The coronavirus SARS-CoV-2 causes the COVID-19 disease and affects primarily the lungs, but also other organs, causing accelerated cell aging. One of main pathways involved in aging is telomere attrition, which ultimately leads to defective tissue regeneration and organ dysfunction. Indeed, short telomeres in aged people aggravate the COVID-19 symptoms and, COVID-19 survivors showed shorter telomeres in blood cells. The SARS-CoV-2 has been detected in testis, but the ovaries, which express the viral entry factors, have not been fully explored. Our objective was the analysis of telomeres and reproductive outcomes in women who had COVID-19 and controls. In this prospective cohort study, granulosa cells (GCs) and blood were collected from 65 women. Telomere length (TL) was measured by high-throughput in situ hybridization. Mean TL of GCs and peripheral blood mononuclear cells (PBMCs) was alike in control and mild cases. However, mean TL of GCs was lower in severe cases compared to controls (p=0.017). Control and COVID groups had similar ovarian reserve and number of total oocytes after puncture. However, the oocyte maturation rate was lower in severe cases (p= 0.018). Interestingly, a positive correlation between the oocyte maturation rate and TL of GCs was found in the control group (p=0.024). Our findings point to a potential impact of the coronavirus infection on telomeres and reproductive outcomes in severe cases. This might be considered upon possible new SARS-CoV threats, to favor treatments that enhance oocyte maturation in women severely affected by coronavirus undergoing ART.

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Purpose of reviewWomen's fertility decay starts at the mid 30 s. However, the current delay of childbearing leads to ovarian aging and the need of assisted reproduction technologies (ART). Telomere biology is one of the main pathways involved in organismal aging. Thus, this review will focus on the knowledge acquired during the last 2 years about the telomere pathway and its influence on female fertility and the consequences for the newborn.Recent findingsNew research on telomere biology reaffirms the relationship of telomere attrition and female infertility. Shorter maternal telomeres, which could be aggravated by external factors, underly premature ovarian aging and other complications including preeclampsia, preterm birth and idiopathic pregnancy loss. Finally, the telomere length of the fetus or the newborn is also affected by external factors, such as stress and nutrition.SummaryRecent evidence shows that telomeres are implicated in most processes related to female fertility, embryo development and the newborn's health. Thus, telomere length and telomerase activity may be good biomarkers for early detection of ovarian and pregnancy failures, opening the possibility to use telomere therapies to try to solve the infertility situation.

Metabolic adaptations are a hallmark of cancer and may be exploited to develop novel diagnostic and therapeutic tools. Only about 50% of the patients who undergo thyroidectomy due to suspicion of thyroid cancer actually have the disease, highlighting the diagnostic limitations of current tools. We explored the possibility of using non-invasive blood tests to accurately diagnose thyroid cancer. We analyzed blood and thyroid tissue samples from 2 independent cohorts of patients undergoing thyroidectomy at the Hospital Universitario 12 de Octubre (Madrid, Spain). As expected, histological comparisons of thyroid cancer and hyperplasia revealed higher proliferation and apoptotic rates and enhanced vascular alterations in the former. Notably, they also revealed increased levels of membrane-bound phosphorylated AKT, suggestive of enhanced glycolysis, and alterations in mitochondrial sub-cellular distribution. Both characteristics are common metabolic adaptations in primary tumors. These data together with reduced mtDNA copy number and elevated levels of the mitochondrial antioxidant Prx3 in cancer tissue samples suggest the presence of mitochondrial oxidative stress. In plasma, cancer patients showed higher levels of cfDNA and mtDNA. Of note, mtDNA plasma levels inversely correlated with those in the tissue, suggesting that higher death rates were linked to lower mtDNA copy number. In PBMCs, cancer patients showed higher levels of PGC-1, a positive regulator of mitochondrial function, but this increase was not associated with a corresponding induction of its target genes, suggesting a reduced activity in cancer patients. We also observed a significant difference in the PRDX3/PFKFB3 correlation at the gene expression level, between carcinoma and hyperplasia patients, also indicative of increased systemic metabolic stress in cancer patients. The correlation of mtDNA levels in tissue and PBMCs further stressed the interconnection between systemic and tumor metabolism. Evaluation of the mitochondrial gene ND1 in plasma, PBMCs and tissue samples, suggested that it could be a good biomarker for systemic oxidative metabolism, with ND1/mtDNA ratio positively correlating in PBMCs and tissue samples. In contrast, ND4 evaluation would be informative of tumor development, with ND4/mtDNA ratio specifically altered in the tumor context. Taken together, our data suggest that metabolic dysregulation in thyroid cancer can be monitored accurately in blood samples and might be exploited for the accurate discrimination of cancer from hyperplasia.

were initially recruited from April 2020 to April 2021. Patients were categorized as acute , confirmed by RT-PCR (COVID-19 group), and healthy individuals with normozoospermic semen samples (n¼22; Control group). Were evaluated seminal parameters, cryosurvival rates (%), mitochondrial activity (%; 3,3 0 -diaminobenzidine stain), reactive oxygen species levels (ROS; chemiluminescent technique) and DNA fragmentation (%; SCSA method) in precryopreservation and post-thaw samples. Samples were cryopreserved by the slow freezing technique. A complementary retrospective study was performed comparing post-thawed samples from COVID-19 group with data from patients with others male diseases: Male infertility (n¼35); Severe infertility (n¼62), caused severe oligozoospermia, grade 3 varicocele, gonadal dysgenesis, testicular nodule, testicular hypotrophy; testicular cancer (n¼55); and other malignant diseases (leukemia, lymphoma, sarcoma, multiple myeloma; n¼30). Was used T-test to statistical analysis (p<0.05). RESULTS: Macroscopy analysis of COVID-group revealed abnormal viscosity in 53.33%, semen volume ¼ 4.50 AE 1.72 ml and pH ¼ 8.13 AE 0.23. COVID-19 fresh samples demonstrated mean of progressive motility ¼ 29.07AE16.83%, sperm morphology ¼ 2.07AE1.58%, and DNA fragmentation index ¼ 42.91AE33.38%. Cryopreservation decreased progressive motility (to 5.39AE7.92%; p¼0.02), sperm vitality (70.46AE8.50 vs. 72.20AE23.27; p¼0.042) and ROS (0.516AE0.978 vs. 4.393AE9.956 x 10 4 cpm; p¼0.018). When we compared with cryopreserved normozoospermic samples, there was observed a significant difference in HDS (p¼0.002). Cryosurvival rate from COVID-19 samples was 19.93; 19.71%, and had significant difference when compared with severe infertility (40.16; 31.05%; p¼0.003), and other malignant diseases (53.14; 28.55%, <0.001).CONCLUSIONS: Seminal samples from patients with COVID-19 showed reduced fertile potential, especially when compared to the reference values. In the comparisons performed with samples from patients with different andrological diagnoses, common in the specialized andrology laboratory routine, we can suggest that samples from patients with the acute form of COVID-19 had the worst quality, with low cryosurvival rates. This information contribute to the conduct of these patients during assisted reproduction routines and preservation of male fertility.IMPACT STATEMENT: It will contribute to conducts in the cryopreservation of sperm in patients with acute COVID-19.

To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the ovarian reserve recovery patterns of women with breast cancer by using a ultra-sensitive Anti-Mullerian Hormone (AMH) assay.DESIGN: Multi-Center Prospective Longitudinal. MATERIALS AND METHODS: One-hundred.-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Metho-trexate+5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI.RESULTS: Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p<0.0001 either regimen vs. tamoxifen for overall trend). The AMH levels sharply declined at 12 months and the level of decline did not differ between the two chemotherapy groups (p¼0.53).There was no significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens (p¼0.97). While the mean/median AMH level was 0.34/0.09 ng/dl at the 12-month time point, it was 0.40/0.06 ng/dl and 0.42/0.07 ng/dl at 18-and 24-month time points for the AC-based regimens group. These values were 0.11/0.03, 0.12/0.02 and 0.20/0.03 at the 3 time points for the CMF group. These mean levels are substantially below the threshold for normal ovarian reserve, which is generally 1.1 ng/mL or higher for the age group. AMH levels remained undetectable in 20% (15/76) vs. 38% (5/13) of women in the AC-based regimens vs. CMF groups at 24 months (p¼0.16 from Fisher exact test). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery.CONCLUSIONS: Our study is the first to assess ovarian reserve changes with serum AMH in a prospective longitudinal fashion, with multiple time points up to 24-month post-completion of chemotherapy, and in comparison with tamoxifen-only treatments. It shows that both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not alter serum AMH levels. The latter also indicates that the ovarian reserve of women who are on long-term tamoxifen treatment can be reliably assessed by serum AMH. This study provides novel information which will be useful in counseling young women with breast cancer for fertility preservation and in assessing post-chemotherapy ovarian damage and recovery.

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