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BACKGROUND: Once a mate choice decision has been made, couples that fail to reach a live birth in natural and/or intrauterine insemination (IUI) cycles will likely visit fertility clinics seeking assisted reproductive technology (ART) treatment. During the more or less prolonged period of infertility experienced, those couples with mild/moderate reproductive anomalies would have advantage over couples displaying more severe reproductive alterations in achieving a natural or IUI conception. Thus, we can expect to find a progressive increase in the proportion of couples with more severe reproductive anomalies as duration of infertility rises. In this study, we aim to ascertain whether there is an association between male and female infertility diagnoses and duration of infertility in couples seeking ART treatment for the first time. METHODS: A cross-sectional analysis of 1383 infertile couples that sought ART treatment for the first time. Forward-stepwise binary logistic regression analyses were applied to calculate exponentiated regression coefficients. RESULTS: Men suffering from any combination of oligo-, astheno-, and teratozoospermia (ACOAT) exhibited higher odds of having a duration of infertility > 2 years compared with non-ACOAT men [odds ratio (95% confidence interval): 1.340 (1.030-1.744)]. Women from ACOAT couples displaying a duration of infertility > 2 years presented shorter menstrual cycles (P ≤ 0.047) and lower antral follicular count (AFC) values (P ≤ 0.008) and serum anti-Müllerian hormone (AMH) levels (P ≤ 0.007) than women from non-ACOAT couples exhibiting > 2 years of infertility. Likewise, AFC values (P ≤ 0.013) and serum AMH levels (P ≤ 0.001) were decreased when compared with women from ACOAT couples displaying ≤ 2 years of infertility. A relative low but significant percentage of ACOAT couples displaying > 2 years of infertility stood out for their smoking habits. CONCLUSIONS: Couples consisting of ACOAT men and women with a relative low ovarian reserve are overrepresented in couples seeking ART treatment for the first time after experiencing > 2 years of infertility. This outcome leads us to develop a general hypothesis proposing that the origin of couple's infertility is a consequence of a process of positive assortative mating shaped by sexual selection forces.

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OBJECTIVE: To determine whether assisted reproductive technology (ART) treatment adds obstetric and neonatal risks over and above that of underlying infertility-related diagnoses. DESIGN: Retrospective study of linked ART, birth certificate, hospital discharge data, and outpatient insurance claims data in Massachusetts (2013-2017). SETTING: Database. PATIENT(S): Singleton deliveries in women with and without diagnoses of tubal disease, polycystic ovarian syndrome (PCOS), other ovulatory conditions, or endometriosis, identified from the insurance claims and ART data. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): ART and non-ART pregnancy and delivery outcomes were compared with each other and with women with no history of infertility or usage of fertility treatment (fertile group). Generalizing estimating equations with Poisson distribution and exchangeable correlation structure were used to obtain adjusted relative risk ratios (aRRs) and 95% confidence intervals (CIs). RESULT(S): Infertility-related diagnoses significantly increased the risks of pregnancy hypertension (PCOS: aRR, 1.13, 95% CI 1.00-1.27), preeclampsia/eclampsia (tubal: aRR 1.28, 95% CI 1.02-1.61; PCOS: aRR 1.23, 95% CI 1.06-1.43; other ovulatory: aRR 1.11, 95% CI 1.02-1.20), gestational diabetes (tubal: aRR 1.28, 95% CI 1.08-1.50; PCOS: aRR 1.58, 95% CI 1.42-1.75; other ovulatory: aRR 1.19, 95% CI 1.12-1.26), and placental problems (tubal aRR 1.47, 95% CI 1.11-1.94), as well as low birthweight and prematurity, compared with deliveries from the fertile group. Within each diagnosis, the use of ART consistently increased the risk of placental problems (aRR 1.49-2.86) but varied for other conditions. CONCLUSION(S): Our study demonstrated that compared with the fertile group, risk was elevated in pregnancies and deliveries from women with tubal, PCOS, other ovulatory, and endometriosis diagnoses who did/did not undergo ART treatment. Placental abnormalities were particularly elevated in ART compared to non-ART deliveries having the same diagnosis.

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The fertilizing spermatozoon is a highly specialized cell that selects from millions along the female tract until the oocyte. The paternal components influence the oocyte activation during fertilization and are fundamental for normal embryo development; however, the sperm-oocyte interplay is in a continuous debate. This review aims to analyze the available scientific information related to the role of the male gamete in the oocyte activation during fertilization, the process of the interaction of sperm factors with oocyte machinery, and the implications of any alterations in this interplay, as well as the advances and limitations of the reproductive techniques and diagnostic tests. At present, both PLCζ and PAWP are the main candidates as oocyte activated factors during fertilization. While PLCζ mechanism is via IP3, how PAWP activates the oocyte still no clear, and these findings are important to study and treat fertilization failure due to oocyte activation, especially when one of the causes is the deficiency of PLCζ in the sperm. However, no diagnostic test has been developed to establish the amount of PLCζ, the protocol to treat this type of pathologies is broad, including treatment with ionophores, sperm selection improvement, and microinjection with PLCζ protein or RNA.

