Vitamin D Intake Attenuated the Association between Pesticides Exposure and Female Infertility.

BACKGROUND: Only a few epidemiological studies have illuminated the association between pesticide exposure and female infertility. However, evidence of the available data is restricted and also controversial. Vitamin D supplement was considered as having a beneficial effect on fertility. So, the purpose of our study is to assess the effect of dietary vitamin D consumption on the relationship between pesticide exposure in home and female infertility. METHODS: There were a total of 2,968 subjects from the National Health and Nutrition Examination Survey (NHANES), 2011 - 2018. The daily vitamin D intake was divided into two groups high intake (≥ 6 µg/d) and low intake (< 6 µg/d). Multi-variable logistic regression analysis was used to assess the relationship among vitamin D intake, pesticide exposure, and female infertility. RESULTS: We found a significant association between household pesticide exposure and infertility on a basis of a fully-adjusted model (OR 1.61; 95% CI 1.1 - 2.37). Furthermore, the relationship between pesticide exposure and in-fertility differed from low vitamin D intake group (OR 3.96; 95% CI 1.77 - 8.86) and high intake group (OR 1.36, 95% CI: 0.86 - 2.16), and p for interaction is 0.043 stratified by vitamin D intake. CONCLUSIONS: A significant association of female infertility with pesticide exposure in home is modified by dietary vitamin D consumption. This was the first study to demonstrate that dietary vitamin D may alter associations of human female infertility with pesticide exposure in home.

Influence of Vitamin D supplementation on reproductive outcomes of infertile patients: a systematic review and meta-analysis.

BACKGROUND: Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regarding the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this systematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive outcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical pregnancy rate. METHODS: We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane Library) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes difference between the intervention (vitamin D) vs. the control (placebo or none). Mantel-Haenszel random effects models were used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database registration number: CRD42022304018. RESULTS: Twelve eligible studies (n = 2352) were included: 9 randomized controlled trials (RCTs, n = 1677) and 3 cohort studies (n = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased clinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24-2.34; I2 = 63%, P = 0.001). However, the implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference (OR: 1.86, 95% CI: 1.00-3.47; I2 = 85%, P = 0.05; OR: 1.49; 0.98-2.26; I2 = 63%, P = 0.06; OR: 0.98, 95% CI: 0.63-1.53; I2 = 0%, P = 0.94 and OR: 3.64, 95% CI: 0.58-11.98; I2 = 68%, P = 0.21). The improvement of clinical pregnancy rate in the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, the duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vitamin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000-50,000 IU or 50,000-500,000 IU), or got vitamin D 1000-10,000 IU daily, lasting for 30-60 days could achieve better pregnancy outcome. CONCLUSION: To the best of our knowledge, this is the first meta-analysis systematically investigated that moderate daily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported the effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high-quality RCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit from this therapy.

Melatonin provides protection against cisplatin-induced ovarian damage and loss of fertility in mice.

RESEARCH QUESTION: Can melatonin provide non-invasive ovarian protection against damage caused by cis-diamminedichloroplatinum (cisplatin) and preserve fertility in female cancer patients? And if so, what is the possible mechanism? DESIGN: Athymic BALB/c nude tumour-bearing female mice were used to demonstrate whether melatonin affects the antineoplastic effect when co-administrated with cisplatin. Sexually mature and newborn C57BL/6 female mice were used to evaluate the potential effects of melatonin on the ovarian follicle pool, pregnancy rate and litter number in cisplatin-treated mice. The ovaries underwent immunohistochemical, TdT (terminal deoxynucleotidyl transferase)-mediated dUTP nick-end labelling (TUNEL) and gene array analysis to explore the underlying mechanism. In addition, granulosa cells were isolated to investigate the potential protective mechanism of melatonin. RESULTS: Melatonin not only enhanced the anti-cancer effect of cisplatin in tumour-bearing nude mice, but also reduced ovarian toxicity and preserved long-term fertility in cisplatin-treated C57BL/6 female mice. When co-administrated, melatonin was able to reduce the DNA damage and toxic effects on lipid peroxidation in the ovaries caused by cisplatin. Specifically, melatonin was able to largely restore lipid peroxidation in granulosa cells and thus prevent ovarian follicles from being depleted. CONCLUSIONS: Melatonin has the potential to be used as a chemotherapeutic adjuvant to simultaneously improve the outcome of anti-cancer treatment and preserve ovarian function during cisplatin chemotherapy. Notably, its properties of DNA protection and antioxidant effects on follicles may benefit female cancer survivors and prevent premature ovarian failure as well as fertility loss caused by chemotherapy.

