ABSTRACT
INTRODUCTION: Anticancer treatments have significantly contributed to increasing cure rates of breast cancer in the last years; however, they can also lead to short- and long-term side effects, including gonadotoxicity, and compromised fertility in young women. Oncofertility is a crucial issue for young patients who have not yet completed their family planning at the time of cancer diagnosis. AREAS COVERED: This review aims to cover all the latest available evidence in the field of oncofertility, including the gonadotoxicity of currently adopted anticancer therapies in the curative breast cancer setting, the available strategies for fertility preservation and the feasibility of achieving a pregnancy following anticancer treatment completion. EXPERT OPINION: Over the past years, a significant progress has been made in oncofertility care for young women with breast cancer. In the context of the currently available evidence, every young woman with newly diagnosed breast cancer should receive a proper and complete oncofertility counseling before starting any anticancer treatment to increase her chances of future pregnancies.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Counseling , Fertility Preservation , Humans , Female , Fertility Preservation/methods , Breast Neoplasms/drug therapy , Breast Neoplasms/therapy , Pregnancy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/administration & dosage , Infertility, Female/etiology , Infertility, Female/prevention & control , Infertility, Female/therapy , Infertility, Female/chemically induced , Adult , Family Planning ServicesABSTRACT
Methodological limitations in studying the association between the use of fertility drugs and cancer include the inherent increased risk of cancer in women who never conceive, the increased risk of cancer because of factors (endometriosis and unopposed estrogen) associated with infertility, the low incidence of most of these cancers, and that the diagnosis of cancer is typically several years after fertility drug use. On the basis of available data, there does not appear to be an association between fertility drugs and breast, colon, or cervical cancer. There is no conclusive evidence that fertility drugs increase the risk of uterine cancer, although women with infertility are at higher risk of uterine cancer. There are insufficient data to comment on the risk of melanoma and non-Hodgkin lymphoma associated with fertility drug use. Women should be informed that there may be an increased risk of invasive and borderline ovarian cancers and thyroid cancer associated with fertility treatment. It is difficult to determine whether this risk is related to underlying endometriosis, female infertility, or nulliparity.
Subject(s)
Neoplasms , Humans , Female , Neoplasms/epidemiology , Neoplasms/chemically induced , Risk Factors , Infertility, Female/chemically induced , Infertility, Female/epidemiology , Infertility, Female/therapy , Infertility, Female/diagnosis , Fertility Agents/adverse effects , Fertility Agents/therapeutic use , Fertility Agents, Female/adverse effects , Fertility Agents, Female/therapeutic use , Risk AssessmentABSTRACT
The therapeutic landscape for early breast cancer (eBC) has expanded by introducing novel anticancer agents into clinical practice. During their reproductive years, women with eBC should be informed of the potential risk of premature ovarian insufficiency (POI) and infertility with the proposed systemic therapy. Although the topic of female fertility is becoming increasingly relevant in patients with cancer, limited information is available on the gonadotoxicity of new agents available for eBC treatment. Analyses from clinical trials and prospective data on ovarian function biomarkers are lacking. The purpose of this systematic review is to report the available preclinical and clinical data on female fertility risk with the use of the new agents that are part of clinical practice use or under development for eBC management. This review highlights the clear need to perform additional research efforts to improve our understanding on the gonoadtoxicity of new anticancer agents.
Subject(s)
Breast Neoplasms , Female , Humans , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Fertility/drug effects , Infertility, Female/chemically induced , Infertility, Female/etiology , Primary Ovarian Insufficiency/chemically induced , Risk AssessmentABSTRACT
The study encompassing research papers documented in the last two decades pertaining to the possible influence of bisphenol A (BPA) on the fertility of females are appraised with emphasis on the influence of BPA in reproductive organs (uterus and ovaries) and pregnancy outcomes including discussion on the reproductive process (implantation, estrous cycle, hormone secretion); outcomes reveal a connection amongst BPA and female infertility. Ovary, uterus, and its shape as well as function can alter a person's ability to become pregnant by influencing the hypothalamus-pituitary axis in the ovarian model. Additionally, implantation and the estrous cycle may be affected by BPA. However, more research is warranted to comprehend the underlying action mechanisms and to promptly identify any imminent reproductive harm.
