Amenorrhea and oligomenorrhea: clinical guidelines

List of Abbreviations

AMH – anti-Müllerian hormone;

ACTH – adrenocorticotropic hormone;

CAH – congenital adrenal hyperplasia;

ART – assisted reproductive technologies;

HA – hyperandrogenism;

HI – hyperinsulinemia;

GnRH – gonadotropin-releasing hormone;

SHBG – sex hormone-binding globulin in blood;

DHEA-S – dehydroepiandrosterone sulfate;

DXA – dual-energy X-ray absorptiometry;

HRT – hormone replacement therapy;

REG – regular menstruation-like reaction;

BMI – body mass index;

CG – clinical guidelines;

LH – luteinizing hormone;

BMD – bone mineral density;

MRI – magnetic resonance imaging;

POI – premature ovarian insufficiency;

RCTs – randomized controlled trials;

PCOS – polycystic ovary syndrome;

GH – growth hormone;

TSH – thyroid-stimulating hormone;

ultrasound – ultrasound examination;

FHA – functional hypothalamic amenorrhea;

FSH – follicle-stimulating hormone;

IVF – in vitro fertilization.

Terms and Definitions

Amenorrhea is a symptom defined as the absence of menstruation or its cessation in a girl or woman of reproductive age [1].

Primary and secondary amenorrhea occur before and after menarche, respectively [2].

Oligomenorrhea is an increased duration of the menstrual cycle of more than 38 days [1].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

The modern definition of the term "amenorrhea" includes the following conditions:

primary amenorrhea – absence of menstruation at age 15 (provided secondary sexual characteristics are developed) or 3 years after thelarche, as well as the absence of secondary sexual characteristics development and menstruation by age 13;

secondary amenorrhea – absence of menstruation for 6 months in women with a previously irregular menstrual cycle, or absence of menstruation for 3 months in women with a previously regular menstrual cycle [2–4].

Comments: The classical definition of "amenorrhea" implies the absence of menstruation for 6 months in a previously menstruating patient.

The term "oligomenorrhea" refers to a menstrual cycle disorder in which its duration exceeds 38 days, or the frequency of menstruation is less than 10 per year [1].

Specific diagnostic criteria for oligomenorrhea depending on the duration of intermenstrual intervals and the number of years post-menarche: no more than 90 days within 1 year post-menarche, no more than 45 days from 1 to 3 years post-menarche, and no more than 38 days when the duration of the condition is more than 3 years post-menarche [1, 3].

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

Physiological amenorrhea includes pregnancy, natural menopause, and breastfeeding [5].

Oligomenorrhea and amenorrhea (except for the uterine form) are generally clinical manifestations of ovulatory dysfunction, ranging from episodic disorders such as luteinizing phase defect to chronic ones like persistent anovulation and amenorrhea. According to the HyPO-P FIGO 2022 classification [1], ovulatory disorders are divided into 3 main types depending on the level of reproductive axis lesion: hypothalamic, pituitary, and ovarian, with a 4th type—polycystic ovary syndrome (PCOS)—categorized separately due to ambiguous interpretations and complex pathogenesis. Oligomenorrhea or amenorrhea most commonly arise from dysfunctions of the hypothalamic-pituitary-ovarian axis accompanied by hypoestrogenemia and/or anovulation (functional hypothalamic amenorrhea (FHA), hyperprolactinemia, premature ovarian insufficiency (POI), polycystic ovary syndrome) [1, 4–9]. Causes of amenorrhea may include developmental malformations of the uterus and vagina (Mayer-Rokitansky-Küster-Hauser syndrome, androgen insensitivity syndrome, hymenal atresia, isolated vaginal agenesis, etc.) or endometrial damage of various origins (Asherman syndrome) [2, 9–10].

Primary amenorrhea associated with hypothalamic dysfunction most commonly manifests as primary hypogonadotropic hypogonadism, mainly caused by mutations in genes responsible for gonadotropin-releasing hormone (GnRH) secretion and sensitivity to it [11]. Primary hypogonadotropic hypogonadism combined with anosmia is a pathognomonic sign of Kallmann syndrome. The development of the syndrome is associated with impaired migration of gonadotropin-releasing neurons to the anterior hypothalamus. The disease is genetically determined, characterized by a defect in the KAL1 gene on the X chromosome, and is inherited in an autosomal recessive manner [12].

The most frequent cause of secondary amenorrhea associated with hypothalamic dysfunction is FHA. This form of amenorrhea is characterized by the cessation of menstruation in the setting of stress, excessive physical activity, and/or weight loss. Leptin plays an important role in the pathogenesis of this form of amenorrhea, acting as a regulator of GnRH secretion and decreasing during chronic energy deficiency [10].

Rare forms of hypothalamic amenorrhea include hypothalamic tumors or infectious lesions of the hypothalamus resulting from tuberculosis, syphilis, encephalitis, or meningitis [2].

Amenorrhea caused by pituitary pathology most frequently develops as a result of hyperprolactinemia. The mechanism of hyperprolactinemia development is due to impaired dopaminergic inhibitory control of prolactin secretion by the hypothalamus, as well as stimulation of prolactin secretion by thyroid-stimulating hormone (TSH), GnRH, acetylcholine, serotonin, endogenous opioids, histamine, oxytocin, and decreased renal and hepatic function [13–16]. Rare causes of pituitary amenorrhea may include empty sella syndrome, pituitary tumors secreting gonadotropins, adrenocorticotropic hormone (ACTH), or growth hormone (GH). Empty sella syndrome is caused by a defect in the diaphragma sellae, resulting in pituitary deformation from cerebrospinal fluid pressure and impaired liberin transport. Pituitary lesions resulting from acute infarction or necrosis can lead to Sheehan syndrome, accompanied by GH, gonadotropin, ACTH, and TSH deficiency, or to panhypopituitarism.

