Continuing Education Activity

Endometrial hyperplasia is a uterine pathology in which morphological changes occur in the cells of the endometrium and represents a precursor to the most common gynecologic malignancy in developed countries, endometrial cancer. The condition is most often caused by increased exposure to estrogens and a relative deficiency of progesterone, often referred to as "unopposed estrogen." The condition's incidence is rising, given the concurrent increase in risk factors, including obesity, diabetes, or other related illnesses. To effectively prevent the progression to endometrial malignancy, clinicians must remain vigilant regarding the signs and symptoms of endometrial hyperplasia, especially when treating patients with polycystic ovarian disease and obesity.

This course is designed to provide healthcare professionals with a comprehensive understanding of endometrial hyperplasia's pathophysiology, diagnosis, and management. The latest advancements in diagnostic techniques, treatment modalities, and preventive strategies are explored, and the critical role of an interprofessional care team in early detection and referral for appropriate intervention is highlighted. This activity emphasizes the importance of facilitating early intervention and sharing decision-making with patients regarding their fertility goals and surgical risk factors. Participants gain the knowledge and skills necessary to effectively identify, evaluate, and manage patients with endometrial hyperplasia, ultimately reducing the progression to endometrial malignancy and improving patient outcomes and quality of care.

Objectives:

• Identify the etiology of endometrial hyperplasia and its implications for progression to endometrial cancer.

• Apply strategies for evaluating endometrial hyperplasia, including the use of appropriate diagnostic tools such as transvaginal ultrasound and endometrial sampling.

• Select evidence-based treatment modalities for endometrial hyperplasia, differentiating instances in which each would be appropriate.

• Implement effective collaboration among interprofessional team members to identify patients with risk factors for endometrial hyperplasia, promoting counseling on lifestyle modifications for risk reduction and facilitating early therapeutic interventions to decrease progression to malignancy.

Introduction

Endometrial hyperplasia, in atypical forms, is the precursor lesion for endometrioid adenocarcinoma of the endometrium, representing the most common gynecologic malignancy in industrialized countries.[1] Defined as the disordered proliferation of endometrial glands, endometrial hyperplasia results from estrogenic stimulation of the endometrial tissue with a relative deficiency of progesterone's counterbalancing effects, often referred to in clinical practice as "unopposed."[2] This imbalance results may occur in patients with obesity, chronic anovulation, early menarche, late menopause, and estrogen-secreting tumors.

This disordered growth of the endometrium results in an abnormal gland-to-stroma ratio involving varying degrees of histopathological complexity and atypical features in the cells and nuclei. Endometrial hyperplasia, if untreated, has the propensity to develop into endometrial cancer. Strategies for clinical management range from surveillance or progestin therapy to hysterectomy, depending on the risk of progression to or concomitant endometrial cancer and the patient's desire to preserve fertility.[3]

Etiology

The most important risk factor for endometrial hyperplasia and, in turn, endometroid adenocarcinoma is the aforementioned chronic imbalance of or "unopposed" estrogen.[4] The source of exposure to excessive estrogen without the protective effects of progestin can be endogenous, exogenous, or genetic.

Endogenous Sources

• Obesity
  • An increase in adrenal secretory activity is often observed in obese patients, leading to increased androgen precursors, which are converted to estradiol in peripheral tissues.
  • The conversion rate of androstenedione to estrone and estradiol by aromatase rises in obese patients.
  • Higher estradiol concentrations can be found in obese patients as plasma levels of estradiol-binding sex hormone-binding globulin (SHBG) are typically diminished in this patient population.[5]           
• Chronic anovulation
  • When anovulation occurs, sex hormone production is not happening cyclically, and estrogen levels dominate without the opposing effect of progesterone produced by the corpus luteum after ovulation. This imbalance leads to a continued proliferation of the endometrium.[6]
  • Conditions associated with anovulation include polycystic ovary syndrome (PCOS), hyperprolactinemia, and perimenopausal hormonal status.             
• Early menarche, typically defined in individuals younger than 12                                                                       
• Late menopause, usually described in those aged 55 and older                                                                                  
• Presence of estrogen-secreting tumors
  • Granulosa cell tumors represent potentially estrogen-secreting tumors of the ovary. Accordingly, endometrial hyperplasia is diagnosed in 25% to 50% of women with granulosa cell tumors of the ovary.[7]
  • If endometrial hyperplasia is diagnosed in a patient without known risk factors, estrogen-secreting tumors should be excluded.

