Paolo Vercellini’s research while affiliated with Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico and other places

Introduction: In recent years, dietary supplements have emerged as popular "natural" alternatives to conventional pharmacological treatments for various conditions, including endometriosis. The growing popularity of supplements for endometriosis-associated pain, fueled by an expanding and minimally regulated market, underscores the need for robust evidence of efficacy, as a prerequisite for any consideration on effectiveness. This meta-analysis synthesizes evidence from randomized, placebo-controlled trials (RCTs), the gold standard in evidence-based medicine, to assess the efficacy of dietary supplements in endometriosis-associated pain. Methods: A systematic search of PubMed, Embase, Scopus, and the Cochrane Library was conducted up to November 5th, 2024, in adherence to PRISMA 2020 guidelines. Two independent reviewers screened studies using PICOS criteria: reproductive-age women with endometriosis (Population), dietary supplements (Intervention), placebo (Comparator), and pain-related outcomes (Outcomes), assessed in placebo-controlled RCTs adhering to CONSORT standards (Study type). Three pain domains were evaluated: i) symptom severity (visual analogue scale (VAS) for pelvic pain, dysmenorrhea, dyspareunia), ii) pain catastrophizing, and iii) quality of life (QoL), as measured by the Short Form-12 Health Survey (SF-12) and the Endometriosis Health Profile-30 (EHP-30). Risk of bias was assessed using the Cochrane RoB2 tool. Random-effects models were used to calculate pooled mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed with the I² statistic, and subgroup analyses explored clinically relevant confounders. Sensitivity analyses excluded studies with conflicts of interest or trustworthiness issues, as defined by the Obstetrics and Gynecology Editors' Integrity Group (OGEIG). Publication bias was evaluated using Egger’s test, Begg’s test, and the trim-and-fill method. All analyses were conducted using STATA version 18. Results: Nine RCTs (n=545 subjects; 274 in the treatment group and 271 in the placebo group) were included. Only three met the ‘absolute’ OGEIG trustworthiness criteria. No significant differences were observed between supplements and placebo for pelvic pain (pooled MD: -1.1; 95% CI, -3.0 to 0.8; I²=96.1%), dysmenorrhea (pooled MD: -2.0; 95% CI, -4.4 to 0.5; I²=93.8%), or dyspareunia (pooled MD: -2.0; 95% CI, -4.9 to 0.9; I²=96.5%). These findings remained consistent when the analysis was restricted to studies without conflicts of interest, those authored by researchers with no retractions, and those meeting OGEIG trustworthiness criteria. Subgroup analyses reduced heterogeneity and confirmed no significant benefits. Pain catastrophizing and quality-of-life measures showed little to no improvement. Conclusion: While limited evidence precludes definitive conclusions about specific dietary supplements, available data suggests they lack efficacy for managing endometriosis-associated pain. Given the absence of demonstrated benefits, along with potential harms and costs, dietary supplements should not be recommended at this time for managing endometriosis-related pain. Study registration: PROSPERO ID CRD42024607058.

