Showing papers by "Csilla Krausz published in 2019"
TL;DR: Meta-regression analysis demonstrated that SRR per cycle was independent of age and hormonal parameters at enrolment, but the SRR increased as a function of testis volume, while micro-TESE/mTESE in subjects with NOA results in SRRs of up to 50%, with no differences when cTESE was compared to mTESE.
Abstract: BACKGROUND: Factor affecting sperm retrieval rate (SRR) or pregnancy rates (PR) after testicular sperm extraction (TESE) in patients with non-obstructive azoospermia (NOA) have not been systematically evaluated. In addition, although micro-TESE (mTESE) has been advocated as the gold standard for sperm retrieval in men with NOA, its superiority over conventional TESE (cTESE) remains conflicting. OBJECTIVE AND RATIONALE: The objective was to perform a meta-analysis of the currently available studies comparing the techniques of sperm retrieval and to identify clinical and biochemical factors predicting SRR in men with NOA. In addition, PRs and live birth rates (LBRs), as derived from subjects with NOA post-ICSI, were also analysed as secondary outcomes. SEARCH METHODS: An extensive Medline, Embase and Cochrane search was performed. All trials reporting SRR derived from cTESE or mTESE in patients with NOA and their specific determinants were included. Data derived from genetic causes of NOA or testicular sperm aspiration were excluded. OUTCOMES: Out of 1236 studies, 117 studies met the inclusion criteria for this study, enrolling 21 404 patients with a mean age (± SD) of 35.0 ± 2.7 years. cTESE and mTESE were used in 56 and 43 studies, respectively. In addition, 10 studies used a mixed approach and 8 studies compared cTESE with mTESE approach. Overall, a SRR per TESE procedure of 47[45;49]% (mean percentage [95% CI]) was found. No differences were observed when mTESE was compared to cTESE (46[43;49]% for cTESE versus 46[42;49]% for mTESE). Meta-regression analysis demonstrated that SRR per cycle was independent of age and hormonal parameters at enrolment. However, the SRR increased as a function of testis volume. In particular, by applying ROC curve analysis, a mean testis volume higher than 12.5 ml predicted SRR >60% with an accuracy of 86.2% ± 0.01. In addition, SRR decreased as a function of the number of Klinefelter's syndrome cases included (S = -0.02[-0.04;-0.01]; P < 0.01. I = 0.12[-0.05;0.29]; P = 0.16). Information on fertility outcomes after ICSI was available in 42 studies. Overall, a total of 1096 biochemical pregnancies were reported (cumulative PR = 29[25;32]% per ICSI cycle). A similar rate was observed when LBR was analysed (569 live births with a cumulative LBR = 24[20;28]% per ICSI cycle). No influence of male and female age, mean testis volume or hormonal parameters on both PR and LBR per ICSI cycle was observed. Finally, a higher PR per ICSI cycle was observed when the use of fresh sperm was compared to cryopreserved sperm (PR = 35[30;40]%, versus 20[13;29]% respectively): however, this result was not confirmed when cumulative LBR per ICSI cycle was analysed (LBR = 30[20;41]% for fresh versus 20[12;31]% for cryopreserved sperm). WIDER IMPLICATIONS: This analysis shows that cTESE/mTESE in subjects with NOA results in SRRs of up to 50%, with no differences when cTESE was compared to mTESE. Retrieved sperms resulted in a LBR of up to 28% ICSI cycle. Although no difference between techniques was found, to conclusively clarify if one technique is superior to the other, there is a need for a sufficiently powered and well-designed randomized controlled trial to compare mTESE to cTESE in men with NOA.
151 citations
TL;DR: The diagnostic performance of sequencing a gene panel based on genes associated with mouse azoospermia was relatively successful in idiopathic NOA patients and allowed the discovery of two novel genes involved in NOA due to meiotic arrest.
