Current status of fertility preservation in a Spanish tertiary public hospital: multidisciplinary approach and experience in over 1500 patients.

PURPOSE: Currently, 15% of gynaecological and 9% of haematological malignancies are diagnosed before the age of 40. The increased survival rates of cancer patients who are candidates for gonadotoxic treatments, the delay in childbearing to older ages, and the optimization of in vitro fertilisation techniques have all contributed to an increased interest in fertility preservation (FP) treatments. This study reviews the experience of the Fertility Preservation Programme (FPP) of a tertiary public hospital with a multidisciplinary approach. METHODS: This retrospective study included all the available (FP) treatments, performed in patients of childbearing age between 2006 and 2022. RESULTS: 1556 patients were referred to the FPP: 332 oocyte vitrification cycles, 115 ovarian cortex cryopreservation with 11 orthotopic autotransplantations, 175 gonadotropin-releasing hormone (GnRH) agonist treatments, 109 fertility-sparing treatments for gynaecological cancer, and 576 sperm cryopreservation were performed. Malignancy was the main indication for FP (the main indications being breast cancer in women and haematological malignancies in men), although non-oncological pathologies, such as endometriosis and autoimmune diseases, have increased in recent years. Currently, the most widely used FP technique is oocyte vitrification, the increase of which has been associated with a decrease in the use of cortex CP and GnRH agonists. CONCLUSIONS: The increase in FP treatment reflects the implementation of reproductive counselling in oncology programmes. A multidisciplinary approach in a tertiary public hospital allows individualised FP treatment for each patient. In recent years, there has been a change in trend with the introduction of new indications for FP and a change in techniques due to their optimisation.

Galectin-1, a novel promising target for outcome prediction and treatment in SCLC.

INTRODUCTION: small-cell lung cancer (SCLC) is one of the most lethal malignancies. Its management is complex due to the lack of biomarkers and limited therapies. Galectin-1 (Gal-1) plays a major role in cancer development and progression. The aim of this study is to assess whether Gal-1 has a predictive role in the disease evolution and its therapeutic potential. MATERIAL AND METHODS: The expression level of Gal-1 was examined by using a public RNA-sequencing (77 SCLC patients) and in-house immunohistochemistry (IHC) performed on biopsies from 81 patients. Survival curves and Cox regression analysis were used to assess the prognostic potential of Gal-1. In addition, a SCLC-PDX model was carried out and treated with either OTX008, an inhibitor of Gal-1, or vehicle to assess the effects of Gal-1 inhibition on this disease in vivo. RESULTS: Galectin-1 gene (LGALS1) expression showed a strong negative correlation with outcome in SCLC patients with advanced disease (p = 0.007). IHC unveiled that overall survival (OS) was significantly lower among extensive-stage SCLC (ES-SCLC) patient group with increased level of Gal-1 and platelet-to-lymphocyte ratio (PLR) (HR=3.07, 95% CI: 1.62, 5.79, p < 0.001). The SCLC-PDX model showed a significant reduction in tumor size (tumor growth inhibition [TGI] index 73%) without side effects. DISCUSSION: in this study, high levels of Gal-1 and PLR were associated with poorer OS in SCLC patients, supporting their utility as clinical prognostic biomarkers. Moreover, the in vivo model suggests the inhibition of Gal-1 as a novel potential therapy for this disease with very poor prognosis.

H4K5 Butyrylation Coexist with Acetylation during Human Spermiogenesis and Are Retained in the Mature Sperm Chromatin.

Male germ cells experience a drastic chromatin remodeling through the nucleo-histone to nucleo-protamine (NH-NP) transition necessary for proper sperm functionality. Post-translational modifications (PTMs) of H4 Lys5, such as acetylation (H4K5ac), play a crucial role in epigenetic control of nucleosome disassembly facilitating protamine incorporation into paternal DNA. It has been shown that butyrylation on the same residue (H4K5bu) participates in temporal regulation of NH-NP transition in mice, delaying the bromodomain testis specific protein (BRDT)-dependent nucleosome disassembly and potentially marking retained nucleosomes. However, no information was available so far on this modification in human sperm. Here, we report a dual behavior of H4K5bu and H4K5ac in human normal spermatogenesis, suggesting a specific role of H4K5bu during spermatid elongation, coexisting with H4K5ac although with different starting points. This pattern is stable under different testicular pathologies, suggesting a highly conserved function of these modifications. Despite a drastic decrease of both PTMs in condensed spermatids, they are retained in ejaculated sperm, with 30% of non-colocalizing nucleosome clusters, which could reflect differential paternal genome retention. Whereas no apparent effect of these PTMs was observed associated with sperm quality, their presence in mature sperm could entail a potential role in the zygote.

