Ovarian microenvironment: challenges and opportunities in protecting against chemotherapy-associated ovarian damage.

BACKGROUND: Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy. OBJECTIVE AND RATIONALE: This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy. SEARCH METHODS: A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine). OUTCOMES: The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors. WIDER IMPLICATIONS: Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field. REGISTRATION NUMBER: Not applicable.

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Chemotherapy is a main treatment option for malignant tumors, but it may cause various adverse effects, including dysfunction of female endocrine system and fertility. Chemotherapy-induced ovarian damage has been concerned with ovarian preservation but also the prevention and treatment of ovarian dysfunction. In this article, the mechanisms of ovarian injury caused by chemotherapy, including apoptosis of the follicle and supporting cells, follicle "burn out", ovarian stromal and microvascular damage; and influencing factors, including age at diagnosis, initial low pre-treatment anti-Müllerian hormone levels, toxicity, dose and regimen of chemotherapy drugs are reviewed based on the latest research results and clinical practice. The article also discusses measures and frontier therapies for the prevention and treatment of ovarian injury, including the application of gonadotropin releasing hormone agonists or antagonists, tyrosine kinase inhibitors, antioxidants, sphingosine-1-phosphate, ceramide-1-phosphate, mammalian target of rapamycin inhibitors, granulocyte-colony stimulating factor, stem cell therapy and artificial ovaries.

Exposure to 7,12-dimethylbenz[a]anthracene impacts ovarian DNA damage sensing and repair proteins differently in lean and obese female mice and weight loss may mitigate obesity-induced ovarian dysfunction.

Obesity impairs oocyte quality, fertility, pregnancy maintenance, and is associated with offspring birth defects. The model ovotoxicant, 7,12-dimethylbenz[a]anthracene (DMBA), causes ovarian DNA damage and follicle loss. Both DMBA-induced chemical biotransformation and the DNA damage response are partially attenuated in obese relative to lean female mice but whether weight loss could improve the DNA damage response to DMBA exposure has not been explored. Thus, at six weeks of age, C57BL/6 J female mice were divided in three groups: 1) Lean (L; n = 20) fed a chow diet for 12 weeks, 2) obese (O; n = 20) fed a high fat high sugar (HFHS) diet for 12 weeks and, 3) slim-down (S; n = 20). The S group was fed with HFHS diet for 7 weeks until attaining a higher body relative to L mice on week 7.5 and switched to a chow diet for 5 weeks to achieve weight loss. Mice then received either corn oil (CT) or DMBA (D; 1 mg/kg) for 7 d via intraperitoneal injection (n = 10/treatment). Obesity increased (P < 0.05) kidney and spleen weight, and DMBA decreased uterine weight (P < 0.05). Ovarian weight was reduced (P < 0.05) in S mice, but DMBA exposure increased ovary weight in the S mice. LC-MS/MS identified 18, 64, and 7 ovarian proteins as altered (P < 0.05) by DMBA in the L, S and O groups, respectively. In S and O mice, 24 and 8 proteins differed, respectively, from L mice. These findings support weight loss as a strategy to modulate the ovarian genotoxicant response.

Comparison of ovarian reserve after cystectomy of ovarian endometrioma by bipolar coagulation, suture method, or hemostatic sealants: An updated meta-analysis.

