Elucidating metformin action on the ovary and fertility in healthy mice.

In brief: The hypoglycemic drug metformin has shown reproductive effects in women, although its mechanism of action is not fully understood. In this study, we demonstrate the direct effects of metformin on the ovary of healthy mice, with no alterations in fertility. Abstract: Metformin is a hypoglycemic drug widely used in type-2 diabetes (T2D) patients. In recent years, this drug has been suggested as a treatment for gestational diabetes and recommended to women with ovarian hyperstimulation syndrome (PCOS) to increase the chances of pregnancy or avoid early miscarriages. However, the exact effects of metformin on the female reproductive tract in general, and on the ovary in particular, are still not completely understood. In this study, we analyzed the effect of metformin on fertility and ovarian physiology in healthy female mice. We found that this drug altered the estrous cycle, early follicular development, serum estradiol and progesterone levels, and ovarian steroidogenic enzyme expression. Moreover, ovarian angiogenesis was lower in metformin-treated animals compared with untreated ones, whereas natural or gonadotropin-induced fertilization rates remained unchanged. However, offspring of metformin-treated animals displayed decreased body weight at birth. In this work, we unraveled the main effects of metformin on the ovary, isolated from other conditions such as hyperglycemia and hyperandrogenism, which is essential for a better understanding of metformin's mechanisms of action on reproduction and fertility.

Brotes por sars-COV-2 en residencias de larga estadía en Argentina: un estudio observacional nacional / SARS-CoV-2 outbreaks in long-term care facilities in Argentina: a national observational study

INTRODUCCIÓN: El impacto de la pandemia por COVID-19 sobre las residencias de larga estadía (RLE) y su población residente fue particularmente severo, sobre todo ante la aparición de brotes por SARS-CoV-2. El objetivo del estudio fue describir la evolución de los brotes por SARS-CoV-2 que ocurrieron en las RLE a nivel nacional en 2020 y 2021, caracterizando a la población afectada y analizando posibles diferencias entre los períodos pre- y posvacunación contra COVID-19. MÉTODOS: Se diseñó un estudio observacional retrospectivo, que utilizó los datos del Sistema Nacional de Vigilancia de la Salud (SNVS 2.0), el Registro Federal de Vacunación Nominalizado (NOMIVAC) y un registro del Instituto Nacional de Servicios Sociales para Jubilados y Pensionados - Programa de Asistencia Médica Integral (INSSJP-PAMI). RESULTADOS: De los 493 brotes ocurridos entre abril de 2020 y diciembre de 2021, se notificaron 363 (con 5643 casos en contexto de brote) en el período prevacunación y 130 (con 1378 casos) en el período posvacunación. A su vez, se registraron mayores tasas de incidencia (34,1%), letalidad (20,7%) y mortalidad (7,1%) en el período prevacunación respecto del período posvacunación (25,2%, 3,9% y 1%, respectivamente). DISCUSIÓN: Los resultados sugieren que las políticas de prevención y control de COVID-19 implementadas por el INSSJP-PAMI en el sector de las RLE lograron reducir el impacto de la pandemia sobre una población vulnerable y de riesgo.

Beneficial effects of metformin on mice female fertility after a high-fat diet intake.

Female fertility is highly dependent on energy balance. High fat diet (HFD) intake entails a risk of infertility and ovulatory disorders. Considering the increase in the prevalence of overweight and obesity over the last decades, it is crucial to understand the mechanisms involved in overweight-associated infertility. In this study, we evaluated the reproductive performance of female mice fed with a HFD and the effects of metformin administration on ovarian function in these mice. We hypothesized that one of the mechanisms involved in subfertility due to a HFD intake is the alteration of ovarian blood vessel formation. We found that mice fed with HFD had altered estrous cycles and steroidogenesis, increased ovarian fibrosis, fewer pups per litter and require more time to achieve pregnancy. HFD-fed mice also presented dysregulated ovarian angiogenesis and an increase in nuclear DNA damage in ovarian cells. Ovulation rates were lower in these animals, as evidenced both in natural mating and after ovulation induction with gonadotropins. Metformin ameliorated ovarian angiogenesis, improved steroidogenesis, fibrosis, and ovulation, decreased the time to pregnancy and increased litter sizes in HFD-fed mice. We conclude that ovarian angiogenesis is one of the mechanisms detrimentally affected by HFD intake. Since metformin could improve ovarian microvasculature, it may be an interesting strategy to study in women to shed light on new targets for patients with metabolic disturbances.

Resveratrol alleviates doxorubicin-induced damage in mice ovary.

