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Cited by 12Endometriosis Research and TreatmentEvolutionary Psychology and Human BehaviorGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

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The sexual selection of endometriosis.

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Crespi, Bernard, Dinsdale, Natalie L.·2023·Evolutionary Behavioral Sciences
DOI 10.1037/ebs0000275
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Abstract

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 part, 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.(7) increased paternal care, which is expected to generate selective conditions favoring male choice of relatively fertile and fecund females (Hrdy, 2009);(8) the evolution of higher levels of monogamy and guarding of females by males (Schacht and Kramer, 2019), which can reinforce male choice and select for male choice of relatively-young females with high nubility and reproductive value (Lassek and Gaulin, 2019) who can be controlled and 'owned' by males for long periods of time (Hrdy, 1997) and ( 9) the recent evolution of reduced hair, eye and skin pigmentation in some populations, which influences availability and metabolism of the key reproductive nutrients vitamin D, folate, and calcium (Parra, 2007;Jablonski and Chaplin, 2017), and which generates new phenotypic and genetic substrates for sexual selection.A final factor important to the current prevalence of endometriosis is evolutionary mismatch, between adaptations to past environmental conditions, and environments that have changed too rapidly for selection and response to selection to track them.By this hypothesis, the current notably high prevalence of endometriosis in women, about 5-10%, is driven by recent secular trends towards earlier menarche and later age of first reproduction, both of which increase numbers of the menstrual cycles that increase the potential for retrograde flow and estrogenic stimulation of endometrial tissue growth.This hypothesis is consistent with epidemiological data linking endometriosis risk with correlates of numbers of menstruations (Scioscia et al., 2019), although directionalities of causality remain unclear because genes underlying endometriosis are also pleiotropically associated with earlier menarche (Ponomarenko et al., 2020).The presence of such mismatch would be expected to exacerbate, rather than generate de novo, the symptoms and severity of endometriosis.

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  • In Mongolian gerbils, female fetuses flanked by either one or no males while in utero had lower postnatal adult serum testosterone, earlier onset of estrus and shorter cycles than female fetuses that were flanked by two males in utero.

    “In Mongolian gerbils, female fetuses flanked by either one or no males while in utero had lower postnatal adult serum testosterone, earlier onset of estrus and shorter cycles than female fetuses that were flanked by two males in utero.27”

    From Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone (2023) · cites this paper as [27]

    The gerbil entry in Additional information (page unavailable) reports that 2M females had later estrus, longer cycles, and higher testosterone than 0M and 1M females, supporting the comparisons. It does not specify that the testosterone measured was postnatal adult serum testosterone. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Female laboratory mice with no adjacent male fetuses, and thus lower exposure to prenatal testosterone, exhibit shorter AGDs, lower postnatal serum testosterone, earlier vaginal opening, and shorter and more regular cycles, compared with females flanked by one or two males in utero.

    “Female laboratory mice with no adjacent male fetuses, and thus with lower exposure to prenatal testosterone, exhibit shorter AGDs, lower postnatal serum testosterone, earlier vaginal opening, and shorter and more regular cycles, when compared with females flanked by one or two males in utero (reviewed in Crespi and Dinsdale27).”

    From Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone (2023) · cites this paper as [27]

    The laboratory-mouse table in Additional information reports that 0M females had lower prenatal testosterone, shorter AGDs, earlier vaginal opening, and shorter, more regular estrus cycles than 2M females. The passage does not establish lower postnatal serum testosterone in these mice, and the stated comparisons for those traits are with 2M females, not also 1M females. Section 4.6 supports the broader association between low prenatal testosterone and earlier opening or shorter, more regular cycles in mice. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Female rats subject to lower testosterone in utero exhibit shorter AGDs, earlier vaginal opening, and shorter estrus cycles.

    “Similarly, female rats subject to lower testosterone in utero exhibit shorter AGDs, earlier vaginal opening, and shorter estrus cycles.”

    From Prenatal Origins of Endometriosis Pathology and Pain: Reviewing the Evidence of a Role for Low Testosterone (2023) · cites this paper as [27]

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Metadata

Authors
Crespi, B., & Dinsdale, N. L.
Affiliations
Simon Fraser University (CA)
ORCID
Venue
Evolutionary Behavioral Sciences
Publisher
American Psychological Association (APA)
Published
2023-04
Volume
17
Issue
2
Pages
123-170
ISSN
  • 2330-2925 (ISSN-L)
  • 2330-2933
DOI
10.1037/ebs0000275
OpenAlex
W3202306738
Cited by
12
References
0
Citations by year
2025: 5 · 2024: 4 · 2023: 1
FWCI
1.51
Type
journal article
Language
en
Open access
Locations
  • Evolutionary Behavioral Sciences (publishedVersion)
  • Summit (Simon Fraser University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Evolutionary Psychology and Human Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
endometriosis, sexual selection, sexually dimorphic traits, sex-limited traits, prenatal testosterone, androgen deficiency, female reproductive fitness, FOXL2, Wnt4, FST, CTNNB1, RSPO1, SOX9, anti-Müllerian hormone, estradiol, oxytocin, paternal care, fecundity

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