Editorial: Endometriosis: a fertility perspective

Understanding the molecular heterogeneity of endometriosis is essen7al for moving toward precision medicine. Situmorang et al. highlighted that the disease's three main phenotypessuperficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltra7ng endometriosis (DIE) -are driven by dis7nct gene ac7va7on profiles. Their findings suggest that DIE is characterized by invasive fibro7c pathways (e.g., FN1, MMP2), while OMA is dominated by oxida7ve stress and iron metabolism regulators, reflec7ng biologically unique en77es rather than simple anatomical varia7ons.Further exploring internal regulatory systems, Olabarrieta et al. inves7gated the endogenous opioid system as a modulator of uterine physiology. They proposed that dysregulated opioid signaling might impair 7ssue remodeling, angiogenesis, and apoptosis, closely mirroring the mechanisms altered in endometriosis-associated subfer7lity. Addi7onally, the regula7on of the corpus luteum (CL) -vital for maintaining early pregnancy -was reviewed by Tariq et al., who detailed how integrated hormonal, metabolic (AMPK-PPARγ), and epigene7c pathways (EZH2mediated histone methyla7on) control CL func7on and poten7al luteal insufficiency.The impact of the external environment and systemic health on fer7lity cannot be overlooked. Iavarone et al. conducted an exploratory study on lead concentra7ons in follicular fluid, finding significantly higher levels in infer7le pa7ents with endometriosis compared to controls. This suggests that heavy metal accumula7on might parallel the disease's pathogenesis and nega7vely affect oocyte quality.Simultaneously, systemic markers such as Body Mass Index (BMI) have been scru7nized for their predic7ve value. Park et al. assessed the associa7on between BMI and An7-Müllerian Hormone (AMH), finding a modest inverse rela7onship across both endometrioma and dermoid cyst cohorts. Their results underscore that systemic BMI may not fully capture the metabolic influences on ovarian reserve, which are likely more influenced by local ovarian microenvironmental factors in endometriosis.Ovarian endometriomas pose a direct threat to the reproduc7ve reserve. Orisaka et al. demonstrated through a rat follicle culture model that endometrioma fluid (EmF) disrupts preantral follicle development. Their research iden7fied that EmF induces oxida7ve stress in granulosa cells and promotes fibrosis in theca cells, thereby impairing the essen7al cellular crosstalk required for follicular growth.The management of these cysts remains a clinical dilemma. Li et al. confirmed that endometrio7c cystectomy is associated with significantly diminished ovarian reserve markers (reduced AMH and AFC) and poorer responses during controlled ovarian s7mula7on. This highlights the need for individualized surgical decision-making that weighs symptom relief against the risk of iatrogenic damage to ovarian func7on.Advancements in technology and pharmacology offer new hope for improving fer7lity outcomes. Zhang et al. conducted a meta-analysis on the diagnos7c accuracy of machine learning, demonstra7ng that models based on gene7c and imaging informa7on possess substan7al precision for the early detec7on of endometriosis.In the realm of therapeu7cs, Sun et al. provided a systema7c review of pharmacological therapies, no7ng that while hormonal suppression (e.g., dienogest, relugolix) is effec7ve for pain, the choice must be tailored to the pa7ent's specific reproduc7ve goals. For pa7ents seeking non-hormonal, concep7on-compa7ble op7ons, Hammond et al. u7lized a network meta-analysis to rank VEGFdirected pharmacotherapies. They iden7fied compounds like curcumin that show signals of lesion regression in pre-clinical models by targe7ng angiogenesis, poten7ally offering a route toward fer7lity-sparing treatment. Complemen7ng these findings, a prospec7ve observa7onal study conducted by Bahar et al. compared dienogest with a levonorgestrel-containing combined oral contracep7ve (COC). This study found that while both treatments significantly reduced chronic pelvic pain and dysmenorrhea over three months, the COC group showed greater short-term pain reduc7on. This suggests that con7nuous COC regimens may represent a vital, cost-effec7ve conserva7ve op7on, par7cularly in resource-limited segngs.For pa7ents with DIE, the sequence of interven7ons is cri7cal. Aase and Khan reviewed surgical management for fer7lity enhancement, emphasizing that while surgery can enhance natural fecundity in superficial disease, its role prior to Assisted Reproduc7ve Technology (ART) must be carefully evaluated based on pa7ent age and ovarian reserve.Op7mizing these sequences was the focus of Tang et al., who reported successful live births in severe DIE cases using a sequen7al strategy: embryo cryopreserva7on first, followed by radical laparoscopic surgery, and finally a natural-cycle frozen embryo transfer (NC-FET). This approach priori7zes fer7lity preserva7on before extensive surgery, which might otherwise compromise ovarian func7on. For pa7ents undergoing less invasive procedures like ethanol sclerotherapy (EST), Liu et al. developed and validated a clinical nomogram to predict cumula7ve live birth rates. This tool, based on predictors like cyst diameter and the number of oocytes retrieved, assists in individualized counseling and shared decision-making.The research presented in this Topic reinforces the view that endometriosis is not a monolithic disease but a complex assembly of biological phenotypes requiring a mul7disciplinary, personalized approach. From the molecular impact of endometrioma fluid to the applica7on of machine learning in diagnos7cs and the strategic sequencing of surgery and ART, these studies advance our understanding of how to manage endometriosis while priori7zing and enhancing a pa7ent's fer7lity. These findings provide a robust founda7on for future clinical trials and the development of targeted, non-hormonal interven7ons tailored to the unique needs of women seeking to conceive despite this challenging condi7on.