Development of a fertility risk calculator to predict individualized chance of ovarian failure after chemotherapy.

PURPOSE: To develop an innovative machine learning (ML) model that predicts personalized risk of primary ovarian insufficiency (POI) after chemotherapy for reproductive-aged women. Currently, individualized prediction of a patient's risk of POI is challenging. METHODS: Authors of published studies examining POI after gonadotoxic therapy were contacted, and six authors shared their de-identified data (N = 435). A composite outcome for POI was determined for each patient and validated by 3 authors. The primary dataset was partitioned into training and test sets; random forest binary classifiers were trained, and mean prediction scores were computed. Institutional data collected from a cross-sectional survey of cancer survivors (N = 117) was used as another independent validation set. RESULTS: Our model predicted individualized risk of POI with an accuracy of 88% (area under the ROC 0.87, 95% CI: 0.77-0.96; p < 0.001). Mean prediction scores for patients who developed POI and who did not were 0.60 and 0.38 (t-test p < 0.001), respectively. Highly weighted variables included age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve. CONCLUSION: We developed an ML-based model to estimate personalized risk of POI after chemotherapy. Our web-based calculator will be a user-friendly decision aid for individualizing risk prediction in oncofertility consultations.

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE-TR mice.

The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

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.

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.

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.

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.

The protective effect of platelet-rich plasma administrated on ovarian function in female rats with Cy-induced ovarian damage.

PURPOSE: We evaluated the protective effect of PRP on ovarian function in female rats with cyclophosphamide (Cy)-induced ovarian damage. METHODS: Thirty-two adult female Sprague-Dawley rats were randomly divided into four groups. Group 1 (control-sodium chloride 0.9%; 1 mL/kg, single-dose ip injection), group 2 (Cy); 75 mg/kg, single-dose ip injection and sodium chloride 0.9% (1 mL/kg, single-dose ip injection), group 3 Cy plus PRP, Cy (75 mg/kg, single-dose and PRP (200 µl, single-dose) ip injection), group 4 (PRP, 200 µl, single-dose ip injection). Primordial, antral, and atretic follicle counts; serum anti-Müllerian hormone (AMH) levels; AMH-positive granulosa cells; and gene expression analysis of Ddx4 were assessed. RESULTS: Serum AMH levels were significantly lower in group 2 compared to groups 1, 3, and 4 (p < 0.01, p < 0.01, and p = 0.04, respectively). A significant difference was found in the primordial, primary, secondary, antral, and atretic follicle counts between all groups (p < 0.01). There was a statistically significant difference in AMH-positive staining primary, secondary, and antral follicles count between the groups (p < 0.01). There was a statistically significant difference in primary, secondary, and antral AMH positive staining follicle intensity score between the groups (p < 0.01). Ddx4 expression in group 4 was highest compared to other groups. CONCLUSION: Our study may provide evidence that PRP could protect ovarian function against ovarian damage induced by Cy. It could lead to improved primordial, primary, secondary, and antral follicle numbers.

Ovarian Follicle Depletion Induced by Chemotherapy and the Investigational Stages of Potential Fertility-Protective Treatments-A Review.

Ovarian follicle pool depletion, infertility, and premature menopause are all known sequelae of cancer treatment that negatively impact the quality of life of young cancer survivors. The mechanisms involved in this undesired iatrogenic ovarian damage have been intensively studied, but many of them remain unclear. Several chemotherapeutic drugs have been shown to induce direct and indirect DNA-damage and/or cellular stress, which are often followed by apoptosis and/or autophagy. Damage to the ovarian micro-vessel network induced by chemotherapeutic agents also seems to contribute to ovarian dysfunction. Another proposed mechanism behind ovarian follicle pool depletion is the overactivation of primordial follicles from the quiescent pool; however, current experimental data are inconsistent regarding these effects. There is great interest in characterizing the mechanisms involved in ovarian damage because this might lead to the identification of potentially protective substances as possible future therapeutics. Research in this field is still at an experimental stage, and further investigations are needed to develop effective and individualized treatments for clinical application. This review provides an overview of the current knowledge and the proposed hypothesis behind chemotherapy-induced ovarian damage, as well as current knowledge on possible co-treatments that might protect the ovary and the follicles from such damages.

Role of epigenetic regulation of Igf2 and H19 in 2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD)-induced ovarian toxicity in offspring rats.

