Reproductive and transgenerational toxicity of bisphenol S exposure in pregnant rats: Insights into hormonal imbalance and steroid biosynthesis pathway disruption.

Bisphenol S (BPS) is an alternative chemical to bisphenol A commonly used in food packaging materials. It raises concerns due to potential adverse effects on human health. However, limited evidence exists regarding reproductive toxicity from BPS exposure, and the mechanism of associated transgenerational toxicity remains unclear. In this study, pregnant SD rats were exposed to two different doses of BPS (0.05 or 20 mg/kg) from GD6 to PND21. The objective was to investigate reproductive and transmissible toxicity induced by BPS, explore endocrine effects, and uncover potential underlying mechanisms in rats. Perinatal exposure to BPS in the F0 generation significantly decreased the rate of body weight, ovarian organ coefficient, and growth and development of the F1 generation. Notably, these changes included abnormal increases in body weight and length, estrous cycle disruption, and embryonic dysplasia in F1. 4D-DIA proteomic and PRM analyses revealed that exposure to 20 mg/kg group significantly altered the expression of proteins, such as Lhcgr and Akr1c3, within the steroid biosynthetic pathway. This led to elevated levels of FSH and LH in the blood. The hypothalamic-pituitary-ovarian (HPO) axis, responsible for promoting fertility through the cyclic secretion of gonadotropins and steroid hormones, was affected. RT-qPCR and Western blot results demonstrated that the expression of GnRH in the hypothalamus was decreased, the GnRHR in the pituitary gland was decreased, and the expression of FSHß and LHß in the pituitary gland was increased. Overall, BPS exposure disrupts the HPO axis, hormone levels, and steroid biosynthesis in the ovaries, affecting offspring development and fertility. This study provides new insights into the potential effects of BPS exposure on the reproductive function of the body and its relevant mechanisms of action.

Transcriptome analysis during 4-vinylcyclohexene diepoxide exposure-induced premature ovarian insufficiency in mice.

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.

Inhibition of cisplatin-induced Acsl4-mediated ferroptosis alleviated ovarian injury.

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.

Accentuated Hippo pathway and elevated miR-132 and miR-195a lead to changes of uteri and ovaries in offspring mice following prenatal exposure to vinclozolin.

Vinclozolin (VCZ) has been identified as a broad-spectrum fungicide and an environmental endocrine disruptor. Also, the Hippo signaling pathway controls organ size by regulating cell proliferation and apoptosis, and moreover, overexpression of microRNA-132 (miR-132) and microRNA-195 (miR-195) inhibits cell proliferation and promotes apoptosis. So, in this study, the experimental mice were orally given 400 mg/kg/day VCZ (suspended in corn oil) at gestational day 12-18, while those of the control group were fed with corn oil of equal volume. Then unilateral ovaries and mid-uteri were isolated from 10 randomly-selected mice at the postnatal 1st week (7 days), 3rd week (20-21 days), and 7th week (48-49 days) respectively to observe gene levels, while 6 of the contralateral ovaries and uteri were subsequently examined for proteins respectively. Besides, 16 from both groups were determined with serum estradiol (E2) at week 7, of which 6 were randomized for histological observation. Here we found the levels of E2 reduced in VCZ-group at week 7, with fewer follicles and injured endometrium. Meanwhile, in VCZ mice of all ages, increased miR-132 and miR-195a, decreased G protein-coupled estrogen receptor (GPER), elevated phosphorylated large tumor suppressor (pLATS) and phosphorylated yes-associated protein (pYAP), and decreased yes-associated protein (YAP) were observed in their ovaries and uteri. These findings suggested ovarian and uterine dysplasia in the offspring induced by gestational VCZ-exposure were mainly attributed to higher miR-132 and miR-195a and accentuated Hippo-pathway.

The type of SARS-CoV-2 vaccine does not affect ovarian function in assisted reproduction cycle.

