Editor's Note

As a widely recognized refractory chronic disease in gynecology, the clinical cognition and diagnosis and treatment of endometriosis (EMS) are undergoing a profound paradigm shift from simply relieving symptoms and pain to implementing full-life cycle chronic disease management.

Characterized as a benign lesion with malignant behaviors, endometriosis poses great clinical challenges. Its invasive lesions, high recurrence rate and hidden malignant transformation risks make it far more complicated to manage than common gynecological disorders.

Against this backdrop, the Director's Interview column on Obstetrics and Gynecology Network invited Professor Lu Jiaqi from Obstetrics and Gynecology Hospital of Fudan University to conduct an in-depth discussion on four core topics: renewed understanding of the nature of endometriosis, key decision-making points for fertility-sparing surgery, diagnostic pitfalls of atypical cases, and precise strategies for stepwise postoperative management. Combining rich clinical experience and cutting-edge research findings, Professor Lu systematically interprets the key points in the diagnosis and treatment of endometriosis for fellow medical practitioners.

Obstetrics and Gynecology Network:

Many patients and even some primary care physicians still regard endometriosis merely as dysmenorrhea. In your opinion, why is endometriosis defined as a benign disease with malignant behaviors? What are its long-term health threats to patients across their entire life cycle?

Professor Lu Jiaqi:

Although endometriosis is a benign disease, it presents multiple malignant characteristics:

Invasive growth (local infiltration). Normal tissues have clear boundaries, while endometriotic lesions actively and destructively invade surrounding healthy tissues. Ovarian chocolate cysts are often poorly demarcated from the ovarian cortex. Deep infiltrating endometriosis can penetrate the rectal wall, invade the ureter, and even affect the bladder and rectovaginal septum. Such tissue destruction is rarely seen in benign diseases.

Distant implantation and dissemination (metastasis). Ectopic endometrial tissues can detach from the primary lesion and grow in distant parts beyond the pelvic cavity via lymphatic vessels, blood circulation or iatrogenic routes such as cesarean section incisions. Ectopic endometrial lesions have been reported in the lungs, pleura, kidneys and even the brain. Though this is not clonal metastasis seen in malignant tumors, the disease has strong dissemination ability.

High recurrence rate and treatment resistance. Despite surgical resection and standard medication, the annual recurrence rate of endometriosis remains 10% to 30%, and the 5-year cumulative recurrence rate reaches 40% to 50%, similar to the high postoperative recurrence risk of certain malignant tumors. In addition, some patients develop resistance to commonly used drugs such as progestogens, requiring stronger treatment regimens like GnRH-a. In some cases, the disease even progresses during treatment.

Estrogen-dependent growth and malignant transformation potential. The growth of endometriotic lesions relies on estrogen. Cyclic bleeding of lesions creates an oxidative stress environment, leading to continuous DNA damage and repair. Long-standing lesions, especially ovarian endometriotic cysts, carry a definite risk of malignant transformation, most commonly evolving into ovarian endometrioid carcinoma or clear cell carcinoma. The overall malignant transformation rate is about 1%, yet this risk cannot be ignored for patients without long-term standardized management. 

Impacts across the full life cycle

We should look beyond periodic abdominal pain and recognize the systemic impacts of endometriosis that evolve dynamically from adolescence to postmenopause.

The disease may emerge in adolescence, a stage that is frequently overlooked. The early manifestation is usually dysmenorrhea. Influenced by traditional perceptions, parents and even doctors tend to downplay the symptom, resulting in a diagnostic delay of 7 to 10 years. During this period, invasive lesions cause pelvic adhesion, structural damage and decreased ovarian reserve, undermining future fertility. Meanwhile, chronic dysmenorrhea leads to central hyperalgesia, accompanied by irritable bowel syndrome, mood swings and other multisystem problems. Patients may miss school, avoid social interaction, and eventually develop anxiety and depression, which affects their mental development.

