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Polycystic ovary syndrome (PCOS) is the most common endocrine-related reproductive disorder in women of reproductive age, accompanied by both the impairment of female fecundity and a risk of metabolic disorders. PCOS is emphasized as a worldwide concern due to its unknown etiology and lack of specific medications. The current study aimed to evaluate the effects of L-tartaric acid, an abundantly occurring compound in fruits, on the histostereological and hormonal changes caused by PCOS. Forty adult Sprague Dawley rats were randomly divided into four groups including controls (no intervention), Tartaric acid (40mg/Kg/day from day 21 onwards for 39 days), PCOS (21 days letrozole and then normal saline orally for 39 days), and PCOS + Tartaric acid. After treatments, the ovarian histostereological analysis as well as the level of reproductive hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, progesterone, and testosterone was measured. PCOS caused a significant decrease in the number of unilaminar, multilaminar, antral, and graafian follicles and increased follicular atresia (p-value < 0.001). Moreover, the weight and volume of ovarian tissue and related structures including cortex, medulla, and cysts increased significantly (p-value < 0.0001). However, corpus luteum volume was significantly decreased (p-value < 0.001). Although significant differences were found in some parameters with the control group (p-value < 0.05), the administration of tartaric acid restored the pathological effects of PCOS on the ovarian histostructure. Furthermore, tartaric acid improved the serum levels of LH, estradiol, progesterone, and testosterone (p-value < 0.05). The obtained findings may suggest tartaric acid as a novel strategy for PCOS management, although further studies are necessary., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

The development of the ovarian follicle requires the presence of several factors that come from the blood and follicular cells. Among these factors, extracellular vesicles (EVs) represent an original communication pathway inside the ovarian follicle. Recently, EVs have been shown to play potential roles in follicular development and reproduction-related disorders, including the polycystic ovary syndrome (PCOS). The proteomic analysis of sEVs isolated from FF in comparison to sEVs purified from plasma has shown a specific pattern of proteins secreted by ovarian steroidogenic cells such as granulosa cells. Thus, a human granulosa cell line exposed to sEVs from FF of normal patients increased their progesterone, estradiol, and testosterone secretion. However, if the sEVs were derived from FF of PCOS patients, the activity of stimulating progesterone production was lost. Stimulation of steroidogenesis by sEVs was associated with an increase in the expression of the StAR gene. In addition, sEVs from FF increased cell proliferation and migration of granulosa cells, and this phenomenon was amplified if sEVs were derived from PCOS patients. Interestingly, STAT3 is a protein overexpressed in sEVs from PCOS patients interacting with most of the cluster of proteins involved in the phenotype observed (cell proliferation, migration, and steroid production) in granulosa cells. In conclusion, this study has demonstrated that sEVs derived from FF could regulate directly the granulosa cell activity. The protein content in sEVs from FF is different in the case of PCOS syndrome and could perturb the granulosa cell functions, including inflammation, steroidogenesis, and cytoskeleton architecture., (© 2024 Federation of American Societies for Experimental Biology.)

Ovarian puncture has been widely used in assisted reproduction, but there are still gaps about its effects on ovarian morphophysiology, as well as the relationship between inflammation caused by this procedure and the follicular growth and fertility. The aim of this study was to investigate the effects of ovarian puncture on folliculogenesis and fertility. Mice (n = 24) were divided into two groups: (1) SHAM-both ovaries were exposed and repositioned and (2) Punctured-ovaries were exposed, punctured, and repositioned. After 96 h of surgery, ovaries were collected for morphofunctional analysis. New females were used for the superovulation (n = 10) and fertility assays (n = 10). Increased volumetric density of inflammatory cells-p = 0.0005, p = 0.0013; hemorrhagic foci-p < 0.0001; and inflammatory exudate-p < 0.0001 could be noticed on the punctured group, compared to SHAM. The percentage of primordial follicles was lower on the punctured ovaries (p = 0.00294). Ovarian puncture has also induced an increase in the proliferation of granulosa cells of primary (p = 0.0321) and antral follicles (p = 0.0395), and an increased apoptotic index of antral follicles (p = 0.0100). There was no influence on expression of some genes related to inflammation, collagen deposition and folliculogenesis progression. The reproductive aspects (oocyte retrieval and number of fetuses per female) were not altered (p > 0.05). Taken together, our findings strongly suggest that ovarian puncture results in a local inflammation that affects follicular growth and atresia. However, it does not affect female fertility, which strengthens the safety of this procedure., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Polycystic ovary syndrome (PCOS) is a type of follicular dysplasia with an unclear pathogenesis, posing certain challenges in its diagnosis and treatment. Cancer susceptibility candidate 15 (CASC15), a long non-coding RNA closely associated with tumour development, has been implicated in PCOS onset and development. Therefore, this study aimed to investigate the molecular mechanisms underlying PCOS by downregulating CASC15 expression in both in vitro and in vivo models. We explored the potential regulatory relationship between CASC15 expression and PCOS by examining cell proliferation, cell cycle dynamics, cell autophagy, steroid hormone secretion capacity, and overall ovarian function in mice. We found that CASC15 expression in granulosa cells derived from patients with PCOS was significantly higher than those of the normal group (P < 0.001). In vitro experiments revealed that downregulating CASC15 significantly inhibited cell proliferation, promoted apoptosis, induced G1-phase cell cycle arrest, and influenced cellular autophagy levels. Moreover, downregulating CASC15 affected the follicular development process in newborn mouse ovaries. In vivo studies in mice demonstrated that disrupting CASC15 expression improved PCOS-related symptoms such as polycystic changes and hyperandrogenism, and significantly affected ovulation induction and embryo implantation in pregnant mice. Overall, CASC15 was highly expressed in granulosa cells of patients with PCOS and its downregulation improved PCOS-related symptoms by influencing granulosa cell function and follicular development in mice., Competing Interests: Declaration of competing interest The authors declared that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Chronic psychological stress is associated with impaired follicular development and ovarian dysfunction. Many aspects of this dysfunction and the underlying mechanisms remain unclear. Using a chronic unpredictable mild stress (CUMS) mouse model, we investigate the influence of chronic stress on ovarian function and explore potential mechanisms., Methods: A CUMS mouse model was constructed over eight months, covering the period from sexual maturity to the onset of declining fertility in mice. At the end of the 2nd, 4th, 6th, and 8th months of exposure to CUMS, behavioral and physiological assays, including the sucrose preference test, tail suspension test, and serum corticosterone levels, were conducted to validate the effectiveness of the stress model. Fertility and ovarian function were assessed by analyzing the estrous cycle, number of offspring, sex hormone levels, follicle counts, granulosa cell proliferation and apoptosis, and the expression levels of fibrosis markers. Furthermore, proteomic analyses were performed on the ovaries to investigate the molecular mechanisms of ovarian fibrosis induced by CUMS., Results: With continued CUMS exposure, there was a gradual decline in both the ovary-to-body weight ratio and the number of offspring. Moreover, the percentage of atretic follicles was notably higher in the CUMS-exposed groups compared to the control groups. It is noticeable that CUMS triggered granulosa cell apoptosis and halted proliferation. Additionally, increased expression of α-SMA and Collagen I in the ovaries of CUMS-exposed mice indicated that CUMS could induce ovarian fibrosis. Proteomic analysis provided insights into the activation of specific biological processes and molecules associated with fibrosis induced by chronic stress., Conclusions: Our results strongly suggest that exposure to CUMS induces ovarian fibrosis, which influences follicular development and ultimately contributes to fertility decline. These findings offer novel perspectives on the impact of chronic stress on ovarian dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