AIM: The purpose of the study was to compare the ovarian reserve after cystectomy of ovarian endometrioma by bipolar coagulation, suture method, or hemostatic sealants (HSs). METHODS: We performed a meta-analysis of studies in which post-cystectomy serum anti-Müllerian hormone (AMH) values were compared between bipolar coagulation and suture method or between bipolar coagulation and HSs. Through a literature search, we retrieved 14 articles which met inclusion criteria and were eligible for final analysis. The articles included 10 randomized trials, 3 prospective studies, and 1 retrospective study (n = 1435). The primary outcome was post-cystectomy serum AMH values. RESULTS: Both bipolar coagulation and suture methods showed significantly lower post-cystectomy AMH values at 3, 6, and 12 months. However, post-cystectomy serum AMH values at 12 months were significantly higher in the suture method group compared to the bipolar coagulation (weighted mean difference [WMD]: -1.10, 95% confidence interval [CI]: -1.83, -0.38, p = 0.003, I2 = 89, n = 3). The suture method also showed a lower decline rate at 3 months post-cystectomy compared to the bipolar coagulation group (WMD: -25.13%, 95% CI: -49.56 to -0.70, p = 0.04, I2 = 95%, n = 2). Overall, pregnancy rates were similar between the two groups. Between the bipolar coagulation and HSs group, serum AMH values at 3 months post-cystectomy were similar (WMD: -0.46, 95% CI: -1.04 to 0.13, p = 0.13, I2 = 0%, n = 3). However, the HSs group showed a less decline rate at 3 months post-cystectomy compared to the bipolar coagulation group (WMD: -17.02%, 95% CI: -22.81, -11.23, p < 0.00001, I2 = 0%, n = 3). CONCLUSIONS: Both the suture method and HSs may have potential benefits in the preservation of ovarian reserve over the bipolar coagulation method when cystectomy for ovarian endometrioma is performed.

Tocilizumab is effective in preventing ovarian injury induced by ischemia- reperfusion in rats.

Ovarian torsion can be defined as the bending of the ovaries on the supporting ligament, disrupting both venous and arterial blood circulation. Insufficient blood flow causes ovarian tissue hypoxia and leads to ischemia. This study aimed to investigate whether tocilizumab has a protective effect on ischemia-reperfusion injury due to ovarian torsion in rats. Eighteen female Wistar albino rats were divided into three equal groups (Sham (SG), ischemia-reperfusion (OIR), and ischemia-reperfusion+tocilizumab (OIRT)). Degeneration, necrosis, vascular dilatation/congestion, interstitial edema, hemorrhage, and polymorphonuclear lymphocyte (PMNL) infiltration scores were significantly different between the groups (p=0.001 for all parameters). Moreover, the OIRT group had a significant improvement in these criteria compared to the OIR group (p<0.05). Additionally, there was a considerable difference between OIRT and OIR groups in the number of primordial, developing, and atretic follicles groups (p<0.05), while there was no difference in the number of corpus luteum (p=0.052). Stress markers or cytokines, such as MDA, tGSH, NF-κB, TNF-α, IL-1ß, and IL-6, were significantly different between groups (p<0.05). Furthermore, a significant improvement was found in the measured variables when the OIRT group was compared with the OIR group (p<0.05). Tocilizumab may be an alternative option for treating ischemia-reperfusion injury due to ovarian torsion.

Effect of protection of enoxaparin against experimental ischemia/reperfusion injury in the rat ovary on in vitro fertilization outcomes.

OBJECTIVE: The study aimed to investigate the protection of enoxaparin (E) against experimental ischemic (I) and ischemic-reperfusion (I/R) injury in rat ovaries on in vitro fertilization outcomes. METHODS: In total, 56 adult female Sprague-Dawley albino rats were randomly assigned to 6 groups of 8 animals each: Sham, Ischemia, I/R, Sham+E, I+E, and I/R+E. Ischemia groups were subjected to bilateral adnexal torsion for 3 h. In contrast, I/R and I/R+E groups received subsequent detorsion for 3 h. Enoxaparin (0.5 mg/kg s.c.) was administered 30 min prior to ischemia (I+platelet-rich plasma) or reperfusion (I/R+I+platelet-rich plasma). Ovaries were stimulated through intraperitoneal injection of 150-300 internal units IU/kg pregnant mare serum gonadotropin. Anti-Müllerian hormone levels were measured before and after surgery in all groups. RESULTS: When the number of metaphase II oocytes was evaluated, statistically significant differences were observed between the I and I+E (p=0.001) and I/R and I/R+E (p=0.000) groups. When both I and I+E groups and I/R and I/R+E groups were compared, it was found that E application increased the number of fertilized oocytes. The number of embryos on the second day was higher in the I/R+E group than that in the I/R group. Statistically significant differences were found in the number of grade 1 embryos between the I/R and I/R+E groups (p=0.003). In comparing anti-Müllerian hormone values within the group, the highest decrease was observed in the I and I/R groups. CONCLUSION: Enoxaparin effectively minimizes ovarian damage and preserves ovarian reserve following ovarian torsion.

