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Premature ovarian failure (POF)is defined as the loss of normal ovarian function before the age of 40 and is characterized by increased gonadotropin levels and decreased estradiol levels and ovarian reserve, often leading to infertility. The incomplete understanding of the pathogenesis of POF is a major impediment to the development of effective treatments for this disease, so the use of animal models is a promising option for investigating and identifying the molecular mechanisms involved in POF patients and developing therapeutic agents. As mice and rats are the most commonly used models in animal research, this review article considers studies that used murine POF models. In this review based on the most recent studies, first, we introduce 10 different methods for inducing murine POF models, then we demonstrate the advantages and disadvantages of each one, and finally, we suggest the most practical method for inducing a POF model in these animals. This may help researchers find the method of creating a POF model that is most appropriate for their type of study and suits the purpose of their research.

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Background: Recent advances in cancer diagnosis and treatment have significantly improved survival rates among women of reproductive age facing cancer. However, the potential iatrogenic loss of fertility caused by chemotherapeutic agents underscores the need to understand and predict chemotherapy-induced ovarian damage. This study addresses this gap by systematically reviewing the literature to investigate genetic markers associated with chemotherapy-induced ovarian failure (CIOF). Objective: The primary objective is to identify genetic markers linked to CIOF, contributing to a comprehensive understanding of the factors influencing fertility preservation in female cancer survivors. Methods: A systematic review was conducted using PubMed, EMBASE, Web of Science, Scopus, and OVID electronic databases from inception through December 2023. Studies were included if they featured genomic assessments of genes or polymorphisms related to CIOF in women with histologically confirmed tumors. Exclusion criteria comprised in vitro and animal studies, reviews, and pilot studies. The resulting four human-based studies were scrutinized for insights into genetic influences on CIOF. Results: Of the 5179 articles initially identified, four studies met the inclusion criteria, focusing on alkylating agents, particularly cyclophosphamide, and anthracyclines. Su et al. explored CYP3A41B variants, revealing modified associations with CIOF based on age. Charo et al. investigated GSTA1 and CYP2C19 polymorphisms, emphasizing the need to consider age and tamoxifen therapy in assessing associations. Oktay et al. delved into the impact of BRCA mutations on anti-Müllerian hormone (AMH) levels post-chemotherapy, supported by in vitro assays. Van der Perk et al. focused on childhood cancer survivors and revealed significant associations of CYP3A43 and CYP2B6*2 SNPs with AMH levels. Conclusions: This systematic review analyzes evidence regarding genetic markers influencing CIOF, emphasizing the complex interplay of age, specific genetic variants, and chemotherapy regimens. The findings underscore the need for a personalized approach in assessing CIOF risk, integrating genetic markers with traditional ovarian reserve testing. The implications of this study extend to potential advancements in fertility preservation strategies, offering clinicians a comprehensive baseline assessment for tailored interventions based on each patient's unique genetic profile. Further research is essential to validate these findings and establish a robust framework for integrating genetic markers into clinical practice.

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Cisplatin is a widely used chemotherapeutic drug that can induce ovarian damage. Icariin (ICA), a natural antioxidant derived from Epimedium brevicornum Maxim., has been found to protect against organ injury. The aim of the present study was to investigate whether ICA can exert an ovarian-protective effect on cisplatin induced premature ovarian failure (POF) and the underlying mechanism involved. The preventive effect of ICA was evaluated using body weight, the oestrous cycle, ovarian histological analysis, and follicle counting. ICA treatment increased body weight, ovarian weight, and the number of follicles and improved the oestrous cycle in POF mice. ICA reduced cisplatin-induced oxidative damage and upregulated the protein expression levels of Nrf2, GPX4 and HO-1. Moreover, ICA reduced the expression levels of Bax and γH2AX and inhibited ovarian apoptosis. In addition, ICA activated the Nrf2 pathway in vitro and reversed changes in the viability of cisplatin-induced KGN cells, reactive oxygen species (ROS) levels, lipid peroxidation, and apoptosis, and these effects were abrogated when Nrf2 was knocked down or inhibited. Molecular docking confirmed that ICA promotes the release of Nrf2 by competing with Nrf2 for binding to Keap1. The inhibitory effects of ICA on cisplatin-induced oxidative stress, ferroptosis, and apoptosis may be mediated by its modulatory effects on the Nrf2 pathway, providing a novel perspective on the potential mechanisms by which ICA prevents POF.

