomy (UO), the treatment of TGCT may include surveillance, radiotherapy, or chemotherapy (CT), basing on tumor histology and stage of disease. It is well known that both radio and CT may have negative effects on testicular function, affecting spermatogenesis, and sex hormones. Many reports investigated these aspects in patients treated with bleomycin, etoposide, and cisplatin (BEP), after UO. In contrast no data are available on the side effects of carboplatin treatment in these patients. We included in this study 212 consecutive subjects who undergone to sperm banking at our Andrology and Human Reproduction Unit after UO for TGCT. Hundred subjects were further treated with one or more BEP cycles (BEP-group), 54 with carboplatin (CARB group), and 58 were just surveilled (S-group). All patients were evaluated for seminal parameters, sperm aneuploidy, sperm DNA, sex hormones, volume of the residual testis at baseline (T0) and after 12 (T1) and 24 months (T2) from UO or end of CT. Seminal parameters, sperm aneuploidies, DNA status, gonadic hormones, and testicular volume at baseline were not different between groups. At T1, we observed a significant reduction of sperm concentration and sperm count in the BEP group versus baseline and versus both Carb and S-group. A significant increase of sperm aneuploidies was present at T1 in the BEP group. Similarly, the same group at 1 had altered sperm DNA integrity and fragmentation compared with baseline, S-group and Carb group. These alterations were persistent after 2 years from the end of BEP treatment. Despite a slight improvement at T2, the BEP group had still higher percentages of sperm aneuploidies than other groups. No impairment of sperm aneuploidies and DNA status were observed in the Carb group both after 1 and 2 years from the end of treatment. Despite preliminary, these data demonstrate that in selected patients with TGCTs CT with carboplatin represents a therapeutic option that that seems to not affect sex hormones, spermatogenesis, and sperm nucleus.
EBioMedicine | 2015
Carlo Foresta; Andrea Garolla; Saverio Giuseppe Parisi; Marco Ghezzi; Alessandro Bertoldo; Andrea Di Nisio; Luca De Toni
BACKGROUND Semen represents a reservoir for human papillomavirus (HPV), rising concern in couples eligible for assisted reproduction techniques (ART). Humoral immunity against HPV is considered to protect from reinfection. We investigated the impact of vaccination on virus clearance in a cohort of infertile male patients showing HPV semen infection. METHODS 179 out of 619 infertile patients, showing HPV-DNA detection in semen by FISH analysis,were enrolled. Subjectswere split into 91 vaccine-sensitive (VSPs) and 88 nonvaccine-sensitive patients (NVSPs) by INNO-LiPA. 19 VSPs showed vaccine-type specific seroconvesion at recruitment. All patients underwent specific counselling. 42 seronegative VSPs were randomly assigned to receive quadrivalent vaccination in 6 months, whilst 49 VSPs, 19 seroconverted and 30 seronegative, served as controls. The prevalence of HPV-DNA semen infection and serology was studied in a follow-up of 24 months. RESULTS Compared to seronegative patients, VSP seroconverted at recruitment showed absence of multiple infections and reduced prevalence of HPV semen infection at 12 (P = 0.039), 18 (P = 0.034) and 24 months (P = 0.034) of follow-up. Vaccinated VSP showed improved healing (P = 0.001 at 6 months and P b 0.001 at 12 months vs seroconverted VSP), achieving clearance in 12 months. DISCUSSION Humoral immunity has a major role in healing from HPV infection. Elder ART patients with HPV semen infection may benefit by the union of both specific counselling and available prophylactic vaccination.
Human Reproduction | 2015
Andrea Garolla; Barbara Sartini; Ilaria Cosci; Damiano Pizzol; Marco Ghezzi; Alessandro Bertoldo; Massimo Menegazzo; Elena Speltra; Alberto Ferlin; Carlo Foresta
STUDY QUESTION Is there a difference between molecular karyotype of single sperm selected by high-magnification microscopy from infertile patients with testicular damage and from proven fertile controls? SUMMARY ANSWER The molecular karyotype of single sperm from patients with testiculopathy had a significantly higher percentage of chromosomal alterations than fertile controls. WHAT IS KNOWN ALREADY Infertile patients with testicular impairment have many sperm with aneuploidies and/or increased structural chromosome alterations. In these patients, sperm use by ICSI has poor outcome and raises concerns about the possible impact on pregnancy loss and transmission of genes abnormalities in offspring. High-magnification microscopy has been recently introduced to select morphologically better sperm aimed at improving ICSI outcome. However, there are no studies evaluating the molecular karyotype of sperm selected by this method. STUDY DESIGN, SIZE, DURATION Three consecutive infertile patients with oligozoospermia due to testicular damage and three age-matched proven fertile men attending a tertiary care center, were enrolled in the study from September to November 2014. Inclusion criteria of patients were age ≥30 ≤35 years, at least 2 years of infertility, oligozoospermia (sperm count below 10 million), reduced testicular volumes high FSH plasma levels and absence of altered karyotype, Y chromosome microdeletions, cystic fibrosis transmembrane conductance regulator gene mutations, sperm infections, cigarette smoking, varicocele, obesity. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were evaluated for sperm parameters, sex hormones and testicular color-doppler ultrasound. From each semen sample, 20 sperm with large vacuoles (LVs), 20 with small vacuoles (SVs) and 20 with no vacuoles (NVs) were retrieved individually by a micromanipulator system. Each cell was further analyzed by whole genome amplification and array comparative genomic hybridization (aCGH). MAIN RESULTS AND THE ROLE OF CHANCE The aCGH allowed us to detect chromosomal aneuploidies, unbalanced translocations and complex abnormalities. Sperm selected from infertile patients showed a higher percentage of abnormal molecular karyotypes than controls (19.4 versus 7.7%, respectively, P < 0.001). In particular, sperm with LV and SV showed 38.3 and 20.0% abnormal karyotype in infertile men versus 18.3 and 5.0% in controls, respectively (both P < 0.01). Complex abnormalities were found only in the LV category. An abnormal karyotype was never found in NV sperm from both patients and controls. LIMITATIONS REASONS FOR CAUTION The main limitation of this study is the low number of included subjects. Moreover, a time of writing we have no data regarding the ICSI outcome using LV, SV or NV sperm. This is the first study evaluating the molecular karyotype of single sperm selected by high-magnification microscopy and further confirmation of the data is needed. WIDER IMPLICATIONS OF THE FINDINGS Our data showed that sperm from infertile patients with testicular impairment have a higher percentage of abnormal molecular karyotypes than sperm from fertile controls. Therefore, if confirmed, our data suggest that the use of individually retrieved NV sperm may improve ICSI outcome in infertile men with testicular damage.
The Journal of Clinical Endocrinology and Metabolism | 2018
Andrea Di Nisio; Luca De Toni; Maria Santa Rocca; Marco Ghezzi; Riccardo Selice; Giuseppe Taglialavoro; Alberto Ferlin; Carlo Foresta
Context The regulation of bone mass by the testis is a well-recognized mechanism, but the role of Leydig-specific marker insulin-like 3 peptide (INSL3) on the most abundant bone cell population, osteocytes, is unknown. In this study, we aimed to investigate the relationship between INSL3 and sclerostin, an osteocyte-specific protein that negatively regulates bone formation. Design Serum sclerostin and INSL3 levels were evaluated in Klinefelter syndrome (KS) and healthy controls. In vitro effect of INSL3 on sclerostin production was evaluated in human cultured osteocytes. Patients A total of 103 KS patients and 60 age- and sex-matched controls were recruited. Main Outcome Measures Serum sclerostin and INSL3 levels were assessed by enzyme-linked immunosorbent assay. Osteocytes were isolated by fluorescence-assisted cell sorting. Sclerostin expression was evaluated by western blot, immunofluorescence, and reverse transcription polymerase chain reaction. Measurement of bone mineral density was done by dual-energy X-ray absorptiometry at lumbar spine (L1-L4) and femoral neck. Results Sclerostin levels were significantly increased in KS subjects, and negatively correlated with INSL3 levels in both cohorts and with bone mineral density in the KS group. Stimulation of cultured osteocytes with INSL3 at 10-7 M significantly decreased both sclerostin messenger RNA and protein expression. Conclusions We report a negative association between the testicular hormone INSL3 and the osteocytic negative regulator of bone formation, sclerostin. We further explored this association in vitro and showed that INSL3 was able to reduce sclerostin expression. These results add further knowledge on the emerging role of sclerostin as a therapeutic target for osteoporosis treatment.