New World monkeys, or platyrrhines, are diverse primates native to Central and South America. They represent one of the two major branches of simian primates, along with the Old World monkeys and apes (catarrhines). “Platyrrhine” means “flat-nosed,” referring to their characteristic broad, outward-facing nostrils. These monkeys are known for their arboreal lifestyles, adaptations to forest environments, and diverse social behaviors.

Old World monkeys (Catarrhines) belong to the superfamily Cercopithecoidea and are primarily distributed across Africa and Asia. They form one of the two major branches of simian primates alongside New World monkeys (Platyrrhines). “Old World” refers to their geographic origins in the Eastern Hemisphere.

NHPs, particularly rhesus macaques and marmosets (Buse et al., 2008), are critical in advancing ART, including IVF (Arthur Chang and Chan, 2011). Optimized protocols for these species, including oocyte retrieval, embryo culture, and transfer, are vital for their conservation and study and serve as highly translational models for human fertility treatments (Bavister et al., 1984; Ramsey and Hanna, 2019). These studies provide insights into human reproduction due to the close physiological and genetic similarities between NHPs and humans (Table 2).

A significant contribution of NHP research lies in overcoming challenges associated with male infertility. Precision techniques such as intracytoplasmic sperm injection (ICSI), which involves the direct injection of a single sperm into an oocyte, have been refined using NHP models (Mitalipov et al., 2001; Nusser et al., 2001). These advancements have improved success rates in cases of severe male infertility, including azoospermia (absence of sperm in semen) or poor sperm motility. In an in vitro follicular maturation setting, optimal culture conditions and ratios of gonadotropin treatment were reported in a rhesus monkey model (Kim et al., 2016). NHP research also supports the development of pre-implantation genetic testing and optimization of cryopreservation methods to ensure high-quality gametes and embryos for IVF procedures (Sun et al., 2008; Ma et al., 2016; Motohashi and Ishibashi, 2016; Curnow and Hayes, 2019; Ma et al., 2019). These innovations directly inform clinical practice, benefiting individuals and couples facing infertility challenges.

Studies on cryopreservation techniques in NHPs have significantly advanced fertility preservation strategies for humans, particularly for individuals facing fertility risks from medical treatments such as chemotherapy (Table 3). Freezing and thawing of sperm, oocytes, and embryos in NHPs offer valuable insights into optimizing protocols for preserving gamete and embryo viability after thawing and minimizing damage caused by ice crystal formation or osmotic stress (Morrell and Hodges, 1998; Jahnukainen et al., 2007; Motohashi and Ishibashi, 2016; Fayomi et al., 2019). These refinements enhance the preservation of human fertility, making options such as embryo or oocyte banking more reliable.

Additionally, NHP models have been instrumental in pioneering ovarian tissue cryopreservation and transplantation (Brito et al., 2017). Research using these models has demonstrated the feasibility of grafting freeze-thawed ovarian tissue to restore endocrine function and fertility (Lee et al., 2017). This technique holds particular promise for patients with prepubertal cancer or women unable to undergo conventional fertility preservation methods. Successes in rhesus macaques and other NHPs have laid the groundwork for translating ovarian tissue transplantation into human clinical applications, where it can restore hormone production, menstrual cycles, and the potential for natural conception.

These advancements underscore the critical role of NHP research in developing innovative fertility preservation techniques, offering hope to individuals facing medical conditions that compromise their reproductive health.

NHPs have been pivotal in advancing stem cell research, primarily through deriving gametes from pluripotent stem cells (PSCs) (Mishra et al., 2016; Wu et al., 2023). Various embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) lines have been derived from NHPs (Fang et al., 2014; Honda et al., 2017; Kishimoto et al., 2021). By leveraging their close genetic and physiological similarities to humans, NHPs provide critical insights into germline development and serve as a robust model for translating findings into human medicine (Hayashi et al., 2012) (Table 4).

