Table 2.

Applying the Bradford Hill (1965) criteria for causation to reiterative ovulatory menstruation and endometriosis-adenomyosis.

Criterion	Strength of evidence*	Argument for fulfilment	Supporting citations
Strength	++	Consistent associations have been observed between age at menarche, regular cycles, and heavy menstrual flow, i.e. indicators of pelvic exposure to refluxed endometrium, and endometriosis	Cramer et al. (1986), Darrow et al. (1993), Parazzini et al. (1995, 2017), Vercellini et al. (1997), Missmer and Cramer (2003), Missmer et al. (2004), Viganò et al. (2004), Treloar et al. (2010), Nnoaham et al. (2012), Hoppenbrouwers et al. (2016), Shafrir et al. (2018), and Lu et al. (2023).
Consistency	++	The above associations have been observed by independent groups in different countries	Missmer and Cramer (2003), Missmer et al. (2004), Viganò et al. (2004), Nnoaham et al. (2012), Hoppenbrouwers et al. (2016), Parazzini et al. (2017), Shafrir et al. (2018), and Lu et al. (2023).
Specificity	++	Although exceptions have been described, in the vast majority of cases adenomyosis and endometriosis develop and progress in menstruators. The distribution of endometriotic lesions is consistent with the dissemination of refluxed endometrial glands according to anatomical and physiological determinants	Vercellini et al. (1998, 2007, 2014), Missmer and Cramer (2003), Viganò et al. (2004), Parazzini et al. (2017, 2020), and Shafrir et al. (2018).
Temporality	+++	Excluding anecdotal cases, adenomyosis and endometriosis are diagnosed after a variable number of years of repetitive ovulatory menstruations	Missmer and Cramer (2003), Missmer et al. (2004), Parazzini et al. (2017), Shafrir et al. (2018), Zondervan et al. (2018, 2020), Bulun et al. (2019, 2021, 2023), Guo (2020, 2023), Wang et al. (2020), Koninckx et al. (2021b), Taylor et al. (2021), Horne and Missmer (2022), and Kobayashi (2023a).
Biological gradient	++	A dose–response relationship has been observed between the number of ovulatory menses and the amount of menstrual flow and the risk of endometriosis	Darrow et al. (1993), Vercellini et al. (1997), Missmer and Cramer (2003), Missmer et al. (2004), Viganò et al. (2004), Matalliotakis et al. (2008), and Parazzini et al. (2017).
Plausibility	+++	An large amount of data supports the mechanistic role of reiterative ovulatory menstruation in the pathogenesis of both adenomyosis and endometriosis	Zondervan et al. (2018, 2020), Bulun et al. (2019, 2021, 2023), Guo (2020, 2023), Wang et al. (2020), Koninckx et al. (2021b), Taylor et al. (2021), Horne and Missmer (2022), and Kobayashi (2023a).
Coherence	++	Epidemiological observations are consistent with several laboratory studies	Greaves et al. (2014), Shen et al. (2016), Zhang et al. (2017), Kusama et al. (2021), and Cordeiro et al., (2022).
Experiment	+	Experimental evidence exists for the validity of pelvic iron overload and secondary oxidative stress as determinants of chronic inflammation and fibrosis. No randomized, controlled trials have been conducted on the effect of early menstrual suppression and risk of endometriosis and adenomyosis	Van Langendonckt et al. (2002a,b), Lousse et al. (2009, 2012), Donnez et al. (2016), Ng et al. (2020), Ansariniya et al. (2022), Kobayashi (2023b), and Wyatt et al. (2023).
Analogy	++	The same pathogenic mechanism (i.e. retrograde menstruation) is supported by epidemiological and laboratory findings in different benign (endometriosis and adenomyosis) and malignant (serous, endometrioid and clear cell ovarian cancer) diseases. In addition, exposure for decades to high oestrogen levels due to reiterative ovulations facilitates the onset of both benign and malignant hormone-sensitive diseases such as endometriosis and adenomyosis as well as breast and endometrial cancer.	Macmahon et al. (1982), Vihko and Apter (1984), Viganò et al. (2004), Vercellini et al. (2006, 2011), Seidman (2013), Lattuada et al. (2015), Huang et al. (2016), Uberti et al. (2016), Farland et al. (2017b), Rockfield et al. (2019), Chhabra et al. (2021), and Bieuville et al. (2023).

 * Strength of evidence: + weak; ++ moderate; +++ strong.