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Home , Amenorrhea, Hypomenorrhea, Menstrual cycle, Oligomenorrhea, Uterine hypoplasia

Disorders of function of . 1. Rationale. In the structure gynecologic diseases disorders of occurs in 20% of cases. Different disorders of menstruation result in high working disability, development of neuropsychic complications, invalidism of women. These complications claim for complex approach and joint treatment by physicians of different specialities – gynecologist, endocrinologist, neurologist and others.

1. Objectives (are described in the terminology of professional activity, taking into account the system of classification of the objectives of the respective levels of cognitive, emotional and psychomotor spheres):

-To analyze the results of main methods of functional diagnostics in gynecology -To explain The levels of regulation of woman`s genital functions -To suggest tactics of management of patients with hormonal imbalance of reproductive system. -To classify mestrual disordes (irregularities) -To interpret the results of laboratory and instrumental examinations of the , , , depending with fazes of MC, the clinical and biochemical, hormonal studies of blood, results of colpocytologycal examination -To draw a diagram scheme of --To make the analysis of the methods of functional diagnosis in gynecology -To make up the models of clinical cases with various hormanal pathology in women of reproductive and premenopausal age.

3. The basic level of expertise, skills, abilities, required for learning the topic

(interdisciplinary integration ) The name of the previous Acquired skills disciplines Normal Anatomy Structure of female genital organs. Topography of abdominal organs and pelvic organs. Histology Histological structure of the cervix, and endometrium in normal and in pathological conditions. Notmal Physiology Physiological changes occurring in the hypothalamic- pituitary-ovarian system of women and target organs of the sex action at different ages. Pathological Physiology Hormonal changes in the body during the menstrual cycle and disorders of the microbiota of the female reproductive system. Pharmacology Groups of medications that affect the function of the , , ovaries, adrenal glands; mechanism of pharmacological action of hormonal, hemostatic, anti-inflammatory, antiviral drugs.

4. Tasks for independent work in preparation for the lesson and in class.

4.1. The list of the major terms, parameters, characteristics to be acquired by a student to be prepared for the lesson The term Definition Basic levels of V level is suprahypothalamic cerebral structures. menstruation regulation IV level — hypothalamus and physical stages of Ш level — . their establishment. II level — ovaries. I level — target organs (, and ).

Biologic action of sex luteonizing (LH) hormones, hypophysis hormones and releasing follicle-stimulating hormone (FSH) hormones.

- Ovarian cycle An ovarian cycle consists of two phases. The first one —, the second — . Uterine cycle the endometrial lining of the uterus builds up under the influence of increasing levels of (labeled as in the image) There are four main stages of the endometrial cycle: desquamation that is mens- truation, regeneration, proliferation, and secretion phases. Menstrual cycle is complex of complicated biological processes in all organism of women, witch characterized cyclical changes in all reproductive organs and provided conception and

Ovulation is the process when the membrane of mature follicle is ruptured and is expelled from the follicle • absence of menses in adult women within 6 months. hypermenorrhea • a excessive amount of blood, more than 100- 150 ml polymenorrhea • — menses' duration is 7-12 days • — a combination of local pain and general algodysmenorrhea state disturbance

dysfunctional uterine acyclic uterine bleeding that is not associated bleedings. with menstrual cycle.

