Menopause and Climacteric State in Women: Clinical Guidelines

List of Abbreviations

• BP – blood pressure

• ALT – alanine aminotransferase

• AMH – anti-Müllerian hormone

• AST – aspartate aminotransferase

• VA – vaginal atrophy

• VVA – vulvovaginal atrophy

• LNG-IUS – levonorgestrel-releasing intrauterine system

• WHO – World Health Organization

• VTE – venous thromboembolism

• VTE – venous thromboembolic events

• GGT – gamma-glutamyl transferase

• GSM – genitourinary syndrome of menopause

• DXA – dual-energy X-ray absorptiometry

• E2 – estradiol

• GSD – gallbladder stone disease

• HRT – hormone replacement therapy

• CHD – coronary heart disease

• BMI – body mass index

• COC – combined oral contraceptives (ATC classification: Hormonal contraceptives for systemic use)

• CEE – conjugated equine estrogens

• HDL-C – high-density lipoprotein cholesterol

• LDL-C – low-density lipoprotein cholesterol

• MHT – menopausal hormone therapy

• MPA – Medroxyprogesterone**

• BMD – bone mineral density

• Russian Ministry of Health – Ministry of Health of the Russian Federation

• IGT – impaired glucose tolerance

• P – progestogen (ATC classification: Progestogens)

• POI – premature ovarian insufficiency

• PCR – polymerase chain reaction

• RCT – randomized controlled trial

• BC – breast cancer

• RF – Russian Federation

• DM – diabetes mellitus

• SSRI – selective serotonin reuptake inhibitor

• SNRI – serotonin-norepinephrine reuptake inhibitor

• TSH – thyroid-stimulating hormone

• US – ultrasound

• FSH – follicle-stimulating hormone

• Chol – cholesterol

• E – estrogen

• ACR – American College of Radiology

• BI-RADS – Breast Imaging Reporting and Data System

• FRAX – Fracture Risk Assessment Tool

• NAMS (North American Menopause Society) – North American Menopause Society

• STRAW (Stages of Reproductive Ageing Workshop) – Stages of Reproductive Aging Workshop classification

• WHI (Women’s Health Initiative) – Women’s Health Initiative randomized controlled clinical trial

Terms and Definitions

Stages of Reproductive Aging in Women – clinical and hormonal characteristics of reproductive aging stages (Stages of Reproductive Aging Workshop – STRAW) developed in 2001 and revised in 2011 (STRAW+10) [1].

Vasomotor symptoms – manifestations of autonomic nervous system dysregulation (hot flashes, night sweats, chills, etc.).

Hot flashes – a sudden feeling of heat in the face and upper body (neck, arms, chest), which may be accompanied by sweating and chills.

Psychoemotional menopausal disorders include mood lability, sleep disturbances, depressive states, anxiety, tearfulness, hyper excitability, aggression, and panic attacks.

Genitourinary syndrome of menopause (GSM) – a symptom complex associated with decreased levels of estrogens and other sex steroids, involving changes in the external genitalia, perineum, vagina, urethra, and bladder.

Vulvovaginal atrophy (VVA) frequently accompanies GSM. The most common symptoms of VVA are vaginal dryness, dyspareunia, burning, and itching.

Urinary incontinence – involuntary loss of urine, representing a social or hygienic problem, with objective evidence of uncontrolled urination.

Postmenopausal osteoporosis – a metabolic skeletal disease characterized by reduced bone mass, impaired bone microarchitecture, and, consequently, fractures resulting from minimal trauma.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Menopause is defined as the final menstrual period [2].

Natural menopause reflects the permanent cessation of menstrual cycles due to declining ovarian function [3]; it is a retrospective clinical diagnosis established after 12 consecutive months of amenorrhea.

Climacteric syndrome – a complex of autonomic-vascular, psychological, and metabolic-endocrine disorders occurring in women against the background of declining (or abrupt loss of) ovarian hormonal function and general somatic aging [4].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The menopausal transition period is accompanied by fluctuations in sex hormone levels, the development of ovulatory dysfunction, decreased progesterone secretion, and, consequently, changes in menstrual cycle characteristics [4].

Perimenopause is characterized by a gradual decrease and subsequent cessation of ovarian function, along with the development of estrogen deficiency. The resulting hypergonadotropic hypogonadism state is characterized by altered limbic system function, disrupted neurohormone secretion, the development of involutional and atrophic processes in reproductive and non-reproductive target organs, and the manifestation of specific symptoms [5].

In postmenopause, estrogen synthesis continues, but at significantly lower concentrations than during the reproductive period. Estrogen synthesis occurs primarily through the conversion of androstenedione to estrone (to a greater extent) and testosterone to estradiol via aromatase action [6], [7]. Obesity, along with increased aromatase activity, may be associated with higher serum estrogen and testosterone concentrations in postmenopausal women [8], [9]. Ovarian testosterone production decreases as a woman ages, and the onset of menopause does not affect testosterone levels [10], [11]; meanwhile, postmenopausal ovarian theca cells continue to synthesize testosterone in response to elevated gonadotropin levels [12].

Against the background of declining estrogen levels, some women may develop abdominal obesity and face increased risks of metabolic disorders, cardiovascular complications, and relative hyperandrogenism, which is accompanied by late-onset acne, alopecia, and hirsutism [13], [14].

1.3 Epidemiology of the Disease or Condition

The average worldwide age of menopause onset is 48.8 years (95% CI 48.3-49.2), with significant regional variations depending on the geographical area where women live [15]; in the Russian Federation, it ranges from 49 to 51 years [4].

About 75% of women aged 45 to 55 report hot flashes, with 28.5% of cases being moderate to severe in intensity [16]; the duration of symptoms can range from 3 to 15 years [17].

Vasomotor symptoms most commonly occur in the late phase of the menopausal transition and are particularly pronounced during the first years of postmenopause [18]. The prevalence of sleep disturbances ranges from 39% to 47% in perimenopausal women and from 35% to 60% in postmenopausal women [19].

Among individuals aged 50 years and older in the Russian Federation, osteoporosis is diagnosed in 34% of women, while the prevalence of osteopenia is 43% [20].

Symptoms of GSM or VVA are reported by 15% of perimenopausal women and up to 80% of postmenopausal women [21], [22], [23]. At least one symptom of VVA is present in 41% of women aged 50-79 years. The prevalence of voiding dysfunction (sudden, compelling urge to urinate that cannot be deferred, urinary incontinence) in women depends on the duration of postmenopause, increasing from 15.5% with a postmenopausal duration of up to 5 years to 41.4% when the duration exceeds 20 years [24].

1.4 Features of Coding the Disease or Condition

N95 Menopausal and other perimenopausal disorders:

N95.1 – Menopausal and female climacteric states

N95.2 – Postmenopausal atrophic vaginitis

N95.3 – Artificial menopause state

N95.8 – Other specified menopausal and perimenopausal disorders

N95.9 – Menopausal and perimenopausal disorder, unspecified

1.5 Classification of the disease or condition

The following types of menopause are distinguished:

By cause of onset:

– spontaneous (natural) menopause;

– menopause resulting from bilateral oophorectomy (surgical menopause) or chemotherapy/radiotherapy.

By timing of onset:

– premature (premature ovarian insufficiency) (under 40 years);

– early (40-44 years);

– timely (45-55 years);

– late (over 55 years).

In 2001, the clinical and hormonal staging of reproductive aging was first developed (Stages of Reproductive Aging Workshop – STRAW) and later revised in 2011 to incorporate findings from large cohort studies conducted over the subsequent 10 years (STRAW+10) (Appendix A3, Fig. 1) [1].