Histone H4 acetylation is dysregulated in active seminiferous tubules adjacent to testicular tumours.

STUDY QUESTION: Is histone H4 acetylation (H4ac) altered in the seminiferous tubules of patients affected by testicular tumours? SUMMARY ANSWER: A considerable dysregulation of H4ac was detected in the cells of the seminiferous tubules adjacent to testicular tumours of different aetiology and prior to any treatment, while no comparable alterations were observed in patients with disrupted spermatogenesis. WHAT IS KNOWN ALREADY: Altered H4ac levels have been associated with a variety of testicular pathological conditions. However, no information has been available regarding potential alterations in the spermatogenic cells adjacent to the neoplasia in testicular tumour patients. STUDY DESIGN, SIZE, DURATION: A retrospective analysis using testicular sections from 33 men aged between 21 and 74 years old was performed. Three study groups were defined and subjected to double-blind evaluation: a control group with normal spermatogenesis (n = 6), patients with testicular tumours (n = 18) and patients with spermatogenic impairments (n = 8). One additional sample with normal spermatogenesis was used as a technical internal control in all evaluations. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry against H4ac and, when needed, Placental-like alkaline phosphatase and CD117, was performed on testicular sections. The H4ac H-score, based on the percentage of detection and signal intensity, was used as the scoring method for statistical analyses. Protein expression data from the Human Protein Atlas were used to compare the expression levels of predicted secreted proteins from testicular tumours with those present in the normal tissue. MAIN RESULTS AND THE ROLE OF CHANCE: We revealed, for the first time, a dramatic disruption of the spermatogenic H4ac pattern in unaffected seminiferous tubule cells from different testicular tumour patients prior to any antineoplastic treatment, as compared to controls (P < 0.05). Since no similar alterations were associated with spermatogenic impairments and the in silico analysis revealed proteins potentially secreted by the tumour to the testicular stroma, we propose a potential paracrine effect of the neoplasia as a mechanistic hypothesis for this dysregulation. LIMITATIONS, REASONS FOR CAUTION: Statistical analyses were not performed on the hypospermatogenesis and Leydig cell tumour groups due to limited availability of samples. WIDER IMPLICATIONS OF THE FINDINGS: To the best of our knowledge, this is the first report showing an epigenetic alteration in cells from active seminiferous tubules adjacent to tumour cells in testicular tumour patients. Our results suggest that, despite presenting spermatogenic activity, the global epigenetic dysregulation found in the testicular tumour patients could lead to molecular alterations of the male germ cells. Since testicular tumours are normally diagnosed in men at reproductive age, H4ac alterations might have an impact when these testicular tumour patients express a desire for fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the European Union Marie Curie European Training Network actions and by grants to R.O. from the 'Ministerio de Economía y Competividad (Spain)' (fondos FEDER 'una manera de hacer Europa', PI13/00699, PI16/00346 and PI20/00936) and from EU-FP7-PEOPLE-2011-ITN289880. J.C. was supported by the Sara Borrell Postdoctoral Fellowship, Acción Estratégica en Salud, CD17/00109. J.C. is a Serra Húnter fellow (Universitat de Barcelona, Generalitat de Catalunya). F.B. has received grants from the Ministerio de Educación, Cultura y Deporte para la Formación de Profesorado Universitario (Spain) (FPU15/02306). A.d.l.I. is supported by a fellowship of the Ministerio de Economía, Industria y Competitividad (Spain) (PFIS, FI17/00224). M.J. is supported by the Government of Catalonia (Generalitat de Catalunya, pla estratègic de recerca i innovació en salut, PERIS 2016-2020, SLT002/16/00337). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Tratamiento antioxidante en hombres con infertilidad idiopática / Antioxidant treatment in men with idiopathic infertility

