The Sexual Selection of Endometriosis

Selection can generate risk of maladaptive extremes in sexually dimorphic and sex-limited traits. In humans, such extremes commonly manifest in diseases associated with sex and reproduction. Endometriosis involves endometrial tissue that proliferates at non-uterine sites. The proximate causes of endometriosis remain enigmatic, and its ultimate, evolutionary basis has only recently come under investigation. We propose and evaluate a new theory for helping to explain the evolution of endometriosis risk in humans. By this theory, endometriosis risk evolved in the context of sexual selection by males for high, relatively female-biased expression of sexually-dimorphic and female-limited phenotypes associated with high female reproductive fitness and low testosterone. The theory is supported by extensive data, from humans and non-human mammals, showing that: (1) endometriosis involves higher expression of major female-biasing genes, and lower expression of major male-biasing genes, that orchestrate prenatal sexual differentiation, including the genes Foxl2, Wnt4, Fst, Ctnnb1, Rspo1, Sox9 and Amh, (2) endometriosis and its correlates are associated with low prenatal and postnatal testosterone, both of which have female-biasing effects on traits, (3) low prenatal and postnatal testosterone, and endometriosis, are associated with relatively female-biased phenotypic expression for a large suite of sexually-dimorphic and sex-limited traits, (4) relatively female-biased expression of these traits is commonly associated with higher fertility and fecundity, (5) some traits, including female facial features, vocal pitch, and breast size, fit with all of the predictions of the model, though they have yet to be studied in relation to endometriosis, and (6) traits linked with low prenatal and postnatal testosterone (or high estradiol), and traits associated with endometriosis in humans, are preferred by males across multiple species of non-human mammals. Risk and symptoms of endometriosis thus appear to involve and represent, in art, maladaptive extremes of sexually selected female-limited and sexually-dimorphic traits. Such trait expression is mediated by genetic and environmental factors that bias development and physiology towards relatively low-testosterone and high-estradiol (as well as high-oxytocin) states. The hypothesis makes many testable predictions, and has direct implications for understanding the causes and treatment of endometriosis.