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD) exposure during embryonic gonadal sex determination had been demonstrated to harm the ovarian development. However, its mechanism was unclear and possibly related to epigenetic regulation. In the present study, the pregnant rats were treated with TCDD (100 ng/kg/day or 500 ng/kg/day) or only vehicle and corn oil on the day 8-14 of gestation through the gavage with a stainless-steel feeding needle. The vaginal opening time and estrous cycle of female offspring rats (F1) were monitored twice a day. The ovarian histology, follicle count, real-time PCR, Western Blotting and DNA methylation analysis for Igf2 and H19 were carried out. The results showed that maternal TCDD exposure disrupted estrous cyclicity, resulted in aberrant concentration of serum E2 and FSH, and affected the number of primordial follicles, secondary follicles and corpus luteum. However, TCDD had no effect on the number of primary follicles and atresia follicles. Furthermore, the mRAN expression of imprinted genes Igf2 and H19 was down-regulated, and the IGF2 protein was also down-regulated. TCDD exposure did not alter the mean methylation rate of Igf2 DMR2 and H19 ICR, and only some CpG sites throughout them were hypermethylated in high-dose TCDD rats. In conclusion, maternal exposure of TCDD could affect the ovary development and functions which were possibly associated with down-regulation expression of IGF2 and H19. However, it was not entirely clear whether the impairment of ovary by TCDD was related to the methylation pattern of Igf2 and H19 ICR.

Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in the cholesterol metabolism by negatively regulating the low-density lipoprotein receptor (LDLR). Lipid metabolic and ovarian disorders are the common clinical manifestation of polycystic ovary syndrome (PCOS). Here, we intended to elucidate the role of PCSK9 in the pathogenesis of PCOS conducted on a human population in case-control design and animal part in an interventional study. METHODS: We firstly investigated the serum levels of PCSK9 in 46 PCOS patients compared with 49 healthy women as controls, and then developed a PCOS mouse model induced by dehydroepiandrosterone (DHEA) and a high-fat diet (HFD) to determine the role of PCSK9 in abnormal lipid metabolism and ovarian dysfunction of PCOS in four groups (n = 40 per group): control, PCOS mice, PCOS plus alirocumab group, and PCOS plus vehicle group. The expression of PCSK9 in their serum, hepatic and ovarian tissues, serum lipid profiles and hormones were measured. Additionally, mRNA and protein expression levels of LDLR in hepatic and ovarian tissues, ovarian morphology and function were determined. Finally, we used freshly isolated theca-interstitial cells (TICs) and granulosa cells (GCs) from prepubertal normal mice to explore the effect of PCSK9 on LDL uptake of the cells. RESULTS: Serum PCSK9 concentrations were higher in PCOS patients than normal controls (P < 0.05). The PCOS model mice exhibited significantly increased serum levels of total cholesterol (TC), LDL-C and high-density lipoprotein-cholesterol (HDL-C; P < 0.001, P < 0.001, P = 0.0004, respectively). Moreover, the serum PCSK9 protein level was significantly increased in PCOS mice (P = 0.0002), which positively correlated with serum LDL-C (r = 0.5279, P = 0.0004) and TC (r = 0.4151, P = 0.035). In both liver and ovary of PCOS mice, PCSK9 mRNA and protein levels were significantly increased (P < 0.05), but LDLR levels were significantly decreased (P < 0.05). Furthermore, alirocumab inhibiting PCSK9 partly increased in LDLR expression in both liver and ovary in PCOS mice, also ameliorated the lipid metabolic disorders and pathological changes of ovarian morphology and function and serum reproductive hormones but not in the PCOS plus vehicle group. In vitro experiment, recombinant PCSK9 decreased LDL uptake in TICs and GCs (P < 0.001, P = 0.0011, respectively), which were partly reversed by alirocumab (P < 0.001, P = 0.012, respectively). CONCLUSION: Abnormal high expression of PCSK9 in the blood, liver and ovary may be involved in the pathogenesis of PCOS by affecting lipid metabolism and ovarian function, and the inhibition of PCSK9 may partly reverse the pathological changes of PCOS. Our research suggests a possibility of PCSK9 as a new attractive target for diagnosis and treatment of PCOS.

Effect of platelet-rich plasma (PRP) on ovarian structures in cyclophosphamide-induced ovarian failure in female rats: a stereological study.

