The persisting presence of absence in female sex development: a critical interdisciplinary reflection.

backgroundFor much of the 20th-century, developmental endocrinology was structured around a binary model that positions male differentiation as an active, hormone-driven process and female development as the passive consequence of androgen absence. This framework has profoundly shaped both experimental practice and conceptual understanding in reproductive and developmental biology. Yet, empirical evidence in molecular endocrinology, combined with insights from feminist science studies and the history of science, invites a revitalization of the long-standing critique of the persistence of this model. MAIN BODY: This review critically re-interrogates the longstanding notion of female sex development as an outcome of mere androgen deprivation. First, through a historical analysis of key experimental systems in 20th-century embryological endocrinology, we trace how this conceptual pattern emerged and became stabilized within the discipline. We show how the methodological privileging of androgenic mechanisms over other hormonal pathways contributed to defining femaleness as absence. Second, drawing on research in developmental and molecular endocrinology, we review the roles of oestrogens and their receptors in mammalian female genital development. Synthesizing these findings, we support a less reductionist model that opens the possibility to more research on oestrogen-dependent female sex differentiation and defines female sex development as an active, regulated process rather than a default state. Finally, we situate the 'absence' model of femaleness within its broader cultural and symbolic contexts. Through a material-semiotic analysis, we demonstrate how scientific concepts of sex are co-constituted with wider social meanings, and how this interplay shapes what is rendered visible or invisible in biological research.

conclusionEmerging from a multidisciplinary dialogue between biomedicine, the history of science, and feminist science studies, our review highlights how cultural assumptions of gender are embedded within scientific practices of analyzing sex-differences. By integrating reflexive humanities perspectives with empirical biomedical research, we argue for a more accurate and equitable understanding of female development - one that recognizes oestrogenic activity as central to sex differentiation and challenges the reduction of femaleness to hormonal absence. This cross-disciplinary engagement illustrates the transformative potential of re-examining foundational scientific paradigms through collaborative, critical inquiry. Research on how sex develops in mammals was based for a long time on a simple binary model: male development is an active process driven by androgens, while female development happens passively when these hormones are absent. Our article re-challenges this long-standing view by referring to the history of the concept of female sex development as a passive process and reinforcing the critical works already available on its continued persistence. First, we trace how this 'female as absence' model emerged in 20th-century developmental endocrinology. Second, we review empirical evidence showing that oestrogens and their receptors play active roles in shaping female genital development, and we present a model of oestrogen-dependent pathways in this process. Third, we situate the idea of femaleness as absence within its wider cultural and symbolic background, showing how scientific concepts are influenced by historical and social meanings. Bringing together perspectives from biomedicine, the history of science, and feminist science studies, we use a multidisciplinary dialogue to show how gender bias becomes embedded in both research design and clinical interpretation. Recognizing these biases is not only a matter of scientific precision but also of improving health outcomes - for example, in the diagnosis and care of people with differences of sex development or in the advancement of women's health.