STUDY QUESTION In patients with Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS; population), is the presence of functional endometrium (FE) in uterine remnants (URs) (exposure), compared with the absence of FE in UR/absence of UR (comparison), associated with a higher prevalence of endometriosis (outcome)? SUMMARY ANSWER The aggregate prevalence of endometriosis was considerably higher in MRKHS patients with FE (MRKHSFE+) than in those without FE (MRKHSFE−). WHAT IS KNOWN ALREADY The pathogenesis of endometriosis is not fully understood. The finding of pelvic endometriosis in patients with MRKHS is one of the main objections to the retrograde menstruation (RM) hypothesis. The recent advent of high-resolution ultrasonography and magnetic resonance imaging (MRI) allowed the reliable preoperative identification of FE concealed within UR, and histopathological examination after UR removal is no longer the only means of verifying the presence of a mucosal component. A similar prevalence of endometriosis in MRKHSFE+ and MRKHSFE− patients, as assessed by preoperative ultrasound (US) and/or MRI, would essentially rule out the RM/implantation theory, whereas a substantially higher prevalence of endometriosis in MRKHSFE+ than in MRKHSFE− patients would challenge the embryonic remnants/coelomic metaplasia hypothesis. STUDY DESIGN, SIZE, DURATION This systematic review was restricted to full-length, English-language articles published in peer-reviewed journals between 1 January 1980 and 1 June 2024. The electronic PubMed and Embase databases were searched in June 2024. The keyword ‘endometriosis’ was used in combination with ‘Mayer–Rokitansky–Küster–Hauser syndrome’, ‘Müllerian agenesis’, ‘uterine agenesis’, ‘vaginal agenesis’, ‘Müllerian anomalies’, and ‘female genital malformations’. References from relevant publications were screened, and PubMed’s ‘similar articles’ and ‘cited by’ functions were used. PARTICIPANTS/MATERIALS, SETTING, METHODS Studies were selected if they reported the presence or absence of FE within UR investigated by preoperative US or MRI or histology after surgical removal, and the presence or absence of surgically confirmed endometriosis. Case series and case reports were deemed eligible for inclusion. Studies not specifically stating the intent to search for the presence of endometrium within UR, or not reporting the results of ultrasonography or MRI, or histological examinations were excluded. Two reviewers independently abstracted data. The risk of bias was assessed using a tool specifically devised to ascertain the methodological quality of case series and case reports. MAIN RESULTS AND THE ROLE OF CHANCE A total of 102 studies (29 case series and 73 case reports), comprising 666 MRKHS patients in whom the presence or absence of FE was verified were included. Endometriosis was detected in 71 participants (10.7%; 95% CI, 8.5–13.2%), and its prevalence was 8.6% (51/593; 95% CI, 6.6–11.2%) in case series and 27.4% (20/73; 95% CI, 18.4–38.6%) in case reports (P<0.0001). When considering only the 19 case series with ≥10 participants, the proportion of MRKHS patients with endometriosis was 3.4% (41/1219; 95% CI, 2.5–4.5%). Among the 71 MRKHS patients with endometriosis, 64 had coexisting FE, and only seven had no evidence of FE within UR or did not have UR. The proportion of patients with endometriosis was 32.0% in the subgroup with FE (64/200; 95% CI, 25.9–38.8%) and 1.5% (7/466; 95% CI, 0.7–3.1%) in the subgroup without FE within UR/without UR. At meta-analysis considering case series, the overall prevalence estimates of endometriosis in patients with and without FE were, respectively, 16.8% (95% CI, 1.8–38.5%) and 0% (95% CI, 0–0%). In order to evaluate the association between FE and endometriosis we also conducted a meta-analysis that included case series reporting both FE+ and FE− patients. A significantly increased risk of endometriosis was observed in MRKHSFE+ patients compared with MRKHSFE− patients (overall odds ratio estimate was 12.0; 95% CI, 5.1–28.3%). The quality of the evidence score was higher in the case series subgroup (median score, 4 points; interquartile range, 3–5 points) than in the case reports subgroup (median score, 3 points; interquartile range, 2–4 points). LIMITATIONS, REASON FOR CAUTION Due to the uncontrolled and non-experimental study design, case series and case reports are associated with an increased risk of selection, performance, detection, attrition, and reporting bias. In the seven cases of endometriosis in patients purportedly without detected FE, a preoperative MRI was not systematically performed or erroneous findings were reported, the anatomical description at surgery was incomplete or inconsistent, the histopathological diagnosis of endometriosis was missing or questionable, and precise microscopic features were not always described. Whether FE (exposure) was truly absent in all these cases and/or whether all lesions diagnosed as endometriosis (outcome) were indeed true disease, seems uncertain. WIDER IMPLICATIONS OF THE FINDINGS Our findings should raise awareness of the importance of accurately assessing and reporting the presence or absence of FE within UR, and of systematically performing biopsies of visually diagnosed endometriosis in MRKHS patients. Considering the high risk of bias, the detection of endometriosis in MRKHS patients allegedly without FE in the few relevant case reports published in the last four decades should no longer be interpreted tout court as proof for the coelomic metaplasia/embryonic remnants theory. STUDY FUNDING/COMPETING INTEREST(S) No funding was received for this review. P.Ve. is a member of the Editorial Board of Human Reproduction Open, the Journal of Obstetrics and Gynaecology Canada, and 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 gynaecological practice. E.S. is Editor-in-Chief of Human Reproduction Open; discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures; and maintains both a public and private gynaecological practice. P.Vi. is Co-Editor-in-Chief of Journal of Endometriosis and Uterine Disorders. All other authors declare they have no conflict of interest. REGISTRATION NUMBER The study protocol was registered on PROSPERO (registration number, CRD42024512351).

Linked article: This Correspondence comments on Knez et al. Click here to view the article.