Subject(s)
Benzhydryl Compounds , Phenols , Reproduction , Benzhydryl Compounds/toxicity , Phenols/toxicity , Female , Humans , Animals , Pregnancy , Reproduction/drug effects , Endocrine Disruptors/toxicity , Infertility, Female/chemically induced , Ovary/drug effects , Fertility/drug effects , Genitalia, Female/drug effects , Uterus/drug effectsABSTRACT
OBJECTIVE: To estimate the effect of platinum-based chemotherapy on live birth (LB) and infertility after cancer, in order to address a lack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer, which limits counseling on fertility preservation decisions. DESIGN: Retrospective cohort study. SETTING: US administrative database. PATIENTS: We identified incident breast, colorectal, and ovarian cancer cases in females aged 15-39 years who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. INTERVENTION: Platinum-based chemotherapy. MAIN OUTCOME MEASURES: We estimated the effect of chemotherapy on the incidence of LB and infertility after cancer, overall, and after accounting for competing events (recurrence, death, and sterilizing surgeries). RESULTS: There were 1,287 survivors in the chemotherapy group, 3,192 in the no chemotherapy group, and 34,147 women in the no cancer group, with a mean age of 33 years. Accounting for competing events, the overall 5-year LB incidence was lower in the chemotherapy group (3.9%) vs. the no chemotherapy group (6.4%). Adjusted relative risks vs. no chemotherapy and no cancer groups were 0.61 (95% confidence interval [CI] 0.42-0.82) and 0.70 (95% CI 0.51-0.93), respectively. The overall 5-year infertility incidence was similar in the chemotherapy group (21.8%) compared with the no chemotherapy group (20.7%). The adjusted relative risks vs. no chemotherapy and no cancer groups were 1.05 (95% CI 0.97-1.15) and 1.42 (95% CI 1.31-1.53), respectively. CONCLUSIONS: Cancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. The estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.
Subject(s)
Cancer Survivors , Infertility, Female , Live Birth , Humans , Female , Adolescent , Cancer Survivors/statistics & numerical data , Young Adult , Adult , Retrospective Studies , Infertility, Female/epidemiology , Infertility, Female/therapy , Infertility, Female/chemically induced , Infertility, Female/diagnosis , Live Birth/epidemiology , Pregnancy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Fertility Preservation/methods , Risk Factors , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/drug therapy , United States/epidemiology , Treatment Outcome , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/drug therapy , Neoplasms/epidemiology , Neoplasms/drug therapy , Fertility/drug effects , Risk AssessmentABSTRACT
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.
Subject(s)
Infertility, Female , Pesticides , Female , Humans , Infertility, Female/chemically induced , Infertility, Female/epidemiology , Nutrition Surveys , Nutritional Status , Vitamin D , Vitamins , Pesticides/adverse effectsABSTRACT
INTRODUCTION: According to the World Health Organization, infertility is a public health problem that affects around 48 million couples and 186 million individuals worldwide. Endocrine disruptors are one of the causes that raise more concern, given that it is a problem that has evolved with the progress of society. Many chemicals are used by food industry, entering food chain, and directly affecting human health. Endocrine disruptors have the capacity of interfering with the normal hormonal action, metabolism, and biosynthesis, which can lead to a variation of the normal hormonal homeostasis. Some of these endocrine disruptors are highly associated with diseases that are positively correlated with female infertility, such as polycystic ovary syndrome, endometriosis, irregular menstrual cycle and also disturbances on processes as steroidogenesis and development of the ovarian follicles. RESULTS: The present literature review covers various aspects of the possible relationship between endocrine disruptors and female infertility. Bisphenol A and its metabolites, phthalates, dioxins, organochlorine, and organophosphate compounds are groups of chemicals considered to have the capacity to disrupt endocrine activity and herein addressed. The results reported in in vivo studies and in clinical trials addressing endocrine disruptors and female infertility were discussed as well as their possible mechanism of action. CONCLUSIONS: Large, double-blind, placebo-controlled randomized clinical trials are needed to better understand the mechanisms of action of endocrine disruptors in female infertility, as well as the doses and frequency of exposure responsible for it.