One of the initial causes of cystic ovarian disease (COD) is a failure in the normal ovulation mechanism. This study aimed to characterize the populations of immune cells (T-lymphocytes, B-lymphocytes, monocytes-macrophages and granulocytes) present in the ovary of cows with COD and induced follicular persistence, and evaluate their relation with follicular persistence and cyst formation. The follicular persistence model was developed using a progesterone (P4) slow-release intravaginal device, to obtain subluteal concentrations of P4. Results evidenced that T-lymphocytes, B-lymphocytes and monocytes-macrophages in the cortex, medulla, and theca externa and interna of dominant follicles were higher in the control group than in the COD and all persistence groups. Granulocytes in the medulla and theca externa of dominant follicles were lower in the control group than in the COD group, and those in the cortex and medulla were lower in the control group than in the persistence groups. The presence of T-lymphocytes, B-lymphocytes and granulocytes in the follicular fluid was abundant, especially that of granulocytes, without differences between control and COD cows. These results suggest that the immune system potentially plays a role in the local mechanisms of COD pathogenesis in dairy cows. In spontaneous COD and in our follicular persistence model, the distribution of the cells studied was different from that in the control group. However, to our knowledge, this is the first report describing the presence of immune cells in bovine follicular fluid samples and the expression of steroid hormone receptors in infiltrating immune cells in the bovine ovary., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Polycystic ovary syndrome (PCOS) is the most common gynaecological, endocrine disorder that occurs during reproductive age and is a significant cause of anovulatory infertility. Letrozole is an aromatase inhibitor which negates the action of the aromatase enzyme, which results in the buildup of male hormones (testosterone) in the females, causing hyperandrogenism, which is a hallmark of Polycystic Ovarian Syndrome. Mifepristone (RU486) is a progestin antagonist that acts to arrest the actions of the progesterone hormone, resulting in follicular atresia and anovulation. DHEA is an androgen which was also administered in a bid to cause hyperandrogenism in the rats.This study aimed to evaluate the effects of these hormones on the cytoarchitecture of the ovaries and uterus to assess their various PCOS-like histological features.Animals were grouped mainly into three: Letrozole, Mifepristone and DHEA groups, which were further divided into two subgroups each, administered low and high doses of letrozole orally, Mifepristone and Dehydroepiandosterone (DHEA) subcutaneously. Each of the subgroups also had a comparison control group. Following the completion of administration, the Wistar rats were euthanized, and their ovaries and uterus were collected for histological analysis.Increased proliferation of ovarian follicles was noted in the treated groups compared to control, as well as thickening of the endometrial layer., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Follicular ovarian cysts (FOCs) are characterized by follicles in the ovaries that are >20 mm in diameter and persist for >10 days without the corpus luteum, leading to anovulation, dysregulation of folliculogenesis and subfertility in humans and livestock species. Despite their clinical significance, the precise impact of FOCs on oocyte reserve, maturation, and quality still needs to be explored. While FOCs are observed in both human and livestock populations, they are notably prevalent in livestock species. Consequently, livestock species serve as valuable models for investigating the molecular intricacies of FOCs. Thus, in this study, using goat FOCs, we performed integrated proteomic, metabolomic and functional analyses to demonstrate that oocyte maturation is hampered due to increased reactive oxygen species (ROS) in FOCs follicular fluid (FF) via downregulation of glutathione peroxidase (GPX1), a critical antioxidant seleno enzyme required to negate oxidative stress. Notably, GPX1 reduction was positively correlated with the FF's decline of free selenium and selenocysteine metabolic enzymes, O-phosphoryl-tRNA (Sec) selenium transferase (SEPSECS) and selenocysteine lyase (SCLY) levels. Adding GPX1, selenocysteine, or selenium to the culture media rescued the oocyte maturation abnormalities caused by FOCs FF by down-regulating the ROS. Additionally, we demonstrate that substituting GPX1 regulator, Insulin-like growth factor-I (IGF-1) in the in vitro maturation media improved the oocyte maturation in the cystic FF by down-regulating the ROS activity via suppressing Non-sense-mediated decay (NMD) of GPX1. In contrast, inhibition of IGF-1R and the target of rapamycin complex 1 (mTORC1) hampered the oocyte maturation via NMD up-regulation. These findings imply that the GPX1 regulation via selenocysteine metabolism and the IGF-1-mediated NMD may be critical for the redox homeostasis of FF. We propose that GPX1 enhancers hold promise as therapeutics for enhancing the competence of FOCs oocytes. However, further in vivo studies are necessary to validate these findings observed in vitro., Competing Interests: Declaration of competing interest The authors have no competing interests related to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diet-induced obesity reduces oocyte quality mainly by impacting oocyte mitochondrial functions. Moreover, maternal obesity is associated with mitochondrial dysfunction in oocytes of their adult offspring. However, these effects were reported only in fully grown oocytes, mainly in the form of abnormal mitochondrial ultrastructure. It is unknown if obesogenic (OB) diets or maternal obesity already impact the primordial and preantral follicles. Considering the long duration and dynamics of folliculogenesis, determining the stage at which oocytes are affected and the extent of the damage is crucial for optimal reproductive management of obese patients and their daughters. Potential interaction between maternal and offspring diet effects are also not described, yet pivotal in our contemporary society. Therefore, here we examined the impact of OB diets on oocyte mitochondrial ultrastructure in primordial and activated preantral follicles in offspring from diet-induced obese or lean mothers. We used an outbred Swiss mouse model to increase the pathophysiological relevance to humans. Female mice were fed control or OB diets for 7 weeks, then mated with control males. Their female offspring were fed control or OB diets after weaning for 7 weeks (2-by-2 factorial design). Adult offspring ovarian sections were examined using transmission electron microscopy. We characterised and classified unique features of oocyte mitochondrial ultrastructure in the preantral follicles. An increase in mitochondrial matrix density was the most predominant change during follicle activation in secondary follicles, a feature that is linked with a higher mitochondrial activity. Maternal obesity increased mitochondrial density already in the primordial follicles suggesting an earlier increase in bioenergetic capacity. Maternal obesity did not induce abberant ultrastructure (abnormalities and defects) in primordial or preantral follicles. In contrast, offspring OB diet increased mitochondrial abnormalities in the primordial follicles. Further investigation of the consequences of these changes on oocyte metabolic regulation and stress levels during folliculogenesis is needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Xhonneux et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Premature ovarian insufficiency (POI) is one of the important causes of female infertility. Yet the aetiology for POI is still elusive. FBXW7 (F-box with 7 tandem WD) is one of the important components of the Skp1-Cullin1-F-box (SCF) E3 ubiquitin ligase. FBXW7 can regulate cell growth, survival and pluripotency through mediating ubiquitylation and degradation of target proteins via triggering the ubiquitin-proteasome system, and is associated with tumorigenesis, haematopoiesis and testis development. However, evidence establishing the function of FBXW7 in ovary is still lacking. Here, we showed that FBXW7 protein level was significantly decreased in the ovaries of the cisplatin-induced POI mouse model. We further showed that mice with oocyte-specific deletion of Fbxw7 demonstrated POI, characterized with folliculogenic defects, early depletion of follicle reserve, disordered hormonal secretion, ovarian dysfunction and female infertility. Impaired oocyte-GCs communication, manifested as down-regulation of connexin 37, may contribute to follicular development failure in the Fbxw7-mutant mice. Furthermore, single-cell RNA sequencing and in situ hybridization results indicated an accumulation of Clu and Ccl2 transcripts, which may alter follicle microenvironment deleterious to oocyte development and accelerate POI. Our results establish the important role of Fbxw7 in folliculogenesis and ovarian function, and might provide valuable information for understanding POI and female infertility., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The objective of this study to examine the effects of curcumin and gallic acid use against oxidative stress damage in the autologous intraperitoneal ovarian transplantation model created in rats on ovarian follicle reserve, ovarian surface epithelium, and oxidant-antioxidant systems. 