Primary ovarian amenorrhea can include various forms of gonadal dysgenesis resulting from chromosomal abnormalities (Turner syndrome, pure gonadal dysgenesis, Swyer syndrome) [17]. Rarer forms of primary ovarian amenorrhea may be associated with defects in enzyme systems—17-alpha-hydroxylase, 17,20-lyase, aromatase—resulting in impaired steroidogenesis, androgen synthesis, or their aromatization into estrogens [18]. Secondary ovarian amenorrhea is most commonly represented by premature ovarian insufficiency (POI), which develops as a result of ovarian reserve depletion and is subdivided into genetic, autoimmune, idiopathic, and iatrogenic forms.

Oligomenorrhea, especially since menarche, is most frequently a characteristic sign of PCOS. The mechanism of oligomenorrhea and amenorrhea in PCOS is associated with various hormonal disorders. These include disorders of gonadotropin, androgen, and insulin secretion and action. Every second patient with PCOS is characterized by hypothalamic GnRH secretory dysfunction, promoting preferential LH synthesis compared to FSH. As a result of LH hypersecretion, theca cells are stimulated, and ovarian androgen production increases. The mechanisms underlying gonadotropic dysfunction are still unclear; the roles of hyperandrogenism (HA), hyperinsulinemia (HI), and leptin are being discussed. In some cases, oligomenorrhea may be a consequence of functional ovarian cysts (follicular cysts and corpus luteum cysts), which maintain a constant level of estradiol or progesterone, thereby preventing cyclic fluctuations of sex hormones and disrupting endometrial shedding.

Uterine forms of amenorrhea associated with the absence of the uterus are represented by 2 forms: Mayer-Rokitansky-Küster-Hauser syndrome and complete androgen insensitivity syndrome. In the first case, the etiology of the disease is not precisely known. A possible cause is a mutation in the AMH gene or its receptor; a mutation in the galactose-1-phosphate uridyltransferase gene has been identified [18]. In the case of complete androgen insensitivity syndrome, the pathogenesis of the disease is due to a mutation in the androgen receptor gene in a male karyotype. As a result, gonads develop, and AMH secretion is preserved, accompanied by regression of the Müllerian ducts and the absence of development of the uterus, its appendages, and the upper third of the vagina. The lack of sensitivity to androgens leads to the absence of development of the epididymis and external genitalia along the male type; however, due to the ongoing conversion of androgens into estrogens, the differentiation of the external genitalia and the development of secondary sex characteristics proceed along the female type with the formation of a female phenotype. Other anatomical defects (vaginal agenesis, hymenal atresia) leading to primary uterine amenorrhea are rare [19]. In 1998, L.V. Adamyan and A.Z. Khashukoeva proposed a classification of uterine and vaginal anomalies [20].

The development of secondary uterine amenorrhea is most frequently caused by intrauterine interventions or past postpartum endometritis, resulting in the formation of intrauterine synechiae. When the uterine cavity is completely obliterated by synechiae, Asherman syndrome develops.

Oligomenorrhea and amenorrhea can be caused by endocrine diseases such as congenital adrenal hyperplasia (CAH), adrenal insufficiency, hypercortisolism, an androgen-producing ovarian or adrenal tumor, and thyroid dysfunction [6], [18].

1.3 Epidemiology of the Disease or Condition

Among women of reproductive age, the prevalence of amenorrhea ranges from 5% to 13%, and oligomenorrhea from 8% to 22% [2], [21-29].

The ratio of primary to secondary amenorrhea is 1:10.

1.4 Features of Coding the Disease or Condition

N91 Absence of menstruation, scanty and rare menstruation

N91.0 Primary amenorrhea

N91.1 Secondary amenorrhea

N91.2 Amenorrhea, unspecified

N91.3 Primary oligomenorrhea

N91.4 Secondary oligomenorrhea

N91.5 Oligomenorrhea, unspecified

N92.5 Other specified forms of irregular menstruation

E28.8 Other ovarian dysfunction

1.5 Classification of the disease or condition

Primary and secondary amenorrhea are distinguished (see section 1.1).

There is no universally accepted classification of oligomenorrhea, but, like amenorrhea, it is subdivided into primary and secondary [2].

Ovulatory disorders are subdivided into 3 main types: hypothalamic, pituitary, ovarian, and PCOS (see Appendix G, Figure 1).

1.6 Clinical presentation of the disease or condition

The clinical presentation is determined by the form of amenorrhea. All forms of amenorrhea lasting more than 1 year are characterized by the presence of infertility.

1. Amenorrhea caused by hypothalamic-level disorders

Primary hypothalamic amenorrhea:

A. Kallmann syndrome is characterized by primary hypogonadotropic hypogonadism, absence of secondary sex characteristic development, and amenorrhea combined with anosmia.

Secondary hypothalamic amenorrhea:

B. Functional hypothalamic amenorrhea. This form of amenorrhea is characterized by the cessation of menstruation against the background of energy deficit due to weight loss, excessive physical exertion, and stress. Subsyndromal mental disorders in the form of eating disorders (anorexia, bulimia), bipolar disorder, and anxiety-depressive disorders are often detected [30].

2. Amenorrhea caused by anterior pituitary-level disorders

In pituitary tumors, progressive headaches, visual field disturbances, and symptoms associated with the over secretion of tropic hormones may be observed: TSH (hyperthyroidism), ACTH (Cushing's disease), GH (acromegaly). Hyperprolactinemia may manifest as galactorrhea and decreased libido.

In non-tumor forms of pituitary lesions, such as empty sella syndrome, Sheehan's syndrome, and panhypopituitarism, symptoms of tropic hormone deficiency are observed.

3. Amenorrhea caused by ovarian-level disorders

A. Gonadal dysgenesis:

- with an abnormal karyotype – Turner syndrome (45,X0, mosaic forms). Turner syndrome is characterized by primary, less frequently secondary, amenorrhea; mammary glands are undeveloped or very poorly expressed; short stature; pterygium colli (webbed neck); high arched palate; barrel chest; valgus deformity of joints; cardiovascular malformations.