Subject(s)
Endocrine Disruptors , Endometriosis , Environmental Pollutants , Infertility, Female , Humans , Female , Infertility, Female/chemically induced , Environmental Pollutants/toxicity , Endocrine Disruptors/toxicity , Ovarian Follicle , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: To review the complex concerns of oncofertility created through increased cancer survivorship and the long-term effects of cancer treatment in young adults. DESIGN: Review chemotherapy-induced ovarian dysfunction, outline how fertility may be addressed before treatment initiation, and discuss barriers to oncofertility treatment and guidelines for oncologists to provide this care to their patients. CONCLUSION: In women of childbearing potential, ovarian dysfunction resulting from cancer therapy has profound short- and long-term implications. Ovarian dysfunction can manifest as menstrual abnormalities, hot flashes, night sweats, impaired fertility, and in the long term, increased cardiovascular risk, bone mineral density loss, and cognitive deficits. The risk of ovarian dysfunction varies between drug classes, number of received lines of therapy, chemotherapy dosage, patient age, and baseline fertility status. Currently, there is no standard clinical practice to evaluate patients for their risk of developing ovarian dysfunction with systemic therapy or means to address hormonal fluctuations during treatment. This review provides a clinical guide to obtain a baseline fertility assessment and facilitate fertility preservation discussions.
Subject(s)
Fertility Preservation , Infertility, Female , Neoplasms , Young Adult , Humans , Female , Fertility Preservation/methods , Fertility , Infertility, Female/chemically induced , Infertility, Female/prevention & control , Neoplasms/drug therapyABSTRACT
OBJECTIVE: In women, agents used in chemotherapy treatment have side effects such as accelerating follicular depletion and early menopause. Thus, cytotoxic treatments may cause various effects ranging from partial damage to the ovary to premature ovarian failure (POI) and infertility. This study aimed to investigate the protective effect of carvacrol on cisplatin (CIS)-induced reproductive toxicity in female rats. MATERIALS AND METHODS: The animals were divided to four groups; a healthy group (HG), administered only cisplatin 2.5 mg/kg (CIS); cisplatin 2.5 mg/kg + carvacrol mg/kg (CC-50), and cisplatin 2.5 mg/kg + carvacrol 100 mg/kg (CC-100). In this study, the CC-50 and CC-100 groups were injected with carvacrol at 50 and 100 mg/kg intraperitoneally (IP). The CIS and HG groupswere administered normal saline as a solvent in the same way. One hour afterwardthe CC-50 and CC-100 groups were injected with cisplatin at 2.5 mg/kg IP. This procedure was continued once a day for 14 days. At the end of this period, six rats from each group were euthanized with high-dose anaesthesia. Biochemical (oxidant-antioxidant and proinflammatory cytokines) and histopathological examinations were performed on the right ovarian tissue removed from the dead rats. The remaining (n = 6 in each group) animals were kept in the laboratory with mature male rats for two months for breeding. Rats that didn't give birth within two months were considered infertile. A one-way ANOVA test was used for the biochemical analysis, the a Kruskal Wallis test was used for the histopathological analysis. RESULTS: It has been observed that cisplatine causes oxidative stress and inflammatory damage in the ovarian tissue of animals and ultimately causes infertility due to this oxidative stress. While carvacrol significantly suppressed cisplatin-related oxidative stress in ovarian tissue at the 50 and 100 mg/kg doses, it could suppress proinflammatory cytokine increase only at thecytokine increase only at the 100 mg/kg dose. In addition, carvacrol significantly reduced the development of cisplatin-related infertility (from 0 to 83.3%) at a dose of 100 mg/kg. CONCLUSION: These findings suggest that carvacrol at high doses can reduce the harmful effects of cisplatin on the ovary and improve ovarian reserve in rats.
Subject(s)
Infertility, Female , Primary Ovarian Insufficiency , Humans , Rats , Female , Male , Animals , Cisplatin/therapeutic use , Cytokines/adverse effects , Oxidative Stress , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/drug therapy , Fertility , Infertility, Female/chemically induced , Infertility, Female/drug therapyABSTRACT
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.