The menopausal transition period is characterized by cycle variability, begins at ages 40-45, and ends with the onset of menopause. Fluctuating levels of follicle-stimulating hormone (FSH) and estradiol (E2) are observed, along with a decrease in inhibin B and anti-Müllerian hormone (AMH). Amidst menstrual irregularities, vasomotor, psychological, and urogenital symptoms associated with estrogen decline may appear, alongside a high incidence of abnormal uterine bleeding linked to ovulatory dysfunction [5]. This phase of reproductive aging can last up to 4-8 years. It is divided into early (variable FSH levels and menstrual cycle length) and late menopausal transition (occurring 1-3 years prior to the final menstrual period, persistently elevated FSH ≥25 IU/L, amenorrhea ≥60 days) [25] [26].

Premenopause. The term "premenopause" is not recommended for denoting the final few years before menopause. Currently, this term should be used to designate the entire reproductive period and the menopausal transition—that is, from menarche to the final menstrual period [27].

Menopause is the permanent cessation of menstruation; it is the final spontaneous menstrual period resulting from age-related decline in hormonal function and the cessation of ovarian reproductive function. The date of menopause is determined retrospectively after 12 months of amenorrhea.

Perimenopause includes the menopausal transition period plus 12 months after the final spontaneous menstrual period.

Postmenopause is the period following the onset of menopause.

The phases of early postmenopause include +1a, +1b, and +1c. They are characterized by a progressive increase in FSH levels and a decrease in E2, AMH and inhibin B. This phase lasts 5-8 years, and climacteric syndrome symptoms frequently persist.

Late postmenopausal phase (+2) – Vasomotor symptoms are less pronounced but may persist long-term in 15% of cases. Somatic aging comes to the forefront. (See Appendix A3)

1.6 Clinical presentation of the disease or condition

Clinical signs arising during peri- and postmenopause due to estrogen deficiency represent the initial manifestations of climacteric (menopausal) syndrome. A clear correlation has been established between estrogen deficiency and vasomotor symptoms, sleep disturbances/insomnia, vaginal dryness, dyspareunia, mood lability, depression, and cognitive impairment [19], [28], as well as the development of visceral (abdominal) obesity and blood pressure fluctuations [29], [30].

Current evidence regarding the association between sexual dysfunction and estrogen deficiency remains inconclusive.

Vasomotor symptoms (hot flashes, sweating, chills) are the most frequent and early manifestations of the peri- and early postmenopausal periods. The average duration of hot flashes is 7.4 years, although increasing prospective data suggest they may persist for ≥10 years in a significant number of women [3]. According to the IMS guidelines (2024), hot flashes are considered an independent cardiovascular risk factor in women [31].

The most typical complaint among patients with sleep disorders is frequent awakenings (sleep fragmentation). Other manifestations include insomnia, difficulty falling asleep, and early morning awakenings. Sleep disturbances are frequently combined with vasomotor symptoms, increased anxiety, and mood lability. Psychosocial factors, stress, and comorbid conditions play a significant role in the onset of sleep disorders during peri- and postmenopause [32].

Vaginal dryness, pruritus, and dyspareunia (pain during intercourse) are symptoms associated with VVA. The development of VVA is rooted in sex hormone deficiency (primarily estrogens), which triggers a series of involutional (atrophic) processes in the urogenital tract and is accompanied by alterations in the microbiota composition. VVA symptoms are frequently combined with voiding dysfunctions (pollakiuria, nocturia, cystalgia, urinary urgency). The symptom complex occurring in women against the background of estrogen deficiency, encompassing physiological and anatomical changes in the vagina, urethra, bladder, and external genitalia, is termed genitourinary syndrome of menopause (GSM) [23].

The onset of depression in the peri- and postmenopausal period is associated with estrogen deficiency in the female body, is often combined with vasomotor symptoms and night sweats, which leads to sleep disturbances and insomnia, and is the result of dysregulation of the noradrenergic and serotonergic systems [19]. These same processes are related to cognitive impairments (typically a decrease in attention span and memory), which are observed to a greater extent in patients during the perimenopausal period, although the relationship between cognitive impairment and estrogen deficiency is more complex [33]. It should be noted that these manifestations often correlate with vasomotor symptoms, depression, and anxiety states in peri- and postmenopausal women [34].

The increase in abdominal/visceral fat and decrease in muscle mass are more pronounced in postmenopause and are associated with an increased risk of mortality even among individuals with a normal BMI [35].

2. Diagnostics, medical indications and contraindications for diagnostic methods

In diagnosing menopause and determining the stage of reproductive aging, taking an anamnestic history is important, including information about menstruation and the presence of menopausal symptoms. Laboratory and instrumental examination data are necessary in case of difficulties in establishing a diagnosis, as well as to identify conditions associated with menopause.

Criteria for establishing the diagnosis/condition based on pathognomonic data:

1) anamnestic data

2) physical examination

3) laboratory tests

4) instrumental examination [4].

2.1 Complaints and Anamnesis

Comments: It should be emphasized that there is a large individual variability of menopausal symptoms among patients both in the time of their onset and in duration and intensity.

Comment: The STRAW +10 terminology and criteria system are applicable to the majority of women because the aging process of the reproductive system is universal. The STRAW +10 reproductive aging stage classification is not applicable in patients with polycystic ovary syndrome, premature ovarian insufficiency, after hysterectomy, endometrial ablation, or those currently using an LNG-IUS, COCs (according to ATC – Hormonal contraceptives for systemic use). In these groups of patients, it is necessary to pay attention to the occurrence of vasomotor and psycho-emotional symptoms as early signs of approaching menopause.

Comment: history taking implies questioning the patient regarding complaints, hereditary pathology (presence of oncological diseases: breast, endometrial, ovarian, intestinal cancer; thromboembolic events; diabetes mellitus; cardiovascular diseases – strokes, myocardial infarctions under the age of 50 [29]; osteoporosis, including fractures), obstetric history (gestational diabetes mellitus, preeclampsia, arterial hypertension), bad habits, concomitant somatic, endocrine, and systemic diseases, surgical interventions, gynecological pathology, current or previous drug therapy. If comorbid conditions are identified, consultation with specialized professionals is indicated.

2.2 Physical Examination

2.3 Laboratory Diagnostics

Comments: serum FSH testing is performed twice on days 2–5 of the menstrual cycle in two consecutive menstrual cycles if menstruation is present; in case of amenorrhea, on any day twice with a 4–6 week interval.

Comments: pH test strips for determining vaginal secretion pH.

Comments: Cervical screening should be carried out in accordance with the order of the Russian Ministry of Health No. 1130n dated 2020 [43].

2.4 Instrumental Diagnostics

Comments: Assessment of the individual 10-year probability of fractures is carried out using the FRAX algorithm as a screening method. The most informative method for assessing bone mineral density and diagnosing osteoporosis is dual-energy X-ray absorptiometry (DXA) (according to NMU – X-ray densitometry of the lumbar spine, X-ray densitometry of the proximal femur) [60].

Comments: To assess BMD, WHO criteria for interpreting DXA results in women are used [61]:

- normal – T-score values ≥-1 standard deviations from peak bone mass;

- osteopenia – T-score values from -1 to -2.5 standard deviations;

- osteoporosis – T-score values of -2.5 standard deviations and below;

- severe osteoporosis – T-score values of -2.5 standard deviations and below with a history of one or more fractures.

Comments: Women diagnosed with POI have both well-known risk factors for osteoporosis and specific ones (such as ovarian failure before achieving peak bone mass, lack of treatment for more than 1 year due to delayed diagnosis, inadequate therapy, and non-compliance with recommendations). It is recommended to interpret DXA results in women with POI [64], [65].

– BMD within the age norm – Z-score values >-2 standard deviations;

– low BMD – Z-score values ≤-2 standard deviations;

– osteoporosis – T-score values <-2.5 standard deviations and below and/or the presence of a low-energy fracture (especially vertebral)

2.5 Other Procedures

Comments: Mandatory examination prior to prescribing MHT includes:

- pelvic ultrasound to rule out organic pelvic pathology; with an endometrial thickness of ≤4 mm in perimenopausal and postmenopausal women, MHT is not contraindicated; >4 mm – during the menopausal transition phase, progestogens are prescribed for 10 days, followed by a follow-up comprehensive pelvic ultrasound (transvaginal and transabdominal) on the 5th–7th day of the menstrual-like bleeding or, in its absence, 7–14 days after discontinuation of progestogens; >4 mm in postmenopause – hysteroscopy and separate diagnostic curettage of the uterine cavity and cervical canal or endometrial aspiration biopsy (according to the Nomenclature of Medical Services – uterine tissue biopsy) are recommended to clarify the state of the endometrium [69].

- breast examination: visual inspection, palpation, mammography in two projections starting from the age of 40, and breast ultrasound under the age of 40 with BI-RADS scoring and ACR mammographic density classification to rule out breast pathology [66], [68]. High mammographic density (ACR density category C or D) is a high-risk factor for breast cancer (BC) and requires additional examination – breast ultrasound [66], [68]. High mammographic density may reduce mammography sensitivity down to 48%, necessitating additional imaging methods alongside mammography (breast ultrasound, contrast-enhanced breast MRI) [66]. In the presence of breast nodules, and/or a BI-RADS category other than 1 or 2, and/or high mammographic density (ACR: C or D), and/or other significant risk factors for BC, a consultation with an oncologist (mammologist) is recommended to determine the presence or absence of contraindications to MHT (sex steroid hormone therapy) from the perspective of breast health.

- Cytological examination of a cervical smear – Pap test [56]. If screening examination data are already available from routine health check-ups (dispanstrizatsia), this examination is not repeated. If screening results are absent, the patient must be ordered the specified examination method.

- Measurement of blood pressure in peripheral arteries

- complete blood count

- general clinical blood chemistry (fasting blood glucose/glycated hemoglobin test, total protein, total and direct bilirubin, serum creatinine) and lipid metabolism blood chemistry (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, serum triglycerides) [4]; if metabolic syndrome or carbohydrate metabolism disorders (impaired glucose tolerance, type 2 diabetes mellitus) are suspected, an oral 2-hour glucose tolerance test is recommended as a reliable indicator of impaired glucose tolerance.

Comment: with appropriate medical history data and indications, a comprehensive ultrasound examination of the abdominal organs and general clinical blood chemistry (ALT, AST, GGT activity in the blood) are performed; coagulogram (exploratory hemostasis screening); detection of prothrombin G20210A polymorphism in coagulation factor II gene; molecular genetic testing for the G1691A mutation in the coagulation factor V gene (Factor V Leiden mutation), colonoscopy.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

3.1.1. Systemic menopausal hormone therapy

Comment: Menopausal hormone therapy (MHT) effectively relieves the symptoms of climacteric syndrome and reduces/delays the development of long-term consequences of estrogen deficiency.

When choosing therapy, the physician must adhere to the principles of the modern concept of personalized menopausal hormone therapy.

1. Initiation of systemic MHT should be considered in women aged under 60 years and with a postmenopausal duration of less than 10 years. The optimal window for starting MHT is the peri- and early postmenopausal period. There are no age restrictions for prescribing local estrogen therapy (estriol) for genitourinary syndrome of menopause (GSM) symptoms.

2. The therapeutic goal should be to use the most appropriate minimum effective dose of MHT in accordance with the treatment goals.

3. Individualization of MHT (choice of dose, dosage form, composition, regimen) is carried out taking into account the patient's age, stage of reproductive aging, gynecological conditions, comorbid states, and the woman's preferences.

4. Presence of indications for MHT and absence of contraindications.

5. The use of MHT requires periodic dosage adjustments depending on the stage of reproductive aging, age, efficacy, and tolerability of treatment. As the patient's age and postmenopausal duration increase, it is advisable to lower the MHT dose.

6. Treatment monitoring and regular (at least once a year) benefit-risk reassessment. The duration of therapy is determined by the treatment goals and the benefit-risk balance.

7. When choosing MHT, the safety profile of the constituent components is taken into account.

8. The prescription, adjustment, or discontinuation of MHT, as well as dynamic monitoring of treatment efficacy and tolerability, falls within the purview of the obstetrician-gynecologist.

Comment: The goal of menopausal hormone therapy (MHT) in perimenopausal and postmenopausal women is to partially replenish sex hormone deficiency using the minimum (optimal) doses of hormonal drugs capable of improving the general condition of patients, relieving climacteric symptoms, and ensuring the prevention of late metabolic disorders. In the presence of other clinical symptoms indicating estrogen deficiency (including arthralgia, muscle pain, memory impairment, sleep disorders, and psycho-emotional disorders) that significantly reduce the quality of life, MHT may be prescribed after additional examination by specialized specialists and the exclusion of other causes for these symptoms [21], [83], [84].

According to cohort and placebo-controlled studies, timely initiation of MHT in perimenopause or within the first 5 years of postmenopause reduces the risk of subclinical atherosclerosis, coronary artery disease (CAD), and cognitive impairment (provided normal cognitive function at the time of MHT initiation) [85], [86], [87].

Comment: Postmenopausal patients (over 40 years of age) are indicated for screening to assess the 10-year risk of major osteoporotic fractures using the FRAX algorithm. If a medium (intermediate) risk is identified (see Appendix D) or in the case of a history of low-energy fractures or other risk factors for osteoporosis, DXA is indicated.

MHT is an effective method for preventing bone mass loss, which is most pronounced in the first 3–5 years of postmenopause, and also contributes to the preservation of bone quality and intervertebral discs in postmenopausal women. The efficacy of MHT has been proven in reducing the risk of fracture in the postmenopausal female population.

The reduction in the risk of osteoporotic fractures depends on the duration of intake and the age of MHT initiation; the protective effect ceases after therapy is discontinued.

There is evidence regarding the prevention of BMD loss with oral and transdermal use of standard and low doses of estradiol as part of MHT (according to the ATC classification – Progestogens and estrogens in combination; Progestogens and estrogens (for sequential "calendar" administration); Progestogens and estrogens (fixed combination)), as well as the prevention of vertebral and other site fractures with the use of tibolone (according to ATC – other estrogens).

Monitoring of therapy efficacy is carried out using DXA once every 1–2 years.

Comment: Indications for the prescription of hormone replacement therapy with sex steroids are the treatment of estrogen deficiency symptoms, as well as the primary prevention of osteoporosis. Hormone replacement therapy should be started as early as possible after the diagnosis of POI in the absence of contraindications.

Comments: the prescription of MHT is possible in the presence of small uterine fibroids (with intermuscular or subserosal location) provided that an ultrasound examination of the uterus and appendages is performed at least once every 6 months during MHT. If growth/increase in the number or changes in the structure of myomatous nodes are detected, MHT must be discontinued [90] [91].

Patients with a history of endometriosis/adenomyosis are indicated for combined estrogen-progestogen therapy or tibolone as MHT, including after hysterectomy [92].

A family history of breast cancer is not a contraindication for MHT and requires additional evaluation of other risk factors.

In the case of detected BRCA1/2 mutation carriership (in the absence of a history of breast cancer), a consultation with an oncologist and selective screening are recommended when prescribing MHT [75], [93].

Comments: If the patient has uterine fibroids with a submucosal node location or an endometrial polyp, surgical treatment is recommended (in the case of uterine fibroids with a submucosal node location – hysteroscopic myomectomy; in the case of an endometrial polyp – hysteroscopy, fractional diagnostic curettage, or hysteroresectoscopy (polypectomy)). After receiving the results of the pathomorphological examination, consider the issue of prescribing MHT.

3.1.1 MHT regimens and characteristics

Comment: MHT drugs registered in the Russian Federation have a wide range of dosage forms, routes, and methods of administration, and also have a favorable safety and efficacy profile, including with respect to the risks of cardiovascular events and VTED [29].

When initiating MHT, it is advisable to select the minimum effective dose of the drug. As the woman's age and duration of postmenopause increase, it is recommended to consider reducing the dosage.

In perimenopause, standard and low doses of estrogens (according to ATC – Estrogens) are used as part of MHT. In postmenopause, low and ultra-low doses of estrogens are used as part of MHT.

In postmenopausal women older than 45 years, low-dose and ultra-low-dose oral estrogens as part of combined monophasic MHT are effective for the treatment of vasomotor symptoms, while having a more favorable safety and tolerability profile compared to standard doses of estrogens.

Oral MHT drugs including standard (2 mg), low (1 mg), and ultra-low (0.5 mg) doses of estradiol are registered in the Russian Federation (according to ATC – Progestogens and estrogens in combination; Antiandrogens and estrogens; Progestogens and estrogens (for sequential "calendar" administration); Progestogens and estrogens (fixed combination)).

Transdermal estrogen formulations for MHT are registered in the Russian Federation: estradiol (ATC: Estradiol) 0.06% transdermal gel comprising a maximum daily dose of 3 mg estradiol (5.0 g of gel), standard daily dose of 1.5 mg estradiol (2.5 g of gel), low daily dose of #0.75 mg estradiol (1.25 g of gel); estradiol (ATC: Estradiol) 0.1% transdermal gel comprising a maximum daily dose of 1.5 mg estradiol (1.5 g of gel), standard daily dose of 1 mg estradiol (1.0 g of gel), low daily dose of 0.5 mg estradiol (0.5 g of gel).

Due to the absence of the first-pass hepatic metabolism, transdermal estrogen formulations have a favorable safety profile in patients with high risks of VTE and gallbladder disease [71], [99], [100], [101].

The main function of progestogen as part of MHT is a protective effect on the endometrium. It is important to consider the properties of progestogen within MHT. Micronized progesterone** (INN: Progesterone**), dydrogesterone**, and a number of other progestogens (ATC: Progestogens) may have other effects in addition to their protective influence on the endometrium. For example, drospirenone in combination with estradiol (ATC: Progestogens and estrogens) possesses antimineralocorticoid and antiandrogen effects, the ability to prevent fluid retention, and improves a number of metabolic parameters [97], [98]. Micronized progesterone** (INN: Progesterone**) and dydrogesterone** are associated with the lowest increase in the risk of breast cancer compared to other progestogens used in MHT [104], [105], [106]. Modern low-dose and ultra-low-dose combined oral MHT containing estradiol used in MHT and progestogens (dydrogesterone** [71] [107] [108] [109] [99] [110] [111], micronized progesterone** (INN: Progesterone**) [71], [101], [107], [108], [109], drospirenone [112], levonorgestrel, etc.) appears to be sufficiently safe regarding thrombotic complications [29]. However, the benefit-risk assessment of MHT, the choice of drug, its composition, and route of administration should be performed individually, taking into account the clinical presentation and the presence of VTE risk factors.

In some countries (including the Russian Federation), the synthetic steroid tibolone (ATC: Other estrogens) is also used for MHT in postmenopausal women. Upon oral administration, the drug is metabolized into three active metabolites, two of which exhibit estrogen-like activity, while the third metabolite exhibits weak progestogen-like and androgen-like activity. Its efficacy in relieving climacteric symptoms is comparable to estradiol as part of MHT (2.5 mg of tibolone is equivalent in action to 1–1.5 mg of estradiol). The drug is used to treat symptoms of estrogen deficiency in postmenopausal women (but no earlier than 12 months after the last menstruation) or immediately after bilateral oophorectomy, for the prevention and treatment of osteoporosis in case of intolerance or contraindications to other drugs used for osteoporosis prevention, and may also favorably affect sexual function in postmenopausal women. Tibolone has no proliferative activity on the endometrium and mammary glands, and no significant effect on the growth of uterine fibroids [40], [96].

Comment: it is necessary to consider the indications for hysterectomy and the extent of surgery (total or subtotal). Estrogen monotherapy is indicated only after total hysterectomy. In the case of supracervical amputation of the uterus, as well as in patients after hysterectomy for adenomyosis or with a history of extensive external genital endometriosis, combined estrogen-progestogen therapy or tibolone is indicated [21], [92], [115]

Preparations containing estradiol are used. Routes of administration: oral (tablets) and parenteral (transdermal gels) continuously.

Comment: micronized progesterone** (INN: Progesterone**) is used at a dose of 200–400 mg daily; #dydrogesterone** 10–20 mg daily [117]. Progesterone and its derivatives are prescribed for a period of at least 10–15 days.

#Levonorgestrel at a dose of 52 mg in the form of an intrauterine therapeutic system (ATC: Plastic intra-uterine devices with progestogen) is indicated for use as the progestogenic component of MHT. The use of #levonorgestrel as an intrauterine therapeutic system (ATC: Plastic intra-uterine devices with progestogen) during the menopausal transition is possible in women requiring contraception, as well as in the presence of heavy menstrual bleeding not associated with organic uterine pathology [69].

Comment: In agreement with the obstetrician-gynecologist, MHT may be prescribed no earlier than 3 months after the last menstruation.

Women should be informed that MHT drugs do not have a contraceptive effect.

Standard and low doses of estrogens as part of MHT are used in perimenopause.

Combined oral formulations containing a standard dose (2 mg) and a low dose (1 mg) of estradiol combined with a progestogen, as well as an oral estradiol preparation (2 mg), are registered in the Russian Federation.

For transdermal MHT, the standard dose is used: 1.5 mg of estradiol in 0.06% transdermal gel (2.5 g of gel); 1.0 mg of estradiol in 0.1% transdermal gel (1.0 g of gel) (used according to the product labeling).

When prescribing the transdermal route of estrogen administration, micronized progesterone** (INN: Progesterone**) (ATC: Progestogens) (orally or vaginally) at a dose of 200–300 mg daily; dydrogesterone** (ATC: Progestogens) orally at 10–20 mg daily depending on BMI are used as the progestogenic component. Progesterone and its derivatives are prescribed for at least 10–14 days.

Comment: When prescribing therapy to patients with POI, the patient's preferences regarding the route and method of administration, as well as the need for contraception, are taken into account. Cyclic estrogen-progestogen therapy is recommended for women with POI to treat climacteric symptoms, improve quality of life, prevent osteoporosis and other age-associated diseases at least until the age of natural menopause—50–51 years. With long-term hormone replacement therapy in POI, switching to continuous monophasic therapy is possible if necessary.

In POI, transdermal or oral estrogen formulations in standard or, if necessary (insufficient symptom relief), high doses can be prescribed as the estrogen component of sex hormone replacement therapy [27], [123].

Transdermal estrogen formulations (ATC: Estradiol) include 0.06% transdermal gel at a daily dose of 1.5–2.25 mg of estradiol (estradiol hemihydrate), up to a maximum of 3.0 mg (2.5–3.75 g of gel, up to a maximum of 5.0 g daily) or 0.1% transdermal gel at a daily dose of 1.0–1.5 mg of estradiol (estradiol hemihydrate) (1.0–1.5 g of gel).

Oral estrogen formulations include estradiol at a daily dose of 2 mg (ATC – Progestogens and estrogens in combination; Progestogens and estrogens (sequential preparations); Progestogens and estrogens (fixed combinations)).

As a progestogen component, it is possible to use (micronized) #progesterone** (INN: progesterone**) (ATC: Progestogens) at a dose of 200–400 mg/day (orally or vaginally) or #dydrogesterone** orally at a dose of 10–20 mg/day for 12–14 days in the second phase of the menstrual cycle for the prevention of endometrial hyperplastic processes [41, 69, 75, 83].

It is possible to use oral fixed combinations of progestogens and estrogens (ATC – Progestogens and estrogens in combination); Progestogens and estrogens (for sequential "calendar" administration); Progestogens and estrogens (fixed combination)): 2 mg estradiol with 10 mg dydrogesterone** or 2 mg estradiol with 150 mcg levonorgestrel daily in a cyclic regimen [65], [78].

Comment: The continuous monophasic MHT regimen is prescribed no earlier than 12 months after the last menstruation. For oral MHT, a low estrogen dose of 1 mg estradiol is used. The following combined oral drug forms are registered in the Russian Federation: estradiol 1 mg / dydrogesterone 5 mg; estradiol 1 mg / drospirenone 2 mg.

For transdermal MHT in early postmenopause, a dose of 1.5 mg of estradiol 0.06% transdermal gel (2.5 g of gel); 1 mg of estradiol 0.1% transdermal gel (1 g of gel) is used, with a subsequent dose reduction after 3–5 years of use [69], [98].

In agreement with the obstetrician-gynecologist, MHT may be prescribed starting from 0.75 mg of estradiol 0.06% transdermal gel (1.25 g of gel) or 0.5 mg of estradiol 0.1% transdermal gel (0.5 g of gel) with individual dose adjustment (if necessary).

When prescribing the transdermal route of estrogen administration, the following are additionally used as a progestogen component: micronized progesterone** (INN: Progesterone**) (orally or vaginally) at a dose of 100 mg per day (when increasing the estrogen dose – 200 mg per day); dydrogesterone** 10 mg per day (when increasing the estrogen dose – 20 mg per day); levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg (ATC: Plastic intrauterine devices with progestogens); progesterone** (vaginal gel) – 90 mg (1 applicator) 2 times a week.

Switching to a monophasic combined MHT regimen when using cyclic combined MHT is possible in the following cases:

- After 1–2 years of taking low-dose MHT in a cyclic regimen if the woman's age at the start of therapy is over 50 years.

- Upon reaching the average age of menopause by the patient (51–52 years), if MHT was started before the age of 50.

- When the nature of the menstruation-like reaction changes: scanty spotting / complete absence for more than 2 consecutive cycles.

- If the patient wishes to stop the menstruation-like reaction after taking low-dose cyclic MHT for at least 12 months (to avoid breakthrough bleeding) [115].

Comments: For oral MHT in postmenopausal women, it is possible to use an ultra-low estrogen dose of 0.5 mg estradiol as part of the drug. The following combined oral drug forms are registered in the Russian Federation: estradiol 0.5 mg / dydrogesterone 2.5 mg; estradiol 0.5 mg / drospirenone 0.25 mg.

Comments: MHT (both oral and transdermal) can be prescribed in the presence of lower extremity varicose veins, smoking (taking into account the combination of all risk factors), as well as provided that blood pressure is controlled using antihypertensive drugs. MHT has a positive effect on the lipid profile in peri- and postmenopausal women. Timely initiated MHT can reduce the risk of type 2 diabetes mellitus by 30%.

If cardiovascular risk factors, cardiovascular and metabolic diseases are identified or suspected, the patient should be recommended a consultation with a general practitioner/internist.

Comment: In the Russian Federation, testosterone preparations for the treatment of climacteric symptoms are not registered. According to a 2019 systematic review and meta-analysis of RCTs, testosterone preparations may be effective for the treatment of postmenopausal women diagnosed with hypoactive sexual desire disorder after a biopsychosocial assessment. Effectiveness in improving general well-being, musculoskeletal and cognitive health, as well as safety indicators require further study [128].

Comments: The decision to continue MHT is made jointly by the patient (who is well-informed) and her physician, taking into account the specific goals of treatment and an objective assessment of the current individual benefits and risks of therapy.

There is no reason to impose strict restrictions on the duration of MHT. Data from major RCTs support the safety of therapy for at least 5 years in healthy women who started it before the age of 60 [105].

NAMS experts in 2015 (and 2022) published a statement on the possible continued use of MHT at the minimum effective dose in women aged >65 years for the treatment of persistent hot flashes, provided that the patient has received detailed information about potential risks and is under close medical supervision [75].

There is no definitive consensus on how best to discontinue MHT: gradually or abruptly. In some women, an ultra-low dose of a hormonal drug is able to maintain general well-being and adequate symptom relief, so they prefer to receive such treatment until their symptoms resolve completely.

3.1.2 Local hormone therapy

Estriol preparations (ATC: Natural and semisynthetic estrogens (G03CA)) are registered in the Russian Federation for vaginal use in the form of suppositories, cream, or gel in various doses: standard 0.5 mg, low 0.2 mg, and ultra-low 0.05 and 0.03 mg. Low- and ultra-low-dose estriol preparations are available both as monotherapy and in combination with lactobacilli (ATC: Other antiseptics and anti-infectives for gynecological use (G01AX)).

Comment: Local (vaginal) estriol therapy is preferred for women complaining of vaginal dryness, dyspareunia, or sexual discomfort associated with this condition. The efficacy of local estriol 0.5 mg in the treatment of GSM/VVA has been proven in RCTs and systematic reviews [127], [128], [129]. At the start of treatment, medications are prescribed daily at a therapeutic dose of 0.5 mg for 2–4 weeks (initial therapy), and as improvement occurs, 2 times a week long-term (maintenance therapy) (see Table 4 in Appendix A3). GSM treatment is considered long-term therapy, as there are no restrictions on breaks and resumption of these drugs. GSM symptoms and the severity of urogenital atrophy are progressive in nature and recur within 1–3 months after discontinuing hormone therapy. Intravaginal estriol has no age restrictions and can be prescribed to women over 60 years of age. Depending on the severity of symptoms, hormonal medications can be used in combination with lubricants. It should be noted for patients receiving systemic MHT that it may not be sufficiently effective for relieving GSM symptoms, which may require the additional prescription of local estrogen therapy. Long-term cohort studies with a follow-up period of 7 to 18 years, as well as RCT data with a follow-up period of up to 52 weeks, show no effect of local estrogens on the endometrium, therefore additional use of progestogens is not required [129].

Local hormonal estrogen therapy is effective for the prevention of recurrent urinary tract infections occurring in postmenopause against the background of urogenital tract trophic changes [131], [132]. The use of local estrogens may have a positive effect on overactive bladder symptoms [133].

Comment: Placebo-controlled and comparative studies have demonstrated the efficacy of local drugs containing low and ultra-low doses of estriol (with or without a lyophilized Lactobacillus culture) for correcting symptoms of vulvovaginal atrophy and maintaining a healthy vaginal ecosystem.

3.2 Non-hormonal treatment

3.2.1. Non-hormonal pharmacological treatments for menopausal symptoms include:

SSRIs, SNRIs, Cimicifuga preparations (INN: Black cohosh root and rhizome extract), beta-alanine, epiphysis polypeptides (INN: Bovine pineal gland [epiphysis] polypeptides) [2], [4], [21], [44], [48], [49], [70], [117], [145], [146], [147], [148], [149], [150], [151], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [167], [168], [169], [170].

Comment: SSRIs and SNRIs are among the drugs that reliably relieve vasomotor symptoms and improve sleep. However, in the Russian Federation, SSRIs and SNRIs do not have registered indications for use in climacteric syndrome.

SSRIs include #paroxetine** (used doses 10-20 mg/day) [150], [156, 195], #citalopram (used doses 10-20 mg/day) [148], [170, 195], #escitalopram (used doses 10-20 mg/day) [149], and #fluoxetine** (used doses 20 mg/day [170, 195]). SNRIs include #venlafaxine (used doses 75 (37.5-150) mg/day) [157], [158, 195].

In women with a history of breast cancer receiving tamoxifen**, preference should be given to #venlafaxine, #escitalopram, or #citalopram [148], [149], [158], and the use of #paroxetine, #fluoxetine, and #sertraline** should be avoided due to their effect on tamoxifen metabolism** [195].

SSRIs do not affect the activity of aromatase inhibitors and can be safely used in women receiving these medications.

The duration of therapy with SSRIs and SNRIs is 3-6 months. The question of continuing therapy is decided on an individual basis.

To minimize side effects of SSRIs and SNRIs, treatment should be initiated at minimal doses with a gradual increase. Drug withdrawal should also be performed with a gradual dose reduction over at least 2 weeks to avoid withdrawal symptoms [160].

Comments: Cimicifuga racemosa rhizome extract (INN: Cimicifuga racemosa rhizome extract) is not a phytoestrogen in the classical sense and acts via serotonin, dopamine, and norepinephrine receptors in the brain [2], [172].

According to a systematic review and meta-analysis, black cohosh rhizome extract (INN: Cimicifuga racemosa rhizome extract) is more effective in treating vasomotor symptoms than placebo, although the effect is less pronounced than that of MHT [2, 171].

Comment: Cattle epiphysis [pineal gland] polypeptides stimulate the production of peptides that block the hypothalamic structures involved in the onset of vasomotor symptoms. The drug does not affect estradiol levels, plasma gonadotropin levels, or endometrial thickness in postmenopausal women. The drug is contraindicated in precancerous or malignant diseases, including estrogen-dependent tumors of the reproductive organs and breast [168], [169], [177].

3.2.2. Non-hormonal non-pharmacological methods for correcting menopausal symptoms include: phytoestrogens, moisturizers and lubricants, lifestyle modification.

Comments: Weight loss is associated with a decrease in the severity and frequency of vasomotor symptoms [178].

The use of phytoestrogens: trans-resveratrol, soy isoflavones, red clover helps reduce the frequency and severity of hot flashes [190], [191], [192], [193], [194], [195].

The use of cognitive behavioral therapy [179], [180], [181], [182], clinical hypnosis [183], [189], and acupuncture [184] reduces the frequency and severity of vasomotor symptoms and can improve sleep and mood.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable

5. Prevention and Dispensary Observation

No specific preventive measures have been developed for peri- and postmenopausal patients. Non-specific prevention includes physical activity, proper nutrition, and a healthy lifestyle.

Comment: Optimal physical activity includes at least 150 minutes of moderate-intensity or 75 minutes of high-intensity aerobic exercise per week, or a combination of moderate- and high-intensity exercise. When choosing the intensity of aerobic activity, the woman's physical condition and age must be taken into account. In addition, it is recommended to walk at least 10,000 steps per day. Physically active individuals show an improved metabolic profile, preserved muscle mass (prevention of sarcopenia) and strength, as well as maintained cognitive function and quality of life. Heart disease, stroke, fractures, and certain types of cancer, such as breast and colon cancer, occur much less frequently [201], [203].

Comment: in women, the frequency and intensity of vasomotor symptoms increase in parallel with rising BMI. Weight loss leads to relief of vasomotor symptoms. Beginning from the menopausal transition, women experience weight gain and redistribution of adipose tissue with preferential accumulation of visceral fat, which leads to insulin resistance and the development of metabolic syndrome. A weight loss of just 5–10% is sufficient to correct many disorders associated with impaired glucose metabolism (impaired glucose tolerance, type 2 diabetes). If applied strategies are ineffective, the patient should be managed in accordance with the clinical guidelines for "Obesity".

Comment: The main components of a healthy diet include multiple daily servings of fruits and vegetables, whole grains, fish twice a week, and a low overall fat intake, with a preference for olive oil. Salt intake should be limited, and daily alcohol consumption should not exceed 20 g.

Comment: An earlier onset of menopause has been proven in smoking women. Large-scale study results indicate that even minor/moderate, yet long-term smoking significantly correlates with sudden cardiac death in women (a 2-fold increase compared to non-smoking peers; the risk of sudden cardiac death increases by 8% for every 5 years of smoking).

Comment: There are three main approaches to preserving cognitive function: - improving brain health through the prevention and treatment of arterial hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity, and smoking cessation; - enhancing cognitive reserve through various leisure activities that stimulate cognitive function and maintaining high social activity; - preventing pathological changes characteristic of Alzheimer's disease, which includes regular physical exercise and the use of stress-resilience techniques.

Menopausal hormone therapy (MHT) initiated at midlife helps reduce the risk of Alzheimer's disease and dementia. A new doctor-patient relationship style is needed, in which the physician acts as an advisor, while the patient takes responsibility for her own health.

Comment: Follow-up for patients receiving systemic MHT includes: comprehensive pelvic ultrasound (transvaginal and transabdominal) (at least once a year; for patients with uterine myoma, at least once every 6 months); two-view mammography with BI-RADS and ACR assessment for women over 40 years of age, and annual breast ultrasound with BI-RADS assessment for women under 40 years of age; general clinical biochemical blood test (fasting blood glucose/glycated hemoglobin, total protein, total and direct bilirubin, creatinine) and biochemical blood test to assess lipid metabolism disorders (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides); complete blood count (CBC); blood thyroid-stimulating hormone (TSH) level (as clinically indicated); coagulogram (screening test of the hemostatic system – as clinically indicated); blood 25-OH vitamin D level (as clinically indicated); determination of the G20210A prothrombin polymorphism in the coagulation factor II gene and molecular genetic testing for the G1691A mutation in the factor V gene (Factor V Leiden mutation) (as clinically indicated); dual-energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur (as clinically indicated).

• Patients receiving local hormone therapy alone undergo examination in accordance with Order No. 1130n of the Ministry of Health of the Russian Federation dated October 20, 2020, "On Approval of the Procedure for Providing Medical Care in the Profile 'Obstetrics and Gynecology'."

• It is recommended that women taking MHT annually evaluate the benefit-risk ratio to decide on the continuation of MHT [21], [82], [209], [210].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comment: The potential link between MHT use and breast cancer is controversial. Data from the Women's Health Initiative (WHI) study showed no increased risk of breast cancer in women newly initiating MHT within 5-7 years of onset. According to WHI results, an increased risk of breast cancer exists with the use of a specific combination of estrogens with a synthetic progestogen (conjugated equine estrogens and medroxyprogesterone acetate) for more than 5 years. However, the adjusted relative risk (controlled for other risk factors) is not statistically significant. The actual risk of breast cancer associated with MHT is low, estimated at less than 0.1% per year or <1 case per 1,000 women-years among MHT users, which is lower than the risk associated with endogenous factors, such as high breast density, or factors such as obesity, physical inactivity, and alcohol consumption. According to several studies, MHT containing micronized progesterone (INN: Progesterone**) or dydrogesterone** does not increase the risk of breast cancer [21], [104], [105], [106], [211].

Clinical study results indicate that the risk of developing breast cancer depends on the duration of MHT, its composition, age at therapy initiation, and the presence of concomitant risk factors (overweight and obesity, smoking, alcohol intake, etc.) [104], [105], [210], [212], [213], [214], [215], [216], [217]. At the same time, randomized controlled trial data show that MHT use is not accompanied by an increase in breast cancer mortality [218].

6. Organization of Medical Care

Inpatient treatment is not required.

7. Additional Information

Not applicable

Criteria for Evaluating the Quality of Medical Care

References

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 Ministry of Health of the Russian Federation, Honored Scientist of Russia, Head of the Department of Reproductive Medicine and Surgery at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Chief Gynecologist of the Russian Ministry of Health, President of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Endometriosis Association, member of the Russian Society of Obstetricians and Gynecologists.

Elena N. Andreeva – Doctor of Medical Sciences, Professor, Deputy Director – Director of the Institute of Reproductive Medicine, Head of the Endocrine Gynecology Department, Professor of the Endocrinology Department at the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, President of the International Association of Obstetricians, Gynecologists and Endocrinologists, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Endometriosis Association, Russian Society of Obstetricians and Gynecologists, and Russian Society of Gynecological Endocrinology and Menopause Specialists.

Inna A. Apolikhina – MD, Professor, Head of the Department of Aesthetic Gynecology and Rehabilitation at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Professor of the Department of Obstetrics, Gynecology, Perinatology and Reproductology at the Institute of Professional Education of the I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health, Professor of the Department of Obstetrics and Gynecology at the Department of Professional Education of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

Natalya V. Artymuk – MD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakov 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".

Lev A. Ashrafyan – Academician of the Russian Academy of Sciences, MD, Professor, Director of the Institute of Oncogynecology and Mammology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, President of the Russian Society of Specialists in the Prevention and Treatment of Reproductive System Tumors.

Vera E. Balan – MD, Professor, Head of the Outpatient Department at the Moscow Regional Research Institute of Obstetrics and Gynecology (MONIKI).

Elena I. Ermakova – PhD in Medical Sciences, Senior Researcher at the Department of Gynecological Endocrinology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health, Vice-President of the Russian Society of Gynecological Endocrinology and Menopause Specialists.

Sergey Yu. Kuznetsov – PhD in Medical Sciences, Radiologist, Obstetrician-Gynecologist at the Department of Gynecological Endocrinology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

Valery V. Rodionov – Head of the Breast Pathology Department at the Institute of Oncogynecology and Mammology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of the Russian Federation, MD, member of the Russian Association of Mammologists, Russian Society of Specialists in the Prevention and Treatment of Reproductive System Tumors, member of the Board of the Russian Society of Gynecological Endocrinology and Menopause Specialists.

Smetnik Antonina Aleksandrovna – Head of the Department of Gynecological Endocrinology at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Candidate of Medical Sciences, Associate Professor, President of the Russian Society of Gynecological Endocrinology and Menopause, Advisor to the European Menopause and Andropause Society (EMAS), Member of the Russian Society of Obstetricians and Gynecologists.

Filippov Oleg Semenovich – Doctor of Medical Sciences, Professor, Deputy Director of the Department of Medical Care for Children and Obstetrics Services of the Ministry of Health of the Russian Federation, Professor at the Department of Obstetrics and Gynecology of the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of Russia (Moscow).

Chernukha Galina Evgenyevna – Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Gynecological Endocrinology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, President of the Interregional Association of Gynecologist-Endocrinologists, Member of the Russian Society of Obstetricians and Gynecologists.

Yureneva Svetlana Vladimirovna – Deputy Director for Scientific Work of the Institute of Oncogynecology and Mammology, Professor at the Department of Postgraduate Education in Obstetrics and Gynecology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Vice-President of the Association of Gynecologist-Endocrinologists, Doctor of Medical Sciences, Professor.

Yarmolinskaya Maria Igorevna – Head of the Department of Gynecology and Endocrinology of the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Head of Gynecological Department No. 2, Head of the Center for Diagnosis and Treatment of Endometriosis, Professor at the Department of Obstetrics and Gynecology of the North-Western State Medical University named after I.I. Mechnikov of the Ministry of Health of Russia, Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Member of the Russian Society of Obstetricians and Gynecologists, Board Member of the Russian Society of Gynecological Endocrinology and Menopause.

Yakushevskaya Oksana Vladimirovna – Candidate of Medical Sciences, Researcher at the Department of Gynecological Endocrinology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation.

Conflict of interest: none declared

Appendix A2. Methodology for Developing Clinical Guidelines

Clinical guidelines for the provision of medical care to female patients in the peri- and postmenopausal periods, as well as patients with early and premature menopause, have been drawn up in accordance with the requirements for the development of clinical guidelines by medical professional non-profit organizations, Part 2 of Article 76 of Federal Law No. 323-FZ dated November 21, 2011, 'On the Fundamentals of Public Health Protection in the Russian Federation', and Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, 'On approval of the procedure and timelines for the development of clinical guidelines, their revision, the standard form of clinical guidelines, and the requirements for their structure, composition, and scientific validity of the information included in clinical guidelines'.

Target audience for these clinical guidelines:

1. obstetrician-gynecologists

2. Endocrinologists

3. urologists

4. general practitioners

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

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

Figure 1. STRAW+10: stages of reproductive aging in women [1].

BI-RADS assessment findings:

Category 0 – incomplete, requires additional imaging evaluation

Category 1 – negative (no significant abnormality)

Category 2 – benign finding(s)

Category 3 – probably benign finding

Categories 4, 5 – high probability of malignancy

Category 6 – biopsy-proven malignancy.

Patient management pathway based on BI-RADS assessment:

Category 0 – referral for oncology consultation for further evaluation

Categories 1, 2 – follow-up by an obstetrician-gynecologist

Category 3 – referral to an oncology dispensary for diagnosis verification

Categories 4, 5, 6 – follow-up by an oncologist

1. Estrogen monotherapy

Administered continuously to women with a removed uterus (excluding supracervical hysterectomy or following hysterectomy for extensive extragenital/peritoneal endometriosis and/or adenomyosis) regardless of the menopausal phase, for the treatment of climacteric symptoms and/or prevention of osteoporosis. Local/systemic MHT in women for the relief of GSM symptoms.

Table 4 Estrogen treatment regimens

2. Progestogen therapy

Administered to women during the menopausal transition for the prevention of endometrial hyperplastic processes and regulation of the menstrual cycle, as well as in peri- and postmenopause as part of MHT.

Table 5 Progestogen treatment regimens

3. Combined estrogen-progestogen therapy

Administered to women with an intact uterus in perimenopause and postmenopause for the treatment of climacteric symptoms and prevention of osteoporosis in cyclic and continuous regimens. Following supracervical hysterectomy or hysterectomy for endometriosis, combined estrogen-progestogen therapy is administered in a continuous regimen.

Table 6 Combined estrogen-progestogen treatment regimens.

Table 7 Non-hormonal therapies for vasomotor symptoms

Appendix B. Physician Action Algorithms

Figure 2. Decision-making algorithm for MHT prescription [29]

Figure 3. Decision-making algorithm for MHT discontinuation [29]

Figure 4. Factors influencing the management of patients with menopausal symptoms

Figure 5. Lines of therapy for menopausal disorders

Estrogen

Sequential progestogen regimen – daily dose for 14 days per month – lowest "safe dose":

Continuous progestogen regimen – daily dose – lowest "safe dose":

Tibolone

Figure 6. Menopausal hormone therapy dosage.

Figure 7. Management of patients with menopausal symptoms

Figure 8. Principles of therapy review.

Figure 9. MHT initiation regimens [115].

Figure 10. Algorithm for switching patients from combined oral contraceptives to menopausal hormone therapy [115]

Appendix C. Patient Information

Menopause is the permanent cessation of menstrual cycles due to a significant depletion of the follicular reserve and ovarian hormonal activity. Menopause can be spontaneous (natural menopause) or iatrogenic, resulting from oophorectomy, chemotherapy, or radiation therapy. Menopause also occurs earlier in smokers. The most substantial changes occur during the transitional period (perimenopause) – 1 to 3 years before the final menstruation (menopause) and in the first two years after it (postmenopause). Early perimenopause is characterized by fluctuations in menstrual cycle duration, as well as a high frequency of uterine bleeding. In late perimenopause, menstrual delays of up to 30 days or more occur. The absence of menstruation for 12 months indicates the onset of postmenopause.

Changes in hormone levels may be accompanied by a number of symptoms known as "climacteric syndrome." During the transitional period, women may present with various complaints. The most frequent symptoms are vasomotor – hot flashes and sweating, but fatigue, irritability, anxiety, tension, frequent night awakenings, sleep disturbances, concentration problems, mood swings, loss of short-term memory, difficulty thinking and remembering new information, joint/lower back pain, vaginal dryness, discomfort and pain during intercourse, urinary incontinence, weight gain and/or changes in body proportions (women note an increase in adipose tissue in the abdominal area), sexual dysfunction, dry skin, deterioration of hair and nails, and a decrease in bone mineral density also frequently occur. If any menopausal symptoms are present, a gynecologist or gynecologist-endocrinologist should be consulted for an examination and recommendations on correcting these disorders using hormonal or non-hormonal therapy, as well as lifestyle and dietary recommendations. The best period to start treatment is perimenopause and early postmenopause, when menopausal symptoms can be corrected in a timely manner and the development of various chronic conditions can be prevented.

The onset of menopause can be suspected if menstruation has been absent for 12 months. To establish a diagnosis, it is necessary to assess the presence of menopausal symptoms, perform a pelvic ultrasound, and, in some cases, a hormonal workup.

The general strategy for maintaining women's health in peri- and postmenopause, along with mandatory adherence to a healthy lifestyle, a balanced diet, and adequate physical activity, may include menopausal hormone therapy (MHT). Replenishing sex hormone deficiency during decreased ovarian function using minimal optimal doses of hormonal drugs will alleviate the manifestations of climacteric syndrome, improve the overall well-being of women, and provide prevention of late metabolic disorders.

Estrogen preparations are available in various doses. Hormone doses and their routes of administration are selected individually, taking into account the woman's preferences and expectations, her age, as well as existing symptoms and the need for disease prevention, the risk of which is identified by analyzing personal and family history data and examination results. It is very important that menopausal hormone therapy not only relieves the manifestations of climacteric syndrome but also, to some extent, possesses anti-aging properties, and contributes to increased life expectancy and improved quality of life.

In the presence of symptoms of vaginal dryness and discomfort, non-hormonal vaginal lubricants and moisturizing gels or local estrogen therapy are used.

MHT is the "gold standard" for treating menopausal symptoms; however, some women have contraindications to such therapy (breast cancer, identified high risk of thrombosis, etc.). Alternative methods can be offered to them: antidepressants (SSRIs and SNRIs), black cohosh extract (INN: Cimicifuga racemosa rhizome and root extract), bovine pineal gland polypeptides (INN: Cattle pineal gland polypeptides), beta-alanine, phytoestrogens, cognitive behavioral therapy, regular exercise, weight loss, and avoiding triggers that promote hot flashes (coffee consumption, direct exposure to high heat), among other methods. Smoking cessation and limiting alcohol abuse are also recommended.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Assessment scales, questionnaires, and other patient evaluation tools presented in the clinical guidelines

Table specifications:

Russian title: Assessment of climacteric syndrome severity using the Greene scale.

Original title: The Greene Climacteric Scale

Source (official developer website, validation publication): Greene Climacteric Scale (GCS). Greene J.G. Constructing a standard climacteric scale. Maturitas, 1998. Vol.29, 25-31 [219].

Type (underline):

- rating scale

- index

- questionnaire

- other (specify):

Content (template):

Note: For each row, select the single answer option that best corresponds to the current state at the time of examination and place a V or X mark in the box next to it. Then, calculate the total score.

Key (interpretation): 0 – no symptom.

1 – mild symptom.

2 – moderate symptom.

3 – severe symptom.

Severity of menopausal syndrome based on testing results:

1–11 – mild.

12–19 – moderate.

20 and above – severe.

Figure 11 a. Intervention threshold based on the 10-year absolute risk of major osteoporotic fractures.

Intervention threshold for the Russian Federation based on the 10-year absolute risk of major osteoporotic fractures: the left graph determines the need for densitometry to refine the risk assessment. FRAX® calculation is performed without densitometry data. If the patient's 10-year risk falls into the lower zone, no additional examination or treatment is required. The patient should be given recommendations on osteoporosis prevention and reassessed in 5 years. If the 10-year risk falls into the upper zone, the patient requires osteoporosis treatment, and densitometry is not required to initiate treatment. If the 10-year risk falls into the middle zone (zone of uncertainty), densitometry (DXA) of the femoral neck is required to refine the risk. Once the results are obtained, FRAX® is recalculated taking densitometry data into account, and the result is evaluated using the right graph [220].

Figure 11 b. Therapeutic intervention threshold proposed for the Russian population based on the 10-year absolute risk of major osteoporotic fractures using FRAX [60].

Appendix G2. Russian eligibility criteria for menopausal hormone therapy in female patients with cardiovascular and metabolic diseases Consensus document of the Russian Society of Cardiology (RSC), Russian Society of Obstetricians and Gynecologists (ROAG), Russian Association of Endocrinologists (RAE), Eurasian Association of Therapists (EAT), and Russian Association for the Study of the Liver (RASL) [29].   Figure 12. MHT eligibility criteria [29]   Figure 13. MHT eligibility criteria (continued) [29]   Figure 14. MHT eligibility criteria (continued) [29]   Figure 15. MHT eligibility criteria (continued) [29] Figure 16. MHT eligibility criteria (continued) [29]   Figure 17. MHT eligibility criteria (continued) [29]