BACKGROUND: Ovarian failure is diagnosed by ovarian destruction and reducing sex hormonal levels. Platelet-rich plasma (PRP) contains several growth factors that induce tissue repair and may induce folliculogenesis. OBJECTIVE: This study evaluates the effect of PRP on ovarian structures and function in cyclophosphamide (Cy)-induced ovarian failure in female rats by a stereological method. METHODS: Thirty-two adult female rats were divided into four groups (Control, Cy, Cy + PRP, and PRP). Female infertility was induced by Cy (75 mg/kg, single dose, intraperitoneally). Animals were treated by PRP which was obtained from age-matched male rats (200 µL, single dose, intraperitoneally). Blood samples were collected for measurement of hormones. The animals were dissected and the right ovaries were removed, fixed, sectioned, and stained by H&E. Stereological methods were used to estimate cortex and medulla volume, and the number and diameter of follicles, follicular cell, and oocyte using light microscopy. RESULTS: Cyclophosphamide had the maximum effect in decreasing on cortex volume, the pre-antral follicles number, a diameter of follicular cells and oocyte diameter in the antral follicle and the reduction of estradiol and progesterone levels compared with the control group. PRP had a dominant positive effect on the ovarian cortex volume, pre-antral follicles number and antral follicle diameter relative to the control group. PRP also decreased oocyte diameter in pre-antral follicle in infertile animals (p < 0.001). CONCLUSION: It seems that PRP has a protective effect on ovarian failure in the infertile female rat model.

Ovarian function, fertility and reproductive lifespan in cancer patients.

INTRODUCTION: The increasing survival of girls and young women after cancer has led to a rapid growth in research into assessment of ovarian function after treatment. AREAS COVERED: This aim of this review is to discuss normal ovarian function over time, the impact of cancer treatment on ovarian function, the assessment of ovarian reserve after treatment, and pretreatment predictors of ovarian recovery. EXPERT COMMENTARY: Ovarian function damage after chemotherapy and radiotherapy will impact on fertility and reproductive lifespan, but with great variability. Age at menopause has implications for the duration of estrogen deficiency, with its own adverse health consequences. This has led to identification of the key treatment and patient factors at the time of treatment, notably age and ovarian reserve that impact on post-treatment ovarian function. However, most studies have used outcome measures such as ongoing menses, or biomarkers such as anti-mullerian hormone (AMH), with few reporting on fertility or age at menopause.

Peroxiredoxin 2 deficiency accelerates age-related ovarian failure through the reactive oxygen species-mediated JNK pathway in mice.

Reactive oxygen species (ROS) produced in biological reactions have been shown to contribute to ovarian aging. Peroxiredoxin 2 (Prx2) is an antioxidant enzyme that protects cells by scavenging ROS; however, its effect on age-related, oxidative stress-associated ovarian failure has not been reported. Here, we investigated its role in age-related ovarian dysfunction and 4-vinylcyclohexene diepoxide (VCD)-induced premature ovarian failure using Prx2-deficient mice. Compared to those in wildtype (WT) mice, serum levels of anti-Müllerian hormone, 17ß-estradiol, and progesterone and numbers of follicles and corpora lutea were significantly lower in 18-month-old Prx2-/- mice. Moreover, levels of Bax, cytochrome c, cleaved caspase-3, and phosphorylated JNK proteins were higher and numbers of apoptotic (terminal deoxynucleotidyl transferase dUTP nick end labeling-positive) cells were considerably greater in 18-month-old Prx2-/- ovaries than WT ovaries. Furthermore, the effects of the ovarian toxicant VCD in significantly enhancing ROS levels and apoptosis through activation of JNK-mediated apoptotic signaling were more pronounced in Prx2-/- than WT mouse embryonic fibroblasts. Expression of the steroidogenic proteins StAR, CYP11A1, and 3ß-HSD and serum levels of 17ß-estradiol and progesterone were also reduced to a greater extent in Prx2-/- mice than WT mice after VCD injection. This reduced steroidogenesis was rescued by addition of the Prx mimic ebselen or JNK inhibitor SP600125. This constitutes the first report that Prx2 deficiency leads to acceleration of age-related or VCD-induced ovarian failure by activation of the ROS-induced JNK pathway. These findings suggest that Prx2 plays an important role in preventing accelerated ovarian failure by inhibiting ROS-induced JNK activation.

The protective effects of gonadotropin-releasing hormone agonist on ovarian functions in breast Cancer patients receiving chemotherapy.