Subject(s)
Infertility, Female , Female , Humans , Pregnancy , Infertility, Female/drug therapy , Infertility, Female/chemically induced , Vitamins/therapeutic use , Vitamin D/therapeutic use , Pregnancy Rate , Dietary SupplementsABSTRACT
OBJECTIVE: To assess the impact of 3 different ovarian stimulation protocols on surrogate biomarkers of coagulation. DESIGN: Observational multicenter cohort study. SETTING: The study was conducted in assisted reproductive technology (ART) units. PATIENTS: Infertile women undergoing ART in 2017-2019 were included. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Our primary outcome was the endogenous thrombin potential (ETP) assessed by the calibrated automated thrombogram. The ETP was measured at baseline (T1), on the day of ovulation triggering (T2), and 7 days after triggering (T3). Three protocols were prescribed according to the standards used and without hormonal before treatment: agonist protocol with human chorionic gonadotropin (hCG) trigger (ag-hCG), antagonist protocol with hCG trigger (atg-hCG), or GnRH agonist trigger. The evolution of ETP was compared among groups using a mixed-effects linear regression model. RESULT(S): Sixty-four women with a mean age of 37.8 years participated in the study: of which 24, 16, 24 received ag-hCG, atg-hCG, and GnRH agonist triggers, respectively. As expected, the mean serum estradiol levels in GnRH agonist trigger were statistically higher at T2 and lower at T3 than that for both ag-hCG and atg-hCG. Overall, the ETP evolution over time was statistically different between the groups. Values were similar between groups at T1 and increased at T2 in each group. The greatest difference occurred between T2 and T3 in each group. The ETP continued to increase at T3 in ag-hCG (+110 nM/L × min) and atg-hCG (+171 nM/L × min), but it remained stable in GnRH agonist trigger (-2 nM/L × min). Sex hormone-binding globulin showed persistent increase at T3 despite the fall in estradiol levels, particularly in the GnRH agonist trigger group. CONCLUSION(S): The ag-hCG and atg-hCG groups were associated with a higher hypercoagulable state at T3 than the GnRH agonist trigger group. However, our results show the persistence of a hypercoagulable state after the GnRH agonist triggering despite a sharp drop in estradiol levels. These findings may support the use of GnRH agonist trigger protocol in patients with high thrombotic risk and gives new insight into the fact that coagulation parameters could be disturbed for long time periods. CLINICAL TRIAL REGISTRATION NUMBER: NCT04188444.
Subject(s)
Infertility, Female , Ovarian Hyperstimulation Syndrome , Pregnancy , Humans , Female , Adult , Ovarian Hyperstimulation Syndrome/etiology , Ovarian Hyperstimulation Syndrome/chemically induced , Fertilization in Vitro , Infertility, Female/diagnosis , Infertility, Female/therapy , Infertility, Female/chemically induced , Pregnancy Rate , Gonadotropin-Releasing Hormone , Cohort Studies , Ovulation Induction/methods , Chorionic Gonadotropin/adverse effects , EstradiolABSTRACT
In patients with early breast cancer, the combination of different systemic treatment strategies, including chemotherapy, endocrine therapy, targeted therapy, and more recently also immunotherapy has demonstrated to significantly improve their survival outcomes. However, this gain is often obtained at the cost of higher toxicity calling for the need of increased attention toward survivorship-related issues, including fertility preservation in young women. According to available guidelines, health care providers should offer oncofertility counseling to all patients with cancer diagnosed at reproductive age. Counselling should focus on the risk of gonadotoxicity of anticancer treatments and on the access to fertility preservation techniques. However, several surveys have demonstrated suboptimal implementation of these recommendations. This review aims at summarizing the available evidence on oncofertility to guide health care providers involved in the management of young women with breast cancer. Available and effective options for fertility preservation include oocyte/embryo cryopreservation or ovarian tissue cryopreservation. Patient, disease, and treatment characteristics should be carefully considered when offering these strategies. Ovarian function preservation with gonadotrophin-releasing hormone agonists during chemotherapy should be discussed and offered to every premenopausal woman concerned about developing premature ovarian insufficiency and independently of her wish to preserve fertility. Current available data confirm that pregnancy occurring after proper treatment for breast cancer is safe, both in terms of long-term clinical outcomes and for the babies. Fertility preservation and pregnancy desire should be pivotal components of the multimodal management of breast cancer in young women, and require a multidisciplinary approach based on close collaborations between oncologists and fertility specialists.