Dietary CCPS from bitter gourd attenuates sodium arsenite induced female reproductive ailments cum infertility in wistar rats: anti-inflammatory and anti-apoptotic role.

This investigation explored a dietary therapy of pectic polysaccharide (CCPS) (2 mg/ Kg BW) against female repro-toxicity and infertility triggered by sodium arsenite (As3+) (10 mg/ Kg BW) in Wistar rats. The isolated CCPS consists of D-galactose and D-methyl galacturonate with a molar ratio of 1: 4. FTIR spectral analysis of CCPS and CCPS- sodium arsenite (As3+) complex indicated a possible chelating property of CCPS in presence of binding sites (OH-/COOH) for As3+. Series of negatively charged galacturonate residues in CCPS provide better potential for cation chelation. CCPS significantly mitigated As3+ induced ovarian, uterine lipid peroxidation, and reactive oxygen species (ROS) generation by the restoration of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) activities. CCPS post-treatment enhanced ovarian steroidogenesis along with a restoration of normal tissue histoarchitecture in As3+ fed rats by regulating the estradiol receptor alpha (ER-α). CCPS suppressed anti-inflammatory properties effectively found since a down-regulation of NF-kappa B (NF-қB), pro-inflammatory tumor necrosis-α (TNF-α) and interleukin-6 (IL-6) were observed in arsenicated rats with CCPS. This study confirmed the up-regulation of uterine pro-apoptotic/ apoptotic proteins caspase-3, poly ADP ribose polymerase (PARP), proliferating cell nuclear antigen (PCNA), phospho p53 and Bax, followed by down-regulation of Bcl-2 and protein Kinase B (AKT) signaling pathway along with uterine tissue regeneration in As3+ exposed rats. Oral CCPS attenuated the above apoptotic expressional changes significantly and dietary CCPS ensured successful fertility with the birth of healthy pups in lieu of infertile condition in As3+ fed rats. Moreover, this study also supports that CCPS treatment attenuated the As3+ toxicity by modulating the S-adenosine methionine (SAM) pool components, B12, folate and homocysteine.

Glucocorticoid exposure affects female fertility by exerting its effect on the uterus but not on the oocyte: lessons from a hypercortisolism mouse model.

STUDY QUESTION: What is the impact of glucocorticoid (GC) on female reproduction? SUMMARY ANSWER: Corticosterone (CORT) exposure causes little damage to oocyte quality or developmental competence but has an adverse effect on the uterus, which causes decreased implantation, embryo death and subsequent infertility. WHAT IS KNOWN ALREADY: Chronic treatment with high GC doses is effective in controlling most allergic diseases but may lead to metabolic disorders such as obesity that are closely related with reproductive function. STUDY DESIGN, SIZE, DURATION: Hypercortisolism was induced in a female mouse model by supplementing the drinking water with 100 µg/ml of CORT. Controls received vehicle (1% v/v ethanol) only. After 4 weeks treatment mice were either mated or killed in estrus for hormone and organ measurements. In the first experiment, treatment with CORT or control continued during pregnancy but in the second CORT treatment was stopped after mating. To identify the effects of GC exposure on the uterus, blastocysts were generated by IVF of oocytes from CORT and control mice and replaced into recipients receiving the opposite treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effects of hypercortisolism on female mice were first characterized by living body fat content, body weight, food intake, hormone and biochemical measurements, a glucose tolerance test and an insulin resistance test. Fertility was determined with or without CORT-treatment during pregnancy. Oocyte quality was assessed by oocyte maturation, mitochondrial distribution, reactive oxygen species production, mitochondrial DNA mutations and morphology of blastocysts produced in vivo or in vitro. Blastocyst cross-transfer was done to evaluate the causes of embryonic development failure. Fetus development and uterus morphology evaluation as well as culture of oocytes in vitro with gradient concentrations of CORT were also carried out. MAIN RESULTS AND THE ROLE OF CHANCE: In the hypercortisolism female mouse model, body weight and food intake were much higher than in the control, and corticosterone, estradiol, cholesterol (CHO) and triglycerides (TG) in the plasma of CORT-treated mice was significantly increased. The hypercortisolism female mice were infertile when CORT-treatment was sustained during pregnancy but fertile if CORT-treatment was stopped after mating. The rate of successful implantation in hypercortisolism mice with sustained CORT-treatment during pregnancy was significantly lower than in the control, and the implanted embryos could not develop beyond 13.5 dpc. Blastocyst cross-transfer showed that blastocysts from CORT-treated mice could develop to term in the uterus of control mice, but blastocysts from control mice failed to develop to term when they were transferred into CORT-treated mice, providing evidence that the infertility was mainly caused by an altered uterine environment. CORT administration did not affect oocyte maturation, mitochondrial distribution, ROS production and blastocyst morphology, but increased mitochondrial DNA mutations. Culture of oocytes in vitro with gradient concentrations of CORT showed that only very high concentrations of CORT caused damage to oocyte developmental competence. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: The mouse model has the advantages of a consistent genetic and physiological background and openness to experimental manipulation over clinical studies but may not represent the human situation. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that special care should be taken when administering CORT during pregnancy, and provide important information concerning female reproduction when treating patients by subjecting them to chronic GC exposure. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key R&D Program of China (Nos. 2016YFA0100400 and 2017YFC1000600) and the National Natural Science Foundation of China (31472055). The authors have no conflicts of interest.

