Abnormal uterine bleeding (AUB) - according to modern concepts - is a comprehensive term that implies any uterine bleeding (i.e. bleeding from the body and cervix) that does not meet the parameters of normal menstruation in a woman of reproductive age.
Parameters of normal menstruation (menstrual cycle). So, according to modern views, its duration ranges from 24 to 38 days. The normal duration of the menstrual phase is 4.5 - 8 days. An objective study of blood loss during menstruation showed that a volume of 30 - 40 ml should be considered normal. Its upper acceptable limit is considered to be 80 ml (which is equivalent to a loss of approximately 16 mg of iron). It is this hemorrhage that can lead to a decrease in hemoglobin levels, as well as to the appearance of other signs of iron deficiency anemia.
The incidence of AUB increases with age. Thus, in the general structure of gynecological diseases, juvenile uterine bleeding accounts for 10%, AUB in the active reproductive period - 25 - 30%, in late reproductive age - 35 - 55%, and in menopause - up to 55 - 60%. The particular clinical significance of AUB is determined by the fact that they can be a symptom not only of benign diseases, but also of precancer and endometrial cancer.
Causes of AMC:
- caused by uterine pathology: endometrial dysfunction (ovulatory bleeding), pregnancy-related AUB (spontaneous abortion, placental polyp, trophoblastic disease, impaired ectopic pregnancy), cervical diseases (cervical endometriosis, atrophic cervicitis, endocervical polyp, cervical cancer and other neoplasms cervix, uterine fibroids with cervical location of the node), diseases of the uterine body (uterine fibroids, endometrial polyp, internal endometriosis of the uterus, hyperplastic processes of the endometrium and endometrial cancer, sarcoma of the uterine body, endometritis, genital tuberculosis, arteriovenous anomaly of the uterus);
not related to uterine pathology: diseases of the uterine appendages (bleeding after ovarian resection or oophorectomy, uterine bleeding due to ovarian tumors, premature puberty), AUB during hormonal therapy (combined oral contraceptives, progestins, hormone replacement therapy), anovulatory bleeding (menarche , perimenopause, polycystic ovary syndrome, hypothyroidism, hyperprolactinemia, stress, eating disorders);
systemic pathology: diseases of the blood system, liver diseases, renal failure, congenital adrenal hyperplasia, Cushing's syndrome and disease, diseases of the nervous system;
iatrogenic factors: bleeding after resection, electrical, thermal or cryodestruction of the endometrium, bleeding from the cervical biopsy area, while taking anticoagulants, neurotropic drugs;
AUB of unknown etiology.
When diagnosing AUB, the first stage of the diagnostic search is to establish the truth of the patient’s complaints regarding the presence of bleeding. It should be noted that in 40 - 70% of women who complain of heavy menstruation, an objective assessment does not always determine the amount of blood loss that exceeds the norm. In such cases, patients rather need psychological help and educational activities. Conversely, about 40% of patients with menometrorrhagia do not consider their menstruation to be heavy. Consequently, it is very difficult to give a qualitative assessment of this clinical symptom based only on the patient’s complaints. In this regard, to objectify the clinical picture, it is advisable to use the method of assessing blood loss developed by Jansen (2001). Women are asked to fill out a special form visual table with counting the number of pads or tampons used on different days of menstruation with a score for the degree of their getting wet (maximum score for pads is 20, for tampons - 10). It should be noted that the count corresponds to standard sanitary material (“normal”, “regular”). However, very often, patients with menorrhagia use “maxi” or “super” tampons or pads, and sometimes even double the amount of them, and therefore actual blood loss may exceed the volumes calculated using a unified table. A score of 185 and above is regarded as a criterion for metrorrhagia.
The second stage of diagnosis is establishing the actual diagnosis of AUB after excluding systemic diseases, coagulopathies and organic pathology of the pelvic organs, which may cause bleeding. At this stage, given the difficulties of diagnosis, there can be no trifles in the doctor’s work. So, when interviewing a patient, it is necessary to collect a “menstrual history”:
- family history: the presence of heavy bleeding, neoplasms of the uterus or ovaries in close relatives;
taking medications that cause metrorrhagia: derivatives of steroid hormones (estrogens, progestins, corticosteroids), anticoagulants, psychotropic drugs (phenothiazines, tricyclic antidepressants, MAO inhibitors, tranquilizers), as well as digoxin, propranolol;
presence of an IUD in the uterine cavity;
the presence of other diseases: bleeding tendency, hypertension, liver disease, hypothyroidism;
previous operations: splenectomy, thyroidectomy, myomectomy, polypectomy, hysteroscopy, diagnostic curettage;
clinical factors combined with metrorrhagia that are subject to targeted identification (differential diagnosis with systemic pathology): nosebleeds, bleeding gums, the appearance of bruises and hematomas, bleeding after childbirth or surgery, family history.
MPT is not recommended as a first-line diagnostic procedure for AUB (benefit and cost of the procedure must be weighed). It is advisable to perform MRI in the presence of multiple uterine fibroids to clarify the topography of the nodes before a planned myomectomy. before embolization of the uterine arteries, before ablation of the endometrium, if adenomyosis is suspected, in cases of poor visualization of the uterine cavity to assess the condition of the endometrium.
The gold standard for diagnosing intrauterine pathology is diagnostic hysteroscopy and endometrial biopsy, which is performed primarily to exclude precancerous lesions and endometrial cancer. This study is recommended if there is a suspicion of endometrial pathology, the presence of risk factors for uterine cancer (with excessive exposure to estrogens - PCOS, obesity) and in all patients with AUB after 45 years. To diagnose the causes of AMK, preference is given to office hysteroscopy and aspiration biopsy, as less traumatic procedures. An endometrial biopsy is informative in cases of diffuse lesions and adequate sampling of material.
The main goals of therapy for AUB are:
- stopping bleeding (hemostasis);
prevention of relapses: restoration of normal functioning of the hypothalamic-pituitary-ovarian system, restoration of ovulation; replenishment of the deficiency of sex steroid hormones.
Among the medicinal methods of hemostasis for AUB with proven effectiveness, antifibrinolytic drugs (tranexamic acid) and nonsteroidal anti-inflammatory drugs (NSAIDs) should be noted. However, so far the most effective among conservative methods of stopping bleeding is hormonal hemostasis with monophasic oral contraceptives containing 0.03 mg of ethinyl estradiol and gestagens of the norsteroid group and having a pronounced suppressive effect on the endometrium. Much less often in clinical practice, progestational hemostasis is used, which is pathogenetically justified in anovulatory hyperestrogenic bleeding.
Surgical hemostasis is ensured primarily by fractional curettage of the uterine cavity and cervical canal under hysteroscopic control. This operation has both diagnostic (to exclude organic pathology of the uterine cavity) and therapeutic purposes, and is the method of choice for women of the late reproductive and menopausal periods, given the increasing frequency of atypical transformation of the endometrium in these age groups. In the case of pubertal bleeding, this operation is possible only for health reasons.
Prevention of relapse. General principles of anti-relapse treatment of AUB: 1. Carrying out general strengthening measures - regulation of sleep, work and rest, rational nutrition, compliance with the rules of psychological hygiene. 2. Treatment of anemia (iron supplements, multivitamin and mineral supplements, in severe cases - blood substitutes and blood products). 3. Inhibitors of prostaglandin synthesis in the first 1 - 3 days of menstruation. 4. Antifibrinolytics in the first 1 - 3 days of menstruation (tranexamic acid). 5. Vitamin therapy – complex preparations containing zinc. 6. Drugs that stabilize the function of the central nervous system. Non-hormonal drugs are recommended for both ovulatory and anovulatory bleeding. 7. Hormonal therapy is prescribed differentially depending on the pathogenetic variant of AUB: in the juvenile period - cyclic hormone therapy with estrogen-gestagens for 3 months, gestagens in the 2nd phase of the menstrual cycle for up to 6 months; in the reproductive period - cyclic hormone therapy with estrogen-gestagens for 3 months, gestagens in the 2nd phase of the menstrual cycle for up to 6 months; in the menopausal period - it is necessary to turn off the ovarian function (gestagens in continuous mode - 6 months).