Subject(s)
Breast Neoplasms , Fertility Preservation , Infertility, Female , Pregnancy , Female , Humans , Breast Neoplasms/drug therapy , Cryopreservation , Fertility , Infertility, Female/chemically induced , Infertility, Female/prevention & controlABSTRACT
BACKGROUND: Based on self-report questionnaires, two previous epidemiological studies investigated the association between the exposure of women to antibiotics and their fertility. However, biomonitoring studies on low-dose antibiotic exposure, mainly from food and water, and its relation to the risk of infertility are missing. METHODS: Based on a case-control study design, 302 women with infertility (144 primary infertility, 158 secondary infertility) and 302 women with normal fertility, all aged 20-49 years, were recruited from Anhui Province, China, in 2020 and 2021. A total of 41 common antibiotics and two antibiotic metabolites in urine samples were determined by liquid chromatography-triple quadrupole tandem mass spectrometry (LC-QqQ-MS/MS). RESULTS: Twenty-eight antibiotics with detection rates from 10% to 100% in both cases (median concentration: â¼2.294 ng/mL) and controls (â¼1.596 ng/mL) were included in the analysis. Logistic regression analysis revealed that after controlling for confounding factors, high concentrations of eight individual antibiotics (sulfamethoxazole, sulfaclozine, sulfamonomethoxine, penicillin G, chlorotetracycline, ofloxacin, norfloxacin, and cyadox) and four antibiotic classes (sulfonamides, tetracyclines, quinoxalines, and veterinary antibiotics) were related to a high risk of female infertility, with odds ratios (ORs) ranging from 1.30 to 2.86, except for chlorotetracycline (OR = 6.34), while another nine individual antibiotics (sulfamethazine, azithromycin, cefaclor, amoxicillin, oxytetracycline, pefloxacin, sarafloxacin, enrofloxacin, and florfenicol) and classes of chloramphenicol analogs and human antibiotics were related to a reduced risk of infertility, with ORs ranging from 0.70 to 0.20. Based on restricted cubic spline models after controlling for confounding factors, we observed that the relationship between all of the above protective antibiotics and infertility was nonlinear: A certain concentration could reduce the risk of female infertility while exceeding a safe dose could increase the risk of infertility. CONCLUSION: These results provide preliminary evidence that the effects of antibiotics on female fertility vary based on the active ingredient and usage and imply the importance of exposure dose. Future studies are needed to verify these results by controlling for multiple confounding factors.
Subject(s)
Chlortetracycline , Infertility, Female , Humans , Female , Anti-Bacterial Agents/analysis , Tandem Mass Spectrometry/methods , Chlortetracycline/analysis , Infertility, Female/chemically induced , Infertility, Female/epidemiology , Case-Control Studies , China/epidemiologyABSTRACT
Infertility is a major problem in modern society that affects a significant number of couples around the world. Heavy metals and a number of other factors have been causally linked to infertility. The aim of this study was to determine the effect of heavy metals lead, cadmium, and copper on the epidemiology of male and female infertility. Searches for articles published from 1982 to 2020 using related keywords such as male and female infertility and heavy metals were performed in scientific databases PubMed, Google Scholar, Science Direct, and others. The results showed that, in recent years, the number of infertile individuals has increased. Various environmental, occupational, and genetic factors have been described as potential causes. Heavy metals lead, cadmium, and copper cause infertility in couples through various mechanisms, such as changes in sperm motility factors, decreased semen quality, or effects on the egg. Exposure to physical phenomena such as radiation (ionized or microwave) and heat; stress and mental disorders; chemicals from cigarettes, respiratory pollutants (lead), insecticides and pesticides; anesthetic gases; and mercury and cytotoxic drugs may also contribute to the onset of infertility.
