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Throughout the individual's reproductive period of life the ovary undergoes continues changes, including cyclic processes of cell death, tissue regeneration, proliferation, and vascularization. Tissue-resident leucocytes particularly macrophages, play a crucial role in shaping ovarian function and maintaining homeostasis. Macrophages crucially promote angiogenesis in the follicles and corpora lutea, thereby supporting steroidogenesis. Recent research on macrophage origins and early tissue seeding has unveiled significant insights into their role in early organogenesis, e.g. in the testis. Here, we review evidence about the prenatal ovarian seeding of leucocytes, primarily macrophages with angiogenic profiles, and its connection to gametogenesis. In the prenatal ovary, germ cells proliferate, form cysts, and undergo changes that, following waves of apoptosis, give rice to the oocytes contained in primordial follicles. These follicles constitute the ovarian reserve that lasts throughout the female's reproductive life. Simultaneously, yolk-sac-derived primitive macrophages colonizing the early ovary are gradually replaced or outnumbered by monocyte-derived fetal macrophages. However, the cues indicating how macrophage colonization and follicle assembly are related are elusive. Macrophages may contribute to organogenesis by promoting early vasculogenesis. Whether macrophages contribute to ovarian lymphangiogenesis or innervation is still unknown. Ovarian organogenesis and gametogenesis are vulnerable to prenatal insults, potentially programming dysfunction in later life, as observed in polycystic ovary syndrome. Experimental and, more sparsely, epidemiological evidence suggest that adverse stimuli during pregnancy can program defective folliculogenesis or a diminished follicle reserve in the offspring. While the ovary is highly sensitive to inflammation, the involvement of local immune responses in programming ovarian health and disease remains to be thoroughly investigated., (© 2024. The Author(s).)

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

CD8+ T cells are the most frequent T cell population in the immune cell compartment at the feto-maternal interface. Due to their cytotoxic potential, the presence of CD8+ T cells in the immune privileged pregnant uterus has raised considerable interest. Here, we review our current understanding of CD8+ T cell biology in the uterus of pregnant women and discuss this knowledge in relation to a recently published immune cell Atlas of human decidua. We describe how the expansion of CD8+ T cells with an effector memory phenotype often presenting markers of exhaustion is critical for a successful pregnancy, and host defense towards pathogens. Moreover, we review new evidence on the presence of long-lasting immunological memory to former pregnancies and discuss its impact on prospective pregnancy outcomes. The formation of fetal-specific memory CD8+ T cell subests in the uterus, in particular of tissue resident, and stem cell memory cells requires further investigation, but promises interesting results to come. Advancing the knowledge of CD8+ T cell biology in the pregnant uterus will be pivotal for understanding not only tissue-specific immune tolerance but also the etiology of complications during pregnancy, thus enabling preventive or therapeutic interventions in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hardardottir, Bazzano, Glau, Gattinoni, Köninger, Tolosa and Solano.)

Objectives: In the current Severe Acute Respiratory Distress Coronavirus 2 (SARS-CoV-2) pandemic there is still great uncertainty about the effects of an infection in pregnancy especially regarding a possible fetal transmission of antibodies to SARS-CoV-2 and the longevity of this immunity., Methods: Sixteen women who were infected with SARS-CoV-2 during pregnancy and their offspring were included. The antibody response to SARS-CoV-2 was measured in mother and umbilical cord blood peripartum and in a follow-up examination 6-11 weeks after birth. Medical history, symptoms regarding SARS-CoV-2, obstetric and neonatal information were queried following recommendations by the WHO., Results: A total of 73% of the women and one third of the infants developed antibodies to SARS-CoV-2 spike (S) protein receptor binding domain (RBD), with a long interval between infection and birth proving favorable for a transplacentar transfer of antibodies to the neonates. All infants showed declining or vanishing antibody-titers in the follow-up examination, while the titers of their mothers were stable or even increased., Conclusions: Our results demonstrate that transplacental transfer of SARS-CoV-2-specific antibodies is possible, but also indicate that the immunity that may be gained as a result might decrease in newborns postpartum. This provides important evidence that could be useful for further studies covering vaccination during pregnancy., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Obesity is a chronic disease that impairs female reproduction. When gestation is achieved, maternal obesity can cause offspring's health complications. We intended to evaluate the effects of maternal pre-conceptional obesity on uterine contractile activity, embryo implantation and offspring development. Using cafeteria diet-induced obesity as an animal model, we found that maternal obesity delays embryo transport from the oviduct to the uterus and alters the intrauterine embryo positioning. Adrenergic receptor (AR) signaling is involved in embryo positioning, so all AR isoforms were screened in the pre-implantation uteri. We found that the β2AR is the dominant isoform in the rat uteri and that obesity causes its upregulation. Although β2AR activation is known to induce uterine relaxation, higher spontaneous contractile activity was detected in obese dams. Uteri from obese dams showed a higher sensitivity to salbutamol (a selective agonist of β2AR) than controls, consistent with the higher β2AR levels detected in those animals. Despite this, in obese dams, some embryos were still in the oviduct at the predicted time of initial embryo attachment, embryo implantation is successfully carried out since the total number of fetuses on gd 18.5 were similar between control and obese dams. These findings show that obesity is modifying the implantation window. Moreover, we found that maternal obesity resulted in macrosomia in the offspring, which is an important predictor of fetal programming of postnatal health. Hence, our results show that maternal obesity prior to pregnancy not only disturbs the implantation process, but also affects offspring development.

