A call to action: unified clinical practice guidelines for oncofertility care.

By 2030, WHO estimates that 1.4 million reproductive-aged women will be diagnosed with cancer annually. Fortunately, cancer is no longer considered an incurable disease in many cases. From 2008-2014, 85% of women under the age of 45 years diagnosed with cancer survived. This increase in survival rate has shifted attention from focusing exclusively on preserving life to focusing on preserving quality of life after treatment. One aspect of this is preserving the ability to have a biological family. Oncofertility, the field that bridges oncology and reproductive endocrinology with the goal of preserving fertility, offers these patients hope. Though it is clear that ASCO and ASRM recognize the importance of fertility preservation as an aspect of comprehensive oncology care, there are not yet unified guidelines for oncologists and fertility specialists for treating oncofertility patients. First, we identify the need for reproductive counseling prior to cancer treatment, as many patients report that their fertility preservation concerns are not addressed adequately. We then delineate multi-modal fertility preservation options that are available and appropriate for different patients with corresponding outcomes using different treatments. We discuss the unique challenges and considerations, including ethical dilemmas, for delivering timely and comprehensive care specifically for oncofertility patients. Finally, we address the multidisciplinary team that includes oncologists, reproductive endocrinologists, surgeons as well as their staff, nurses, genetic counselors, mental health professionals, and more. Since oncofertility patient care requires the coordination of both physician teams, one set of unified guidelines will greatly improve quality of care.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

A 2019 reproductive update from the Midwest Reproductive Symposium International.

"Mystery, Medicine, and the Magnificent Mile," the theme for the annual Midwest Reproductive Symposium International (MRSi) in Chicago, IL, captured the attention of reproductive professionals all over the world. Each year, the conference agenda encompasses emerging technologies in assisted reproduction, updates in the management of reproductive diseases, and common challenges encountered in clinical practice. The structure of the meeting, offering a mixture of lectures, panel discussions, and interactive workshops, creates a collaborative environment for physicians, geneticists, embryologists, nurses, mental health professionals, basic scientists, business administrative professionals, reproductive endocrinology and infertility fellows, and obstetrics and gynecology residents. The goal of the MRSi meeting is to provide all reproductive professionals the opportunity to exchange ideas, foster relationships, and deliver quality patient care. As the field continues to evolve, MRSi provides an exciting venue to uncover the mysteries of reproductive medicine with enthusiasm and collaboration.

Melatonin prevents hypochlorous acid-mediated cyanocobalamin destruction and cyanogen chloride generation.

Hypochlorous acid (HOCl) is a potent cytotoxic oxidant generated by the enzyme myeloperoxidase (MPO) in the presence of hydrogen peroxide (H2 O2 ) and chloride (Cl- ). Elevated levels of HOCl play an important role in various pathological conditions through oxidative modification of several biomolecules. Recently, we have highlighted the ability of HOCl to mediate the destruction of the metal-ion derivatives of tetrapyrrole macrocyclic rings such as hemoproteins and vitamin B12 (VB12 ) derivatives. Destruction of cyanocobalamin, a common pharmacological form of VB12 mediated by HOCl, results in the generation of toxic molecular products such as chlorinated derivatives, corrin ring cleavage products, the toxic blood agents cyanide (CN- ) and cyanogen chloride (CNCl), and redox-active free cobalt. Here, we show that melatonin prevents HOCl-mediated cyanocobalamin destruction, using a combination of UV-Vis spectrophotometry, high-performance liquid chromatography analysis, and colorimetric CNCl assay. Identification of several melatonin oxidation products suggests that the protective role of melatonin against HOCl-mediated cyanocobalamin destruction and subsequent CNCl generation is at the expense of melatonin oxidation. Collectively, this work highlights that, in addition to acting as an antioxidant and as a MPO inhibitor, melatonin can also prevent VB12 deficiency in inflammatory conditions such as cardiovascular and neurodegenerative diseases, among many others.

Essential learning tools for continuing medical education for physicians, geneticists, nurses, allied health professionals, mental health professionals, business administration professionals, and reproductive endocrinology and infertility (REI) fellows: the Midwest Reproductive Symposium International.

Essential learning tools for continuing medical education are a challenge in today's rapidly evolving field of reproductive medicine. The Midwest Reproductive Symposium International (MRSi) is a yearly conference held in Chicago, IL. The conference is targeted toward physicians, geneticists, nurses, allied health professionals, mental health professionals, business administration professionals, and reproductive endocrinology and infertility (REI) fellows engaged in the practice of reproductive medicine. In addition to the scientific conference agenda, there are specific sessions for nurses, mental health professionals, and REI fellows. Unique to the MRSi conference, there is also a separate "Business Minds" session to provide education on business acumen as it is an important element to running a department, division, or private clinic.

Review and recap of the Midwest Reproductive Symposium International: learning tool for continuing medical education for reproductive endocrinologists, geneticists, embryologists, mental health, and other infertility providers.

Conferences serve an essential means of learning and staying up to date in all aspects of medicine. Reproductive endocrinology and infertility is a young and constantly evolving field. The Midwest Reproductive Symposium International (MRSi) is a yearly conference held in Chicago, IL, and is one of the most intimate yet influential conferences in the fertility world. This conference is geared towards all professions and roles in the fertility world such as physicians, geneticists, nurses, allied health professionals, basic scientists, mental health professionals, business administration professionals, reproductive endocrinology and infertility fellows, and obstetrics and gynecology residents alike. The goal of MRSi is to continue to understand this revolutionary field in order to improve patient outcomes while staying up to date with the latest technology.

The value of delaying hCG administration to enable maturation of medium-sized follicles in patients undergoing superovulation for IVF/ICSI.

PURPOSE: The purpose of the study is to determine whether continued stimulation of mature follicles to allow "catch up" growth of medium-sized follicles in assisted reproductive technology compromises the clinical pregnancy (CPR) and live birth (LBR) rates in IVF/ICSI cycles. METHODS: This retrospective cohort study reviewed 200 first IVF ± ICSI cycles out of a total of 340 cycles with complete data. Women underwent stimulation protocols with gonadotropins (Gn) and GnRH antagonist. Treatment cycles were divided into two groups (Gp): hCG administration delayed despite the presence of two mature follicles, defined as ≥ 18 mm [Gp1, n = 79] and hCG administration given when there were two mature follicles [Gp2, n = 121]. RESULTS: The patients in Gp1 were significantly younger than those in Gp2 [32.9 (4.5) vs. 34.3 (4.8), p = 0.04] and needed a median of one more day of superovulation before ovulation was triggered with hCG. The extra days was associated with the use of 450 [75-2025] more Gn, such that at the time the hCG was administered, patient's in group 1 had developed significantly greater number of follicles ≥ 18 mm [mean (SD), 4.9 (1.8) vs. 3.4 (1.7), p < 0.0001]. The clinical pregnancy (48.1 vs. 38.0%, [OR (95% CI)] [1.6 (1.0-2.5), p = 0.09]) and live birth (43.0 vs. 35.5%, [1.4 (0.9-2.3), p = 0.21]) rates per cycle started were not significantly different between the two groups. Forward stepwise logistic regression showed that only maternal age (p = 0.04) influenced clinical pregnancy rates (OR = 0.88, CI 0.78-0.99) and only the number of days for superovulation influenced live birth rates (OR = 0.65, CI 0.486-0.869). CONCLUSION: This study demonstrated that delaying hCG administration to allow further growth of the medium-sized follicles added further days of superovulation and cost without improvement in CPR and LBR.

Imaging and the Infertility Evaluation.

Ultrasound (US) has transformed the fertility evaluation. With 1 consultation, blood work and 1 to 2 USs, the female fertility status can be fully evaluated. The initial US is best done early in the follicular cycle to evaluate the pelvic anatomy and ovarian reserve. A three-dimensional US is important to evaluate for uterine anomalies and color Doppler for any masses. A mid-cycle saline infusion sonohysterogram assesses the endometrial cavity better than a hysterosalpingogram as it identifies the cause of any filling defects. By concurrently adding contrast or agitated saline, tubal patency can be tested. This US-based approach reliably, efficiently, and cost-effectively assesses female infertility.

Clinical guidelines for IVF with PGD for HLA matching.

Preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) typing is an established procedure for conceiving a child who may donate cord blood or haematopoietic stem cells for transplantation to save an ill sibling. Haematopoietic stem cell transplantation (HSCT) from related matched donors improves overall survival compared with unrelated or non-matched donors. Since HSCT from related matched-donors is unavailable for 70% of patients, IVF for PGD-HLA is a relevant clinical option. Recent success of HSCT after PGD-HLA, and excellent health and family support of the children born, suggests that debate over this kind of 'designer baby' and 'gift of life' should subside. Discussions about IVF for PGD-HLA should be held with families when a related matched-donor is unavailable, when HSCT can wait at least 9-12 months, within weeks of diagnosis irrespective of prognosis, and when the mother is of reproductive age. Related half-matched egg donors may also be considered. National and international collaborations should be established, and couples choosing this modality should be referred to experienced IVF and PGD centres. Clinical guidelines will improve physician and patient awareness of IVF for PGD-HLA and its role in advancing the clinical care of children in need of HSCT.

A rare case of a mosaic unbalanced translocation after chorionic villous sampling.

BACKGROUND: Most of the literature suggests that unbalanced chromosomal translocations may lead to poor obstetrical outcomes. We present a case of an unbalanced translocation resulting in trisomy 1q and partial monosomy 20p identified on chorionic villous sampling (CVS). METHOD: Case report with expert-derived clinical management and guidance. RESULTS: After the abnormal CVS result, a subsequent amniocentesis revealed a normal 46,XX fetal karyotype. Detailed second trimester ultrasound of the fetus revealed no gross structural abnormalities. The CVS karyotype results were attributed to confined placental mosaicism (CPM) of the unbalanced translocation. The infant is 18 months old and has normal phenotype and karyotype. CONCLUSION: We recommend that if CPM with an unbalanced translocation is diagnosed on CVS, parental karyotype and an amniocentesis should be offered in conjunction with genetic counseling. In rare instances, such as this one, an unbalanced translocation may have a favorable outcome.

Barriers to Family Building Among Physicians and Medical Students.

Importance: Physicians and medical students who desire to build families face significant barriers due to the structure and culture of medicine. Objective: To understand the barriers and facilitators to family building for all people in medicine-not only individuals who can become pregnant-through an open-ended, qualitative analysis of survey responses. Design, Setting, and Participants: This qualitative study used a survey conducted in April and May 2021 with a broad sample of physicians and medical students. Participants were recruited through social media, targeting physician and medical student communities. Physicians (residents, fellows, and physicians in independent practice) and medical students of all gender identities and sexual orientations were included. Informed by a postpositivist approach, coding reliability thematic analysis was performed on 3 open-ended survey questions on family-building experiences (what they would do differently, what advice they have for others, and anything else they wished to share). Main Outcomes and Measures: Identified themes were mapped to the social-ecological model, a model used in public health to examine how a spectrum of factors is associated with health outcomes. Results: A total of 2025 people (1860 [92%] women; 299 [15%] Asian, 151 [8%] Black, and 1303 [64%] White; 1730 [85%] heterosexual; and 1200 [59%] physicians who had completed training) responded to at least 1 of 3 open-ended questions. Themes mapped to social-ecological model levels included: (1) cultural, eg, medical training being at odds with family building; (2) organizational, eg, lack of institutional support for the range of family-building routes; (3) interpersonal, eg, impact of social support on family building; and (4) individual, eg, socioeconomic status and other individual factors that facilitate or inhibit family building. Recommendations to improve family-building experiences include implementing family-building curricula at medical schools, providing adequate parental leave for all physicians and medical students who become parents, and providing insurance coverage for all family-building routes. Conclusions and Relevance: In this qualitative study of physicians and medical students, self-reported barriers to family building were identified at each level of the social-ecological model. Addressing these barriers is critical to creating a more equitable family-building environment for physicians and medical students.

Human implantation: The complex interplay between endometrial receptivity, inflammation, and the microbiome.

Human embryo implantation is an intricate spatiotemporal process that involves the intimate association between the embryo and the endometrium of the mother. During implantation, the endometrium undergoes a dynamic cascade of gene activation and repression, largely driven by autocrine, paracrine, and endocrine action. Steroid hormones, such as estrogen and progesterone, act on a variety of targets including cellular adhesion molecules (CAMs), cytokines, and growth factors to facilitate the implantation process. Given the synchrony required to achieve implantation, it is unsurprising that embryo implantation represents a substantial problem for infertility patients. This is due to a complex interplay taking place at the level of the endometrium. This review discusses the intricacies of embryo implantation including the window of implantation, the cyclical phases of the endometrium, the implantation process itself, and features of endometrial receptivity. Additionally, we will discuss new research regarding inflammatory reproductive biology, epigenetics and microRNA, and the role of the vaginal and endometrial microbiome in implantation. A better understanding of embryo implantation and the interactions occurring at the level of the blastocyst and the endometrium will improve patient care for infertile patients who experience this frustrating challenge.

Hypochlorous acid reversibly inhibits caspase-3: a potential regulator of apoptosis.