42 adult female Sprague Dawley rats (n=7) were allocated into 6 groups. Group 1 served as the control. In Group 2, rats underwent ovarian transplantation (TR) to their peritoneal walls. Group 3 received corn oil (CO) (0.5 ml/day) one day before and 14 days after transplantation. Group 4 was administered curcumin (CUR) (100 mg/kg/day), Group 5 received gallic acid (GA) (20 mg/kg/day), and Group 6 was treated with a combination of curcumin and gallic acid via oral gavage after transplantation. Rats were sacrificed on the 14th postoperative day, and blood along with ovaries were collected for analysis. The removed ovaries were analyzed at light microscopic, fluorescence microscopic, and biochemical levels. In Group 2 and Group 3, while serum and tissue Total Oxidant Levels (TOS) and Oxidative Stress Index (OSI) increased, serum Total Antioxidant Levels (TAS) decreased statistically significantly (p˂0.05) compared to the other groups (Groups 1, 4, 5, and 6). The ovarian follicle reserve was preserved and the changes in the ovarian surface epithelium and histopathological findings were reduced in the antioxidant-treated groups (Groups 4, 5, and 6). In addition, immunofluorescence examination revealed that the expression of Cytochrome C and Caspase 3 was stronger and Ki-67 was weaker in Groups 2 and 3, in comparison to the groups that were given antioxidants. It can be said that curcumin and gallic acid have a histological and biochemical protective effect against ischemia-reperfusion injury due to ovarian transplantation, and this effect is stronger when these two antioxidants are applied together compared to individual use., Competing Interests: Declaration of Competing Interest There is no conflict of interest, (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Follicular maturation arrest is a prevalent endocrine disorder characterized by hormonal imbalance, ovarian dysfunction, and metabolic disturbances leading to Polycystic ovarian syndrome (PCOS). Tanshinone IIA (TIIA), a bioactive compound derived from Salvia miltiorrhiza, has shown promising therapeutic potential in various diseases, including cardiovascular diseases and cancer. However, its effects on reproductive health and gynecological disorders, particularly PCOS, remain poorly understood. In this study, we investigated the potential therapeutic effects of TIIA on ovarian function. Using a combination of experimental and computational approaches, we elucidated the molecular mechanisms underlying TIIA's pharmacological impact on ovarian function, follicular development, and androgen receptor signaling. Molecular docking and dynamics simulations revealed that TIIA interacts with the human androgen receptor (HAR), modulating its activity and downstream signaling pathways. Our results demonstrate that TIIA treatment alleviates PCOS-like symptoms in a zebrafish model, including improved follicular development, lowered GSI index, improved antioxidant status (SOD, CAT), decreased LDH levels, and enhanced AChE levels by regulating Tox3 and Dennd1a pathway. Our findings suggest that TIIA may hold promise as a novel therapeutic agent for the management of PCOS or ovulation induction., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Phthalates are found in everyday items like plastics and personal care products. There is an increasing concern that continuous exposure can adversely affect female fertility. However, experimental data are lacking to establish causal links between exposure and disease in humans. To address this gap, we tested the effects of a common phthalate metabolite, mono-(2-ethylhexyl) phthalate (MEHP), on adult human ovaries in vitro using an epidemiologically determined human-relevant concentration range (2.05 nM - 20.51 mM). Histomorphological assessments, steroid and cytokine measurements were performed on human ovarian tissue exposed to MEHP for 7 days in vitro. Cell viability and gene expression profile were investigated following 7 days of MEHP exposure using the human granulosa cancer cell lines KGN, and COV434, the germline tumor cell line PA-1, and human ovarian primary cells. Selected differentially expressed genes (DEGs) were validated by RT-qPCR and immunofluorescence in human ovarian tissue. MEHP exposure reduced follicular growth (20.51 nM) and increased follicular degeneration (20.51 mM) in ovarian tissue, while not affecting steroid and cytokine production. Out of the 691 unique DEGs identified across all the cell types and concentrations, CSRP2 involved in cytoskeleton organization and YWHAE as well as CTNNB1 involved in the Hippo pathway, were chosen for further validation. CSRP2 was upregulated and CTNNB1 downregulated in both ovarian tissue and cells, whereas YWHAE was downregulated in cells only. In summary, one-week MEHP exposure of human ovarian tissue can perturb the development and survival of human follicles through mechanisms likely involving dysregulation of cytoskeleton organization and Hippo pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Currently, three crucial questions regarding the reliability of ovarian reserve measures in women with ovarian endometrioma during the reproductive age are being discussed. Firstly, the effects of endometriotic cystectomy on short and long-term ovarian reserve. Secondly, the accuracy of serum anti-Müllerian hormone (AMH) and antral follicle count (AFC) in estimating ovarian reserve in these cases. Thirdly, the impact of endometrioma itself on the ovarian reserve over time in such cases. The purpose of the present review is to critically assess available systematic reviews and meta-analyses that have explored these questions. Nine eligible reviews were found following a systematic search on PubMed.com and similarly assessed. These reviews varied considerably regarding the level of evidence, as per an identical comprehensive scoring system. Moderate to high-quality evidence demonstrates that endometriotic cystectomy, by the stripping technique, adversely affects ovarian reserve in the short and long term, up to 9-18 months post-surgery. Damage to ovarian reserve was considerable but more pronounced in bilateral cases than unilateral cases, equivalent to 39.5% and 57.0%, respectively. Repeat endometriotic cystectomy is detrimental to ovarian reserve. The impact of endometrioma diameter on ovarian reserve before or after surgery is still unclear. Moderate to high-quality evidence, relying on simultaneous assessment of both ovarian reserve measures, shows that AMH is sensitive while AFC is not in cases undergoing ovarian cystectomy. AMH should be the biomarker of choice for counseling and managing women with endometrioma in their reproductive age, especially before surgery. While there is some evidence to show that endometrioma per se may harm ovarian reserve, this evidence is not robust, and there is good-quality evidence to challenge this notion. It is necessary to conduct further targeted RCTs, systematic reviews, and meta-analyses based on solid methodological grounds to increase the level of evidence, refine quantitative estimates, investigate open questions, and decrease heterogeneity., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Younis and Taylor.)