Abstract: Study question What is the diagnostic potential of next generation sequencing (NGS) based on a 'mouse azoospermia' gene panel in human non-obstructive azoospermia (NOA)? Summary answer The diagnostic performance of sequencing a gene panel based on genes associated with mouse azoospermia was relatively successful in idiopathic NOA patients and allowed the discovery of two novel genes involved in NOA due to meiotic arrest. What is known already NOA is a largely heterogeneous clinical entity, which includes different histological pictures. In a large proportion of NOA, the aetiology remains unknown (idiopathic NOA) and yet, unknown genetic factors are likely to play be involved. The mouse is the most broadly used mammalian model for studying human disease because of its usefulness for genetic manipulation and its genetic and physiological similarities to man. Mouse azoospermia models are available in the Mouse Genome Informatics database (MGI: http://www.informatics.jax.org/). Study design, size, duration The first step was to design of a 'mouse azoospermia' gene panel through the consultation of MGI. The second step was NGS analysis of 175 genes in a group of highly selected NOA patients (n = 33). The third step was characterization of the discovered gene defects in human testis tissue, through meiotic studies using surplus testicular biopsy material from the carriers of the RNF212 and STAG3 pathogenic variants. The final step was RNF212 and STAG3 expression analysis in a collection of testis biopsies. Participants/materials, setting, methods From a total of 1300 infertile patients, 33 idiopathic NOA patients were analysed in this study, including 31 unrelated men and 2 brothers from a consanguineous family. The testis histology of the 31 unrelated NOA patients was as follows: 20 Sertoli cell-only syndrome (SCOS), 11 spermatogenic arrest (6 spermatogonial arrest and 5 spermatocytic arrest). The two brothers were affected by spermatocytic arrest. DNA extracted from blood was used for NGS on Illumina NextSeq500 platform. Generated sequence data was filtered for rare and potentially pathogenic variants. Functional studies in surplus testicular tissue from the carriers included the investigation of meiotic entry, XY body formation and metaphases by performing fluorescent immunohistochemical staining and immunocytochemistry. mRNA expression analysis through RT-qPCR of RNF212 and STAG3 was carried out in a collection of testis biopsies with different histology. Main results and the role of chance Our approach was relatively successful, leading to the genetic diagnosis of one sporadic NOA patient and two NOA brothers. This relatively high diagnostic performance is likely to be related to the stringent patient selection criteria i.e. all known causes of azoospermia were excluded and to the relatively high number of patients with rare testis histology (spermatocytic arrest). All three mutation carriers presented meiotic arrest, leading to the genetic diagnosis of three out of seven cases with this specific testicular phenotype. For the first time, we report biallelic variants in STAG3, in one sporadic patient, and a homozygous RNF212 variant, in the two brothers, as the genetic cause of NOA. Meiotic studies allowed the detection of the functional consequences of the mutations and provided information on the role of STAG3 and RNF212 in human male meiosis. Limitations, reasons for caution All genes, with the exception of 5 out of 175, included in the panel cause azoospermia in mice only in the homozygous or hemizygous state. Consequently, apart from the five known dominant genes, heterozygous variants (except compound heterozygosity) in the remaining genes were not taken into consideration as causes of NOA. We identified the genetic cause in approximately half of the patients with spermatocytic arrest. The low number of analysed patients can be considered as a limitation, but it is a very rare testis phenotype. Due to the low frequency of this specific phenotype among infertile men, our finding may be considered of low clinical impact. However, at an individual level, it does have relevance for prognostic purposes prior testicular sperm extraction. Wider implications of the findings Our study represents an additional step towards elucidating the genetic bases of early spermatogenic failure, since we discovered two new genes involved in human male meiotic arrest. We propose the inclusion of RNF212 and STAG3 in a future male infertility diagnostic gene panel. Based on the associated testis phenotype, the identification of pathogenic mutations in these genes also confers a negative predictive value for testicular sperm retrieval. Our meiotic studies provide novel insights into the role of these proteins in human male meiosis. Mutations in STAG3 were first described as a cause of female infertility and ovarian cancer, and Rnf212 knock out in mice leads to male and female infertility. Hence, our results stimulate further research on shared genetic factors causing infertility in both sexes and indicate that genetic counselling should involve not only male but also female relatives of NOA patients. Study funding/competing interest(s) This work was funded by the Spanish Ministry of Health Instituto Carlos III-FIS (grant number: FIS/FEDER-PI14/01250; PI17/01822) awarded to CK and AR-E, and by the European Commission, Reproductive Biology Early Research Training (REPROTRAIN, EU-FP7-PEOPLE-2011-ITN289880), awarded to CK, WB, and AE-M. The authors have no conflict of interest.
59 citations
TL;DR: The screening for FANCA pathogenic variants in a specific subgroup of azoospermic patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease.
35 citations
TL;DR: There is very limited evidence that empiric therapy leads to better live birth rates, spontaneous pregnancy, or pregnancy following assisted-reproductive techniques, however, the findings should be interpreted with caution.
