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Why we need stem-cell derived gametes
Abstract
In-vitro gametogenesis (IVG) is almost exclusively discussed as a potential solution for people who have no (functional) gametes. However, IVG could also be seen as an alternative to standard IVF. Instead of submitting women to ovarian stimulation and invasive oocyte retrieval, the creation of oocytes from stem cells should be the first treatment option (assuming it to be reasonably safe and effective). The primary reason for the application of this method would not be for these women to become genetic parents but to alleviate the physical and psychological burden of standard IVF treatment on them.
... In vitro production of stem cell-derived (SCD) gametes promises new possibilities for human procreation. The scope of potential reproductive applications ranges from a more "women-friendly" alternative for regular fertility treatment, over unique genetic parenthood options for those who presently cannot fulfill such a desire through any other means, to unprecedented forms of genetic relatedness between parent and child (see below) (Pennings, 2023;Segers et al., 2017a). ...
In her recent paper, Emanuele Mangione proposes combining maternal spindle transfer (MST) and reciprocal effortless in vitro fertilisation (ReIVF) to enable both females to have genetic and gestational ties with the same child, which can particularly benefit lesbian couples. This response rejects Mangione’s proposal for the reason that the additional biological ties created by MST+ReIVF, compared with the reception of oocytes from partner (ROPA), are unnecessary. ROPA is currently the most effective method for redistributing biological ties within lesbian couples, allowing one member to provide the egg and the other to carry the fetus. The additional biological ties created by MST+ReIVF are quantitatively too small to significantly enhance parental bonding or couple relationships, and their potential harms to both prospective parents and children outweigh any minor benefits. Furthermore, like ROPA, MST+ReIVF fails to address deeper feminist concerns. Therefore, I propose a new idea: combining in vitro gametogenesis with ectogenesis, which can offer far more reproductive choices and greater potential to address deeper feminist concerns than MST+ReIVF.
Preimplantation genetic testing (PGT) has emerged as a powerful companion to assisted reproduction technologies. The origins and history of PGT are reviewed here, along with descriptions of advances in molecular assays and sampling methods, their capabilities, and their applications in preventing genetic diseases and enhancing pregnancy outcomes. Additionally, the potential for increasing accuracy and genome coverage is considered, as well as some of the emerging ethical and legislative considerations related to the expanding capabilities of PGT.
There seems to be a consensus that enucleated oocyte donation (EOD) should only be used to reduce the risk of having a child with mitochondrial disorders. However, this paper argues that in the initial phase in which we are at the moment, EOD should first be used to remedy infertility caused by poor oocyte quality or poor embryonic development. That learning period will allow researchers to improve their technical skills and the knowledge of the best procedure before starting on high-risk cases. Mitochondrial carryover of pathologic mtDNA is the main cause of concern for the offspring. That risk does not exist in infertility cases. The application of EOD to treat infertility should at present be performed in a clinical research setting to obtain more evidence about efficacy and safety.
Given the controversial nature of research into in-vitro gametogenesis (IVG), this study set out to investigate the current attitudes towards IVG in the general Belgian population in order to anticipate potential future barriers and misunderstandings. A questionnaire was developed and incorporated into a web-based online survey and sent out to Belgians aged ≥18 years in September 2018 until a representative sample (by age, gender and region) of 1000 participants was reached. Respondents expressed an overall positive attitude towards IVG and its possible future applications, with the exception of the use of IVG in postmenopausal women. They were ambivalent about the importance of genetic parenthood and about the necessary experiments on animals and embryos to bring IVG to the clinic. While the willingness to accept greater risks for IVG than for other assisted reproductive technology treatments was low (17.5%), the use of spare in-vitro fertilization embryos to study those risks was acceptable for 55.8% of participants; embryo creation was acceptable for 38.1%; and experiments on mice and monkeys were acceptable for 45.3% and 30.4%, respectively. Finally, 85.6% of participants agreed that the Belgian Government should strictly regulate IVG. In conclusion, preclinical research into IVG and other reproductive technologies elicits a great diversity of attitudes towards the importance of genetic parenthood and the acceptability of embryo and animal research. There is a need for public dialogue on these topics.