The occupational chemical 4-Vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure, leading to premature ovarian insufficiency (POI), which significantly impacts a woman's physical health and fertility. Investigating VCD's pathogenic mechanisms can offer insights for the prevention of ovarian impairment and the treatment of POI. This study established a mouse model of POI through intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. The results were then compared with those of the control group, including a comparison of phenotypic characteristics and transcriptome differences, at two time points: day 15 and day 30. Through a comprehensive analysis of differentially expressed genes (DEGs), key genes were identified and validated some using RT-PCR. The results revealed significant impacts on sex hormone levels, follicle number, and the estrous cycle in VCD-induced POI mice on both day 15 and day 30. The DEGs and enrichment results obtained on day 15 were not as significant as those obtained on day 30. The results of this study provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis are pivotal in VCD-mediated ovarian dysfunction. This dysfunction may have been caused by VCD damage to the primordial follicular pool, impairing follicular development and aggravating ovarian damage over time, making it gradually difficult for the ovaries to perform their normal functions., Competing Interests: The authors declare there are no competing interests., (©2024 Li et al.)

Objective: To establish the safety and quality of ovarian cortex surrounding epithelial ovarian tumors in women eligible for fertility-sparing surgery by identifying occult malignant lesions and characterizing the ovarian follicle pool., Methods: Multicentric retrospective study of 48 subjects (15-45 years), diagnosed with borderline ovarian tumors (BOTs) or early-stage epithelial ovarian cancers (EOCs) and eligible for fertility-sparing surgery. Histological samples of ovarian cortex surrounding tumors were analyzed to characterize the follicle pool, find any occult malignant lesion using tumor-specific markers (cytokeratin 7 and mucin 1), and quantify tumor-infiltrating lymphocytes (TILs) by CD3 and tumor associated macrophages (TAMs) by CD68., Results: Occult ovarian lesions were observed in 6 out of 45 cases investigated (14.6%), including one mucinous stage-I BOT (1/14), one serous stage-I BOT (1/13), 3 advanced-stage serous BOTs (3/11) and one early-stage serous EOC (1/7). Notably, follicle density was significantly lower in subjects diagnosed with ovarian tumors compared to controls (p < 0.001) and at a younger age. Significantly higher follicle atresia was encountered in the ovarian tumor group then in controls (20.1 ± 8.8% vs 9.2 ± 9.4%, p < 0.001) at all ages. Both TILs and TAMs were found in ovarian tumors irrespective of histotype, but no link was established with the status of the ovarian reserve., Conclusions: Personalized counseling for fertility preservation is required in the event of BOTs and early-stage EOCs. Fertility-sparing surgery and adjuvant gamete preservation should be considered, balancing the oncological risks according to tumor stage and histotype and fertility potential, especially at a younger age., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A systematic review and meta-analysis were performed to identify if there is a subset of patients with POI who are more likely to show follicular growth after ovarian fragmentation for follicular activation (OFFA) or in vitro activation (IVA). Five studies met inclusion criteria for meta-analysis with a total of 164 patients. Forty-three patients showed follicle development (26.21%). Of those, the pregnancy rate was 35.58% (11/43) and the live birth rate was 20.93% (9/43). Our meta-analysis showed that age was not associated with follicle growth. However, lower baseline FSH, lower duration of amenorrhea/diagnosis, and presence of follicles remaining in biopsy were statistically significant for follicle development. Patients with basal characteristics mentioned before may have more chances to show follicle growth after OFFA or IVA. Taking into account that approximately 20% of patients with follicle growth had live birth, these results are very promising. Given the overall certainty of evidence, future studies are needed to confirm said results., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: When resecting endometriomas with the stripping technique, in the majority of cases, a thin line of adjacent ovarian cortex is attached to the endometrioma. In this study, we performed histological analysis to determine (antral) follicle density in the ovarian cortex tissue attached to stripped endometriomas and assessed patient- and surgical characteristics that could affect this., Methods: Histological slides of previously removed endometriomas were assessed. Follicles in the attached ovarian tissue were classified according to maturation, and follicular density was determined. Immunofluorescent staining of antral follicles in a subset of endometriomas was also performed., Results: In 90 out of 96 included endometriomas (93.7%), ovarian tissue attached to the cyst wall was observed. One thousand nine hundred forty-four follicles at different maturation stages were identified (3 follicles/mm 3 ). Follicle density was negatively associated with age (p < 0.001). Antral follicles (< 7-mm diameter) were present in the ovarian tissue attached to 35 endometriomas (36.5%) derived from younger patients compared to endometriomas where none were detected (30 versus 35 years, p = 0.003). Antral follicle density was 1 follicle/mm 3 . Based on immunofluorescence, healthy antral follicles were identified in two out of four examined endometriomas., Conclusions: Ovarian tissue attached to stripped endometriomas holds potential as a non-invasive source for antral follicles. In theory, application of IVM could be an interesting alternative FP option in young patients with endometriomas who undergo cystectomy in order to transform the surgical collateral damage to a potential oocyte source. Our results encourage future research with fresh tissue to further assess the quality and potential of these follicles., Trial Registration: Clinical Trials.gov Identifier: B21.055 (METC LDD), date of registration 12-08-2021, retrospectively registered., (© 2024. The Author(s).)