FIGO classification of is now being increasingly used for categorising cause: ‘PALM-COEIN’ causes: Polyp, , Leiomyoma, Malignancy (and hyperplasia), Coagulopathy,Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified The ‘PALM’ are assessed visually (imaging and histopathology) and the ‘COEIN’ are non- structural. 4.2 Theoretical questions for the lesson: 1. Classification of the menstrual function disorders. 2. Amenorrhea. 3. Dysfunctional uterine bleeding. Classification. Methods of diagnostic and treatment. 4. Juvenile uterine bleeding. Etiology, symptomatic diagnosis and treatment. 5. Postmenopausal uterine bleeding. Etiology< symptomatic, diagnosis and treatment. 6. Algodismenorrhea. Symptomatic, diagnosis and treatment. 7. Neuroendocrine syndromes in gynecology. 4.3 Practical activities (tasks) to be performed on the lesson:  To perform gynecological examination (bivalve vaginal speculum, bimanual, rectal, rectovaginal).  To analyze the results of main methods of functional diagnostics in gynecology  To suggest tactics of management of patients with hormonal imbalance of female reproductive system.  To classify mestrual disordes (irregularities)  To interpret the results of laboratory and instrumental examinations of the cervix, endometrium, ovaries, depending with fazes of MC, the clinical and biochemical, hormonal studies of blood, results of colpocytologycal examination  To draw a diagram scheme of menstrual cycle  To make up the models of clinical cases with various hormanal pathology in women of reproductive and premenopausal age. 4.4 Topic content Disorders of function of reproductive system. 1. Amenorrhea. 1.1. Primary amenorrhea. 1.1.1. Primary amenorrhea with no sexual development: - (Shereshevsky–, Swayer syndrome); - testicular (Morris syndrome). 1.1.2. Primary amenorrhea with sexual development delay: - resistant syndrome (in case it arises in the prepubertal period); - hypogonadotropic . 1.1.3. Primary amenorrhea without sexual maldevelopments: - Maldevelopments of the vagina and uterus (uterine and vaginal aplasia – Rokitansky–Kuestner syndrome; atresia of the hymen, vagina, and cervical canal of uterus). 1.2. Secondary amenorrhea: - hypogonadotropic hypogonadism; - hypergonadotropic hypogonadism; - emotional amenorrhea; - weight loss amenorrhea; - Asherman’s syndrome (intrauterine synechias as a consequence of traumatic injuries of the uterus). 2. Hyperprolactinemia. 3. Dysfunctional bleedings. 3.1. Ovulatory bleedings. 3.2. Anovulatory bleedings: - dysfunctional bleedings of (juvenile); - dysfunctional bleedings of the reproductive period; - dysfunctional bleedings of the premenopausal period. 4. Neuroendocrine syndromes (the most widespread): - ; - postcastration syndrome; - climacteric syndrome; - postnatal obesity syndrome; - polycystic ovary syndrome; - adrenogenital syndrome; - Sheehan’s syndrome. 5. . 3.2. Amenorrhea Amenorrhea is the absence of during 6 months and longer in women aged 16–45 years. The incidence of amenorrhea in population among women of childbearing age makes approximately 3.5 %, and in the structure of reproductive system disorders – 10–15 %. There are differentiated physiological (the absence of menstruations till the pubertal period, during pregnancy, , and in the postmenopause) and pathological types of amenorrhea. The etiology of pathological amenorrhea is very diverse. It is a symptom of a gynecological and extragenital pathology, may be primary and secondary: primary amenorrhea is the absence of menstruations at the age older than 16 years; secondary amenorrhea is the absence of menstruations during 6 months and longer after a period of regular and irregular menstruations. Amenorrhea is considered secondary even if there is a history of one menstruation only. If the interval between the episodes of bloody discharge makes less than half a year, the state is considered a hypomenstrual syndrome, a variety of which is the so-called spaniomenorrhea – menstruations take place 2–3 times a year. Besides, there are singled out true and false types of amenorrhea. The reasons for false amenorrhea are: atresia of the virginal membrane, vagina, cervical canal, and transversal membrane of the vagina. This is accompanied by cyclic changes in the hypothalamo-pituitary-ovarian system and uterus, but the outlet of the menstrual blood is blocked. This leads to menstrual blood accumulation in the upper genital tract with the formation of and accompanied by pain syndrome. Pathological amenorrhea is also classified depending on the level of affection of a certain part of the reproductive system. According to this there are differentiated hypothalamic-pituitary, ovarian, and uterine forms of amenorrhea, and also amenorrhea conditioned by a pathology of the adrenal glands, gland, and the presence of extragenital diseases.

Primary Amenorrhea Primary amenorrhea is observed much less frequently than the secondary one and makes 8–10 % in the structure of amenorrhea. Primary amenorrhea is more frequently combined with other signs of sexual development delay (SDD), less frequently it arises at all the signs of sexual development preserved. Therefore there are singled out two forms of primary amenorrhea: - with a derangement of sexual development (SDD, hermaphroditism); - without sexual development disorders. All over the world much attention is paid to the problem of SDD, which conditioned the fact that this pathology is marked put as a disease entity by the World Health Organization. Underdevelopment or absence of the secondary sexual characters at the age of 13–14 years and absence of menstruation at the age of 15– 16 years should be regarded as SDD. Depending on the primary level of reproductive system affection there are differentiated central (as a result of insufficient gonadotropic stimulation there secondarily arises ovarian insufficiency) and ovarian (primary affection of the accompanied by the increased gonadotropin secretion) forms of SDD. Thus, the central and ovarian forms of SDD are regarded as hypo- and hypergonadotropic. To the ovarian form of SDD we refer gonadal dysgenesis (GD, hypergonadotropic hypogonadism) – the most widespread reason for primary amenorrhea against the background of SDD. The onset of gonadal dysgenesis is based on X-chromosome monosomy or mosaicism and X-chromosome aberration. This state is characterized by the absence of the follicular apparatus, which leads to estrogen deficiency and, as a result, to the increase of gonadotropin concentration in blood. Clinical-diagnostic criteria. The severity of clinical symptoms depends on the quantitative and qualitative pathology of sex chromosomes and the ratio of normal and aberrant clones, which determines the singling out of clinical forms of gonadal dysgenesis. The typical form of GD – Turner’s syndrome (45,ХО) – is characterized by: - the GD phenotype – small stature, wide and short neck, skin folds, which go from the mammillary process to the acromion one, micrognathia, high palate, low-set auricles, numerous pigment spots on the skin, nipples located wide apart, cubitus valgus (Fig. 2); - evident genital infantilism; - primary amenorrhea; - anomalies of occlusion; - strabismus; - shield-shaped chest; - winged scapulas; - malformations of the kidneys and cardiovascular system; - gonads in the form of connective-tissues bands. At the pure form of GD (46,ХХ or 46,ХY – Swyer’s syndrome) there is observed normal stature, the absence of somatic malformations, eunuchoid or intersexual phenotype at Swyer’s syndrome, secondary sexual character underdevelopment, hypoplasia. The mixed form of GD (45,ХО/46,ХY): - the clinical presentation is characterized by manifestation variability; - secondary sexual character underdevelopment; - hypoplastic uterus; - gonad asymmetry (a fibrous tissue band on one side, underdeveloped elements of testicles – on the other side). The obliterated form of GD (mosaicism 45,ХО/46,ХХ) is characterized by a variety of clinical signs, whose severity is determined by the ratio of normal and aberrant cell clones. The patients have a small stature less frequently, is possible at normal terms, the development of the secondary sexual characters may be spontaneous (but not complete). Investigation of the hormonal status at all forms detects high concentrations of gonadotropins in the blood plasma and estradiol decrease. Treatment. The GD therapy depends on the presence of Y-chromosome in the caryotype. Since the risk of gonad malignization is high if Y-chromosome is present, they must be removed surgically. If there is no Y-chromosome in the karyotype or if the gonads have been removed surgically Y-chromosome being present, substitutive hormonotherapy (SHT) is provided aimed at feminization, gonadotropin level lowering, cyclic changes in the endometrium with a menstruation-like reaction, prophylaxis of estrogen deficit conditions, and social adaptation. In order to become pregnant one carries out the program of extracorporal fertilization (in vitro fertilization, IVF) with oocyte donation. The ovarian forms of SDD in patients with the normal karyotype include the syndrome of resistant ovaries, which develops in the prepubertal period and declares itself with hypoestrogenia, primary amenorrhea, and sexual infantilism. In this disease the morphologically full-value ovaries do not respond to endogenous gonadotropic stimulation, which leads to gonadotropin hypersecretion. The central form of SDD, which is defined as hypogonadotropic hypogonadism, is accompanied by estrogen deficit and primary or, less frequently, secondary amenorrhea. The most common reasons for this disease are genetic factors (congenital hypogonadotropic hypogonadism) and unfavourable exogenous factors (acquired hypogonadotropic hypogonadism against the background of infection-toxic illnesses, pituitary tumors, , low body weight, considerable exercise ). The onset of this pathology may also be conditioned by asphyxia and birth injury of newborn. There is differentiated hypogonadotropic hypogonadism of hypothalamic and hypophysial origin. Hypogonadotropic hypogonadism of hypothalamic origin is based on the disorder of LH formation, which leads to the inhibition of gonadotropin production by the hypophysis and is accompanied by the lack of follicle growth and . Hypogonadotropic hypogonadism of hypophysial genesis is characterized by violated gonadotropin release (Fig. 3). Clinicodiagnostic criteria: - primary, less frequently secondary amenorrhea; - the eunuchoid type of the organization of the body; - underdevelopment of the secondary sexual characters; - hypoplasia of the external and internal genital organs;

