The value of low-intensity pulsed ultrasound in reducing ovarian injury caused by chemotherapy in mice.

BACKGROUND: Ovarian damage and follicle loss are major side effects of chemotherapy in young female patients with cancer. However, effective strategies to prevent these injuries are still lacking. The purpose of this study was to verify low-intensity pulsed ultrasound (LIPUS) can reduce ovarian injury caused by chemotherapy and to explore its underlying mechanisms in mice model. METHODS: The mice were randomly divided into the Control group, Cisplatin group, and Cisplatin + LIPUS group. The Cisplatin group and Cisplatin + LIPUS group were intraperitoneally injected with cisplatin every other day for a total of 10 injections, and the Control group was injected with saline. On the second day of each injection, the Cisplatin + LIPUS group received irradiation, whereas the other two groups received sham irradiation. We used a variety of biotechnologies to detect the differences in follicle count, granulosa cell apoptosis, fibrosis, transcriptome level, oxidative damage, and inflammation in differently treated mice. RESULT: LIPUS was able to reduce primordial follicle pool depletion induced by cisplatin and inhibit the apoptosis of granulosa cells. Transcriptomic results confirmed that LIPUS can reduce ovarian tissue injury. We demonstrated that LIPUS can relieve ovarian fibrosis by inhibiting TGF-ß1/Smads pathway. Meanwhile, it can reduce the oxidative damage and reduced the mRNA levels of proinflammatory cytokines caused by chemotherapy. CONCLUSION: LIPUS can reduce the toxic effects of chemotherapy drugs on ovaries, inhibit ovarian fibrosis, reduce the inflammatory response, and redcue the oxidative damage, reduce follicle depletion and to maintain the number of follicle pools.

Practical Prediction Model for Ovarian Insufficiency after Radiation / Modelo prático de predição para insuficiência ovariana após radiação

Abstract Objective The present study aimed to develop a useful mathematical model that predicts the age at which premature ovarian insufficiency might occur after teletherapy radiation. A diagnosis of premature or early menopause has physical and psychological consequences, so women may need support and long-term medical follow-up. Methods To correlate ovarian radiation dose with ovarian function, we used the formula described by Wallace et al.: √g(z) = 10(2-0,15z), where "g(z)" and "z" represent oocyte survival rate and the radiation dose (in Gray), respectively. By simulating different ages and doses, we observed a pattern that could be used to simplify the relationship between radiation dose and remaining time of ovarian function. Results We obtained a linear function between ovarian radiation dose and loss of ovarian function (LOF) that is the percentage of decrease in the time to the ovarian failure compared with the time expected for a woman at the same age without irradiation exposition. For patients <40 years old and with ovarian radiation doses < 5 Gy, the equation LOF = 2.70 + (11.08 × Dose) can be applied to estimate the decrease in time to premature ovarian insufficiency. Conclusion The present study reports a practicable theoretical method to estimate the loss of ovarian function. These findings can potentially improve the management and counseling of young women patients submitted to radiotherapy during their reproductive years.

Resumo Objetivo O presente estudo teve como objetivo desenvolver um modelo matemático útil que prediz a idade na qual a insuficiência ovariana prematura pode ocorrer após a radioterapia externa (teleterapia). O diagnóstico de menopausa prematura ou precoce tem consequências físicas e psicológicas; portanto, as mulheres podem precisar de apoio e acompanhamento médico de longo prazo. Métodos Para correlacionar a dose de radiação ovariana com a função ovariana, foi usada a fórmula descrita por Wallace et al.: √g(z) = 10(2-0,15z), na qual "g(z)" e "z" representam a taxa de sobrevivência do oócito e a dose de radiação (em Gray), respectivamente. Ao simular diferentes idades e doses, observamos um padrão que poderia ser usado para simplificar a relação entre a dose de radiação e o tempo restante da função ovariana. Resultados Obtivemos uma função linear entre a dose de radiação ovariana e a perda da função ovariana (LOF, na sigla em inglês) que é a porcentagem de diminuição no tempo até a falência ovariana em relação ao tempo esperado para uma mulher da mesma idade sem exposição à radiação. Para pacientes<40 anos de idade e com doses de radiação ovariana < 5 Gy, a equação LOF = 2,70 + (11,08 × Dose) pode ser aplicada para estimar a redução no tempo até a insuficiência ovariana. Conclusão O presente estudo relata um método teórico viável para estimar a perda da função ovariana. Estes achados podem melhorar potencialmente o manejo e o aconselhamento de pacientes jovens submetidas à radioterapia durante seus anos reprodutivos.