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With the postponement of female reproductive age and the higher incidence of cancer in young people, fertility preservation has become increasingly important in childbearing age. Chemotherapy during pregnancy is crucial for maternal cancer treatments and fetal outcomes. It is a need to further study ovarian damage caused by chemotherapy drug combinations and long-term effects on offspring development, and a detailed understanding of side effects of chemotherapy drugs. In this study, chemotherapy drug combinations significantly impacted on ovarian function, especially epirubicin/cyclophosphamide (EC) combination led to an unbalance in the development of the left and right ovary. Exposure to EC and cisplatin/paclitaxel (TP) increased the number of progenitor follicles while decreased the count of antral follicles and corpora luteum. As to the estrus cycle, EC exposure resulted in a longer estrus period and diestrus period, while TP exposure only extended the diestrus period. EC and TP affected steroid biosynthesis by reducing the expression of SF1 and P450arom.γ-H2AX was detected in both EC and TP exposure groups. As to the impact on the offspring from 4T1 tumor-bearing pregnant mice injected with EC, no significant difference was observed in the physical and neurological development compared to the control, but the ovarian weights, estrus cycles of the offspring were significantly different. Chemotherapy drug combinations exhibit ovarian toxicity, not only causing direct damage on the follicle cells but also disrupting steroid biosynthesis. The reproductive system of offspring from maternal tumor-bearing mice exposed to chemotherapy drugs was observed disorder, but the concrete mechanism still needs further exploration.

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Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. This was a secondary analysis of gonadal hormone production, future infertility risk assessment, and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (interquartile range [IQR]) or percentages. There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 to 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3388 to 9706 mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent proxies (for patients <18 years old) and patients ≥18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty-five percent of parent proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. There are high rates of gonadal dysfunction post-HCT, but many parent proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

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With the rapid development of industrialization and urbanization, the issue of copper (Cu) and cadmium (Cd) pollution in aquatic ecosystems has become increasingly severe, posing threats to the ovarian tissue and reproductive capacity of aquatic organisms. However, the combined effects of Cu and Cd on the ovarian development of fish and other aquatic species remain unclear. In this study, female Nile tilapia (Oreochromis niloticus) were individually or co-exposed to Cu and/or Cd in water. Ovarian and serum samples were collected at 15, 30, 60, 90, and 120 days, and the bioaccumulation, ovarian development, and hormone secretion were analyzed. Results showed that both single and combined exposure significantly reduced the gonadosomatic index and serum hormone levels, upregulated estrogen receptor (er) and progesterone receptor (pr) gene transcription levels, and markedly affected ovarian metabolite levels. Combined exposure led to more adverse effects than single exposure. The data demonstrate that the Cu and Cd exposure can impair ovarian function and structure, with more pronounced adverse effects under Cu and Cd co-exposure. The Cu and Cd affect the metabolic pathways of nucleotides and amino acids, leading to ovarian damage. This study highlights the importance of considering combined toxicant exposure in aquatic toxicology research and provides insights into the potential mechanisms underlying heavy metal-induced reproductive toxicity in fish.

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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 (106 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.

