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ABSTRACT To investigate the synergistic effect of astaxanthin and curcumin on ovarian function in polycystic ovary syndrome (PCOS) mice and to elucidate the underlying mechanisms, fifty 4‐week‐old female mice were randomly divided into five groups: (i) normal control group; (ii) PCOS model group; (iii) PCOS + astaxanthin group; (iv) PCOS + curcumin group; and (v) PCOS + astaxanthin–curcumin. Throughout the study, various parameters were meticulously evaluated, including serum levels of key reproductive hormones (testosterone (T), estradiol (E2), follicle‐stimulating hormone (FSH), luteinizing hormone (LH), and anti‐Müllerian hormone (AMH)), as well as monitoring alterations in the estrous cycle, follicle development, and ovulation rates. Additionally, markers of oxidative stress and inflammation were measured. Findings revealed that PCOS mice exhibited disordered estrous cycle, polycystic ovarian morphologies, abnormal serum reproductive hormones and lipid metabolism, heightened oxidative stress, and augmented inflammatory responses. Notably, upon administration of the combined astaxanthin and curcumin, PCOS mice exhibited significant improvements in their estrous cyclicity and ovarian histology. The treatment led to a significant reduction in serum total cholesterol (TC) levels and normalization of T, E2, FSH, LH, and AMH levels. Moreover, there was a marked decrease in the levels of serum reactive oxygen species (ROS) and malondialdehyde (MDA), indicating attenuation of oxidative stress. Concurrently, the activity of the antioxidant enzyme catalase (CAT) significantly increased, while proinflammatory cytokines interferon‐γ (IFN‐γ) and interleukin‐6 (IL‐6) in the ovarian tissue were notably decreased. The combined treatment also resulted in a substantial increase in the number of ova and a significant decline in the rate of abnormal ova, with these therapeutic effects proving more effective compared to either astaxanthin or curcumin alone. In conclusion, the co‐administration of astaxanthin and curcumin demonstrated a remarkable effect in improving abnormal lipid metabolism and restoring reproductive endocrine functions in PCOS mice. Furthermore, it effectively mitigated systemic and local oxidative stress and chronic inflammatory injury, thereby promoting follicular growth and enhancing ovulatory function in the context of PCOS. [ABSTRACT FROM AUTHOR]

Objective: Premature ovarian insufficiency (POI) is a disease with medical, psychological and reproductive implications, but its common therapies have limited efficacy and a likelihood of complications. This study delves into the therapeutic role of human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSCs-EVs) in POI mice through the insulin-like growth factor 1 (IGF-1)/nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/autophagy pathway. Methods: hUC-MSCs were transfected with lentiviral short hairpin RNA of IGF-1 before EV extraction. Cyclophosphamide (CTX)-induced POI mouse models were administrated with hUC-MSCs-EVs. Mouse ovarian granulosa cells (GCs) were induced with CTX, then treated with hUC-MSCs-EVs and ML385. Ovarian histopathological changes were observed, changes in follicle number at all levels were counted and serum sex hormones were evaluated, as well as LC3II/I and Beclin-1 expression. GCs were subject to detection of proliferation, deaths, oxidative stress, and Nrf2 nuclear translocation. Results: After CTX exposure, mice showed thinner GCs layer in the ovary, reduced number of GCs and follicles at all levels, disturbed serum sex hormones, enhanced oxidative stress and autophagy, and downregulated ovarian IGF-1; whereas, hUC-MSCs-EVs upregulated IGF-1 to improve the ovarian function. hUC-MSCs-EVs carrying IGF-1 activated Nrf2/HO-1 signaling to inhibit CTX-induced excessive autophagy of GCs, but this ameliorative effect was partially weakened by inhibiting Nrf2/HO-1 signaling. hUC-MSCs-EVs inhibited excessive autophagy of GCs and improved ovarian function of CTX-induced mice through IGF-1/Nrf2/HO-1 pathway. Conclusion: hUC-MSCs-EVs activate the Nrf2/HO-1 signaling by carrying IGF-1, which in turn inhibits excessive autophagy and damage of GCs, thus improving ovarian function in POI mice. [ABSTRACT FROM AUTHOR]

Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune‐mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)‐KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL‐KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)‐dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep‐deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD. [ABSTRACT FROM AUTHOR]

Particulate matter 2.5 (PM2.5) pollution has emerged as a major global public health concern because of its adverse effects on human health. Our group has previously demonstrated that PM2.5 exposure can seriously impair ovarian function. However, the underlying mechanisms remain a mystery. This study verifies ovarian damage in mice, evidenced by inflammatory cell infiltration and follicular atresia, following 5 months of PM2.5 exposure via tracheal drip (35 µg/m³ for low dose and 150 µg/m³ for high dose). In addition, PM2.5 exposure inhibited the cell viability of human granulosa cells (KGN) and induced apoptosis at the concentrations of 50, 100, and 150 µg/mL for 24 h. The apoptosis of KGN cells induced by inflammation contributes to follicular atresia. Furthermore, we conducted RNA-sequencing analysis to identify the genes and pathways triggered by PM2.5 (100 µg/mL) exposure, which decreases the KGN cell viability. We found a significant increase in Activating Transcription Factor 3 (ATF3). Further mechanistic studies reveal a strong association between PM2.5-induced apoptosis, inflammation, and ATF3 with its downstream oxidative stress signals. In summary, the ATF3 pathway serves a vital role in the ovarian injury caused by PM2.5 exposures. [ABSTRACT FROM AUTHOR]

Abnormal apoptosis of ovarian cells caused by oxidative stress is an important cause of premature ovarian failure (POF). Previous studies revealed that proanthocyanidins (PCs) are powerful natural antioxidants that can safely prevent oxidative damage in humans. However, the protective effect and mechanism of PCs on ovarian function during the course of POF remain unknown. In this study, female mice were injected with 3-nitropropionic acid (3-NPA) to establish an ovarian oxidative stress model; at the same time, the mice were treated with PC via gavage. Thereafter, the expression of various apoptosis genes, hormones, and related molecules was assessed. Compared with those in the control group, the ovarian index, follicle count at all levels, expression of MVH, PCNA and BCL2, and estradiol (E2) and progesterone (P) levels were significantly lower in the POF group, but significant recovery was observed in terms of MVH and PCNA expression and E2 and P levels in the POF + PCs group. The apoptosis marker genes BAX and ROS were significantly increased in the POF group but were notably restored in the POF + PCs group. In addition, the expression of Sestrin2, an antiapoptotic protein, was significantly increased in the PCs treatment group, as were the upstream and downstream regulatory factors NRF2 and SOD2, and the indices of the Sestrin2 overexpression group were similar to those of the PCs treatment group. In summary, these findings suggest that PCs have potential as innovative therapeutic agents for preventing and treating POF by activating the protective SESTRIN2-NRF2 pathway against oxidative stress. [ABSTRACT FROM AUTHOR]

