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Oogonial stem cells: the unexpected superheroes
The time has come for stem cell technologies to be used in fertility studies
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The rights of transgender and intersex people have become a contentious issue in our current political climate. Whether it be the rights of intersex athletes such as Caster Semenya (who identifies as a woman) to compete in elite sport, or the rights of transgender women to use women’s only spaces, there is an increasingly fierce debate as to the legitimacy of people’s gender and sexual identities and what parameters should be used to define them. A common argument accepted by most in our society is that while gender may be a spectrum, sex is an inalienable binary.
IRCCS Ospedale Policlinico San Martino, Genova, Italy
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IRCCS Ospedale Policlinico San Martino, Genova, Italy
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In the registration trials, follitropin delta was compared with a fixed dose of 150 UI of follitropin alpha/beta, finding higher chances to reach a target response of 8–14 oocytes compared to controls. For this reason, follitropin delta is marketed as particularly useful in expected hyper-responder patients. The main outcome of this study is to report if comparable results are reached in a real-life scenario with follitropin alpha/beta doses chosen by the physician, based on patients’ characteristics. This is a retrospective study performed in two public fertility centres. All first cycles from January 2020 to June 2022 with either follitropin delta (cases) or alpha/beta (controls) in patients with anti-Müllerian hormone >2.5 ng/mL were compared by an inverse probability weighting approach based on propensity score. The follitropin total dose was higher in controls (1179.06 ± 344.93 vs 1668.67 ± 555.22 IU, P < 0.001). The target response of 8–14 oocytes was reached by 40.2% of cases and 40.7% of controls (odds ratio (OR): 0.99, 95% confidence interval (CI): 0.65–1.53, P = 0.98). Fewer than 8 oocytes were collected in 24.1% of cases and 22% of controls (OR: 1.10, 95% CI: 0.71–1.69, P = 0.67); more than 14 oocytes in 35.7% of cases and 37.3% of controls (OR: 0.83, 95% CI: 0.54–1.28, P = 0.40). Our experience did not find worse results in term of proportion of patients who reached the target response with an algorithm-chosen dose of follitropin delta compared to a personalised starting dose of follitropin alpha/beta, with follitropin delta having the advantage of objectivity. However, larger numbers are needed to confirm these results.
Lay summary
The starting dose of the drugs used to stimulate the ovaries in IVF (gonadotropins) is usually decided by the doctor, using their clinical experience and expertise and tailored to the individual patient. Recently one type of stimulating drug (follitropin delta) was marketed with an algorithm for deciding the starting dose based on the patient’s anti-Müllerian hormone (AMH) levels and weight. In the initial trials, it was compared with a fixed dose of standard follitropins (alpha/beta), and it was found to reduce the likelihood of an excessive response in patients at risk of ovarian hyperstimulation syndrome. We report on these results, in terms of number of eggs obtained, in patients with an expected high ovarian response, compared to doses of standard follitropins that were not fixed, but personalised, to see if this did not make a difference. We found similar results in the two groups, suggesting that using the algorithm to decide the dose of follitropin delta does not work less well than a personalised starting dose of follitropin alpha/beta, but has the advantage of being objective.
Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
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Priority Research Centre for Geotechnical Science and Engineering, University of Newcastle, Callaghan, NSW, Australia
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Infertility and Reproduction Research Program, Hunter Medical Research Institute, New Lambton Heights, Newcastle, NSW, Australia
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Graphical abstract
Abstract
Poly- and per-fluoroalkyl substances (PFAS) are synthetic environmentally persistent chemicals. Despite the phaseout of specific PFAS, their inherent stability has resulted in ubiquitous and enduring environmental contamination. PFAS bioaccumulation has been reported globally with omnipresence in most populations wherein they have been associated with a range of negative health effects, including strong associations with increased instances of testicular cancer and reductions in overall semen quality. To elucidate the biological basis of such effects, we employed an acute in vitro exposure model in which the spermatozoa of adult male mice were exposed to a cocktail of PFAS chemicals at environmentally relevant concentrations. We hypothesized that direct PFAS treatment of spermatozoa would induce reactive oxygen species generation and compromise the functional profile and DNA integrity of exposed cells. Despite this, post-exposure functional testing revealed that short-term PFAS exposure (3 h) did not elicit a cytotoxic effect, nor did it overtly influence the functional profile, capacitation rate, or the in vitro fertilization ability of spermatozoa. PFAS treatment of spermatozoa did, however, result in a significant delay in the developmental progression of the day 4 pre-implantation embryos produced in vitro. This developmental delay could not be attributed to a loss of sperm DNA integrity, DNA damage, or elevated levels of intracellular reactive oxygen species. When considered together, the results presented here raise the intriguing prospect that spermatozoa exposed to a short-term PFAS exposure period potentially harbor an alternate stress signal that is delivered to the embryo upon fertilization.