Exogenous source: Tamoxifen, a selective estrogen receptor modulator (SERM), one of the most common medications used for endocrine treatment of hormone receptor-positive breast cancer, has been associated with an increased risk for developing endometrial hyperplasia in postmenopausal women.[8]

Genetic source: Lynch syndrome is a genetic disease of autosomal dominant inheritance caused by mutation of 1 of 4 genes of the DNA mismatch repair system (MSH2, MLH1, MSH6, and PMS2), leading to microsatellite instability, which confers a markedly elevated risk for several types of cancers, particularly colon, and endometrial. Patients with hereditary nonpolyposis colorectal cancer have a lifetime risk of 40% to 60% for the development of endometrial cancer.[9] Recent studies have recommended screening patients diagnosed with atypical endometrial hyperplasia or endometrial cancer for microsatellite instability.[10]

Epidemiology

EC is the most common gynecologic malignancy in developed countries, the fourth leading cause of cancer, and the sixth cause of cancer death among women.[11] Cancer of the endometrium is rising in the United States, with an estimated incidence of 66,200 cases and 13,030 deaths in 2023.[12] The incidence of EC has increased in many countries over the past few decades, a trend which is hypothesized to be due to the rising prevalence of obesity, as well as shifts towards delaying childbearing.[13] EH is a recognized precursor lesion of the most common type of EC (endometrioid), and its detection offers opportunities for prevention. Prompt diagnosis and treatment can effectively reduce the number of cases of endometrial malignancy.

Pathophysiology

Estrogenic stimulation of the endometrium, unopposed by progestins, causes proliferative glandular epithelial changes or hyperplasia. Endometrial hyperplasia results from estrogen predominance and relative progesterone insufficiency. The typical causes for endogenous estrogen excess include anovulatory cycles (perimenopause, PCOS, obesity, and estrogen-secreting ovarian tumors). The exogenous causes include unopposed estrogen therapy, hormone replacement therapy, and tamoxifen (utilized in breast cancer treatment).[2] Hyperplasia, due to prolonged exposure to estrogens, is biologically distinct from the precancerous lesion—atypical endometrial hyperplasia.

Histopathology

Histologically, endometrial hyperplasia describes the abnormal proliferation of endometrial glands with a greater gland-to-stroma ratio than healthy proliferative endometrium but without endometrial stromal invasion.[2] Diagnosis is based upon histological assessment of a tissue sample obtained surgically via endometrial biopsy, curettage, or hysterectomy. The most widely used classification system for endometrial hyperplasia is the 2014 World Health Organization (WHO) Classification System, which differentiates between endometrial hyperplasia without atypia (benign endometrial hyperplasia) and atypical endometrial hyperplasia/endometrial intraepithelial neoplasia.

This clinical management of the 2 conditions differs depending on the presence or absence of nuclear atypia. Nuclear atypia is defined as nuclear enlargement with or without prominent nucleoli.[14] Endometrial hyperplasia without atypia is a benign lesion without significant somatic genetic changes, caused by extensive exposure to estrogen that is not counterbalanced by the protective effects of progestins. The hyperplastic changes often regress if physiological progesterone levels are resumed or therapeutic progestins are utilized.[15] Endometrial hyperplasia without atypia rarely progresses to endometrial cancer.

On the molecular level, atypical endometrial hyperplasia shares many similarities with endometrioid endometrial cancer.[16] Studies have documented a risk of as high as 50% for concomitant endometrial cancer in patients with atypical endometrial hyperplasia.

The risk for the development of endometrial cancer in women with atypical endometrial hyperplasia is diminished approximately threefold to fivefold when treated with progestin. However, the risk of progression to endometrial cancer among women with endometrial hyperplasia undergoing progestin treatment remains considerable at 15% to 28%. A retrospective cohort study investigated 242 women with atypical endometrial hyperplasia, of whom 74% received progestin therapy.[16]

Additionally, when considering the concurrent or future risk of endometrial cancer among women with atypical endometrial hyperplasia, clinicians must understand that atypical endometrial hyperplasia/endometrial intraepithelial neoplasia may be difficult to histopathologically from endometrial cancer. Trimble et al found overdiagnosis or underdiagnosis in nearly every third endometrial specimen, which illustrates the difficulty of this distinction.[17] This challenge suggests that treating atypical endometrial hyperplasia as the equivalent of early endometrial cancer when counseling affected patients is reasonable.

History and Physical

Most patients who receive a diagnosis of endometrial hyperplasia present with abnormal uterine bleeding (eg, abnormal postmenopausal bleeding, persistent or recurrent uterine bleeding).[4] This symptom prompts most patients to seek medical attention almost immediately, contributing to the detection of endometrial cancer at an early stage and, in turn, its relatively favorable prognosis (80%-90% 5-year survival rate at stage I) when diagnosed and treated.[18] This favorable outcome stands in contrast to other cancers, such as ovarian cancer, whose symptoms are more vague and can remain indolent for many years, allowing it to progress and metastasize.

The history obtained from the patient at the time of presentation should include the history of the present illness (such as the duration, intensity, and presence or absence of clots associated with the current episode of bleeding) and menstrual history (whether or not the patient has reached menopause, length, and regularity of cycles, flow, the passage of clots, intermenstrual bleeding, and postmenopausal bleeding).

Attention should be paid to the patient’s obstetric history, as nulliparity or delayed childbearing are risk factors for endometrial hyperplasia. Additionally, a patient’s desire to conceive in the future may alter the treatment of endometrial hyperplasia and cause the provider to consider nonsurgical options and close surveillance over hysterectomy.

As with any patient, medical and surgical history should be taken in detail as they may determine contraindications to hormonal treatment or a patient’s candidacy for surgery. For instance, a patient with uncontrolled cardiopulmonary disease may have to undergo medical optimization before surgery or may attempt medical management first. Similarly, a patient with a history of breast cancer or liver disease is not a candidate for oral progestins.[19]

The physical examination should include a general routine examination, including vital signs. If a patient is hypotensive, tachycardic, and actively bleeding, she may need fluid resuscitation or a blood transfusion. As most patients present with menorrhagia, pallor should be assessed, which may suggest anemia. A breast examination should be performed to rule out any suspicious lesions, and in women of the appropriate age, normal mammography results within the last year should be confirmed. Most importantly, a pelvic exam should be performed. A speculum should be placed to visualize the quantity of bleeding, flow, and presence of clots. A foul-smelling discharge may suggest active infection and pose a contraindication to potential intrauterine device (IUD) placement. A bimanual exam can ascertain the size of the uterus and the presence of coexisting fibroids or adnexal masses. During the pelvic exam, an endometrial biopsy can be performed to confirm the diagnosis.[20][21][20]

Evaluation

Confirming a diagnosis of endometrial hyperplasia and subsequently distinguishing between endometrial hyperplasia with and without atypia requires a histological examination of endometrial tissue, which can be obtained either by outpatient or inpatient endometrial sampling.

Transvaginal Ultrasound in Premenopausal Women

In premenopausal women, the utility of transvaginal ultrasound (TVUS) mainly lies in the ability to detect myomas, endometrial polyps, pregnancy, and other potential etiologies of abnormal uterine bleeding. The endometrial thickness varies physiologically with the different phases of the menstrual cycle and can reach as high as 18 mm during the secretory phase.[22]

Transvaginal Ultrasound in Postmenopausal Women

An endometrial thickness of ≤4 mm in postmenopausal women has a >99% negative predictive value for endometrial cancer. Therefore, TVUS is pivotal in the initial evaluation of postmenopausal bleeding. There is no consensus regarding which endometrial thickness cut-off should be used when recommending an endometrial biopsy for asymptomatic patients.[23] Failure to adequately identify a thin, distinct endometrial echo in a postmenopausal woman with bleeding should trigger the need for an ultrasound, office hysteroscopy, or endometrial sampling.[24] 

Endometrial Sampling

Multiple methods are available to sample the endometrium. The simplest method, in-office suction endometrial sampling (also known as endometrial biopsy) performed with a plastic cannula (Pipelle), has a long history of safety and efficacy.[25] Endometrial biopsy involves obtaining a tissue sample by inserting a Pipelle into the uterus via the cervix and obtaining a tissue sample via suction technique. Biopsy should be offered to young women with abnormal uterine bleeding and risk factors for EH, as well as nonobese women with unopposed hyperestrogenism, such as those with PCOS or estrogen-producing ovarian masses.[23] In both postmenopausal and premenopausal women, the Pipelle has been shown to have detection rates of 99.6% and 91%, respectively.[26]

However, more recent studies demonstrate a higher rate of endometrial cancer in hysterectomy specimens from patients with preoperative office Pipelle biopsy when compared with uterine dilation and curettage, suggesting that the former method failed to detect endometrial pathology in these instances.[27] It is believed that “mass lesions” that distort the endometrial cavity may deflect the pliable suction catheter and lead to ineffective sampling, potentially missing endometrial pathology.