- low concentrations of FSH, , and Е2 in the blood; - as a result of low estrogen saturation there is noted a negative progesterone test, a negative clomiphene test; - a positive hormonal test with estrogens and gestagens; - a positive test with LH at the hypothalamic level of affection; a negative test at hypophysial hypogonadotropic hypogonadism. The treatment depends on the reasons, which have caused SDD. If the patient has pituitary tumors, the treatment is surgical. The therapy of all the forms of SDD should be complex, aimed at the normalization of the function of the diencephalic area (if there are appropriate indications, the treatment is carried out together with a neurologist, a psychoneurologist). There is recommended general health-improving cyclic vitamin therapy, physiotherapy. If the form of SDD is not full-blown, the mentioned treatment is usually sufficient to normalize the menstrual cycle. If the SDD form is full-blown, which declares itself with underdevelopment or absence of the secondary sexual characters, hormonal treatment is indicated. The diseases of the reproductive system, which are accompanied by primary amenorrhea, also include male pseudohermaphrodite (testicular feminization, Morris’ syndrome). In this pathology there is marked the congenital absence of the 5α-reductase , which turns into dehydrotestosteron (the most active ). The patients lack androgen receptors in the target tissues. The karyotype is 46,ХУ. The presence of the Y-chromosome conditions the development of the testicles, whose hormonal secretion is deficient. Since estrogen receptors are preserved in such patients, there takes place complete feminization under the influence of a small amount of estrogens produced in the male organism, the external genital organs are formed by the female phenotype. The secondary sexual characters are underdeveloped. The diagnosis of testicular feminization is confirmed with the help of genetic methods and ultrasound investigation. Treatment. An obligatory stage of treatment is removal of the defective testicles, because they present a potential hazard of malignant tumor development. Besides, the external genital organs are corrected: , dissection of the outer wall of the urogenital sinus, colpopoiesis, etc. Mayer–Rokitansky–Kuestner’s syndrome is a monogenic mutation at the genotype 46,ХХ. The typical signs are: - ametria and absence of vagina; - normal , ovulation and yellow body formation in the ovaries; - primary amenorrhea (uterine form); - malformations (noted in 40 % patients). The diagnosis is given with the help of gynecological, ultrasound investigation, genetic counseling, and endoscopic methods of diagnostics. Treatment. Menstruation function recovery is impossible. The operation of colpopoiesis is carried out to provide sex life.

