Hyperestrogenic Imprinting and Developmental Origins of Endometriosis and Adenomyosis

Abstract

The pathogenesis of endometriosis and adenomyosis remains incompletely understood, and a notable gap persists between the reported heritability and the disease variation explained by identified susceptibility loci. In this manuscript, we showcase key epidemiological and clinical observations—including associations with early menarche, shorter anogenital distance, specific childhood growth trajectories, hypospadias in males, and developmental exposure to endocrine-disrupting chemicals-—that collectively point to the influence of early-life developmental programming. Recent evidence revealing a hyperestrogenic/hypoandrogenic hormonal imbalance in the umbilical cord blood of pregnant women with endometriosis provides a critical link between these seemingly disparate findings. We propose a novel hypothesis of hyperestrogenic imprinting: Female offspring of women with endometriosis and/or adenomyosis are exposed in utero to a distinct hormonal environment, which induces lasting epigenetic changes in the developing reproductive tract, thereby imprinting a lifelong susceptibility to these two diseases. This mechanism offers a cohesive explanation for the familial aggregation of endometriosis and possibly adenomyosis, addresses the issue of “missing heritability”, and integrates various risk factors rooted in early development. A limitation of this opinion piece is that its hypothesis is primarily informed by animal studies and conceptual synthesis, and would benefit from further validation through original human data. As a falsifiable hypothesis, it presents a clear pathway for future validation and, if proven, opens avenues for novel preventive strategies.