Obesity is a metabolic disorder that predisposes to numerous diseases and has become a major global public health concern. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects Western diet habits. Previously, we described that CAF administration for 60 days induces obesity in female rats and their fetuses develop macrosomia. Given that, in our model, rats are not genetically modified and that obese mothers were fed standard chow during pregnancy, the aim of the current study was to test the hypothesis that obesity alters the intrauterine environment prior to pregnancy, and this may explain the exacerbated fetal weight gain. We found that uteri from obese rats during the estrous phase developed insulin resistance through mechanisms that involve the induction of uterine hypoxia and the down-regulation of the insulin receptor gene. Moreover, uterine cell proliferation was induced by obesity concomitantly with the reduction in the uterine contractile response to a β2 AR agonist, salbutamol, and this may be consequence of the down-regulation in the uterine β2 AR expression. We conclude that CAF-induced obesity alters the uterine environment in rats during the estrous phase and may cause the fetal macrosomia previously described by us in obese animals. The lower sensitivity of the uterus to a relaxation stimulus (salbutamol) is not a minor fact given that for implantation to occur the uterus must be relaxed for embryo nidation. Thus, the alteration in the uterine quiescence may impair implantation and, consequently, the foregoing pregnancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Obesity constitutes a health problem of increasing worldwide prevalence related to many reproductive problems such as infertility, ovulation dysfunction, preterm delivery, fetal growth disorders, etc. The mechanisms linking obesity to these pathologies are not fully understood. Cafeteria diet (CAF) is the animal model used for the study of obesity that more closely reflects western diet habits. Previously we described that CAF induces obesity associated to hyperglycemia, reduced ovarian reserve, presence of follicular cysts and ovulatory impairments. The aim of the present study was to contribute in the understanding of the physiological mechanisms altered as consequence of obesity. For that purpose, female Wistar rats were fed ad libitum with a standard diet (control group) or CAF (Obese group). We found that CAF fed-rats developed obesity, glucose intolerance and insulin resistance. Ovaries from obese rats showed decreased glucose uptake and became insulin resistant, showing decreased ovarian expression of glucotransporter type 4 and insulin receptor gene expression respect to controls. These animals showed an increased follicular nitric oxyde synthase expression that may be responsible for the ovulatory disruptions and for inflammation, a common feature in obesity. Obese rats resulted subfertile and their pups were macrosomic. We conclude that obesity alters the systemic and the ovarian glucidic homeostasis impairing the reproductive outcome. Since macrosomia is a risk factor for metabolic and obstetric disorders in adult life, we suggest that obesity is impacting not only on health and reproduction but it is also impacting on health and reproduction of the offspring., (Published by Elsevier Inc.)

Obesity constitutes a health problem of increasing worldwide prevalence. Among the health detriments caused by obesity, reproduction is disrupted. However, the mechanisms involved in this disruption are not fully understood. Animals fed a cafeteria diet constitute the model for the study of obesity that most closely reflects Western diet habits. The aims of this study were to evaluate whether a cafeteria diet affects ovarian function and to contribute to the understanding of the mechanisms involved. For that purpose, 22-day-old female Wistar rats were fed ad libitum with a standard diet (control group; n = 20) or cafeteria diet (CAF group; n = 20). The cafeteria diet induced obesity and hyperglycaemia, without altering serum triglycerides, cholesterol or C-reactive protein concentrations. This diet also altered ovarian function: the rats showed prolonged dioestrous phases, decreased serum oestradiol concentrations and increased number of antral atretic follicles. Moreover, follicular cysts were detected in the CAF group, concomitantly with a decrease in the number of anti-Müllerian hormone immunoreactive pre-antral follicles and COX-2-positive antral and pre-ovulatory follicles. The authors conclude that a cafeteria diet reduces ovarian reserve, induces the presence of follicular cysts and disturbs the ovulatory process, leading to the delayed pregnancy observed in these animals., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: In assisted reproduction cycles, gonadotropins are administered to obtain a greater number of oocytes. A majority of patients do not have an adverse response; however, approximately 3-6% develop ovarian hyperstimulation syndrome (OHSS). Metformin reduces the risk of OHSS but little is known about the possible effects and mechanisms of action involved., Objective: To evaluate whether metformin attenuates some of the ovarian adverse effects caused by OHSS and to study the mechanisms involved., Material and Methods: A rat OHSS model was used to investigate the effects of metformin administration. Ovarian histology and follicle counting were performed in ovarian sections stained with Masson trichrome. Vascular permeability was measured by the release of intravenously injected Evans Blue dye (EB). VEGF levels were measured by commercially immunosorbent assay kit. COX-2 protein expression was evaluated by western blot and NOS levels were analyses by immunohistochemistry., Results: Animals of the OHSS group showed similar physiopathology characteristics to the human syndrome: increased body weight, elevated progesterone and estradiol levels (P<0.001), increased number of corpora lutea (P<0.001), higher ovarian VEGF levels and vascular permeability (P<0.001 and P<0.01); and treatment with metformin prevented this effect (OHSS+M group; P<0.05). The vasoactive factors: COX-2 and NOS were increased in the ovaries of the OHSS group (P<0.05 and P<0.01) and metformin normalized their expression (P<0.05); suggesting that metformin has a role preventing the increased in vascular permeability caused by the syndrome., Conclusion: Metformin has a beneficial effect preventing OHSS by reducing the increase in: body weight, circulating progesterone and estradiol and vascular permeability. These effects of metformin are mediated by inhibiting the increased of the vasoactive molecules: VEGF, COX-2 and partially NOS. Molecules that are increased in OHSS and are responsible for a variety of the symptoms related to OHSS.