Preventing ovarian failure associated with chemotherapy.

Alkylating chemotherapy is often used to treat pre-menopausal women for various malignancies and autoimmune diseases. Chemotherapy-associated ovarian failure is a potential consequence of this treatment which can cause infertility, and increases the risk of other long term adverse health sequelae. Randomised trials, predominantly of women undergoing alkylating chemotherapy for breast cancer, have shown evidence for the efficacy of gonadotropin-releasing hormone agonists (GnRHa) in preventing chemotherapy-associated ovarian failure. The European St Gallen and United States National Comprehensive Cancer Network guidelines recommend the use of concurrent GnRHa to reduce the risk of ovarian failure for pre-menopausal women undergoing chemotherapy for breast cancer. The GnRHa goserelin, a monthly 3.6 mg depot subcutaneous injection, has recently been listed on the Australian Pharmaceutical Benefits Scheme to reduce risk of ovarian failure for pre-menopausal women receiving alkylating therapies for malignancy or autoimmune disease. The first dose of goserelin should ideally be administered at least 1 week before commencement of alkylating treatment and continued 4-weekly during chemotherapy. Concurrent goserelin use should now be considered for all pre-menopausal women due to commence alkylating chemotherapy (except those with incurable cancer), regardless of their childbearing status, in an effort to preserve their ovarian function. For women who have not completed childbearing, consideration of other fertility preservation options, such as cryopreservation of embryos or oocytes, is also important.

High Consumption of Iron Exacerbates Hyperlipidemia, Atherosclerosis, and Female Sterility in Zebrafish via Acceleration of Glycation and Degradation of Serum Lipoproteins.

Elevated serum iron level is linked with an increased risk of diabetes and atherosclerosis. However, the pathological mechanism by which iron affects serum lipoprotein levels is unknown. To elucidate the mechanism, a high dose of ferrous ion was applied (final 60 µM, 120 µM) to human serum lipoproteins, macrophages, and human dermal fibroblast (HDF) cells. Iron-treated lipoproteins showed loss of antioxidant ability along with protein degradation and multimerization, especially co-treatment with fructose (final 10 mM). In the presence of fructose, HDF cells showed 3.5-fold more severe cellular senescence, as compared to the control, dependent on the dosage of fructose. In macrophages, phagocytosis of acetylated low-density lipoprotein (acLDL) was more accelerated by ferrous ion, occurring at a rate that was up to 1.8-fold higher, than acLDL alone. After 24 weeks supplementation with 0.05% and 0.1% ferrous ion in the diet (wt/wt), serum total cholesterol (TC) level was elevated 3.7- and 2.1-fold, respectively, under normal diet (ND). Serum triglyceride (TG) was elevated 1.4- and 1.7-fold, respectively, under ND upon 0.05% and 0.1% ferrous ion supplementation. Serum glucose level was elevated 2.4- and 1.2-fold under ND and high cholesterol diet (HCD), respectively. However, body weight was decreased by the Fe2+ consumption. Iron consumption caused severe reduction of embryo laying and reproduction ability, especially in female zebrafish via impairment of follicular development. In conclusion, ferrous ion treatment caused more pro-atherogenic, and pro-senescence processes in human macrophages and dermal cells. High consumption of iron exacerbated hyperlipidemia and hyperglycemia as well as induced fatty liver changes and sterility along with reduction of female fertility.