32 citations
TL;DR: HBO men should be considered at high cardiovascular risk like MCO men and followed-up for erectile dysfunction and prostate abnormalities overtime, and MHO is associated with subclinical ED, increased cardiovascular risk, and prostate enlargement.
29 citations
TL;DR: It is suggested that key areas of research/evidence gaps should be identified, so that appropriate funding and policy actions could be undertaken to help address key questions.
Abstract: In attempting to formulate potential WHO guidelines for the diagnosis of male infertility, the Evidence Synthesis Group noted a paucity of high‐quality data on which to base key recommendations. As a result, a number of authors suggested that key areas of research/evidence gaps should be identified, so that appropriate funding and policy actions could be undertaken to help address key questions.
26 citations
TL;DR: The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.
Abstract: Spermatogenesis is a highly complex biological process during which germ cells undergo recurrent rounds of DNA replication and cell division that may predispose to random mutational events. Hence, germ cells are vulnerable to the introduction of a range of de novo mutations, in particular chromosomal aberrations, point mutations and small indels. The main mechanisms through which mutations may occur during spermatogenesis are (i) errors in DNA replication, (ii) inefficient repair of non-replicative DNA damage between cell divisions and (iii) exposure to mutagens during lifetime. Any genetic alteration in the spermatozoa, if not repaired/eliminated, can be passed on to the offspring, potentially leading to malformations, chromosomal anomalies and monogenic diseases. Spontaneous de novo mutations tend to arise and accumulate with a higher frequency during testicular aging. In fact, there is an increased incidence of some chromosomal aberrations and a greater risk of congenital disorders, collectively termed paternal age effect (PAE), in children conceived by fathers with advanced age. PAE disorders are related to well-characterized de novo point mutations leading to a selective advantage on the mutant spermatogonial stem cells that cause a progressive enrichment over time of mutant spermatozoa in the testis.The purpose of this chapter is to provide a summary on the spontaneous genetic alterations that occur during spermatogenesis, focusing on their underlying mechanisms and their consequences in the offspring.
23 citations
TL;DR: Thanks to the widespread diffusion of Next-Generation Sequencing, a continuously increasing number of monogenic causes of male infertility are being discovered and their validation is currently ongoing.
Abstract: Male infertility is a multifactorial and heterogeneous pathological condition affecting 7% of the general male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2000 genes are predicted to be involved in spermatogenesis. Genetic factors have been described in each etiological category of male reproductive impairment: (1) hypothalamic–pituitary axis dysfunction; (2) quantitative and qualitative alterations of spermatogenesis; (3) ductal obstruction/dysfunction. In 25% of azoospermic and in 10% of oligozoospermic men, a genetic anomaly can be diagnosed with the current genetic testing. However, up to now, only a relatively low number of monogenic factors have a clear-cut cause–effect relationship with impaired reproductive function. Thanks to the widespread diffusion of Next-Generation Sequencing, a continuously increasing number of monogenic causes of male infertility are being discovered and their validation is currently ongoing. The identification of genetic factors is of outmost clinical importance since there is a risk of transmission of genetic defects through natural or assisted reproductive techniques. The benefit of the genetic diagnosis of infertility has an obvious clinical significance for the patient itself with implications not only for his reproductive health but in many instances also for his general health.
11 citations
TL;DR: Homozygous and compound heterozygous mutations in the GNRHR gene (4q13.2) are the most frequent genetic causes of ncHH, which causes delayed puberty and azoospermia.