Subject(s)
Infertility, Female , Infertility, Male , Metals, Heavy , Male , Female , Humans , Cadmium/toxicity , Semen Analysis , Copper , Infertility, Female/chemically induced , Infertility, Female/epidemiology , Sperm Motility , Metals, Heavy/toxicity , Infertility, Male/chemically induced , Infertility, Male/epidemiologyABSTRACT
RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) alters oocyte developmental competence and so the treatment of PCOS patients with assisted reproductive techniques is a major challenge for an infertility specialist. Does ovulation induction therapy with clomiphene citrate, metformin and flutamide affect abnormal PCOS follicle gene expression, its quality, and nuclear and cytoplasmic maturation in the oocyte matured in vitro? DESIGN: Fifty NMRI mice (7-8 weeks old) were randomly divided into five groups, including non-PCOS, PCOS and PCOS groups treated with clomiphene citrate (18 mg/kg body weight for 2 days), metformin (50 mg/100 g body weight for 30 days) and flutamide (10 mg/kg body weight injection for 15 days). The oocytes were collected for quantitative real-time polymerase chain reaction analysis (the evaluation of genes associated with oocyte maturation), transmission electron microscopy (the evaluation of cytoplasmic maturation) and in-vitro maturation (IVM) and IVF outcomes. RESULTS: The dysregulated expression of some genes of insulin-like growth factor (IGF) families involved in oocyte competence and steroid metabolism (e.g. Cyp19a1 and Cyp11a1), transforming growth factor beta (TGF-ß) family (e.g. Tgfb1, Gdf9, Bmp15, Inhbb and Bmpr1a), and oestrogen receptor signalling (e.g. Ncoa3, Pgr) was, to some extent, restored in the PCOS follicles following their with clomiphene citrate, metformin and flutamide. The improved cytoplasmic maturation was observed particularly in the PCOS mice treated with clomiphene citrate. The better IVM-IVF outcomes were also observed in the clomiphene citrate and metformin groups compared with the PCOS group. CONCLUSIONS: This study opens up a new perspective on knowing the effect of ovulation induction therapy on not only nuclear maturation but also ultrastructural characteristics, IVM-IVF outcomes and PCOS oocyte developmental competence.
Subject(s)
Infertility, Female , Metformin , Polycystic Ovary Syndrome , Animals , Body Weight , Clomiphene/pharmacology , Female , Fertility Agents, Female/pharmacology , Fertility Agents, Female/therapeutic use , Flutamide/pharmacology , Humans , Infertility, Female/chemically induced , Metformin/pharmacology , Mice , Oocytes , Ovulation Induction/methods , Polycystic Ovary Syndrome/drug therapyABSTRACT
We reviewed the available animal and human reproductive function studies of recently approved noncytotoxic oncology drugs. We reviewed the oncofertility information in the prescribing information for the US Food and Drug Administration (FDA)-approved products and/or the product information and consumer medicine information for Therapeutic Goods Administration (TGA)-approved drugs of 32 novel oncology drugs approved between 2014 and 2018 in the United States and/or Australia supplemented by a literature review for additional reproductive effects. No human studies were available on the reproductive effects of all 32 drugs. A systematic literature review of animal reproductive toxicity studies provided only very limited data with nine drugs displaying impaired male fertility, three impaired female fertility, and nine producing impaired fertility in both male and female animals. Two drugs in the study are reported to have no demonstrable impact on fertility in animal reproductive toxicity studies and nine are reported to have unknown effects on fertility. Of the 32 newly listed drugs, only 4 had recommendations regarding potential human fertility risks and accordingly advised clinicians about fertility preservation procedures for patients. The lack of human data and limited animal reproductive toxicity data raises concerns about the potential impact of these novel oncology drugs on human fertility and reproductive function. Consequently, adequate oncofertility recommendations, including for fertility preservation procedures, counselling for psychological or cost implications, and future prognosis for fertility are hindered by this paucity of relevant data. More data on human reproductive effects of novel oncology drugs is urgently required to facilitate effective use of the growing array of oncofertility care options available.
Subject(s)
Antineoplastic Agents/adverse effects , Fertility Preservation , Fertility/drug effects , Infertility, Female/chemically induced , Infertility, Male/chemically induced , Animals , Female , Humans , Infertility, Female/physiopathology , Infertility, Female/therapy , Infertility, Male/physiopathology , Infertility, Male/therapy , Male , Risk Assessment , Risk FactorsABSTRACT
Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women's health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data - the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.
