Ethical considerations of in vitro gametogenesis: an Ethics Committee opinion

KEY POINTS

• In vitro gametogenesis (IVG) has been proposed as a method for the creation of mature gametes (both spermatozoa and oocytes) from pluripotent stem cells in the laboratory, offering new reproductive possibilities for individuals who might otherwise be unable to produce the gametes necessary for procreation. Preliminary studies of gametogenesis within mouse stem cells have shown some success, though the process is highly inefficient.
• No data, including safety data, currently exists for the use of IVG in humans. The viability of IVG in humans is unknown.
• Two potential sources of stem cells for the derivation of in vitro-derived gametes include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).
• Future applications of IVG might include: addressing infertility because of absence of or inability to produce mature gametes; extending reproductive capacity in aging individuals; avoiding the risks associated with oocyte retrieval; combining gametes of same sex couples to produce offspring that are genetically related to both; allowing solo reproduction; genetically modifying stem cells for the derivation of gametes devoid of heritable diseases; and increasing the number of embryos for preimplantation genetic testing.
• Medical unknowns related to IVG include long-term safety and the potential for unexpected genetic and epigenetic abnormalities in offspring born utilizing in vitro-derived gametes. In vitro gametogenesis should not be considered for reproductive purposes in humans until robust research studies in nonhuman primates are undertaken and found to be reassuring.
• Ethical concerns with the use of IVG include: potential health risks to offspring; commodification of gametes; the creation of supernumerary embryos on a large scale; justice and equity concerns; increased discrimination against those with disease and disability; the devaluation of traditional reproduction; and the possibility of unauthorized use of an individual’s deoxyribonucleic acid (DNA) to create offspring against their wishes or without their knowledge, including posthumously.
• Public debate and education are crucial prerequisites that should occur before society considers developing and offering IVG for human reproduction. Collaboration among scientists, physicians, policymakers, and ethicists is a crucial component of this process.
• Strong regulation and oversight are imperative as society considers whether and how IVG might be utilized in the future. The IVG research should initially occur only under the supervision of institutional review boards (IRBs), and future use in humans should occur only if safety, efficacy, and ethical and societal concerns can be fully addressed.

In vitro gametogenesis (IVG) represents a potentially transformative yet currently experimental frontier in reproductive science. It refers to the manipulation of pluripotent stem cells with the aim of inducing them to differentiate into mature spermatozoa and oocytes within a laboratory environment (1). In theory, these permatozoa and oocytes could be utilized for reproduction, particularly in individuals who lack gametes for a variety of reasons.

In vitro gametogenesis might allow people who are unable to produce viable gametes to have genetically related offspring. This could include individuals unable to produce gametes because of age-related fertility decline, premature ovarian insufficiency, azoospermia, absent ovaries or testes, or gonadal failure because of gonadotoxic treatments for cancer and other conditions. This might be especially impactful for in prepubescent children who require gonadotoxic treatments and are not able to produce mature gametes for cryopreservation. The IVG might also enable same-sex couples to have children genetically related to both by creating oocytes from male somatic cells or spermatozoa from female somatic cells. Moreover, IVG might facilitate the creation of embryos devoid of genetic diseases by increasing the quantity of gametes and embryos developed in vitro and selecting unaffected ones for reproduction. It could theoretically allow for large-scale germline editing by modifying the induced pluripotent stem cell (iPSC) line before the derivation of gametes. This would allow for the possibility of screening edited cells to ensure that the intended edits were achieved, allowing for the creation of gametes unaffected by heritable diseases. In vitro gametogenesis could potentially extend reproductive age, offering individuals the opportunity to have biological children later in life without the limitations imposed by the age-related fertility decline because of decreased ovarian reserve or male factors. Furthermore, IVG could enable solo reproduction by creating offspring from egg and sperm cells derived from a single individual without cloning. However, this scenario raises issues related to the risks of consanguinity, given that autosomal recessive disorders, however rare, would be inherited by 25% of offspring. Alongside these possibilities, IVG raises profound ethical concerns regarding safety, consent, genetic manipulation, and the broader societal impacts inherent in the utilization of this technology for reproduction.