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Resumen ANTECEDENTES: Chlamydia trachomatis es uno de los principales microorganismos de trasmisión sexual asociado de manera importante con infertilidad femenina. La detección de genotipos y nuevas variantes de Chlamydia trachomatis permite conocer su prevalencia, distribución geográfica, identificar la aparición de resistencia antimicrobiana y las asociaciones clínicas o comportamientos sexuales y desarrollar vacunas. Este caso clínico es el primer informe de infección endocervical por una cepa diferente a C trachomatis. CASO CLÍNICO: Paciente de 25 años, con diagnóstico de infertilidad primaria de 2 años de evolución por factor endocrino-ovárico (sobrepeso e hipotiroidismo subclínico) y por factor masculino de hipospermia y teratozoospermia. El cultivo microbiológico endocervical detectó la infección por Ureaplasma spp y Chlamydia spp. La identificación de la cepa de Chlamydia mediante secuenciación del gen 16S del ARNr informó que era Chlamydia pneumoniae. La existencia de un plásmido en esta cepa de C pneumoniae confirmó que la infección endocervical fue por una cepa de Chlamydia pneumoniae no humana. CONCLUSIÓN: Este caso clínico sugiere la posibilidad de que una cepa de C pneumoniae no humana sea capaz de trasmitirse sexualmente a los humanos, estar circulando en la población mexicana y causar infertilidad, aunque aún se desconocen el origen y la dirección de la trasmisión.

Abstract BACKGROUND: Chlamydia trachomatis is one of the leading sexually transmitted microorganisms that is significantly associated with the development of female infertility. The detection of genotypes and new variants ofChlamydia trachomatisallows us to know their prevalence and geographic distribution, identify the appearance of antimicrobial resistance, clinical associations, or sexual behaviors, and develop vaccines. This clinical case reports for the first time endocervical infection by a strain other thanC. trachomatis. CLINICAL CASE: A 25-year-old woman with primary infertility of 2 years of evolution due to endocrine-ovarian factor (overweight and subclinical hypothyroidism) and male factor characterized by hypospermia and teratozoospermia. Endocervical microbiological culture detected infection byUreaplasma urealyticumandChlamydiaspp. Identification of theChlamydiastrain by sequencing the 16S rRNA gene reported that it wasChlamydia pneumoniae. The presence of plasmid in this strain ofC. pneumoniaeconfirmed that the endocervical infection was by a non-humanChlamydia pneumoniaestrain. CONCLUSION: This clinical case suggests that a non-human strain ofC. pneumoniaecan be sexually transmitted to humans, circulating in the Mexican population, and causing infertility, although the origin and direction of transmission are still unknown.

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Tubal diseases are responsible for 25% to 35% of female infertility. Laparoscopic chromopertubation is the gold standard for assessing tubal patency when female infertility is suspected. Intravasation is a complication of intrauterine procedures involving the passage of fluid filling the uterine cavity into the bloodstream through endometrial vessels (from the myometrial veins to the uterine venous plexuses). This complication has been described during hysterosalpingography and sonohysterosalpingography. We herein present a report of three cases in which severe intravasation occurred during laparoscopic chromopertubation using methylene blue as a contrast agent. The intravasation manifested as green urine (i.e., the "green urine sign"). The presence of methylene blue in the urine and blood was confirmed by laboratory tests. All three patients had risk factors for intravasation as described in the literature (unilateral or bilateral tubal obstruction, endometriosis, and previous intrauterine procedures for Mullerian duct anomalies and Asherman's syndrome). The green urine sign appeared a few hours after laparoscopic chromopertubation and spontaneously resolved after 24 hours. Cystoscopy was performed to rule out bladder injury. All three patients required only clinical observation.