Hysteroscopic-guided uterine sampling is another recommended method of obtaining endometrial tissue, and data demonstrate its utility for diagnosing endometrial polyps, endometrial cancer, and endometrial hyperplasia.[28] Several tissue-removal devices, such as morcellators or tissue forceps, allow for targeted hysteroscopic-guided resection of the endometrium or any discrete lesions visualized hysteroscopically.[29][30]

Treatment / Management

The risk of benign endometrial hyperplasia without atypia progressing to invasive malignancy is less than 5% over 10 years.[31] Endometrial hyperplasia (and even low-grade endometrioid cancers) can be conservatively managed by progestin therapies (eg, oral or intrauterine progestogens), especially among women who wish to maintain fertility. Spontaneous resolution can occur if reversible causes of estrogen excess are corrected.[29][32]

Disease resolution is more likely with progesterone treatment (89%-96%) than with expectant management (74%-81%).[33] Progestins have historically been the cornerstone of conservative management for atypical endometrial hyperplasia and stage IA endometrioid endometrial cancer without myometrial invasion. GnRH analogs, metformin, and hysteroscopic resection, combined with progestins, appear to increase the overall efficacy of treatment.[34] Although oral progestins (medroxyprogesterone 10 mg to 20 mg daily or norethisterone 10 mg to 15mg daily) have been used historically as the first line for medical management, the levonorgestrel IUD has been shown to achieve a higher histologic regression rate when compared to oral progestogens for complex hyperplasia without atypia (92% vs 66%) and atypical hyperplasia (90% vs 69%).[35] Additionally, levonorgestrel IUDs provide a local higher dose concentration of progestins than the oral route, avoiding the adverse effects linked to the systemic administration of progestogens, with expected increased patient compliance.[34] Lifestyle changes like weight loss may also be advised alongside progesterone therapy.[36]

If fertility preservation is not desired, total hysterectomy is generally recommended for women with atypical endometrial hyperplasia due to the presumed significant risk of concurrent future endometrial cancer and for women with persistent non–atypical endometrial hyperplasia.[37] Postmenopausal women should be offered a total hysterectomy with bilateral salpingo-oophrectomy. Accurately quantifying endometrial cancer risk in women diagnosed with endometrial hyperplasia is, therefore, pivotal to informed shared decision-making regarding the most appropriate clinical management strategies.

The most recent clinical guidelines recommend that in women with endometrial hyperplasia who undergo medical management, an endometrial biopsy should be undertaken at least every 3 months until 2 consecutive negative biopsies are obtained, especially in patients with atypical endometrial hyperplasia.[21] More extensive evaluations, such as sentinel lymph node assessment in patients with atypical endometrial hyperplasia, have not been shown to be beneficial in current studies and are not recommended.[38]

Differential Diagnosis

The differential diagnosis for endometrial hyperplasia includes conditions that can result in focal or generalized thickening of the endometrium as follows:

• Endometrial cancer: Histopathological examination of the endometrial tissue can show markers of invasion in endometrial cancer.                         
• Endometrial polyp: Hydrosonography can enhance visualization and help diagnose endometrial polyps. Diagnostic hysteroscopy can confirm the presence of a polyp.                                                                                                                               
• Endometritis: An irregular-appearing endometrium and increased focal thickness are hallmarks of endometritis.[39]

Prognosis

While endometrial hyperplasia can progress to endometrial cancer, the rate of progression depends on factors such as the degree of architectural abnormality and the presence or absence of nuclear atypia.[14] It is well-established that progression to endometrial cancer is higher in women with atypical compared with non–atypical endometrial hyperplasia. Recent meta-analyses describe the concurrent prevalence of endometrial cancer in those diagnosed with atypical endometrial hyperplasia as approximately 33%. The risk of progression to cancer in those with atypical endometrial hyperplasia was approximated at 8.2% annually if untreated and 2.6% annually in those with non–atypical endometrial hyperplasia in the same study.[21]

Studies have found high rates of disease regression in patients who decide against surgical management and, instead, are managed medically. A systematic review of outcomes in patients with endometrial intraepithelial neoplasia–atypical endometrial hyperplasia or grade 1 adenocarcinoma demonstrated an initial response to progestins of 86%, with a complete response of 66% for those with atypical endometrial hyperplasia. Oral, intrauterine, and combined modes of administration are effective. Recent studies have identified complete response rates of 43% and 82% for endometrial adenocarcinoma and atypical endometrial hyperplasia, respectively, after 6 months of treating these conditions with the levonorgestrel IUD.[40]