- normal karyotype – pure gonadal dysgenesis 46,XX, Swyer syndrome 46,XY. During puberty, Swyer syndrome is characterized by primary amenorrhea, absence of mammary gland development, scanty pubic and axillary hair growth, male body habitus, and tall stature.

B. Enzyme system deficiency – 17-alpha-hydroxylase, 17,20-lyase, aromatase.

The clinical presentation of the disease is determined by the level of steroidogenesis impairment. In the case of a 17-alpha-hydroxylase defect caused by a mutation in the *CYP17A1* gene, primary amenorrhea, absence of secondary sex characteristic development, and water-electrolyte balance disturbances due to increased aldosterone levels—accompanied by arterial hypertension—are characteristic. In 17,20-lyase deficiency, clinical manifestations are similar, except for arterial hypertension, which is not typical for these patients. Patients frequently complain of lower abdominal pain associated with the development of multiple functional ovarian cysts [31].

C. Premature ovarian insufficiency – characterized by the development of secondary hypergonadotropic amenorrhea in women under the age of 40 due to ovarian reserve depletion. Mild estrogen deficiency symptoms are noted in the form of vasomotor and psycho-emotional disorders, vulvovaginal atrophy, and decreased libido.

D. Polycystic ovary syndrome – characterized by oligo-amenorrhea since menarche (oligo/anovulation), hyperandrogenism, and signs of insulin resistance (in every third case) (see Clinical guidelines "Polycystic ovary syndrome") [32].

4. Uterine forms of amenorrhea

Lesions at the level of the uterus and vagina, accompanied by the absence of cyclic endometrial changes and menstrual bleeding and/or impaired menstrual blood outflow.

Primary uterine amenorrhea:

A. Mayer-Rokitansky-Küster-Hauser syndrome – primary absence of menstruation with normally developed primary and secondary sex characteristics, complete or partial absence of the uterus and vagina in 1/3 of cases associated with urinary tract malformations (ectopic kidney, renal duplication, agenesis, etc.).

B. Androgen insensitivity syndrome (testicular feminization) - primary absence of menstruation, adrenarche. Female phenotype, as a rule, tall stature, inadequately developed mammary glands, absent or scanty pubic and axillary hair growth.

Anatomical defects leading to primary uterine amenorrhea, such as isolated vaginal agenesis and hymenal atresia, are characterized by primary absence of menstruation and cyclic pelvic pain caused by hematocolpos, hematometra, and hematosalpinx.

Secondary uterine amenorrhea

C. Intrauterine synechiae (Asherman syndrome): scanty menstruation progressing to amenorrhea.

5. Amenorrhea Caused by Disorders of Other Endocrine Glands

A. Congenital adrenal hyperplasia (CAH) – signs of hyperandrogenism in women with classic forms of 21-hydroxylase deficiency are usually prominent and, if untreated, manifest as virilization of the external genitalia, amenorrhea, pronounced alopecia, and hirsutism. The non-classic form of CAH is not accompanied by signs of adrenal insufficiency and manifests quite late—usually after puberty. Signs of mild hyperandrogenism are noted: acne, hirsutism, alopecia; oligomenorrhea, recurrent pregnancy loss, and infertility are frequently observed.

B. Cushing's syndrome – the clinical presentation is diverse and can affect virtually all organs and systems: weight gain with uneven subcutaneous fat deposition, thinning of the arms and legs, prominent facial swelling, elevated blood pressure, muscle weakness (predominantly in the lower extremities), appearance of bright striae (stretch marks) on the abdomen, shoulders, and thighs, and progressive hirsutism.

C. Androgen-secreting tumors of the ovaries and adrenal glands, manifested by the rapid development of virilization and symptoms of hyperandrogenism. In adrenal tumors with mixed secretion, along with manifestations of hyperandrogenism, there are various signs of hypercortisolism.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for "amenorrhea" are the absence of secondary sexual characteristic development and menstruation by the age of 13 years, the absence of menstruation given the development of secondary sexual characteristics by 15 years or 3 years after thelarche, as well as the absence of menstruation for 6 months in previously irregular menstrual cycles or for 3 months in previously regular menstrual cycles.

The criteria for "oligomenorrhea" are menstrual cycle irregularities in which the cycle duration exceeds 38 days [1].

2.1 Complaints and Anamnesis

Comments: When interviewing the patient, attention should be paid to the age at menarche, presence of secondary sexual characteristics, menstrual cycle pattern, dietary habits and physical activity levels, psychosocial stressors, weight changes, fractures, use of medications or psychoactive substances, chronic diseases, and history of postpartum hemorrhage [2-3, 33]. Weight loss, severe stress, and excessive physical activity preceding the onset of amenorrhea indicate functional hypothalamic amenorrhea (FHA). Galactorrhea, newly appearing or progressive chronic headaches, especially in combination with visual field defects, may indicate a hypothalamic or pituitary tumor (including a prolactin-secreting pituitary tumor) [34, 35], while acne or hirsutism may indicate hyperandrogenism [32, 33, 36]. Vasomotor symptoms, such as hot flashes or night sweats, may indicate primary ovarian insufficiency (POI) [17, 19]. Intrauterine surgical interventions may be the cause of uterine amenorrhea [37].

It is necessary to obtain informed voluntary consent from a parent or other legal representative of a minor under the age of 15 (or a drug addict under the age of 16) or a person recognized as legally incompetent in the manner established by law, if such a person is unable by their condition to give consent for medical intervention, as well as from the minor themselves aged 15-17 years inclusive, in the manner and form approved by the order of the Russian Ministry of Health dated December 20, 2012, No. 1177n "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention Regarding Certain Types of Medical Interventions, Forms of Informed Voluntary Consent to Medical Intervention, and Forms of Refusal of Medical Intervention."

2.2 Physical Examination

Comments: When conducting a physical examination in children, the following are important: measuring height, body weight, and BMI in comparison with age-specific growth chart percentiles, and determining the stage of puberty according to Tanner staging with a score for mammary gland development and pubic hair growth (see Appendix G2).