Endometriosis occurs most frequently during the reproductive age, when its harms are the most prominent. It impairs fertility through multiple mechanisms: the inflammatory microenvironment and excessive oxidative stress around lesions damage oocyte quality; lesions destroy normal ovarian cortex; pelvic and tubal adhesions hinder ovum pickup; and reduced endometrial receptivity further lowers conception chances. Statistics show that 30% to 50% of endometriosis patients suffer from infertility, and the natural pregnancy rate after surgery is only 20% to 30%, which brings about corresponding family and social issues.

The threats of endometriosis still persist in perimenopausal and postmenopausal women.

High-risk factors for malignant transformation of endometriosis:

1. Patients aged over 45 years, especially postmenopausal women, or those with altered pain patterns.

2. Disease duration longer than 10 years, particularly in patients without regular long-term management.

3. Ovarian endometriotic cysts measuring 8 cm or larger, especially those with rapid enlargement, solid components or abundant blood flow detected in a short period.

4. Endometriosis complicated with infertility.

5. High estrogen status, including obesity or exogenous estrogen use.

In conclusion, endometriosis requires long-term, proactive and staged management just like hypertension and diabetes. Early diagnosis, psychological support, lifestyle intervention, fertility preservation, individualized treatment and long-term maintenance therapy are all indispensable.

Obstetrics and Gynecology Network:

What special fertility preservation strategies are adopted during surgery for young patients with fertility requirements?

Professor Lu Jiaqi:

First of all, fertility preservation for young patients desiring pregnancy starts with preoperative evaluation and individualized decision-making, rather than intraoperative management alone.

Before surgery, ovarian reserve function must be assessed via detecting AMH, reproductive hormones and counting antral follicles on ultrasound. For patients over 35 years old, those with significantly diminished ovarian reserve (DOR), or those combined with male infertility factors, expert consensus recommends joint diagnosis and treatment with reproductive medicine departments. Direct surgery is not advisable. Assisted reproductive technology should be prioritized to complete childbearing, and cysts can be removed afterwards to avoid further damage to ovarian function caused by surgery.

For patients with definite surgical indications such as large bilateral ovarian cysts or suspected malignant lesions, precise and restrained intraoperative operation is critical for ovarian protection. When stripping cyst walls, surgeons should preserve normal ovarian cortex to the maximum extent, just like peeling grapes. Sharp dissection with cold knives is preferred, and electrocoagulation hemostasis should be minimized. Thermal damage from electrocoagulation impairs blood supply and normal ovarian tissues, which will cause secondary harm to ovaries with fragile reserve function.

Nevertheless, chocolate cysts are characterized by repeated bleeding, adhesion, fibrosis and abundant new blood vessels. The blurred tissue planes and frequent bleeding during cyst stripping easily lead to loss of normal ovarian cortex and residual lesions. Severe bleeding also forces surgeons to use electrocautery more often. Therefore, clarifying anatomical layers, preserving ovarian cortex and reducing bleeding to limit the use of electrosurgical instruments are the key to protecting ovarian function during cyst stripping.

Our team is currently exploring improved surgical techniques. Previous literature has reported the application of hydrodissection: mechanical expansion separates cyst walls from normal ovarian cortex. Liquid containing pituitrin can constrict small blood vessels on the wound surface for clear visualization, lowering the risk of damaging normal ovarian cortex due to indistinct tissue boundaries. This technique has been applied in small-scale clinical trials in our hospital. Preliminary data has proven its efficacy in protecting ovarian reserve, and we look forward to further research results for verification.

Obstetrics and Gynecology Network:

For silent or atypical endometriosis, what are the most common diagnostic pitfalls for clinicians? What suggestions do you have?