The effect of protection of platelet-rich plasma against experimental ischemia/reperfusion injury in the rat ovary on in vitro fertilization outcomes.

OBJECTIVE: Ovarian torsion is a common cause of local ischemic damage, reduced follicular activity and infertility. This study aimed to investigate how well platelet-rich plasma (PRP) protects against experimental ischemic (I) and ischemia-reperfusion (I/R) injury in rat ovaries and its effect on in vitro fertilization (IVF) outcomes. METHOD: Fifty-six adult female Sprague-Dawley albino rats were randomly assigned to six groups of eight animals each: Sham, Ischemia, I/R, Sham + PRP, I + PRP, and I/R + PRP. The remaining eight animals were used to prepare the PRP. The ischemia groups were subjected to bilateral adnexal torsion for 3 h, while the I/R and I/R + PRP groups received subsequent detorsion for 3 h. Intraperitoneal (i.p.) PRP was administered 30 min prior to ischemia (I + PRP) or reperfusion (I/R + PRP). The ovaries were stimulated through an intraperitoneal injection of 150-300 internal units of IU/kg PMSG. After ovulation induction, oocytes were taken from the ovaries, and IVF was performed. RESULTS: The number of MII oocytes reached the highest number with 4.63 ± 0.74 in the S group and had the lowest number with 0.50 ± 0.53 in the I/R group. There were statistically significant differences for the number of embryos obtained on the second day between the I and I + PRP groups and the I/R and I/R + PRP groups (p = 0.000). In comparing anti-Müllerian hormone 1 (AMH1) and AMH2 values within the group, the highest decrease was observed in the I and I/R groups. CONCLUSION: PRP is effective in minimizing ovarian damage and preserving ovarian reserves following ovarian torsion.

Protective Effects of Platelet-rich plasma for in vitro Fertilization of Rats with Ovarian Failure Induced by Cyclophosphamide.

OBJECTIVE: Premature ovarian insufficiency (POI) contributes significantly to female infertility. Cyclophosphamide (CYC has adverse effects on folliculogenesis. Platelet-rich plasma (PRP) is an autologous product rich in many growth factors. We evaluated the protective effect of PRP on in vitro fertilization in female rats with CYC-induced ovarian damage. METHODS: Twenty-eight adult female Sprague-Dawley rats were randomly divided into four groups. Group 1 (control-sodium chloride 0.9%; 1 mL/kg, single-dose intraperitoneal [IP] injection); group 2 (CYC), 75 mg/kg, single-dose IP injection and sodium chloride 0.9% (1 mL/kg, single-dose IP injection); group 3 CYC plus PRP, CYC (75 mg/kg, single-dose and PRP (200 µl, single-dose) IP injection); and group 4 (PRP, 200 µl, single-dose IP injection). RESULTS: In the comparisons in terms of M1 and M2 oocytes, it was observed that the CYC group presented a significantly lower amount than the control, CYC/PRP, and PRP groups. (for M1, p = 0.000, p = 0.029, p = 0.025; for M2, p = 0.009, p = 0.004, p = 0.000, respectively). The number of fertilized oocytes and two-celled good quality embryos was found to be statistically significant between the CYC and control groups, CYC + PRP and PRP groups (p = 0.009, p = 0.001, p = 0.000 for oocytes, respectively. For embryos; p = 0.016, p = 0.002, p = 0.000). CONCLUSION: Platelet-rich plasma can protect the ovarian function against damage caused by CYC, and, in addition, it improves oocyte count and the development of embryos as a result of oocyte stimulation during the IVF procedure.