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Given that the severity of the chemotherapy-induced ovarian damage, effective fertility preservation is a necessary part of the treatment process. Ferroptosis is a regulated cell death triggered by excessive phospholipid peroxidation caused by iron and the role of ferroptosis in chemotherapy-induced ovarian damage remains unclear. In this study, we demonstrated that cisplatin treatment caused the accumulation of iron ions which induced ferroptosis in ovarian tissue. And our results show that ferrostatin-1 was able to suppress the ovarian injury and granulosa cell death caused by cisplatin (Cis) in vivo and in vitro. At the same time, we observed significant changes in the expression levels of Acyl-CoA synthetase long-chain family member 4 (Acsl4) and glutathione peroxidase 4 (GPX4). Similarly, Rosiglitazone, an inhibitor of Acsl4, administration alleviated the ovary damage of the mice undergoing chemotherapy. Further mechanistic investigation showed that cisplatin increased the expression level of specificity protein 1 (SP1), and SP1 could bind to the promoter of Acsl4 to increased Acsl4 transcription. Overall, ferroptosis plays an important role in Cis induced ovarian injury, and inhibition of ferroptosis protects ovarian tissues from damage caused by cisplatin, and for the first time, we have identified the potential of Fer-1 and Rosi to protect ovarian function in female mice undergoing chemotherapy.

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The aim of this study was to determine the possible therapeutic effect of chlorogenic acid (CGA) on cisplatin (CDDP)-induced ovarian damage in rats. Rats were first exposed to CDDP (5 mg/kg) and then treated CGA (1.5 and 3 mg/kg) for three days. Oxidative stress (OS), inflammation and apoptosis markers were determined using spectrophotometric methods. Ovarian tissues were also evaluated histologically. The levels of OS, inflammation and apoptosis biomarkers increased by CDDP administration (p < 0.05). Treatments with CGA significantly alleviated these markers dose-dependently (p < 0.05). These data reveal that CGA may exert an ovoprotective effect by reducing pro-inflammatory mediators and enhancing antioxidant status in ovarian tissue.

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More than 9.2 million women worldwide suffer from cancer, and about 5% of them are at reproductive age. Chemotherapy-induced impairment of fertility affects the quality of life of these women. Several chemotherapeutic agents have been proven to cause apoptosis and autophagy by inducing DNA damage and cellular stress. Injuries to the ovarian stroma and micro-vessel network are also considered as pivotal factors resulting in ovarian dysfunction induced by chemotherapeutic agents. Primordial follicle pool over-activation may also be the mechanism inducing damage to the ovarian reserve. Although many studies have explored the mechanisms involved in chemotherapy-induced reproductive toxicity, the exact molecular mechanisms have not been elucidated. It is essential to understand the mechanisms involved in ovarian damage, in order to develop potential protective treatments to preserve fertility. In this article, we reviewed the current knowledge on the mechanism of chemotherapy-induced ovarian damage and possible protective strategies that prevent the ovary from such damages.

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Objective: We conducted a biochemical and histological evaluation of whether berberine has a protective and/or therapeutic effect in a cyclophosphamide-induced premature ovarian failure (POF) model. Materials and Methods: We divided 28 Wistar albino female rats into 4 groups [control group, POF group, cyclophosphamide (CP)+berberine (Bb) group, and POF+Bb group]. The POF model was established by intraperitoneal administration of 50 mg/kg CP on day 1 followed by 8 mg/kg/day CP dissolved in saline for the following 14 days. The CP+Bb group received Bb concurrently for two weeks with CP. The POF+Bb group received berberine for two weeks following the completion of CP administration. Left ovaries were used for histopathological evaluation and right ovaries were used for biochemical analysis [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-6 levels in tissue]. Results: Ovarian damage scoring was significantly higher in the POF group than in the other groups (p<0.005). In the POF group, primordial and primary follicle counts were the lowest, while secondary and corpus luteum counts were the highest (p<0.005). There was no significant difference between the other groups. The POF group had significantly elevated levels of TNF-α, IL-1, and IL-6 in the biochemistry results (p<0.005). Conclusion: We demonstrated that berberine could be effective in the protection and treatment of POF by reducing proinflammatory cytokines. We believe that our study can make a considerable contribution to the literature in terms of POF protection and/or treatment.

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Perfluorooctanoic acid (PFOA) alternatives such as hexafluoropropylene oxide homologs (HFPOs) cause concern due to increased occurrence in the environment as well as potential bioaccumulation and toxicity. HFPOs have been demonstrated to activate the estrogen receptor (ER) pathway. The ER pathway is homologous and connected to the estrogen-related receptor (ERR) pathway, but HFPOs effects on the ERR pathway have not been studied. Hence, we assessed the potential estrogenic effects of HFPOs via ERRγ pathway. In vitro assays revealed that HFPO dimeric, trimeric, and tetrameric acids (HFPO-DA, -TA, and -TeA, respectively), acted as ERRγ agonists, activating the transcription of both human and zebrafish ERRγ at low concentrations, but inhibiting zebrafish ERRγ at high concentrations. We also found that HFPO-TA promoted the human endometrial cancer cells (Ishikawa cells) proliferation via ERRγ/EGF, Cyclin D1 pathway. The HFPO-TA-induced proliferation of Ishikawa cells was inhibited by co-exposure with a specific antagonist of ERRγ, GSK5182. In vivo exposure of female zebrafish to HFPO-TA disturbed sex hormone levels, interfered with the gene expression involved in estrogen synthesis and follicle regulation, and caused histopathological lesions in the ovaries, which were similar to those induced by a known ERRγ agonist GSK4716. Taken together, this study revealed a new mechanism concerning the estrogenic effect of HFPOs via activation of the ERRγ pathway.

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Chemotherapy to treat cancer is usually responsible for early ovarian follicle depletion. Ovarian damage induced by cancer treatments frequently results in infertility in surviving patients of childbearing age. Several fertility preservation techniques have been developed. Nowadays, oocyte or embryo cryopreservation with or without ovarian stimulation and cryopreservation of the ovarian cortex are the most commonly used. However, these methods may be difficult to implement in some situations, and subsequent use of the cryopreserved germ cells remains uncertain, with no guarantee of pregnancy. Improved knowledge of the molecular mechanisms and signaling pathways involved in chemotherapy-induced ovarian damage is therefore necessary, to develop new strategies for fertility preservation. The effects of various chemotherapies have been studied in animal models or in vitro on ovarian cultures, suggesting various mechanisms of gonadotoxicity. Today the challenge is to develop molecules and techniques to limit the negative impact of chemotherapy on the ovaries, using experimental models, especially in animals. In this review, the various theories concerning ovarian damage induced by chemotherapy will be reviewed and emerging approaches for ovarian protection will be explained.