Across studies, the percentage of individuals reporting regularly engaging in menstrual coitus ranges between 4% and 43%. Although no clinical guideline recommends avoiding sexual activity during menstruation, according to some researchers such practice may favor both retrograde menstruation and sexually transmitted diseases, two phenomena that are thought to play a role in endometriosis’ pathogenesis. Given this background, we analyzed the existing evidence regarding the association between menstrual coitus and the prevalence of endometriosis by conducting a PubMed database search on February 15, 2024. We considered all original, full-length studies written in English. Results were conflicting. When interviewing 489 infertile women, Filer and Wu found that the frequency of surgically diagnosed endometriosis was significantly higher among those engaging in menstrual coitus (17.5% versus 10.9%; p < 0.05). In their case-control study on 555 women with (n = 185) and without (n = 370) endometriosis, Mollazadeh and co-workers confirmed an increased risk of endometriosis among those engaging in menstrual coitus compared to those who did not (OR 5.23; 95% CI 2.16–12.66). However, in Meaddough and colleagues’ retrospective case-control study on 2012 women, with (n = 1517) and without (n = 495) endometriosis, menstrual coitus was significantly less frequent in women with endometriosis compared to controls (27% versus 35%; p = 0.002). Treloar and co-workers also failed to prove such an association. The evidence available at the present moment is insufficient to confirm the hypothesis that menstrual coitus plays a role in the pathogenesis of endometriosis.

Recent research has proven that peripheral (PS) and central sensitization (CS), mental health, and myofascial dysfunction all play a role, alongside nociception, in the genesis and in the perpetuation of endometriosis’ symptoms. However, such components of pain are still largely ignored in clinical practice, although not considering such contributors may entail serious consequences on women’s health, including the choice of unnecessary surgery and leaving the real causes of pain untreated. At the present time, we are facing a paradox by which 25–40% of women who undergo laparoscopic surgery for pelvic pain do not have an obvious diagnosis, while the percentage of women with endometriosis who have signs of CS, of depressive or anxiety disorders, or who have an increased pelvic muscle tone ammounts to 41–55%, 15–88% and 28–73%, respectively. Moving from the widely-accepted stepwise approach suggested for endometriosis management, which consists in the initial prescription of low-dose combined oral contraceptives (COCs) or of a progestin monotherapy, followed by GnRH analogues and, ultimately, by surgery, when COCs and progestins have proven ineffective or are not tolerated or contraindicated, we propose an integration of such model which takes into account the identification and the simultaneous treatment of all pain contributors. Our objective is to encourage physicians’ awareness of the need of a multidisciplinary, multimodal approach to endometriosis-related pain, and ultimately to promote a reduction in the number of unnecessary surgeries.

Background: No conceptually new drugs for the safe and successful cure of endometriosis are likely to become available soon. Hormonal modulation of ovarian function and suppression of menstruation remain the pillars of disease control. However, existing drugs may be used following novel modalities to limit the consequences of endometriosis progression. Objectives: The aims of this review were to propose a pharmacological approach aimed at limiting the potential detrimental effects of the recent dramatic increase in postmenarcheal repetitive ovulatory menses and to define the type of hormones and the routes of administration that can be used to maximize safety and tolerability in the medical treatment of endometriosis. Methods: For this narrative review, we selected the best quality evidence, prioritizing RCTs, systematic reviews, meta-analyses, network meta-analyses, and international guidelines, preferably published in the last decade. Outcome: Medical treatment of endometriosis should be included into all aspects of prevention. Very-low-dose combined oral contraceptives can be used for years to counteract the increased risk of ovarian cancer observed in patients with endometriosis. This primary prevention measure saves lives and can effectively integrate targeted risk-reducing surgery. Secondary pharmacological prevention, based on a working diagnosis of early onset adenomyosis-endometriosis selectively in adolescents with severe dysmenorrhea and heavy menstrual bleeding, can potentially impede the development of advanced disease forms, and reduce the need for management of complications due to a delay in diagnosis and treatment. Tertiary prevention, i.e., medical therapy of established disease, is based initially on the safest available estrogen-progestogen combinations and progestogen monotherapies. Whenever possible, ethinyl estradiol and cyproterone acetate should be avoided because of thromboembolic and meningioma risks, respectively. Estradiol can be administered transdermally. Switching to gonadotropin-releasing hormone agonists and antagonists should not be delayed when the first-line agents fail. Conclusions and outlook: Two-thirds of symptomatic endometriosis patients can be managed satisfactorily for many years using, with the right modality, the existing safe, effective, and well-tolerated medications. Despite the constant plea for new drugs, this already appears to be an excellent clinical outcome, unsurpassed when managing other human chronic inflammatory diseases. Cohort studies are needed to verify whether turning off the recurrent inflammation caused by repeated ovulation and menstruation could also affect the risk of systemic conditions associated with endometriosis.