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Capsule: This expert opinion summarizes current knowledge on risk factors for infertility and identifies a practical clinical and diagnostic approach for the male and female partners of an infertile couple aimed to improve the investigation and management of fertility problems. Background: Infertility represents an important and growing health problem affecting up to 16% of couples worldwide. In most cases, male, female, or combined factor can be identified, and different causes or risk factors have been related to this condition. However, there are no standardized guidelines on the clinical-diagnostic approach of infertile couples and the recommendations concerning infertility are sometimes lacking, incomplete, or problematic to apply. Objective: The aim of this work is to provide an appropriate clinical and diagnostic pathway for infertile couples designed by a multidisciplinary-team of experts. The rationale is based on the history and physical examination and then oriented on the basis of initial investigations. This approach could be applied in order to reduce variation in practice and to improve the investigation and management of fertility problems. Methods: Prominent Italian experts of the main specialties committed in the ART procedures, including gynecologists, andrologists, embryologists, biologists, geneticists, oncologists, and microbiologists, called "InfertilItaly group", used available evidence to develop this expert position. Outcomes: Starting from the individuation of the principal risk factors that may influence the fertility of females and males and both genders, the work group identified most appropriate procedures using a gradual approach to both partners aimed to obtain a precise diagnosis and the most effective therapeutic option, reducing invasive and occasionally redundant procedures. Conclusions: This expert position provides current knowledge on risk factors and suggests a diagnostic workflow of infertile couples. By using this step-by-step approach, health care workers involved in ART, may individuate a practical clinical management of infertile couples shared by experts.

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Sirtuins are a family of deacetylases that modify structural proteins, metabolic enzymes, and histones to change cellular protein localization and function. In mammals, there are seven sirtuins involved in processes like oxidative stress or metabolic homeostasis associated with aging, degeneration or cancer. We studied gene expression of sirtuins by qRT-PCR in human mural granulosa-lutein cells (hGL) from IVF patients in different infertility diagnostic groups and in oocyte donors (OD; control group). Study 1: sirtuins genes' expression levels and correlations with age and IVF parameters in women with no ovarian factor. We found significantly higher expression levels of SIRT1, SIRT2 and SIRT5 in patients ≥40 years old than in OD and in women between 27 and 39 years old with tubal or male factor, and no ovarian factor (NOF). Only SIRT2, SIRT5 and SIRT7 expression correlated with age. Study 2: sirtuin genes' expression in women poor responders (PR), endometriosis (EM) and polycystic ovarian syndrome. Compared to NOF controls, we found higher SIRT2 gene expression in all diagnostic groups while SIRT3, SIRT5, SIRT6 and SIRT7 expression were higher only in PR. Related to clinical parameters SIRT1, SIRT6 and SIRT7 correlate positively with FSH and LH doses administered in EM patients. The number of mature oocytes retrieved in PR is positively correlated with the expression levels of SIRT3, SIRT4 and SIRT5. These data suggest that cellular physiopathology in PR's follicle may be associated with cumulative DNA damage, indicating that further studies are necessary.

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OBJECTIVE: To compare the occurrence and degree of stress attributed to life events during childhood/adolescence and adulthood between individuals diagnosed with infertility and presumably fertile individuals, and to examine the effect of life events occurrence and stress levels on an infertility diagnosis. BACKGROUND: Although stress has been explored as a consequence of the experience of infertility, its role as a predictor of this disease still lacks research, particularly regarding the use of adequate control groups composed of non-parents. METHODS: The final sample had 151 infertile subjects (74 males and 77 females) and 225 presumably fertile participants (95 males and 130 females), who completed a questionnaire indicating occurrence (y/n) and degree of stress of life events (1-5) during childhood/adolescence and adulthood. RESULTS: Significant differences regarding occurrence were found in seven stressful life events in men and in nine events in women, with infertile groups presenting higher occurrence than presumably fertile groups. Eleven stressful life events were rated differently by men and women regarding the degree of stress, with group significant differences observed in both directions. While most events were rated as more stressful by infertile men, infertile women reported less stress resulting from these events than presumably fertile women. After controlling for age, the degree of stress induced by life events in childhood/adolescence and adulthood were not significant predictors of infertility diagnosis, for both men and women. CONCLUSION: The amount of stress associated with earlier or concurrent life events does not seem to be related with infertility. Further prospective research is needed to validate these findings.