Subject(s)
Endocrine Disruptors/adverse effects , Endocrine System Diseases/chemically induced , Environmental Exposure/adverse effects , Environmental Pollutants/adverse effects , Fertility/drug effects , Hydrocarbons, Fluorinated/adverse effects , Menstrual Cycle/drug effects , Reproduction/drug effects , Endocrine System Diseases/metabolism , Endocrine System Diseases/physiopathology , Female , Humans , Infertility, Female/chemically induced , Infertility, Female/metabolism , Infertility, Female/physiopathology , Pregnancy , Pregnancy Complications/chemically induced , Pregnancy Complications/metabolism , Pregnancy Complications/physiopathology , Prognosis , Risk Assessment , Risk FactorsABSTRACT
Immunotherapy has emerged at the forefront of cancer treatment. Checkpoint inhibitor pembrolizumab (KEYTRUDA), a chimeric antibody which targets programmed cell death protein 1 (PD-1), has been approved by the Food and Drug Administration (FDA) for use in pediatric patients with relapsed or refractory classical Hodgkin's lymphoma. However, there is currently no published data regarding the effects of pembrolizumab on the ovary of female pediatric patients. In this study, prepubertal immunocompetent and immunodeficient female mice were injected with pembrolizumab or anti-mouse PD-1 antibody. The number of primordial follicles significantly decreased post-injection of both pembrolizumab and anti-mouse PD-1 antibody in immunocompetent mice. However, no changes in follicle numbers were observed in immunodeficient nude mice. Superovulation test and vaginal opening experiments suggest that there is no difference in the number of cumulus-oocyte complexes (COCs) and the timing of puberty onset between the control and anti-mouse PD-1 antibody treatment groups, indicating that there is no effect on short-term fertility. Elevation of pro-inflammatory cytokine TNF-α following COX-2 upregulation was observed in the ovary. CD3+ T-cell infiltration was detected within some ovarian follicles and between stromal cells of the ovaries in mice following treatment with anti-mouse PD-1 antibody. Thus, PD-1 immune checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation following CD3+ T-cell infiltration.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Ovarian Follicle/drug effects , Sexual Maturation/drug effects , Animals , Animals, Newborn , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/pharmacology , Cell Count , Female , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/pharmacology , Infertility, Female/chemically induced , Infertility, Female/pathology , Mice , Mice, Nude , Oocytes/cytology , Oocytes/drug effects , Ovarian Reserve/drug effects , Ovary/drug effects , Ovary/physiology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Infertility, Female/diagnosis , Models, Statistical , Neoplasms/drug therapy , Ovarian Diseases/diagnosis , Precision Medicine , Primary Ovarian Insufficiency/diagnosis , Adult , Cancer Survivors , Cross-Sectional Studies , Female , Humans , Infertility, Female/chemically induced , Infertility, Female/epidemiology , Neoplasms/pathology , Ovarian Diseases/chemically induced , Ovarian Diseases/epidemiology , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/epidemiology , Risk Assessment/methods , Surveys and Questionnaires , United States/epidemiologyABSTRACT
Since the survival rates of pediatric patients undergoing cancer treatment or hematopoietic stem cell transplantation (HSCT) have increased rapidly in recent decades, the late effects of treatment are now an important focus of patient care. Access to fertility preservation (FP) procedures as well as their financing differs considerably across Europe. However, some countries in Europe have recently changed the legal basis for financing FP procedures; therefore, the implementation of structures is mandatory to give patients access to FP. In this prospective cohort study, we characterized the process for establishing pediatric fertility counseling, including the development of an in-house standard procedure for recommendations regarding FP with potentially gonadotoxic treatment and valuating data from all FP counseling sessions. All data concerning patient characteristics (pubertal status, disease group) and recommendation of FP measures were prospectively collected and adoption of FP measures analyzed. Prior to the establishment of a structured process for FP in our pediatric oncology and stem cell transplantation center, there was no standardized FP counseling. We demonstrate that with the establishment of an inhouse standard procedure, it is possible to give consistent yet individualized FP counseling to approximately 90% of our patients facing gonadotoxic treatment, counseling over 200 patients between 2017 and 2019. This pilot study could potentially be adapted in other pediatric hematology, oncology, and stem cell transplantation centers to allow a more standardized handling of FP counseling for all patients facing gonadotoxic treatment.