Technical aspects

The two sources of cells that may be used for IVG in experimental animal models currently include embryonic stem cells (ESCs) and iPSCs derived from somatic cells. Considerable progress has been made over the past decade in reconstituting germ cell development in these models (1). Mouse embryonic stem cells (mESCs) have been successfully induced to differentiate into primordial germ cell-like cells (mPGCLCs). In male mice, mPGCLCs have contributed to spermatogenesis when transplanted into the testes of neonatal mice lacking endogenous spermatogenesis (2). Similarly, female mPGCLCs have contributed to oogenesis when aggregated with mouse embryonic ovarian somatic cells (reconstituted ovaries) and transplanted under the ovarian bursa of immune-deficient mice. The resultant spermatozoa and fully grown oocytes produced fertile offspring in mice (2, 3). These milestones in murine models provide proof of concept for the IVG approach and underscore the potential of IVG to offer solutions for infertility and genetic disorders in humans. However, these methods remain highly inefficient in animal models.

It is important to note that significant biological and methodological barriers remain before IVG from mouse models can be translated to humans (4). These challenges include low efficiency, genetic and epigenetic abnormalities, chromosomal errors in in vitro-derived gametes, incomplete or improper imprinting, and the need for human gonadal somatic cells to be used as a matrix for proper gamete development (5, 6). Key biological safety concerns include the risk of genetic and epigenetic abnormalities, incomplete or improper imprinting, and mutations arising during reprogramming or differentiation. These abnormalities may not be immediately apparent, necessitating long term follow-up of offspring for developmental, metabolic, and reproductive outcomes. Additionally, preclinical models must evaluate the risk of tumorigenicity, especially when using iPSCs, which have inherent risks of reversion or uncontrolled growth (7).

The use of human fetal tissues or advanced three-dimensional organ culture systems may be necessary, which raises both technical and ethical concerns. An alternative approach involves using somatic cells derived from pluripotent stem cells, although research exploring this strategy is currently limited (8). Low efficiency in producing functionally competent gametes is another significant obstacle. In the mouse models, only one to three percent of in vitro-developed and fertilized mouse embryos have developed to term. Efficiency must be significantly improved for human medical applications to be considered (9). Finally, establishing proper methodologies for assessing the development and safety of the resulting gametes is crucial.

Preclinical pathway and biological safety requirements for IVG

To advance IVG toward clinical use in humans, a rigorous sequence of biological and preclinical studies must be completed that would establish safety, reliability, and functional viability. The foundational step involves refining protocols to consistently generate mature, functional gametes from either ESCs or iPSCs in animal models. The partial success demonstrated in mice remains highly inefficient and prone to variability, underscoring the need for optimization and translation into nonhuman primate models to assess the functional capacity of IVG-derived gametes, including fertilization, embryo development, and the birth and health of offspring across generations. The accumulation of reliable, reproducible safety data in primates is an essential prerequisite before any human trials can be ethically or scientifically initiated. Without these steps, the biological risks to future offspring remain too great to justify clinical use (7, 10, 11).

Ethical and social considerations

Proactive engagement with ethicists, policymakers, scientists, and the broader public is essential to establish robust regulatory frameworks that uphold the principles of autonomy, beneficence, nonmaleficence, and justice. In vitro gametogenesis raises numerous ethical and social concerns that are discussed below.

Risks to offspring. A potential risk for IVG-derived embryos is the development of genetic and epigenetic abnormalities, which can pose serious health risks to offspring. The manipulation of gametes outside the body may lead to errors in the genetic code or alterations in gene expression, which could manifest as developmental issues, congenital disorders, or health complications at birth or later in life (12). These risks are further compounded by the lack of long-term safety data, as the technology remains in its early stages. Without extensive research, the full implications of IVG for future generations remain unknown, raising questions about whether and when this technology can be ethically pursued in humans.

Creation of supernumerary embryos on a large scale and the commodification of human life. The prospect of using IVG to select for ‘‘healthy or healthiest’’ among a large set of embryos also raises concern about the commodification of human life by choosing gametes with specific traits that are preferentially utilized for reproduction. In vitro fertilization (IVF) laboratories could, in theory, be used to produce large numbers of embryos for patients to consider and compare. Although the same concern has been raised with regard to IVF, the scale at which embryos could be created with IVG magnifies the concern. An additional concern involves the commodification of cell lines from which IVG-derived gametes could be created. Certain cell lines could be considered ‘‘superior’’ and preferentially used to create gametes with certain desirable traits that would be propa-
gated within a society.

Justice and equity concerns. Justice and equity are central to ethical discussions surrounding IVG. If access to IVG is limited to those who can afford it, this technology risks further exacerbating disparities in reproductive healthcare. Such inequity may give rise to a scenario where genetic selection determines social status and opportunities. Although social inequalities already exist, choosing specific qualities in gametes that will be propagated by a certain subset of the population might fundamentally alter the concept of fairness and opportunity, making inequality inescapable from birth. This raises profound moral questions about whether society should allow the use of technologies that could further deepen social divides. Although these concerns could also relate to other reproductive technologies such as IVF, the quantity of embryos potentially created via IVG is of particlar concern.

Increased discrimination against those with diseases and disability. If IVG allows for the possibility of effectively selecting against disease and disability, there may be fewer efforts on a societal level for those affected by these conditions. This could include decreased research funding for diseases that become ever less common and decreased clinical expertise in managing diseases and disabilities that may become ever rarer. This is also true for other technologies such as preimplantation genetic testing (PGT).

Devaluation of existing family-building practices. The availability of IVG could impact existing family-building practices, including adoption and gamete donation. By offering prospective parents the ability to create genetically related children through nontraditional means, IVG risks reinforcing genetic exceptionalism, the idea that genetic ties are essential to forming a ‘‘real’’ family. This focus on genetic connection could marginalize families formed through adoption or gamete donation, which could disproportionately affect LGBTQ+ families. The societal emphasis on genetic ties might further erode acceptance of nongenetically connected families, challenging the broader understanding of what it means to be a family.

Reproduction without consent of the gamete source. The possibility of creating gametes from an individual's DNA without their knowledge or consent also introduces significant ethical, privacy, and consent concerns. These include the possibility that an individual who may not have consented to this outcome might have genetically related offspring posthumously. Such risks highlight the need for stringent safeguards to prevent misuse of this technology.

Regulation and oversight

To ensure the ethical development and application of IVG, robust regulatory frameworks and oversight mechanisms are essential. Premature commercialization, especially before IVG is deemed safe and effective in humans, must be prevented to avoid exploitative practices and to maintain public trust in the technology. Collaboration among scientists, policymakers, and ethicists is critical for establishing guidance that prioritizes safety, equity, and ethical conduct, and compliance with existing federal and state laws. This should start during the earliest phases of preclinical research and be overseen by dedicated stem cell oversight committees with expertise in these technologies. Transparent public engagement and robust debate are necessary to navigate the complex societal implications of IVG, ensuring that decisions are informed by diverse perspectives. To mitigate risks, IVG should be offered only under an Institutional Review Board (IRB) protocol when animal studies, including in nonhuman primates, suggest reassuring safety and efficacy data. In such cases, clear protocols must be developed for the protection of the human subjects in a manner that rigorously adheres to ethical standards. This approach will help balance the technology's potential benefits with its profound ethical and societal challenges, fostering responsible innovation in reproductive science.

The International Society for Stem Cell Research (ISSCR) has developed standards for the classification of human stem cell and embryo research activities, evaluating technical, safety, and ethical aspects of studies and recommending specialized scientific and ethics oversight processes accordingly (13). In vitro gametogenesis for human reproductive purposes falls under one of the most restrictive categories of research according to these standards. The ISSCR acknowledges the transformative potential of IVG within the landscape of reproductive medicine while emphasizing the need for rigorous ethical scrutiny and responsible research conduct. Their framework can be used as a guide to direct the development of IVG for eventual use in humans.

CONCLUSION

In vitro gametogenesis represents a potentially groundbreaking future advancement in reproductive medicine. It may ultimately allow for promising novel solutions for infertility and the possibility of genetically related offspring for individuals and couples who are unable to produce gametes. However, IVG poses major challenges before it can be implemented in humans. Scientific, ethical, legal, and societal implications must be carefully considered before clinical applications can be realized. Although experimental models have demonstrated promising results, technical inefficiencies, genetic and epigenetic abnormalities, and ethical concerns remain major barriers to human use. These issues extend beyond individual health risks to broader societal implications, such as consent, privacy, disability rights, and the potential commodification of human life.

If IVG moves closer to becoming a reality, a proactive and comprehensive regulatory framework is essential to ensure its responsible development. Close coordination among scientists, policymakers, and ethicists, coupled with open and transparent public dialogue, is essential to responsibly weigh the potential benefits of IVG against its associated risks. By addressing the safety, equity, and ethical considerations early, society can guide the responsible advancement of this technology, fostering innovation while safeguarding the health and well-being of future generations.

Acknowledgments

This report was developed under the direction of the Ethics and Practice Committees of the American Society for Reproductive Medicine as a service to its members and other practicing clinicians. Although this document reflects appropriate management of a problem encountered in the practice of reproductive medicine, it is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs of the individual patient, available resources, and institutional or clinical practice limitations. The Ethics and Practice Committees and the Board of Directors of the American Society for Reproductive Medicine (ASRM) have approved this report.

This document was reviewed by ASRM members, and their input was considered in the preparation of the final document. The following members of the ASRM Ethics Committee participated in the development of this document: Sigal Klipstein, M.D.; Sina Abhari, M.D.; Paula Amato, M.D.; Aishwarya Arjunan, M.S., M.P.H.; Tolulope Bakare, M.D.; Kim Bergman, Ph.D.; Michelle Bayefsky, M.D.; Zeki Beyhan, Ph.D.; Katherine Cameron, M.D.; Susan Crockin, J.D.; Jessica Goldstein, R.N.; Insoo Hyun, Ph.D.; Jennifer Kawwass, M.D.; Joshua Morris, M.D.; Jeanne O’Brien, M.D.; Torie Comeaux Plowden, M.D., M.P.H.; Gwendolyn Quinn, Ph.D.; Robert Rebar, M.D.; Jared Robins, M.D., M.B.A.; Chevis N. Shannon, Dr.P.H., M.P.H., M.B.A.; Michael Thomas, M.D.; Sean Tipton, M.A.

The Ethics Committee acknowledges the special contribution of Zeki Beyhan, Ph.D.; Gwendolyn Quinn, Ph.D.; and Michelle Bayefsky, M.D., in the preparation of this document. All committee members disclosed commercial and financial relationships with manufacturers or distributors of goods or services used to treat patients. Members of the committees who were found to have conflicts of interest on the basis of the relationships disclosed did not participate in the discussion or development of this document.

REFERENCES

1. National Academy of Science, Engineering, Medicine. In vitro-derived human gametes as a reproductive technology, science, ethical, and regulatory implications: proceedings of a workshop (2023). Available at: https://nap. nationalacademies.org/catalog/27259/in-vitro-derived-human-gametes-as-a-reproductive-technology-scientific. Accessed January 3, 2026.
2. Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 2011;146:519–32.
3. Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, Saitou M. Offspring from oocytes derived from in vitro primordial germ cell–like cells in mice. Science 2012;338:971–5.
4. Berridge BR. Animal study translation: the other reproducibility challenge. ILAR J 2021;62:1–6.
5. Nichols J, Smith A. Naive and primed pluripotent states. Cell Stem Cell 2009;4:487–92.
6. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145–7.
7. Lin YC, Ku CC, Wuputra K, Liu CJ, Wu DC, Satou M, et al. Possible strategies to reduce the tumorigenic risk of reprogrammed normal and cancer cells. Int J Mol Sci 2024;25:5177.
8. Mikhalchenko A, Gutierrez NM, Frana D, Safaei Z, Van Dyken C, Li Y, et al. Induction of somatic cell haploidy by premature cell division. Sci Adv 2024; 10:eadk9001.
9. Horer S, Feichtinger M, Rosner M, Hengstschl€ager M. Pluripotent stem cell-derived in vitro gametogenesis and synthetic embryos—it is never too early for an ethical debate. Stem Cells Transl Med 2023;12:569–75.
10. Clark AT, Brivanlou A, Fu J, Kato K, Mathews D, Niakan KK, et al. Human embryo research, stem cell-derived embryo models and in vitro gametogenesis: considerations leading to the revised ISSCR guidelines. Stem Cell Reports 2021;16:1416–24.
11. Czukiewska SM, Roelse CM, Chuva de Sousa Lopes SM. Human and non-human primate female in vitro gametogenesis toward meiotic entry: a systematic review. Fertil Steril 2025;124:6–21.
12. Sciorio R, Tramontano L, Gullo G, Fleming S. Association between human embryo culture conditions, cryopreservation, and the potential risk of birth defects in children conceived through assisted reproduction technology. Medicina (Kaunas) 2025;30:1194.
13. International Society for Stem Cell Research Guidelines. Available at: https:// www.isscr.org/guidelines. Accessed September 9, 2025.