At the initial stage, it is necessary to analyze height-weight parameters and their dynamics. Primary amenorrhea and the absence of secondary sexual characteristic development (Tanner stage I, II) indicate hypogonadism and indirectly point to the possible presence of hypogonadotropic hypogonadism, gonadal dysgenesis, or hereditary steroidogenesis defects [12]. Normal mammary gland development (Tanner stage III, IV) indicates initially preserved estrogen levels, and the differential diagnostic search should be conducted between uterine forms of amenorrhea (androgen insensitivity syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, hymenal atresia, isolated vaginal agenesis) and hyperandrogenic states (PCOS, CAH) [39].

Secondary amenorrhea combined with striae, "buffalo hump," central obesity, hypertension, or proximal muscle weakness may point toward hypercortisolism (Cushing's disease or syndrome). Amenorrhea combined with hyperandrogenism (acne, hirsutism) points toward PCOS, while combination with marked virilization points toward an androgen-secreting ovarian or adrenal tumor.

Comments: The absence of the uterus and the upper third of the vagina in the presence of normally developed secondary sexual characteristics may indicate Mayer-Rokitansky-Küster-Hauser syndrome. The combination of uterine and upper vaginal aplasia with sparsely developed pubic hair may indicate androgen insensitivity syndrome [39].

2.3 Laboratory Diagnostics

Comments: In primary amenorrhea, a decrease in FSH or LH below 3.0 IU/L may strongly indicate primary hypogonadotropic hypogonadism [11]. In hypergonadotropic states (FSH greater than 25.0 IU/L), differential diagnosis is required between various forms of gonadal dysgenesis and, in rare cases, enzymopathies leading to impaired sex hormone synthesis at various stages of steroidogenesis [40-41]. In the normogonadotropic form of primary amenorrhea, differential diagnosis must be performed between uterine malformations, PCOS, and the non-classic form of CAH [2].

In cases of secondary amenorrhea, a decreased gonadotropin level (LH less than 3.0 IU/L) indicates disorders of the hypothalamic-pituitary system, most often of a functional nature (e.g., FHA). Elevated FSH levels (greater than 25.0 IU/L) upon repeated determination at an interval of 4-6 weeks indicate a reduction or absence of ovarian reserve and point to the presence of POI [42]. Normogonadotropic secondary amenorrhea is observed in PCOS, uterine amenorrhea, less frequently in CAH, and in functional disorders of the hypothalamic-pituitary system.

Comments: Elevated levels of total and free testosterone are the most informative indicators for diagnosing PCOS [32, 43, 44]. Blood levels of dehydroepiandrosterone sulfate (DHEA-S) and androstenedione should be tested when total and free testosterone levels are not elevated, although these markers provide limited additional information in the diagnosis of PCOS [32]. To diagnose non-classic congenital adrenal hyperplasia (NCAH), it is advisable to measure blood levels of 17-hydroxyprogesterone in the morning [45]. If the 17-hydroxyprogesterone concentration exceeds 6 nmol/L or 2 ng/mL, genetic testing of the CYP21A2 gene may be required (if adrenocorticotropic hormone stimulation testing is not feasible) [45]. A DHEA-S level above 700 ng/dL or a total testosterone level above 200 ng/dL may indicate an androgen-secreting adrenal tumor [44, 45]. In female patients with primary amenorrhea due to the absence of the uterus, a testosterone level within the normal male reference range indicates androgen insensitivity syndrome [46].

Comments: Blood AMH concentration is an indicator of ovarian reserve; elevated levels can be informative in women with PCOS. Currently, AMH measurement is considered one of the diagnostic criteria for PCOS [43]. However, evidence is emerging that with the improvement and standardization of AMH assays and the establishment of threshold values across different age groups and ethnicities, the AMH marker will hold greater diagnostic significance [47–49].

Comments: In hypergonadotropic amenorrhea, it is advisable to perform cytogenetic testing (karyotyping) using differential chromosome staining for various genetic disorders to verify the diagnosis. A 45,X0 or 45,X0/46,XX karyotype indicates Turner syndrome, a 46,XY karyotype indicates Swyer syndrome, and a 45,X0/46,XY karyotype indicates mixed gonadal dysgenesis [50]. In the presence of secondary sexual characteristics and uterine agenesis, cytogenetic testing is advisable for the differential diagnosis of Mayer-Rokitansky-Küster-Hauser syndrome (46,XX karyotype) versus androgen insensitivity syndrome (46,XY karyotype). It is advisable to test for the FMR1 gene premutation (CGG repeat expansion in the 55–200 range) in patients with primary ovarian insufficiency (POI) to identify the genetic form of POI [46]. Women with an FMR1 premutation (55–200 repeats) have a 13–26% increased risk of developing POI and an increased risk of having a child with fragile X syndrome (males present with intellectual disability and >200 CGG repeats) [42].

2.4 Instrumental Diagnostics

Comments: If a uterine or adnexal malformation is suspected in unclear cases, or for differential diagnosis, pelvic MRI is recommended [2, 48].

Comments: It is advisable for patients to undergo an MRI when amenorrhea is combined with:

– severe or persistent headache;

– persistent vomiting (not self-induced);

– visual field defects;

– thirst or increased urination;

– focal neurological signs;

– clinical signs and/or laboratory results indicating pituitary hormone deficiency or excess.

Comments: If amenorrhea lasts for more than 6 months, a baseline assessment of bone mineral density (BMD) is required [9]. The purpose of bone DEXA is to identify individuals at risk of fractures, determine the degree of bone loss in patients with established low BMD, and monitor treatment efficacy. Additional nutritional assessment should be performed in patients with amenorrhea if the baseline BMD Z-score is -2.0 SD or lower at any skeletal site. For female athletes with amenorrhea, the Z-score should be monitored if it drops below -1.0 SD [51].