In recent decades, the incidence rate of breast cancer has increased dramatically worldwide and has become one of the most prevalent cancers in women. According to the global data provided by the WHO, there were more than 1.7 million new cases of breast cancer in 2012, accounting for 25% of all reported cancer cases and 15% of all reported deaths among females. To most young patients, especially those younger than 40 years of age, chemotherapy should be taken into consideration as a treatment modality, even if the tumor size is small or without lymphatic metastasis. A significant portion of the patients will suffer from the side effects that result from long-term chemotherapy regimens, such as myelosuppression, heart failure, and development of a second primary malignancy. Ovarian suppression and premature ovarian failure (POF) are the most common side effects reported as they have notable clinical symptoms; the incidence rates have been reported to be in a range of 10-90%. Gonadotropin-releasing hormone agonists (GnRH-a), also termed luteinizing hormone release hormone agonists (LHRH-a), may very well offer a solution to treating these side effects. This article aims to summarize advanced studies concerning protective effects of GnRH-a on ovarian functions in the setting of breast cancer under chemotherapy.

Lycium barbarum polysaccharide attenuates chemotherapy-induced ovarian injury by reducing oxidative stress.

AIM: We aimed to examine the effects of Lycium barbarum polysaccharide (LBP) on ovarian damage induced by cyclophosphamide (CTX) and to investigate the underlying mechanism. METHODS: A total of 240 female Sprague-Dawley rats were randomly divided into five groups: the control group, the CTX-induced ovarian injury (OI) group, and three LBP groups. Different concentrations of LBP solution were administered to the LBP groups by gastric infusion for 15 days, and the OI group and LBP groups were then subjected to CTX treatment for another 15 days. On days 7, 14, and 28 after CTX injection, femoral vein blood and ovarian tissues were collected for the measurements of antioxidant enzymes and oxidation products. Serum indicators were measured by enzyme-linked immunosorbent assay; and Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein levels were detected by Western blot analysis. RESULTS: LBP attenuated CTX-induced ovarian damage and reversed associated adverse effects. LBP reduced oxidative stress by enhancing the potency of antioxidant enzymes and attenuating elevated levels of oxidation products following CTX injection. Furthermore, LBP upregulated Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein expression. CONCLUSION: LBP exerts protective effects against CTX-induced ovarian injury by reducing oxidative stress and activating the Nrf2/ARE-signaling pathway.

A gonadotropin-releasing hormone agonist for the prevention of docetaxel-induced gonadal damage.

This study aimed to evaluate the protective effect of a gonadotropin-releasing hormone (GnRH) agonist against docetaxel-induced gonadotoxicity in a mouse model. Forty mice (female B6, 6-8 weeks old, weighing 16-18 g) were divided randomly into four groups. Groups 1 and 2 were treated with a single intraperitoneal dose of 0.1 mL normal saline; Groups 3 and 4 received 30 mg/kg docetaxel. Groups 2 and 4 were pre-treated with a subcutaneous injection of 0.3 mg leuprolide acetate, 2 weeks before the administration of docetaxel. The ovaries were removed 6 weeks after docetaxel or saline injection. Total follicle number decreased in Group 3 compared to Group 1. There was a significant difference between the Groups 3 and 4 in the total follicle number. Many ovarian follicles were stained for Ki-67 in Groups 1, 2, and 4; however, in Group 3, only a small number were stained and destruction of the ovarian structure was observed. There was no immunohistochemistry staining with γ-H2AX in Groups 1, 2, and 4. However, γ-H2AX staining of the primordial follicles was observed in Group 3. GnRH agonists may protect ovarian follicles from docetaxel-induced ovarian damage considering the total follicle number, follicle proliferation, and double-strand DNA breaks. Impact statement Protection of the ovarian reserve and prevention of infertility are the primary quality of life issues in young cancer patients. In this study, ovarian suppression by gonadotropin-releasing hormone agonists protected ovarian follicles from docetaxel-induced ovarian damage considering the total follicle number, follicle proliferation, and double-strand DNA break. The findings of our study will provide useful information for fertility preservation in women with cancer, undergoing chemotherapy with docetaxel.

Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure.

Background: Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen. Methods: We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis. Results: The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR. Conclusions: The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.

Blueberry (Vaccinium ashei Reade) extract ameliorates ovarian damage induced by subchronic cadmium exposure in mice: Potential δ-ALA-D involvement.

Females are born with a finite number of oocyte-containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ-aminolevulinate dehydratase activity, and partially improved the viability of cadmium-disrupted follicles. This therapy was not able to restore the 17 ß-hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 188-196, 2017.