Abstract: Background Normosmic congenital hypogonadotropic hypogonadism (ncHH) is caused by the deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH). Its typical clinical manifestation is delayed puberty and azoospermia. Homozygous and compound heterozygous mutations in the GNRHR gene (4q13.2) are the most frequent genetic causes of ncHH. Objectives (i) Characterization at the molecular level (genetic origin and functional effect) of a unique homozygous mutation (p.Gly99Glu) in a ncHH man; (ii) to provide a comprehensive catalog of GNRHR mutations with genotype-phenotype correlation and comparison of in vitro studies vs. in silico prediction tools. Material and methods A ncHH man and his parents, in whom we performed the following: (i) Sanger sequencing, qPCR of the GNRHR gene; (ii) chromosome 4 SNP array; and (iii) competition binding assay and inositol phosphate signaling assay. PubMed and Human Genome Mutation Database (HGMD) search for GNRHR mutations. Bioinformatic analysis of 55 reported variants. Results qPCR showed two GNRHR copies in the index case. SNP array revealed the inheritance of two homologous chromosomes 4 from the mother (maternal heterodisomy; hUPD) with two loss of heterozygosity regions, one of them containing the mutated gene (maternal isodisomy; iUPD). Functional studies for the p.Gly99Glu mutation demonstrated a right-shifted GnRH-stimulated signaling response. Bioinformatic tools show that commonly used in silico tools are poor predictors of the function of ncHH-associated GNRHR variants. Discussion Functional analysis of the p.Gly99Glu mutation is consistent with severely decreased GnRH binding affinity (a severe partial loss-of-function mutation). Complete LOF variants are associated with severe and severe/moderate phenotype, whereas partial LOF variants show wide range of clinical manifestations. Conclusion This is the first ncHH patient carrying a novel causative missense mutation of GNRHR with proven 'severe pLOF' due to maternal hUPD/iUPD of chromosome 4. Our literature review shows that functional studies remain essential both for diagnostic and potential therapeutic purposes.
10 citations
TL;DR: The predisposing effect of gr/gr deletion to TGCT as an independent risk factor from impaired spermatogenesis is reported in the largest European study population and implies regular tumour screening/follow-up in male family members of TGCT patients with gr/ Gr deletion and in infertile gr/ gr deletion carriers.
Abstract: The association between impaired spermatogenesis and TGCT has stimulated research on shared genetic factors. Y chromosome-linked partial AZFc deletions predispose to oligozoospermia and were also studied in TGCT patients with controversial results. In the largest study reporting the association between gr/gr deletion and TGCT, sperm parameters were unknown. Hence, it remains to be established whether this genetic defect truly represents a common genetic link between TGCT and impaired sperm production. Our aim was to explore the role of the following Y chromosome-linked factors in the predisposition to TGCT: (i) gr/gr deletion in subjects with known sperm parameters; (ii) other partial AZFc deletions and, for the first time, the role of partial AZFc duplications; (iii) DAZ gene dosage variation. 497 TGCT patients and 2030 controls from two Mediterranean populations with full semen/andrological characterization were analyzed through a series of molecular genetic techniques. Our most interesting finding concerns the gr/gr deletion and DAZ gene dosage variation (i.e., DAZ copy number is different from the reference sequence), both conferring TGCT susceptibility. In particular, the highest risk was observed when normozoospermic TGCT and normozoospermic controls were compared (OR = 3.7; 95% CI = 1.5–9.1; p = 0.006 for gr/gr deletion and OR = 1.8; 95% CI = 1.1–3.0; p = 0.013 for DAZ gene dosage alteration). We report in the largest European study population the predisposing effect of gr/gr deletion to TGCT as an independent risk factor from impaired spermatogenesis. Our finding implies regular tumour screening/follow-up in male family members of TGCT patients with gr/gr deletion and in infertile gr/gr deletion carriers.
9 citations
TL;DR: This patient presented with a pubertal course suggestive of a delayed puberty with gynecomastia, reduced growth rate, and infertility that need testosterone treatment to induce the appearance of the secondary sex characteristics and emphasizes the importance of appropriate management of puberty in people with 45,X/46,X,i(Yp.
Abstract: The Y-chromosome genes are primarily involved in sex determination, stature control, spermatogenesis, and fertility. Among structural rearrangements of the Y chromosome, the isochromosome of Yp, i(Yp), appears to be the most uncommon. We describe a detailed evolution of puberty in a boy with 45,X/46,X,i(Yp). Array CGH found 2 cell lines, one with i(Yp) and the other with monosomy X. Genetic analysis of currently known genes involved in Kallmann syndrome/normosomic central hypogonadotropic hypogonadism showed no abnormality. The patient presented with a pubertal course suggestive of a delayed puberty with gynecomastia, reduced growth rate, and infertility that need testosterone treatment to induce the appearance of the secondary sex characteristics. This patient shows the potential effects of i(Yp) and emphasizes the importance of appropriate management of puberty in people with 45,X/46,X,i(Yp). Early hormone treatment, concerns regarding fertility, emotional support, and a successful transition to adult care may help improve the physical and psychosocial well-being of affected patients.
TL;DR: There is very limited evidence that empiric therapy leads to improved live birth rates, spontaneous pregnancy or pregnancy following assisted-reproductive techniques, as a number of studies were judged to be either at high or unclear risk of bias for many domains.
