Is retrograde menstruation a universal, recurrent, physiological phenomenon? A systematic review of the evidence in humans and non-human primates.

STUDY QUESTION: What are the quantitative, qualitative, and temporal patterns of retrograde mentruation? SUMMARY ANSWER: The extreme quantitative and qualitative heterogeneity of the available studies prevents the definitive conclusion that retrograde menstruation is a universal and consistent phenomenon during the reproductive period. WHAT IS KNOWN ALREADY: Retrograde menstruation has been defined as a universal, physiological phenomenon that occurs similarly in about 90% of menstruators during the reproductive period. However, uncertainties still exist in terms of the event frequency, total amount, and cellular composition of retrograde menstruation and the differences between individuals with versus those without endometriosis. STUDY DESIGN SIZE DURATION: Two systematic reviews were performed, one for human studies, and one for non-human primate studies. We retrieved studies from the PubMed and Embase databases published between 1 January 1980 and 1 November 2023. Studies published in the English language were included and identified using a combination of MeSH terms. References from relevant publications were systematically screened and further articles were identified using PubMed's 'similar articles' and 'cited by' functions. PARTICIPANTS/MATERIALS SETTING METHODS: Results were reported in accordance with the PRISMA guidelines. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included human study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: Fifteen studies were finally included in the human systematic review, mostly with limited sample sizes. The macroscopic visualization of blood in PF during menses was reported with a frequency ranging from 9% to 100%. A prevalence of endometrial cells detected in peritoneal fluid ranging from 8% to 75% was reported in the various studies. Controversial findings were reported in relation to patients with endometriosis. Retrograde menstruation has been evaluated cross-sectionally on single occasions, and no information is available on the course of the phenomenon within an entire cycle and between subsequent cycles. Two studies were included in the non-human primate systematic review; one of them showed that retrograde menstruation was observed more frequently in baboons with naturally occurring endometriosis (83%) than in those with a normal pelvis (51%). LIMITATIONS REASONS FOR CAUTION: In humans, peritoneal fluid has often been collected at different cycle phases and not systematically during menstruation. The indication for laparoscopy was not always clear for all participants. A wide variety of methods were used to detect endometrial cells, including cytological staining, cell block analysis, immunocytochemistry, and various methods of cell culture. WIDER IMPLICATION OF THE FINDINGS: The idea that almost all women experience retrograde menstruation regularly and similarly during their reproductive life is currently unsubstantiated. It is an academic notion accepted uncritically. Development of endometriosis may derive from differences in the frequency or severity of the event. STUDY FUNDING/COMPETING INTERESTS: The review was partially funded by Italian Ministry of Health-Current Research IRCCS. P.Vi. serves as co-editor in Chief of Journal of Endometriosis and Uterine Disorders. E.S. serves as Editor in Chief of Human Reproduction Open and discloses research grants from Ferring, Ibsa, Gedeon Richter, and Theramex, and honoraria from Ibsa and Gedeon Richter. P.Ve. serves as Associate Editor for Human Reproduction Open; is a member of the Editorial Board of the Journal of Obstetrics and Gynaecology Canada, of the Italian Journal of Obstetrics and Gynaecology, and of the International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters on endometriosis management in the clinical decision support resource UpToDate; and maintains both a public and private gynecological practice. All other authors declare they have no conflict of interest. REGISTRATION NUMBER: N/A.

Functional determinants of uterine contractility in endometriosis and adenomyosis: A systematic review and meta-analysis.

IMPORTANCE: Evidence suggests that aberrant uterine contractility in nonpregnant women with endometriosis and adenomyosis contributes to symptoms and potentially heralds their pathogenesis. However, uterine peristalsis remains understudied, inconsistently measured, and poorly understood. OBJECTIVE: To summarize evidence on uterine contractility across the menstrual cycle phases in women with endometriosis and adenomyosis. DATA SOURCES: PubMed/MEDLINE, Embase and Scopus databases searched up to May 2nd, 2024. STUDY SELECTION AND SYNTHESIS: Observational studies compared quantitative measures of uterine contractility using MRI, ultrasound, electrophysiology or direct intrauterine pressure recording across different menstrual cycle phases between women with endometriosis/adenomyosis and controls based on pre-defined PICOS criteria. Study quality was assessed using the Newcastle-Ottawa Scale. Pooled estimates for primary (risk ratios (RR) with 95% confidence intervals (CIs)) and secondary outcomes (mean difference (MD) with 95% CIs) were calculated using random-effects models. MAIN OUTCOMES: Pooled risk of retrograde menstruation uterine contraction pattern in cases versus controls; pooled MD in continuous measures of uterine contractility (frequency, amplitude, and velocity of contractions) across all the menstrual cycle phases in cases versus controls. RESULTS: Nine studies met the inclusion criteria; most were studies that evaluated women with endometriosis. An increased risk of retrograde uterine contractions during menstruation was observed in women with endometriosis compared to controls (RR, 8.63; 95% CI, 3.24-22.95; I2=0%). The pooled MD in contraction frequency between cases and controls was 0.82 (95% CI, 0.13-1.52; I2=18.61%) in the menstrual phase and 0.52 (95% CI, 0.22-0.83; I2=27.18%) in the luteal phase. Results for the follicular and peri-ovulatory phases were more heterogeneous. Higher contraction amplitudes in women with endometriosis or adenomyosis were reported across all menstrual cycle phases. Due to the paucity of data, especially for adenomyosis, evidence certainty was graded as low for most comparisons. CONCLUSION AND RELEVANCE: The approximately 9-fold increased risk of retrograde pattern during menstruation in endometriosis supports the potential role of retrograde menstruation in its etiopathogenesis. Abnormal uterine contractility, likely not limited to the menstrual phase, may be a mechanical factor contributing to development of endometriosis and related symptoms, including menstrual pain and infertility, with limited, mostly concordant evidence for adenomyosis.

Impact of endometriosis on the ovarian follicles.

A significant body of evidence has supported a negative impact of endometriosis on ovarian follicles; however, the origin and relevance of this ovarian impairment in endometriosis is still a matter of debate. The ovarian damage can be caused by endometriosis itself or by surgeries aiming to remove endometriotic lesions. In this review, we summarized the existing knowledge on the mechanisms by which endometriosis can impact the ovarian follicles, from molecular to clinical points of view. From a molecular standpoint, the presence of endometriosis or its consequences can induce oxidative stress, inflammation, aberrant mitochondrial energy metabolism and inappropriate steroid production in granulosa cells, phenomena that may impair the quality of oocytes to variable degrees. These alterations may have clinical relevance on the accelerated exhaustion of the ovarian reserve, on the ovarian response to gonadotrophin stimulation in IVF cycles and on the competence of the oocytes. Critical points to be considered in current clinical practices related to fertility issues in endometriosis are discussed.

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

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.

Insights into the chaotropic tolerance of the desert cyanobacterium Chroococcidiopsis sp. 029 (Chroococcidiopsales, Cyanobacteria).

The mechanism of perchlorate resistance of the desert cyanobacterium Chroococcidiopsis sp. CCMEE 029 was investigated by assessing whether the pathways associated with its desiccation tolerance might play a role against the destabilizing effects of this chaotropic agent. During 3 weeks of growth in the presence of 2.4 mM perchlorate, an upregulation of trehalose and sucrose biosynthetic pathways was detected. This suggested that in response to the water stress triggered by perchlorate salts, these two compatible solutes play a role in the stabilization of macromolecules and membranes as they do in response to dehydration. During the perchlorate exposure, the production of oxidizing species was observed by using an oxidant-sensing fluorochrome and determining the expression of the antioxidant defense genes, namely superoxide dismutases and catalases, while the presence of oxidative DNA damage was highlighted by the over-expression of genes of the base excision repair. The involvement of desiccation-tolerance mechanisms in the perchlorate resistance of this desert cyanobacterium is interesting since, so far, chaotropic-tolerant bacteria have been identified among halophiles. Hence, it is anticipated that desert microorganisms might possess an unrevealed capability of adapting to perchlorate concentrations exceeding those naturally occurring in dry environments. Furthermore, in the endeavor of supporting future human outposts on Mars, the identified mechanisms might contribute to enhance the perchlorate resistance of microorganisms relevant for biologically driven utilization of the perchlorate-rich soil of the red planet.

Common loss of far-red light photoacclimation in cyanobacteria from hot and cold deserts: a case study in the Chroococcidiopsidales.

Deserts represent an extreme challenge for photosynthetic life. Despite their aridity, they are often inhabited by diverse microscopic communities of cyanobacteria. These organisms are commonly found in lithic habitats, where they are partially sheltered from extremes of temperature and UV radiation. However, living under the rock surface imposes additional constraints, such as limited light availability, and enrichment of longer wavelengths than are typically usable for oxygenic photosynthesis. Some cyanobacteria from the genus Chroococcidiopsis can use this light to photosynthesize, in a process known as far-red light photoacclimation, or FaRLiP. This genus has commonly been reported from both hot and cold deserts. However, not all Chroococcidiopsis strains carry FaRLiP genes, thus motivating our study into the interplay between FaRLiP and extreme lithic environments. The abundance of sequence data and strains provided the necessary material for an in-depth phylogenetic study, involving spectroscopy, microscopy, and determination of pigment composition, as well as gene and genome analyses. Pigment analyses revealed the presence of red-shifted chlorophylls d and f in all FaRLiP strains tested. In addition, eight genus-level taxa were defined within the encompassing Chroococcidiopsidales, clarifying the phylogeny of this long-standing polyphyletic order. FaRLiP is near universally present in a generalist genus identified in a wide variety of environments, Chroococcidiopsis sensu stricto, while it is rare or absent in closely related, extremophile taxa, including those preferentially inhabiting deserts. This likely reflects the evolutionary process of gene loss in specialist lineages.

Enabling deep-space experimentations on cyanobacteria by monitoring cell division resumption in dried Chroococcidiopsis sp. 029 with accumulated DNA damage.

Cyanobacteria are gaining considerable interest as a method of supporting the long-term presence of humans on the Moon and settlements on Mars due to their ability to produce oxygen and their potential as bio-factories for space biotechnology/synthetic biology and other applications. Since many unknowns remain in our knowledge to bridge the gap and move cyanobacterial bioprocesses from Earth to space, we investigated cell division resumption on the rehydration of dried Chroococcidiopsis sp. CCMEE 029 accumulated DNA damage while exposed to space vacuum, Mars-like conditions, and Fe-ion radiation. Upon rehydration, the monitoring of the ftsZ gene showed that cell division was arrested until DNA damage was repaired, which took 48 h under laboratory conditions. During the recovery, a progressive DNA repair lasting 48 h of rehydration was revealed by PCR-stop assay. This was followed by overexpression of the ftsZ gene, ranging from 7.5- to 9-fold compared to the non-hydrated samples. Knowing the time required for DNA repair and cell division resumption is mandatory for deep-space experiments that are designed to unravel the effects of reduced/microgravity on this process. It is also necessary to meet mission requirements for dried-sample implementation and real-time monitoring upon recovery. Future experiments as part of the lunar exploration mission Artemis and the lunar gateway station will undoubtedly help to move cyanobacterial bioprocesses beyond low Earth orbit. From an astrobiological perspective, these experiments will further our understanding of microbial responses to deep-space conditions.