PurposeIntracytroplasmatic sperm injection (ICSI) is a common procedure used to improve reproductive results, even among couples without male factor infertility. However, the evidence available is still uncertain on the possible advantages and deficiencies that this procedure may have in patients with no formal indication for ICSI.MethodsA SWOT (strengths, weaknesses, opportunities, threats) analysis examines the possible advantages and deficiencies of performing ICSI in these patients with no formal indication.ResultsThe evidence suggests that ICSI is not justified for non-male factor infertile couples requiring in vitro conception. One of the major strengths associated to the procedure is the virtual elimination of cases further complicated by total fertilization failure and a combination between IVF and ICSI on sibling oocytes has been advised in the literature. Greater technical difficulties, higher costs and performing an unnecessary invasive technique in some cases represent some of the weaknesses of the procedure, and questions regarding safety issues should not be ruled out.Conclusion
Despite the widespread use of ICSI in patients without a formal diagnosis of male factor infertility, evidence demonstrating its effectiveness in this population is still lacking. Additional large and well-designed randomized controlled trials are needed to clarify definitive indications for ICSI in non-male factor infertility.
In this paper we will look at the various ways in which infertility can be understood and at how need for reproductive therapies can be construed. We will do this against the background of research with artificial gametes (AGs). Having explored these questions we will attempt to establish the degree to which technologies such as AGs could expand the array of choices that people have to reproduce and/or become parents. Finally, we will examine whether and in what ways the most promising developments of such technologies are likely to bring about the "end of infertility".
BACKGROUND
Chances of achieving parenthood are high for couples who undergo fertility treatment. However, many choose to discontinue before conceiving. A systematic review was conducted to investigate patients' stated reasons for and predictors of discontinuation at five fertility treatment stages.
METHODS
Six databases were systematically searched. Search-terms referred to fertility treatment and discontinuation. Studies reporting on patients' stated reasons for or predictors of treatment discontinuation were included. A list of all reasons for discontinuation presented in each study was made, different categories of reasons were defined and the percentage of selections of each category was calculated. For each predictor, it was noted how many studies investigated it and how many found a positive and/or negative association with discontinuation.
RESULTS
The review included 22 studies that sampled 21 453 patients from eight countries. The most selected reasons for discontinuation were: postponement of treatment (39.18%, postponement of treatment or unknown 19.17%), physical and psychological burden (19.07%, psychological burden 14%, physical burden 6.32%), relational and personal problems (16.67%, personal reasons 9.27%, relational problems 8.83%), treatment rejection (13.23%) and organizational (11.68%) and clinic (7.71%) problems. Some reasons were common across stages (e.g. psychological burden). Others were stage-specific (e.g. treatment rejection during workup). None of the predictors reported were consistently associated with discontinuation.
CONCLUSIONS
Much longitudinal and theory led research is required to explain discontinuation. Meanwhile, treatment burden should be addressed by better care organization and support for patients. Patients should be well informed, have the opportunity to discuss values and worries about treatment and receive advice to decide about continuing treatment.
Objective:
To gain insights into the technical feasibility of maternal spindle transfer (MST) applied in the context of repeated IVF failures for treatment of idiopathic infertility.
Design:
Prospective pilot study (trial registration number: ISRCTN11455145).
Subjects:
Twenty-five infertile couples with multiple previous unsuccessful IVF cycles (range 3-11), no previous pregnancy and no history of mtDNA disease participated. The study focused on women <40 years, with previous IVF attempts characterized by a pattern of low fertilization rates and/or impaired embryo development. Couples with severe male-factor infertility were not eligible. Oocyte donors with previous successful IVF outcomes were matched with patients according to standard practice.
Intervention:
MST was performed by transferring metaphase II spindles from the patients' oocytes into previously enucleated donor oocytes, followed by intracytoplasmic sperm injection, in vitro embryo culture, blastocyst biopsy and vitrification. Only euploid blastocysts were considered for embryo transfer.
Main outcome measures:
Outcome measures included oocyte fertilization, blastocyst development, clinical pregnancy and live birth, incidence of mitochondrial carryover and potential mtDNA reversal, as well as general health of the children born.