TL;DR: The President of EAA, Ewa Rajpert-De Meyts, edited a commemorative book to offer you insights into the history of the EAA and summarize the achievements of the Academy, which was a remarkable success with a record number of participants from more than 50 different countries.
Abstract: Dear EAA Members, Let me begin by expressing my deepest gratitude to all of you for giving me the opportunity to undertake my second mandate as the President of EAA. I have served our community in this important position since 2014 with the precious help of an excellent Executive Council composed of Dimitrios Goulis (Secretary), Hermann Behre (Treasurer), Gert Dohle, Andrea Isidori, Osvaldo Rajmil, Wolfgang Weidner, Jorma Toppari (Past President), Ewa Rajpert-De Meyts (2014–16, ex-Editor-in-Chief, Andrology) and Manuela Simoni (since 2017, current Editor-in-Chief of Andrology). The new election, which took place in Budapest during the European Congress of Andrology (ECA 2018), led to the renewal of the Executive Council. The two new officers are Ewa Rajpert-De Meyts (Secretary) and Frank T€ uttelmann (Treasurer), and the new Council members are Davor Je zek (Croatia), Zsolt Kopa (Hungary) and Eduard Ruiz Casta~ n e (Spain). Our Congress in Budapest (11–13 October 2018) was a special event, not only because it was the 10th ECA but also because it coincided with the 25th anniversary of the EAA. For this occasion, I edited a commemorative book to offer you insights into the history of the EAA and summarize the achievements of the Academy. The electronic version of the EAA book is now available on the Academy’s website. On the occasion of this special anniversary, some of our Academicians have been honoured for their outstanding contributions to the EAA: Eberhard Nieschlag, Ilpo Huhtaniemi, Jorma Toppari, Ewa Rajpert-De Meyts and Gy€ orgy Papp. For the second time, a meeting of the Directors of EAA Training Centres took place just before ECA 2018, allowing an open discussion on EAA educational strategies. The training centres are the backbone of the EAA and indeed, they were promoters of the outstanding EAA activities, such as educational courses and summer schools. I am proud to announce that this year we had the largest ever number of applicants for the EAA Clinical Andrologist examination, clearly reflecting the constantly increasing interest of young MDs in our field and the excellent work carried out in the EAA centres. These activities resulted in a growing number of EAA Members and I warmly welcome all the new Members who joined the EAA in 2018. To promote education, we have increased the number of scholarships and travel grants available for young EAA Members. ECA 2018 was a remarkable success with a record number of participants from more than 50 different countries. ECA represents a unique scientific forum in Europe, entirely dedicated to all aspects of andrology, thus providing a platform for interaction between clinical andrologists with different backgrounds (endocrinology, urology, gynaecology and dermatology) and basic/translational scientists. A significant number of non-European delegates attended the Congress. Their presence underlined the fact that the EAA Congress is the leading biennial scientific event not only for European andrologists. My sincere gratitude goes to the Chairman of the Local Organising Committee, Zsolt Kopa and his team, who have organized this meeting with great dedication, giving all attendees an unforgettable ECA 2018. I would also like to thank the Members of the Programme Organising Committee, chaired by Dimitrios Goulis, with vice-Chairmen Giovanni Corona and Rafael Oliva, for the excellent scientific programme which has been highly appreciated by the attendees. [Correction added on March 29, 2019, after online publication: the name Giuseppe Corona has been corrected to Giovanni Corona.] At the ECA 2018, we have further strengthened our collaboration with the ESAU by organizing three joint EAA/ESAU courses. In this regard, I would like to thank the Chairman of ESAU, Professor Nikolaos Sofikitis for his support. Finally, it is my pleasure to inform you that our next ECA will take place in M€ unster in early December 2020 and will be held together with the 12th International Congress of Andrology (ICA). We are now approaching the end of 2018, a year full of scientific breakthroughs and outstanding events. I am confident that 2019 will be a busy and productive year and will bring a series of new activities. I would like to involve all of you in this innovating process,
TL;DR: This research presents a novel and scalable approach that combines traditional and innovative approaches to provide real-time information about the immune system’s response to prolapse preoperatively and over the course of treatment.
Abstract: D. T. Carrell, M. Simoni, C. Krausz and G. L. Gerton Departments of Surgery (Urology) and Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA, Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy, Sexual Medicine and Andrology Unit, Department of Clinical and Experimental Biosciences ‘Mario Serio’, University of Florence, Florence, Italy, and Department of Obstetrics and Gynecology, Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA