Lower testosterone as a cause of endometriosis

Two recent genomic studies have demonstrated that lower genetically-predicted testosterone is associated with higher risk of endometriosis. These results are concordant with a suite of additional findings, including: (1) links of endometriosis and its correlates with shorter anogenital distance (an indicator of lower prenatal testosterone), (2) higher pain sensitivity under lower testosterone in humans and animal models, (3) associations of lower testosterone levels with key endocrine correlates of endometriosis, including lower antimullerian hormone, luteinizing hormone, and β-endorphin, and (4) data from animal models showing that development under lower prenatal testosterone results in shorter anogenital distances, earlier onset of estrus, and more-regular ovulatory cycles. Taken together, this evidence supports a 'two-hit' model of endometriosis, whereby low prenatal testosterone differentially programs the hypothalamic-pituitary-ovarian axis in such a way as to increase vulnerability, and low adult testosterone, combined with early menarche, high pain sensitivity, and other genetic and environmental factors, leads to increased rates of endometriosis in high-risk women. Most importantly, these genetic and phenotypic findings suggest that endometriosis represents a disorder of low testosterone as well as high estrogen, and indicate that additional studies of testosterone levels and effects in women with endometriosis are urgently needed.