Proposal for targeted, neo-evolutionary-oriented, secondary prevention of early-onset endometriosis and adenomyosis. Part I: pathogenic aspects

Abstract

The potential for repeated ovulation and menstruation is thought to have provided a Darwinian advantage during the Palaeolithic. Reproductive conditions remained relatively stable until the pre-industrial era, characterized by late menarche, very young age at first birth, multiple pregnancies, and prolonged periods of lactational amenorrhoea. For hundreds of thousands of years, menstruators experienced few ovulatory cycles, even though they were genetically adapted to ovulate and menstruate every month. In the post-industrial era, the age at menarche gradually declined, the age at first birth progressively increased, and breastfeeding became optional and often of short duration. This created a mismatch between genetic adaptation and socio-environmental evolution, so that what was initially a probable reproductive advantage subsequently contributed to increased susceptibility to diseases associated with lifetime oestrogen exposure, such as ovarian, endometrial and breast cancer and, hypothetically, also those associated with the number of ovulatory menstruations, such as endometriosis and adenomyosis. The incidence of endometriosis shows a steep and progressive increase around the age of 25 years, but given the consistently reported delay in diagnosis, the actual incidence curve should be shifted to the left, supporting the possibility that the disease has its roots in adolescence. This raises the question of whether, from an evolutionary point of view, anovulation and amenorrhoea should not still be considered the physiological state, especially in the postmenarchal period. However, an increase in the frequency of endometriosis in recent decades has not been demonstrated, although this deserves further epidemiological investigation. In addition, as endometriosis occurs in a minority of individuals exposed to retrograde menstruation, other important pathogenic factors should be scrutinised. Research should be resumed to explore in more detail the transtubal reflux of not only blood, but also endometrial cells, and whether they are systematically present in the peritoneal fluid after menstruation. If repetitive ovulatory menstruation during the early reproductive years is shown to increase the risk of endometriosis and adenomyosis development and progression in susceptible individuals, hormonal interventions could be used as secondary prevention in symptomatic adolescents.

Endometriosis: from iron and macrophages to exosomes. Is the sky clearing?

“…For more than 20 years now, we have been claiming that iron plays a crucial role in endometriosis ( Van Langendonckt et al , 2002a , b ) and advocating use of iron chelators, since they were shown to prevent initiation and progression of the disease in murine models ( Defrère et al , 2011 ). Despite our findings, iron chelators were never developed in clinical research for treatment of endometriosis, but the role of highly toxic Hb by-products like iron was highlighted in two recent reviews published by Wyatt et al (2023) and Vercellini et al (2024) .…”

“…Determining the pathogenesis of endometriosis remains a challenge for gynecologists, reproduction specialists, endocrinologists, and researchers alike. Multifactorial causes have been reported, including ectopic endometrial tissue, altered immunity, unbalanced cell proliferation and apoptosis, oxidative stress and reactive oxygen species (ROS), aberrant endocrine signaling, and genetic factors ( Bulun et al , 2019 ; Kapoor et al , 2021 ; Taylor et al , 2021 ; Donnez and Cacciottola, 2022 ; Vercellini et al 2024 ). However, a very comprehensive understanding is needed to detect and investigate the physiological, cytological and immunological events, as well as biochemical factors like oxidative stress and inflammation, encountered in the pelvic microenvironment of endometriosis patients.…”

Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance

“…Certain risk factors like a larger number of ovulatory cycles (early menarche/late menopause) [13], less pregnancies (infertility, nulliparity) [14], and a shorter breastfeeding duration [15] contribute to the malignant transformation of endometriosis into ovarian cancer [16]. Generally, a hormonal imbalance with an estrogen excess and progesterone deficit promotes the development of EOAC [17].…”

Is Neonatal Uterine Bleeding Involved in Early-Onset Endometriosis?

“…Consequently, they concluded that the role of retrograde menstruation should not be taken for granted, as it has not been conclusively proven. This has implications when considering the pathogenesis of EOE [40]. Another important but poorly understood question is the duration of time needed from first exposure to retrograde menstruation to disease development.…”