Background: The administration of a gonadotropin releasing factor (GnRF) analog to pigs has proven to induce antibodies against endogenous GnRF. In gilts (young female pigs), the subsequent blocking of GnRF activity by specific antibodies results in a temporary suppression of ovarian activity and sexual maturation. One pre-clinical and two clinical studies were conducted to assess the ability of the GnRF analog to produce immunologically suppression of the ovarian function, preventing gilts from reaching puberty before harvest, at 27 weeks of age. Results: In the three studies, a significant reduction of size and weight of reproductive organs and gilts in oestrus was demonstrated in vaccinated gilts compared with intact gilts. A significant increase in anti-GnRF antibody levels in sera was observed after the 2nd dose, which lasted until the end of the study in each of the protocols used. Progesterone levels were significantly reduced from 6 to 8 weeks after 2nd vaccination in clinical studies 2 and 1 respectively, and from 6 weeks after 2nd vaccination in the pre-clinical study. Estradiol levels were below the limit of detection for clinical study 2 and significantly reduced in vaccinated gilts at the end of the pre-clinical study and the clinical study 1. Conclusions: Vaccination of gilts with a GnRF analog with two different protocols (1st dose from 10 to 14 weeks of age, and a 2nd dose 8 or 4 weeks later) was effective in reducing the development of puberty for at least 9 weeks post 2nd dose. These results confirm the flexibility of vaccination programs for veterinarians and producers which can be adapted to pig management practices in commercial farms. [ABSTRACT FROM AUTHOR]

Background: AI medical image analysis shows potential applications in research on premature aging and skin. The purpose of this study was to explore the mechanism of the Zuogui pill based on artificial intelligence medical image analysis on ovarian function enhancement and skin elasticity repair in rats with premature aging. Materials and Methods: The premature aging rat model was established by using an experimental animal model. Then Zuogui pills were injected into the rats with premature aging, and the images were detected by an optical microscope. Then, through the analysis of artificial intelligence medical images, the image data is analyzed to evaluate the indicators of ovarian function. Results: Through optical microscope image detection, we observed that the Zuogui pill played an active role in repairing ovarian tissue structure and increasing the number of follicles in mice, and Zuogui pill also significantly increased the level of progesterone in the blood of mice. Conclusion: Most of the ZGP‐induced outcomes are significantly dose‐dependent. [ABSTRACT FROM AUTHOR]

The objective of the study was to characterise the expression patterns of the two key components of cortisol action namely HSD11B1 (11‐beta‐hydroxysteroid dehydrogenase type 1) and NR3C1 (nuclear receptor subfamily 3, group C, member 1, also known as the glucocorticoid receptor) in superovulation induced bovine follicles during the periovulation and subsequent corpus luteum (CL) formation. Bovine ovaries containing preovulatory follicles or CL were timely defined during induced ovulation as follows: 0 h before GnRH (Gonadotropin‐releasing hormone) application, and 4, 10, 20, 25 (follicles) and 60 h (early CL) after GnRH. The low mRNA expression of HSD11B1 and NR3C1 in the follicle group before the GnRH application increased significantly in the follicle group 20 h after GnRH and remained high afterward also in the early CL group. In contrast, the high NR3C1 mRNA decreased in follicles 25 h after GnRH (close to ovulation) and significantly increased again after ovulation (early CL). Our results indicated the involvement of HSD11B1 and NR3C1 as the two key components of cortisol action in the local mechanisms coordinating final follicle maturation, ovulation, follicular‐luteal transition and CL development in the cow. [ABSTRACT FROM AUTHOR]

Abstract Particulate matter 2.5 (PM2.5) pollution has emerged as a major global public health concern because of its adverse effects on human health. Our group has previously demonstrated that PM2.5 exposure can seriously impair ovarian function. However, the underlying mechanisms remain a mystery. This study verifies ovarian damage in mice, evidenced by inflammatory cell infiltration and follicular atresia, following 5 months of PM2.5 exposure via tracheal drip (35 µg/m³ for low dose and 150 µg/m³ for high dose). In addition, PM2.5 exposure inhibited the cell viability of human granulosa cells (KGN) and induced apoptosis at the concentrations of 50, 100, and 150 µg/mL for 24 h. The apoptosis of KGN cells induced by inflammation contributes to follicular atresia. Furthermore, we conducted RNA-sequencing analysis to identify the genes and pathways triggered by PM2.5 (100 µg/mL) exposure, which decreases the KGN cell viability. We found a significant increase in Activating Transcription Factor 3 (ATF3). Further mechanistic studies reveal a strong association between PM2.5-induced apoptosis, inflammation, and ATF3 with its downstream oxidative stress signals. In summary, the ATF3 pathway serves a vital role in the ovarian injury caused by PM2.5 exposures.

Abstract Abnormal apoptosis of ovarian cells caused by oxidative stress is an important cause of premature ovarian failure (POF). Previous studies revealed that proanthocyanidins (PCs) are powerful natural antioxidants that can safely prevent oxidative damage in humans. However, the protective effect and mechanism of PCs on ovarian function during the course of POF remain unknown. In this study, female mice were injected with 3-nitropropionic acid (3-NPA) to establish an ovarian oxidative stress model; at the same time, the mice were treated with PC via gavage. Thereafter, the expression of various apoptosis genes, hormones, and related molecules was assessed. Compared with those in the control group, the ovarian index, follicle count at all levels, expression of MVH, PCNA and BCL2, and estradiol (E2) and progesterone (P) levels were significantly lower in the POF group, but significant recovery was observed in terms of MVH and PCNA expression and E2 and P levels in the POF + PCs group. The apoptosis marker genes BAX and ROS were significantly increased in the POF group but were notably restored in the POF + PCs group. In addition, the expression of Sestrin2, an antiapoptotic protein, was significantly increased in the PCs treatment group, as were the upstream and downstream regulatory factors NRF2 and SOD2, and the indices of the Sestrin2 overexpression group were similar to those of the PCs treatment group. In summary, these findings suggest that PCs have potential as innovative therapeutic agents for preventing and treating POF by activating the protective SESTRIN2-NRF2 pathway against oxidative stress.

Abstract Background The administration of a gonadotropin releasing factor (GnRF) analog to pigs has proven to induce antibodies against endogenous GnRF. In gilts (young female pigs), the subsequent blocking of GnRF activity by specific antibodies results in a temporary suppression of ovarian activity and sexual maturation. One pre-clinical and two clinical studies were conducted to assess the ability of the GnRF analog to produce immunologically suppression of the ovarian function, preventing gilts from reaching puberty before harvest, at 27 weeks of age. Results In the three studies, a significant reduction of size and weight of reproductive organs and gilts in oestrus was demonstrated in vaccinated gilts compared with intact gilts. A significant increase in anti-GnRF antibody levels in sera was observed after the 2nd dose, which lasted until the end of the study in each of the protocols used. Progesterone levels were significantly reduced from 6 to 8 weeks after 2nd vaccination in clinical studies 2 and 1 respectively, and from 6 weeks after 2nd vaccination in the pre-clinical study. Estradiol levels were below the limit of detection for clinical study 2 and significantly reduced in vaccinated gilts at the end of the pre-clinical study and the clinical study 1. Conclusions Vaccination of gilts with a GnRF analog with two different protocols (1st dose from 10 to 14 weeks of age, and a 2nd dose 8 or 4 weeks later) was effective in reducing the development of puberty for at least 9 weeks post 2nd dose. These results confirm the flexibility of vaccination programs for veterinarians and producers which can be adapted to pig management practices in commercial farms.

Abstract Diminished ovarian reserve (DOR) is associated with reduced fertility and poor reproductive outcomes. The association between dietary patterns and DOR was not well studied. The purpose of this study was to evaluate the relationship between adhering to the healthy eating index (HEI-2015) and the risk of DOR. In this case–control study, 370 Iranian women (120 with DOR and 250 age- and BMI-matched controls) were examined. A reliable semi-quantitative food frequency questionnaire was used to collect diet-related data. We analyzed the HEI-2015 and their dietary intake data to determine major dietary patterns. The multivariable logistic regression was used in order to analyze the association between HEI-2015 and risk of DOR. We found no significant association between HEI-2015 score and risk of DOR in the unadjusted model (OR 0.78; 95%CI 0.59, 1.03). After controlling for physical activity and energy intake, we observed that women in the highest quartile of the HEI-2015 score had 31% decreased odds of DOR (OR 0.69; 95%CI 0.46, 0.93). This association remained significant even after adjusting for all potential confounders. Overall, increased adherence to HEI may lead to a significant reduction in the odds ratio of DOR. Clinical trials and prospective studies are needed to confirm this association.

Abstract Background Industrial progress has led to the omnipresence of chemicals in the environment of the general population, including reproductive-aged and pregnant women. The reproductive function of females is a well-known target of endocrine-disrupting chemicals. This function holds biological processes that are decisive for the fertility of women themselves and for the health of future generations. However, insufficient research has evaluated the risk of combined mixtures on this function. This study aimed to assess the direct impacts of a realistic exposure to eight combined environmental toxicants on the critical process of folliculogenesis. Methods Female rabbits were exposed daily and orally to either a mixture of eight environmental toxicants (F group) or the solvent mixture (NE group, control) from 2 to 19 weeks of age. The doses were computed from previous toxicokinetic data to reproduce steady-state serum concentrations in rabbits in the range of those encountered in pregnant women. Ovarian function was evaluated through macroscopic and histological analysis of the ovaries, serum hormonal assays and analysis of the expression of steroidogenic enzymes. Cellular dynamics in the ovary were further investigated with Ki67 staining and TUNEL assays. Results F rabbits grew similarly as NE rabbits but exhibited higher total and high-density lipoprotein (HDL) cholesterol levels in adulthood. They also presented a significantly elevated serum testosterone concentrations, while estradiol, progesterone, AMH and DHEA levels remained unaffected. The measurement of gonadotropins, androstenedione, pregnenolone and estrone levels yielded values below the limit of quantification. Among the 7 steroidogenic enzymes tested, an isolated higher expression of Cyp19a1 was measured in F rabbits ovaries. Those ovaries presented a significantly greater density/number of antral and atretic follicles and larger antral follicles without any changes in cellular proliferation or DNA fragmentation. No difference was found regarding the count of other follicle stages notably the primordial stage, the corpora lutea or AMH serum levels. Conclusion Folliculogenesis and steroidogenesis seem to be subtly altered by exposure to a human-like mixture of environmental toxicants. The antral follicle growth appears promoted by the mixture of chemicals both in their number and size, potentially explaining the increase in atretic antral follicles. Reassuringly, the ovarian reserve estimated through primordial follicles number/density and AMH is spared from any alteration. The consequences of these changes on fertility and progeny health have yet to be investigated.

Diminished ovarian reserve (DOR) is associated with reduced fertility and poor reproductive outcomes. The association between dietary patterns and DOR was not well studied. The purpose of this study was to evaluate the relationship between adhering to the healthy eating index (HEI-2015) and the risk of DOR. In this case–control study, 370 Iranian women (120 with DOR and 250 age- and BMI-matched controls) were examined. A reliable semi-quantitative food frequency questionnaire was used to collect diet-related data. We analyzed the HEI-2015 and their dietary intake data to determine major dietary patterns. The multivariable logistic regression was used in order to analyze the association between HEI-2015 and risk of DOR. We found no significant association between HEI-2015 score and risk of DOR in the unadjusted model (OR 0.78; 95%CI 0.59, 1.03). After controlling for physical activity and energy intake, we observed that women in the highest quartile of the HEI-2015 score had 31% decreased odds of DOR (OR 0.69; 95%CI 0.46, 0.93). This association remained significant even after adjusting for all potential confounders. Overall, increased adherence to HEI may lead to a significant reduction in the odds ratio of DOR. Clinical trials and prospective studies are needed to confirm this association. [ABSTRACT FROM AUTHOR]

Introduction: There is a decline in the quality and nutritive value of eggs in aged laying hens. Fruit pomaces with high nutritional and functional values have gained interest in poultry production to improve the performance. Methods: The performance, egg nutritive value, lipidmetabolism, ovarian health, and cecal microbiota abundance were evaluated in aged laying hens (320 laying hens, 345-day-old) fed on a basal diet (control), and a basal diet inclusion of 0.25%, 0.5%, or 1.0% fermented Aronia melanocarpa pomace (FAMP) for eight weeks. Results: The results show that 0.5% FAMP reduced the saturated fatty acids (such as C16:0) and improved the healthy lipid indices in egg yolks by decreasing the atherogenicity index, thrombogenic index, and hypocholesterolemia/hypercholesterolemia ratio and increasing health promotion index and desirable fatty acids (P < 0.05). Additionally, FAMP supplementation (0.25%-1.0%) increased (P < 0.05) the ovarian follicle-stimulating hormone, luteinizing hormone, and estrogen 2 levels, while 1.0% FAMP upregulated the HSD3B1 expression. The expression of VTG II and ApoVLDL II in the 0.25% and 0.5% FAMP groups, APOB in the 0.5% FAMP group, and ESR2 in the 1% FAMP group were upregulated (P < 0.05) in the liver. The ovarian total antioxidant capacity was increased (P < 0.05) by supplementation with 0.25%-1.0% FAMP. Dietary 0.5% and 1.0% FAMP downregulated (P < 0.05) the Keap1 expression, while 1.0% FAMP upregulated (P < 0.05) the Nrf2 expression in the ovary. Furthermore, 1.0% FAMP increased cecal acetate, butyrate, and valerate concentrations and Firmicutes while decreasing Proteobacteria (P < 0.05). Conclusion: Overall, FAMP improved the nutritive value of eggs in aged laying hens by improving the liver-blood-ovary function and cecal microbial and metabolite composition, which might help to enhance economic benefits. [ABSTRACT FROM AUTHOR]

Background: Industrial progress has led to the omnipresence of chemicals in the environment of the general population, including reproductive-aged and pregnant women. The reproductive function of females is a well-known target of endocrine-disrupting chemicals. This function holds biological processes that are decisive for the fertility of women themselves and for the health of future generations. However, insufficient research has evaluated the risk of combined mixtures on this function. This study aimed to assess the direct impacts of a realistic exposure to eight combined environmental toxicants on the critical process of folliculogenesis. Methods: Female rabbits were exposed daily and orally to either a mixture of eight environmental toxicants (F group) or the solvent mixture (NE group, control) from 2 to 19 weeks of age. The doses were computed from previous toxicokinetic data to reproduce steady-state serum concentrations in rabbits in the range of those encountered in pregnant women. Ovarian function was evaluated through macroscopic and histological analysis of the ovaries, serum hormonal assays and analysis of the expression of steroidogenic enzymes. Cellular dynamics in the ovary were further investigated with Ki67 staining and TUNEL assays. Results: F rabbits grew similarly as NE rabbits but exhibited higher total and high-density lipoprotein (HDL) cholesterol levels in adulthood. They also presented a significantly elevated serum testosterone concentrations, while estradiol, progesterone, AMH and DHEA levels remained unaffected. The measurement of gonadotropins, androstenedione, pregnenolone and estrone levels yielded values below the limit of quantification. Among the 7 steroidogenic enzymes tested, an isolated higher expression of Cyp19a1 was measured in F rabbits ovaries. Those ovaries presented a significantly greater density/number of antral and atretic follicles and larger antral follicles without any changes in cellular proliferation or DNA fragmentation. No difference was found regarding the count of other follicle stages notably the primordial stage, the corpora lutea or AMH serum levels. Conclusion: Folliculogenesis and steroidogenesis seem to be subtly altered by exposure to a human-like mixture of environmental toxicants. The antral follicle growth appears promoted by the mixture of chemicals both in their number and size, potentially explaining the increase in atretic antral follicles. Reassuringly, the ovarian reserve estimated through primordial follicles number/density and AMH is spared from any alteration. The consequences of these changes on fertility and progeny health have yet to be investigated. [ABSTRACT FROM AUTHOR]