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STUDY QUESTION: Can a standardized assessment of abnormal human sperm morphology provide additional useful information by identifying men with more severe disturbances in different types of abnormalities? SUMMARY ANSWER: Definition-based categorization of sperm head, midpiece and tail defects has shown how differently these abnormalities are distributed in fertile men and other groups of men, thus providing high and low thresholds, a starting point for diagnosis or research purposes. WHAT IS KNOWN ALREADY: Several recent studies have reported indisputable genetic origins for various sperm defects. A few studies have also identified associations between environmental factors and low percentages of morphologically normal spermatozoa. Nevertheless, with the exception of rare situations in which the vast majority of spermatozoa have specific, easily characterized defects, such as 'globozoospermia', little attention has been paid to the description and precise quantification of human sperm abnormalities. The lack of standardization in the phenotyping of sperm morphological defects by conventional microscopy is a limiting factor for diagnosis and for intra- or inter-observer or centre consistency in studies investigating the causal factors and possible functional consequences of the abnormalities detected. There are currently no baseline data for abnormalities of sperm morphology based on a standardized classification, in the general population, among fertile or other groups of men. STUDY DESIGN, SIZE, DURATION: This study is based on detailed sperm abnormality datasets acquired by a standardized classification method, from several groups of men, over the same 5-year period. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied cross-sectional data from fertile men (n = 926), male partners from infertile couples (n = 1747) and testicular cancer patients (n = 239). We used a standardized classification to analyse Shorr-stained slides, taking into account all the abnormalities encountered. MAIN RESULTS AND THE ROLE OF CHANCE: Most sperm defects were significantly more frequent in infertile than in fertile men, with 20-30% of infertile men having frequencies of abnormalities above the 95th percentile in fertile men for 9 out of the 15 categories of abnormalities. Interestingly, several head abnormalities were significantly more frequent in patients with testicular cancer than in infertile men, highlighting the particular impact of this condition on sperm morphogenesis. We used the 95th percentile in fertile men as the lower threshold and the 99th percentile in infertile men as an extreme upper threshold, for the classification of morphological abnormality frequencies into three levels: low, intermediate and high. The assessment of several semen samples, with or without a genetic background, for abnormal sperm morphology, based on the percentage of normal spermatozoa, a teratozoospermia index, and the detailed profile of abnormalities categorized according to the three levels proposed, has highlighted the value of detailed phenotyping for diagnosis and research purposes. LIMITATIONS, REASONS FOR CAUTION: The thresholds proposed for the various categories of sperm abnormality should be considered relative rather than absolute, owing to the known sampling error related to the limited number of spermatozoa assessed per sample, or when studying the general population or populations from regions other than Western Europe. The standardized assessment of abnormal sperm morphology requires time and experience. We therefore suggest that this assessment is carried out during a first andrological check-up or for epidemiological or research studies, rather than in the routine management of infertile couples for assisted reproductive technologies. WIDER IMPLICATIONS OF THE FINDINGS: The study design used for the fertile group of men was similar to that previously used for the WHO reference values, providing a rationale for considering the 95th percentile in fertile men as the level below which abnormalities may be considered to occur at a frequency representing random background variations of a normal spermiogenesis process. The crude frequencies obtained, and the three levels of abnormality frequency proposed for each standardized category of sperm defect, provide baseline data useful for diagnosis and a starting point for future studies aiming to identify associations with genetic or environmental factors. STUDY FUNDING/COMPETING INTERESTS: Part of this study was supported by contract BMH4-CT96-0314 from the European Union. The authors have no competing interests to declare.

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Horses are characterized as having a greater rate of chromosomal abnormalities than other species, which are mainly related to the sex chromosome pair and produce a series of different anomalies known as disorders in sexual development (DSD). In the present study, three Pura Raza Española (PRE) and one Menorquín (MEN) horses were studied and an incompatibility in their genetic and phenotypic sex were detected. Animals were karyotyped by conventional and molecular cytogenetic analyses and characterized using genomic techniques. Although all individuals, were totally unrelated, these animals had the same abnormality (64,XY SRY negative DSD) despite having an anatomically normal external mare phenotype. Therefore, this syndrome could remain undiagnosed in a large percentage of cases because the physiological and morphological symptoms are rare. In the present study, a slight gonadal dysgenesis was observed only in older individuals. Interestingly this chromosomal abnormality has been previously reported less than twenty times, and never in the PRE or MEN horses. With the present research, it is demonstrated that the use of genetic and cytogenetic diagnostic tools in veterinary practice could be an important complementary test to determine the origin of unexplained reproductive failures among horses.

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Sex chromosome aberrations are known to cause congenital abnormalities and unexplained infertility in horses. Most of these anomalies remain undiagnosed because of the complexity of the horse karyotype and the lack of specialized laboratories that can perform such diagnoses. On the other hand, the utilization of microsatellite markers is a technique widely spread in horse breeding, mostly because of their usage in parentage tests. We studied the usage of a novel combination of diagnostic approaches in the evaluation of a very uncommon case of chromosomal abnormalities in a Spanish purebred colt, primarily detected using a commercial panel of short tandem repeat (STR) makers. Based on these results, we performed a full cytogenetic analysis using conventional and fluorescent in situ hybridization techniques with individual Equus caballus chromosome X and Equus caballus chromosome Y painting probes. We also tested the presence of two genes associated with the sexual development in horses and an extra novel panel of eight microsatellite markers specifically located in the sex chromosome pair. This is the first case report of a leukocyte chimerism between chromosomally normal (64,XY) and abnormal (63,X0) cell lines in horses. Our results indicate that the use of the short tandem repeat markers as a screening technique and as a confirmation utilizing cytogenetic techniques can be used as a very interesting, easy, and nonexpensive diagnostic approach to detect chromosomal abnormalities in the domestic horse.

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