About 65% of women of reproductive age go to antenatal clinics regarding bleeding from the genital tract. In fact, uterine bleeding is not a diagnosis, but a symptom that occurs in various obstetric, gynecological and other pathologies.
According to modern concepts, the term “dysfunctional uterine bleeding” is a thing of the past. Currently, all obstetrician-gynecologists in the world use the same terminology, according to which they now use a different name - abnormal uterine bleeding, or AUB.
Abnormal uterine bleeding is any bleeding that does not correspond to the parameters of normal menstrual function in women of reproductive age.
Let us recall normal physiology.
Menarche (first menstruation) occurs on average at 12–14 years of age. After about 3–6 months, a normal menstrual cycle is established. It ranges from 21–35 days. Menstruation itself lasts from 3 to 7 days, blood loss ranges from 40 to 80 ml. Around 45–50 years of age, the menopause begins, which with the last menstruation passes into the period of menopause.
Deviations from the norm that fall under the definition of abnormal uterine bleeding:
- During the formation of menstruation.
- Between menstruation.
- After a missed period.
- Lasting more than 7 days, with blood loss exceeding 80 ml.
- In menopause or menopause.
If you notice blood on your underwear, and your period should not appear yet, contact a specialist immediately. This may be a sign of serious pathologies.
Causes and classification
These classifications have been used since 2010 by all obstetricians and gynecologists in the world. Let's consider two modern classifications - by the causes of bleeding and by their types. The first classification was based on the causes of pathology:
- AUB associated with pathology of the uterus and appendages.
- AUB associated with disruption of the ovulation process.
- AUB that occurs in various systemic pathologies (blood diseases, adrenal pathology, Cushing's disease or syndrome, hypothyroidism).
- Iatrogenic forms of AUB, that is, associated with certain medical influences. For example, those arising as a result of disturbances in the hemostasis system (blood clotting) after or during taking a number of medications (anticoagulants, hormones, tricyclic antidepressants, tranquilizers, adrenal hormones, etc.). This group includes AUB that occurred after medical manipulation. For example, bleeding after taking a biopsy, after performing cryodestruction of hyperplastic endometrium.
- AUB of unknown etiology (causes).
Finding out the causes of bleeding is the basis for choosing treatment tactics.
The second classification determines the types of uterine bleeding:
- Heavy. The degree of severity is determined by the subjective state of the woman.
- Irregular menstrual bleeding.
- Long lasting.
Obviously, the classification includes bleeding that originates only from the body, cervix and appendages. Bloody discharge in women from the vulva or vaginal walls does not apply to AUB.
Let's take a closer look at the causes of dysfunctional uterine bleeding.
Pathology of the uterus and appendages
Let us examine in more detail AUB that occurs in connection with diseases of the uterus.
Myoma nodes can be found directly in the body of the uterus, as the most common cause of bleeding. Other reasons include:
- Endometrial polyps.
- Adenomyosis.
- Endometrial hyperplasia.
- Endometriosis.
- Cancer of the uterus.
- Sarcoma.
- Chronic endometritis.
Internal bleeding with clots in women can occur with the following diseases of the cervix:
- Atrophic cervicitis.
- Cervical erosion.
- Polyp of the cervical canal.
- Myomatous nodes located in the neck.
Causes also include cervical cancer. With this pathology, as a rule, there are contact bleedings, that is, those that occur after sexual intercourse or douching.
Internal uterine bleeding can occur as a result of pregnancy complications. Spontaneous miscarriage, placental polyp, ectopic pregnancy and placental abruption are accompanied by very significant blood loss with clots. Bleeding from the uterus may be a symptom of organ rupture due to the scar from surgery.