Secondary amenorrhea Secondary amenorrhea arises after a period of normal or disturbed menstrual cycle and makes up to 75 % in the structure of amenorrhea. This form of amenorrhea is not accompanied by sexual development derangement. Depending on the degree of reproductive system affection there are differentiated hypothalamic, hypophysial, ovarian, and uterine forms of amenorrhea. 1) Hypothalamic amenorrhea: - emotional amenorrhea, including at anorexia nervosa; - amenorrhea at ; - Chiari–Frommel’s syndrome – amenorrhea and galactorrhea, which arises as a complication of the puerperal period, often after an abnormal labor and pathological pregnancy; - Forbes–Albright’s syndrome – amenorrhea and galactorrhea, which arises as a consequence of a psychogenic trauma, a hypothalamic- pituitary tumor, and also after intake of some medications, namely hormonal contraceptives, neuroleptics, hypotensive and antihistaminic preparations in nulliparae. 2) Hypophysial amenorrhea is most often met in the following pathologies: - Sheehan’s syndrome (puerperal ); - amenorrhea against the background of hyperprolactinemia as a consequence of pituitary micro- or macroadenoma; - Morphan’s syndrome (a hereditary disease, which is transmitted by the dominant type); - Itsenko–Cushing’s disease. 3) Ovarian amenorrhea: - resistant ovary syndrome; - ovarian exhaustion syndrome. 4) Uterine secondary amenorrhea: - Asherman’s syndrome (the presence of intrauterine synechias); - cervical canal stenosis. Emotional amenorrhea at anorexia nervosa makes up to 25 % in the structure of secondary amenorrhea among teenagers. At anorexia nervosa amenorrhea results from hypothalamic dysfunction. Inhibition of the rhythmical gonadoliberin secretion leads to the reduction of the synthesis of gonadotropins and, as a consequence, estrogens. Aromatization of into estrogens is taking place in the . When the volume of the adipose tissue reduces, there also drops the quantity of androgens subject to aromatization. Estrogen metabolism alteration leads to the formation of catechol estrogens, which do not have direct estrogen activity, instead of the active form of estrogens, estradiol. Catechol estrogens compete with catecholamines for the enzyme catechol-ortho-methyltransferase, and catechol estrogens are affined to this enzyme to a greater degree. This leads to catecholamine metabolism deceleration, particularly there reduces the amount of DA, which exerts inhibiting influence on the rhythmical secretion of LH and brings to the reduced estrogen production. Hypoestrogenia results in the reduced size and volume of the mammary glands, uterus, and ovaries. Developing leads to bone loss and increases the frequency of bone fractures. If weight loss makes 5–18 %, menstruations cease sharply, without a period of . Against the background of ongoing weight loss there accumulate starvation symptoms – bradycardia, hypotension, hypoglycemia, hypothermia, gastritis, and constipations. Later on there develops cachexia with a complete loss of appetite and aversion to food. Typical signs of this pathology are sticking to a diet, fear of gaining weight or obesity despite being . The treatment of such patients should be conducted by a gynecologist together with a psychotherapeutist. There is administered a full-value diet in small portions, vitamins, and sedatives. Administration of neuroleptics during 2–4 weeks is also effective. Menstruation cycle may recover only after body weight normalization and psychotropic medication cessation. One should remember that the latter inhibit the gonadotropic function of the hypophysis. If there is no effect, one administers a hormonal therapy with combined oral contraceptives (COCs) during 2–3 cycles. The resistant ovary syndrome is a complex of pathological symptoms, which arise in women younger than 35 years, characterized by amenorrhea (primary or secondary), sterility, normal development of the secondary sexual characters, micro-and macroscopically unaltered ovaries with a high level of gonadotropins (Smetnyk V.P., 2005). It should be added that the resistant ovary syndrome is accompanied by hypoestrogenia and genital infantilism if it develops in the prepubertal period. Disordered binding of gonadotropins with their receptors in the ovaries underlies the development of the resistant ovary syndrome. As a result, folliculogenesis is violated, which brings to hypoestrogenia, which causes an increase of the gonadotropins level by the feedback mechanism. The syndrome may be congenital (a genetically conditioned damage of the receptor apparatus) and acquired (caused by iatrogenic reasons, particularly roentgenotherapy, intake of cytotoxic preparations, immunosuppressants, operative interventions on the ovaries, tuberculous lesion of the ovaries, etc.). Clinicodiagnostic criteria: - women of childbearing age with normal body-build, well-marked secondary sexual characters; - amenorrhea – primary (if the syndrome develops in the prepubertal period) or secondary (in 5–10 years after a timely menarche); - episodical flashes and menstruation-like discharge;

- Е2 decrease or FSH and LH increase in the blood plasma; - the first test with progesterone is positive, but later on it is negative; - a positive cyclic hormonal test; - , the ovaries of normal or decreased size, the presence of primordial and preantral follicles. The treatment of patients with the resistant ovary syndrome is very complicated, which is first of all conditioned by the fact that the etiology and pathogenesis have not been thoroughly studied yet. Unfortunately, replacement hormonal therapy has positive results only in some cases. Besides, the data concerning the efficiency of the treatment gonadotropins are also questionable. In order to become pregnant women with the resistant ovary syndrome should undergo IVF with oocyte donation. The ovarian exhaustion syndrome is a complex of pathological symptoms (amenorrhea, sterility, fever flushes, hyperhidrosis, etc.) arising in young women, who used to have normal menstrual and reproductive functions (Smetnyk V.P., 2005). The ovarian exhaustion syndrome may be caused by genetic factors leading to the formation of ovaries with a deficit of the follicular apparatus, and also arise as a result of unfavorable exogenous influences (stress, intoxications, viral infections, etc.), which may lead to the atresia of the follicular apparatus against the background of genetic propensity. Hypoestrogenia, which arises by the mechanism, brings to the increase of the FSH and LH levels. Clinicodiagnostic criteria: - female phenotype, normal body-build; - timely menarche; - amenorrhea after a period of regular menstrual and reproductive functions; - a complex of symptoms characteristic of the climacteric syndrome (well- marked flashes, hyperhidrosis, dryness in the vagina, atrophic vulvovaginitis, lowered , etc.); - US shows hypoplasia of the uterus and ovaries, follicular apparatus absence;

- A sharp increase of the FSH and LH concentration and Е2 reduction in the blood plasma. Treatment. Women with the ovarian exhaustion syndrome are sure to be administered a replacement hormonal therapy until the age of natural . Preference is given to preparations containing estrogens and gestagens. Estrogen deficit conditions are prevented. In order to become pregnant women undergo an IVF program with oocyte donation after 3–6 months of preparation therapy with replacement hormonal therapy drugs. Asherman’s syndrome (intrauterine synechias) arises as a result of frequent endometrectomies or endometritises. Clinicodiagnostic criteria: - secondary amenorrhea; - of the uterine cavity, a history of endometritises; - no cyclic pain as opposed to cervical canal atresia; - transvaginal echography findings allow suspecting intrauterine synechias; - the level of sex and gonadotropic hormones is normal, therefore this form of amenorrhea is called normogonadotropic; - a negative test with estrogens and gestagens; - hysteroscopy and hysterosalpingography show a typical picture of intrauterine synechias. The treatment is surgical, consists in dissection at hysteroresectoscopy. If an infectious genesis of the syndrome is suspected (according to the anamnestic data), there is conducted dilating and curettage of the endometrium followed by bacteriological and microbiological investigations. After synechias are dissected, there is provided an antibacterial therapy and during 3 months – a cyclic hormone therapy: estrogens from the 5th to the 15th day of the cycle, gestagens from the 16th to the 16th day of the cycle. COCs should not be used because they hamper endometrium proliferation.

3.3. Dysfunctional Uterine Bleedings

Dysfunctional uterine bleedings (DUB) are the bleedings conditioned by disturbances of the cyclic secretion of ovarian hormones and not connected with organic diseases or extragenital pathologies. DUB incidence makes 15–20 % of all gynecological pathologies. DUB development is based on the dysfunction of the hypothalamo-pituitary- ovarian system, which leads to the disturbance of folliculo- and steroidogenesis. DUB may arise at any age. However, they have their peculiarities in different age periods. These differences are the basis of DUB classification. Age DUB classification: - DUB at the puberty age (juvenile uterine bleedings); - DUB at the childbearing age; - DUB at the premenopausal age. DUB classification by the character of menstrual irregularities and functional-morphological changes: І. Anovulatory DUB: a) short-term follicle persistence; b) long-term follicle persistence. c) Immature follicle atresia. ІІ. Ovulatory DUB. According to the estrogen level DUB divided into hyperestrogenic (most DUB) and та hypoestrogenic (more frequent in the puberty, but may also be observed at the childbearing age). Though all DUB forms are observed at different age periods of the woman’s life, in the puberty and premenopausal period anovulatory DUB are more frequent, at the childbearing age – ovulatory.

Juvenile Uterine Bleedings

Juvenile uterine bleedings (JUB) are referred to the most frequent pubertal gynecological disorders, their incidence reaches 10 %. Etiology and pathogenesis. JUB pathogenesis is based on the functional immaturity of the hypothalamic pituitary structures in the puberty, which declares itself in the absence of a formed circhoral rhythm of gonadoliberin secretion. This brings to a disbalance of gonadotropin production, and in consequence of that follicle maturing is disturbed, more frequently by the type of immature follicle atresia, and then comes anovulation. The etiologic factors, which promote JUB development are very versatile. An important role is played by chronic and acute infectious diseases, hypovitaminoses, psychic traumas, overload, which violate the functioning of the hypothalamo-pituitary-ovarian system. As a result, against the background of low estrogen level a couple of follicles begin to grow to the antral condition. Further development of the follicles is taking place under the action of FSH, whose cyclic production is violated in this case. Owing to this the follicles do not mature completely and undergo atresia (immature follicle atresia). At that, steroidogenesis in the ovaries is disturbed. In immature follicle atresia in the ovaries insufficient amount of estrogens is produced, but their long- term action on the endometrium leads to the development of hyperplastic processes. Anovulation results in yellow body absence, and that accordingly leads to progesterone deficit. Progesterone deficit conditions the absence of the secretory transformation of the endometrium. In case of follicle involution there arises bleeding as a reaction to hormone decrease. Bleedings lead to , which is the most marked in JUB. Clinicodiagnostic criteria of JUB: - bleedings last up to 20–30 days, but usually they are not that voluminous in comparison with follicle persistence. Bleedings are preceded by 2–3-month menstruation delay (usually lasting longer than in case of follicle persistence); - anemia; - anovulation; - functional diagnostic tests: • hypothermic single-phase character of the temperature profile, the basal rectal temperature does not reach 37° С; • pupil phenomenon “±” or “+”; • the cariopicnotic index (CPI) in this pathology does not exceed 28–35 %; - pelvic ultrasound may show hypoplastic uterus or endometrium hyperplasia; - hormone research: low progesterone level in blood; - histological study of the endometrium in most cases (87 %) shows hyperplastic processes.

