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Human Reproduction Open 2024Is pronuclear transfer (PNT) capable of restoring embryo developmental arrest caused by cytoplasmic inferiority of -grown (IVG) mouse oocytes?
STUDY QUESTION
Is pronuclear transfer (PNT) capable of restoring embryo developmental arrest caused by cytoplasmic inferiority of -grown (IVG) mouse oocytes?
SUMMARY ANSWER
PNT to matured cytoplasm significantly improved embryo development of IVG mouse oocytes, leading to living, fertile offspring.
WHAT IS KNOWN ALREADY
follicle culture has been considered as a fertility preservation option for cancer patients. Studies describing the culture of human follicles remain scarce, owing to low availability of tissue. Mouse models have extensively been used to study and optimize follicle culture. Although important achievements have been accomplished, including the production of healthy offspring in mice, IVG oocytes are of inferior quality when compared to -grown oocytes, likely because of cytoplasmic incompetence.
STUDY DESIGN SIZE DURATION
The study was carried out from September 2020 to February 2022. In total, 120 15-day-old B6D2 mice were used to perform secondary follicle culture and assess the quality of IVG oocytes. -grown control oocytes were obtained from 85 8- to 12-week-old B6D2 mice, following ovarian stimulation. For sperm collection, four B6D2 males between 10 and 14 weeks old were used. For embryo transfer, 14 8- to 12-week-old CD1 females served as surrogate mothers and 10 CD1 vasectomized males 10-24 weeks old were used to generate pseudo-pregnant females. Finally, for mating, four B6D2 female mice aged 8-10 weeks and two B6D2 male mice aged 10 weeks old were used to confirm the fertility of nuclear transfer (NT)-derived pups.
PARTICIPANTS/MATERIALS SETTING METHODS
Secondary follicles from 15-day-old B6D2 mice were isolated from the ovaries and cultured for 9 days, before a maturation stimulus was given. Following 16-18 h of maturation, oocytes were collected and evaluated on maturation rate, oocyte diameter, activation rate, spindle morphology, calcium-releasing ability, and mitochondrial membrane potential. For every experiment, -grown oocytes were used as a control for comparison. When cytoplasmic immaturity and poor embryo development were confirmed in IVG oocytes, PNT was performed. For this, the pronuclei from IVG oocytes, created following parthenogenetic activation and IVF, were transferred to the cytoplasm of fertilized, -grown oocytes. Genetic analysis and embryo transfer of the generated embryos were implemented to confirm the safety of the technique.
MAIN RESULTS AND THE ROLE OF CHANCE
Following 9 days of follicle culture, 703 oocytes were collected, of which 76% showed maturation to the metaphase II stage. Oocyte diameters were significantly lower in IVG oocytes, measuring 67.4 μm versus 73.1 μm in controls ( < 0.001). Spindle morphology did not differ significantly between IVG and control oocytes, but calcium-releasing ability was compromised in the IVG group. An average calcium release of 1.62 arbitrary units was observed in IVG oocytes, significantly lower than 5.74 in control oocytes ( < 0.001). Finally, mitochondrial membrane potential was inferior in IVG compared to the control group, reaching an average value of 0.95 versus 2.27 ( < 0.001). Developmental potential of IVG oocytes was assessed following parthenogenetic activation with strontium chloride (SrCl). Only 59.4% of IVG oocytes cleaved to two cells and 36.3% reached the blastocyst stage, significantly lower than 89.5% and 88.2% in control oocytes, respectively ( < 0.001 and 0.001). Both PNT and spindle transfer (ST) were explored in pilot experiments with parthenogenetically activated oocytes, as a means to overcome poor embryo development. After the added value of NT was confirmed, we continued with the generation of biparental embryos by PNT. For this purpose, IVG and control oocytes first underwent IVF. Only 15.5% of IVG oocytes were normally fertilized, in contrast to 45.5% in controls ( < 0.001), with resulting failure of blastocyst formation in the IVG group (0 versus 86.2%, < 0.001). When the pronuclei of IVG zygotes were transferred to the cytoplasm of control zygotes, the blastocyst rate was restored to 86.9%, a similar level as the control. Genetic analysis of PNT embryos revealed a normal chromosomal profile, to a rate of 80%. Finally, the generation of living, fertile offspring from PNT was possible following embryo transfer to surrogate mothers.
LARGE-SCALE DATA
N/A.
LIMITATIONS REASONS FOR CAUTION
Genetic profiles of analysed embryos from PNT originate from groups that are too small to draw concrete conclusions, whilst ST, which would be the preferred NT approach, could not be used for the generation of biparental embryos owing to technical limitations. Even though promising, the use of PNT should be considered as experimental. Furthermore, results were acquired in a mouse model, so validation of the technique in human IVG oocytes needs to be performed to evaluate the clinical relevance of the technology. The genetic profiles from IVG oocytes, which would be the ultimate characterization for chromosomal abnormalities, were not analysed owing to limitations in the reliable analysis of single cells.
WIDER IMPLICATIONS OF THE FINDINGS
PNT has the ability to overcome the poor cytoplasmic quality of IVG mouse oocytes. Considering the low maturation efficiency of human IVG oocytes and potential detrimental effects following long-term culture, NT could be applied to rescue embryo development and could lead to an increased availability of good quality embryos for transfer.
STUDY FUNDING/COMPETING INTERESTS
A.C. is a holder of FWO (Fonds voor Wetenschappelijk Onderzoek) grants (1S80220N and 1S80222N). B.H. and A.V.S. have been awarded with a special BOF (Bijzonder Onderzoeksfonds), GOA (Geconcerteerde onderzoeksacties) 2018000504 (GOA030-18 BOF) funding. B.H. has been receiving unrestricted educational funding from Ferring Pharmaceuticals (Aalst, Belgium). The authors declare that they have no conflict of interest.
PubMed: 38425578
DOI: 10.1093/hropen/hoae009 -
Diagnostics (Basel, Switzerland) Apr 2024Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of... (Review)
Review
Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of therapeutic interventions, thereby ameliorating pulmonary function, addressing nutritional deficits, averting complications, mitigating morbidity, and ultimately enhancing the quality of life and extending longevity. This review aims to amalgamate existing knowledge to provide a comprehensive appraisal of contemporary diagnostic modalities pertinent to CF in the 21st century. Deliberations encompass discrete delineations of each diagnostic modality and the elucidation of potential diagnostic quandaries encountered in select instances, as well as the delineation of genotype-phenotype correlations germane to genetic counseling endeavors. The synthesis underscores that, notwithstanding the availability and strides in diagnostic methodologies, including genetic assays, the sweat test (ST) retains its position as the preeminent diagnostic standard for CF, serving as a robust surrogate for CFTR functionality. Prospective clinical investigations in the realm of CF should be orchestrated with the objective of discerning novel diagnostic modalities endowed with heightened specificity and sensitivity.
PubMed: 38611676
DOI: 10.3390/diagnostics14070763 -
Radiology Case Reports Feb 2024Phyllodes tumors of the breast are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors. They tend to affect middle-aged women, who present...
Phyllodes tumors of the breast are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors. They tend to affect middle-aged women, who present with a rapidly growing, palpable mass. Here we present a case of a 34-year-old female surrogate mother without any reported personal or family history of breast cancer who presented with a rapidly growing left breast mass, pathologically proven to be a phyllodes tumor. The patient was a G7P7 surrogate mother who received estrogen and progesterone injections for her twin surrogate pregnancy starting 4 months before embryo implantation, after which, she discovered a large palpable mass in the left breast at approximately week 7 gestational age. At the initial presentation, the patient was at week 23 gestational age. She underwent C-section delivery of the twins at this time and obtained further work-up of the mass. She had a core needle biopsy which yielded a benign fibroepithelial tumor. Due to the size of her breast mass and atypical morphology, including extension to the nipple, and skin ulceration, the patient subsequently underwent left mastectomy. At the time of mastectomy, which was 8 months after the initial work-up, the mass had grown to measure approximately 12 × 10 cm on physical examination and took up most of her left breast. It was completely resected and was pathologically determined to be a borderline phyllodes tumor. Only a few cases have been reported about the development of phyllodes tumor during pregnancy in the literature, and we believe this is the first case report of phyllodes tumor related to a surrogate pregnancy. Although the relationship between exogenous hormones and fibroepithelial tumors is not well understood, the case poses the clinical question if screening mammograms should be offered to patients undergoing exogenous hormonal therapy, regardless of age to establish a baseline and monitor for the development (if any) or growth of these tumors.
PubMed: 38111558
DOI: 10.1016/j.radcr.2023.11.019 -
Health and Human Rights Dec 2023In 2022, the global commercial surrogacy industry was valued at approximately US$14 billion. This paper explores the issue of surrogacy to reveal how international human...