Ovarian Function Preservation in Patients With Cervical Cancer Undergoing Hysterectomy and Ovarian Transposition Before Pelvic Radiotherapy.

To examine the factors associated with ovarian failure (OF) and assess the effectiveness of ovarian transposition (OT) before pelvic irradiation for preserving ovarian function in patients with cervical cancer (CC) undergoing hysterectomy. During 2003 to 2017, patients who underwent hysterectomy with preservation of one or both ovaries were retrospectively enrolled. Patients were divided into 4 groups, depending on whether radiotherapy (RT) and OT were performed: group 1, RT(+) and OT(+); group 2, RT(+) and OT(-); group 3, RT(-) and OT(+); group 4, RT(-) and OT(-). OF was defined as serum follicle-stimulating hormone levels of ≥30 mIU/mL. Sixty-six patients (59 [89.4%] invasive CC and 7 [10.6%] cervical intraepithelial neoplasia) were included. The 2-year OF-free survival rate was 61.4% (95% confidence interval [CI] 37.8-86.0), 0%, 91.7% (95% CI 76.0-100), and 75.8% (95% CI 58.2-93.4) for groups 1, 2, 3, and 4, respectively. In groups 1 and 2 receiving RT, OT, and combination of external beam radiotherapy and vaginal brachytherapy were associated with OF on multivariate analysis (MVA) (P-value = .002 and .046, respectively). In groups 3 and 4 without RT, older age (40 years old) and OT did not affect OF; however, the number of remaining ovaries was independently associated with OF in MVA (P = .035). OT could effectively preserve ovarian function in patients treated with adjuvant RT, while OT procedure itself did not affect ovarian failure. OT should be considered in the management of premenopausal cervical cancer patients.

Mouse model of radiation-induced premature ovarian insufficiency reveals compromised oocyte quality: implications for fertility preservation.

RESEARCH QUESTION: What is the impact of radiation exposure on oocyte quality and female fertility? DESIGN: Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined. RESULTS: Radiation exposure induced a massive loss of primordial follicles with LD50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035). CONCLUSIONS: The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes.

Dosimetric evaluation of ovaries and pelvic bones associated with clinical outcomes in patients receiving total body irradiation with ovarian shielding.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients' ovaries were shielded with cylinder-type lead blocks. The dose-volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose-volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.

Fertility preservation in childhood and adolescent female tumor survivors.

OBJECTIVE: To assess the proportion of female childhood and adolescent tumor survivors who could benefit from oocyte cryopreservation. DESIGN: Case series of female childhood and adolescent tumor survivors referred for fertility counseling. SETTING: A referral cancer center and an infertility unit of an academic hospital. PATIENT(S): Young female childhood and adolescent tumor survivors who received gonadotoxic treatments. INTERVENTION(S): Patients were prescribed tests of ovarian reserve and a personalized counseling was given. Oocyte cryopreservation was considered in subjects aged ≥18 years who were diagnosed with diminished ovarian reserve (DOR) (antimüllerian hormone level <2 ng/mL or total antral follicle count ≤10). MAIN OUTCOME MEASURE(S): Rate of women with DOR who stored their oocytes. RESULT(S): Ninety out of 126 evaluated women completed the assessments. We documented preserved ovarian reserve, DOR, and premature ovarian insufficiency in 36 (40%), 35 (39%), and 19 (21%) cases, respectively. Overall, 13 subjects with DOR were eligible for oocyte cryostorage, of whom 9 (69%) underwent the procedure. Considering the whole cohort of evaluated young women (n = 90), the rate of those who had egg freezing was 10%. Finally, nine women started seeking pregnancy after the counseling (six with DOR), and seven of them became pregnant. When the data were analyzed separately according to most gonadotoxic treatments, considerable differences emerged but the evidence did not support the idea that counseling should be restricted to particular subgroups of women. CONCLUSION(S): Ovarian reserve impairment is common in female childhood and adolescent tumor survivors. Postcancer oocyte cryopreservation may be part of the armamentarium of fertility preservation options.