Dysfunctional Uterine Bleedings at the Childbearing Age At the childbearing age DUB are observed les frequently than in the puberty, because the reproductive system is already developed and the cyclic function of all its parts is already formed. DUB incidence among gynecological disorders at this age makes 4–5 %. Among DUB at the childbearing age ovulatory bleedings are more frequent than anovulatory DUB. Ovulatory Dysfunctional Uterine Bleedings In this pathology the ovulatory capacity of follicles and the menstrual function are preserved. However, there is observed menstrual cycle shortening at the expense of shortened folliculin and lutein phases, or cycle extension at lutein phase prolongation. To this pathology we may also refer intermenstrual bleedings, which do not change cycle duration. Ovulatory DUBs are conditioned by deficiency of the maturing follicle (hypo- or hyperfunction) or the yellow body (hypo- or hyperfunction), which is connected with the disturbance of gonadotropic hormone production (FSH and LH) or their ratio. І. Folliculin phase shortening is conditioned by deficiency of the maturing follicle; is characterized by a low estrogen level from the first days of the cycle. Clinicodiagnostic criteria: - regular, frequent (usually the menstrual cycle is shortened and makes 14– 21 days) and extended menstruations (voluminous during the first 2–3 days and scarce later on). This is conditioned by deceleration of the processes of endometrium regeneration and proliferation; - functional diagnostic tests show that ovulation is shifted to the 8th–10th day of the cycle. There is observed the two-phase character of the temperature profile with the shortening of the 1st phase to 6–8 days (basal temperature rise takes place on the 7th–9th day of the cycle); - hormone research: the estradiol level in blood is normal, but its maximum value is detected on the 8th–10th day of the menstrual cycle. In the lutein phase hormones are within norm; - histological study of the endometrium shows secretory changes. ІІ. Lutein phase shortening is connected with premature involution of the yellow body. This is the most frequently observed type of ovulatory bleedings at the childbearing age. In this condition follicle maturing is normal, and the yellow body functions for a short time. Clinicodiagnostic criteria: - menstrual cycle shortening (less than 21 days); - scarce discharge before and after menstruation connected with insufficient amount of progesterone; - sterility (quite often); - functional diagnostic tests show timely ovulation. The two-phase character of the temperature profile with the shortening of the 2nd phase to 3–7 days is noted; - hormone research: the estradiol level in blood is normal, in the 2nd phase of the cycle blood progesterone increases, but not for a long time; - histological study of the endometrium scrape shows deficient secretory phase. ІІІ. Lutein phase extension is connected with yellow body persistence. Yellow body hyperfunction may have two forms. Yellow body persistence is possible when menstruation is delayed by a couple of days or even weeks and is accompanied by profuse bleeding. Another form of DUB in yellow body persistence is the syndrome of deficient endometrium rejection. In such a case the yellow body continues persisting but maturing of a new follicle has already begun. Clinicodiagnostic criteria: - prolonged voluminous menstruations, slightly delayed; the uterus is softened and enlarged; - the basal temperature is 37° С and higher during 12–14 days, including during menstruation; - hormone research: a rise of the progesterone level in blood is observed before menstruation and in case of its delay; - histological study: in the endometrium scrape obtained during bleeding there are found secretory changes, sometimes in combination with a low-grade endometrium regeneration.

Anovulatory Dysfunctional Uterine Bleedings at the Childbearing Age Etiology and pathogenesis. At the childbearing age impairment of the cyclic function of the hypothalamo-pituitary-ovarian system, whose ultimate result is anovulation, may be caused by mental stresses, hormonal dyscrasia in consequence of , extragenital pathology, infectious diseases, craniocerebral injury, intake of some medicinal preparations (particularly neuroleptics), improper feeding, inflammatory diseases of the small organs. If in JUB anovulation is a result of immature follicle atresia, in DUB at the childbearing age short-term persistence of a mature follicle is taking place in the ovaries with an increased estrogen production (hyperestrogenic DUB). At hyperestrogenic anovulatory cycle the follicle reaches maturity, but its rupture does not take place. The follicle continues existence and undergoes involution (rhythmical persistence of a mature follicle). Since ovulation does not take place and the yellow body does not form, there develops progesterone deficit condition. At that, absolute is observed. Under the influence of a large amount of estrogens first there takes place proliferation, and later hyperplasia of the endometrium, which is more apparent than in JUB (hyperplasia glandulocystica, endometrial polyps). Clinicodiagnostic criteria: - regular menstruations; - anovulation; - sterility; - functional diagnostic tests testify to a high degree of estrogen saturation: • hypothermal monophase temperature profile; • the pupil phenomenon is positive until the beginning of the next menstruation “++” or “+++” (normally it is negative after the 15th day); • a positive spinnbarkeit sign during the cycle “++” or “+++”; • colpocytological study findings: there prevail surface cells, which corresponds to a high degree of estrogen saturation; • CPI 60–70 %. - hormone research: • a sharp decrease of progesterone in blood, the absence of its increase in the 2nd phase; • gonadotropins content without evident cyclical fluctuations, corresponds to the values in the folliculin phase of the cycle; • estrogen content during the cycle is the same as in the folliculin phase or higher , without an evident increase in the middle of the cycle; - histological study shows the absence secretory endometrium changes, hyperplasia glandulocystica, endometrial polyps, and sometimes adenomatous . The diagnosis is given by dynamic medical observation during 2–3 months, since anovulatory cycle may alternate with ovulatory ones.