Professor Lu Jiaqi:

Clinically, many adolescent and adult patients present with gastrointestinal symptoms rather than dysmenorrhea, including chronic abdominal pain, abdominal distension and altered bowel habits such as alternating diarrhea and constipation. Such patients often visit pediatric or gastroenterology departments and are initially diagnosed with irritable bowel syndrome or somatoform disorder caused by anxiety. Some patients experience frequent urination, urgent micturition and dysuria, and are misdiagnosed with chronic cystitis in urology departments. In rare cases, recurrent hemoptysis leads patients to thoracic surgery or respiratory departments with an unclear diagnosis. For patients without typical dysmenorrhea or pelvic space-occupying lesions on imaging, clinicians tend to ignore the possibility of gynecological diseases. The following measures can help identify occult endometriosis and avoid misdiagnosis:

Correlate symptoms with the menstrual cycle. Clinicians should carefully inquire about the relationship between symptoms and menstruation. Symptoms such as hematuria and hemoptysis caused by endometriosis are almost strictly synchronized with the menstrual cycle. Gynecological endometriosis should be highly suspected even if pelvic imaging shows no abnormal signs.

Regular triple pelvic examination. For women with periodic symptoms, triple pelvic examination or digital rectal examination should be performed routinely. Transvaginal ultrasound has a detection rate of less than 30% for deep infiltrating endometriosis (DIE) involving the rectum, rectovaginal septum and uterosacral ligaments, while triple pelvic examination can detect 70% to 80% of DIE lesions. Typical signs include tender nodules on uterosacral ligaments or induration and cord-like changes on the anterior rectal wall.

Advanced imaging, proper examination timing and diagnostic medication. For highly suspected cases with negative ultrasound results, enhanced pelvic MRI is recommended to improve diagnostic accuracy. Gastroscopy or cystoscopy performed during menstruation may reveal submucosal blue-purple nodules or bleeding foci, which can confirm the diagnosis pathologically. Short-term diagnostic medication can also be adopted for highly suspicious cases.

Diagnostic laparoscopy as the gold standard. For long-term unexplained periodic pelvic pain after excluding other systemic diseases, diagnostic laparoscopy is the gold standard. It allows direct visualization of peritoneal and occult lesions and biopsy sampling.

Moreover, clinicians must stay alert to malignant transformation of silent or atypical endometriosis. Current routine screening for ovarian cancer mainly relies on serum CA125 detection and transvaginal ultrasound. Compared with other epithelial ovarian cancers, patients with endometriosis-associated ovarian carcinoma (EAOC) usually have relatively low CA125 levels. Therefore, CA125 alone has low sensitivity for EAOC screening and easily leads to missed diagnosis. Clinicians who simply attribute elevated CA125 to common endometriosis may ignore malignant transformation.

The following clinical manifestations and imaging findings indicate a high risk of malignant transformation: recurrent endometriosis after menopause, altered pain patterns, rapid enlargement of ovarian cysts within a short period, solid nodules or papillary structures and abundant blood flow inside cysts on imaging, and serum CA125 level exceeding 200 U/L. Our team is also committed to developing new biomarkers tailored for EAOC, and exploring the value of OCS in early diagnosis is one of our research directions.

Obstetrics and Gynecology Network:

Regarding long-term postoperative management, what is your recommended specific drug transition route during the GnRH-a de-escalation therapy? How to grasp the optimal switching window to prevent pain recurrence caused by estrogen rebound during drug transition?

Professor Lu Jiaqi:

For de-escalation therapy after GnRH-a treatment, international guidelines and clinical practice do not advocate a unified drug transition regimen for all patients. Instead, individualized sequential treatment is formulated based on pain types, residual lesions, age and fertility needs. The core goal is to maintain estrogen levels within the therapeutic window: estradiol should be suppressed to ≤50 pg/mL to inhibit lesion activity, while excessive estrogen suppression leading to bone loss and menopausal symptoms should be avoided. Based on evidence-based medicine, mainstream drug transition regimens and seamless switching strategies are as follows.