OBJECTIVE: To assess whether vaccination or the type of vaccine against SARS-CoV-2 affects ovarian function in an assisted reproduction treatment. DESIGN: A retrospective and observational study. SETTING: University-affiliated private in vitro fertilization (IVF) center. PATIENT(S): Five hundred one patients who had received the complete vaccination schedule. INTERVENTION(S): Treatment before and after vaccination. MAIN OUTCOME MEASURE(S): Parameters for both reproductive outcomes and IVF results in patients vaccinated RESULT(S): We included 510 patients, distributed as follows: 13.5% (n = 69) received a viral vector vaccine, either the adenovirus serotype 26 vector vaccine (Ad26.CoV2.S; Janssen; n = 31) or the chimpanzee adenovirus vector vaccine (ChAdOx; AstraZeneca; n = 38). The remaining 86.5% (n = 441) received an messenger RNA vaccine from either Pfizer-BioNTech (n = 336) or Moderna (n = 105). Sample size for the unexposed women was n = 1190. No differences were found in any of the evaluated parameters for both reproductive outcomes and IVF results in patients vaccinated with any adenovirus or messenger RNA vaccine. When we compared the results after vaccination with different types of vaccines between the exposed and unexposed groups, and similar results were obtained in the days of stimulation or the doses of administered follicle stimulating hormone. Finally, the numbers of oocytes were as follows: Johnson & Johnson (9.2 ± 2.6), AstraZeneca (7.7 ± 1.2), Moderna (11.3 ± 1.8), Pfizer (12.6 ± 1.0), and the unvaccinated group (10.2 ± 1.5), P=0.057. CONCLUSION(S): These early results suggest no measurable detrimental effect on reproductive outcomes, regardless of the type of vaccine received.

Toxicity of polystyrene nanoparticles for mouse ovary and cultured human granulosa cells.

The issue of global environmental contamination of microplastics has recently been receiving widespread attention. However, the effects of polystyrene nanoparticles (Nano-PS) on the female reproductive system remain unclear. We investigated the toxicity and explored the potential underlying mechanisms of Nano-PS in both mouse ovarian tissue in vivo and human ovarian granulosa cell lines in vitro. In vivo experiments: Mice were fed different concentrations of Nano-PS for 8 weeks. In vitro experiments: COV434 cells were treated with increasing concentrations of Nano-PS. In the present study, ovarian reserve was found to decrease significantly, while oxidative stress and apoptosis levels increased. Nano-PS increased the proportion of metestrum and diestrus periods, and decreased the proportion of estrous period. The implantation rates and the number of pups per litter decreased. In COV434 cells, Nano-PS reduced cell viability and mitochondrial membrane potential, increased the expression of apoptotic and oxidative stress markers and led to subsequent cell cycle arrest. Specifically, Nano-PS exert their toxic effects on mouse ovarian tissue and COV434 cells by inducing oxidative stress. A potential strategy to overcome this could be to activate the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway to mitigate Nano-PS-induced oxidative stress.

Protective effect of nebivolol on rat ovary exposed to deltamethrin toxicity

Purpose: We aimed to investigate the antioxidant activity of nebivolol against possible damage to the ovarian tissue due to the application of deltamethrin as a toxic agent, by evaluating histopathological proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) signal molecules immunohistochemically. Methods: The animals were divided into three groups as control, deltamethrin and deltamethrin + nebivolol groups. Vaginal smears were taken after the animals were mated and detected on the first day of pregnancy. After the sixth day, deltamethrin (0.5 mL of 30 mg/kg BW undiluted ULV), and 2 mL of sterile nebivolol solution were administered intraperitoneally every day for 6-21 periods. After routine histopathological follow-up, the ovarian tissue was stained with hematoxylin and eosin stain. Results: Control group showed normal histology of ovarium. In deltamethrin group, hyperplasic cells, degenerative follicles, pyknotic nuclei, inflammation and hemorrhagic areas were observed. Nebivolol treatment restored these pathologies. Deltamethrin treatment increased TNF-α and PCNA reaction. However, nebivolol decreased the expression. Conclusions: It was thought that deltamethrin toxicity adversely affected follicle development by inducing degeneration and apoptotic process in preantral and antra follicle cells, and nebivolol administration might reduce inflammation and slow down the apoptotic signal in the nuclear phase and regulate reorganization.