Background: Bisphenol-A (BPA) has a well-proven deleterious effect on the hypothalamicpituitary- gonadal axis., Objectives: The current study investigated the therapeutic potentials of mesenchymal stem cells (MSCs) in a murine model of BPA-induced ovarian damage., Methods: Fifty adult female rats were divided into: Group 1; control group, Group IIa, IIb: rats were given oral gavage of BPA (25 and 50 mg/Kg body weight respectively) on a daily basis for 15 days, and Group IIIa, IIIb; rats were intravenously treated with of MSCs (10 6 cells) after receiving the last dose of BPA as in group II. Plasma and ovarian tissue levels of Malondialdehyde (MDA) and gonadal axis hormones were assessed. Apoptosis was evaluated by TUNNEL assay and by apoptosis markers (FAS, FASL, Caspase 3, SLTM). A histological examination of ovarian tissue was also conducted., Results: BPA resulted in a significant elevation in plasma levels of LH, FSH, and ovarian tissue levels of MDA and a significant decrease in estradiol and progesterone. All genetic and protein markers of apoptosis were elevated in BPA treated group with decreased oestrogen receptor expression in the ovarian tissue. Increased apoptotic cells were confirmed by TUNEL assay. A high dose of BPA was able to increase the number of atretic follicles in the ovarian tissue whereas the numbers of primordial, primary, secondary and Graafian follicles were decreased. All the laboratory and histological abnormalities were ameliorated by treatment with MSCs., Conclusion: The antioxidant and anti-apoptotic effects of MSCs could possibly explain the ability of this therapeutic modality to ameliorate BPA-induced-ovarian damage., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Follicle dysplasia can cause polycystic ovary syndrome, which can lead to anovulatory infertility. This study explored gene(s) that may contribute to polycystic ovary syndrome., Methods: Three animal models of polycystic ovary syndrome were created by treating 3-week-old rats respectively with estradiol valerate, testosterone propionate, or constant illumination for 8 weeks. Granulosa cells from the three disease groups and from healthy controls were transcriptionally profiled to identify differentially expressed genes. The phosphodiesterase-4d (Pde4d) was screened as the most promising candidate pathogenic gene. The Pde4d was overexpressed in rats via intrabursal infection with recombinant lentivirus to see the effect of Pde4d on ovarian morphology. The potential roles of the candidate gene and interactors of the encoded protein were explored using polymerase chain reaction, western blotting, transfection and co-immunoprecipitation., Results: All three rat models of polycystic ovary syndrome showed polycystic ovary phenotype. Seven promising candidate genes were obtained by transcriptomics and verifications. Pde4d was further investigated because it could trigger downstream signaling pathways. The Pde4d overexpression in rat ovary induced cystic follicles. It inhibited follicle maturation through a mechanism involving inhibition of cAMP-PKA-CREB signaling. The Pde4d also inhibited phosphorylation of c-Jun N-terminal kinase to reduce apoptosis in the ovary, through a mechanism involving interaction of its poly-proline domain with the protein POSH., Conclusion: Upregulation of Pde4d may contribute to polycystic ovary syndrome by impeding follicle maturation and preventing apoptotic atresia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Ovarian ultrasonography and measurement of circulating concentrations of anti-Müllerian hormone (AMH) have been used to estimate follicle number and predict fertility in mammalian females, but no study has evaluated follicle number and circulating concentrations of AMH in ewes known to differ in fertility. We tested the hypothesis that ewes that had failed to lamb (BARREN) in four consecutive annual breeding seasons of 21-35 d have fewer follicles and diminished circulating concentrations of AMH compared to closely matched ewes that consistently produced lambs (FERTILE) under the same breeding protocols. Once identified, BARREN ewes (n = 19) were paired by breed and sire to a FERTILE control ewe (n = 19) and reproductive tracts were recovered at necropsy. Visible antral follicles in both ovaries were counted and a representative cross section of one ovary was embedded for histological evaluation of pre-antral follicle numbers. Paired t-tests indicated that BARREN ewes had fewer antral follicles, fewer primordial follicles, and decreased circulating concentrations of AMH compared to FERTILE ewes (P ≤ 0.01), but there were ewes in each fertility classification that had ovarian phenotypes like the opposite fertility classification. The best technologies we have currently for estimating follicle numbers are ultrasonography and measurement of circulating concentrations of AMH, but no single technique is perfect for predicting fertility. A better understanding of the under-lying biological mechanisms linking AMH, folliculogenesis, and fertility is required to improve the use of measurements of follicle number for predicting fertility in livestock., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Ovarian tissue transplantation makes it possible to restore fertility; however, the success of this technique depends on the transplant region used. Therefore, this study aimed to evaluate the effect of two subcutaneous regions on canine ovarian transplantation, pinna (Pi) and neck (Ne), for 7 and 15 days. Ovaries collected by ovariosalpingohysterectomy were fragmented using a punch device. Fresh fragments were fixed, and the others were immediately grafted onto the animal itself in the Pi and Ne regions for 7 and 15 days. Recovered fragments were evaluated for histology (morphology, development and stromal density), picrosirius (collagen fibers), and immunohistochemistry (fibrosis and cell proliferation). The results showed that follicular normality rates were lower in Pi-7 (78%) vs. control (90%) and Pi-15 (86%), similar in Ne-7 (92%) and superior in Ne-15 (97%) compared to the control, with the effect of the region Ne (94%) superior (P < 0.05) to Pi (82%). Stromal density reduced in both regions vs. control but was similar within 15 days. Fragments from both regions showed higher fibronectin labeling and deposition of type I and lower type III collagen fibers (P < 0.05) vs. control. Proliferation rates in Ne-7 were higher (P < 0.05) than in control, and Pi-15 was higher (P < 0.05) than Ne-15. In conclusion, the pinna may be a region with greater potential than the neck after a 15-day autotransplantation of canine ovarian tissue., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. This study was aimed at exploring the improving effects of miR-22-3p on the symptoms of POF in mice by inhibiting chemokine-like receptor 1 (CMKLR1) expression. Female mice were intraperitoneally injected with cyclophosphamide to construct POF mice models. Lentiviral vectors containing miR-22-3p, short hairpin RNA (sh)-CMKLR1, and overexpression (oe)-CMKLR1, respectively, or in combination, were injected into the ovaries of both sides of POF mice. miR-22-3p and CMKLR1 expression in ovarian tissues of mice was assessed, and the targeting relationship between miR-22-3p and CMKLR1 was predicted and verified. Serum estradiol (E2), anti-Mullerian hormone, and follicle-stimulating hormone levels were assessed. Ovarian weight was weighed, and pathological changes and the number of primordial follicles, primary follicles, secondary follicles, and atresia follicles were observed. Apoptosis of ovarian tissues was determined. In ovarian tissues of POF mice, miR-22-3p expression was decreased while CMKLR1 expression was increased. miR-22-3p up-regulation or CMKLR1 down-regulation restored sex hormone levels, improved ovarian weight and the number of primordial follicles, primary follicles, and secondary follicles, and reduced the number of atresia follicle and ovarian granulosa cell apoptosis in POF mice. miR-22-3p targeted CMKLR1, and overexpressing CMKLR1 reversed the ameliorative effects of miR-22-3p overexpression on POF mice. Our research highlights that overexpressed miR-22-3p down-regulates CMKLR1 to ameliorate the symptoms of POF in mice. Therefore, the miR-22-3p/CMKLR1 axis could improve the symptoms of POF., Competing Interests: None