In 2022, the global commercial surrogacy industry was valued at approximately US$14 billion. This paper explores the issue of surrogacy to reveal how international human rights standards and labor laws treat reproduction as work, building on previous scholarship analyzing similar framing at the grassroots level in Mexico. I argue that the failure to recognize surrogacy as labor is rooted in three lacunae: (1) contemporary policies and practices around surrogacy globally pay little attention to the well-being and rights fulfillment of surrogates themselves, particularly the economic rights of surrogates; (2) the stigma of surrogacy as sexualized care work results in neglect of the labor rights of surrogates in mainstream economic rights discourses; and (3) relevant international rights law has not yet addressed the economic rights of surrogates, nor has it effectively articulated the interdependent relationship between economic rights and reproductive rights. Lastly, I discuss where reproductive rights and economic rights overlap in existing human rights conventions and standards and what possibilities these offer for articulating the interdependence of reproductive and economic rights and for advancing the labor rights of surrogates.
Topics: Pregnancy; Female; Humans; Surrogate Mothers; Reproduction; Reproductive Rights; Labor, Obstetric; Mexico
PubMed: 38145146
DOI: No ID Found -
Theoretical Medicine and Bioethics Aug 2023In a thought-provoking article - or how she herself named it, 'a thought experiment' - the philosopher-medical ethicist Anna Smajdor analyzed in this journal the idea of...
In a thought-provoking article - or how she herself named it, 'a thought experiment' - the philosopher-medical ethicist Anna Smajdor analyzed in this journal the idea of whole-body gestational donation (WBGD) in brain-dead female patients, as an alternative means of gestation for prospective women who cannot or prefer not to become pregnant themselves. We have serious legal, economical, medical and ethical concerns about this proposal. First, consent for eight months of ICU treatment can never be assumed to be derived from consent for post-mortem organ donation; these two are of an incomparable and entirely different medical and ethical order. Moreover, the brain-dead woman is very likely to be medically unfit for high-tech surrogacy and the brain-dead state poses a high risk for deficient embryo/fetal development. Second, from a scarcity perspective, occupying an ICU bed for eight months appears to be unjust. The costs for eight months of ICU treatment are far too high compared to the costs of surrogacy for a living, selected, and healthy woman. Neither insurance companies nor prospective parents will want to pay these exceptionally high costs for a dead woman if a living surrogate mother can be hired for a considerably lower amount. Third, there is an increased risk for harm of the child to be in WBGD. And finally, WBGD risks violating the brain-dead woman's dignity and harming the interests of her loved ones. In short, there is simply no need for brain-dead women as surrogates.
Topics: Female; Child; Pregnancy; Humans; Prospective Studies; Brain Death; Health Status; Parents
PubMed: 37606813
DOI: 10.1007/s11017-023-09642-2 -
Reproductive Biomedicine Online Oct 2023How did Danish permanently infertile couples experience surrogacy when going abroad and what impact did the war in Ukraine and the COVID-19 pandemic have on this?
RESEARCH QUESTION
How did Danish permanently infertile couples experience surrogacy when going abroad and what impact did the war in Ukraine and the COVID-19 pandemic have on this?
DESIGN
A qualitative study was performed between May and September 2022. The in-depth semi-structured interviews were conducted with 14 permanently infertile couples across Denmark who were in different stages of using surrogacy. The interviews were transcribed and analysed using systematic text condensation.
RESULTS
All except one couple went abroad, mainly to Ukraine, to have an enforceable transparent contract, professionals to advise them and the possibility of using the eggs of the intended mother. They did not feel that this was a 'choice' but rather the only option they had to have the longed-for child. According to current Danish legislation, the intended mother could not obtain legal motherhood over the child, not even through stepchild adoption, and this increased the feeling of not being a 'worthy mother'. This study expanded on the term 'reproductive exile' by identifying four different forms of exile: the exiled Danish couple, the gestational carrier in exile, exile at home and, finally, the reproductive body in exile.
CONCLUSIONS
Understanding infertile couples' experiences when crossing borders is important for several reasons. It may, among others, assist politicians and authorities in developing a sound Danish legal policy on surrogacy to address the current issues of legal parenthood and avoid missing reproductive opportunities for permanently infertile couples.
