Hyperestrogenic imprinting and developmental origins of endometriosis and adenomyosis.

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.