Infertile human endometrial organoid apical protein secretions are dysregulated and impair trophoblast progenitor cell adhesion

IntroductionEmbryo implantation failure leads to infertility. As an important approach to regulate implantation, endometrial epithelial cells produce and secrete factors apically into the uterine cavity in the receptive phase to prepare the initial blastocyst adhesion and implantation. Organoids were recently developed from human endometrial epithelium with similar apical-basal polarity compared to endometrial gland making it an ideal model to study endometrial epithelial secretions.MethodsEndometrial organoids were established using endometrial biopsies from women with primary infertility and normal fertility. Fertile and infertile organoids were treated with hormones to model receptive phase of the endometrial epithelium and intra-organoid fluid (IOF) was collected to compare the apical protein secretion profile and function on trophoblast cell adhesion.ResultsOur data show that infertile organoids were dysregulated in their response to estrogen and progesterone treatment. Proteomic analysis of organoid apical secretions identified 150 dysregulated proteins between fertile and infertile groups (>1.5-fold change). Trophoblast progenitor spheroids (blastocyst surrogates) treated with infertile organoid apical secretions significantly compromised their adhesion to organoid epithelial cell monolayers compared to fertile group (P < 0.0001).DiscussionThis study revealed that endometrial organoid apical secretions alter trophoblast cell adhesiveness relative to fertility status of women. It paves the way to determine the molecular mechanisms by which endometrial epithelial apical released factors regulate blastocyst initial attachment and implantation

Anti-Müllerian Hormone Serum Concentrations of Women with Germline BRCA1 or 2 BRCA2 Mutations

Study funding/competing interest(s): kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation Practitioner Fellow. JLH is a NHMRC Senior Principal Research Fellow. MH is a NHMRC Practitioner Fellow. RA reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and CS reports other from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.Study question: Do women with BRCA1 and BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-müllerian hormone (AMH) concentration?  Summary answer: Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH.  What is known already: The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.  Study design, size, duration: Cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer (kConFab) cohort study (recruitment from 19/08/1997 until 18/9/2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.  Participants/materials, setting, methods: Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25 to 45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.  Main results and the role of chance: Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5% - 41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11-303, P=0.02). There was no evidence of an association between AMH concentration and BRCA2 mutation status (P = 0.94).  Limitations, reasons for caution: The clinical implications of the lower AMH concentrations seen in BRCA1 mutation carriers cannot be assessed by this study design.  Wider implications of the findings: Women with a germline mutation in BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan. Publisher PDFPeer reviewe

Fertility preservation for female patients with childhood, adolescent, and young adult cancer:recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Female patients with childhood, adolescent, and young adult cancer are at increased risk for fertility impairment when treatment adversely affects the function of reproductive organs. Patients and their families desire biological children but substantial variations in clinical practice guidelines reduce consistent and timely implementation of effective interventions for fertility preservation across institutions. As part of the PanCareLIFE Consortium, and in collaboration with the International Late Effects of Childhood Cancer Guideline Harmonization Group, we reviewed the current literature and developed a clinical practice guideline for fertility preservation in female patients who were diagnosed with childhood, adolescent, and young adult cancer at age 25 years or younger, including guidance on risk assessment and available methods for fertility preservation. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to grade the available evidence and to form the recommendations. This clinical practice guideline leverages existing evidence and international expertise to develop transparent recommendations that are easy to use to facilitate the care of female patients with childhood, adolescent, and young adult cancer who are at high risk for fertility impairment. A complete review of the existing evidence, including a quality assessment, transparent reporting of the guideline panel's decisions, and achievement of global interdisciplinary consensus, is an important result of this intensive collaboration.info:eu-repo/semantics/publishe

Installing oncofertility programs for common cancers in optimum resource settings (Repro-Can-OPEN Study Part II): a committee opinion

The main objective of Repro-Can-OPEN Study Part 2 is to learn more about oncofertility practices in optimum resource settings to provide a roadmap to establish oncofertility best practice models. As an extrapolation for oncofertility best practice models in optimum resource settings, we surveyed 25 leading and well-resourced oncofertility centers and institutions from the USA, Europe, Australia, and Japan. The survey included questions on the availability and degree of utilization of fertility preservation options in case of childhood cancer, breast cancer, and blood cancer. All surveyed centers responded to all questions. Responses and their calculated oncofertility scores showed three major characteristics of oncofertility practice in optimum resource settings: (1) strong utilization of sperm freezing, egg freezing, embryo freezing, ovarian tissue freezing, gonadal shielding, and fractionation of chemo- and radiotherapy; (2) promising utilization of GnRH analogs, oophoropexy, testicular tissue freezing, and oocyte in vitro maturation (IVM); and (3) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, in vitro spermatogenesis, and stem cell reproductive technology as they are still in preclinical or early clinical research settings. Proper technical and ethical concerns should be considered when offering advanced and experimental oncofertility options to patients. Our Repro-Can-OPEN Study Part 2 proposed installing specific oncofertility programs for common cancers in optimum resource settings as an extrapolation for best practice models. This will provide efficient oncofertility edification and modeling to oncofertility teams and related healthcare providers around the globe and help them offer the best care possible to their patients

The Impact of Uterine Radiation on Subsequent Fertility and Pregnancy Outcomes

Future fertility is of paramount importance to younger cancer survivors. Advances in assisted reproductive technology mean that young women treated with radiation involving the uterus may require clinical guidance regarding whether to attempt a pregnancy themselves. We performed a review of the literature regarding radiation involving uterus (total body irradiation (TBI) and pelvic radiation), fertility, and pregnancy outcomes to come up with a recommendation for our patients. Limited evidence suggests lower fecundity and an increased incidence of pregnancy complications after uterine radiation. Higher radiation doses and direct uterine radiation both significantly increase the risk of an adverse pregnancy outcome. Uterine radiation doses of &lt;4 Gy do not appear to impair uterine function. Adult TBI data (usually 12 Gy) suggest pregnancy is possible but with lower fecundity and more complications. Although there is no clear data indicating the dose of radiation to the uterus, above which a pregnancy would not be sustainable, we suggest patients receiving &gt;45 Gy during adulthood and &gt;25 Gy in childhood be counselled to avoid attempting pregnancy. There is preliminary evidence that menopausal hormone therapy and a combination of pentoxifylline and tocopherol may improve uterine function following irradiation

Live birth rates in day 5 fresh versus vitrified single blastocyst transfer cycles: A cross-sectional analysis

Abstract Background: The use of frozen embryo transfers (FET) in assisted reproduction has increased worldwide. Controlled ovarian hyperstimulation in a fresh transfer may impair endometrial-embryo synchronicity. However, there is conflicting evidence on live birth rates (LBR) and clinical pregnancy rates (CPR). Objective: To compare LBRs and CPRs between single autologous day 5 fresh vs. vitrified blastocyst transfer cycles, to investigate the impact of controlled ovarian hyperstimulation on embryo-endometrium asynchrony. Materials and Methods: A large cross-sectional analysis of 6002 embryo transfers (ET) comprised 3774 fresh and 2228 FET cycles from 2016 to 2019. Multivariate and subgroup analysis were performed for high responders ( > 20 oocytes). Results: Univariate analysis showed no difference in LBR (28.3% vs. 27.4%, p = 0.43) and CPR (32.2% vs. 30.9%, p = 0.30); however, multivariate analysis demonstrated significantly lower LBR (OR 0.864, p = 0.046, 95% CI 0.749-0.997) and CPR (OR 0.852, p = 0.024, 95% CI 0.742-0.979) in FET compared to fresh ETs. Younger participant age, previous in vitro fertilization pregnancy, advanced blastocyst expansion, higher trophectoderm quality, and lower cumulative number of ETs all improved the odds of LBR and CPR. Conventional in vitro fertilization, rather than intracytoplasmic sperm injection, improved CPR but not LBR. Body mass index affected neither LBR nor CPR. In the subgroup, multivariate analysis of high responders showed no difference in LBR or CPR. Conclusion: This study demonstrates relatively higher LBR and CPR of nearly 14% for fresh ETs compared to FETs, in multivariate analysis. A universal freeze-all strategy, without appropriate indication, may lead to suboptimal outcomes. In high responders, freeze-all cycles may be beneficial, as outcomes appear similar

Cryopreservation of reproductive material before cancer treatment: a qualitative study of health care professionals’ views about ways to enhance clinical care

Abstract Background Cancer treatment can diminish fertility in women and men. The need for fertility preservation is growing as increasing numbers of people survive cancer. Cryostorage of reproductive material to preserve potential for conception for cancer survivors has moved from being experimental to being a part of clinical management of women and men who are diagnosed with cancer in their reproductive years. There is little existing evidence about how fertility preservation services can be enhanced to meet the complex needs of patients who are diagnosed with cancer in their reproductive years. The aim of this research was to inform clinical practice development by drawing on the collective experience and knowledge of staff at well-established clinics that offer fertility preservation before cancer treatment. Methods A qualitative research model was adopted using semi-structured interviews with professionals involved in the care of people who freeze reproductive material before cancer treatment. In the state of Victoria, Australia, two large assisted reproductive technology (ART) centres have been providing fertility preservation services for more than two decades. An invitation to participate in a semi-structured interview about clinical care in the context of fertility preservation was emailed to past and current staff members. To capture diverse perspectives, informants were sought from all relevant professions: fertility specialists, andrologists, nurses, embryologists/scientists, counsellors, and administrative staff. Transcripts were analysed thematically. Results Thirteen key informants were interviewed from August 2013 to February 2014. The identified themes relating to enhancing clinical care in a fertility preservation service were communication between oncology and ART specialists; managing urgency; managing patients’ expectations; establishing and implementing protocols, systems, and data bases; and maintaining contact with patients. Conclusion The collective knowledge of this study’s informants, who represent multidisciplinary teams with more than two decades’ experience in fertility preservation, yields important insights into strategies that fertility preservation services can employ to promote the integration of oncology and fertility care, the psychosocial care of patients, data recording and monitoring, and reporting of outcomes

Additional file 1: of Cryopreservation of reproductive material before cancer treatment: a qualitative study of health care professionals’ views about ways to enhance clinical care

Discussion Guide. (DOCX 14 kb