Lay summary
PFAS are synthetic chemicals widely used in non-stick cookware, food packaging, and firefighting foam. Such extensive use has led to concerning levels of environmental contamination and reports of associations with a spectrum of negative health outcomes, including testicular cancer and reduced semen quality. To investigate the effects of PFAS on male reproduction, we incubated mouse sperm in a cocktail of nine PFAS at environmentally relevant concentrations before checking for a range of functional outcomes. This treatment strategy was not toxic to the sperm; it did not kill them or reduce their motility, nor did it affect their fertilization capacity. However, we did observe developmental delays among pre-implantation embryos created using PFAS-treated sperm. Such findings raise the intriguing prospect that PFAS-exposed sperm harbor a form of stress signal that they deliver to the embryo upon fertilization.
Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
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Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
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The decreasing rate of successful pregnancies, both naturally and through assisted conception, has led to innovations in the way eggs, sperm, and embryos are stored. Despite these advances, the use of assisted reproductive techniques to preserve endangered or rare species remains unexplored. Since the location where samples are collected and facilities are often far apart, we aim to address part of this challenge by comparing different methods to store and handle ovarian tissue before freezing. This may pave the way for further research in preserving endangered species, despite the challenges posed by the distance between sample collection sites and suitable facilities.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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We aimed to investigate the effects of the position of the transferred air bubble with the clinical pregnancy rate (PR) in frozen-thawed embryo transfer (FET) cycles. A prospective clinical study was carried out at Reproductive Medicine Center of West China Second University Hospital between June 2020 and May 2021. A total of 1159 women who underwent FET were included in this study. Transabdominal ultrasonographic guidance was used during the transfer procedure. The distance from the air bubble to endometrial cavity fundus (DAF) was measured in the freeze-frame ultrasound immediately after ET. In DAF ≤3 mm, 3–15 mm, and ≥15 mm group, the clinical PR in women transferred with cleavage embryos was 33.3% (7/21), 55.0% (153/280), and 31.3% (5/16), respectively, and the difference was statistically significant (P < 0.05). Among women transferred with blastocysts, the clinical PR was 63.0% (34/54), 68.5% (485/708), and 55.0% (44/80), respectively, and the difference was statistically significant (P < 0.05). In multivariate logistic regression model for clinical PR, the clinical PR was associated with age, embryo quality, number of embryo transferred, and endometrial thickness. DAF was an independent risk factor influencing clinical PR in blastocyst FET cycles rather than in cleavage embryo FET cycles. In conclusion, our results suggested that DAF was associated with the clinical PR and DAF between 3 mm and 15 mm is the optimal position in blastocyst FET cycles.
Lay summary
Embryo transfer is the last step in the IVF process. The position of the transferred embryo in the uterine cavity may affect the clinical pregnancy rate. The relationship between the position of the embryo in the uterine cavity at the time of transfer and the clinical pregnancy rate is disputed. In this study, the distance from the air bubble to endometrial cavity fundus measured using the freeze-frame ultrasound immediately after embryo transfer was used to indicate the position of the embryo in the uterine cavity. This study demonstrates that the position of the transferred air bubble in the uterine cavity is an independent factor on clinical pregnancy rate in blastocysts (embryos on the fifth day of fertilization) frozen-thawed embryo transfer cycles but not in cleavage embryos (embryos on the third day of fertilization) frozen-thawed embryo transfer cycles. The distance from the air bubble to endometrial cavity fundus between 3 mm and 15 mm is the optimal position in blastocyst frozen-thawed embryo transfer cycles.
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA
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Approximately 50% of pregnancies in humans fail, mostly before or during implantation. One factor contributing to pregnancy loss is abnormal glucose metabolism in the endometrium. Glucose contributes to preimplantation embryo development, uterine receptivity, and attachment of the embryo. Across multiple species, the epithelium stores glucose as the macromolecule glycogen at estrus. This reserve is mobilized during the preimplantation period. Glucose from circulation or glycogenolysis can be secreted into the uterine lumen for use by the embryo or metabolized via glycolysis, producing ATP for the cell. The resulting pyruvate could be converted to lactate, another important nutrient for the embryo. Fructose is an important nutrient for early embryos, and the epithelium and placenta can convert glucose to fructose via the polyol pathway. The epithelium also uses glucose to glycosylate proteins, which regulates embryo attachment. In some species, decidualization of the stroma is critical to successful implantation. Formation of the decidua requires increased glucose metabolism via the pentose phosphate pathway and glycolysis. After decidualization, the cells switch to aerobic glycolysis to produce ATP. Paradoxically, the decidua also stores large amounts of glucose as glycogen. Too little glucose or an inability to take up glucose impairs embryo development and decidualization. Conversely, too much glucose inhibits these same processes. This likely contributes to the reduced pregnancy rates associated with conditions like obesity and diabetes. Collectively, a precise control of glucose metabolism is important for several endometrial processes required to establish a successful pregnancy. The factors regulating these metabolic processes remain poorly understood.
Lay summary
Pregnancy failure soon after an egg has been fertilized is common in humans and cattle. The inner lining of the womb (endometrium) plays a role in the development and implantation of an embryo. The levels of glucose needed by the endometrium and embryo change dramatically during early pregnancy. The inner layer of tissue (epithelium) uses glucose and other nutrients to help the embryo develop and attach to the endometrium. In some species, the layer underneath the epithelium (stroma) goes through a series of major changes that alter the function of the cells and the levels of energy they require. This review discusses the way glucose is used in the epithelium and stroma to provide insights into the role this has in ongoing pregnancy.
Reproductive Biology Unit, Royal Women’s Hospital, Melbourne, Australia
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Reproductive Biology Unit, Royal Women’s Hospital, Melbourne, Australia
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The field of fertility preservation (FP) for oncology patients has evolved significantly in recent years, offering new possibilities for individuals with life-threatening illnesses. We commend Jones et al. for their comprehensive ethical review of offering FP to patients with poor prognoses, acknowledging the potential benefits that it may bring. ‘Poor prognosis’ in this context implies a high likelihood of death due to cancer progression. We highlight the importance of considering posthumous reproduction, involving the use of cryopreserved gametes or embryos to conceive a child after one or both partners have passed away, a topic briefly mentioned by Jones et al. Posthumous reproduction raises complex ethical, logistical, and legal questions. Distinctions between cryopreserved sperm and oocytes are discussed, with each scenario presenting unique challenges. The article also examines the complexities faced by same-sex couples in posthumous reproduction, addressing issues related to donor selection, legal parentage, and rights. Legal and regulatory aspects play a crucial role, including obtaining clear and legally valid consent, defining parental rights, navigating surrogacy laws, and addressing inheritance and estate planning. Ethical dilemmas require healthcare professionals to ensure informed decision-making, consider psychological impacts, and offer information on alternative family-building options.
Lay summary
Cancer treatments can have a negative impact on a person’s ability to have children, and some cancer survivors may end up being unable to conceive. Fortunately, there are currently available technologies that can help preserve fertility for these patients. These options include freezing eggs or sperm before starting cancer treatment. For patients who have been diagnosed with cancer and have a poor prognosis, meaning they are not likely to survive their illness, it is crucial to think about what happens to their frozen eggs and sperm in case of their death. This process of conceiving a child after someone's passing is known as ‘posthumous reproduction’. In our article, we explore the ethical, legal, and logistical challenges that the surviving partners of patients who may not live long enough to have a child with their frozen eggs or sperm might face. We pay particular attention to same-sex couples because their surviving partners often encounter more obstacles. In some countries, posthumous reproduction in these circumstances is even prohibited by law. There is a significant variation in the regulations related to posthumous reproduction, both between different countries and within individual countries. These differences need to be carefully considered when healthcare professionals counsel patients and their family members.
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Gynaecological Research and Clinical Research (GRACE) Unit, Royal Hospital for Women, UNSW, Sydney NSW Australia
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Gynaecological Research and Clinical Research (GRACE) Unit, Royal Hospital for Women, UNSW, Sydney NSW Australia
The George Institute for Global Health, UNSW, Sydney, Australia
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Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
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Translational Health Research Institute, Western Sydney University, Sydney, NSW, Australia
Medical Research Institute of New Zealand (MRINZ), Wellington, New Zealand
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Previous quantitative research has shown that cannabis use, mostly illicit, is used for symptom management amongst those with endometriosis living in Australia or New Zealand, but the drivers and barriers for use of legal, medicinal cannabis in this population are currently unclear. This study sought to investigate, via online focus groups, the perceptions, barriers, drivers, and experiences associated with cannabis use, whether legal or illicit, amongst 37 Australians and New Zealanders, aged 18–55, with a medical diagnosis of endometriosis. Previous cannabis usage was not required to participate. Discussion topics included strategies employed to manage symptoms, exploration of current medications, previous use of cannabis for pain management, and interest in using medicinal cannabis as a management strategy. Participants with moderate-to-severe symptoms of medically diagnosed endometriosis reported inadequacies with their current medical and self-management strategies and were inclined to try medicinal cannabis, both as part of their medical management and as part of a clinical trial. Barriers to medicinal cannabis adoption identified in this cohort included high costs of legal cannabis products, lack of clarity and fairness in current roadside drug testing laws and workplace drug testing policies, concern over the impact of stigma affecting familial, social and workplace life domains, and subsequent judgement and the lack of education/engagement from their medical providers regarding cannabis use. Given the interest in medicinal cannabis and the reported lack of effective symptom management, clinical trials are urgently required to determine the potential role that medicinal cannabis may play in reducing the symptoms of endometriosis.
Lay summary
Previous research has demonstrated that cannabis, either medically or illicitly obtained, is being used to manage the pain and associated symptoms of endometriosis in people across Australia and New Zealand. However, there are no clinical trials yet to determine how safe and effective medicinal cannabis might be for endometriosis symptoms. Before we design our clinical trial we wanted to get input from people in the community who have endometriosis to understand what kind of barriers there might be to both being in a clinical trial and using medicinal cannabis for their symptoms. Overall, the vast majority of participants were open to trying medicinal cannabis as a management option, driven mainly by inadequacies in their current medical and self-management strategies. Several barriers to adoption were identified, including the high costs of legal cannabis products, current drug driving laws or workplace drug testing policies, and the negative stigma around cannabis usage.