Topics: Female; Humans; Pregnancy; COVID-19; Denmark; Infertility; Mothers; Pandemics; Surrogate Mothers; Ukraine; Male
PubMed: 37517186
DOI: 10.1016/j.rbmo.2023.06.013 -
Neuropsychiatric Disease and Treatment 2023The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations....
INTRODUCTION
The gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.
METHODS
We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.
RESULTS
We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.
DISCUSSION
We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.
PubMed: 37881807
DOI: 10.2147/NDT.S379703 -
Journal of Clinical Epidemiology Oct 2023We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm...
OBJECTIVES
We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm birth prevention met predefined criteria for usefulness.
STUDY DESIGN AND SETTING
The usefulness tool included eight criteria combining 13 items. RCTs were evaluated for compliance with each item by multiple assessors (reviewer agreement 95-98%). Proportions of compliances with 95% confidence interval (CI) were calculated and change over time was assessed using ≧ 2010 as a cutoff.
RESULTS
Among 347 selected RCTs, published within 56 preterm birth Cochrane reviews, only 36 (10%, 95% CI = 7-14%) met more than half of the usefulness criteria. Compared to trials before 2010, recent trials used composite or surrogate (less informative) outcomes more often (13% vs. 25%, relative risk 1.91, 95% CI = 1.21-3.00). Only 16 trials reflected real practice (pragmatism) in design (5%, 95% CI = 3-7%), with no improvements over time. No trials reported involvement of mothers to reflect patients' research priorities and outcomes selection. Recent trials were more transparent.
CONCLUSION
Few preterm birth prevention RCTs met more than half of the usefulness criteria but most of usefulness criteria are improving after 2010. Use of informative outcomes, patient centeredness, pragmatism and transparency should be key targets for future research planning.
Topics: Infant, Newborn; Female; Humans; Premature Birth; Randomized Controlled Trials as Topic
PubMed: 37657614
DOI: 10.1016/j.jclinepi.2023.08.016 -
Ciencia & Saude Coletiva Apr 2024Comprehensive access to medically assisted reproduction procedures and techniques in Argentina has been assured by National Law No. 26,862 since 2013. This Law does not...
Comprehensive access to medically assisted reproduction procedures and techniques in Argentina has been assured by National Law No. 26,862 since 2013. This Law does not include surrogacy procedures, and the lack of specific regulation shifts practices to a paralegal setting. In this context, planned parenthood by male couples through surrogacy is performed through actions that convey demands for access rights and active State policies. For these couples, the argument is that surrogacy is the only option to have a child with a genetic bond with at least one of the two parents and recognize both filiatory bonds. This work results from field work in progress with parents from the Province of Buenos Aires running this practice in Argentina. Based on in-depth interviews, we attempted to rebuild personal experiences and analyze the meanings that the narratives construct regarding their parenting, the biological connections in establishing or defining family relationships, and the importance of genetics in constructing and maintaining affiliations.
Topics: Argentina; Surrogate Mothers; Humans; Male; Female; Reproductive Techniques, Assisted; Parenting; Parents; Interviews as Topic; Decision Making; Choice Behavior; Family Relations; Adult
PubMed: 38655962
DOI: 10.1590/1413-81232024294.19122023 -
Reproductive Biomedicine Online May 2024The practice of surrogacy is frequently the subject of media, scientific, social, regulatory and policy attention. Although it is, for many, an accepted form of assisted... (Review)
Review
The practice of surrogacy is frequently the subject of media, scientific, social, regulatory and policy attention. Although it is, for many, an accepted form of assisted reproduction for those who would otherwise not be able to have children, surrogacy often generates strong feeling, particularly where there is any possibility of exploitation. Therefore, there is disagreement about how it should be regulated. In some countries, surrogacy is prohibited in any form, although this does not stop people using it. In others, it is unregulated but still practised. In some nations it is regulated in either a 'commercial' or an 'altruistic' model. This review article considers the possible regulatory future of surrogacy, initially from a UK perspective considering a recent review of the legal framework in a country where surrogacy works well (although some cross borders to access it), and then through an assessment of global trends and other national perspectives. It concludes that the international regulation of surrogacy, although potentially desirable, is unlikely. This being the case, it would be preferable for individual nations to regulate surrogacy so it can be undertaken in ways that are safe, ethical and protective of the best interests of children, surrogates, intended parents and families.
Topics: Surrogate Mothers; Humans; Female; Pregnancy; Reproductive Techniques, Assisted; United Kingdom
PubMed: 38428344
DOI: 10.1016/j.rbmo.2023.103764