2.5 Other Procedures

Comments: The progestin challenge test should be performed after a comprehensive pelvic ultrasound (transvaginal and transabdominal). Options for the progestin challenge test include a 10-day course of micronized #progesterone** (INN: progesterone) at 400 mg/day or #dydrogesterone** at 20 mg/day for 10 days [48, 54–56]. The onset of predictable withdrawal bleeding (a positive test) rules out uterogenic amenorrhea and low estrogen status. Conversely, the absence of withdrawal bleeding (a negative test) indicates pronounced hypoestrogenism or uterogenic amenorrhea [2].

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

Treatment of amenorrhea and oligomenorrhea depends on their underlying etiology [1–2, 48].

3.1 Pharmacological and non-pharmacological therapy for conditions accompanied by amenorrhea and oligomenorrhea

3.1.1 Amenorrhea due to hypothalamic disorders

Comments: Transdermal or oral estrogen formulations in standard doses may be prescribed as the estrogen component of hormone replacement therapy (ATC: Natural and semisynthetic estrogens).

Transdermal forms:

o #Estradiol transdermal gel (0.6 mg/g) at a daily dose of 1.5 mg of estradiol (2.5 g of gel)

o #Estradiol transdermal gel (0.1%) at a daily dose of 1.0 mg of estradiol (1 g of gel) [57–59].

Oral estrogen formulations include #estradiol valerate at a daily dose of 2 mg (ATC: Natural and semisynthetic estrogens; progestogens and estrogens, sequential preparations; progestogens and estrogens, fixed combinations) [57].

Micronized #progesterone** (INN: progesterone) (ATC: Progestogens) at a dose of 200 mg/day for 12 days, or oral #dydrogesterone** at a dose of 10 mg/day (e.g., combined with #estradiol at a daily dose of 2 mg) for 14 days during the second phase of the menstrual cycle, can be used as the progestogen component to prevent endometrial hyperplasia [2, 56, 58–66].

Oral fixed combinations of progestogens and estrogens (ATC: progestogens and estrogens, fixed combinations; progestogens and estrogens, sequential preparations) may be used:

o #Dydrogesterone+Estradiol and Estradiol [pack] – 2 mg estradiol with 10 mg #dydrogesterone [42, 63–64, 66], or

o For adult patients, #Norgestrel+Estradiol valerate; Estradiol valerate [pack] – 2 mg estradiol valerate with 0.5 mg norgestrel daily in a cyclic regimen [55, 66, 67].

Comment: Due to the high frequency of comorbid psychiatric conditions (eating disorders, depressive, anxiety, and bipolar disorders), obstetrician-gynecologists should refer patients with functional hypothalamic amenorrhea (FHA) for a psychiatric consultation [10, 67, 68].

Comment: The goal of dietary counseling is to normalize the energy value of the diet and nutrient balance [10]. After nutrition is normalized and body weight is restored, the resumption of menstruation can be expected within 6–12 months [10].

Comment: Systemic combined hormonal contraceptives should not be prescribed to patients with amenorrhea for the prevention of bone mineral density (BMD) loss. Sex steroid HRT has a positive effect on BMD because, unlike hormonal contraceptives, it does not affect the secretion of insulin-like growth factor 1, which has an anabolic effect on bone formation [65, 67]. HRT is performed using oral or transdermal forms of estrogens combined with progestogens in a cyclic regimen at standard doses, including fixed-dose combinations [2, 10, 62–64, 67, 69, 70]. Transdermal estrogen forms are preferred in FHA due to a more pronounced positive effect on BMD [10, 67–69].

3.1.2 Amenorrhea due to disorders at the level of the anterior pituitary

Comments: The first-line drug for medical therapy is cabergoline, with an initial dose of 0.5 mg per week, with a possible subsequent increase in dose until prolactin levels normalize [13]. The initial dose of bromocriptine** is 1.25 mg per day, with a therapeutic range of 2.5–7.5 mg/day [13, 82, 83]. Reducing the dose of the drug or discontinuing it is recommended no earlier than 2 years of continuous treatment, provided there is a persistent normalization of prolactin levels and a significant reduction or absence of the tumor according to brain MRI. In patients with resistant or partially resistant prolactinomas, before considering surgical intervention, it is advisable to increase the dose of prolactin inhibitors to the maximum tolerated. Transsphenoidal surgery is performed in patients with intolerance to high doses of cabergoline and resistance to other drugs of this group. In case of difficulties in diagnosis or choosing management tactics for patients with hyperprolactinemia, an endocrinologist consultation is prescribed [71–81].

3.1.3 Amenorrhea caused by ovarian disorders

Comment: As the estrogen component of HRT, transdermal or oral forms of estrogens may be prescribed in standard doses. Transdermal estrogen forms (according to ATC: Natural and semisynthetic estrogens) include a 0.6 mg/g transdermal gel at a daily dose of 1.5 mg of #estradiol (2.5 g of gel) or a 0.1% transdermal gel at a daily dose of 1.0 mg of #estradiol (1.0 g of gel) [42, 57, 59, 85, 86].

Oral forms of estrogens include #estradiol valerate at a daily dose of 2 mg [86] (according to ATC: progestogens and estrogens, fixed combinations; progestogens and estrogens, sequential preparations (for sequential use); progestogens and estrogens, fixed combinations) [88].

As the progestogen component, it is possible to use micronized #progesterone** (INN: progesterone) (according to ATC: Progestogens) at a dose of 200 mg/day or #dydrogesterone** orally at a dose of 10 mg/day for 12–14 days in the second phase of the menstrual cycle to prevent endometrial hyperplastic processes [42, 87].

It is possible to use oral fixed combinations of progestogens and estrogens (according to ATC: progestogens and estrogens fixed combinations; progestogens and estrogens, sequential preparations (for sequential use); progestogens and estrogens, fixed combinations): #Dydrogesterone+Estradiol and Estradiol [pack] — 2 mg estradiol with 10 mg dydrogesterone, or Norgestrel+Estradiol valerate and Estradiol valerate [pack] (for adults only) — 2 mg estradiol valerate with 0.5 mg norgestrel daily in a cyclic regimen [42, 55, 66, 86].

Comment: it is advisable to prescribe estrogen-progestogen therapy in a cyclic regimen at least until the age of natural menopause — 50–51 years. With long-term HRT use in POI, it is possible to switch to continuous monophasic therapy if necessary. In POI, as the estrogen component of sex hormone replacement therapy, transdermal or oral forms of estrogens can be prescribed in standard or, if necessary (insufficient symptom relief), high doses [89].

Transdermal estrogen forms (according to ATC: Natural and semisynthetic estrogens) include a 0.6 mg/g transdermal gel at a daily dose of 1.5–2.25 mg of #estradiol, up to a maximum of 3.0 mg (2.5–3.75 g of gel, up to a maximum of 5.0 g per day) or a 0.1% transdermal gel at a daily dose of 1.0–1.5 mg of #estradiol, up to a maximum of 2.0 mg (off-label) (1.0–1.5 g of gel, up to a maximum of 2.0 g per day) [42, 57, 59, 84–86].

Oral forms of estrogens include #estradiol valerate at a daily dose of 2 mg (if necessary, up to a maximum of 4 mg per day (off-label)) (according to ATC: progestogens and estrogens, fixed combinations; progestogens and estrogens, sequential preparations (for sequential use); progestogens and estrogens, fixed combinations) [86, 88].

As the progestogen component, it is possible to use micronized #progesterone** (INN: progesterone) (according to 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 [42, 67, 84, 87, 88].

It is possible to use oral fixed combinations of progestogens and estrogens (according to ATC: progestogens and estrogens fixed combinations; progestogens and estrogens, sequential preparations (for sequential use); progestogens and estrogens, fixed combinations): #Dydrogesterone+Estradiol and Estradiol [pack] — 2 mg estradiol with 10 mg dydrogesterone, or 2 mg estradiol with 150 mcg levonorgestrel, or Norgestrel+Estradiol valerate and Estradiol valerate [pack] (for adults only) — 2 mg estradiol valerate with 0.5 mg norgestrel daily in a cyclic regimen daily in a cyclic regimen [42, 55, 66, 86, 90].

Comments: Patients, not desiring pregnancy, undergo monotherapy with systemic hormonal contraceptives with an antiandrogenic effect as first-line therapy for menstrual irregularities, hirsutism, and acne. In the presence of metabolic disorders accompanied by insulin resistance, metformin** is indicated [43]. For the treatment of obesity and overweight in patients with PCOS, therapeutic lifestyle modification (TLM) should be used, including physical exercise and diet [32, 43, 92].

Comment: Micronized #progesterone** at a dose of 200–400 mg/day or #dydrogesterone** at a dose of 10–20 mg/day in a cyclic regimen for at least 10–15 days is preferred as progestogen therapy [55, 56, 59, 93–95].

3.1.4 Uterine form of amenorrhea

Comments: HRT is not indicated for patients with Mayer-Rokitansky-Küster-Hauser syndrome due to preserved ovarian function.

Comments: As the estrogen component of HRT, transdermal or oral forms of estrogens in standard doses (ATC: Natural and semisynthetic estrogens) can be prescribed daily in a continuous regimen. Additional progestogen therapy is not required [102–105].

Comments: HRT is carried out using oral or transdermal forms of estrogens in standard or high doses combined with progestogens in a cyclic regimen, including fixed-dose combinations [107–116].

3.2 Medical and non-medical therapy of infertility in patients with amenorrhea or oligomenorrhea

3.2.1 Amenorrhea caused by hypothalamic disorders

Comments: Pregnancy in patients with hypogonadotropic hypogonadism can be achieved through ovulation induction using GnRH preparations (ATC: G03G Gonadotropins and other ovulation stimulants), FSH (INN: follitropin alfa**), or LH (INN: lutropin alfa). The goal of ovulation induction therapy is to achieve a single ovulation [110, 111, 117–120].

Comments: Ovulation induction in women with FHA should only be initiated after achieving a BMI of more than 18.5 kg/m² due to the increased risk of obstetric complications (fetal loss, small-for-gestational-age newborns, preterm birth) [10]. Gonadotropin preparations (INN: menotropins) should be used for ovarian stimulation [122–123]. In patients with FHA and sufficient estradiol levels, clomifene** can be used for ovarian stimulation [122, 123]. If ovarian stimulation using gonadotropins and other ovulation stimulants is ineffective, assisted reproductive technology (ART) programs are recommended.

3.2.2 Amenorrhea caused by anterior pituitary disorders

Comments: It is advisable to administer prolactin inhibitor therapy to lower prolactin levels, reduce tumor size, and restore ovarian function. When choosing a prolactin inhibitor, cabergoline should be preferred because it is more effective in normalizing prolactin levels and reducing pituitary tumor size. The most favorable background for conception is the complete normalization of prolactin levels and a tumor size reduction to less than 10 mm. Upon confirmation of pregnancy, prolactin inhibitor therapy should be discontinued [34].

3.2.3 Amenorrhea caused by ovarian disorders

Comments: Spontaneous pregnancy occurs in 4.8–7.6% of patients with Turner syndrome, with a miscarriage rate of 30.8–45.1% [124–127]. ART programs with controlled ovarian stimulation followed by oocyte cryopreservation can be performed in patients with the mosaic variant [127].

Comments: Women with POI must be informed about the lack of reliable and proven interventions capable of improving ovarian function and increasing the rate of spontaneous conception. With ongoing HRT using progestogens combined with estrogens, the pregnancy rate reaches 5–10%. The use of donor oocytes from sisters of patients with POI should be considered due to the high risk of failed IVF attempts [42].

Comments: For the treatment of anovulatory infertility in patients with PCOS and obesity, lifestyle modification with weight normalization is recommended. Clomifene** has traditionally been used for ovulation induction. However, letrozole is currently used as first-line therapy for anovulatory infertility in PCOS patients in global practice [32, 43]. According to randomized controlled trials and meta-analyses, letrozole is 1.5–2 times more effective than clomifene** in achieving ovulation, pregnancy, and live birth without increasing the risk of multiple pregnancy or miscarriage [128–136].