OBJETIVO: A insuficiência ovariana prematura (POI) contribui significativamente para a infertilidade feminina. A ciclofosfamida (CYC) tem efeitos adversos na foliculogênese. O plasma rico em plaquetas (PRP) é um produto autólogo rico em muitos fatores de crescimento. Avaliamos o efeito protetor do PRP na fertilização in vitro em ratas com lesão ovariana induzida por CYC. MéTODOS: Vinte e oito ratas Sprague-Dawley adultas foram divididas aleatoriamente em quatro grupos. Grupo 1 (controle - cloreto de sódio 0,9%; 1 mL/kg, injeção intraperitoneal [IP] em dose única); grupo 2 (CYC), 75 mg/kg, injeção IP de dose única e cloreto de sódio 0,9% (1 mL/kg, injeção ip de dose única); grupo 3 CYC + PRP, CYC (75 mg/kg, dose única e PRP (200 µl, dose única) injeção IP); e grupo 4 (PRP, 200 µl, injeção IP de dose única). RESULTADOS: Nas comparações em termos de ovócitos M1 e M2, observou-se que o grupo CYC apresentou uma quantidade significativamente menor que os grupos controle, CYC/PRP, e PRP. (Para M1, p = 0,000, p = 0,029, p = 0,025; para M2, p = 0,009, p = 0,004, p = 0,000, respectivamente). O número de oócitos fertilizados e embriões bicelulares de boa qualidade foi considerado estatisticamente significativo entre os grupos CYC e controle, CYC + PRP e grupos PRP (p = 0,009, p = 0,001, p = 0,000 para oócitos, respectivamente. Para embriões, p = 0,016, p = 0,002, p = 0,000). CONCLUSãO: O PRP pode proteger a função ovariana contra os danos causados pelo CYC e, além disso, proporciona melhora na contagem de oócitos e no desenvolvimento de embriões como resultado da estimulação ovariana durante o procedimento de fertilização in vitro.

Protective effect of astaxanthin on experimental ovarian damage in rats.

This study aimed to investigate the protective effect of astaxanthin (AS) on 3-nitropropionic acid (3-NPA) induced experimental ovarian damage in rats. Thirty two female Wistar rats were divided into four equal groups of eight each: control group (C); phosphate-buffered saline, AS group; AS (80 mg/kg) for 14 days, 3-NPA group; 3-NPA (6.25 mg/kg) twice a day for 7 days, 3-NPA + AS group; administered AS (80 mg/kg) for 14 days and 3-NPA (6.25 mg/kg) for 7 days. All injections were administered intraperitoneally. Rats were fed ad libitum with standard rat chow and tap water. Plasma and ovarian tissue total antioxidant capacity (TAC), total oxidant capacity (TOC) and oxidative stress index (OSI) levels, whole blood reduced glutathione (GSH), plasma paraoxonase 1 (PON1) activity, lipid profile, malondialdehyde (MDA), nitric oxide (NO), total sialic acid (TSA) and total thiol (TT) concentrations were analysed spectrophotometrically. Also, ovarian tissue histopathology was performed. We observed 3-NPA-induced histopathological ovarian damage significantly decreased the TAC (p < 0.001), GSH (p < 0.001), high-density lipoprotein (p < 0.01) levels and PON1 activity (p < 0.01), and significantly increased TOC, OSI (p < 0.001), MDA, NO, TSA, cholesterol, low-density lipoprotein (p < 0.01) and triglyceride (p < 0.05) levels. In conclusion, cotreatment with AS restored the negative effect of 3-NPA on all biochemical parameters cited above and improved the histopathological ovarian damage. Ovarian toxicity induced by 3-NPA might be due to oxidative damage. The improvement of AS seems to be related to its antioxidant properties.

Research progress of melatonin (MT) in improving ovarian function: a review of the current status.

Melatonin (MT) is an endogenous hormone mainly synthesized by pineal cells, which has strong endogenous effects of eliminating free radicals and resisting oxidative damages. Melatonin (MT) can not only regulate the body's seasonal and circadian rhythms; but also delay ovarian senescence, regulate ovarian biological rhythm, promote follicles formation, and improve oocyte quality and fertilization rate. This review aimd to provide evidence concerning the synthesis and distribution, ovarian function, and role of MT in development of follicles and oocytes. Moreover, the role of MT as antioxidative, participating in biological rhythm regulation, was also reviewed. Furthermore, the effects of MT on various ovarian related diseases were analyzed, particularly for the ovarian aging and polycystic ovary syndrome (PCOS).

Decision regret and associated factors following oocyte cryopreservation in patients with diminished ovarian reserve and/or age-related fertility decline.