Dysfunctional Uterine Bleedings in the Premenopausal Period

DUB incidence in the premenopausal period makes 15 % in the structure of gynecological disorders. Etiology and pathogenesis. In most women of this age the main pathological mechanism of DUB is anovulatory dysfunction of the ovary with long-term follicle persistence. Long-term follicle persistence (2–6 weeks) with considerable menstruation delays (up to 1.5 months) followed by severe long-term bleedings is called metropathia hemorrhagica, or Shroeder’s disease. While JUB is a consequence of nonsteady cyclic function of the hypothalamo-pituitary-ovarian system, premenopausal bleedings are a consequence its involutional disturbances. Age-related changes of the hypothalamic structures, which regulate the gonadotropin function, condition disturbance of the rhythm and amount of gonadotropins released. FSH formation and release prevail, the LH level also rises, acquires a monotonous character. The decrease of gonadotropin receptors amount in the ovaries leads to a disorder of the feedback mechanism. This is accompanied by disturbed folliculogenesis and anovulation. Yellow body absence, decreased progesterone secretion lead to hyperestrogenism development (relative hyperestrogenism against the background of hypoprogesteronemia) and endometrial hyperplasia of different level. In consequence of endometrium growth and insufficient trophism there develop dystrophic changes of the endometrium, which declare themselves with thrombosis, necrosis and orregular desquamation accompanied by long-term bleeding. Clinicodiagnostic criteria: - profuse long-term uterine bleedings with delays up to 1.5 months. It should be noted that menstruation delay is observed in the period of follicle growth and persistence; - anovulation; - functional diagnostic tests: • hypothermal monophase temperature profile; • the pupil phenomenon, spinnbarkeit sign “+++”; • colpocytology study shows a higher degree of estrogen saturation than in short-term follicle persistence; • a higher CPI – 80–100 %; - gynecological examination and pelvic ultrasound show somewhat oversized uterus and endometrial hyperplasia; - histological study of the endometrium scrape shows endometrial hyperplasia more often than at the childbearing age – glandular hyperplasia, hyperplasia glandulocystica, endometrial polyps. In long-term bleeding accompanied by mucosa desquamation the scrape may be scanty, but secretion signs are also absent in it.

Dysfunctional Uterine Bleeding Treatment

DUB treatment is complex and depends on the character of the ovarian- menstrual cycle irregularities, age, intensity and remoteness of the bleeding, the degree of anemia severity, the data of the laboratory methods of investigation, particularly hormonal status before the initiation of treatment. The treatment is provided in three stages: І. Hemostasis. ІІ. Pathogenetic treatment aimed at rebleeding prevention (hormonal disorder correction, menstrual cycle restoration, or achieving menopause). ІІІ. Aftertreatment (recovery of the reproductive function in women of the childbearing age). Hemostasis (the 1st treatment stage). In order to achieve hemostasis one takes surgical, hormonal, and symptomatic measures. Surgical hemostasis. DUB treatment at the childbearing and premenopausal age is begun with diagnostic and therapeutic dilatation and curettage of cervical and uterine mucous membranes. Under modern conditions surgical hemostasis may be conducted using the so-called little-invasive surgical procedures, which are applied under endoscopic control: cryodestruction, laser ablation, and thermal balloon ablation of the endometrium. In JUB surgical hemostasis is carried out according to the following indications: - profuse uterine bleeding, which threatens the patient’s life; - Hb 70 g/L and less, Ht below 25 %; - Suspected pathological changes of the endometrium structures (an shown by pelvic ultrasound); - In patients with frequent rebleedings and disease duration exceeding 2 years. Hormonal hemostasis. For hormonal hemostasis one most often uses estrogens, gestagens and monophase combined estrogen-gestagen preparations, androgens, gonadoliberin agonists, gonadotropin antagonists. The choice of preparations depends on the pathogenetic variety of DUB, the patient’s age, and contraindications. The action of the preparations is based on the inhibition of pituitary gonadotropic hormones and maintenance of the steroid hormone concentration at a high level. Monophase combined oral contraceptives (COCs) are used for hormonal hemostasis the most often. Hemostasis regimen: on the first day 1 COC pill per hour is administered up to 4–6 pills (at the age of 14–15 years – up to 3 pills), then the preparation dosage is reduced daily to 1 pill a day. The preparation is taken during 21 days. Hormonal hemostasis with COCs is not provided in the premenopausal period. Estrogens have a quick and rather high hemostatic effect. For hormonal hemostasis one may use preparations of natural estrogens (non-synthetic), for example, progynova (), estraferm (17β-estradiol). These preparations are administered in the same way as oral contraceptives, but after hemostasis and intake of these preparations for 2 more weeks one should necessarily administer gestagens during 10 days. Estrogens may be used for hemostasis at any age, but in the premenopausal period their use must be limited and conducted after a histological study of the endometrium. Gestagens have a hemostatic effect at the expense of influencing the endometrium transformation. They block proliferative processes and shift the endometrium into the secretory phase. For hormonal hemostasis one uses gestagens of two classes: derivatives of 17-ОН-progesterone ( – duphaston 10 mg twice a day, medroxyprogesterone acetate – Depo-Provera 200–400 mg i.m. once a week; 17- oxyprogesterone capronate 2 ml 12.5 % i.m., etc.) and derivatives of 19- nortestosterone (, norgestrel, lynestrenol – orgametryl, acetate – primalut-nor, norcalut – 10 mg twice a day, etc.). Unlike estrogen hemostasis, gestagen introduction does not produce a quick bleeding arrest. In 1–2 days after the cessation of gestagen action there is noted intensive bleeding of the menorrhagia type. Taking into account the ability of gestagens to cause endometrium atrophy and central effect inhibition in the juvenile age, it is not advisable to administer them at this age. For hormonal hemostasis one may also use antagonists of pituitary gonadotropic hormones: - (danoval, danogen, danol) – 200–400 mg/day, treatment duration makes 3–6 months; - (nemestran) – 2.5 mg twice a week during 6 months, etc. DUB may also be treated with gonadoliberin agonists: - (zoladex) – 1 injection (3.6 mg) during 28 days subcutaneously; - (decapeptyl, dipherelin) – 3.75 mg i.m. once in 28 days. It should be added that androgen hemostasis is resorted to very rarely nowadays because of numerous contraindications and also in connection with pronounced effects. One should remember that administration of hormonal treatment in teenager girls requires special caution and systematic control of the hormonal status of the organism with 3–6-month intervals. The doses of hormonal preparations in the period of menstrual function formation must be rationally limited. In girls one may use estrogens or combined estrogen-gestagen preparations for hormonal hemostasis. In all DUB types there are administered symptomatic hemostatic and uterotonics preparations. There is used sodium etamsylar, ε-aminocapronic acid, tranexamic acid, 10 % calcium chloride solution. Among uterotonics preference is given to ergot preparations, since unlike they do not cause tonic contractions of the uterus (methylergometryl). The doctor also administers vitamin therapy, tinctures of nettle, water pepper, and buckthorn. The 2nd treatment stage foresees recovery of the menstrual cycle and recurrent bleeding prevention. At this stage there are administered general health- improving preparations, hemostimulating and vitamin therapies are continued. Hormonal correction is carried out depending on the patient’s age and is determined by the defined goal (menstrual cycle recovery, pregnancy planning, or menopause onset). At this stage gestagens and COCs are used more often. The 2nd treatment stage is aimed at the recovery of the reproductive function in women of the childbearing age. When the rhythmical menstrual cycle is recovered, ovulation is induced with the application of direct (clomiphene, anestrozol, letrozol) and indirect ovulation inductors (gonadoliberin agonists, recombinant gonadotropins, human menopausal gonadotropins, etc.).

Materials for self-control:

TESTS

1.For the clinical manifestations of dysmenorrhoea are not typical: A. excessive blood loss B. headache C. nausea D. abdominal pain E. irritability 2.How is the state named, when less than 2 days proceed to menstruation? A. oligomenorrhea B. spaniomenorrhea C. D. proyomenorrhea E. opsomenorrhea 3.What menorrhagia is? A. duration of menstruation over 12 days B. bleeding unconnected with a menstrual cycle C. more than 150ml blood during menstruation D. duration of menstruation 5-10 days E. duration of menstruation 7-12 day 4.Which of the following method is used to diagnose uterine form of amenorrhea? A. hysteroscopy B. tests of functional diagnostics C. hysterosalpingography D. none of the above E. all listed 5.Duration of menstruation less than 2 days is called: A. oligomenorrhea B. opsomenorhea C. hypomenorhea D. hypermenorrhea E. all listed 6.Which of the following is the cause of ovarian form of amenorrhea? A. all of the above B. congenital gonades’ dysgenesia C. the Shereshevsky-Terner’s syndrome D. the Shtein-Levental syndrome E. none of the above 7. the Shereshevsky-Terner’s syndrome is the result of A. a complex of genetic defects, connected with chromosomes anomaly B. presence of double uterus C. absence of ovaries D. E. polycystic ovarian syndrome 8.Hypomenorhea - is: A. reduced amount of blood, less than 50 ml B. an excessive amount of blood, more than 100-150 ml C. the absence of menstruation for 6 months D. duration of menstruation more than 12 days E. reduced amount of blood, less than 150 ml 9. The uterine form of amenorrhea can result from all specified below diseases, except: A. none of the below B. frequent curettage of the uterine cavity C. genital infantilism D. chronic inflammation nonspecific etiology E. tuberculosis of endometrium 10.What is not used for diagnosis of disorders of the menstrual cycle? A. use all of the above B. tests of functional diagnostics C. investigation of the hormone levels in the blood D. x-ray of sella turcica E. determining the level of TTH

SITUATIONAL TASKS 1.A 25-year-old female patient complains about having amenorrhea for 3 years. She associates it with difficult labour complicated by massive hemorrhage. She also complains of loss of weight, hair fragility and loss, lack of appetite and . Objective examination reveals no pathological changes of uterus and its appendages. What is the desease pathogenesis? 2.26 years old woman 6 months ago have delivered. A child is on feeding. Came to the survey because of absence of menses, they do not appear after birth once. When bimanual examination the uterus is not enlarged, dense, andexa are not determined. What is the most likely diagnosis? 3.A 51-year-old patient complains of having intensive bloody discharges from vagina for 15 days after delay of menstruation for 2,5 months. In anamnesis: disorders of menstrual function during a year, at the same time she felt extreme irritability and had sleep disorders. US examination results: uterus corresponds with age norms, appendages have no pecularities, endometrium is 14 mm thick. What is the doctor's tactics? 4.A 15-year-old girl presents to your office with her because she has never had a period. They report that she seemed to grow and develop breasts at the same time as the other girls in school, but that she has not yet started to menstruate. She is active in sports at her school and plays the piano. She is 5940 , 128 lb; an examination reveals Tanner IV breast and pelvic examination reveals a blind