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The nonapeptide oxytocin is a multifaceted and evolutionarily conserved hormone and neuromodulator. The domains it has been implicated in since its discovery approximately 130 years ago (Howell, 1898; Oliver & Schäfer, 1895) range from galactagogue (I. Ott & Scott, 1910) and uterotonic (Dale, 1906, 1909), over energy and bone metabolic (Colaianni et al., 2014; Leng & Sabatier, 2017), cardiovascular (Gutkowska & Jankowski, 2012), to social (H. K. Caldwell, 2017), cognitive (Brambilla et al., 2016), and psychiatric (Young, 2001). It is predominantly synthesized in the brain within the hypothalamus, where its structurally and functionally related paralog vasotocin (Theofanopoulou et al., 2021) is produced, too (Bethlehem et al., 2013; Brownstein et al., 1980; Buijs et al., 2021; Ivell, 1986; Meyer-Lindenberg et al., 2011). From there, the neuropeptide is released centrally (Landgraf & Neumann, 2004; Leng et al., 2008; Neumann, 2007) and into the periphery via the circulation (Meyer Lindenberg et al., 2011). The mentioned functions are often well conserved across mammals (Bielsky & Young, 2004), in early vertebrates (Goodson, 2005; Gwee et al., 2009), and even in some invertebrate species (Odekunle & Elphick, 2020).
However, many of the results in the different domains, mostly but not exclusively, in humans, are marked by inconsistency and unsuccessful replication attempts (Audunsdottir et al., 2024; Brede et al., 2019; Declerck et al., 2020; Kosfeld et al., 2005; Sikich et al., 2021; Thienel et al., 2016), or appear to be highly dependent on (latent) context variables (Bartz et al., 2011; Ford & Young, 2022; Olszewski et al., 2016). More rigorous open science practices could help with reducing questionable research practices, increasing reproducibility and standardizing experimental designs. This indirectly promotes result consistency (Crüwell et al., 2019; Yamada, 2018). At the same time, the oxytocin research field is currently still lacking an overarching theoretical framework. The lack of such an interdisciplinary, comprehensive framework and the persistence of research conceptualized in isolated domains perpetuates heterogeneity in study designs, which leads to heterogeneity in outcomes (Muthukrishna & Henrich, 2019; Winterton, Westlye, et al., 2021). Adopting a more open scientific approach and reiterating on basic questions regarding a phenotype’s evolution, mechanisms, and physiology (Tinbergen, 1963) can aid with developing a comprehensive theory and with homogenizing findings. This in turn may aid with reconciling the scattered landscape of oxytocin research findings.
To this end, this doctoral thesis focused on exploring the oxytocin system from the ground up from an evolutionary genetics, imaging genetics, and meta-analytical perspective. A suite of different methods was chosen to represent the broad range of oxytocinergic properties and to cover a variety of ultimate and proximate angles. Open science principles were adopted wherever possible. Potential theoretical frameworks are discussed based on the findings and the reviewed literature. Paper I (Sartorius et al., 2024) assumed a comprehensive evolutionary perspective by delineating the timeline of the oxytocin signaling pathway genes over the course of the past 3.5 billion years using comparative genetics and positive selection analyses. The assigned evolutionary ages of each gene indicated that the majority of the pathway genes were modern (~64%), but that some genes were conserved in species as ancient as descendants of early cellular life. The analyses confirmed that OXT, OXTR, and CD38 emerged with the evolution of jawless and jawed vertebrates 540 – 530 million years ago. Modern oxytocin pathway genes were found to be enriched in muscle tissue and the brain, specifically in fronto cortical regions. In Paper II (Sartorius et al., 2026a), a specific aspect of the oxytocin systems physiology was investigated. The shared genetic architecture between oxytocinergic-vasotocinergic hypothalamus subunits and selected psychiatric/neurodevelopmental and metabolic traits was explored using bivariate mixture models, and subsequently functionally annotated. Moderate-to-extensive genetic overlap was found between all subunits and traits, on average more so between the subunits and psychiatric/neurodevelopmental than metabolic traits. The most extensive overlap, however, was found between the two anterior hypothalamic subunits and systolic blood pressure. The genes were up- and down-regulated in different tissues and enriched in gene sets related to cortical morphology and cognitive impairment. Given the lack of unanimity of study designs investigating and results describing oxytocin’s energy regulatory properties, Paper III (Sartorius et al., 2026b) was set out to synthesize data within this domain. Effects of exogenous oxytocin on caloric intake and appetite in healthy and clinical individuals were collected and pooled in a preregistered living systematic review and meta-analysis. Oxytocin administration was linked to appetite outcomes in some clinical populations, and to caloric intake conditional on the diagnostic group, that is, in patients with obesity. The results in healthy populations were inconclusive, possibly due to low power and high heterogeneity within and between the included studies.
Based on these findings and contemporary literature, five different potential theoretical frameworks were explored. This included among other the option that oxytocin could be a behavioral flexibility hormone (Quintana & Guastella, 2020; Walle et al., 2026), that it could be a hormone with the primary function to facilitate successful reproduction (Feldman & Bakermans-Kranenburg, 2017; Insel et al., 1997; Wathes & Swann, 1982), or that the current multifunctionality is rooted in conserved contractile and osmoregulatory properties that diversified during evolution. Beyond that, the clinical utility of the findings was discussed, as well as methodological considerations and future directions. For instance, the quality of invertebrate and vertebrate genomes was addressed together with further open science perspectives. Prospective studies may focus on exploring the ontogenic angle of the oxytocin system, and using the openly shared code and analysis pipelines from the three papers here to, for instance, explore bivariate mixture models with additional ‘social’ traits.
To conclude, the findings highlight the complexity of the oxytocin system – which goes beyond sociality – and the breadth of the undertaking of proposing an overarching theoretical framework for it. The results support the notion that the oxytocin signaling pathway is evolutionary conserved and evolved gradually, and that central oxytocin-vasotocin signaling may be connected to psychiatric/neuro developmental and metabolic traits by a shared set of genetic variants. The results also show that the hypothalamic peptide affects appetite in clinical groups, and corroborates that respective studies are underpowered and heterogenous, showcasing again the need for more open science and a unifying theoretical framework. While this thesis neither seeks nor claims to conclusively resolve the mysteries of the oxytocin system, its results aid in better understanding the endocrine system and add to the pool of knowledge to inspire future oxytocin research.