Premature Ovarian Insufficiency (POI) Induced by Dynamic Intensity Modulated Radiation Therapy via P13K-AKT-FOXO3a in Rat Models.

This study is aimed to investigate the mechanisms of radiation-induced mouse models of premature ovarian insufficiency (POI). Wistar female rats were grouped into the control, 3.2 Gy, 4.0 Gy, and 4.8 Gy groups. Overall ovarian functions were assessed with the H&E staining and ELISA. Proinflammatory cytokine secretion was analyzed ELISA, and the reactive oxygen species (ROS) levels were analyzed with immunohistochemistry. Protein expressions were analyzed by Western blot analysis. The 4.0 Gy and 4.8 Gy groups had significantly lower ovarian weight coefficients than the control and 3.2 Gy groups (after only one irradiation therapy). The 3.2 Gy radiation group induced periodic disturbance and hormone change at 4 weeks after radiation. In the 4.0 Gy and 4.8 Gy groups, the preantral follicles and antral follicles were decreased, while Atresia follicles were increased. E2 was decreased, while FSH and LH secretions were increased. The ovaries in the 4.0 Gy group were not completely atrophied, and some preantral follicles remained. Ovarian atrophy and follicular Atresia were found in the 4.8 Gy group. Inflammatory and oxidative markers were upregulated. PI3K and AKT were downregulated in the 4.0 Gy and 4.8 Gy groups, while FOXO3a was upregulated. Ovarian injuries may lead to oxidative damages and inflammatory injuries, downregulate the expression of P13k and Akt, upregulate the expression of FOXO3a, and lead to follicular atresia in the ovary.

Local application of low level laser therapy in mice ameliorates ovarian damage induced by cyclophosphamide.

The aim of the present study is to assess whether low level laser therapy (LLLT) can protect ovaries from chemotherapy-induced gonadotoxicity using a mice model of premature ovarian failure induced by cyclophosphamide (CTX). LLLT (64 J/cm2) increased the number of antral follicles whilst decreasing the number of atretic follicles compared to CTX alone. LLLT increased the number of primordial follicles compared with those in the CTX group but they did not differ from those in the control group. LLLT treatment increased the number of AMH-positive follicles compared to CTX alone. LLLT application increased ovarian weight, serum progesterone concentration and P450scc protein levels compared to CTX alone. LLLT reduced the apoptosis in antral follicles and the BAX/BCL-2 ratio compared to CTX alone. Vascular morphology, analysed by CD31 and α-SMA immunostaining, was restored in LLLT-treated ovaries compared to CTX alone. In conclusion, application of LLLT prior to CTX might serve as a promising and novel protocol to preserve female fertility in cancer survivors.