Effects of daidzein on rat ovary against ischemia-reperfusion

Purpose: Our aim was to investigate protective effects of daidzein treatment on ischemia-reperfusion (I/R) injury-induced ovarian tissue by immunohistochemical techniques. Methods: Thirty Sprague Dawley female rats were categorized into three groups as sham, I/R group, and I/R+daidzein groups. Bloods were analyzed for malondialdehyde (MDA), glutathione peroxidase (GSH), and myeloperoxidase (MPO), and ovaries were processed for histological tissue protocol. Results: Both MDA and MPO values were increased in I/R group compared to sham and I/R+daidzein groups. GSH content was increased in I/R+daidzein group compared to I/R groups. In I/R group, theca and follicular cells were degenerated with apoptosis and dilatation and congestion, edema. In I/R+daidzein group, daidzein improved pathologies. In the I/R group, Bax expression was positive with follicular cells, granulosa cells and inflammatory cells. In the I/R+daidzein group, positive Bax reaction was observed in the epithelial, antral, and inflammatory cells. In I/R group, Bcl-2 reaction was in germinative epithelial cells, cells of antral follicle. In the I/R+daidzein group, Bcl-2 expression level was reduced after daidzein treatment. Conclusions: After the I/R procedure, ovarian cells and follicles were degenerated with apoptosis and inflammation. After daidzein treatment, Bax and Bcl-2 signal were decreased. It was observed that daidzein stopped the apoptotic process.

Effect of intraperitoneal docetaxel on ovarian function in mice.

Taxanes are important chemotherapeutic agents used to manage breast cancer and gynaecological malignancies. However, ovarian toxicity induced by the taxane docetaxel (DOC) is of great concern. We investigated DOC-induced toxicity in the ovaries of female CD1 strain mice. The mice were divided into control (saline), DOC-5 (5 mg/kg DOC), and DOC-10 (10 mg/kg DOC) groups and administered saline or DOC on the first day of the study and two weeks later. Two weeks after the second dose, the ovaries were removed for analysis after inducing superovulation. Ovary weight, the number of secondary follicles, and the total number of follicles were reduced after DOC administration. Additionally, the expression levels of caspase-3 and the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) increased. Our findings suggest that high-dose DOC induces damage to growing follicles; however, it may not affect primordial follicles.Impact statementWhat is already known on this subject? Docetaxel (DOC) is one of the most effective chemotherapeutic agents used to manage various cancers. Some in-vitro studies have examined paclitaxel-induced ovarian toxicity; however, limited research on DOC is available.What do the results of this study add? We investigated DOC-induced ovarian toxicity in female CD1 strain mice at 5 mg/kg and 10 mg/kg. We found that DOC reduced ovary weight, the number of secondary follicles, and the total number of follicles, with the higher dose having a higher effect.What are the implications of these findings for clinical practice and/or further research? We believe that our study makes a significant contribution to the knowledge about the effect of DOC on ovarian function.

Widening the Lens on Prothioconazole and Its Metabolite Prothioconazole-Desthio: Aryl Hydrocarbon Receptor-Mediated Reproductive Disorders through in Vivo, in Vitro, and in Silico Studies.

Reproductive disorders are a serious public health problem worldwide. Epidemiological data suggest that exposure to environmental pollutants is associated with the onset of reproductive disorders. However, the effects in reproductive health and exact mechanism of action of representative agricultural compounds prothioconazole (PTC) and its metabolite prothioconazole-desthio (dPTC) on mammals remain unclear. Here, we studied the physiological effects of the exposure to environmentally relevant doses of PTC and dPTC in mice reproductive systems. Combining in vivo, in vitro, and in silico studies, we observed that PTC and dPTC disrupt reproductive health by inducing metabolic perturbation, induction of apoptosis, and inflammation in gonadal tissue, which are achieved via activation of the aryl hydrocarbon receptor (AhR). Convincingly, the addition of alternate-day injections of CH223191 (an AhR inhibitor) to the 30-day exposure regimen ameliorated ovarian tissue damage, as evidenced by decreased TUNEL-positive cells and partially restored the inflammation and apoptotic factor levels. This study comprehensively reports the toxic effects of low-dose PTC and dPTC in the reproductive system in vivo and identifies AhR as a potential therapeutic target for the amelioration of reproductive disorders caused by similar endocrine-disrupting chemicals.

Understanding the barriers to, and facilitators of, ovarian toxicity assessment in breast cancer clinical trials.

BACKGROUND: Detailed toxicity data are routinely collected in breast cancer (BC) clinical trials. However, ovarian toxicity is infrequently assessed, despite the adverse impacts on fertility and long-term health from treatment-induced ovarian insufficiency. OBJECTIVES: To determine the barriers to and facilitators of ovarian toxicity assessment in BC trials of anti-cancer drugs. METHODS: Semi-structured interviews were conducted with purposively selected stakeholders from multiple countries involved in BC clinical trials (clinicians, consumers, pharmaceutical company representatives, members of drug-regulatory agencies). Participants were asked to describe the perceived benefits and barriers to evaluating ovarian toxicity. Interviews were transcribed verbatim, coded in NVivo software and analysed using inductive thematic analysis. RESULTS: Saturation of the main themes was reached and the final sample size included 25 participants from 14 countries (9 clinicians, 7 consumers, 5 members of regulatory agencies, 4 pharmaceutical company representatives); half were female. The main reported barrier to ovarian toxicity assessment was that the issue was rarely considered. Reasons included that these data are less important than survival data and are not required for regulatory approval. Overall, most participants believed evaluating the impact of BC treatments on ovarian function is valuable. Suggested strategies to increase ovarian toxicity assessment were to include it in clinical trial design guidelines and stakeholder advocacy. CONCLUSION: Lack of consideration about measuring ovarian toxicity in BC clinical trials that include premenopausal women suggest that guidelines and stronger advocacy from stakeholders, including regulators, would facilitate its more frequent inclusion in future trials, allowing women to make better informed treatment decisions.

Baicalin improves the functions of granulosa cells and the ovary in aged mice through the mTOR signaling pathway.

BACKGROUND: The mammalian follicle is the basic functional unit of the ovary, and its normal development is required to obtaining oocytes capable of fertilization. As women get older or decline in ovarian function due to certain pathological factors, the growth and development of follicles becomes abnormal, which ultimately leads to infertility and other related female diseases. Kuntai capsules are currently used in clinical practice to improve ovarian function, and they contain the natural compound Baicalin, which is a natural compound with important biological activities. At present, the role and mechanism of Baicalin in the development of ovarian follicles is unclear. METHODS: Human primary granulosa cells collected from follicular fluid, and then cultured and treated with Baicalin or its normal control, assessed for viability, subjected to RT-PCR, western blotting, flow cytometry, and hormone analyses. The estrus cycle and oocytes of CD-1 mice were studied after Baicalin administration and compared with controls. Ovaries were collected from the mice and subjected to hematoxylin-eosin staining and immunohistochemistry analysis. RESULTS: We showed that Baicalin had a dose-dependent effect on granulosa cells cultured in vitro. A low concentration of Baicalin (for example, 10 µM) helped to maintain the viability of granulosa cells; however, at a concentration exceeding 50 µM, it exerted a toxic effect. A low concentration significantly improved the viability of granulosa cells and inhibited cell apoptosis, which may be related to the resultant upregulation of Bcl-2 expression and downregulation of Bax and Caspase 3. By constructing a hydrogen peroxide-induced cell oxidative stress damage model, we found that Baicalin reversed the cell damage caused by hydrogen peroxide. In addition, Baicalin increased the secretion of estradiol and progesterone by upregulating P450arom and stAR. The results of the in vivo experiment showed that the intragastric administration of Baicalin to aged mice improved the estrous cycle and oocyte quality. Furthermore, we observed that Baicalin enhanced the viability of granulosa cells through the mTOR pathway, which in turn improve ovarian function. CONCLUSION: These results indicate that Baicalin could improve the viability of ovarian granulosa cells and the secretion of steroid hormones and thus could help to improve degenerating ovarian function and delay ovarian aging.

Resveratrol improves ovarian function in aged rat by inhibiting oxidative stress and activating the Sirt1.

Oxidative stress is a leading driver of ovarian aging. Silent mating-type information regulation 2 homolog-1 (Sirt1) plays an role in ovarian function. Resveratrol has numerous effects, including anti-oxidant and Sirt1 activator. The aim of the study was to investigate the effect of resveratrol on aging-induced ovarian change in rats. The female Sprague Dawley rats were randomly divided into three groups: young control (Con), Aged+Res (20 mg/kg/day resveratrol for 45 days), and Aged. Anti-Müllerian hormone (AMH) was detected by ELISA assay. Malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were detected by conventional method. The ovarian structure and follicles were observed by hematoxylin staining, the caspase-3 and Sirt1 were detected by immunohistochemistry and Western blotting. The AMH in the Aged+Res group was elevated, compared to that in Aged group (p < 0.05). The MDA was decreased and GSH-Px and SOD were increased in the Aged+Res group (p < 0.05). The primordial and primary follicles were increased in the Aged+Res group (p < 0.05). The Sirt1 was increased and caspase-3 was decreased in the Aged+Res group (p < 0.05). These results indicate that resveratrol can delay ovarian aging, probably by reducing oxidative damage and increasing Sirt1.

TrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice.

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.

Ovarian response to intraovarian platelet-rich plasma (PRP) administration: hypotheses and potential mechanisms of action.

PURPOSE: Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent literature in both humans and animals suggest that intraovarian PRP administration in the setting of poor ovarian reserve may help ovarian function and increase the chances of pregnancy. METHODS: A comprehensive literature search through PubMed, MEDLINE databases, and recent abstracts published at relevant society meetings was performed and resulted in 25 articles and 2 abstracts published that studied effect of PRP on the ovaries for the purpose of reproduction. RESULTS: This review article presents all the data published to date pertaining to intraovarian PRP injection and pregnancy, both naturally and after in vitro fertilization. It also presents the most recent data on the use of ovarian PRP in in vitro and animal model studies highlighting the possible mechanisms by which PRP could impact ovarian function. CONCLUSIONS: Even though recent commentaries questioned the use of PRP as an "add-on" therapy in fertility treatment because it has not been thoroughly studied, the recent basic science studies presented here could increase awareness for considering more serious research into the efficacy of PRP as an adjunct for women with poor ovarian reserve, premature ovarian insufficiency, and even early menopause who are trying to conceive using their own oocytes. Given its low-risk profile, the hypothetical benefit of PRP treatment needs to be studied with larger randomized controlled trials.

Role of Groucho and Groucho1-like in Regulating Metamorphosis and Ovary Development in Nilaparvata lugens (Stål).

Juvenile hormone and ecdysone are key regulators in the metamorphosis and development. Grocho (Gro) is a highly conserved protein required for metamorphosis and development. Brown planthopper (Nilaparvata lugens) is a major pest affecting rice production in China and many Asian countries. Although the molecular function of Gro has been investigated in holometabolous insects such as Aedes aegypti and Drosophila melanogaster, their role in the hemimetabolous insect, brown planthopper, and the relationship between NlGro/NlGro1-L and JH/ecdysone signaling pathway, remained unknown. In this study, NlGroucho (NlGro) and NlGroucho1-like (NlGro1-L) were cloned. An analysis of the predicted protein sequence showed that NlGro has highly conserved Q domain and WD40 domain, and NlGro1-L has a highly conserved WD40 domain. The expression profiles of both genes were studied by quantitative real-time PCR (qRT-PCR). Their relative expressions were high in egg, head, wing, ovary, and testis. NlGro and NlGro1-L were found to interact genetically with juvenile hormone and ecdysone signaling by hormone treatment and RNAi of JH/ecdysone signaling-related genes. Moreover, when NlGro or NlGro1-L was down-regulated alone, the survival rate was decreased, the ovarian development was delayed, and the oviposition was also affected. All defects were aggravated when NlGro and NlGro1-L were down-regulated together. This study will help to develop new pesticides on the basis of the function of NlGro and NlGro1-L, and provide new possibilities for the control of Nilaparvata lugens.

The effectiveness of desogestrel for endometrial protection in women with abnormal uterine bleeding-ovulatory dysfunction: a non-inferiority randomized controlled trial.

Women with chronic abnormal uterine bleeding-ovulatory dysfunction (AUB-O) are at increased risk of endometrial neoplasia. We conducted a non-inferiority randomized controlled trial to determine the effectiveness of two cyclic-progestin regimens orally administered 10 d/month for 6 months on endometrial protection and menstruation normalization in women with AUB-O. There were 104 premenopausal women with AUB-O randomized to desogestrel (DSG 150 µg/d, n = 50) or medroxyprogesterone acetate (MPA 10 mg/d, n = 54) group. Both groups were comparable in age (44.8 ± 5.7 vs. 42.5 ± 7.1 years), body mass index (24.8 ± 4.7 vs. 24.9 ± 4.7 kg/m2), and AUB characteristics (100% irregular periods). The primary outcome was endometrial response rate (the proportion of patients having complete pseudodecidualization in endometrial biopsies during treatment cycle-1). The secondary outcome was clinical response rate (the proportion of progestin withdrawal bleeding episodes with acceptable bleeding characteristics during treatment cycle-2 to cycle-6). DSG was not inferior to MPA regarding the endometrial protection (endometrial response rate of 78.0% vs. 70.4%, 95% CI of difference - 9.1-24.4%, non-inferiority limit of - 10%), but it was less effective regarding the menstruation normalization (acceptable bleeding rate of 90.0% vs 96.6%, P = 0.016).Clinical trial registration: ClinicalTrials.gov (NCT02103764, date of approval 18 Feb 2014).