Simple Summary: Though chemotherapy is generally known to be effective in the fight against cancer, its application is associated with a number of side effects, including toxic impacts on the ovaries. The most ovotoxic cytostatic chemotherapeutics are the classical alkylating compounds, particularly cyclophosphamide. Thus, it is of utmost importance to find effective means to protect ovaries against the negative influence of chemotherapeutic agents. This review paper presents the results of the current research work on the hitherto proposed agents potentially protecting the functions and state of ovaries exposed to chemotherapy. A large body of promising results have been reported, but as presented, it is necessary to undertake thorough and comprehensive studies aimed at providing an explicit evaluation of the efficacy of selected ovoprotecting agents and their possible clinical use in the future. Chemotherapy is one of the leading cancer treatments. Unfortunately, its use can contribute to several side effects, including gynotoxic effects in women. Ovarian reserve suppression and estrogen deficiency result in reduced quality of life for cancer patients and are frequently the cause of infertility and early menopause. Classic alkylating cytostatics are among the most toxic chemotherapeutics in this regard. They cause DNA damage in ovarian follicles and the cells they contain, and they can also induce oxidative stress or affect numerous signaling pathways. In vitro tests, animal models, and a few studies among women have investigated the effects of various agents on the protection of the ovarian reserve during classic chemotherapy. In this review article, we focused on the possible beneficial effects of selected hormones (anti-Müllerian hormone, ghrelin, luteinizing hormone, melatonin), agents affecting the activity of apoptotic pathways and modulating gene expression (C1P, S1P, microRNA), and several natural (quercetin, rapamycin, resveratrol) and synthetic compounds (bortezomib, dexrazoxane, goserelin, gonadoliberin analogs, imatinib, metformin, tamoxifen) in preventing gynotoxic effects induced by commonly used cytostatics. The presented line of research appears to provide a promising strategy for protecting and/or improving the ovarian reserve in the studied group of cancer patients. However, well-designed clinical trials are needed to unequivocally assess the effects of these agents on improving hormonal function and fertility in women treated with ovotoxic anticancer drugs. [ABSTRACT FROM AUTHOR]

In this study, we aimed to explore the effect and underlying mechanism of aging in female ovarian function in mice. The mice at the age of 10 months and 7 weeks were used as the aged model and the young control. The estrus cycle and serum peripheral blood and the number of follicles, oocytes and litter size were also calculated for analysis of ovarian function. Ovarian cells were collected for reactive oxygen species (ROS) and Annexin V staining. Antioxidant and apoptotic proteins BAX and Caspase-3 and phosphoinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in ovaries were also detected. The results showed that compared to the young control, the aged mice exhibited ovarian dysfunction with disrupted estrus cycle and hormone production, accompanied by decreases in the numbers of follicles, oocytes and litter size. The oxidative damage in aged ovarian tissues was induced with increased Malondialdehyde content and reduced activities of Catalase and Superoxide Dismutase enzymes, as well as high level of ROS accumulation and apoptosis in ovarian cells. Furthermore, the expression levels of BAX, Caspase-3 and PI3K, Akt, mTOR and their phosphorylated forms were obviously regulated in the aged ovaries. Thus, these results above suggest oxidative damage with high level of ROS is obviously induced in ovarian tissues of aged mice, and this accumulation mediates apoptosis of ovarian cells, involving with improved expression of apoptotic protein BAX and Caspase-3, ultimately leads to ovarian dysfunction through the PI3K/Akt/mTOR pathway. [ABSTRACT FROM AUTHOR]

Purpose: To determine the impact of dose-dense chemotherapy administration on ovarian reserve in women undergoing treatment for breast cancer. Patients and Methods: We conducted a retrospective cohort study of reproductive age women who underwent dose-dense chemotherapy regimens with doxorubicin hydrochloride and cyclophosphamide with or without paclitaxel for a new diagnosis of breast cancer. We compared pre- and post-treatment serum antimullerian hormone (AMH) levels and assessed changes in AMH over time. Results: Fifty-seven patients met inclusion criteria. Median pre-treatment AMH was 2.9 ng/mL, whereas post-treatment AMH was 0.1 ng/mL, demonstrating a dramatic reduction in AMH levels after treatment with a dose-dense regimen. This change was independent of age and was sustained over 12 months from treatment completion. Conclusions: Dose-dense chemotherapy regimens for breast cancer lead to marked and sustained decreases in AMH irrespective of patient age. [ABSTRACT FROM AUTHOR]

The mouse estrous cycle is divided into four stages: proestrus (P), estrus (E), metestrus (M), and diestrus (D). The estrous cycle affects reproductive hormone levels in a wide variety of tissues. Therefore, to obtain reliable results from female mice, it is important to know the estrous cycle stage during sampling. The stage can be analyzed from a vaginal smear under a microscope. However, it is time-consuming, and the results vary between evaluators. Here, we present an accurate and reproducible method for staging the mouse estrous cycle in digital whole-slide images (WSIs) of vaginal smears. We developed a model using a deep convolutional neural network (CNN) in a cloud-based platform, Aiforia Create. The CNN was trained by supervised pixel-level multiclass semantic segmentation of image features from 171 hematoxylin-stained samples. The model was validated by comparing the results obtained by CNN with those of four independent researchers. The validation data included three separate studies comprising altogether 148 slides. The total agreement attested by the Fleiss kappa value between the validators and the CNN was excellent (0.75), and when D, E, and P were analyzed separately, the kappa values were 0.89, 0.79, and 0.74, respectively. The M stage is short and not well defined by the researchers. Thus, identification of the M stage by the CNN was challenging due to the lack of proper ground truth, and the kappa value was 0.26. We conclude that our model is reliable and effective for classifying the estrous cycle stages in female mice. [ABSTRACT FROM AUTHOR]

Reproductive success is crucial in dairy farming as it heavily relies on the consumption of a complete mixed ration for the diet. The current study investigated the effects of adding saturated (SFA) and polyunsaturated fatty acids (PUFAs) to dairy cows' diets on reproductive performance and reproductive hormones during the transition period. A total of 30 Holstein dairy cows were randomly divided into three groups (10 animals in each group), based on parity and body condition score. The cows had an initial body weight of 567.5 ± 40.3 kg (mean ± SD), a body condition score of 3.5 ± 0.26 out of 5 (mean ± SD), and a parity of 1.7 ± 0.02 (mean ± SD). The control group received a balanced ration meeting all the nutrient requirements according to the National Research Council (NRC) guidelines. The SFA group received 1.4% of dry matter (DM) as palm oil (RumiFat®), while the omega group had 5% of DM as safflower (a source of n-6 fatty acids) added from 21 days before parturition to 21 days after, and 4% of DM as flaxseed (a source of n-3 fatty acids) added from 21 to 42 days after parturition. In the Omega group, estradiol concentration significantly increased on artificial insemination (AI) day (12.54 pg/mL). Additionally, serum prostaglandin F2-alpha concentration was significantly higher in the omega group (0.732 pg/mL on day 7 and 1.68 pg/mL on day 14) compared to other groups. The control group exhibited the highest progesterone concentrations at 14 and 21 days post-calving compared to the other groups, other groups. whereas the omega group highest concentration five days after AI. The omega group also showed a significantly higher mean number of follicles >10mm and larger ovulatory follicle diameter. Moreover, a higher percentage of pregnant cows at 120 days in milk, fewer open days, and lower service per conception were observed in the omega group compared to the other groups. In conclusion, supplementing dairy cows' diets with PUFAs during the transition period positively influenced ovarian function, hormone levels, and reproductive performance. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) have attracted significant attention due to their environmental toxicity. However, the detrimental impact of PFAS on the development of the female reproductive system remains controversial. In this study, we investigated the effects of three specific PFAS compounds perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) on ovarian development. Among these compounds, PFDA demonstrated the most pronounced cytotoxic effect on ovarian granulosa cells. The results showed that a 200 μM concentration of PFDA induced cell apoptosis via the intrinsic pathway by elevating reactive oxygen species (ROS) levels and activating Caspase-9 and Caspase-3. Furthermore, 200 μM PFDA triggered necroptosis, a form of regulated cell death (RCD), through the receptor-interacting serine/threonine kinase 1 (RIPK1), receptor interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like protein (MLKL) axis, mediated by inhibition of the canonical apoptosis proteolytic enzyme Caspase-8. In vivo experiments confirmed that mice exposed to PFDA displayed a significantly reduced ovarian index compared to the control group, accompanied by evident follicular atresia. Ovarian tissues from the PFDA-exposed group showed upregulated necroptosis markers, which were effectively mitigated by inhibiting the phosphorylation of RIPK1 at Ser166. Importantly, this study provides the first evidence that PFDA disrupts ovarian development through a novel mechanism involving the RIPK1-mediated necroptosis pathway, alongside the detection of the intrinsic apoptosis pathway. This greatly expands our insight into the effects of PFDA on cell death. This finding highlights the potential public health hazards associated with PFDA exposure and emphasizes the need for further research to fully understand its broader implications.

Abstract Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune‐mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)‐KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL‐KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)‐dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep‐deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

Objective We aimed to predict the risk of postoperative adjuvant therapy using preoperative variables in young patients with early stage cervical cancer. The predicted risk can guide whether ovarian transposition should be performed during surgery. Methods In total, 886 patients with stage IB1-IIA cervical cancer aged 20–45 years who underwent modified radical or radical hysterectomy between January 2000 and December 2008 were included. Preoperative variables, preoperative laboratory findings, International Federation of Gynaecology and Obstetrics stage, tumor size, and pathological variables were collected. Patients with high risk factors or those who met the Sedlis criteria were considered adjuvant therapy risk (+); others were considered adjuvant therapy risk (−). A decision-tree model using preoperative variables was constructed to predict the risk of adjuvant therapy. Results Of 886 patients, 362 were adjuvant therapy risk (+) (40.9%). The decision-tree model with four distinct adjuvant therapy risks using tumor size and age were generated. Specifically, patients with tumor size ≤2.45 cm had low risk (49/367; 13.4%), those with tumor size ≤3.85 cm and >2.45 cm had moderate risk (136/314; 43.3%), those with tumor size >3.85 cm and age ≤39.5 years had high risk (92/109; 84.4%), and those with tumor size >3.85 cm and age >39.5 years had the highest risk (85/96; 88.5%). Conclusion The risk of postoperative adjuvant therapy in young patients with early stage cervical cancer can be predicted using preoperative variables. We can decide whether ovarian transposition should be performed using the predicted risk.

Abstract Objectives Currently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence. Materials and methods In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function. Results The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow. Conclusions Multiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women.

Abstract Background Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF. Methods 10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells. Results We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells. Conclusion Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF. Graphical abstract

Long non-coding RNAs (lncRNAs) have attracted significant scientific attention due to their central role in regulating gene expression and their profound impact on the intricate mechanisms of ovarian function. These versatile molecules exert their influence through various mechanisms, including the coordination of transcription processes, modulation of post-transcriptional events, and the shaping of epigenetic landscapes. Furthermore, lncRNAs function as competitive endogenous RNAs (ceRNAs), engaging in intricate interactions with microRNAs (miRNAs) to finely adjust the expression of target genes. The intricate lncRNA-miRNA-mRNA network serves as a crucial determinant in governing the multifaceted physiological functions of the ovaries. It holds substantial potential in unraveling the causes and progression of reproductive disorders and, importantly, in identifying new therapeutic targets and diagnostic markers for these conditions. A comprehensive comprehension of lncRNAs and their ceRNA activities within the domain of ovarian biology could potentially lead to groundbreaking advancements in clinical interventions and management strategies. This exploration of lncRNAs and their intricate involvement in the regulatory framework provides an extensive platform for deciphering the complex nature of ovarian physiology and pathology. The ongoing progress in this field, which encompasses in-depth investigations into the functional roles of specific lncRNAs, the elucidation of their complex interactions with miRNAs, and the comprehensive profiling of their expression patterns, holds the promise of making significant contributions to our understanding of ovarian biology and reproductive disorders. Ultimately, these breakthroughs will have wide-ranging translational implications, paving the way for the development of precision therapies and personalized medicine strategies to address the myriad challenges in the realm of reproductive health.

AbstractThe global rise in life expectancy corresponds with a delay in childbearing age among women. Ovaries, seen as the chronometers of female physiological aging, demonstrate features of sped up aging, evidenced by the steady decline in both the quality and quantity of ovarian follicles from birth. The multifaceted pathogenesis of ovarian aging has kindled intensive research interest from the biomedical and pharmaceutical sectors. Novel studies underscore the integral roles of gut microbiota in follicular development, lipid metabolism, and hormonal regulation, forging a nexus with ovarian aging. In this review, we outline the role of gut microbiota in ovarian function (follicular development, oocyte maturation, and ovulation), compile and present gut microbiota alterations associated with age-related ovarian aging. We also discuss potential strategies for alleviating ovarian aging from the perspective of gut microbiota, such as fecal microbiota transplantation and probiotics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Diminished ovarian reserve has a serious impact on female reproduction with an increasing incidence every year. An important cause of this is oxidative stress. Rubi fructus, a traditional medicinal and edible plant, has shown therapeutic effects against gynecological diseases. Vanillic acid, isoquercitrin, kaempferol‐3‐O‐rutinoside, kaempferol‐3‐O‐sophoroside, oleanolic acid, tormentic acid, tiliroside, and ellagic acid are the major bioactive components in R. fructus. However, studies involved in the effectiveness and mechanism of these components in oxidative stress‐induced ovarian dysfunction are scarce. RESULTS: In this study, the protective mechanisms of the bioactive components were evaluated in human ovarian granulosa cells. Isoquercitrin was significantly superior to other bioactive components in relieving damage in human ovarian granulosa cells induced by 2,2‐azobis (2‐methylpropionamidine) dihydrochloride, considering enhanced cell viability, reduced reactive oxygen species accumulation, and improved mitochondrial membrane potential level. Isoquercitrin protected human ovarian granulosa cells from oxidative stress by regulating the enzyme activity of glutathione peroxidase, inhibiting cell apoptosis, improving the expression of genes related to oxidative stress, and ameliorating heme oxygenase 1 protein expression. CONCLUSION: Isoquercitrin, a bioactive component in R. fructus, has a significant protective effect on oxidative damage induced by 2,2‐azobis (2‐methylpropionamidine) dihydrochloride in human ovarian granulosa cells, providing evidence for its potential application in protecting ovarian function. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF. Methods: 10 × Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells. Results: We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells. Conclusion: Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF. [ABSTRACT FROM AUTHOR]