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STUDY QUESTION: Which biological mechanisms are responsible for physiological ovarian reserve decline owing to aging, or pathological follicle depletion triggered by inflammation or a pro-oxidant environment throughout a woman's lifetime? SUMMARY ANSWER: Ovarian follicle pool size is modulated by both apoptosis and autophagy, the first responsible for its physiological decline over time and increasing in the event of prior chemotherapy in children, and the latter playing a major role in physiological ovarian follicle pool diminution before puberty. WHAT IS KNOWN ALREADY: Among the different pathways of controlled cell death, apoptosis and autophagy are implicated in follicle loss. Apoptosis participates in eliminating damaged follicles, such as those impaired by chemotherapy (CHT), but its involvement in physiological age-related follicle decline is less well understood. Autophagy has proved crucial in follicle quiescence maintenance in murine models, but its contribution to human follicle pool modulation is still unclear. STUDY DESIGN, SIZE, DURATION: This retrospective study included 84 patients with benign or malignant extra-ovarian conditions aged between 1 and 35 years, with ovarian tissue stored for histological analyses at the time of cryopreservation (between 2012 and 2021) at a tertiary care center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian fragments were used for the following analyses: hematoxylin and eosin staining for follicle count and classification; cleaved caspase-3 immunostaining to identify follicle apoptosis; and microtubule-associated proteins 1A/1B light chain 3B immunolabeling to detect follicle autophagy. Transmission electron microscopy was also carried out to investigate ultrastructural features of oocytes and granulosa cells. All analyses stratified patients by age, menarchal status (premenarchal = 32; postmenarchal = 52), potentially gonadotoxic CHT before cryopreservation (n = 14), presence of endometriosis and use of hormonal treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Premenarchal patients had a larger follicle pool in terms of total follicle density [mean, range 4979.98 (342.2-21789) versus 918.8 (26.18-3983), P < 0.001], but higher rates of morphologically abnormal [8.52 (0-25.37)% versus 3.54 (0-17.5)%, P < 0.001] and atretic [15.8 (0‒31.85)% versus 10.6 (0-33.33)%, P < 0.01] follicles than postmenarchal subjects. Apoptosis rates did not change with increasing age [27.94 (0-93.2)% in prepubertal subjects and 29.5 (0-100)% in postpubertal subjects], but autophagic follicles were around 10 times more common in premenarchal than postmenarchal subjects [10.21 (0-62.3)% versus 1.34 (0-25)%, P < 0.001], playing a crucial role in age-related follicle decline and elimination of 'abnormal' follicles, that are rarely seen after menarche. The impact of diagnosis and previous CHT varied according to age. In premenarchal patients with previous CHT, significantly more apoptotic [40.22 (0-100)% versus 26.79 (0-87)%, P < 0.05] and fewer abnormal [3.84 (0-10-76)% versus 9.83 (0-25.37)%, P < 0.01] follicles were detected than in subjects with no CHT prior to ovarian tissue cryopreservation, suggesting a direct effect on follicle elimination, especially of those with abnormalities. In postmenarchal subjects with previous CHT, quiescent follicle rates were lower than in patients with no CHT before tissue freezing [71.57 (0-100)% versus 85.89 (50-100)%, P < 0.05], suggesting accelerated follicle activation and growth. Moreover, increased autophagic activity was observed in the event of a cancer diagnosis compared to benign conditions after puberty [26.27 (0-100)% versus 9.48 (0-29.41)%, respectively, P < 0.05]. LIMITATIONS, REASONS FOR CAUTION: The impact of specific CHT protocols could not be investigated since the group of patients with previous CHT was highly heterogeneous. WIDER IMPLICATIONS OF THE FINDINGS: This study yields a deeper understanding of regulation of the follicle pool decline, showing for the first time that both apoptosis and autophagy pathways are involved in physiological follicle depletion, the latter being crucial before puberty. Moreover, our data showed a different response to non-physiological damage according to age, with higher apoptosis rates only in premenarchal subjects with previous CHT, confirming that this pathway is activated by drugs known to induce DNA damage in oocytes, such as alkylating agents, but not by cancer itself. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Fonds National de la Recherche Scientifique de Belgique (F.R.S.-FNRS/FRIA FC29657 awarded to L.C., CDR J.0063.20 and grant 5/4/150/5 awarded to M.M.D.), grants from the Fondation contre le Cancer (grant 2018-042 awarded to A.Ca.), the Fondazione Comunitaria del Varesotto and Provincia di Varese ('Amalia Griffini' Fellowship in Gynecology and Obstetrics awarded to A.Ce.), Fonds Spéciaux de Recherche, Fondation St Luc and donations from the Ferrero family. The authors have no competing interests to declare. TRIAL REGISTRAION NUMBER: N/A.

