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Telomeres are the protective structures located at the ends of linear chromosomes. They were first described in the 1930s, but their biology remained unexplored until the early 70s, when Alexey M. Olovnikov, a theoretical biologist, suggested that telomeres cannot be fully copied during DNA replication. He proposed a theory that linked this phenomenon with the limit of cell proliferation capacity and the “duration of life” (theory of marginotomy), and suggested a potential of telomere lenghthening for the prevention of aging (anti-marginotomy). The impact of proliferative telomere shortening on life expectancy was later confirmed. In humans, telomere shortening is counteracted by telomerase, an enzyme that is undetectable in most adult somatic cells, but present in cancer cells and adult and embryonic stem and germ cells. Although telomere length dynamics are different in male and female gametes during gametogenesis, telomere lengths are reset at the blastocyst stage, setting the initial length of the species. The role of the telomere pathway in reproduction has been explored for years, mainly because of increased infertility resulting from delayed childbearing. Short telomere length in ovarian somatic cells is associated to decreased fertility and higher aneuploidy rates in embryos. Consequently, there is a growing interest in telomere lengthening strategies, aimed at improving fertility. It has also been observed that lifestyle factors can affect telomere length and improve fertility outcomes. In this review, we discuss the implications of telomere theory in fertility, especially in oocytes, spermatozoa, and embryos, as well as therapies to enhance reproductive success.

Background: A healthy pregnancy begins with an adequate endometrial state, even before the arrival of a blastocyst. Proper endometrial priming and the development of a tolerogenic decidua are key steps in creating the perfect environment for implantation and pregnancy. In these processes, the involvement of the maternal immune system seems to be of great relevance, modulating the different decidual immune populations to prepare the endometrium for a potential pregnancy. However, certain local pathologies of an inflammatory and autoimmune nature appear to have a direct impact on these phenomena, thus altering patients’ reproductive outcomes. Methods: This literature review analyzes original articles, reviews, systematic reviews, and meta-analyses published between 1990 and 2024, concerning the impact of different inflammatory and autoimmune conditions on endometrial status and fertility. The included papers were obtained from Medline (Pubmed) and the Cochrane library. Results: There is evidence that endometriosis, adenomyosis, and chronic endometritis, through the promotion of a chronic inflammatory environment, are capable of altering endometrial immune populations, and, thus, processes essential for early pregnancy. Among other effects, these conditions have been linked to impaired decidualization, alterations in progesterone responsiveness, and hindered placentation. Similarly, antiphospholipid syndrome (APS), thyroid dysfunction, diabetes, and other pathologies related to glucose and gluten metabolism, due to their autoimmune nature, also appear to have a local impact on the uterine environment, affecting reproductive success through different mechanisms, including altered hormonal response and, again, impaired decidualization. Conclusions: The management of inflammatory and autoimmune diseases in assisted reproduction patients is gaining importance due to their direct impact on the endometrium. It is necessary to follow current expert recommendations and established therapeutic approaches in order to improve patients’ prospects, ranging from antibiotic treatment in chronic endometritis to heparin and aspirin in APS, as well as hormonal treatments for endometriosis/adenomyosis or a gluten-free diet in celiac disease. All of them and the rest of the therapeutic perspectives, both current and under investigation, are presented throughout this work, assessing the possible improvements for reproductive outcomes.

Nowadays, recurrent pregnancy loss (RPL) is an undesirable condition suffered by many patients of reproductive age. In this scenario, certain immune cell populations and molecules, involved in maternal–fetal compatibility, have emerged as factors related with the pathogenesis of RPL. Among them, uterine Natural Killer cells (uNKs) appear to be of great relevance. These cells are involved in numerous processes during pregnancy, such as the remodeling of uterine spiral arteries or the control of trophoblast invasion. These functions are regulated by the interactions that these cells establish with the extravillous trophoblast, mainly through their Killer Immunoglobulin-like Receptors (KIRs) and the Human Leukocyte Antigen-C (HLA-C) molecules expressed by the embryo. A high level of polymorphism has been reported for both molecules involved in this interaction, with some of the possible KIR–HLA-C combinations being associated with an increased risk of RPL. However, the complexity of the maternal–fetal interface goes beyond this, as other HLA molecules also appear to be related to this reproductive pathology. In this review, we will discuss the role of uNKs in pregnancy, as well as the polymorphisms and clinical implications of KIR–HLA-C binding. We will also address the involvement of other, different HLA molecules in RPL, and the current advice on the appropriate management of patients with ‘immunological mismatch’, thus covering the main aspects regarding the involvement of maternal–fetal compatibility in RPL.

Characterization of long non-coding telomeric repeat-containing RNAs in sperm of normozoospermic and oligoasthenozoospermic men as new biomarker of idiopathic male infertility. We conducted an observational prospective study with two groups of men with normal or orligoasthenozoospermic spermiogram, aged 40 and above. Fertility parameters were analyzed in men undergoing intracytoplasmic sperm injection with donor oocytes, to avoid the female factor. Telomeric RNAs and telomere length were measured by quantitative fluorescent in situ hybridization. Data from seminal parameters and in-vitro fertilization were assessed according to IVIRMA protocols. Patients with oligoasthenozoospermia, who had worse seminal parameters, also obtained embryos with lower inner-cell-mass quality ( p  = 0.04), despite using donor oocytes. While mean levels of telomeric RNAs were similar for both groups, the percentage of spermatozoa with more than 3 foci was higher in oligoasthenozoospermic men ( p  = 0.02). Regarding telomere length, oligoasthenozoospermic men had shorter mean, a higher accumulation of short telomeres (15th percentile; p  = 0.03) and a lower percentage of very-long telomeres (85th percentile; p  = 0.01). Finally, a positive correlation was found between telomeric-RNAs intensity and total progressive motility in the spermatozoa of normozoospermic patients (r = 0.5; p  = 0.03). Telomeric parameters were altered in the spermatozoa of the oligoasthenozoospermic group, which also showed lower quality embryos. Interestingly, in the normozoospermic group, a correlation was found between progressive motility and telomeric RNA levels, suggesting that they could be a good biomarker of sperm quality. Further studies are required to confirm these results and translate them into the clinical practice. Trial registration number: 1711-MAD-109-CB, 07/07/2021.