Researchers have successfully reprogrammed iPSCs and ESCs into germline-like cells in NHPs, enabling detailed investigations into mechanisms regulating spermatogenesis and oogenesis (Makar and Sasaki, 2020). These studies have identified key signaling pathways and genetic factors required for proper germ cell differentiation (Sasaki et al., 2016; Liu et al., 2018). They also offer a controlled environment for exploring interactions between germline cells and their surrounding somatic niches, which are essential for gamete maturation (Seita et al., 2023).

The ability to derive functional gametes from stem cells represents a groundbreaking advancement in addressing infertility. This research offers hope for future therapeutic interventions for individuals with conditions such as gonadal dysgenesis, cancer treatment-induced gonadal damage, or genetic mutations impairing germ cell production (Tan et al., 2021; Roodgar et al., 2022). By generating gametes in vitro, researchers aim to restore fertility in cases where native germ cells are absent or non-functional.

NHP models are also instrumental in ensuring the safety and efficacy of these approaches, particularly in validating whether stem cell-derived gametes can undergo regular fertilization and produce healthy offspring (Rodriguez-Polo and Behr, 2022). These findings are critical for clinical applications, ensuring these techniques are robust and applicable to human reproductive medicine.

Tissue engineering of NHPs has opened new frontiers in reproductive medicine by providing a platform for the development of artificial uterine and ovarian tissues. These advances could replace damaged reproductive organs and enhance the success of ART (Johannesson et al., 2012) (Table 5).

NHPs have advanced our understanding of hormonal reproductive regulation. They offer insight into diagnosing and treating human reproductive disorders (Fazleabas, 2006; Kyama et al., 2007; Taylor et al., 2017). Their close resemblance to human reproductive physiology makes them invaluable for studying complex hormonal interactions during the menstrual cycle, pregnancy, and related conditions (Braundmeier et al., 2012) (Table 6).

PCOS studies in NHPs have examined the effects of excess androgens on follicular development and insulin resistance, thereby providing a preclinical model for testing treatments (Abbott et al., 1998; Abbott et al., 2017). Similarly, NHP studies on menstrual physiology and endometrial lesions have advanced our understanding of the inflammatory and hormonal mechanisms underlying endometriosis (Barrier et al., 2007; Wang et al., 2009).

In particular, marmosets have contributed significantly to understanding hormone signaling between the mother and fetus (Barnett et al., 2006). These studies have revealed how maternal hormones, such as progesterone and cortisol, influence fetal development, placental function, and labor timing (Einspanier et al., 1997; Rutherford et al., 2014). Disruptions in these signaling pathways are implicated in pregnancy complications such as preeclampsia, preterm birth, and intrauterine growth restriction (Wedi et al., 2011).

For instance, research on maternal cortisol regulation in marmosets has highlighted its role in programming fetal stress responses and metabolism, which may have long-term implications for offspring health. These studies provide a foundation for developing interventions to mitigate pregnancy-related complications in humans.

Studies of early embryonic development in NHPs have provided crucial data on implantation and developmental milestones, offering insights into miscarriage and congenital disorders (Table 7). Research on NHPs has revealed the molecular and cellular processes underlying embryonic attachment to the uterine lining and trophoblast invasion (Zhou et al., 1993), which are crucial for successful implantation (Tardif and Bales, 2004; Ochoa-Bernal and Fazleabas, 2020). These findings help clarify the causes of implantation failure, which is a significant factor in infertility and early pregnancy loss. NHP models allow a detailed examination of embryonic genome activation, cell differentiation, and the formation of critical structures, such as the blastocyst and germ layers (Bergmann et al., 2022; Zhai et al., 2022; Gong et al., 2023; Li X. T. et al., 2023). Insights from these studies are essential to understand how disruptions during early development contribute to miscarriages or congenital disorders.

NHP models, such as macaques, have been used to study ovarian aging, menopause, and associated health issues. These models help researchers explore potential interventions to extend reproductive lifespan or mitigate age-related infertility (Hernandez-Lopez et al., 2012). Studies on rhesus macaques have helped to identify biomarkers of ovarian reserves, aiding fertility assessments in humans (Alberts et al., 2013; Lee et al., 2021) (Table 8).