Objetivo. Los espermatozoides son vulnerables al estrés oxidativo, lo que ha llevado al uso de antioxidantes en hombres con infertilidad idiopática. Nuestro objetivo fue analizar los resultados del tratamiento antioxidante en hombres con infertilidad idiopática. Material y métodos. Estudio retrospectivo de 133 hombres con infertilidad idiopática que consultaron nuestro servicio entre 2010 y 2014. Evaluamos el número total de espermatozoides (NTE), formas progresivas (PR) y formas normales (FN) previo a tratamiento, tras 3 meses de tratamiento antioxidante y tras 3 meses más de tratamiento. Este consistió en ácido docosahexaenoico, coenzima Q10, zinc y selenio. Valoramos también la FSH e inhibinaB pretratamiento. Se utilizó el test de Wilcoxon para comparar los parámetros seminales antes y después del tratamiento y el coeficiente de correlación de Spearman para analizar la correlación entre variables pretratamiento y mejoría seminal. Resultados. La edad fue de 36,8±5,1 años y los valores de inhibinaB y FSH, de 128,5±66ng/l y 7±7U/l, respectivamente. Había 35 (26,3%) oligozoospérmicos, 99 (74,4%) astenospérmicos y 23 (17,2%) teratospérmicos. Encontramos mejoría significativa en el NTE, las PR y las FN tras 3 meses de antioxidantes respecto a los valores pretratamiento. Valores pretratamiento más bajos de NTE, PR y FN se correlacionaron con una mayor mejoría en el NTE (rs: −0,31; p=0,004), PR (rs: −0,27; p=0,002) y FN (rs: −0,48; p<0,001), respectivamente. No hubo correlación entre los valores hormonales y los resultados del tratamiento. Conclusiones. Los hombres con infertilidad idiopática pueden beneficiarse de 3 meses de tratamiento antioxidante. Aquellos con mayores alteraciones en el seminograma podrían obtener un mayor beneficio del tratamiento (AU)

Objective. Spermatozoa are susceptible to oxidative stress, which has lead to the use of antioxidants in men with idiopathic infertility. Our objective was to analyze results of antioxidant treatment in men with idiopathic infertility. Material and methods. Retrospective study of those 133 consecutive men with idiopathic infertility who attended our department between 2010-2014. We collected data about total sperm number (TSN), progressive forms (PF) and normal forms (NF) previous to treatment, after 3 months of antioxidant treatment and after 3 more months of treatment. We also assessed FSH and inhibinB levels before treatment. Antioxidant treatment was based on docosahexaenoic acid, coenzyme Q10, zinc and selenium. Wilcoxon test for paired samples was performed to compare semen parameters before and after treatment and Spearman's rank correlation coefficient to analyze any correlation between pretreatment variables and seminal improvement. Results. Mean age was 36.8±5.1 years. InhibinB and FSH values were 128.5±66ng/l and 7±7U/l, respectively. There were 35 (26.3%) oligozoospermic, 99 (74.4%) asthenospermic and 23 (17.2%) teratospermic patients. We found significant improvement in TSN, PF and NF after 3 months compared to before treatment. Lower pretreatment levels of TSN, PF percentage and NF percentage significantly correlated with a greater improvement of TSN (rs: −0.31; p=0.004), PF percentage (rs: −0.27; p=0.002) and NF percentage (rs: −0.48; p<0.001), respectively. No correlation was found between pretreatment hormonal values and results of treatment. Conclusions. Men with idiopathic infertility can benefit from 3 months of antioxidants. Those with greater deficiencies in sperm analysis could benefit the most from treatment (AU)

Efecto de la administración de un complejo de antioxidantes en pacientes afectos de astenoteratozoospermia idiopática / Effect of the administration of an antioxidant complex in patients with idiopathic asthenoteratozoospermia