Effect of 150 kHz electromagnetic radiation on the development of polycystic ovaries induced by estradiol Valerate in Sprague Dawley rats.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common complex endocrine disorder affecting approximately 2-20% of reproductive aged females. Tumour Treating Fields (100-300 kHz) is a recent innovative, non-invasive therapeutic approach to cancer therapy. This frequency as an alternative therapy for the management of polycystic ovaries has not yet been explored. OBJECTIVES: To explore the effect of full-body exposure of 150 kHz Electromagnetic Radiation (EMR), on the development of polycystic ovaries in an estradiol valerate-induced PCO rat model. METHOD: Twenty-one female adult rats were divided into three groups (n = 7 each): control, Estradiol Valerate (EV) and EV + EMR groups. The EV + EMR group was subjected to full body exposure at 150 kHz EMR continuously for eight consecutive weeks. Estradiol valerate was administered orally to induce polycystic ovaries in EV and EV + EMR groups. Body and ovarian weights were recorded and analysed. The regularity of the estrous cycle was assessed in all three groups. The histological study of ovarian tissue was carried out by haematoxylin and eosin staining. The serum concentration levels of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH) and testosterone were measured using the ELISA method. RESULTS: The body and ovary weights did not differ significantly between the EV and EV + EMR groups. The estrous cycle was found to be irregular in both the EV and EV + EMR groups. Ovarian histology revealed near normal morphology with little or no degenerative and morphological changes in developing follicles in the exposed group. Histometrical analysis showed an increased number of developing follicles and a significant reduction in the number and size of follicular cysts (p < 0.05) in the EV + EMR group. Hormonal analysis revealed no significant difference in the testosterone and FSH levels between the EV + EMR and EV groups. However, the LH, LH/FSH ratio decreased significantly in the EV + EMR group compares to the EV group. CONCLUSION: The 150 kHz EMR appear to have little or no degenerative and morphological changes in the developing follicles, an increased number of typical developing follicles and a significant reduction in the number and size of the follicular cysts (p < 0.05).

Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation.

PURPOSE: Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after in vivo mouse pelvic GRT versus PRT. METHODS AND MATERIALS: One hundred twenty-four female prepubertal mice received sham, GRT, or PRT with ovaries positioned at various depth with respect to the proton SOBP, with single doses of 1.8 or 0.2 Gy. AMH was measured at baseline, 1, 3, and 8 weeks after treatment, and the total number of surviving primordial follicles was counted. Multivariable linear mixed-effects modeling was used to assess the relationship between radiation therapy modality and dose on AMH and primordial follicle survival. RESULTS: For ovaries beyond the SOBP, ovarian function (P = .5) and ovarian primordial follicle (OPF; P = 1.0) were spared relative to sham controls. For ovaries in the SOBP plateau, ovarian function and primordial follicle reserve 8 weeks after treatment were reduced for all groups: 1.8 Gy GRT (ßAMH = -4.9 ng/mL; ßOPF = -728.2/animal), 1.8 Gy (relative biological effectiveness [RBE] = 1.1) PRT (ßAMH = -5.1 ng/mL; ßOPF = -728.2/animal), 0.2 Gy GRT (ßAMH = -2.5 ng/mL; ßOPF = -595.1/animal), and 0.2 Gy (RBE = 1.1) PRT (ßAMH = -3.0 ng/mL; ßOPF = -555.4/animal) relative to sham controls (all differences P < .001). CONCLUSIONS: This study uses an animal model to demonstrate the safety of proton therapy in sparing fertility. Ovaries positioned beyond the SOBP during PRT maintain ovarian reserve, suggesting that a proton beam has no energy and exit dose beyond SOBP. This study proposes that proton therapy is much safer than photon radiation therapy to protect ovarian follicles with the same dose, and it supports further testing of proton therapy for abdominopelvic tumors in young women.

The Effect of Radioactive Iodine Therapy on Ovarian Function and Fertility in Female Thyroid Cancer Patients: A Systematic Review and Meta-Analysis.