Caspase-3 is involved in apoptosis. Here, we examine whether hypochlorous acid (HOCl), a final product of myeloperoxidase (MPO), is a modulator of caspase-3 at relatively low concentrations and also its application on metaphase II mouse oocytes. We utilised caspase-3 activity assay, TUNEL assay, the CellEvent caspase 3/7 fluorescent assay, and the MPO/hydrogen peroxide (H2O2) system on mouse oocytes with and without cumulus cells to examine whether low concentrations of HOCl mediate apoptosis by inhibition of caspase-3. A UV-visible spectrophotometer was used to study caspase-3 activity. To determine whether HOCl mediates apoptosis in mouse oocytes, two different concentrations (10 and 100 µM) of HOCl generated by the MPO/H2O2 system were used as treatments (10 µM had little effect on oocyte quality, while 100 µM showed significant deterioration). Induction of apoptotic cell death was determined by TUNEL Assay and the CellEvent caspase 3/7. HOCl mediates caspase-3 inactivation in a dose dependent manner. Subsequent addition of dithiothreitol caused recovery of caspase-3 activity indicating involvement of the oxidation of the Cys-thiol group. Accumulation of HOCl generated by MPO in the presence of caspase-3 also inhibits MPO but requires higher HOCl concentrations, indicating specificity of lower HOCl concentrations to inhibition of caspase-3. Exposure of oocytes to lower HOCl concentrations generated by MPO-H2O2 system prevents MPO-mediated apoptosis whereas exposure to higher HOCl (100 µM) showed apoptosis. Similar results were observed by using the CellEvent caspase 3/7 assay. Low concentrations of HOCl inhibit caspase-3 activity, and may play a role in regulating apoptosis, thus affecting oocyte quality.HighlightsCaspase-3 is involved in apoptosis pathway and loss of this regulation is seen in several diseases.These conditions are associated with inflammation and higher myeloperoxidase (MPO) activity.We examined whether hypochlorous acid (HOCl), generated by MPO, is a modulator of caspase-3.Caspase-3 activity showed a dose dependent decrease with HOCl and this reaction was reversible.HOCl modulates caspase-3 activity and may play a physiological role in regulating apoptosis.

Is Patient Advocacy the Solution to Physician Burnout?

Physician burnout has been on the rise over the last several decades in a variety of specialties, leading to high rates of physician suicide and poor health outcomes for patients. As leaders in healthcare attempt to combat this issue through mental health initiatives and changes in medical training policies, we propose patient advocacy as a powerful technique to combat physician burnout and restore autonomy, purpose, and meaning into physicians' lives.

Measurements of Intra-oocyte Nitric Oxide Concentration Using Nitric Oxide Selective Electrode.

Precise information about the intracell nitric oxide (NO) concentration [NO] of a single cell are necessary in designing accurate experiments to further knowledge and develop treatment plans in certain disorders. The direct quantitative measurement of [NO] in situ in an intact cellular complex should be useful in tracking real-time and rapid changes at nanomolar levels. In this work, we describe the direct, real-time, and quantitative intracellular [NO] measurement utilizing an L-shaped amperometric integrated NO-selective electrode. This method not only provides an elegant and convenient approach to real-time the measurement of NO in physiological environments but also mimics the loss of NO caused by rapid NO diffusion combined with its reactivity in the biological milieu.

Acrolein, a commonly found environmental toxin, causes oocyte mitochondrial dysfunction and negatively affects embryo development.

Recent studies have revealed that acrolein, a commonly found toxin and a potent metabolite of cyclophosphamide (CTX), can cause deterioration of mouse oocyte quality through a mechanism involving the generation of reactive oxygen species (ROS). We extend these studies to evaluate the effects of acrolein, in varying concentrations, on the oocyte mitochondrial membrane and oocyte apoptosis and its effect on embryo development in vitro. Metaphase II mouse oocytes were exposed for 45 minutes to acrolein and CTX (10 & 25 µM) and mitochondrial dysfunction, a major source of ROS overproduction, was evaluated by the 5,5,6,6-tetrachloro-1,1,3,3-tetraethyl-ß-benzimidazolylcarbocyanine iodide (JC-10) mitochondrial membrane potential assay. Treatment with acrolein led to mitochondrial membrane damage as well as induction of apoptosis compared to untreated control (p < 0.05). Similar results were obtained when oocytes were exposed to CTX (p < .05). Subsequently, the effect of acrolein exposure was evaluated by observing in vitro development of embryos after exposure. Acrolein treatment caused higher proportions of arrested and poor-quality embryos, evidenced by irregular cleavage, severe asymmetry of blastomeres, presence of large percentage of anuclear fragments, and dark granularity of the cytoplasm. Development at various durations in culture revealed that optimal embryo growth was significantly inhibited in a dose dependent manner, when compared to control (p < .05). A global model that links acrolein accumulation, generation of ROS, and mitochondrial dysfunction and their effect on oocyte and embryo quality is discussed further. Collectively, understanding the mechanism by which CTX and acrolein impact fertility is helpful in finding potential alternative or supplemental treatment options.