Estrogen rebound after drug withdrawal is the main trigger for recurrent pain. Targeted regimens are selected according to disease severity to prevent this issue:

Add-back therapy: Suitable for patients with severe symptoms, residual lesions, adenomyosis with uterus preservation, or those requiring prolonged GnRH-a treatment. This regimen does not involve drug withdrawal. The minimum effective dose of estrogen is supplemented while continuing GnRH-a administration, maintaining a low-estrogen status without inducing menopausal symptoms. When serum estradiol drops below 20 pg/mL (70 pmol/L) during GnRH-a therapy, combined dydrogesterone and estradiol valerate can stabilize bone mineral density and effectively control pain recurrence during a 31-month follow-up period.

Direct transition to progestogens: Applied for postoperative consolidation therapy. After 3 to 6 months of GnRH-a injection, progestogens are administered consecutively to ensure continuous therapeutic effect. Levonorgestrel intrauterine system (LNG-IUS) is an option for patients requiring contraception or complicated with adenomyosis. Studies show that placing LNG-IUS under the hypoestrogenic state induced by GnRH-a can significantly reduce the expulsion rate, and the 12-month postoperative recurrence rate is controlled at around 4.8%. Dienogest, a progestogen specially developed for endometriosis, can also be used as sequential therapy after GnRH-a to sustain low estrogen levels.

Direct transition to combined oral contraceptives: For patients under 35 years old with no fertility requirements, contraception needs and no thrombotic risks. Low-dose estrogen oral contraceptives are selected. Contraindications must be excluded: smoking (especially in women over 35 years old), obesity, history of thrombosis, migraine with aura, severe liver and kidney diseases, and inherited thrombophilia.

Drug discontinuation plus on-demand treatment: For patients with mild symptoms. If lesions are completely resected and the visual analogue scale (VAS) score of pain is lower than 3 points, regular follow-up without medication is feasible. Attention should be paid to pain rebound 2 to 3 months after discontinuation, as estrogen levels may rise above 50 pg/mL during the follicular phase.

Grasping the optimal switching window to avoid estrogen rebound

The core principle is to utilize the down-regulation effect of GnRH-a to inhibit the rebound of endogenous FSH and LH. Clinically, the rise of serum estradiol is taken as the signal to initiate sequential treatment. The optimal time point is 24 to 28 days after the last GnRH-a injection, when serum FSH < 5 U/L, LH < 5 U/L and E2 < 50 ng/L. These indicators confirm profound ovarian suppression, forming a safe window for switching to subsequent medications.

Starting progestogens such as LNG-IUS during this low-estrogen phase leads to endometrial atrophy and stable intrauterine environment, so withdrawal bleeding and foreign body rejection are rare. This seamless transition fills the treatment gap after GnRH-a discontinuation and fundamentally prevents rapid estrogen rebound.

Summary

From in-depth analysis of benign lesions and exploration of fertility-sparing surgical techniques to full-life cycle medication strategies, Professor Lu Jiaqi’s sharing provides valuable clinical references for standardized diagnosis and treatment of endometriosis. Though endometriosis is a benign disease, it requires the same vigilance as managing malignant tumors. We expect these practical clinical experiences to help more clinicians avoid diagnostic and therapeutic pitfalls, and improve the quality of life of patients through comprehensive lifelong care.

Expert Profile

Lu Jiaqi 

Chief Physician, Obstetrics and Gynecology Hospital of Fudan University Doctor of Medicine, Master’s Supervisor Visiting Scholar, Department of Obstetrics and Gynecology, University of Pennsylvania

With over 20 years of clinical experience, she devotes herself to the comprehensive diagnosis and treatment of benign and malignant gynecological tumors, and is proficient in minimally invasive gynecological surgery.

She was named one of the Top Ten Outstanding Medical Staff of Fudan University and served as a member of the 9th Shanghai Medical Team for Xinjiang Assistance.

She has presided over 11 research projects including those funded by the National Health Commission of the People's Republic of China and the Natural Science Foundation of Shanghai, and published more than ten high-impact-factor SCI papers focusing on gynecological oncology.

Editor: Qinghuan

Reviewer: Ma Ye