Administration of hemin ameliorates ovarian ischemia reperfusion injury via modulation of heme oxygenase-1 and p-JNK/p-NF-κBp65/iNOS signaling pathway.

AIMS: Ovarian torsion is the fifth common gynecological emergency that can affect females of all ages particularly during reproductive age and its management by detorsion leads to ovarian ischemia reperfusion (IR) injury. Therefore, prophylactic measures are required to protect the ovarian function after detorsion. So that, our study aimed to assess the effect and underlying mechanisms of heme oxygenase-1 (HO-1) inducer; hemin against ovarian damage induced by IR injury in rats. MAIN METHODS: Female rats were divided into: sham group, hemin group, ovarian IR (OIR) groups with and without hemin treatment. Serum levels of reduced glutathione (GSH) and interleukin 1 ß (IL-1ß) were measured in addition to ovarian levels of malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD). Ovarian phospho-Janus kinase (p-JNK) levels and gene expressions of HO-1 and inducible nitric oxide synthase (iNOS) were determined. Moreover, histopathological changes and expressions of phospho-nuclear factor kappa B p65 (p-NF-κB p65) and cleaved caspase-3 were done. KEY FINDINGS: Treatment of OIR rats with hemin led to significant attenuation of ovarian damage through histological examination which was associated with significant increase in ovarian expression of HO-1, ovarian SOD and serum GSH levels with significant decrease in ovarian p-JNK levels, expressions of p-NF-κB p65, iNOS and cleaved caspase-3 in addition to serum IL-1ß levels. SIGNIFICANCE: The protective effect of hemin can be attributed to the increased expression of HO-1 which showed antioxidant, anti-inflammatory and anti-apoptotic effects. Therefore, hemin can be administered to prevent ovarian IR injury which occurs after detorsion.

GnRH Analogues as a Co-Treatment to Therapy in Women of Reproductive Age with Cancer and Fertility Preservation.

In this review, we analyzed existing literature regarding the use of Gonadotropin-releasing Hormone (GnRH) analogues (agonists, antagonists) as a co-treatment to chemotherapy and radiotherapy. There is a growing interest in their application as a prophylaxis to gonadotoxicity caused by chemotherapy and/or radiotherapy due to their ovarian suppressive effects, making them a potential option to treat infertility caused by such chemotherapy and/or radiotherapy. They could be used in conjunction with other fertility preservation options to synergistically maximize their effects. GnRH analogues may be a valuable prophylactic agent against chemotherapeutic infertility by inhibiting rapid cellular turnover on growing follicles that contain types of cells unintentionally targeted during anti-cancer treatments. These could create a prepubertal-like effect in adult women, limiting the gonadotoxicity to the lower levels that young girls have. The use of GnRH agonists was found to be effective in hematological and breast cancer treatment whereas for ovarian endometrial and cervical cancers the evidence is still limited. Studies on GnRH antagonists, as well as the combination of both agonists and antagonists, were limited. GnRH antagonists have a similar protective effect to that of agonists as they preserve or at least alleviate the follicle degradation during chemo-radiation treatment. Their use may be preferred in cases where treatment is imminent (as their effects are almost immediate) and whenever the GnRH agonist-induced flare-up effect may be contra-indicated. The combination treatment of agonists and antagonists has primarily been studied in animal models so far, especially rats. Factors that may play a role in determining their efficacy as a chemoprotective agent that limits gonadal damage, include the type and stage of cancer, the use of alkylating agents, age of patient and prior ovarian reserve. The data for the use of GnRH antagonist alone or in combination with GnRH agonist is still very limited. Moreover, studies evaluating the impact of this treatment on the ovarian reserve as measured by Anti-Müllerian Hormone (AMH) levels are still sparse. Further studies with strict criteria regarding ovarian reserve and fertility outcomes are needed to confirm or reject their role as a gonadal protecting agent during chemo-radiation treatments.