Objectives: Currently, no approved stem cell-based therapies for preserving ovarian function during aging. To solve this problem, we developed a long-term treatment for human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs). We investigated whether the cells retained their ability to resist ovarian aging, which leads to delayed reproductive senescence. Materials and methods: In a middle-aged female model undergoing natural aging, we analyzed whether hESC-MPCs benefit the long-term maintenance of reproductive fecundity and ovarian reservoirs and how their transplantation regulates ovarian function. Results: The number of primordial follicles and mice with regular estrous cycles were increased in perimenopausal mice who underwent multiple introductions of hESC-MPCs compared to age-matched controls. The estradiol levels in the hESC-MPCs group were restored to those in the young and adult groups. Embryonic development and live birth rates were higher in the hESC-MPC group than in the control group, suggesting that hESC-MPCs delayed ovarian senescence. In addition to their direct effects on the ovary, multiple-treatments with hESC-MPCs reduced ovarian fibrosis by downregulating inflammation and fibrosis-related genes via the suppression of myeloid-derived suppressor cells (MDSCs) produced in the bone marrow. Conclusions: Multiple introductions of hESC-MPCs could be a useful approach to prevent female reproductive senescence and that these cells are promising sources for cell therapy to postpone the ovarian aging and retain fecundity in perimenopausal women. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, which is frequently accompanied by insulin resistance, oxidative stress (OS), and dyslipidemia. Astragalus polysaccharide (APS)—as a water-soluble heteropolysaccharide—can lower blood sugar and lipid and exert anti-aging effects and thus has been proven to be beneficial to various types of metabolic diseases. However, specific mechanisms of the action of APS on PCOS are yet to be studied. Methods: Herein, BALB/C female mice aged 3 weeks were randomly divided into three groups (10 mice/group): oil + PBS group, DHEA + PBS group, and DHEA + APS group. Changes in the estrous cycle, ovarian tissue sections, serum levels of the hormone, blood glucose, blood lipid, and OS were studied. The intestinal microbiome was sequenced and Spearman correlation analysis was used to analyze the correlation between serum metabolic indexes and microflora. Results: The results revealed that APS treatment ameliorated insulin resistance, OS, and dyslipidemia in PCOS mice. The results of 16S rDNA sequencing indicated that there were significant differences in the composition and diversity of intestinal microorganisms between DHEA and APS treatments. Firmicutes, Lachnospiraceae, Bacilli, Lactobacillaceae, and Lachnospiraceae_NK4A13_group were abundant in the oil + PBS group. Bacteroidota and Muribaculaceae were enriched in the DHEA + PBS group, while Rikenellaceae, Odoribacter, and Marinifilaceae were enriched in the DHEA + APS group. Furthermore, Spearman correlation analysis showed that there were close interactions and correlations between intestinal bacteria and indicators of blood glucose, blood lipids, steroid hormones, and OS in PCOS mice. Conclusions: Overall, the study showed that APS improved PCOS in mice by correcting serum metabolic disorders and increasing microbiome diversity, which may provide insight into understanding the pathogenesis and be a beneficial intervention for PCOS. [ABSTRACT FROM AUTHOR]

ABSTRACT: Little information is available on the effect of Hericium erinaceus polysaccharides (HEP) on laying hens, especially on improving liver and ovarian health and function. Therefore, this study was conducted to investigate the impacts of HEP on liver and ovarian function to delay the decline in the laying performance of aged hens. A total of 360 fifty-eight-wk-old laying hens were randomly allocated to 4 treatments, with 6 replicates of 15 birds each. After 2 wk of adaptation, the birds were fed basal diet (CON) or basal diets supplemented with 250, 500, and 750 mg/kg of HEP (HEP250, HEP500, and HEP 750, respectively) for 12 wk. The results showed that, compared with CON, hens fed HEP had significantly increased laying performance (P < 0.05) and promoted follicle development, as evidenced by the increased numbers of hierarchical follicles, small follicles, and total follicles (P < 0.05). Birds fed 500 mg/kg of HEP improved the liver function by increasing T-AOC activity (P < 0.05) and decreasing hepatic oxidative stress and inflammatory responses (inflammatory cell infiltration) caused by aging. The lipid metabolism was improved, and yolk precursor synthesis was promoted in the liver of HEP-treated laying hens by upregulating the mRNA expression of FAS, MTTP, PPAR-α, APOVLDL-Ⅱ, and VTG-Ⅱ (P < 0.05). In addition, HEP significantly decreased ovarian inflammation by regulating the mRNA levels of NF-κB, IL-1β, IL-6, and TNF-α (P < 0.05). As a result, the contents of E2, LH, and FSH in serum and the gene expression of ERα of the liver and FSHR of the ovary increased in HEP-treated hens (P < 0.05). In conclusion, dietary HEP supplementation exhibited potential hepatic and ovarian protective effects, thereby increasing the laying performance of aged hens by enhancing reproductive hormone secretion hormone secretion and promoting yolk precursor synthesis and follicle development via the liver–blood–ovary axis. The optimal supplementation level of HEP in aged hens was 500 mg/kg.

ABSTRACT: Studies have reported that theabrownin can moderate the lipid metabolism and intestinal microbiota, thereby affecting the health of humans and model animals, however the research on laying hens is scarce. The present study aimed to investigate the effects of dietary theabrownin supplementation on lipid metabolism, microbial composition and ovarian function in laying hens. A total of 80 laying hens (25 wk of age) were fed with normal diet (CON) and normal diet +100 mg/kg theabrownin (PT group) for 12 wk. The results showed that the addition of theabrownin enhanced villus height of duodenum and decreased crypt depth of jejunum (P < 0.05). At the same time, compared with CON, the concentration of IL-6 and the mRNA expression of IL-1β and IL-6 were decreased significantly in PT group (P < 0.05). Dietary theabrownin reduced the concentration of total cholesterol and glycerol, while decreased lipid droplet optical density in liver (P < 0.05). Compared with CON group, the mRNA expression of PPARγ, HMG-CoAS, ACC were down-regulated and the mRNA expression of CYP8B1 was up-regulated in PT group (P < 0.05). The ACE, Chao1 and Observed_species indexes in cecum microbiota were increased by PT group intervention (P < 0.05). Dietary PT supplementation enhanced the relative abundance of Firmicutes (phylum), Lactobacillus (genus) and the Firmicutes to Bacteroidetes ratio, and reduced the relative abundance of Bacteroidetes (phylum) in cecum (P < 0.05). The organic acids and its derivatives were up-regulated by theabrownin intervention in serum metabolites (P < 0.05). Dietary theabrownin supplementation resulted in higher mRNA expression of Bcl-2 and SIRT1 in ovary and increased the concentration of estradiol in serum (P < 0.05). These discovering indicated that dietary theabrownin supplementation enhanced the intestinal function and influenced serum metabolism by improving intestinal morphology, microbiota community structure and reducing the concentration and expression of inflammatory cytokines in intestine. Dietary theabrownin reduced hepatic lipid deposition and it also decreased the cell apoptosis rate to improve ovarian function and egg weight which were associated with the SIRT1 pathway.

Abstract Purpose PAQR7 plays a key role in cell apoptosis as a progesterone membrane receptor. The physiological mechanism of PAQR7 in ovarian function and its anti-apoptotic action in mammals remain poorly understood. Methods We first added 0.2 µM aminoglutethimide (AG), an inhibitor of endogenous progesterone (P4) secretion, and transfected siPAQR7 co-incubated with P4 in human KGN cells to identify granulosa cell apoptosis, respectively. Additionally, we used Paqr7 knockout (PAQR7 KO) mice to assess the role of PAQR7 in the ovary. Results The PAQR7 deficiency significantly increased apoptosis of KGN cells, and this significant difference disappeared following P4 supplementation. The Paqr7 −/− female mice showed a prolonged estrous cycle, reduced follicular growth, increased the number of atresia follicles, and decreased the concentrations of E2 and AMH. The litters, litter sizes, and spontaneous ovulation in the Paqr7−/− mice were significantly decreased compared with the Paqr7+/+ mice. In addition, we also found low expression of PAQR7 in GCs from human follicular fluids of patients diagnosed with decreased ovarian reserve (DOR) and ovaries of mice with a DOR-like phenotype, respectively. Conclusions The present study has identified that PAQR7 is involved in mouse ovarian function and fertilization potential. One possible mechanism is mediating the anti-apoptotic effect of P4 on GC apoptosis via the BCL-2/BAX/CASPASE-3 signaling pathway. The mechanism underlying the effect of PAQR7 on ovarian development and aging remains to be identified.

Purpose: PAQR7 plays a key role in cell apoptosis as a progesterone membrane receptor. The physiological mechanism of PAQR7 in ovarian function and its anti-apoptotic action in mammals remain poorly understood. Methods: We first added 0.2 µM aminoglutethimide (AG), an inhibitor of endogenous progesterone (P4) secretion, and transfected siPAQR7 co-incubated with P4 in human KGN cells to identify granulosa cell apoptosis, respectively. Additionally, we used Paqr7 knockout (PAQR7 KO) mice to assess the role of PAQR7 in the ovary. Results: The PAQR7 deficiency significantly increased apoptosis of KGN cells, and this significant difference disappeared following P4 supplementation. The Paqr7−/− female mice showed a prolonged estrous cycle, reduced follicular growth, increased the number of atresia follicles, and decreased the concentrations of E2 and AMH. The litters, litter sizes, and spontaneous ovulation in the Paqr7−/− mice were significantly decreased compared with the Paqr7+/+ mice. In addition, we also found low expression of PAQR7 in GCs from human follicular fluids of patients diagnosed with decreased ovarian reserve (DOR) and ovaries of mice with a DOR-like phenotype, respectively. Conclusions: The present study has identified that PAQR7 is involved in mouse ovarian function and fertilization potential. One possible mechanism is mediating the anti-apoptotic effect of P4 on GC apoptosis via the BCL-2/BAX/CASPASE-3 signaling pathway. The mechanism underlying the effect of PAQR7 on ovarian development and aging remains to be identified. [ABSTRACT FROM AUTHOR]

Background: Hysterectomy is the commonest gynecological surgery in females. The aim of this study was to assess the effect of doing hysterectomy with ovarian conservation on the ovarian function. Methods: It was an observational cross-sectional study which was conducted in the department of obstetrics and gynecology, Zagazig University Hospitals on 80 cases scheduled to undergo hysterectomy with ovarian preservation due to benign condition during the period from August 2015 to August 2018. Participants were subjected to assessment of ovarian function by ultrasonographic assessment of ovarian volume, morphology and hormonal levels pre-operative and postoperative. The research was accepted by the Institutional Review Board of the Faculty of Medicine in Zagazig University. The research was done according to the Code of Ethics of the World Medical Association (Declaration Helsinki) for Studies involving humans. Results: There was a statistically non-significant decrease in FSH level preoperatively to one month postoperatively that significantly increased again three months postoperatively.. There was a non-significant difference between right ovarian volume preoperatively and one month postoperatively. There was a significant difference between right ovarian volume preoperatively and three months postoperatively. Conclusions: we concluded that there was no evidencve of adverse effect on the ovarian function of the conserved ovaries 3 months after doing hysterectomy in premenopausal patients as by hormonal and U/S criteria. [ABSTRACT FROM AUTHOR]

Prostaglandins are synthesized from arachidonic acid through the catalytic activities of cyclooxygenase, while the production of different prostaglandin types, prostaglandin F2 alpha (PGF) and prostaglandin E2 (PGE), are regulated by specific prostaglandin synthases (PGFS and PGES). Prostaglandin ligands (PGF and PGE) bind to specific high‐affinity receptors and initiate biologically distinct signalling pathways. In the ovaries, prostaglandins are known to be important endocrine regulators of female reproduction, in addition to maintaining local function through autocrine and/or paracrine effect. Many research groups in different animal species have already identified a variety of factors and molecular mechanisms that are responsible for the regulation of prostaglandin functions. In addition, prostaglandins stimulate their intrafollicular and intraluteal production via the pathway of prostaglandin self‐regulation in the ovary. Therefore, the objective of the review article is to discuss recent findings about local regulation patterns of prostaglandin ligands PGF and PGE during different physiological stages of ovarian function in domestic ruminants, especially in bovine. In conclusion, the discussed local regulation mechanisms of prostaglandins in the ovary may stimulate further research activities in different methodological approaches, especially during final follicle maturation and ovulation, as well as corpus luteum formation and function. [ABSTRACT FROM AUTHOR]

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The vascular network contributes to the development of follicles. However, the therapeutic mechanism between vascular remodeling and ovarian functions is still unclear. Therefore, we demonstrated whether increased HGF by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in an ovariectomized rat model via vascular remodeling by Wnt signaling activation. We established a half-ovariectomized rat model in which damaged ovaries were induced by ovariectomy of half of each ovary, and PD-MSCs (5 × 105 cells) were transplanted by intravenous injection. Three weeks after transplantation, rats in all groups were sacrificed. We examined the secretion of HGF by PD-MSCs through culture medium. The vascular structure in injured ovarian tissues was restored to a greater extent in the PD-MSC transplantation (Tx) group than in the nontransplantation (NTx) group (* p < 0.05). The expression of genes related to Wnt signaling (e.g., LRP6, GSK3β, β-catenin) was significantly increased in the Tx group compared to the NTx group (* p < 0.05). However, the expression of genes related to vascular permeability (e.g., Asef, ERG3) was significantly decreased in the Tx group compared to the NTx group (* p < 0.05). Follicular development was improved in the Tx group compared to the NTx group (* p < 0.05). Furthermore, to evaluate vascular function, we cocultivated PD-MSCs after human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and we analyzed the vascular formation assay and dextran assay in HUVECs. Cocultivation of PD-MSCs with injured HUVECs enhanced vascular formation and decreased endothelial cell permeability (* p < 0.05). Also, cocultivation of PD-MSCs with explanted ovarian tissues improved follicular maturation compared to cocultivation of the Wnt inhibitor-treated PD-MSCs with explanted ovarian tissues. Therefore, HGF secreted by PD-MSCs improved ovarian function in rats with ovarian dysfunction by decreasing vascular permeability via Wnt signaling. [ABSTRACT FROM AUTHOR]

Abstract Background Follicular development in mammalian ovaries is a complex and dynamic process, and the interactions and regulatory-feedback loop between the follicular microenvironment, granulosa cells (GCs), and oocytes can affect follicular development and normal ovary functions. Abnormalities in any part of the process may cause abnormal follicular development, resulting in infertility. Hence, exploring the pathogenesis of abnormal follicular development is extremely important for diagnosing and treating infertile women. Methods RNA sequencing was performed with ovarian cortical tissues established in vitro. In situ-hybridization assays were performed to study microRNA-338-3p (miR-338-3p) expressed in GCs and oocytes. In vitro culture models were established with GCs and neonatal mouse ovaries to study the biological effects of miR-338-3p. We also performed in vivo experiments by injecting adeno-associated virus vectors that drive miR-338-3p overexpression into the mouse ovarian bursae. Results Sequencing analysis showed that miR-338-3p was expressed at significantly higher levels in ovarian cortical tissues derived from patients with ovarian insufficiency than in cortical tissues derived from patients with normal ovarian function; miR-338-3p was also significantly highly expressed in the GCs of patients with diminished ovarian reserve (P

Cervical cancer in pregnancy (CCIP) refers to cervical cancer diagnosed during pregnancy, the most common gynecological malignant tumor. Because of the special physiological changes of CCIP, although preserving ovarian function and fertility is very important, the methods are very limited. There is no guideline or consensus on the preservation methods of ovarian function and fertility in this special period. Therefore, the Committee of Fertility Protection and Preservation of China Association for the Promotion of Health Science and Technology, combined with the Chinese Society of Gynecological Endocrinology affiliated to the International Society of Gynecological Endocrinology, Society Endocrinology Branch of Beijing Institute of Obstetrics & Gynecology, combined with Society on Fertility Preservation affiliated with the Chinese Preventive Medicine Association, organized relevant experts from different disciplines to formulate this consensus, in order to guide ovarian function and fertility preservation of CCIP patients.

Objective: The purpose of this study was to explore the effect of removal of different volumes of ovarian tissue on fertility and offspring development of SD rats. Methods: SD rats were randomly divided into 6 groups according to different volumes of ovariectomy: Sham group (n=6), non-ovariectomized; 25%-OVX group (n=6), with half of the left ovary excised; 50%-OVX group (n=5), with the left ovary excised; 75%-OVX group (n=5), with the left ovary and half of the right ovary excised; 87.5%-OVX group (n=6), with the left ovary and three quarters of the right ovary excised; 100%-OVX group (n=6), with bilateral ovaries excised. These female rats (F0) were mated with healthy male rats one and four months after the surgery, and the offspring of F0 rats were named F11mon and F14mon, respectively. The number of days from mating to delivery and number of live cubs were recorded. At postnatal day 21 (P21), the body weight, length and anogenital distance (AGD) of the cubs were measured. Results: There were no differences in the number of live cubs between 25%- OVX, 50%-OVX and sham groups. Rats in the 87.5%-OVX group did not give birth at 1 month and 4 months after the operation. When compared with the sham group, the body weight and length of F11mon at P21 were increased in 25%-OVX group and 50%-OVX group. However, after the second delivery, we controlled each mother’s lactation to no more than eight pups. As a result, there were no differences in the body weight, length and AGD of F14mon compared with sham group. Conclusion: Removal of less than 50% of the ovaries did not affect the fertility of rats and offspring development of rats. [ABSTRACT FROM AUTHOR]

Macrophages (MΦs) are the most abundant leukocytes in mammalian ovaries that have heterogeneity and plasticity. A body of evidence has indicated that these cells are important in maintaining ovarian homeostasis and they play critical roles in ovarian physiological events, such as folliculogenesis, ovulation, corpus luteum formation and regression. As females age, ovarian tissue microenvironment is typified by chronic inflammation with exacerbated ovarian fibrosis. In response to specific danger signals within aged ovaries, macrophages polarize into different M1 or M2 phenotypes, and specialize in unique functions to participate in the ovarian aging process. In this review, we will focus on the physiologic roles of MΦs in normal ovarian functions. Furthermore, we will discuss the roles of MΦs in the process of ovarian senescence, as well as the novel techniques applied in this field. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a common immune disease with early symptoms of joint swelling, morning stiffness, pain, and swelling. It could develop into a joint deformity as the disease progresses, resulting in the loss of normal joint function and seriously affecting the patient's quality of life. Methotrexate is the "anchor drug" for rheumatoid arthritis treatment, which has an immunosuppressive effect and could effectively prevent the abnormal activation of B cells in vivo, inhibit the abnormal generation of cytokines, and relieve related symptoms. However, in some cases, methotrexate alone is not ideal and often needs to be combined with other drugs like xianlinggubao capsules. This study has provided an experimental basis for the combined efficacy of methotrexate and xianlinggubao capsules for female patients with moderate to severe rheumatoid arthritis and their impact on ovarian function. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association between the polymorphic variants of chromosomes and menstrual disorders. Methods: The data from our previous retrospective, single-center cohort study were re-analyzed. Women with regular menstruation were included as controls. Women with menstrual cycle abnormalities were subgrouped according to reproductive causes. The frequency of chromosomal polymorphisms was compared between groups. Regression analysis was used to adjust for potential confounding variables. Result: A total of 24,578 women composed of 8062 women with regular cycles as the control group and 16,516 women as the menstrual cycle irregularity group were included. When compared with the control group, the incidence of chromosomal polymorphisms in the total menstrual cycle irregularity group, Polycystic ovary syndrome group, and Primary ovarian insufficiency group were significantly higher (4.49% versus 5.34%, P = 0.004, 4.49% versus 5.35%, P = 0.018 and 4.49% versus 5.94%, P = 0.002, respectively). The incidences of inv(9) in the Primary ovarian insufficiency group were significantly higher than that in the control individuals (1.0% versus 1.6%, P = 0.024). Logistic regression analysis showed an effect of chromosomal polymorphisms on menstrual cycle irregularity (OR: 1.62, 95% CI: 1.234–2.187, P = 0.007; adjusted OR: 1.46, 95% CI: 1.153–1.819, P < 0.001). The result demonstrated an effect of chromosomal polymorphisms on the Primary ovarian insufficiency group (OR: 2.52, 95% CI: 1.307–5.177, P < 0.001; adjusted OR: 2.61, 95% CI: 1.371–4.605, P < 0.001). Conclusion: The study suggests chromosomal polymorphisms adversely affect female menstrual cycle irregularity. [ABSTRACT FROM AUTHOR]