PURPOSE: To evaluate the prevalence and factors associated with decision regret following oocyte cryopreservation (OC) in women with diminished ovarian reserve (DOR) and/or age-related fertility decline (ARFD). METHODS: A cross-sectional survey study was conducted to five hundred fifty-two women with DOR and/or ARFD who underwent OC between 2014 and 2019 in two private-assisted reproductive units in Istanbul, Turkey. Decision regret was measured using the validated Decision Regret Scale (DRS). RESULTS: The median and mean DRS scores were 10 (interquartile range: 25) and 13.4 (SD: 13.2, range 0-70), respectively. Eighty-five (52.5%) women reported mild regret and 26 (16%) had moderate to severe regret. Decision regret was inversely associated with the belief in fate regarding childbearing and trust in the efficacy of OC. CONCLUSIONS: The prevalence of severe decision regret among patients with DOR and/or ARFD undergoing OC is low. Women who had belief in fate and trusted in the efficacy of oocyte cryopreservation had significantly lower decisional regret.

The protective effects of resveratrol pretreatment in cyclophosphamide-induced rat ovarian injury: an vivo study.

OBJECTIVES: To explore whether resveratrol (Res) pretreatment could exert a protective effect on cyclophosphamide (Cy) induced ovarian toxicity in a rat model. METHODS: Twenty-four female 7-week old Sprague-Dawley rats were randomly divided into four groups: Con, administered with vehicle solutions; Cy, treated with Cy; Res + Cy, treated with Cy + Res combined; Res, treated with Res. After 21 d of treatments, the rats were euthanized and blood samples were collected to evaluate the levels of anti-Müllerian hormone (AMH). The Ovaries were processed for immunohistochemical and western blotting. RESULTS: Cy-treat caused the decrease of body weights and ovarian weight. AMH was lower in Cy group, whereas AMH levels were similar among other groups. Histomorphology showed a large number of primordial follicles were activated in Cy groups, whereas the primordial follicles were inhibited in the Res and Res + Cy groups. The expressions of Sirt1, Foxo3a were up-regulated and p53, Caspase-3, and Bax were down-regulated in Res + Cy and Res groups (p < .05). CONCLUSIONS: Res can prevent the primordial follicle activation and decrease apoptosis induced by Cy. Res may be an effective protection for ovarian function during chemotherapy, which means a new nonsurgical application for protection of ovarian reserve.

The Protective Effects of L-Carnitine and Zinc Oxide Nanoparticles Against Diabetic Injury on Sex Steroid Hormones Levels, Oxidative Stress, and Ovarian Histopathological Changes in Rat.

Diabetes mellitus is a common chronic metabolic disorder. This study aimed to investigate the effects of co-treatment with L-carnitine (LC) and zinc oxide nanoparticles (ZnONPs) on serum levels of sex hormones, oxidative stress, and ovarian histopathology in streptozotocin (STZ)-induced diabetic rats. Female Wistar rats (n = 56, 180-220 g) received a single intraperitoneal (IP) injection of STZ (65 mg/kg). They were randomly assigned into the following groups: diabetic group (Dia), Dia+Met group (100 mg metformin/kg/day), Dia+LC group (200 mg/kg/day), Dia+ZnONPs group (10 mg/kg/day), and Dia+LC+ZnONPs group (200 mg LC/kg/day and 10 mg ZnONPs/kg/day). Control group (Ctl) received the same volume of STZ solvent. After 21 days of treatment, blood serum was centrifuged for sex hormone assays. The right ovary was used for biochemical analysis, and the left ovary was fixed in 10% neutral buffered formalin for histological assessment. The levels of estradiol, progesterone, FSH, and LH significantly increased in the Dia+ZnONPs+LC group (P < 0.001) compared with the Dia group. Co-treatment with LC and ZnONPs reduced malondialdehyde and carbonyl protein and increased glutathione, catalase, and superoxide dismutase activities in ovarian tissue compared with the Dia group (P < 0.05). Moreover, the number of all ovarian follicles significantly increased in this group compared with the Dia group (P < 0.05). The results of this study indicated that co-treatment with LC and ZnONPs could preserve ovarian function by increasing sex hormones levels and antioxidant activity and decreasing lipid peroxidation in diabetic rats. Therefore, this compound supplementation may improve ovulation and fertility in people with diabetes mellitus.