Introducción: El factor masculino se observa en casi el 50% de las parejas que acuden a consulta por dificultades reproductivas, y puede ser consecuente a una disminución en el número de espermatozoides (oligozoospermia) o a una diminución en su calidad por defectos en su movilidad (astenozoospermia) o en su morfología (teratozoospermia). Existen diversos estudios que relacionan estos defectos de calidad espermática con alteraciones en la fragmentación del ADN espermático y plantean el posible efecto beneficioso de tratamientos antioxidantes, si bien existe una gran disparidad en los resultados obtenidos. Objetivos: A fin de contribuir a esclarecer el posible efecto beneficioso de la administración empírica de antioxidantes, en el presente trabajo abordamos el estudio del efecto de la administración de un complejo antioxidante (Androferti® Laboratorios Q Pharma), en pacientes afectos de astenoteratozoospermia idiopática. Pacientes y métodos: Para ello, se incluyeron un total de 69 varones a los que se administró el tratamiento antioxidante, a dosis de 1,5 g/día, durante tres meses. Concluido el tratamiento, se detectó una mejoría significativa en la movilidad (la movilidad global a+b pasó de 22,04 a 28,95%; p = 0,001) y en la morfología (las formas normales pasaron de 9,86 a 14,78%; p < 0,001). Discusión: Numerosas publicaciones refieren efectos beneficiosos, mediante la administración de sustancias antioxiadantes, sobre la fragmentación de ADN espermático, lo que se podría traducir en una mejoría de la calidad seminal y embrionaria, en caso de gestación. Nuestro estudio se halla en la misma línea, mostrando una mejoría en la mayoría de los parámetros seminales como consecuencia de la administración de L-carnitina asociada a otras sustancias de acción antioxidante, tratamiento que parece ser especialmente eficaz en pacientes más jóvenes. Conclusiones: Nuestros resultados confirman el efecto beneficioso de la administración de un complejo de antioxidantes en pacientes afectos de astenoteratozoospermia idiopática mejorando la calidad seminal y, en consecuencia, favoreciendo la deseada gestación (AU)

Introduction: The male factor is seen in almost 50% of the couples attending a reproductive clinic, and may be a result of a decrease in sperm count (oligozoospermia) or in sperm quality due to mobility defects (asthenozoospermia) or in its morphology (teratozoospermia). There are several studies that related the these sperm quality defects with the presence of sperm DNA fragmentation and suggest the possible beneficial effect of antioxidant treatments, although there is wide disparity in the results obtained. Objectives: We have studied the effect of the administration of an antioxidant complex (Androferti® Laboratory Q Pharma) in patients with idiopathic asthenoteratozoospermia in order to contribute to the clarification of the possible beneficial effect of the empirical administration of antioxidants, in the present work. Patients and methods: A total of 69 males in whom the antioxidant treatment was administered at a day dose of 1.5 g for 3 months were included. After completing the treatment, significant improvement was detected in sperm mobility (global mobility a+b improved from 22.04% to 28.95%; p = 0.001) and sperm morphology (the normal forms increased from 9.86 % to 14.78%, p <0.001). Discussion: Numerous publications have reported the beneficial effects of administering antioxidant substances on sperm DNA fragmentation. These effects could be translated into an improvement in semen and embryo quality, in case of pregnancy. Our study is in line with these finding, showing an improvement in most of the seminal parameters resulting from the administration of L-carnitine in association with other antioxidants, a treatment that appears to be particularly effective in younger patients. Conclusions: Our results confirm the beneficial effect of the administration of an antioxidant complex in patients with idiopathic asthenoteratozoospermia, this improving their sperm quality, consequently favoring the desired pregnancy (AU)

NADP-malate dehydrogenase from unicellular green alga Chlamydomonas reinhardtii. A first step toward redox regulation?

The determinants of the thioredoxin (TRX)-dependent redox regulation of the chloroplastic NADP-malate dehydrogenase (NADP-MDH) from the eukaryotic green alga Chlamydomonas reinhardtii have been investigated using site-directed mutagenesis. The results indicate that a single C-terminal disulfide is responsible for this regulation. The redox midpoint potential of this disulfide is less negative than that of the higher plant enzyme. The regulation is of an all-or-nothing type, lacking the fine-tuning provided by the second N-terminal disulfide found only in NADP-MDH from higher plants. The decreased stability of specific cysteine/alanine mutants is consistent with the presence of a structural disulfide formed by two cysteine residues that are not involved in regulation of activity. Measurements of the ability of C. reinhardtii thioredoxin f (TRX f) to activate wild-type and site-directed mutants of sorghum (Sorghum vulgare) NADP-MDH suggest that the algal TRX f has a redox midpoint potential that is less negative than most those of higher plant TRXs f. These results are discussed from an evolutionary point of view.

Recurrencia uretral de carcinoma transicional en varon cistectomizado

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