Dimercapto-1-propanesulfonic acid (DMPS) induces metaphase II mouse oocyte deterioration.

In light of the recent lead contamination of the water in Flint, Michigan and its potential adverse outcomes, much research and media attention has turned towards the safety profile of commonly used chelators. Dimercapto-1-propanesulfonic acid (DMPS) typically used in the treatment of lead, mercury and arsenic poisoning also displays a high affinity towards transition metals such as zinc and copper, essential for biological functioning. It is given in series of dosages (0.2-0.4g/day) over a long period, and has the ability to enter cells. In this work, we investigated the mechanism through which increasing concentrations of DMPS alter oocyte quality as judged by changes in microtubule morphology (MT) and chromosomal alignment (CH) of metaphase II mice oocyte. The oocytes were directly exposed to increasing concentration of DMPS (10, 25, 50, 100 and 300µM) for four hours (time of peak plasma concentration after administration) and reactive oxygen species (mainly hydroxyl radical and superoxide) and zinc content were measured. This data showed DMPS plays an important role in deterioration of oocyte quality through a mechanism involving zinc deficiency and enhancement of reactive oxygen species a major contributor to oocyte damage. Our current work, for the first time, demonstrates the possibility of DMPS to negatively impact fertility. This finding can not only help in counseling reproductive age patients undergoing such treatment but also in the development of potential therapies to alleviate oxidative damage and preserve fertility in people receiving heavy metal chelators.

Mesna (2-mercaptoethane sodium sulfonate) functions as a regulator of myeloperoxidase.

Myeloperoxidase (MPO), an abundant protein in neutrophils, monocytes, and macrophages, is thought to play a critical role in the pathogenesis of various disorders ranging from cardiovascular diseases to cancer. We show that mesna (2-mercaptoethanesulfonic acid sodium salt), a detoxifying agent, which inhibits side effects of oxazaphosphorine chemotherapy, functions as a potent inhibitor of MPO; modulating its catalytic activity and function. Using rapid kinetic methods, we examined the interactions of mesna with MPO compounds I and II and ferric forms in the presence and absence of chloride (Cl-), the preferred substrate of MPO. Our results suggest that low mesna concentrations dramatically influenced the build-up, duration, and decay of steady-state levels of Compound I and Compound II, which is the rate-limiting intermediate in the classic peroxidase cycle. Whereas, higher mesna concentrations facilitate the porphyrin-to-adjacent amino acid electron transfer allowing the formation of an unstable transient intermediate, Compound I*, that displays a characteristic spectrum similar to Compound I. In the absence of plasma level of chloride, mesna not only accelerated the formation and decay of Compound II but also reduced its stability in a dose depend manner. Mesna competes with Cl-, inhibiting MPO's chlorinating activity with an IC50 of 5µM, and switches the reaction from a 2e- to a 1e- pathway allowing the enzyme to function only with catalase-like activity. A kinetic model which shows the dual regulation through which mesna interacts with MPO and regulates its downstream inflammatory pathways is presented further validating the repurposing of mesna as an anti-inflammatory drug.

Cyclophosphamide and acrolein induced oxidative stress leading to deterioration of metaphase II mouse oocyte quality.

Cyclophosphamide (CTX) is a chemotherapeutic agent widely used to treat ovarian, breast, and hematological cancers as well as autoimmune disorders. Such chemotherapy is associated with reproductive failure and premature ovarian insufficiency. The mechanism by which CTX and/or its main metabolite, acrolein, affect female fertility remains unclear, but it is thought to be caused by an overproduction of reactive oxygen species (ROS). Here, we investigated the effect of CTX on metaphase II mouse oocytes obtained from treated animals (120mg/kg, 24h of single treatment), and oocytes directly exposed to increasing concentrations of CTX and acrolein (n=480; 0, 5, 10, 25, 50, and 100µM) with and without cumulus cells (CCs) for 45min which correlates to the time of maximum peak plasma concentrations after administration. Oocytes were fixed and subjected to indirect immunofluorescence and were scored based on microtubule spindle structure (MT) and chromosomal alignment (CH). Generation of ROS was evaluated using the Cellular Reactive Oxygen Species Detection Assay Kit. Deterioration of oocyte quality was noted when oocytes were obtained from CTX treated mice along with CTX and acrolein treated oocytes in a dose-dependent manner as shown by an increase in poor scores. Acrolein had an impact at a significantly lower level as compared to CTX, plateau at 10µM versus 50µM, respectively. These variation is are associated with the higher amount of ROS generated with acrolein exposure as compared to CTX (p<0.05). Utilization of antioxidant therapy and acrolein scavengers may mitigate the damaging effects of these compounds and help women undergoing such treatment.