An assessment of the protective effect of gonadotropin-releasing hormone agonist and antagonist on bleomycin-induced ovarian toxicity in rats.

The aim of this study is to evaluate the effect of GnRH agonist or GnRH antagonist therapy on bleomycin-administered rats by examining ovarian follicle counts and AMH levels. A total of 30 female Wistar albino rats aged 4-6 months were randomly divided into 4 groups. First, an intramuscular injection of bleomycin (30 mg/m2) was administered to all except the control group on the 1st, 8th and 15th days. The control group (Group I) was administered 0.1 mL intramuscular saline on those days. The bleomycin group (Group II) was followed up without any further treatment. The bleomycin + GnRH agonist group (Group III) was administered subcutaneous GnRH agonist triptorelin (1 mg/kg) at the same time as the bleomycin injections. The bleomycin + GnRH antagonist group (Group IV) was administered 1 mg/kg cetrorelix acetate subcutaneously, concurrently with the bleomycin. Although AMH levels were lower in the bleomycin group than in all the other groups, there was no statistically significant difference between the groups in terms of AMH levels (p > .05). In the bleomycin + cetrorelix acetate and bleomycin + triptorelin groups, significantly higher primordial, secondary and tertiary follicle counts were determined compared to the bleomycin group (p < .001). In conclusion the harmful effects of bleomycin on ovarian reserve can be reduced by the simultaneous administration of GnRH agonist or GnRH antagonist.

Postoperative hormonal treatment for prevention of endometrioma recurrence after ovarian cystectomy: a systematic review and network meta-analysis.

BACKGROUND: The efficacy of hormonal regimens for the prevention of endometrioma recurrence in women who have undergone conservative surgery is still controversial. OBJECTIVE: To compare the efficacy of different hormonal regimens in this context and to rank them. SEARCH STRATEGY: MEDLINE and Scopus databases were searched through January 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) or cohorts, comparing the effect of any pair of interventions (i.e. cyclic oral contraceptives [OC], continuous OC, gonadotropin-releasing hormone agonist [GnRHa], dienogest [DNG], levonorgestrel-releasing intrauterine system [LNG-IUS] and expectant management) on endometrioma recurrence were selected. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two reviewers. Relative treatment effects were estimated using network meta-analysis (NMA) and ranked in descending order. MAIN RESULTS: Six RCTs (675 patients) and 16 cohorts (3089 patients) were included. NMA of the RCTs involving expectant management, cyclic OC, continuous OC, GnRHa and GnRHa + LNG-IUS, showed that all hormonal regimens had a nonsignificant lower risk of endometrioma recurrence compared with expectant management. NMA of the cohorts involving expectant, cyclic OC, continuous OC, GnRHa, DNG, LNG-IUS, GnRHa + OC, and GnRHa + LNG-IUS indicated that LNG-IUS, DNG, continuous OC, GnRHa + OC and cyclic OC had a significantly lower risk of endometrioma recurrence than expectant management. LNG-IUS was ranked highest, followed by DNG and GnRHa + LNG-IUS. Long-term use of hormonal treatment either OC or progestin had a significantly lower risk of endometrioma recurrence than expectant treatment. CONCLUSION: In the NMA of RCTs, there was no evidence supporting hormonal treatment for postoperative prevention of endometrioma recurrence. This was at odds with the cohort evidence, which found the protective effect of OC and progestin regimens, especially long-term treatment. Large-scale RCTs of these agents are still required. TWEETABLE ABSTRACT: Hormonal regimens given as long-term treatment tend to reduce risk of endometrioma recurrence after conservative surgery.

Involvement of PTEN and FOXO3a Proteins in the Protective Activity of Protocatechuic Acid Against Cisplatin-Induced Ovarian Toxicity in Mice.