Females are born with a finite number of oocytes, collectively termed the ovarian reserve, established within the developing fetal ovary. Consequently, maternal exposure to reproductive toxicants can have harmful effects on the future fertility of her unborn female fetus. The chemical benzo[a]pyrene (B[a]P) is a prominent component of cigarette smoke. Despite it being a known ovotoxicant, around 8% of women in Europe smoke during pregnancy. The purpose of this research was to examine the effect of B[a]P on the developing ovary, using the mouse as a model and with experiments carried out in vitro. B[a]P-exposure to the fetal ovary prior to follicle formation reduced the number of germ cells and subsequently, the number of healthy primordial follicles, by up to 76%; however, while proliferation of germ cells was not affected, the germ cells contained higher levels of DNA double-strand breaks. Exposure to B[a]P also affected the proportion of oocytes progressing through prophase I of meiosis. B[a]P exposure to neonatal mouse ovaries, after follicle formation, resulted in an 85% reduction in the number of healthy follicles, with a corresponding increase in apoptotic cell death and reduction in somatic cell proliferation. Although there was a trend towards a higher level of oxidative stress in B[a]P-exposed ovaries, this was not statistically significant; likewise, the antioxidant melatonin failed to protect against the B[a]P-induced ovarian damage. Together, the results here demonstrate that B[a]P-exposure damages the developing ovary, both before and shortly after follicle formation, an effect that could lead to a subsequent decrease in fertility., Competing Interests: Norah Spears is Co-Editor-in-Chief of Reproduction and Fertility and was therefore not involved in the review or editorial process associated with this paper of which she is a co-author., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Objective: Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are critical paracrine regulators of female fertility and are predominantly expressed by oocytes. However, it is unknown if serum concentrations reflect changes in ovarian function and/or reproductive endocrine disorders. This study aimed to determine if serum GDF9/BMP15 are associated with ovarian, pituitary, oestrogenic, androgenic and metabolic characteristics and the ovarian pathologies, polycystic ovarian morphology (PCOM) and polycystic ovary syndrome (PCOS)., Design: Women aged 21-45 years (n = 381) were included from a cross-sectional study at the National University Hospital, Singapore., Patients: Participants were volunteers and patients with possible PCOS., Measurements: Anthropometric measurements, transvaginal ultrasound scans and serum sampling were performed and a questionnairecompleted. Serum GDF9 and BMP15 concentrations were matched with menstrual cycle length, ovarian protein and steroid hormone production, pituitary hormone production and metabolic assessments in women with PCOM or PCOS and those with neither (control)., Results: Serum GDF9 and BMP15 were detectable in 40% and 41% of women, respectively and were positively correlated with each other (r = 0.08, p = 0.003). GDF9, but not BMP15, was positively correlated with ovarian volume (p = 0.02) and antral follicle count (AFC) (p = 0.004), but not with anti-Müllerian hormone (p = 0.05). However, serum GDF9 and BMP15 concentrations were not significantly different between control, PCOM and PCOS women, nor associated with androgenic or metabolic PCOS features. However, the relationship between GDF9 and AFC differed between control, PCOM and PCOS women (p = 0.02)., Conclusions: Serum GDF9 and BMP15 concentrations somewhat reflect ovarian but not androgenic or metabolic characteristics of PCOS, with increased GDF9 reflecting high AFC as seen in PCOM/PCOS., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objectives: Patients scheduled to receive chemotherapy should be counselled on fertility preservation. Known gonadotoxic chemotherapies such as alkylating agents have a high risk of altering ovarian reserve. In some cases, the urgency of treatment requires the use of chemotherapy before fertility preservation, which will be carried out at a later stage. Usually the ovarian tissue is cryopreserved. The aim of our study is to investigate the impact of chemotherapies on follicular density and the apoptosis of reserve follicles., Methods: We included 140 patients: 63 patients, mean age 18.8 years, were included in the group "no chemotherapy" (group A) and 77 patients, mean age 17.1 years, in the group "received chemotherapy before ovarian conservation" (group B). None of the patients had had pelvic radiotherapy prior to ovarian cryopreservation. The histological parameters studied were follicular density and the presence of malignant cells. We selected 12 patients from group A and 15 patients from group B, comparable in age and pathology, for whom we evaluated follicle apoptosis by immunostaining cleaved caspase-3., Results: We demonstrated an inverse relationship between follicular density and age (p < 0.0001), as well as a lack of effect of chemotherapy on follicular density (p = 0.87). We showed the impact of various chemotherapies, especially with alkylating agents, on the apoptosis of ovarian follicles (p < 0.0001). Three patients had ovarian tissue infiltration, two of which were malignant., Conclusion: This work underlines the fact that conservation of ovarian tissue after chemotherapy remains possible., (© 2022 The Authors. Cytopathology published by John Wiley & Sons Ltd.)

Our previous study demonstrated that ovarian wild-type P53-induced phosphatase 1 (WIP1) expression decreased with age. We hypothesized that WIP1 activity was related to ovarian aging. The role of WIP1 in regulating ovarian aging and its mechanisms remain to be elucidated. Adult female mice with or without WIP1 inhibitor (GSK2830371) treatment were divided into three groups (Veh, GSK-7.5, GSK-15) to evaluate the effect of WIP1 on ovarian endocrine and reproductive function and the ovarian reserve. In vitro follicle culture and primary granulosa cell culture were applied to explore the mechanisms of WIP1 in regulating follicular development. This study revealed that WIP1 expression in atretic follicle granulosa cells is significantly lower than that in healthy follicles. Inhibiting WIP1 phosphatase activity in mice induced irregular estrous cycles, caused fertility declines, and decreased the ovarian reserve through triggering excessive follicular atresia and primordial follicle activation. Primordial follicle depletion was accelerated via PI3K-AKT-rpS6 signaling pathway activation. In vitro follicle culture experiments revealed that inhibiting WIP1 activity impaired follicular development and oocyte quality. In vitro granulosa cell experiments further indicated that downregulating WIP1 expression promoted granulosa cell death via WIP1-p53-BAX signaling pathway-mediated apoptosis. These findings suggest that appropriate WIP1 expression is essential for healthy follicular development, and decreased WIP1 expression accelerates ovarian aging by promoting follicular atresia and primordial follicle activation.

Random start protocols are commonly used for oocytes cryopreservation in women with cancer. However, evidence to support their effectiveness is yet modest. This study aims to compare the quality of ovarian response between the ovary carrying the dominant follicle or the corpus luteum (active ovary) and the contralateral ovary (resting ovary). Women with a diagnosis of malignancy who underwent oocytes cryopreservation were reviewed. The main inclusion criterion was the presence of a unilateral dominant follicle or a unilateral corpus luteum on the first day of ovarian hyperstimulation. The primary outcome was the number of mature oocytes retrieved. Intra-patient comparisons between the two ovaries were made using the nonparametric Wilcoxon test for paired data. Forty-three women were included. The number of mature oocytes retrieved from the active and the resting ovaries did not differ, the median [interquartile range-IQR] being 4 [2-7] and 5 [2-8], respectively (p = 0.09). The rate [IQR] of mature oocytes per developed follicle was 58% [40-80%] and 65% [33-87%], respectively (p = 0.42). In addition, no significant difference emerged when repeating the analyses separately for women carrying dominant follicles and for those carrying corpora lutea. This study failed to detect any detrimental effect of the presence of a dominant follicle or a corpus luteus on the ovarian response to hyperstimulation, thus supporting the validity of random start protocols., (© 2022. The Author(s).)

Pituitary gonadotropins directly govern ovarian functions, which are in turn regulated by the ovarian steroid hormones. The precise interplay of gonadotropins and steroid hormones is critical for follicle growth and differentiation. Furthermore, autophagy regulates ovarian follicle differentiation. However, how the high-fat-high fructose (HFD-HF) diet regulates gonadotropins and facilitates autophagy-mediated follicular differentiation in the ovary is obscure. We fed prepubertal rats (PND 25) an HFD-HF diet until PND 90. The results showed diminished adenohypophyseal GnRHR, PR, and aromatase expression, whereas AR, ERα, PRLR, and inhibin were augmented, resulting in gonadotropins decline. Interestingly, autophagy biomarkers, Beclin-1, ATG5, ATG12, LC3-II, and LAMP1 were reduced but SQSTM1/p62 was augmented in the ovaries of HFD-HF-fed rats, causing autolysosome to aggregation. The diet altered T, E2, P4, PRL, and their receptors status in the ovary, disturbed estrous cyclicity, and delayed vaginal opening. Ovarian histomorphology exhibited numerous cystic and atretic follicles, along with disturbed follicular maturation and ovulation. Moreover, the reduction of FSHR; steroidogenic proteins; receptor proteins AR, ERβ, PR; and signaling proteins Wnt2 and β-catenin was also noticed in the ovary, whereas PRLR, inhibin, and pGSK3β were augmented. In conclusion, exposure to a prepubertal HFD-HF diet leads to hypogonadotropism and the autophagy-mediated defective differentiation of ovarian follicles, abating fertility in adult rats.

We aimed to compare the ovarian reserve of rats exposed to oral D-galactose during prenatal and early life with rats exposed to D-galactose only during the prenatal period. Fifteen female pregnant Wistar rats were randomly divided into three groups. The first and second groups were fed a D-galactose enriched diet (35%) from the third day of pregnancy to parturition (PP) and the third day to the end of lactation (PL), respectively. The control group (C group) was fed a standard diet. The study population was the female offspring of three groups (PP', PL', and C'), in which some reproductive factors were examined between 45 and 50 days of age. When compared with the PP' group, the number of primordial follicles was significantly higher in the PL' group at PND 45-50 (40 vs. 30; p = .01); however, the antimullerian hormone level was significantly reduced in the PL' group versus control group (-2.2, 95% confidence interval [CI]: -2.83, -1.53 ng/ml p = .000), and follicle-stimulating hormone level significantly increased in PP' group versus control (4.5 mIU/ml, 95% CI: 1.40-7.62, p = .005). There was no significant difference in leukocyte infiltration or antiovarian antibody among the groups. Continued exposure to D-galactose during the lactation period inhibits the primordial follicle loss in rats in terms of producing fewer atretic follicles., (© 2022 Wiley Periodicals LLC.)

While most ovarian follicle cysts are <8 cm in greatest dimension, much larger follicle cysts (up to 18.5 cm) have been reported. To our knowledge, the FOXL2 mutation status of such cases has not been documented in the literature. Here, we report the features of a 14 cm ovarian cyst with no FOXL2 mutation detected by targeted next-generation sequencing. While adult granulosa cell tumor was the chief entity in our differential diagnosis, the absence of convincing nuclear grooves, lack of architectural variability, presence of a theca layer, and absence of FOXL2 mutation were consistent with a diagnosis of ovarian follicle cyst., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Microplastics (MPs) may have an impact on the reproductive development of humans and mammals. However, any effects of MPs exposure on male and female reproductive systems and fertility are still ambiguous. In this study, male and female C57BL/6 mice were exposed to saline or 0.1 mg/d polystyrene microplastics (PS-MPs) for 30 days or 44 days to determine the effects of MPs on reproductive systems, following which some of the mice were caged for 10 days to mate to test fertility. Another group of mice were given fluorescent PS-MPs to determine the accumulation of MPs. The results show that PS-MPs exposure resulted in more significant accumulation and oxidative stress in the ovary than in the testis. In male mice, the number of viable epididymis sperm and spermatogenic cells in the testes after PS-MPs exposure was significantly reduced, and the rate of sperm deformity increased. In female mice, PS-MPs exposure induced a decrease in ovary size and number of follicles. After exposure to PS-MPs, the levels of Follicle stimulating hormone, Luteinizing hormone and testosterone were reduced, and the estradiol levels increased in the serum of male mice, while the changes in these hormone levels of female mice was the opposite. The mice exposed to PS-MPs had a reduced pregnancy rate and produced fewer embryos. These findings suggest that exposure to PS-MPs damaged the testes and ovaries, induced oxidative stress, altered the serum hormone levels, and induced changes in reproduction and fertility. Female mice appear to be more susceptible to MPs in reproduction and fertility than male mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility., Design: Cohort study., Setting: Academic fertility center., Patients: A total of 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study., Interventions: None. Folate intake was measured with a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, body mass index, physical activity, education, smoking status, year of AFC, and intakes of vitamin B 12 , iron, and vitamin D. Nonlinearity was assessed with restricted cubic splines., Main Outcome Measure: AFC as measured by transvaginal ultrasonography as part of routine care., Results: Among the 552 women (median age, 35.0 years; median folate intake, 1,005 μg/d), total and supplemental folate intake had a significant nonlinear relationship with AFC. There was a positive linear association with AFC up to approximately 1,200 μg/d for total folate intake and up to 800 μg/d for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of the association was modest; for example, the predicted adjusted difference in AFC between a woman consuming 400 vs. 800 μg/d of supplemental folate was approximately 1.5 follicles., Conclusion: Higher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center., Clinical Trial Registration Number: This trial was registered at clinicaltrials.gov as NCT00011713., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Pentraxin 3 (PTX3) - a crucial humoral innate immunity component - is related to obesity and cardiovascular complications in women who suffer from polycystic ovary syndrome (PCOS). However, the circulating PTX3 level in PCOS is still debated. In this study, we aimed to evaluate PTX3 plasma levels in PCOS women of childbearing age, and find possible endocrine/metabolic factors that could affect this level., Methods: A total of 360 women were enrolled: 120 PCOS women and 240 body mass index (BMI) matched normally ovulating women. Blood samples were collected on the third day of natural menstrual cycle or from the bleeding after progesterone withdrawal. The PTX3 concentration was measured by immunoassay., Results: The PTX3 plasma level was significantly higher in PCOS women compared to controls. There was a positive correlation between PTX3 plasma level and PCOS diagnosis, overweight, cycle length, serum LH to FSH ratio, estradiol, total testosterone (TT) on the third day of menstrual cycle, antral follicle count (AFC), as well as uric acid. Multivariant linear regression analysis indicated that participants' serum PTX3 levels were proportional to the circulating TT level, existence of PCOS, basal estradiol level and AFC., Conclusions: Overall, the circulating PTX3 level was elevated in PCOS women and significantly associated with the presence of hyperandrogenism. This study provided the basis for further in-depth researches regarding PTX3 role in PCOS pathophysiology., (© 2021. The Author(s).)

Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-β (TGF-β) superfamily. BMP4 is a secreted protein that was originally identified due to its role in bone and cartilage development. Over the past decades, extensive literature has indicated that BMP4 and its receptors are widely expressed in the ovary. Dysregulation of BMP4 expression may play a vital role in follicular development, polycystic ovary syndrome (PCOS), and ovarian cancer. In this review, we summarized the expression pattern of BMP4 in the ovary, focused on the role of BMP4 in follicular development and steroidogenesis, and discussed the role of BMP4 in ovarian diseases such as polycystic ovary syndrome and ovarian cancer. Some studies have shown that the expression of BMP4 in the ovary is spatiotemporal and species specific, but the effects of BMP4 seem to be similar in follicular development of different species. In addition, BMP4 is involved in the development of hyperandrogenemia in PCOS and drug resistance in ovarian cancer, but further research is still needed to clarify the specific mechanisms., (© 2021. Society for Reproductive Investigation.)

Spermatogenesis and folliculogenesis involve cell-cell interactions and gene expression orchestrated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH). FSH regulates the proliferation and maturation of germ cells independently and in combination with LH. In humans, the requirement for high intratesticular testosterone (T) concentration in spermatogenesis remains both a dogma and an enigma, as it greatly exceeds the requirement for androgen receptor (AR) activation. Several data have challenged this dogma. Here we report our findings on a man with mutant LH beta subunit (LHβ) that markedly reduced T production to 1-2% of normal., but despite this minimal LH stimulation, T production by scarce mature Leydig cells was sufficient to initiate and maintain complete spermatogenesis. Also, in the LH receptor ( LHR ) knockout (LuRKO) mice, low-dose T supplementation was able to maintain spermatogenesis. In addition, in antiandrogen-treated LuRKO mice, devoid of T action, the transgenic expression of a constitutively activating follicle stimulating hormone receptor ( FSHR ) mutant was able to rescue spermatogenesis and fertility. Based on rodent models, it is believed that gonadotropin-dependent follicular growth begins at the antral stage, but models of FSHR inactivation in women contradict this claim. The complete loss of FSHR function results in the complete early blockage of folliculogenesis at the primary stage, with a high density of follicles of the prepubertal type. These results should prompt the reassessment of the role of gonadotropins in spermatogenesis, folliculogenesis and therapeutic applications in human hypogonadism and infertility.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-aged women. It is characterized by chronic anovulation, hyperandrogenism, and the presence of polycystic ovary in ultrasound examination. PCOS is specified by an increased number of follicles at all growing stages, mainly seen in the preantral and small antral follicles and an increased serum level of Anti-Müllerian Hormone (AMH). Because of the strong correlation between circulating AMH levels and antral follicle count on ultrasound, Anti-Müllerian Hormone has been proposed as an alternative marker of ovulatory dysfunction in PCOS. However, the results from the current literature are not homogeneous, and the specific threshold of AMH in PCOS and PCOM is, therefore, very challenging. This review aims to update the current knowledge about AMH, the pathophysiology of AMH in the pathogenesis of PCOS, and the role of Anti-Müllerian Hormone in the treatment of this syndrome.

Purpose: To evaluate whether young women with idiopathic early ovarian aging, as defined by producing fewer oocytes than expected for a given age over multiple in vitro fertilization (IVF) cycles, have changes in telomere length and epigenetic age indicating accelerated biological aging (i.e., increased risk of morbidity and mortality)., Methods: A prospective cohort study was conducted at two Danish public fertility clinics. A total of 55 young women (≤ 37 years) with at least two IVF cycles with ≤ 5 harvested oocytes despite sufficient stimulation with follicle-stimulating hormone (FSH) were included in the early ovarian aging group. As controls, 52 young women (≤ 37 years) with normal ovarian function, defined by at least eight harvested oocytes, were included. Relative telomere length (rTL) and epigenetic age acceleration (AgeAccel) were measured in white blood cells as markers of premenopausal accelerated biological aging., Results: rTL was comparable with a mean of 0.46 (± SD 0.12) in the early ovarian aging group and 0.47 (0.14) in the normal ovarian aging group. The AgeAccel of the early ovarian aging group was, insignificantly, 0.5 years older, but this difference disappeared when adjusting for chronological age. Sub-analysis using Anti-Müllerian hormone (AMH) as selection criterion for the two groups did not change the results., Conclusion: We did not find any indications of accelerated aging in whole blood from young women with idiopathic early ovarian aging. Further investigations in a similar cohort of premenopausal women or other tissues are needed to fully elucidate the potential relationship between premenopausal accelerated biological aging and early ovarian aging., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)