Protective effect of alpha-lipoic acid in methotrexate-induced ovarian oxidative injury and decreased ovarian reserve in rats.

To determine whether the possible oxidative effect of methotrexate (Mtx) on ovary and to evaluate the effectiveness of alpha lipoic acid (ALA), which may be useful in many oxidative stress models. Thirty-two female Wistar-albino rats were randomly divided into four groups; control group, alpha lipoic acid group (ALA 100 mg/kg, 10 days), multiple dose Mtx group (Mtx 1 mg/kg 1, 3, 5, 7 days) and Mtx and ALA group (Mtx 1 mg/kg 1, 3, 5, 7 days and ALA 100 mg/kg, 10 days). Serum total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI), tumor necrosis factor-alpha (TNF-α), tissue malondialdehyde (MDA) and activities of glutathione peroxidase (GSH-Px) and catalase (CAT) and anti-Mullerian hormone (AMH) and total ovarian follicle count were evaluated. Mtx administration caused a significant decrease in TAS, a significant increase in TOS and OSI, a significant increase in MDA levels and a decrease in GSH-Px and CAT activity. Moreover the proinflammatory cytokine (TNF-α) was increased in the Mtx group. And AMH values and total follicle count were significantly decreased in Mtx group. However, ALA treatment reversed biochemical results and AMH levels and total follicle count. Alpha lipoic acid ameliorates methotrexate induced oxidative damage of ovarian in rats.

The use of medicinal herbs in gynecological and pregnancy-related disorders by Jordanian women: a review of folkloric practice vs. evidence-based pharmacology.

Context National statistical reports in Jordan indicate a decrease in the total fertility rate along with a parallel increase in contraceptive use. The folkloric use of medicinal herbs in gynecological disorders has been growing in Jordan, despite of deficient reports on the evidence-based safety and efficacy of these practices. Objective The aim of this comprehensive article is to review medicinal plants with claimed ethnonpharmacological usage in various gynecological and pregnancy-related issues in Jordan, and to assess their evidence-based pharmacological studies as well as their phytochemistry. Methods The published literature was surveyed using Google Scholar entering the terms "ethnopharmacology AND Jordan AND infertility AND gynecology OR gestation". We included ethnopharmacological surveys in Jordan with available full-text. Results Twelve articles were reviewed. Plant species which are commonly used for female gynecological issues such as Artemisia monosperma Del. and A. herba-alba Asso. (Asteraceae) have been found to exert an antifertility effect. Ricinus communis L. (Euphorbiaceae) and Citrullus colocynthis (L.) Schrad. (Cucurbitaceae) had antifertility effects in male rats, but Nigella sativa oil L. (Ranunculaceae) and Cinnamon zeylanicum J. Presl (Lauraceae) were found to enhance it. Conclusion Using plants for gynecological disorders is a common practice in Jordan. Many of them, whether utilised for gynecological or non-gynecological conditions equally, were found to have detrimental effects on female or male fertility. Thus, couples planning pregnancy should be discouraged from the consumption of these herbs. Further local studies are warranted to confirm the appreciable beneficial pharmacological effects and safety of these plants.

The role of N-Acetylcysteine in preventing cyclophosphamide-induced gonadotoxicity: An experimental study in rats.

This study assessed whether NAC could prevent cyclophosphamide (CY)-induced damage, by measuring the anti-Müllerian hormone (AMH) levels. Forty-eight Sprague-Dawley female rats were divided into four groups: CY + NAC, CY, NAC and control, each including 12 rats. There was no significant difference among the 24-h AMH values of the groups (p = 0.452), whereas a significant difference was found in terms of 72-h values (p = 0.003). Paired comparisons revealed no significant difference between CY and CY + NAC (p>0.699) and NAC (p = 0.065) groups regarding 72-h AMH values. However, AMH concentrations of the CY group at 72 hours were significantly lower than those of the control group (p = 0.015). AMH concentrations of the CY + NAC group at 72 hours were also significantly lower than those of the NAC group (p = 0.002) and the control group (p = 0.002). The AMH levels of CY and CY + NAC groups at 72 hours were significantly lower than those at 24 hours. The 24-h and 72-h AMH levels in the NAC and control groups were similar. In the present study, a single dose of NAC failed to prevent the cytotoxic effects of CY.