The present study evaluated the effects of protocatechuic acid (PCA) after cisplatin-induced ovarian toxicity in mice and if PTEN and FOXO3a proteins are involved in PCA action. The mice were divided into five experimental groups (five animals per group) and treated once a day for 3 days as follows: (1) the control group was pretreated with oral administration (o.p.) of saline solution, followed by an intraperitoneal (i.p.) injection of saline solution. The other groups were pretreated (o.p.) with (2) saline solution (cisplatin group), (3) N-acetylcysteine (150 mg/kg of body weight), or with (4) 20 or (5) 50 mg/kg body weight of PCA, followed by 5 mg/kg body weight (i.p.) of cisplatin. Next, the ovaries were destined to histological (morphology and activation), immunohistochemical (PCNA and cleaved caspase-3 expression), and fluorescence (reactive oxygen species [ROS], glutathione [GSH], and active mitochondria levels) analyses. Moreover, the immunoreactivity for p-PTEN and p-FOXO3a was evaluated to investigate a potential mechanism by which PCA could prevent the cisplatin-induced ovarian damage. Pretreatment with N-acetylcysteine or 20 mg/kg PCA before cisplatin preserved the percentage of normal follicles and cell proliferation as observed in the control, reduced apoptosis and ROS levels, and showed higher active mitochondria and GSH levels than the cisplatin treatment (P < 0.05). Moreover, pretreatment with 20 mg/kg PCA decreased cisplatin-induced p-PTEN and increased (P < 0.05) nuclear export of p-FOXO3a. In conclusion, PCA at 20 mg/kg reduced apoptosis, maintained cell proliferation and mitochondrial function, reduced ROS production, and increased GSH expression likely through the involvement of PTEN and FOXO3a proteins.

Protective effects of nebivolol on ovarian ischemia-reperfusion injury in rat.

AIM: Ovarian torsion is a common gynecological emergency of reproductive ages, occurring at rates of 2.7-7.4%. This study aimed to evaluate the antioxidant effects of Nebivolol (NEB) and histopathological changes in experimental ischemic (I) and ischemic-reperfusion (I/R) injury in rat ovaries. METHODS: Forty-eight adult female rats were randomly separated into six groups as group 1 (control) receiving an oral saline solution for 3 days; group 2 (I) that underwent ischemia for 3 h with the application of atraumatic vascular clips; group 3 (I/R); group 4 (I + NEB) receiving 10 mg/kg NEB by oral gavage 30 min prior to the ischemia induction; group 5 (I/R + NEB) receiving 10 mg/kg NEB, and group 6 (control + NEB) receiving oral 10 mg/kg NEB for 3 days before ischemia induction followed by consequent reperfusion. Ovarian tissue damage was scored by histopathological analysis. Ovarian tissue malondialdehyde (MDA) and glutathione (GSH) levels were measured biochemically. RESULTS: The levels of MDA and tumor necrosis factor-alpha (TNF-α), and TUNEL assay positivity scores increased in the I and I/R groups. GSH levels decreased in all case groups (P < 0.05). The oral administration of NEB (10 mg/kg) to the I- and I/R-groups reduced the levels of MDA and TNF-α and TUNEL assay immunopositivity scores (P < 0.05). GSH levels increased in the treatment groups. CONCLUSION: The current experimental ovarian torsion study suggests a protective role for NEB against I and I/R injury in rat ovaries. NEB may be a novel agent for decreasing ovarian I/R injury.

Cilostazol protects against cyclophosphamide-induced ovarian toxicity in female rats: role of cAMP and HO-1.

Purpose: Cancer rates have been increased among women of reproductive age nowadays. Hence, many young female will be exposed to chemotherapeutic agents as cyclophosphamide (CP), carrying the hazards on female fertility. Cilostazol is a selective phosphodiesterase-3 inhibitor drug which exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities. We aimed in this study to explore the possible protective effects of cilostazol against CP-induced ovarian damage in female rats.Methods: Cilostazol (10 mg/kg/day) was administered orally for 10 days in presence and absence of CP (150 mg/kg IP single dose) treatment. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), and anti-Müllerian hormone (AMH) levels were determined. Ovarian oxidative stress parameters along with inflammatory biomarkers were measured. 3,5-Cyclic adenosine monophosphate (cAMP) ovarian level was detected. Ovarian histopathological examination and caspase-3 immunohistochemical study were evaluated.Results: CP-treated rats showed a significant increase in serum levels of FSH and LH with decreased serum E2 and AMH levels with an increase in the ovarian inflammatory and oxidative stress biomarkers besides a significant decrease in cAMP ovarian level with an evident histopathological picture of ovarian damage and a high caspase-3 immunoexpression. Cilostazol pretreatment significantly restored the distributed hormonal levels, the oxidative stress and inflammatory biomarkers to their normal levels with marked improvement in histopathological picture of ovarian damage with a significant decrease in caspase-3 immunoexpression.Conclusions: These data suggest that cilostazol protects against CP- induced ovarian damage, which may be related to an increase in cAMP with subsequent anti-inflammatory, antioxidant, and anti-apoptotic properties.

