List of Abbreviations
GnRH agonists — gonadotropin-releasing hormone agonists (ATC analogs of gonadotropin-releasing hormone)
AEH — atypical endometrial hyperplasia
AUB – abnormal uterine bleeding
WHO – World Health Organization
EH — endometrial hyperplasia
HSC — hysteroscopy
BMI – body mass index
LNG-IUS — levonorgestrel-releasing intrauterine system (levonorgestrel in the form of a therapeutic intrauterine system)
US – ultrasound examination
MRI – magnetic resonance imaging
EC — endometrial cancer
PCOS — polycystic ovary syndrome
EA — endometrioid adenocarcinoma
EIN — endometrial intraepithelial neoplasia
Terms and Definitions
Endometrial hyperplasia is a pathological process of the uterine mucosa characterized by glandular proliferation and an increased gland-to-stroma ratio.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Endometrial hyperplasia (EH) is a pathological process of the uterine mucosa characterized by glandular proliferation and an increased gland-to-stroma ratio [1].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
One of the leading causes of EH development is absolute or relative hyperestrogenism. Pathogenetic mechanisms of EH formation also include the suppression of apoptosis, as evidenced by an imbalance in the activity of the anti-apoptotic Bcl-2 gene family and the pro-apoptotic Fas/FasL gene system [2], [3]. EH may occur in the presence of mutations in the tumor suppressor gene PTEN (phosphatase and tensin homolog) [4].
Risk factors for EH can be divided into three groups: (1) early menarche or late menopause, infertility, anovulation due to the menopausal transition phase and/or polycystic ovary syndrome (PCOS); (2) iatrogenic factors (estrogen monotherapy or tamoxifen**); and (3) comorbidities (obesity, type 2 diabetes mellitus, arterial hypertension, Lynch syndrome, and estrogen-secreting ovarian tumors, such as granulosa cell tumors) [5], [6].
Non-atypical EH is the proliferation of endometrial glands of varying shapes and sizes without cytologic atypia. AEH is the proliferation of endometrial glands with the glandular component predominating over the stroma and atypical changes in the glandular epithelium in a focal area of the endometrium distinct from the surrounding uterine body mucosa [7].
The risk of progression from non-atypical EH to endometrial cancer over 20 years reaches 5%, while in AEH the risk increases to 27.5% [8].
1.3 Epidemiology of the Disease or Condition
According to a population-based study on the age-specific incidence of various EH types (testing 63,688 endometrial samples), the overall incidence of EH is 133 cases per 100,000 woman-years, with a peak (386 per 100,000 woman-years) occurring at age 50–54, and a minimum (6 per 100,000 woman-years) at age under 30. The incidence of simple EH is 58 cases per 100,000 woman-years, complex EH is 63 per 100,000, and AEH is 17 per 100,000 [9].
1.4 Features of Coding the Disease or Condition
N85.0 Glandular endometrial hyperplasia
N85.1 Adenomatous endometrial hyperplasia
1.5 Classification of the disease or condition
Currently, clinical practice utilizes the 2014 World Health Organization (WHO) binary classification (retained unchanged in the 2020 edition). According to this classification, two forms are distinguished [1], [10].
- endometrial hyperplasia without atypia;
- endometrial hyperplasia with atypia.
Previously, international clinical practice used the 2003 WHO classification, which included 4 categories of EH: simple and complex EH without atypia, simple and complex AEH; however, due to low diagnostic reproducibility, it was simplified into a binary classification [11], [12], [13].
There is also an alternative system based on the identification of EIN (endometrial intraepithelial neoplasia). EIN refers to an endometrial lesion characterized by: 1) architectural distortion (the area of the glandular component prevails over the stromal component), 2) cytologic alterations (in the affected endometrium, the characteristics of the glandular epithelial cells differ from those in the surrounding unaffected uterine mucosa), 3) a lesion size greater than 1 mm, 4) exclusion of "mimicking" lesions (polyps, reparative changes, cystic atrophy, menstrual breakdown, artifacts, etc.), 5) exclusion of malignant lesions. The EIN classification also includes a category of benign endometrial hyperplasia (EH). The American College of Obstetricians and Gynecologists (2015) recommends the clinical application of the EIN classification as more objective and based on morphometric parameters [14]. Since 2014, the term "EIN" has been incorporated into the WHO classification system, which recommends its use alongside the term "AEH", sharing a single histological code (8380/2) [1], [10].
1.6 Clinical presentation of the disease or condition
EH manifests as abnormal uterine bleeding (AUB) in the form of heavy menstrual bleeding or intermenstrual bleeding during a regular menstrual cycle, or as oligomenorrhea [15]. The pattern of AUB does not allow prediction of the specific type of EH. EH typically develops against the background of a progesterone-deficient state and can be a cause of anovulatory infertility [5], [6], [16], [17]. Women who are overweight or obese and have prolonged anovulatory menstrual cycles with increased conversion of androgens to estrogens in adipose tissue have an increased risk of developing EH and endometrial cancer [18], [19].
2. Diagnostics, medical indications and contraindications for diagnostic methods
The diagnosis of EH is established based on complaints of AUB, medical history, physical examination, and comprehensive pelvic ultrasound (transvaginal and transabdominal) findings [20], [21], [22]. The definitive diagnosis of EH is confirmed by pathomorphological examination of the uterus (endometrium) [1], [23], [10], [24], [25], [26], [27].
2.1 Complaints and Anamnesis
See section 1.6 "Clinical Presentation".
2.2 Physical Examination
It is recommended that all patients with EH undergo a physical examination according to standard propedeutics principles, as well as a speculum examination of the cervix and a bimanual pelvic examination [20], [21], [27], [28].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: BMI must be calculated for all patients with EH to diagnose overweight or obesity. BMI is calculated using the formula: BMI (kg/m2) = body mass / height2 (m2). Obesity is a proven risk factor for EH and endometrial cancer, affects the restoration of reproductive function and pregnancy outcomes, and increases the risk of cardiovascular diseases. Obesity reduces the effectiveness of therapy and the likelihood of subsequent EH remission.
2.3 Laboratory Diagnostics
It is recommended to perform laboratory monitoring to identify comorbid conditions, conduct preoperative evaluation, and determine management tactics for all patients with suspected EH [20], [21], [29], [30], [31].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: It is advisable to include the following in the complex of laboratory tests: complete blood count, general clinical blood chemistry panel with evaluation of liver enzymes and ferritin levels, coagulogram (exploratory hemostasis test), and serum hormone evaluation to diagnose and identify the causes of anovulation and oligomenorrhea (assessment of serum levels of follicle-stimulating hormone, luteinizing hormone, anti-Müllerian hormone, testosterone, sex hormone-binding globulin, prolactin, thyroid-stimulating hormone), as well as serum human chorionic gonadotropin (free beta-subunit) testing [29], [32], [30], [31], [33].
It is recommended when infection is suspected, to perform molecular biological testing of female genital mucosal discharge for sexually transmitted pathogens (Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, Mycoplasma genitalium) for timely detection and selection of treatment tactics [28], [29], [30], [31], [33].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform microscopic examination of vaginal smears in patients with suspected EH to rule out pelvic inflammatory disease [20], [21], [30], [31], [32], [33], [34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform cervical cytology in patients with suspected EH to rule out cervical intraepithelial neoplasia [20], [21], [30], [31], [35], [33].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
2.4 Instrumental Diagnostics
It is recommended that all patients with suspected EH undergo comprehensive pelvic ultrasound (transvaginal and transabdominal) to assess the state of the endometrium and myometrium [22], [25], [26], [27], [36], [37], [38].