Spleen content of selected polyphenols, splenocytes morphology and function in mice fed Rhodiola kirilowii extracts during pregnancy and lactation.

UNLABELLED: The genus Rhodiola (Crassulaceae) consists of many species, growing mainly in Asia and traditionally used as adaptogens and anti-inflammatory drugs. In order to elaborate herbal immunostimulator which could be safely given to pregnant women, we performed a study on immunotropic effects of feeding pregnant and lactating mice Rhodiola kirilowii extracts. This paper presents the results of the first part of our study - spleen content of selected polyphenols, spleen cellularity, splenocytes phenotype and their response to mitogens. Experiments were performed on adult inbred females of Balb/c strain, mated with adult males. Females, since copulatory plug was noted, up to the 28-th day after delivery were fed daily with 20 mg/kg b.m. water (RKW) or hydro-alcoholic (RKW-A) extracts of Rhodiola kirilowii. RESULTS: 1. Significantly lower proportion of pregnant mice in experimental groups than in the control. 2. Cellularity of spleen and flavonol quercetin spleen concentration were significantly lower in experimental groups in comparison to the controls. 3. Flavanols ((+)-catechin and epicatechin) levels were significantly higher in the spleens of experimental mice than in the controls. 4. Positive correlation between spleen cellularity and quercetin, and negative correlation between spleen cellularity and epicatechin content were observed. 5. Spleen mass and spleen lymphocytes phenotype and proliferation in RKW and RKW-A fed mice did not differ from the control. These results, together with suspicion of some embryo-toxicity, are worrying and eliminate the possibility of use Rhodiola kirilowii extracts for long-term treatment in pregnant females.

Protective effect of dienogest on chemotherapy-induced reduced fertility in female rats.

Reduced fertility is one of the main long-term consequences of chemotherapy given for lymphoma, leukemia, and other malignancies in young women. We examined with a female rat model whether and how dienogest, a fourth-generation progestin, modulates reduced fertility following exposure to gonadotoxic chemotherapy. Female rats were administered cyclophosphamide with or without GnRH agonist and different concentrations of dienogest for 20 days. Animals were sacrificed on Day 29, and the numbers of follicle at primordial, preantral and antral stage in the ovaries were counted histologically. Rats treated with sterile saline solution (as control), cyclophosphamide, cyclophosphamide plus GnRH agonist, and cyclophosphamide plus dienogest were also mated with male rats to evaluate their fertility and pregnancy outcomes. Cyclophosphamide significantly reduced the number of primordial follicles, whereas dienogest suppressed depletion of primordial follicle pool induced by chemotherapy. Although the rats exposed to cyclophosphamide alone failed to deliver live births, co-treatment with dienogest improved the pregnancy outcomes of treated rats. The protective effect of dienogest on chemotherapy-induced ovarian damage and reduced fertility was comparable to that of GnRH agonist. The present results suggest that the co-administration of dienogest and chemotherapy may be a useful strategy in preserving ovarian function and fertility in premenopausal women facing gonadotoxic chemotherapy.

[Effect of Bushen Tiaojing Recipe and Xiaoyao Pill on adenohypophysis and ovary in androgen-induced sterile rats: a comparative study].

OBJECTIVE: To observe the effect of Bushen Tiaojing Recipe (BTR) and Xiaoyao Pill (XYP) on the morphology and sex hormones secretion of adenohypophysis and ovaries in androgen-induced sterile rats (ASR). METHODS: Fifty 9-day old SD female rats randomly recruited from total 60 rats were subcutaneously injected with testosterone propionate to establish the ASR model. And the rest 10 rats were recruited as the normal group. Thirty successfully modeled rats were recruited and randomly divided into the model group, the BTR group (administered with BTR suspension), and the XYP group (administered with XYP suspension), 10 in each group. Five weeks later, rats were decapitated in the proestrus. Serum levels of estradiol (E2), progesterone (P), testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were detected by radioimmunoassay. The morphologies of adenohypophysis and ovary were observed after HE staining. RESULTS: Compared with the normal group, serum E2 and T levels increased, while FSH and LH levels decreased in the model group (all P < 0.01). The morphology of adenohypophysis and ovary was abnormal in the model group. Compared with the model group, serum E2 and T levels decreased, while FSH and LH levels increased in the BTR group and the XYP group (P < 0.05, P < 0.01). Besides, E2 and T levels in the BTR group and FSH levels in the XYP group restored to normal (all P > 0.05). The damaged structure of adenohypophysis and ovary got restored to different degrees. CONCLUSION: BTR and XYP both could improve ovulation failure.

Effects of sub-chronic aluminum chloride exposure on rat ovaries.

AIMS: This experiment investigated the effects of sub-chronic aluminum chloride (AlCl3) exposure on rat ovaries. MAIN METHODS: Eighty female Wistar (5weeks old) rats, weighed 110-120g, were randomly divided into four treatment groups: control group (CG), low-dose group (LG, 64mg/kg BW AlCl3), mid-dose group (MG, 128mg/kg BW AlCl3) and high-dose group (HG, 256mg/kg BW AlCl3). The AlCl3 was administered in drinking water for 120days. The ovarian ultrastructure was observed. The activities of acid phosphatase (ACP), alkaline phosphatase (ALP), succinate dehydrogenase (SDH), Na(+)-K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase, the contents of Fe, Cu and Zn, and the protein expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) in the ovary were determined. KEY FINDINGS: The results showed that the structure of the ovary was disrupted, the activities of ALP, ACP, SDH, Na(+)-K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase, the contents of Zn, Fe and the protein expression of FSHR and LHR were lowered, and the content of Cu was increased in AlCl3-treated rats than those in control. SIGNIFICANCE: The results indicate that sub-chronic AlCl3 exposure caused the damage of the ovarian structure, the disturbed metabolism of Fe, Zn and Cu and the decreased activities of Na(+)-K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase in the ovary, which could result in suppressed energy supply in the ovary. A combination of suppression of energy supply and reduction of expression of FSHR and LHR could inhibit ovulation and corpus luteum development, leading to infertility in female rats.

Early and late long-term effects of adjuvant chemotherapy.

Adjuvant chemotherapy continues to play an important role in breast cancer management. Exposure to chemotherapy can lead to a variety of early and late long-term toxicities, including ovarian failure (with resultant infertility and sexual dysfunction), bone loss, weight gain, neurotoxicity, neurocognitive changes, cardiac toxicity and secondary malignancy. Although chemotherapy effects may vary in medical severity, all effects have the potential to lead to a decrease in quality of life and a decrement on overall health status. Improved understanding of the etiology and management of chemotherapy-related toxicity may allow optimization of patient selection for treatment and ameliorate the concerns of patients who are considering embarking on a chemotherapy program. This article presents an overview of relevant early and late long-term toxicities, with a focus on recent advances and clinical management.

Palmitic acid in chicken granulosa cell death-lipotoxic mechanisms mediate reproductive inefficacy of broiler breeder hens.

In vivo and in vitro approaches were used to elucidate mechanisms of palmitate-induced cytotoxicity of follicle granulosa cells in fuel-overloaded broiler hens. In contrast to their energy-restricted counterparts, broiler breeder hens fed ad libitum for 2 wk had dyslipidemia, atresia within hierarchical ovarian follicles, and a 34% reduction in egg production (P < 0.05). Based on vital staining of freshly isolated granulosa cells with annexin V/propidium iodide, there were increases in apoptosis consistent with suppressed Akt activation (P < 0.05). Supplementing primary granulosa cell cultures with 0.5 mM palmitate for 48 or 96 h increased apoptosis (P < 0.05). Palmitate-induced cell death was accompanied by increased acyl-CoA oxidase, carnitine palmitoyl transferase-1, serine palmitoyl transferase, and sphingomyelinase transcripts and increased concentrations of proinflammatory interleukin-1ß (P < 0.05). Triacsin-C inhibition of fatty acyl-CoA synthesis blunted interleukin-1ß production and rescued granulosa cultures from palmitate-induced cell death. That there was partial to complete prevention of cell death with addition of the free radical scavenger pyrrolidine dithiocarbamate, the sphingomyelinase inhibitor imipramine, or the de novo ceramide synthesis inhibitor fumonisin B1, supported the notion that palmitate-induced granulosa cell cytotoxicity operated through a palmitate-derived metabolite. Palmitoyl-CoA may be channeled into ß-oxidation and/or into bioactive metabolites that increase free radical generation, an inflammatory response, and ceramide production. In conclusion, palmitate-derived metabolites activated apoptotic machinery in avian granulosa cells, which caused ovarian follicular atresia and reduced egg production in fuel-overloaded broiler breeder hens.

Neonatal phytoestrogen exposure alters oviduct mucosal immune response to pregnancy and affects preimplantation embryo development in the mouse.

Treatment of neonatal mice with the phytoestrogen genistein (50 mg/kg/day) results in complete female infertility caused in part by preimplantation embryo loss in the oviduct between Days 2 and 3 of pregnancy. We previously demonstrated that oviducts of genistein-treated mice are "posteriorized" as compared to control mouse oviducts because they express numerous genes normally restricted to posterior regions of the female reproductive tract (FRT), the cervix and vagina. We report here that neonatal genistein treatment resulted in substantial changes in oviduct expression of genes important for the FRT mucosal immune response, including immunoglobulins, antimicrobials, and chemokines. Some of the altered immune response genes were chronically altered beginning at the time of neonatal genistein treatment, indicating that these alterations were a result of the posteriorization phenotype. Other alterations in oviduct gene expression were observed only in early pregnancy, immediately after the FRT was exposed to inflammatory or antigenic stimuli from ovulation and mating. The oviduct changes affected development of the surviving embryos by increasing the rate of cleavage and decreasing the trophectoderm-to-inner cell mass cell ratio at the blastocyst stage. We conclude that both altered immune responses to pregnancy and deficits in oviduct support for preimplantation embryo development in the neonatal genistein model are likely to contribute to infertility phenotype.

Effect of astragaloside IV on the general and peripartum reproductive toxicity in Sprague-Dawley rats.

Fertility and early embryonic developmental toxicity in rats were evaluated by intravenously administering astragaloside IV (AS-IV) daily at 0.25, 0.5, and 1.0 mg/kg for 4 weeks before mating, throughout the mating period, and continuing to day 6 of gestation period in females. Perinatal toxicity in rats was evaluated on gestational days (GD) 15 to 21 and lactational days LD (LD) 1 to 21. Astragaloside IV had no maternal toxicity at 0.25 to 1.0 mg/kg in rats. Although it has an inhibitory effect on female fertility in F0/F1 rats, AS-IV was devoid of early embryonic developmental toxicity in F0/F1 rats and in the survival parameters of F1 postnatal rats. Maternal AS-IV exposure at the dose of 1.0 mg/kg per d resulted in a significant delay in time for fur development, eye opening, and cliff parry reflex of pups compared to control group (P < .05), whereas it did not affect the memory and learning of F1 pups.

Assessment of fertility protection and ovarian reserve with GnRH antagonist in rats undergoing chemotherapy with cyclophosphamide.

BACKGROUND: Reproductive function following chemotherapy is of increasing importance given that survival rates are improving. We assessed whether a gonadotropin-releasing hormone antagonist (GnRHant; cetrorelix) could promote ovarian protection against damage due to chemotherapy. METHODS: Forty-two female Wistar rats were used in this study. Animals were divided into four groups: group I (n=9) received placebo twice; group II (n=12) received placebo+cyclophosphamide (CPA); group III (n=12) received GnRHant+CPA; and group IV (n=9) received GnRHant+placebo. After medication, the estrous cycle was studied through vaginal smears. Rats were mated, pregnancy was documented and the number of live pups evaluated. Afterwards, rat ovaries were removed and prepared for histological studies. The ovarian cross-sectional area was measured and follicles were counted. RESULTS: Cyclic changes in vaginal smears were observed in all but one animal after treatment, but group II had a significantly lower rate of animals with proestrus or estrus (p<0.01). The offspring was markedly reduced by CPA treatment (group II, 3.00+/-1.33 pups vs. group I, 11.44+/-0.78 pups, p<0.01) and this effect was partly reversed by pre-treatment with GnRHant (group III, 7.00+/-1.31 pups). The ovarian cross-sectional area was not significantly different between groups, neither was the number of individual follicle types. However, rats in Group IV had a higher total number of ovarian follicles than those in the control group (17.1+/-1.22 vs. 10.9+/-0.70, p<0.05). CONCLUSION: The use of a GnRHant before CPA chemotherapy provided protection of fertility.

Involvement of connexin 43 in the acupuncture effect of improving rat blastocyst implantation.

Acupuncture can improve blastocyst implantation in rats. Connexin 43 may be involved in this effect.