Complications

Endometrial hyperplasia, if left untreated or poorly managed, can lead to various complications, the most significant being the development of endometrial cancer. The abnormal proliferation of endometrial cells increases the risk of malignant transformation, particularly in cases of complex or atypical endometrial hyperplasia. Furthermore, untreated hyperplasia can exacerbate abnormal uterine bleeding, leading to chronic anemia and its associated complications, such as fatigue and impaired physical functioning. In cases where hyperplasia is hormonally driven, such as in estrogen-secreting tumors or conditions like PCOS, there's a heightened risk of exacerbating hormonal imbalances, potentially leading to further reproductive health issues or metabolic disturbances. Additionally, the psychological impact of living with a condition linked to cancer risk can induce significant anxiety and distress in affected individuals. Prompt diagnosis and appropriate management of endometrial hyperplasia are crucial to mitigate these potential complications and improve patient outcomes.[41]

Consultations

Managing endometrial hyperplasia effectively often involves a multidisciplinary approach, with various specialists collaborating to tailor treatment plans to each patient's unique needs and fertility objectives. Consultations that may be necessary to ensure thorough evaluation, personalized management, and optimal outcomes for individuals affected by endometrial hyperplasia include the following:

• Gynecologist
• Gynecologic oncologist
• Endocrinologist
• Fertility specialist
• Radiologist
• Pathologist
• Nutritionist
• Psychologist

Deterrence and Patient Education

Women, particularly those who are obese, have PCOS, increased exposure to estrogens, and heavy menstrual bleeding, should be encouraged by their primary care providers to have regular follow-ups with their gynecologist. This patient cohort should be encouraged to make lifestyle modifications such as diet modification and increased exercise to achieve weight loss. They should be worked up for endometrial hyperplasia with endometrial biopsy and/or hysteroscopy with dilation and curettage (D&C). Those individuals diagnosed with endometrial hyperplasia should be engaged in a discussion regarding their reproductive goals. The women who desire future fertility should be educated regarding the importance of obtaining regular endometrial biopsies and counseled on the risks and benefits of a levonorgestrel IUD versus oral progesterone. Those with satisfied parity should be counseled regarding hysterectomy as the definitive treatment for endometrial hyperplasia and should be engaged in a thorough discussion regarding risks, benefits, and different routes of hysterectomy, including total vaginal, laparoscopic-assisted vaginal, total laparoscopic, and abdominal.

Enhancing Healthcare Team Outcomes

In the management of endometrial hyperplasia, an interprofessional healthcare team comprising physicians, advanced care practitioners, nurses, pharmacists, nutritionists, and other health professionals plays a pivotal role in enhancing patient-centered care, improving outcomes, ensuring patient safety, and optimizing team performance. The most common presentation of endometrial hyperplasia is abnormal uterine bleeding, often in the form of heavy menstrual bleeding, inter-menstrual bleeding, or postmenopausal bleeding. Although this condition is usually ultimately managed by a gynecologist, these patients frequently present initially to other clinicians such as internists, emergency medicine providers, family medicine practitioners, and pediatricians in the case of young teens who present with this condition.

A thorough understanding of the etiology, risk factors, and treatment of endometrial hyperplasia is crucial not only so that these clinicians recognize the condition and organize a prompt referral to a gynecologist but also because of the pivotal role that lifestyle modifications can play in reducing risk factors for endometrial hyperplasia. For instance, emphasis on maintaining a healthy weight can be echoed by all of a patient's healthcare professionals, inspiring compliance among those at risk.

Additionally, radiologists and histopathologists are crucial when making the diagnosis of endometrial hyperplasia. Namely, a radiologist’s identification of a thickened endometrial stripe (>4 mm) in a postmenopausal woman or a 20-mm endometrial stripe in an obese young woman with heavy menstrual bleeding prompts the need for tissue diagnosis. Specimens obtained via dilation and curettage or endometrial biopsy are subsequently sent to a histopathologist, whose analysis yields a diagnosis of endometrial hyperplasia. Further investigation by a pathologist trained in analyzing gynecologic specimens may help distinguish between atypical and benign endometrial hyperplasia. These providers should be given the relevant clinical history when possible to aid in a correct diagnosis.

Pharmacists guide dosing and duration of treatment in patients desiring medical management who aim to preserve their fertility. Nutritionists and physical therapists may help patients be mindful of their weight and help mitigate obesity and its associated risk factors. Nurses monitor patients' symptoms and response to treatment and provide patient education. Collaboratively, the team of healthcare professionals can enhance patient-centered care, improve outcomes, promote patient safety, and optimize performance in managing patients with endometrial hyperplasia.