Comments: If clomifene** or letrozole is ineffective, gonadotropin stimulation or ovarian drilling is performed as second-line therapy. If second-line therapy fails, ART programs are used as third-line therapy. Detailed data regarding the diagnosis and treatment of women with PCOS, including indications for ART programs, are presented in the relevant clinical guidelines.

3.2.4 Uterine forms of amenorrhea

Comments: Following surgical treatment of intrauterine adhesions, reproductive function is restored in more than 50% of women [140].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comment: A healthy lifestyle in patients with FHA after the restoration of menstrual rhythm implies increased stress resilience, moderate physical activity, and an adequate diet [141].

5. Prevention and Dispensary Observation

Primary amenorrhea cannot be prevented.

Prevention of secondary amenorrhea can be addressed in relation to FHA and Asherman syndrome.

Comments: If subclinical signs of eating disorders or anxiety-depressive disorder appear, the patient should be referred to a psychotherapist for counseling to correct stress adaptation.

Comments: All patients with amenorrhea are subject to dispensary follow-up.

6. Organization of Medical Care

Patients with amenorrhea and oligomenorrhea are managed and treated on an outpatient basis. Exceptions include patients with impaired menstrual outflow due to genital malformations or anatomical changes in the pelvic organs.

Indications for patient hospitalization: impaired menstrual outflow due to genital malformations or anatomical changes in the pelvic organs.

Discharge criteria: Clinical recovery

7. Additional Information

If the development of amenorrhea or oligomenorrhea is associated with changes in lifestyle, diet, or stressful events, modification of the factors that led to the development of the underlying disease or aggravate it is recommended in order to restore the menstrual rhythm. Modifiable factors affecting the outcome of amenorrhea or oligomenorrhea, as well as their correction, should be considered in the context of conditions such as functional hypothalamic amenorrhea and polycystic ovary syndrome.

In cases of functional hypothalamic amenorrhea, significant factors determining the restoration of menstrual rhythm include nutrition, physical activity, and adaptation to psychological stress. Timely correction of the aforementioned factors (balanced diet, reduction in physical activity, normalization of psychological well-being) accelerates the restoration of menstrual rhythm.

In cases of polycystic ovary syndrome and overweight or obesity, lifestyle modification is recommended as the first stage of treatment, which should include dietary normalization and physical activity. The goal of correction is weight loss, which helps restore menstrual rhythm and ovulation.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Leyla V. Adamyan – Academician of the RAS, Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Honored Worker of Science of Russia, Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine, Chief Freelance Gynecologist of the Russian Ministry of Health, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Endometriosis Association, 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 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 Gynecological Endoscopists, Russian Endometriosis Association, Russian Society of Obstetricians and Gynecologists, ROSGEM.

Natalya V. Artymuk – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova 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, 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".

Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology at the Faculty of Continuing Professional Education, 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, member of the Russian Society of Obstetricians and Gynecologists, President of the Trans-Baikal Society of Obstetricians and Gynecologists.

Larisa A. Marchenko – Leading Researcher at the Department of Gynecological Endocrinology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Doctor of Medical Sciences, Professor, member of the Russian Society of Obstetricians and Gynecologists.

Antonina A. Smetnik – Candidate of Medical Sciences, Head of the Department of Gynecological Endocrinology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Russian Society of Gynecological Endocrinology and Menopause Specialists.

Larisa V. Suturina – Doctor of Medical Sciences, Professor, Head of the Reproductive Health Protection Department at the Scientific Centre for Family Health and Human Reproduction Problems, member of the Association of Gynecological Endocrinologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.

Gyuzal I. Tabeeva – Candidate of Medical Sciences, Senior Researcher at the Department of Gynecological Endocrinology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Scientific Secretary of the Russian Society of Gynecological Endocrinology and Menopause Specialists.

Narine M. Tonoyan – Candidate of Medical Sciences, Obstetrician-Gynecologist at the Department of Operative Gynecology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

Elena V. Uvarova – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Honored Worker of Science of the RF, Head of the 2nd Gynecological Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductology of the Institute of Professional Education at the I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of the Russian Federation, Chief Freelance Pediatric and Adolescent Gynecologist of the Ministry of Health of the Russian Federation, President of the Association of Pediatric and Adolescent Gynecologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.

Elena P. Khashchenko – PhD, Leading Research Fellow, 2nd Gynecological Department, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

Oleg S. Filippov – MD, PhD, Professor, Honored Physician of the Russian Federation, Chief Freelance Obstetrician-Gynecologist of the FMBA of Russia, Deputy Director of the Federal Scientific and Clinical Center for Children and Adolescents of the FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine.

Galina E. Chernukha – MD, PhD, Professor, Chief Research Fellow, Department of Gynecological Endocrinology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Association of Gynecologist-Endocrinologists of Russia.

Maria I. Yarmolinskaya – Professor of the RAS, MD, PhD, Professor, Head of the Department of Gynecology and Reproductive Endocrinology, Ott Research Institute of Obstetrics and Gynecology; Professor at the Department of Obstetrics and Gynecology, 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:

1. obstetrician-gynecologists, endocrinologists

2. residents in obstetrics and gynecology, residents in endocrinology

3. students of educational institutions

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 clinical guideline update mechanism provides for their systematic review at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of well-founded additions/comments to previously approved clinical guidelines (CGs), but no more frequently than once every 6 months.

Appendix A3. Reference Materials

• Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

• Gynecology: National Guidelines / ed. by G.M. Savelieva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky. - 2nd ed. - M.: GEOTAR-Media, 2018.

• Guide to Outpatient Care in Obstetrics and Gynecology / ed. by V.N. Serov, G.T. Sukhikh, V.N. Prilepskaya, V.E. Radzinsky. – 3rd ed. - M.: GEOTAR-Media, 2016.