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Chemotherapeutics' development has enhanced the survival rate of cancer patients; however, adverse effects of chemotherapeutics on ovarian functions cause fertility loss in female cancer patients. Cisplatin (CP), an important chemotherapeutic drug for treating solid tumors, has adversely affected ovarian function. Melatonin (MT) has been shown to have beneficial effects on ovarian function owing to its antioxidative function. In this research, an animal model was established to explore the effect of MT on CP-induced ovarian damage. Immunohistochemical analysis and Western blot were also used to explore its mechanism. This study reported that MT protects mouse ovaries from CP-induced damage. Specifically, MT significantly prevented CP-induced ovarian reserve decline by maintaining AMH and BMP15 levels. We also found that MT ameliorated CP-induced cell cycle disorders by up-regulating CDC2 expression, and inhibited CP-induced ovarian inflammation by decreasing IL-1ß and IL-18 levels. Moreover, MT protected the ovary from CP-induced mitochondrial damage, as reflected by restoring mitochondria-related protein expression. Furthermore, CP caused ovarian apoptosis, as indicated by up-regulated BAX expression. MT was also shown to activate the MAPK pathway. Our results showed that MT could ameliorate ovarian damage induced by CP, implying that MT may be a viable alternative to preserve female fertility during CP chemotherapy.

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Ovarian damage and infertility are the main side effects of chemotherapy for women of childbearing age with cancer. The main objective of this study was to investigate the protective effects and mechanisms of hyperoside against cyclophosphamide (Cy) -induced ovarian damage and reduced fertility. This study consists of two parts: in vivo experiments using Cy intraperitoneal injections to simulate clinical chemotherapy sessions and in vitro experiments using 4-HC, a precursor of an activated form of Cy, to intervene in human granulosa-like cell line (KGN). We found that Cy disrupted the estrous cycle in mice, resulting in decreased serum Anti-Mullerian hormone (AMH) levels, loss of primordial follicles, primary follicle and secondary follicle, increased atretic follicles, and diminished ovarian reserve function. Cy prolonged the time between mating and pregnancy in mice and increased the number of absorbed embryos. Western Blot analysis demonstrate that Cy activated key proteins of HIF-1α/BNIP3-associated autophagy both in vivo and in vitro, while in vivo experiments we also found that 4-HC increased KGN cell apoptosis, damaged mitochondrial membrane potential, and activated autophagic flow. Co-treatment with hyperoside diminished follicular depletion of the primordial follicles, decreased follicular atresia, prevented Cy-induced excessive hypoxia and autophagy activation, increased mitochondrial membrane potential, thereby increasing follicular reserve and rescuing fertility in Cy-treated mice. It suggests that HIF-1α/BNIP3-mediated autophagy is an essential mechanism by which Cy impairs ovarian function and fertility in mice, by blocking this activation, hyperoside shows potential as an ovarian protectant that may be capable of preserving fertility in women undergoing chemotherapy.

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OBJECTIVES: This study sought to further verify the protective mechanism of Melatonin (MT) against ovarian damage through animal model experiments and to lay a theoretical and experimental foundation for exploring new approaches for ovarian damage treatment. METHOD: The wet weight and ovarian index of rat ovaries were weighted, and the morphology of ovarian tissues and the number of follicles in the pathological sections of collected ovarian tissues were recorded. And the serum sex hormone levels, the key proteins of the autophagy pathway (PI3K, AKT, mTOR, LC3II, LC3I, and Agt5) in rat ovarian tissues, as well as the viability and mortality of ovarian granulosa cells in each group were measured by ELISA, western blotting, CCK8 kit and LDH kit, respectively. RESULTS: The results showed that MT increased ovarian weight and improved the ovarian index in ovarian damage rats. Also, MT could improve autophagy-induced ovarian tissue injury, increase the number of primordial follicles, primary follicles, and sinus follicles, and decrease the number of atretic follicles. Furthermore, MT upregulated serum AMH, INH-B, and E2 levels downregulated serum FSH and LH levels in ovarian damage rats and activated the PI3K/AKT/mTOR signaling pathway. Besides, MT inhibited autophagic apoptosis of ovarian granulosa cells and repressed the expression of key proteins in the autophagic pathway and reduced the expression levels of Agt5 and LC3II/I. CONCLUSIONS: MT inhibits granulosa cell autophagy by activating the PI3K/Akt/mTOR signaling pathway, thereby exerting a protective effect against ovarian damage.

