Variation among human populations in endometriosis and PCOS A test of the inverse comorbidity model

Evidence linking endometriosis to low prenatal testosterone, and evidence that risk of polycystic ovary syndrome (PCOS) is associated with high prenatal testosterone, have motivated the hypothesis that endometriosis and PCOS exhibit inverse comorbidity. The inverse comorbidity hypothesis predicts that populations exhibiting higher prevalence of one disorder should show lower prevalence of the other. To test this prediction, data were compiled from the literature on the prevalence of endometriosis and PCOS, levels of serum testosterone in women during pregnancy and digit ratios as indicators of prenatal testosterone, in relation to variation in inferred or observed population ancestries. Published studies indicate that rates of endometriosis are highest in women from Asian populations, intermediate in women from European populations and lowest in women from African populations (i.e. with inferred or observed African ancestry); by contrast, rates of PCOS show evidence of being lowest in Asian women, intermediate in Europeans and highest in individuals from African populations. Women from African populations also show higher serum testosterone during pregnancy (which may increase PCOS risk, and decrease endometriosis risk, in daughters), and higher prenatal testosterone (as indicated by digit ratios), than European women. These results are subject to caveats involving ascertainment biases, socioeconomic, cultural and historical effects on diagnoses, data quality, uncertainties regarding the genetic and environmental bases of population differences and population variation in the causes and symptoms of PCOS and endometriosis. Despite such reservations, the findings provide convergent, preliminary support for the inverse comorbidity model, and they should motivate further tests of its predictions. Lay Summary: Given that endometriosis risk and risk of polycystic ovary syndrome show evidence of having genetically, developmentally, and physiologically opposite causes, they should also show opposite patterns of prevalence within populations: where one is more common, the other should be more rare. This hypothesis is supported by data from studies of variation among populations in rates of endometriosis and PCOS and studies of variation among populations in levels of prenatal testosterone, which mediaterisks of both conditions.