Results:
28 MST cycles produced 6 children (19 embryo transfers, 7 clinical pregnancies). Paediatric follow-up of the children, performed at intervals from birth to 12-24 months of age, revealed their development to be unremarkable. DNA-fingerprinting confirmed that nuclear DNA of MST children was inherited from both parents, without any contribution from the oocyte donor. For five of the children, mtDNA was derived almost exclusively (>99%) from the donor. However, one child, who had similarly low mtDNA carryover (0.8%) at the blastocyst stage, showed an increase in the maternal mtDNA haplotype, accounting for 30-60% of the total at birth.
Conclusion:
This pilot study provides the first insights into the feasibility of applying MST for patients with idiopathic infertility and repeated IVF failures. Reconstructed oocytes produced embryos capable of implanting, developing to term and producing apparently healthy newborns/babies. However, claims concerning the efficacy of MST with respect to infertility treatment would be premature considering the limitations of this study. Importantly, mtDNA reversal was detected in one child born following MST, a finding with possible implications for mitochondrial replacement therapies.
Recent developments in generating gametes via in vitro gametogenesis (IVG) from induced pluripotent stem cells (iPSCs) and their successful use for reproductive purposes in animals strongly suggest that soon these methods could also be used in human reproduction. At least two questions emerge in this context: (a) if a legislator should permit their use and (b) if ethical claims emerge that support their provision, e.g., by public health care systems. This urges an ethical reflection of the new reproductive options this technique might offer. Since the concept of reproductive freedom is a key aspect for the ethical evaluation of artificial reproductive technologies (ARTs), it is necessary to analyze if the new possibilities emerging from IVG fall within the scope of this concept. The results may constitute a morally relevant difference between different imaginable applications of IVG and potentially justify differences in claims to access this technology.
Elevated estradiol levels associated with ovulation-stimulating drugs used to treat infertility and ovarian punctures involved with in vitro fertilization (IVF) have led to concerns regarding long-term cancer effects. Assessed risks, however, have been contradictory. This may reflect small sample sizes and short follow-up times, as well as an inability of many studies to adjust for appropriate potential confounders, such as causes of infertility and parity. While early studies of ovulation-stimulating drugs suggested large increases in large ovarian cancer risk, more recent studies have not confirmed this. However, several investigations have noted risk elevations associated with drug use or IVF among women who remain nulliparous, possibly due to resistant infertility. Studies also suggest increases in borderline ovarian tumors, although the effects of surveillance bias are unclear. Investigations have not shown large increases in breast cancer risk, although a few studies suggest possible increases in select subgroups, including nulliparous women or those with high drug dosages in the distant past. A few studies have evaluated risks of other cancers (endometrium, colorectum, thyroid, and melanoma), without definitive results. Since women exposed to fertility treatments are just beginning to enter typical cancer age ranges, further well-designed investigations are needed to fully delineate long-term effects.
Conventional ovarian stimulation protocols for IVF are designed to achieve maximum oocyte yields. Conventional protocols, however, are associated with patient discomfort, increased risk of ovarian hyperstimulation syndrome and higher costs. In recent years, mild stimulation protocols have risen in popularity. These protocols typically use lower doses (≤150 IU/day), shorter duration of exogenous gonadotrophins compared with conventional protocols, or both, with the goal of limiting the number of retrieved oocytes to less than eight. The pregnancy rate per cycle (fresh embryo transfer only) is lower with mild stimulation compared with conventional stimulation; however, the cumulative pregnancy rate seems to be comparable between the approaches. Reports are conflicting on the effects of mild versus conventional stimulation on embryo quality. This article expands on a live debate held at the American Society for Reproductive Medicine 2015 Annual Meeting to compare the advantages and disadvantages of the ‘more is better’ (conventional protocol) versus ‘less is best’ (mild protocol) approaches to ovarian stimulation. Both protocols are associated with benefits and challenges, and physicians must consider the needs of the individual patient when determining the best treatment options. Further prospective studies comparing a variety of outcomes with conventional and mild stimulation are needed.