Introduction: Thyroid cancer is one of the most common carcinomas diagnosed in adolescents and young adults, with a rapidly rising incidence for the past three decades. Surgery is the standard treatment for patients with differentiated thyroid carcinoma (DTC), and when indicated, followed by radioactive iodine (RAI) treatment. The aim of this study was to evaluate the possible effects of RAI therapy on ovarian function and fertility in women. Methods: The PubMed, Embase, and Web of Science databases were systematically searched up to January 2020. In addition, a meta-analyses were performed for anti-Mullerian hormone (AMH) levels after RAI, comparison of AMH levels prior and 1 year after RAI, and pregnancy rates in patient with thyroid cancer receiving RAI compared with patients with thyroid cancer who did not receive RAI. Results: A total of 36 studies were eligible for full-text screening and 22 studies were included. The majority of the studies had a retrospective design. Menstrual irregularities were present in the first year after RAI in 12% and up to 31% of the patients. Approximately 8-16% of the patients experienced amenorrhea in the first year after RAI. Women who received RAI treatment (median dose 3700 MBq [range 1110-40,700 MBq]); had menopause at a slightly younger age compared with women who did not receive RAI treatment, 49.5 and 51 years, respectively (p < 0.001). Pooled AMH of the seven studies reporting AMH concentrations after RAI was 1.79 ng/mL. Of these, four studies reported AMH concentrations prior and 1 year after RAI. The mean difference was 1.50 ng/mL, which was significant. Finally, meta-analysis showed that patients undergoing RAI were not at a decreased risk of becoming pregnant. Conclusions: Most of the studies indicate that RAI therapy for DTC is not associated with a long-term decrease in pregnancy rates although meta-analyses show a significant decrease in AMH levels after RAI therapy. Prospective studies are needed to confirm these results. We recommend counseling patients about the possible effects of 131I and incorporate today's knowledge in multidisciplinary counseling.

Protective effect of edaravone against radiation-induced ovarian injury: a histopathological and immunohistochemical evaluation in an experimental rat model.

PURPOSE: We aimed to evaluate the protective effect of edaravone on radiation-induced ovarian damage in an experimental rat model. METHODS: Thirty-two Wistar albino female rats were randomly divided into four groups. Group 1: control, no treatment, and radiation was applied throughout the study; Group 2: sham, only radiation was applied; Group 3: 45 mg/kg edaravone and radiation were applied; Group 4: 450 mg/kg edaravone and radiation were applied. Edaravone was administered intraperitoneally 30 min before radiotherapy (5 Gy). Two days after radiation exposure, the rats were sacrificed and the ovaries were removed. Histologic changes under light microscopy and immunoreactivity for anti-caspase-3 were noted and compared between the four groups. RESULTS: There was a statistically significant difference in follicle counts, vascular congestion, edema, cytoplasmic vacuolization, hemorrhage, and interstitial cell degeneration between the groups. Radiation causes deterioration in most histopathological parameters. Administration of edaravone at different doses seems to reverse these alterations and alleviate the injury. Antioxidant defense mechanisms appear to be enhanced by edaravone as shown by histopathologically and decreased apoptosis by reducing the expression of anti-caspase-3 activity as demonstrated immunohistochemically. CONCLUSION: This is the first study evaluating the protective effects of edaravone on radiation-induced ovarian damage. Edaravone decreased the follicular apoptosis and attenuates the radiation-induced ovarian damage in rats.

Bone health and osteoporosis screening in gynecologic cancer survivors.

Cancer treatment-induced bone loss is a known side effect of cancer therapy that increases the risk of osteoporosis and bone fracture. Women with gynecologic cancer are at increased risk of bone loss secondary to the combined effect of oophorectomy and adjuvant therapies. Data regarding bone loss in women with gynecologic cancers are overall lacking compared to other cancer populations. Consequently, guidelines for osteoporosis screening in women with cancer are largely based on data generated among non-gynecologic cancer survivors. This article reviews current available data of bone health in women with gynecologic cancer, summarizes best-available guidelines for screening for osteoporosis in women with cancer, and provides guidance for osteoporosis screening in women with gynecologic cancers based on best available evidence.

The effects of prenatal and postnatal exposure to electromagnetic field on rat ovarian tissue.