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Allogeneic hematopoietic cell therapy (HCT) is an established cure for sickle cell disease (SCD); however, HCT conditioning regimens are known to be gonadotoxic. Anti-mullerian hormone (AMH) measures ovarian reserve, and follicle-stimulating hormone (FSH) defines premature ovarian insufficiency (POI) at values >40 mIU/mL in pubertal females. The present study was conducted to assess ovarian reserve and function before and after transplantation in pediatric and adolescent females with SCD treated with allogeneic HCT between January 2015 and June 2020 at Children's Healthcare of Atlanta. In this retrospective review of 17 females age <21 years with SCD who had AMH levels measured at baseline and at 2 years post-HCT, AMH levels were categorized as normal, low, or undetectable, and FSH levels were measured and used to identify pubertal females who had developed POI. Demographic and treatment data were abstracted from the institutional database and medical records, and a descriptive statistical analysis was conducted. Of the 17 patients in the study cohort, 14 had been treated with hydroxyurea and 3 had chronic transfusions but with no significant iron overload. AMH levels were normal in 15 patients (88%) and low in 2 patients (12%) at baseline. The median age at HCT was 7.5 years (range, 3.7 to 20.3 years), and 14 patients (82%) underwent matched related donor HCT. After HCT, 15 patients (88%) had undetectable AMH and 2 (12%) had low AMH, with no apparent differences by HCT conditioning regimen. No pubertal patients had POI at baseline, whereas 55% of pubertal patients had progressed to POI by 2 years post-HCT. In this cohort, the majority of females had normal AMH levels at baseline but undetectable levels after HCT. Females with SCD considering HCT should be counseled about the treatment-related risk of gonadal dysfunction. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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PROBLEM: Ghrelin has been thought of as a potential link between energy homeostasis and fertility. The aim of this study was to evaluate levels of ghrelin in obese and non-obese systemic lupus erythematosus (SLE) patients, and to reveal a possible association between ghrelin and Anti-Mullerian hormone (AMH) in SLE patients. METHOD OF STUDY: One hundred SLE patients (50 obese and 50 non-obese subjects) at childbearing age and 100 age-matched healthy controls (50 obese and 50 non-obese subjects) were included. Ghrelin and leptin were examined by enzyme-linked immunosorbent assay. AMH was tested through electrochemiluminescence. Demographics, clinical and laboratory indicators were obtained from medical records. RESULTS: Ghrelin levels were significantly lower in obese SLE patients than non-obese SLE patients (P = .000) and obese controls (P = .002). Non-obese SLE patients and non-obese controls had similar ghrelin levels. Ghrelin levels were correlated positively with AMH (r = .2683, P = .0070) in SLE patients. And ghrelin were negatively associated with leptin (r = -.1969, P = .0496) and BMI (r = - .2401, P = .0161). CONCLUSION: Our results provide evidence for a potential relationship between ghrelin and AMH in SLE patients, indicating that ghrelin may play a part in energy homeostasis and ovarian damage of SLE patients.

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The incidence of cancer in reproductive-aged women is 7%, but, despite the increased number of cancer cases, advances in early diagnosis and treatment have raised the survival rate. Furthermore, in the last four decades, there has been a rising trend of delaying childbearing. There has been an increasing number of couples referred to Reproductive Medicine Centers for infertility problems after one partner has been treated for cancer. In these cases, the main cause of reduced fertility derives from treatments. In this review, we describe the effects and the risks of chemotherapy, radiotherapy, and surgery in women with cancer, and we will focus on available fertility preservation techniques and their efficacy in terms of success in pregnancy and live birth rates.