• The FIGO Ovulatory Disorders Classification System.  Munro MG, Balen AH, Cho S, Critchley HOD, Díaz I, Ferriani R, Henry L, Edgar Mocanu, van der Spuy ZM; FIGO Committee on Menstrual Disorders and Related Health Impacts, and FIGO Committee on Reproductive Medicine, Endocrinology, and Infertility. Fertil Steril. 2022 Oct;118(4):768-786.

• ACOG Committee opinion no. 651: menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015; 126(6): e143-e146.

• Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008; 90(5 suppl): S219-S225.

• The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. International Journal of Gynecology & Obstetrics.

• ACOG Practice Bulletin no. 194: polycystic ovary syndrome. Obstet Gynecol.2018; 131(6): e157-e171.

• Amenorrhea: A Systematic Approach to Diagnosis and Management. David A. Klein, MD, MPH; Scott L. Paradise, MD; and Rachel M. Reeder, MD. Am Fam Physician. 2019; 100(1): 39-48.

• American Family Physician 781 Amenorrhea: An Approach to Diagnosis and Management. 2013. Vol. 87. №11.

• Clinical guidelines for the diagnosis and correction of nutritional status disorders. National Association for Clinical Nutrition. 2013

• Federal clinical guidelines (protocol) for the management of patients with Turner syndrome

• Female infertility: modern approaches to diagnosis and treatment) clinical guidelines (treatment protocol), 2018.

Appendix B. Physician Action Algorithms

Diagram 1. Diagnostic algorithm for primary amenorrhea

Diagram 2. Diagnostic algorithm for secondary amenorrhea

Appendix C. Patient Information

Menstrual rhythm disorders are a serious problem occurring in women of reproductive age, often associated with hormonal imbalances.

Menstrual rhythm disorders refer to two conditions: delayed menstruation (oligomenorrhea) or complete absence of menstruation (amenorrhea). In practice, oligomenorrhea and amenorrhea are always divided into two forms: primary (when cycle disturbances are present from the very beginning, from an early age, from the moment of menarche) and secondary (when disorders occur after a period of spontaneous regular menstruation).

There are numerous causes of menstrual cycle disorders. In cases of infrequent menstruation, the most common causes are polycystic ovary syndrome (PCOS), functional cysts, hyperprolactinemia, congenital adrenal hyperplasia, stress, or nutritional deficiency.

In cases of amenorrhea, we are dealing with more profound disorders of the reproductive system that can occur at various levels. For example, at the level of the brain – in such a situation, the hypothalamus and pituitary gland do not produce gonadotropic hormones (which regulate ovarian function), namely luteinizing hormone (LH) and follicle-stimulating hormone (FSH), in the required mode. Therefore, follicular growth does not begin, female sex hormones (estrogens) are not produced in the necessary quantities, and endometrial growth does not occur.

Another cause of amenorrhea can be disorders at the ovarian level, when normal ovarian tissue fails to form during intrauterine development. This is one of the so-called developmental anomalies of the internal genital organs.

Possible causes may include the absence of the uterus or impaired anatomy of the vagina and cervix. Imperforate hymen is a rare occurrence.

Amenorrhea may be associated with premature ovarian insufficiency (POI), when the intrauterine follicular (ovarian) reserve is depleted much faster than usual and runs out prematurely. Consequently, 'menopause' occurs much earlier.

A fairly common cause of the absence of menstruation in the modern world is chronic stress, excessive physical exertion, or insufficiently balanced nutrition, causing the reproductive function to 'shut down' temporarily.

Rare causes of amenorrhea include intrauterine interventions or postpartum inflammatory uterine diseases (endometritis). This leads to inflammation and the formation of adhesions in the uterine cavity (Asherman syndrome).

To formulate the correct course of action, it is important for the physician to understand the cause of the menstrual cycle disorders. To this end, clinical practice utilizes various diagnostic methods, such as gynecological examination, hormonal testing, genetic analysis, ultrasound examination, bone densitometry, and magnetic resonance imaging.

Female sex hormones are extremely vital for the adequate functioning of the entire organism. Amenorrhea accompanied by hypoestrogenism can lead to an increased risk of diseases associated with estrogen deficiency. Such diseases include osteoporosis (decreased bone mineral density), cardiovascular diseases, and memory and cognitive impairment.

Moreover, oligomenorrhea and amenorrhea lead to a decreased likelihood of pregnancy, which determines the social significance of these conditions.

In view of the above, an urgent task is the treatment of diseases accompanied by menstrual cycle disorders.

There are two principal approaches: the first is the elimination of the factor that caused the development of menstrual cycle disorders; the second is hormone replacement therapy (HRT) in situations where it is impossible to restore natural estrogen production.

Menstrual cycle disorders largely prevent natural pregnancy because ovulation is often absent. For this reason, it is necessary to resort to ovulation induction methods, including the use of in vitro fertilization techniques. The artificial insemination program is selected on an individual basis.

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

Appendix G1. Classification of anovulatory disorders by the level of reproductive system dysfunction

Russian title: Classification of anovulatory disorders by the level of reproductive system dysfunction

Source (official developer website, validated publication): [1].

Type (underline): classification

Content (template): The table consists of 5 rows (5 levels of reproductive system dysfunction), with each subdivided into primary and secondary amenorrhea.

Figure 1. HyPO-P FIGO Classification (2022) [1].

Explanations: The table also presents the nosologies corresponding to the level of lesion.

Appendix G2. Age characteristics of girls' puberty stages (according to Tanner J.M., Marshal W.A.) [145]

Russian title: Age characteristics of girls' puberty stages

Original title (if any): Tanner Stages

Source (official developer website, validated publication): Hamlin A., Robertson M., Wilson D. R. Tanner Stages and Pubertal Development // Journal of Pediatric Surgical Nursing. – 2022

Type (underline): rating scale

Purpose: Assessment of the degree of secondary sexual characteristics development

Content (template): The degree of secondary sexual characteristics development is assessed by stages (breast development and pubic hair growth)

Key (interpretation): Correspondence of secondary sexual characteristics development to the patient's age

Explanations: If the development of secondary sexual characteristics does not correspond to the patient's age, a diagnosis of puberty disorder is established