Exposure to an electromagnetic field (EMF) can have adverse effects on many organs and tissues, including the reproductive system. This study aimed to investigate the effects of EMF exposure during prenatal and postnatal periods on ovarian development in rat offspring. In this study, rat pups born from eight pregnant rats were used. EMF exposure was initiated on the first day of pregnancy and continued until the 42nd postnatal day. The blood and ovarian tissue samples of female offspring in sham and EMF groups were collected when they reached the age of 42 days. Follicle-stimulating hormone levels were significantly higher in the EMF group than in the sham group. Estradiol levels were significantly lower in the EMF group than in the sham group. Tissue-inducible nitric oxide synthase (iNOS) levels and expression were significantly greater in the EMF group than in the sham group. In the EMF group, congestion, bleeding areas, and degeneration of follicle structures were observed in ovarian tissue. The findings suggest that exposure to 50-Hz, 3-mT EMF used in this study during prenatal and postnatal periods may lead to impaired ovarian structure and function in female offspring. EMF may affect ovarian physiology by increasing iNOS levels and may lead to fertility disorders.

Sphingosine 1-phosphate protects against radiation-induced ovarian injury in female rats-impact on mitochondrial-related genes.

The toxic effects of ionizing radiation on the gonads have been widely recognized. Sphingosine 1-phosphate (S1P) has a protective effect on ovarian injury, and although it is known that mitochondria are involved in this process, the specific mechanism is not fully understood. The present study analysed the changes in the serum AMH and ovarian histology in Sprague-Dawley female rats exposed to X-ray radiation only or co-administered with S1P. The mRNA expression profile of ovarian tissue was further analysed via next-generation sequencing and bioinformatics approaches to screen out candidate mitochondria-related genes. Finally, differentially expressed target genes were verified by real-time PCR. The results showed that ionizing radiation could reduce the serum AMH level, destroy ovarian structure and decrease the number of follicles in rats, while S1P administration significantly attenuated the impairment of ovarian function. Gene ontology (GO) and KEGG pathway analysis revealed that a variety of genes related to mitochondrial function were differentially expressed, and the protective effect of S1P on mitochondria was more obvious in the acute phase 24 h after radiation. The differentially expressed mitochondrial function-related genes associated with the protective effect of S1P were UQCRH, MICU2 and GPX4, which were subsequently verified by RT-PCR. Therefore, ionizing radiation has a significant effect on ovarian function, and S1P has a protective effect on radiation-induced ovarian injury, in which mitochondria may play an important role. This study sheds new light on the mechanism of radiation-induced ovarian injury and helps develop a novel potential strategy to control it.

Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats.

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.

Phytoestrogen genistein hinders ovarian oxidative damage and apoptotic cell death-induced by ionizing radiation: co-operative role of ER-ß, TGF-ß, and FOXL-2.

Radiotherapy is a well-known cause of premature ovarian failure (POF). Therefore, we investigated the molecular influence of genistein (GEN) on the ovarian reserve of rats exposed to ϒ-radiation. Female Sprague Dawley rats were exposed to a 3.2 Gy γ-radiation to induce POF and/or treated with either GEN (5 mg/kg, i.p.) or Ethinyl estradiol (E2; 0.1 mg/kg, s.c.), once daily for 10 days. GEN was able to conserve primordial follicles stock and population of growing follicles accompanied with reduction in atretic follicles. GEN restored the circulating estradiol and anti-Müllerian hormone levels which were diminished after irradiation. GEN has potent antioxidant activity against radiation-mediated oxidative stress through upregulating endogenous glutathione levels and glutathione peroxidase activity. Mechanistically, GEN inhibited the intrinsic pathway of apoptosis by repressing Bax expression and augmenting Bcl-2 expression resulted in reduced Bax/Bcl-2 ratio with subsequent reduction in cytochrome c and caspase 3 expression. These promising effects of GEN are associated with improving granulosa cells proliferation. On the molecular basis, GEN reversed ovarian apoptosis through up-regulation of ER-ß and FOXL-2 with downregulation of TGF-ß expression, therefore inhibiting transition of primordial follicles to more growing follicles. GEN may constitute a novel therapeutic modality for safeguarding ovarian function of females' cancer survivors.

Modeling Variation in the Reproductive Lifespan of Female Adolescent and Young Adult Cancer Survivors Using AMH.

CONTEXT: Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. OBJECTIVE: To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. DESIGN: In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone (AMH) levels were measured using the Ansh DBS AMH enzyme-linked immunosorbent assay. The mean AMH trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. RESULTS: 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). AMH trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, AMH levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, AMH levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001). CONCLUSIONS: In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.

The madness of Princess Alice: Sigmund Freud, Ernst Simmel and Alice of Battenberg at Kurhaus Schloß Tegel.

During the winter of 1930, Princess Alice of Battenberg was admitted to Kurhaus Schloß Tegel, where she was diagnosed with schizophrenic paranoia. When Freud was consulted about her case by Ernst Simmel, the Sanatorium's Director, he recommended that the patient's ovaries be exposed to high-intensity X-rays. Freud's suggestion was not based on any psychoanalytic treatment principles, but rooted in a rejuvenation technique to which Freud himself had subscribed. In recommending that psychotic patients should be treated with physical interventions, Freud confirmed his conviction that the clinical applicability of psychoanalysis should not be extrapolated beyond the neuroses, yet he also asserted that a proper consideration of endocrinological factors in the aetiology and treatment of the psychoses should never be excluded.

Do cancer therapies damage the uterus and compromise fertility?

BACKGROUND: As cancer survival rates improve, understanding and preventing the adverse off-target and long-term impacts of cancer treatments, including impacts on fertility, have become increasingly important. Cancer therapy-mediated damage to the ovary and depletion of the primordial follicle reserve are well characterised. However, our knowledge of the full extent of damage to the rest of the female reproductive tract, in particular the uterus, is limited. OBJECTIVE AND RATIONALE: Improving our understanding of the off-target effects of cancer therapies on the entire female reproductive tract is a critical step towards developing truly effective strategies to protect the fertility of cancer survivors. The objective of this narrative review was to critically evaluate the available literature regarding the capacity for the uterus to sustain a healthy pregnancy following exposure to radiotherapy or chemotherapy. SEARCH METHODS: The authors performed PubMed (Medline) searches using the following key words: uterus, cancer survivors, radiotherapy, chemotherapy, pregnancy outcome, fertility preservation, infertility. There were no limits placed on time of publication. OUTCOMES: Overall, there were major limitations to the current available literature, meaning that interpretations should be taken with caution. Despite these drawbacks, data suggest that the uterus may sustain off-target damage, with the extent of damage dependent on the type of cancer treatment and patient age. Specifically, uterine growth is stunted and resistant to hormone replacement therapy in prepubertal girls receiving abdominal, pelvic or whole-body radiotherapy. In contrast, females treated with radiotherapy post-puberty can benefit from hormone replacement therapy, as demonstrated by increased uterine volume and function. No live births have been reported in women previously exposed to radiotherapy after transplantation of cryopreserved ovarian tissue, even when menstruation returns. However, this technique has proven to be a successful fertility preservation method for women previously treated with chemotherapy. Obstetricians commonly report that women who maintain sufficient ovarian function can achieve pregnancy naturally following radiotherapy, but they have thin and/or fibrotic myometrium at delivery, compromising safe delivery and subsequent pregnancy. Furthermore, women exposed to either radiotherapy or chemotherapy have a higher prevalence of preterm birth and low birth weight infants, even in those with normal ovarian function or when oocyte donation is utilised. The mechanisms of potential uterine damage are poorly understood. While the myometrium, vasculature and endometrial progenitor cells are possibly targets, further studies are clearly required and well-controlled animal models could provide the best avenue for these types of future investigations. WIDER IMPLICATIONS: Female cancer survivors experience greater rates of early pregnancy loss and complications, suggesting that cancer therapy-induced damage to the uterus contributes to infertility. Despite clinical reports dating back to 1989, we highlight a surprising lack of detail in the literature regarding the precise nature and extent of off-target damage inflicted to the uterus in response to cancer therapies. Young women requiring cancer treatment, and the clinicians treating them, must be equipped with accurate information to aid informed decision-making regarding cancer treatment regimens as well as the development and use of effective fertility preservation measures. As the current literature on the impacts of cancer treatments is limited, we hope that our narrative review on this subject will stimulate more research in this important field.