Macaques exhibit reproductive aging patterns similar to humans, including a decline in ovarian reserve, irregular menstrual cycles, and eventual menopause. Research using these models has provided critical insights into mechanisms underlying ovarian aging and menopause (Brenner et al., 2004). Studies in rhesus macaques have highlighted the decline in follicular quantity and quality with age, along with changes in hormone levels (e.g., estradiol, progesterone, and FSH) that mirror human menopausal transitions (Downs and Urbanski, 2006; Johnson and Kapsalis, 2008). NHP models have also been used to explore the systemic effects of ovarian aging, such as increased risks of osteoporosis, cardiovascular disease, and cognitive decline (Garber et al., 2020). These parallels make them ideal models for studying postmenopausal health.

Transcriptomic analyses of NHP models have revolutionized our understanding of gene expression dynamics in reproduction, development, aging, and disease (Wang S. et al., 2020; Bergmann et al., 2022) (Table 9). These studies have provided insights into the molecular mechanisms underlying normal physiological and pathological conditions by analyzing a full range of RNA transcripts (Han et al., 2022; Tu et al., 2022).

Transcriptomic analyses of NHPs have examined age-related changes in various tissues, including ovaries, testes, brain, and muscles (Xu et al., 2011; Zhao et al., 2020; Kim et al., 2024). Comparative transcriptomic analyses between NHPs and humans can help identify evolutionary changes in gene expression that may explain species-specific traits, including cognitive abilities, immune responses, and reproductive strategies.

NHP embryos have been used to refine CRISPR-Cas9 genome-editing techniques and test the precision and safety of this technology in correcting genetic mutations (Nusser et al., 2001; Liu et al., 2014; Chen et al., 2015; Sato et al., 2016; Kumita et al., 2019; Abe et al., 2021; Ryu et al., 2022; Seita et al., 2023). Generating genetically modified marmosets enables researchers to study gene functions related to reproduction and developmental biology, such as genes controlling spermatogenesis or the ovarian reserve (Sasaki et al., 2009; Yoshimatsu et al., 2019; Tomioka et al., 2020; Drummer et al., 2021).

These studies are valuable in addressing infertility associated with hereditary diseases or genetic mutations. Moreover, research involving NHPs ensures these methods are safe and effective before transitioning to human clinical applications (Table 10).

Non-human primates (NHPs) use in reproductive engineering, particularly in fields like assisted reproductive technology (ART) and stem cell research, raises several ethical concerns related to animal welfare. These concerns stem from the study’s complexity, the procedures’ invasiveness, and the potential for suffering in NHPs. For the welfare of the NHP, the following points should be considered.

Reproductive engineering techniques often involve highly invasive procedures such as oocyte retrieval, embryo transfer, or hormonal manipulation. To minimize distress and harm, these procedures should be performed with the utmost care and precision, ideally under anesthesia or appropriate analgesia, and only when necessary for the research objectives. Effective anesthesia and analgesia should be administered to minimize pain and discomfort, and the animals should be monitored continuously to detect signs of distress or discomfort. Where possible, researchers should explore non-invasive or minimally invasive techniques to gather data, such as non-invasive imaging, blood or urine analysis, and genomic studies.

Genetic modifications (e.g., CRISPR) for reproductive engineering in NHPs raise additional ethical concerns, especially regarding unintended genetic consequences and the long-term impact on animal welfare. Ethical review is crucial to ensure that such experiments are conducted with appropriate safeguards and that potential risks are minimized.

Ethical considerations regarding using NHPs in reproductive engineering are complex but crucial. They revolve around minimizing harm, ensuring scientific necessity, and providing appropriate animal care throughout their lives. Ethical guidelines, such as those offered by IACUCs and institutional review boards, exist to ensure that NHPs are treated with respect, their welfare is a top priority, and their use is scientifically justified. Adhering to these principles ensures humane treatment and enhances the credibility and legitimacy of the research.