While oocytes and embryos cryopreservation can favor some patients with cancer-induced infertility to achieve pregnancy, the development of effective therapeutic strategies to preserve ovarian function during chemotherapy would be a significant advantage. The aim of the present study is to analyze whether Resveratrol treatment (Res) can preserve ovarian function from doxorubicin (Doxo)-induced gonadotoxicity using a mice model of premature ovarian failure. Res (7 and 15 mg/kg) increased the percentage of primary and antral follicles whilst decreasing the percentage of atretic follicles compared to Doxo alone. Res preserved the number of primordial follicles compared with those in the Doxo group but they did not change from those in the control group. Res treatment increased the number of AMH positive follicles compared to Doxo alone. Res increased proliferation index in follicular cells and reduced the DNA damage and apoptosis in preantral and early antral follicles compared to Doxo alone. Additionally, Doxo administration caused a severe endothelial damage and affected microvasculature stability in the ovary. However, Res was able to increase the recruitment of pericytes and smooth muscle cells in the Doxo-treated group. We also found that Res increased the expression of VEGF compared to Doxo alone. By H&E staining, Doxo-treated mice demonstrated endometrial alterations compared to controls, affecting both epithelial and stromal compartments. Nonetheless, Res restored the architecture of uterine tissue. Moreover, we also showed that Res administration is able to maintain antioxidant defenses through the increase of SOD expression in the Doxo-induced POF model. In conclusion, Res administration prior to and during Doxo treatment might serve as a noninvasive and low-cost protocol to preserve ovarian function in female cancer survivors.

Promoting early neovascularization by allotransplanted adipose-derived Muse cells in an ovine model of acute myocardial infarction.

BACKGROUND: Recent preclinical studies have demonstrated that bone marrow (BM)-derived Muse cells have a homing mechanism to reach damaged cardiac tissue while also being able to reduce myocardial infarct size and improve cardiac function; however, the potential of BM-Muse cells to foster new blood-vessel formation has not been fully assessed. Up to date, adipose tissue (AT)-derived Muse cells remain to be studied in acute myocardial infarction (AMI). The aim of the present study was to analyze in vitro and in vivo the neovascularization capacity of AT-Muse cells while exploring their biodistribution and differentiation potential in a translational ovine model of AMI. METHODS AND RESULTS: AT-Muse cells were successfully isolated from ovine adipose tissue. In adult sheep, one or more diagonal branches of the left anterior descending coronary artery were permanently ligated for thirty minutes. Sheep were randomized in two groups and treated with intramyocardial injections: Vehicle (PBS, n = 4) and AT-Muse (2x107 AT-Muse cells labeled with PKH26 Red Fluorescent Dye, n = 4). Molecular characterization showed higher expression of angiogenic genes (VEGF, PGF and ANG) and increased number of tube formation in AT-Muse cells group compared to Adipose-derived mesenchymal stromal cells (ASCs) group. At 7 days post-IAM, the AT-Muse group showed significantly more arterioles and capillaries than the Vehicle group. Co-localization of PKH26+ cells with desmin, sarcomeric actin and troponin T implied the differentiation of Muse cells to a cardiac fate; moreover, PKH26+ cells also co-localized with a lectin marker, suggesting a possible differentiation to a vascular lineage. CONCLUSION: Intramyocardially administered AT-Muse cells displayed a significant neovascularization activity and survival capacity in an ovine model of AMI.

SARS-CoV-2 infection negatively affects ovarian function in ART patients.

Several organs, such as the heart, breasts, intestine, testes, and ovaries, have been reported to be target tissues of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To date, no studies have demonstrated SARS-CoV-2 infection in the female reproductive system. In the present study, we investigated the effects of SARS-CoV-2 infection on ovarian function by comparing follicular fluid (FF) from control and recovered coronavirus disease 2019 (COVID-19) patients and by evaluating the influence of these FF on human endothelial and non-luteinized granulosa cell cultures. Our results showed that most FFs (91.3%) from screened post COVID-19 patients were positive for IgG antibodies against SARS-CoV-2. Additionally, patients with higher levels of IgG against SARS-CoV-2 had lower numbers of retrieved oocytes. While VEGF and IL-1ß were significantly lower in post COVID-19 FF, IL-10 did not differ from that in control FF. Moreover, in COV434 cells stimulated with FF from post COVID-19 patients, steroidogenic acute regulatory protein (StAR), estrogen-receptor ß (Erß), and vascular endothelial growth factor (VEGF) expression were significantly decreased, whereas estrogen-receptor α (ERα) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) did not change. In endothelial cells stimulated with post COVID-19 FF, we observed a decrease in cell migration without changes in protein expression of certain angiogenic factors. Both cell types showed a significantly higher γH2AX expression when exposed to post COVID-19 FF. In conclusion, our results describe for the first time that the SARS-CoV-2 infection adversely affects the follicular microenvironment, thus dysregulating ovarian function.

Metformin has a direct effect on ovarian cells that is dependent on organic cation transporters.

Metformin (MET) is the most widely prescribed hypoglycemic drug in type 2 diabetes and Polycystic Ovary Syndrome. Besides its effects on glucose metabolism, MET exerts beneficial effects on these patients' fertility. However, the exact mechanisms of action of MET on female fertility are still unclear. In this work, we analyzed a possible direct effect of MET on ovarian cells. We found expression of the organic cation transporters OCT1, OCT2 and OCT3, responsible for MET uptake into the cells, in rat granulosa cells and human cumulus cells. Furthermore, MET increased pAMPK and decreased VEGF levels both in vivo and in rat granulosa cells in culture. These last effects were reversed when OCTs were inhibited. Our results suggest that MET acts directly on ovarian cells regulating cell metabolism and VEGF expression. Our findings are relevant to optimize PCOS fertility treatment and to explore ovarian MET actions in other female pathologies.