For adults – Grade of Recommendation B (Level of Evidence – 2), for children – Grade of Recommendation C (Level of Evidence – 5)
Comments: Comprehensive pelvic ultrasound (transvaginal and transabdominal), performed if possible in the 1st phase of the cycle or during AUB, is considered a screening procedure to evaluate the endometrium and myometrium. In reproductive age, an M-echo thickness greater than 7–8 mm on days 5–7 of the cycle with a heterogeneous structure and echogenic inclusions suggests possible EH. There are no clear ultrasonographic signs of EH in reproductive age; therefore, the diagnostic value of ultrasound for detecting EH in women of this age group is limited. In postmenopause, with an endometrial thickness of 3–4 mm, the probability of endometrial cancer is less than 1% [22]. In postmenopausal women with AUB, when endometrial thickness is less than 5 mm, the risk of developing endometrial cancer is approximately 0.07%, and 7.3% when the endometrium is greater than 5 mm [36], [39].
It is not recommended to routinely use pelvic magnetic resonance imaging (MRI) as a diagnostic method for EH. However, this method is considered promising in the differential diagnosis of atypical endometrial hyperplasia and endometrial cancer, since diffusion-weighted MRI can detect early signs of endometrial tissue invasion into the myometrium, which are characteristic of early-stage endometrial cancer [27], [40].
For adults – Grade of Recommendation C (Level of Evidence – 4), for children – Grade of Recommendation C (Level of Evidence – 5)
It is recommended when EH is suspected based on pelvic ultrasound data, to perform a pathomorphological examination of uterine (endometrial) biopsy (surgical) material obtained via uterine (endometrial) tissue biopsy or diagnostic curettage of the uterine cavity (according to NOM – Fractional diagnostic curettage of the uterine cavity), if possible under hysteroscopic control [27], [37], [41], [42], [43], [44], [45], [46].
For adults – Grade of Recommendation B (Level of Evidence – 2), for children – Grade of Recommendation C (Level of Evidence – 4)
Comments: Hysteroscopy (HSC) allows for biopsy or diagnostic curettage of the uterine cavity with the removal of focal lesions, including endometrial polyps or submucosal myoma nodes, under visual control [37], [41], [42], [43], [44], [45].
It is recommended when EH is suspected based on pelvic ultrasound data, to perform uterine (endometrial) tissue biopsy in patients of reproductive age with a regular menstrual cycle [27], [37], [41], [42], [43], [44].
For adults – Grade of Recommendation B (Level of Evidence – 2), for children – Grade of Recommendation C (Level of Evidence – 5)
It is recommended to establish the definitive diagnosis of EH in patients with recurrent EH and risk factors for endometrial cancer in perimenopause and postmenopause based on the results of pathomorphological examination of uterine (endometrial) biopsy (surgical) material obtained during diagnostic curettage of the uterine cavity (if conditions for performing hysteroscopy are absent) [1], [23], [25], [26], [27], [37], [45].
For adults – Grade of Recommendation B (Level of Evidence – 2), for children – Grade of Recommendation C (Level of Evidence – 5)
2.5 Other Procedures
Not applicable
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
EH therapy includes conservative (hormonal) and surgical treatment. The choice of management tactics for EH depends on the pathomorphological report, the patient's age, her reproductive plans, the presence of EH risk factors, and concomitant gynecological and extragenital pathology [25], [26], [27]. The goal of EH therapy is to stop AUB, prevent EH relapses, and prevent the development of endometrial cancer.
3.1 Management of patients with EH without atypia
It is recommended after pathomorphological verification of the diagnosis of EH, as medical therapy, to use localized action of #levonorgestrel in the form of a 52 mg intrauterine therapeutic system (according to ATC – Intrauterine contraceptives) [47], [48], [49], [50].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: The efficacy of the 52 mg levonorgestrel-releasing intrauterine system (LNG-IUS) for non-atypical EH is 72–100% with minimal systemic effects and side effects [6], [23], [47], [48], [49], [50].
It is recommended that, following pathomorphological verification of the diagnosis of endometrial hyperplasia (EH), progestogen therapy (according to the Anatomical Therapeutic Chemical (ATC) classification – progestogens) be administered in continuous or prolonged cyclic regimens as an alternative to the levonorgestrel-releasing intrauterine system (LNG-IUS) [47], [48], [49], [50], [51], [52].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
Comments: Progestogens in a cyclic regimen are less effective for the regression of non-atypical EH compared to the continuous regimen and the LNG-IUS [6], [23], [45], [47], [48], [49], [50], [52]. According to a 2020 review of 11 randomized clinical trials, the efficacy of the LNG-IUS reached up to 92%, while that of oral progestogens reached up to 72% [49].
It is recommended to use gonadotropin-releasing hormone agonists (GnRH agonists) (according to the ATC – Gonadotropin-releasing hormone analogues) when EH is combined with uterine fibroids and endometriosis [26], [27], [53], [54], [55], [56].
For adults – Grade of Recommendation C (Level of Evidence – 4), for children – Grade of Recommendation C (Level of Evidence – 5)
Comments: The use of GnRH agonists is advisable when EH is combined with uterine fibroids or endometriosis [53], [54], [55], [56]. In cases of severe estrogen-deficiency symptoms and the need for therapy exceeding 6 months, it is advisable to prescribe add-back therapy with continuous menopausal hormone therapy preparations [56].
It is recommended, following pathomorphologically verified EH, to administer therapy with #levonorgestrel in the form of a 52 mg intrauterine therapeutic system (according to the ATC – Intrauterine contraceptives) or progestogens for 6 months, followed by a pathomorphological examination of endometrial biopsy (surgical) material (without removing the intrauterine therapeutic system, if present) to determine further management tactics [26], [27], [48], [50], [51], [52], [57], [58], [59].
For adults – Level of Evidence B (confidence level of evidence – 3), for children – Level of Evidence C (confidence level of evidence – 5)
Comments: To monitor the efficacy of non-atypical EH treatment, endometrial tissue sampling for pathomorphological examination can be performed via biopsy, hysteroscopy, or diagnostic curettage of the uterine mucous membrane. A 6-month course of LNG-IUS therapy (compared to a 3-month course) increases the EH regression rate from 84% to 100%, and oral progestogens from 50% to 72% [57]. In the absence of side effects and if the patient is not seeking pregnancy, it is advisable to extend LNG-IUS therapy for up to 5 years to reduce the risk of EH recurrence, with annual ultrasound monitoring of the endometrium and endometrial biopsy if necessary [58], [59].
It is recommended to inform the patient about the possibility of EH recurrence after completing the course of therapy [26], [27], [51], [58], [59].
For adults – Level of Evidence B (confidence level of evidence – 3), for children – Level of Evidence C (confidence level of evidence – 5)
Comments: The LNG-IUS and oral progestogens (in prolonged cyclic or continuous regimens) are effective in achieving regression of non-atypical EH. Despite the higher efficacy of the LNG-IUS compared to oral progestogens, after discontinuation of a 6-month course of therapy, the recurrence rate in both groups reached 40% at 2 years [50]. Recurrences occur significantly more often in patients with a BMI ≥35 kg/m2.
It is recommended, in the absence of an effect from conservative treatment and upon progression of EH, to consider surgical treatment (hysterectomy, preferably via a laparoscopic approach, or endometrial resection under hysteroscopic control (hysteroresectoscopy)) [26], [27], [60], [61], [62].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: The issue of hysterectomy is addressed if the patient is not interested in preserving reproductive function, if EH progresses to atypical endometrial hyperplasia (AEH), if EH recurs after a 12-month course of treatment, or if the patient refuses conservative treatment [27].
It is not recommended to perform endometrial ablation for the treatment of EH [27].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
3.2 Management of women with AEH
It is recommended that hysterectomy, preferably via a laparoscopic approach, be performed for AEH [26], [27], [61], [62], [63], [64], [65].
For adults – Grade of Recommendation C (Level of Evidence – 4), for children – Grade of Recommendation C (Level of Evidence – 5)
Comments: Hysterectomy is necessary due to the high probability of concomitant endometrial cancer (diagnosed in 30–40% of cases according to some data) [63], [64], [65].
The final scope of surgery—hysterectomy with fallopian tubes, and in some cases hysterectomy with adnexa—is determined based on concomitant pathology and risk factors [65].
It is recommended that, upon detection of AEH in reproductive-age patients with a strong desire to preserve childbearing potential and refusal of hysterectomy, a medical board be convened to determine the feasibility of conservative treatment via local administration of #levonorgestrel in the form of an intrauterine therapeutic system (according to the ATC – Intrauterine contraceptives) or progestogens (according to the Anatomical Therapeutic Chemical (ATC) classification – Progestogens) in a continuous regimen, with mandatory pathomorphological examination of uterine (endometrial) biopsy (surgical) material every 3 months to refine further management tactics [26], [27], [66], [67], [68], [69], [63], [64], [65], [70], [71], [72], [73], [74], [75], [76], [77], [78].
For adults – Level of Evidence B (confidence level of evidence – 2), for children – Level of Evidence C (confidence level of evidence – 5)
Comments: The feasibility of conservative therapy is supported by literature data on a disease regression rate of 85.6%, while recurrence is possible in 26% of cases [73]. Evaluation of the results of LNG-IUS and oral progestogen use (according to the ATC – Progestogens and estrogens (fixed combinations)) revealed that EH regression induced by the LNG-IUS occurs significantly more often (90% compared to 69%) [48]. In AEH, the probability of concomitant endometrial cancer is diagnosed in 30–40% of cases, which indicates the advisability of hysterectomy in AEH [63], [64].
4. Medical Rehabilitation and Sanatorium-Resort Treatment
There is no specific rehabilitation.
5. Prevention and Dispensary Observation
It is recommended to perform follow-up monitoring with annual comprehensive pelvic ultrasound (transvaginal and transabdominal) and, if indicated, uterine (endometrial) tissue biopsy in patients at high risk of EH recurrence and endometrial cancer development [66], [79], [67].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: The monitoring schedule may vary depending on the clinical situation. The optimal frequency and timing of examinations are not clearly defined due to the scarcity of published data. During the first year, uterine (endometrial) tissue biopsy is recommended every 6 months, with removal from follow-up if no EH is detected on 2 consecutive pathomorphological examinations of uterine (endometrial) biopsy (surgical) material [25], [26], [27].
Risk factors for EH recurrence and endometrial cancer development include: overweight and obesity, polycystic ovary syndrome (PCOS), etc. [16], [18], [19], [66], [79], [67], [80].
Obesity reduces the efficacy of therapy and the probability of subsequent EH remission. Risk factor modification, treatment of obesity, diabetes mellitus, arterial hypertension, PCOS, and normalization of body weight are necessary. The comprehensive measures should include physical exercise and a rational, balanced diet, with a 30% calorie reduction to achieve and maintain a normal body weight. Physical activity should be at least 150 minutes per week, including muscle-strengthening exercises on 2 days per week. The schedule and intensity of workouts are selected individually [18], [19], [67].
It has been shown that long-term progestogen intake reduces the risk of EH, and the use of combined oral contraceptives (ATC – Progestogens and estrogens (fixed combinations)) leads to a reduced risk of endometrial cancer development [50], [81], although there is no evidence base regarding the efficacy of combined oral contraceptives for preventing EH recurrence.
6. Organization of Medical Care
Indications for hospital admission to a medical organization:
- Surgical treatment;
- AUB.
Indications for discharge from the medical organization:
- cessation of AUB.
7. Additional Information
Not required.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1. | Pathomorphological examination of uterine (endometrial) biopsy (surgical) material was performed (upon diagnosis) | Yes/no |
2. | Complex pelvic ultrasound (transvaginal and transabdominal) was performed | Yes/no |
3. | Hormonal treatment for non-atypical EH was prescribed | Yes/no |
4. | Pathomorphological examination of uterine (endometrial) biopsy (surgical) material was performed to assess the cure of endometrial hyperplasia | Yes/no |
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Appendix A1. Working Group Composition
Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Honored Scientist of Russia, Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, Chief Freelance Specialist in Gynecology of the Russian Ministry of Health; member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecologic Endoscopists, the Russian Endometriosis Association, and the Russian Society of Obstetricians and Gynecologists.
Elena N. Andreeva – Doctor of Medical Sciences, Professor, Deputy Director and Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology, Professor at the Department of Endocrinology of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine, President of the International Association of Obstetricians, Gynecologists and Endocrinologists, member of the Russian Association of Gynecologic Endoscopists, the Russian Endometriosis Association, the Russian Society of Obstetricians and Gynecologists, and ROSGEM.
Natalya V. Artymuk – Doctor of Medical Sciences, Professor, Head of the Professor G.A. Ushakov Department of Obstetrics and Gynecology at Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo), member of the Presidium of the Board of the Russian Society of Obstetricians and Gynecologists, President of the Kemerovo Regional Public Organization «Association of Obstetricians and Gynecologists».
Nadezhda V. Bashmakova – Doctor of Medical Sciences, Professor, Head of the Department of Assisted Reproductive Technologies, Chief Researcher at the Research Institute of Maternity and Infancy Care of the Russian Ministry of Health, Honored Doctor of Russia, Chief Obstetrician-Gynecologist of the Ural Federal District.
Vitaly F. Bezhenar – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Neonatology at the First Pavlov State Medical University of St. Petersburg of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the St. Petersburg Health Committee, member of the Society for Reproductive Medicine and Surgery, the Russian Association of Gynecologic Endoscopists, and the Russian Society of Obstetricians and Gynecologists.
Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Additional Professional Education at Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita), member of the Russian Society of Obstetricians and Gynecologists, President of the Trans-Baikal Society of Obstetricians and Gynecologists.
Madina R. Dumanovskaya – Candidate of Medical Sciences, Senior Researcher at the Department of Gynecologic Endocrinology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, member of the Executive Committee of ROSGEM.
Antonina A. Smetnik – Head of the Department of Gynecologic Endocrinology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Candidate of Medical Sciences, member of the Russian Society of Obstetricians and Gynecologists, President of the Russian Society of Gynecological Endocrinology and Menopause Specialists.
Larisa V. Suturina – Doctor of Medical Sciences, Professor, Head of the Department of Reproductive Health Protection at the Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk), member of the Association of Gynecologic Endocrinologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.
Narine M. Tonoyan – Candidate of Medical Sciences, Obstetrician-Gynecologist at the Department of Operative Gynecology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.
Oleg S. Filippov – Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Chief Freelance Obstetrician-Gynecologist of the FMBA of Russia, Deputy Director of the Federal Research and Clinical Center of Children and Adolescents of the FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine.
Svetlana V. Khokhlova – Doctor of Medical Sciences, Head of the Oncology Department of Antitumor Drug Therapy at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.
Galina E. Chernukha – Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Gynecologic Endocrinology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, President of the Interregional Public Organization «Association of Gynecologic Endocrinologists».
Maria I. Yarmolinskaya – Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Gynecology and Reproductive Endocrinology at the D.O. Ott Research Institute of Obstetrics and Gynecology, Professor at the Department of Obstetrics and Gynecology at the North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, member of the Russian Society of Obstetricians and Gynecologists.
Conflict of interest: All members of the working group declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Obstetricians-gynecologists, general practitioners, family physicians;
Students, residents, postgraduate students;
Faculty members, researchers.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
These clinical guidelines were developed taking into account the following regulatory legal documents:
1) Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020, «On Approval of the Procedure for Providing Medical Care in the Profile «Obstetrics and Gynecology (Excluding the Use of Assisted Reproductive Technologies)» (as amended);
2) Order of the Ministry of Health of the Russian Federation No. 803n dated July 31, 2020, «On the Procedure for Using Assisted Reproductive Technologies, Contraindications and Restrictions on Their Use».
Appendix B. Physician Action Algorithms
Endometrial hyperplasia without atypia
Endometrial hyperplasia with atypia
Appendix C. Patient Information
Endometrial hyperplasia is a pathological process characterized by excessive proliferation of the uterine mucosa, most commonly occurring against the background of delayed menstruation. In most cases, this process is non-malignant, but under certain circumstances, it can lead to endometrial cancer.
The endometrium undergoes cyclic changes throughout each menstrual cycle in response to hormones produced in the ovaries. During the first phase of the menstrual cycle (the follicular phase), the ovaries actively produce female sex hormones (estrogens), which promote endometrial growth (proliferation). Approximately in the middle of the menstrual cycle, ovulation occurs in one of the ovaries, followed by the formation of the corpus luteum (a temporary endocrine gland necessary for the establishment and maintenance of pregnancy), which secretes the hormone progesterone. Progesterone is necessary to prepare the endometrium for embryo implantation and its subsequent development. If pregnancy does not occur, estrogen and progesterone levels decrease, leading to the shedding of the uterine mucosa (menstruation). This process is cyclical and repeats every menstrual cycle.
Why does endometrial hyperplasia develop?
In most cases, endometrial hyperplasia occurs in the absence of ovulation, against the background of excessive estrogen production and decreased progesterone. In these cases, menstruation is delayed, and the endometrium continues to grow in response to the action of estrogens. This entire process can lead to impaired cellular differentiation and is a risk factor for oncogenesis.
Endometrial hyperplasia can manifest at any age, but it most commonly occurs in association with obesity, polycystic ovary syndrome, or infertility, during the menopausal transition when ovulation becomes infrequent, as well as during menopause.
In addition to the aforementioned conditions, endometrial hyperplasia may develop:
during the use of estrogen medications and tamoxifen**, used in breast cancer treatment
Risk factors for endometrial hyperplasia:
age over 35 years
nulliparity (no history of pregnancy and childbirth)
late onset of menopause
early menarche
burdened somatic history: diabetes mellitus, arterial hypertension
obesity
smoking;
family history of uterine, ovarian, or colon cancer
A definitive diagnosis of endometrial hyperplasia is established based on the results of pathomorphological examination of endometrial tissue.
There are two types of endometrial hyperplasia:
- benign endometrial hyperplasia (endometrial hyperplasia without atypia)
- precancerous changes of the endometrium (endometrial hyperplasia with atypia).
The most common symptom of endometrial hyperplasia is abnormal uterine bleeding.
If you experience at least one of the symptoms listed below, you should consult an obstetrician-gynecologist:
- heavy bleeding with clots during menstruation,
- menstruation lasting more than 8 days (usually following a missed period)
- menstrual cycles shorter than 24 days (counted from the first day of the menstrual cycle to the first day of the next one)
- intermenstrual bleeding
- any bleeding against the background of postmenopause.
In the presence of bleeding, a pelvic ultrasound examination with measurement of the endometrial thickness is required (endometrial thickening may suggest endometrial hyperplasia).
To establish a definitive diagnosis and stop the bleeding, an endometrial biopsy or diagnostic curettage under hysteroscopic control is performed, followed by microscopic evaluation of the endometrium. Endometrial hyperplasia can be treated with progesterone preparations (ATC classification: Progestogens), either via the introduction of a hormonal intrauterine device or orally or vaginally. The duration of therapy is determined individually and depends on the patient's age and the type of hyperplasia.
If a precancerous form of endometrial hyperplasia is detected, removal of the uterus (hysterectomy) is possible.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable