Endometrial hyperplasia is a condition characterized by abnormal proliferation of the endometrial glands, resulting in an increased gland-to-stroma ratio compared with normal proliferative endometrium.¹ Endometrial hyperplasia is a significant precursor to endometrial cancer, the most common gynecological malignancy in developed countries.² The overall incidence of endometrial hyperplasia is estimated to be approximately 133 per 100,000 woman-years, with peak incidence occurring in women who are transitioning to or just completed menopause.³ According to the American College of Obstetricians and Gynecologists (ACOG), the incidence of endometrial cancer in the United States is rising, with an estimated 66,200 new cases and 13,030 deaths in 2023.⁴

Endometrial hyperplasia is primarily caused by an imbalance in hormones, specifically an excess of estrogen without adequate progesterone to counterbalance its effects.² This hormonal imbalance, often referred to as "unopposed estrogen," leads to the abnormal thickening of the endometrium, the lining of the uterus. Several factors contribute to this condition, including both endogenous and exogenous sources of estrogen.² Obesity is a significant risk factor, as excess body fat increases estrogen production through various mechanisms, such as increased conversion of androstenedione to estrone and estradiol by aromatase and decreased levels of sex hormone-binding globulin (SHBG).² Chronic anovulation, which can result from conditions like polycystic ovary syndrome (PCOS), hyperprolactinemia, and perimenopausal hormonal status, also contributes to endometrial hyperplasia by causing continuous estrogen production without cyclical progesterone production. Other endogenous risk factors include early menarche, late menopause, and estrogen-secreting tumors like granulosa cell tumors of the ovary.²

Exogenous sources of estrogen can also lead to endometrial hyperplasia.² Tamoxifen, a selective estrogen receptor modulator (SERM) used in breast cancer treatment, has been associated with an increased risk of endometrial hyperplasia in postmenopausal women.² Hormone replacement therapy, particularly unopposed estrogen therapy in women with an intact uterus, can also contribute to the development of this condition. Genetic factors play a role as well, with Lynch syndrome significantly increasing the risk of endometrial hyperplasia and cancer.² Other risk factors identified in various studies include hypertension, diabetes, infertility, and a family history of related cancers.⁵ The risk of progression from endometrial hyperplasia to endometrial cancer varies depending on the type of hyperplasia, with atypical endometrial hyperplasia carrying a higher risk of progression.² These findings emphasize the importance of early detection and appropriate management of endometrial hyperplasia, particularly in women with identified risk factors.^5,6

Screening and diagnosing endometrial hyperplasia involve a combination of clinical assessment, imaging, and histological examination. The process typically begins with identifying patients at risk, particularly those experiencing abnormal uterine bleeding.² According to ACOG, women with abnormal uterine bleeding should be evaluated for endometrial cancer if they are older than 45 years or have a history of unopposed estrogen exposure.⁷

Transvaginal ultrasound (TVUS) is often used as an initial screening tool, especially in postmenopausal women. An endometrial thickness of ≤4 mm in postmenopausal women has a >99% negative predictive value for endometrial cancer.² However, in premenopausal women, TVUS is primarily useful for detecting other potential causes of abnormal bleeding, such as myomas or polyps, as the endometrial thickness varies with the menstrual cycle.²

The definitive diagnosis of endometrial hyperplasia requires histological examination of endometrial tissue.² This is typically obtained through endometrial sampling, which can be performed in an outpatient setting using endometrial biopsy techniques.² In cases where outpatient sampling fails or is non-diagnostic, diagnostic hysteroscopy should be considered. Hysteroscopy offers direct visualization of the endometrial cavity and can be performed with focal biopsy or curettage.²

The World Health Organization (WHO) classification system, updated in 2014, is widely used to categorize endometrial hyperplasia.⁸ It separates endometrial hyperplasia into two groups based on the presence of cytological atypia: hyperplasia without atypia and atypical hyperplasia. This classification is important as it guides management and helps assess the risk of progression to endometrial cancer.⁸

Recent studies have explored using biomarkers and advanced imaging techniques to improve diagnosis. A study highlighted the potential of using immunohistochemical analysis of proteins such as HAND2, PTEN, and PAX2 to aid in identifying benign versus premalignant endometrial tissue.⁹ Additionally, ongoing research is investigating computer-aided image analysis to enhance the accuracy of EIN (Endometrial Intraepithelial Neoplasia) diagnosis.⁹

Current guidelines recommend regular surveillance for patients diagnosed with endometrial hyperplasia. The Royal College of Obstetricians and Gynecologists (RCOG) suggests that endometrial surveillance should include sampling by outpatient endometrial biopsy.¹ For patients undergoing medical management, an endometrial biopsy should be performed at least every three months until two consecutive negative biopsies are obtained, especially in cases of atypical endometrial hyperplasia.²

Screening and diagnosing endometrial hyperplasia involve a multifaceted approach that combines clinical assessment, imaging studies, and histological examination. Research continues to refine these methods, potentially improving diagnostic accuracy and patient outcomes.

Treatment for endometrial hyperplasia varies depending on the type of hyperplasia, the patient's age, and their desire for fertility preservation. For benign endometrial hyperplasia without atypia, the risk of progression to invasive malignancy is relatively low, at less than 5% over 10 years.¹⁰ Conservative management with progestin therapies is often the first-line treatment, especially for women who wish to maintain fertility.²

Progestin therapy, either oral or intrauterine, has shown high efficacy in disease resolution.² Options for progestin therapy include oral progestins like medroxyprogesterone acetate (MPA) and megestrol acetate, levonorgestrel-releasing intrauterine device (LNG-IUD), and injectable progestins.^11,12 The LNG-IUD has demonstrated superior histologic regression rates compared to oral progestogens for both complex hyperplasia without atypia (92% vs 66%) and atypical hyperplasia (90% vs 69%).¹³ The LNG-IUD also offers the advantage of providing a higher local dose concentration of progestins while minimizing systemic side effects. For women with atypical endometrial hyperplasia or persistent non-atypical hyperplasia who do not desire fertility preservation, total hysterectomy is generally recommended. Postmenopausal women are typically offered a total hysterectomy with bilateral salpingo-oophrectomy.²

Regular monitoring is crucial for patients undergoing medical management. Current clinical guidelines recommend endometrial biopsies at least every 3 months until two consecutive negative biopsies are obtained, particularly for patients with atypical endometrial hyperplasia.¹

Emerging treatments and adjunct therapies are being explored to enhance the efficacy of traditional progestin therapy. These include the use of GnRH analogs, metformin, and hysteroscopic resection in combination with progestins.² Metformin, typically used for diabetes treatment, has shown promise in reversing endometrial hyperplasia in some studies. While evidence is still limited, research suggests that combining metformin with progestins may enhance the regression of endometrial hyperplasia compared to progestin therapy alone.¹⁴ Additionally, lifestyle modifications such as weight loss and improved glycemic control are often recommended as part of the overall management strategy.²

Effective management of endometrial hyperplasia often involves a multidisciplinary approach, with various specialists collaborating to tailor treatment strategies and provide comprehensive care for patients. This approach is particularly crucial given the condition's complex nature and its potential to progress to endometrial cancer. The multidisciplinary team (MDT) typically includes gynecologists, oncologists, radiologists, pathologists, and nurses, each contributing their expertise to ensure optimal patient outcomes.²

The management process begins with accurate diagnosis and risk assessment. Gynecologists and radiologists work together to evaluate patients using transvaginal ultrasound and endometrial sampling techniques.² Pathologists play a critical role in accurately classifying the type of hyperplasia, which is essential for determining the appropriate treatment approach. Once diagnosed, the MDT collaborates to develop a personalized treatment plan, considering the patient's age, fertility desires, and overall health status.^2,15

Conservative management with progestin therapy is often the first-line approach for patients with non-atypical hyperplasia or those wishing to preserve fertility. Gynecologists and endocrinologists may collaborate to monitor the patient's response to treatment and adjust dosages as needed.² In cases where surgical intervention is necessary, such as for atypical hyperplasia or persistent non-atypical hyperplasia, gynecologic oncologists become key members of the team.^2,15

Long-term management of endometrial hyperplasia extends beyond initial treatment. Primary care providers play a crucial role in encouraging regular follow-ups and promoting lifestyle modifications, particularly for patients with risk factors such as obesity or polycystic ovary syndrome (PCOS).² Nutritionists and exercise specialists may be involved in helping patients achieve and maintain a healthy weight, which is an important aspect of risk reduction.²

The MDT approach also facilitates shared decision-making, ensuring that patients are well-informed about their condition, treatment options, and potential outcomes. This collaborative effort extends to managing clinical trial opportunities, aligning treatment recommendations with patient expectations, and providing comprehensive support for patients' various needs throughout their care journey.¹⁶

Endometrial hyperplasia is a complex condition characterized by the abnormal proliferation of endometrial glands, which can progress to endometrial cancer if left untreated. It is primarily caused by hormonal imbalances, particularly prolonged exposure to excess estrogen without adequate progesterone. Diagnosis requires a multifaceted approach that combines clinical evaluation, imaging, and histological examination, with endometrial biopsy serving as the gold standard. Treatment options are tailored to the type of hyperplasia, patient age, and fertility preferences, ranging from conservative progestin therapy to definitive surgical interventions like hysterectomy. Effective management often necessitates a multidisciplinary approach, which integrates the expertise of gynecologists, oncologists, radiologists, pathologists, and other healthcare professionals to deliver personalized and comprehensive care. Regular monitoring and follow-up are critical, particularly for patients receiving medical management. Advances in research have allowed for innovative diagnostic tools and therapeutic strategies to enhance outcomes further and reduce the risk of progression to malignancy.

1. Royal College of Obstetricians & Gynaecologists. Management of Endometrial Hyperplasia (Green-top Guideline No. 67). Accessed December 9, 2024. https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/management-of-endometrial-hyperplasia-green-top-guideline-no-67/
2. Singh G, Cue L, Puckett Y. Endometrial Hyperplasia. In: StatPearls. StatPearls Publishing; 2024. Accessed December 9, 2024. http://www.ncbi.nlm.nih.gov/books/NBK560693/
3. Cleveland Clinic. What Is Endometrial Hyperplasia? Accessed December 9, 2024. https://my.clevelandclinic.org/health/diseases/16569-atypical-endometrial-hyperplasia
4. The American College of Obstetricians and Gynecologists. Management of Endometrial Intraepithelial Neoplasia or Atypical Endometrial Hyperplasia. Accessed December 9, 2024. https://www.acog.org/clinical/clinical-guidance/clinical-consensus/articles/2023/09/management-of-endometrial-intraepithelial-neoplasia-or-atypical-endometrial-hyperplasia
5. Wang L, Wei W, Cai M. A Review of the Risk Factors Associated with Endometrial Hyperplasia During Perimenopause. Int J Womens Health. 2024;16:1475-1482. doi:10.2147/IJWH.S481509
6. The American College of Obstetricians and Gynecologists. Endometrial Hyperplasia. Accessed December 9, 2024. https://www.acog.org/womens-health/faqs/endometrial-hyperplasia
7. The American College of Obstetricians and Gynecologists. Management of Acute Abnormal Uterine Bleeding in Nonpregnant Reproductive-Aged Women. Accessed December 9, 2024. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2013/04/management-of-acute-abnormal-uterine-bleeding-in-nonpregnant-reproductive-aged-women
8. Emons G, Beckmann MW, Schmidt D, Mallmann P. New WHO Classification of Endometrial Hyperplasias. Geburtshilfe Frauenheilkd. 2015;75(2):135-136. doi:10.1055/s-0034-1396256
9. Sanderson PA, Esnal-Zufiaurre A, Arends MJ, et al. Improving the Diagnosis of Endometrial Hyperplasia Using Computerized Analysis and Immunohistochemical Biomarkers. Front Reprod Health. 2022;4. doi:10.3389/frph.2022.896170
10. Lacey JV, Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28(5):788-792. doi:10.1200/JCO.2009.24.1315
11. Yale Medicine. Endometrial Hyperplasia. Accessed December 10, 2024. https://www.yalemedicine.org/conditions/endometrial-hyperplasia
12. Mittermeier T, Farrant C, Wise MR. Levonorgestrel‐releasing intrauterine system for endometrial hyperplasia - Mittermeier, T - 2020. Accessed December 10, 2024. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012658.pub2/full
13. Gallos ID, Krishan P, Shehmar M, Ganesan R, Gupta JK. LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Hum Reprod Oxf Engl. 2013;28(11):2966-2971. doi:10.1093/humrep/det320
14. Shiwani H, Clement NS, Daniels JP, Atiomo W. Metformin for endometrial hyperplasia - Shiwani, H - 2024. Accessed December 10, 2024. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012214.pub3/full
15. Chandra V, Kim JJ, Benbrook DM, Dwivedi A, Rai R. Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol. 2016;27(1):e8. doi:10.3802/jgo.2016.27.e8
16. European Medical Journal. The Importance of the Multidisciplinary Team in the Management of Patients with Endometrial Cancer: Interviews with Two Key Opinion Leaders. Published online October 27, 2023. Accessed December 10, 2024. https://www.emjreviews.com/oncology/article/the-importance-of-the-multidisciplinary-team-in-the-management-of-patients-with-endometrial-cancer-interviews-with-two-key-opinion-leaders/