Protective effect of Tualang honey against cadmium-induced morphological abnormalities and oxidative stress in the ovary of rats.

BACKGROUND: To investigate the protective effects of Tualang honey against the toxicity effects induced by cadmium (Cd) on the ovary. METHODS: A total of 32 female Sprague Dawley rats were taken and randomly divided into four groups (n = 8). Throughout the experimental period of 6 weeks, negative control-NC (vehicle deionized water), positive control-CD (Cd at 5 mg/kg), Tualang honey followed by Cd exposure-TH (Tualang honey at 200 mg/kg and Cd at 5 mg/kg) and Tualang honey control-THC (Tualang honey at 200 mg/kg) groups, were administered orally on a daily basis. RESULTS: Rats exposed to Cd were significantly higher in ovarian weight, number of antral and atretic follicles as compared to the NC group. The disruptive effects of Cd on ovarian follicles were associated with a disruption in gonadotropin hormones and decreases in follicular stimulating hormone (FSH) and luteinizing hormone (LH). Moreover, a significant formation of oxidative stress in ovarian Cd-exposed rats has been proven by increasing the level of lipid peroxidation products (malondialdehyde) and decreasing the levels of enzymatic antioxidant (catalase). Interestingly, a daily supplementation of high antioxidant agents such as Tualang honey in these animals, caused significant improvements in the histological changes. Additionally, less atretic follicles were observed, restoring the normal level of LH and FSH (P < 0.001), and normalizing the ovarian malondialdehyde (P < 0.05) and catalase levels in comparison with CD group (P < 0.05). CONCLUSIONS: Tualang honey has protective effects against Cd-induced ovarian toxicity by reducing morphological abnormalities, restoring the normal levels of gonadotropin hormones and stabilizing equilibrium levels of lipid peroxidation and antioxidant enzyme in ovaries of rats.

Ameliorative effect of nicorandil in ovarian ischemia-reperfusion-induced injury in rats: role of potassium channel.

Ovarian torsion is a gynecological emergency that leads to serious outcomes. Nicorandil (NIC) is an ATP-sensitive potassium (KATP) channel activator that protects the heart from ischemia. The current study aimed to investigate the role and mechanism of action of NIC in ovarian ischemia-reperfusion (OIR) and possible KATP participation. Twenty-four female albino rats were classified into 4 groups: sham control, OIR, OIR + NIC, OIR + NIC+ glibenclamide (GLB) groups. Serum anti-Müllerian hormone (AMH), ovarian malondialdehyde (MDA), total nitrites (NOx) contents, and superoxide dismutase (SOD) activity were evaluated. Bax and Bcl2 mRNA were also assessed. Histological and immunohistochemical (anti-COX-2 and anti CD68) studies were done. The OIR non-treated group showed histopathological ovarian injury with decreased AMH level. Ovarian MDA, NOx, and Bax mRNA and the expression of COX-2 and CD68 were increased; however, SOD activity and Bcl2 mRNA level were decreased by OIR. NIC significantly ameliorated the histopathological ovarian injury with the restoration of AMH level. NIC significantly corrected oxidative stress and apoptotic biomarkers with decreased COX-2 and CD68 immunostaining. GLB co-administration significantly decreased the protection afforded by NIC. These results imply that NIC has a protective role against OIR via antioxidant, anti-inflammatory, and anti-apoptotic effects and such protection relies, at least partially, on the KATP channel.