Injuries to the uterus of non-iatrogenic origin also lead to uterine bleeding.
Ovulation disorders
Anovulatory uterine bleeding occurs after menarche, during the formation of menstruation. They are also possible during the perimenopausal period, when menstrual function is fading. When the ovulation process is disrupted, bleeding in reproductive women is also often observed in the practice of gynecologists.
Depending on the situation, the following may occur:
- Against the background of an absolute increase in estrogen levels, if a persistent follicle has arisen.
- Against the background of a relative increase in estrogen with a decrease in progestogen production (follicular atresia).
Clinical signs of these hormonal abnormalities appear in the form of follicular cyst and corpus luteum cyst.
Irregular periods with intervals of several months are characteristic of polycystic ovary syndrome.
While taking combined oral contraceptives (COCs), especially at the beginning of the course, breakthrough bleeding may occur. This is due to the fact that the body adapts to the formation of a thinner layer of the endometrium. That is why, at the end of the dose, it is not menstruation as such that will occur, but a more scanty menstrual-like reaction.
In other cases, the appearance of breakthrough bleeding indicates that there are signs of ineffectiveness of taking COCs. This is possible if a woman is simultaneously taking antibiotics or has suffered food poisoning during which she vomited.
In practice, there have been cases when the cause could be called smoking - this is how nicotine sometimes affects a woman’s body.
Systemic pathology
Signs of disturbances in the hemostatic system may appear even before the onset of menstruation. For example, after a tooth is removed, the hole bleeds for a long time, or the bleeding after minor injuries or cuts cannot be stopped for a long time. Usually one of the relatives experiences similar symptoms. Abnormalities in blood clotting factors are detected by detailed laboratory testing.
Liver diseases affect the synthesis of many hormones and biologically active substances, which can also have an adverse effect on blood clotting processes and the processes of regulation of the menstrual cycle.
Iatrogenesis
This term refers to a negative impact on a patient's health as a result of a physician's actions. It would be completely wrong to understand it as a malicious act of a health worker. None of the doctors wants to harm the patient.
This situation can occur, for example, during a medical abortion in a woman who has given birth repeatedly and who has a history of many abortions, moreover complicated by endometritis. The fact is that the operation is performed blindly with a sharp instrument. And if the uterine wall is overly pliable and thin, perforation can occur, that is, damage to the uterine wall with access to the abdominal cavity. If large vessels are damaged during perforation, internal bleeding may occur.
Or another example. The doctor, suspecting an oncological process on the cervix, takes a piece of cervical tissue for histological examination, that is, he simply plucks it off with a sharp instrument. Due to existing changes in the tissues of the affected cervix, the area from which the biopsy was taken may bleed for a long time with clots.
Treatment with digoxin, which is prescribed by a cardiologist according to indications, can also affect blood clotting. One of the side effects will be a possible decrease in platelet count.
Symptoms
Symptoms of bleeding depend on what is causing it. The main manifestation is bleeding outside or during menstruation.
The intensity of uterine bleeding may vary. There is often profuse bleeding with clots. Moreover, a woman’s subjective well-being depends not only on the amount of blood lost, but also on the speed and intensity of blood loss.
Profuse bleeding is dangerous because compensatory and protective mechanisms do not have time to turn on. This creates a risk of developing hemorrhagic shock. Signs of shock:
- Paleness of the skin, coldness to the touch.
- Weakness, up to loss of consciousness.
- A sharp decrease in blood pressure with simultaneous tachycardia. The pulse is weak, thread-like.
- In severe cases, urination is rare.
- Hemoglobin and red blood cells are reduced.
- The volume of circulating fluid is sharply reduced.
This situation requires immediate resuscitation measures with mandatory replacement of blood loss.
In less dangerous cases, bloody discharge from the genital tract of moderate intensity, sometimes with clots, is observed. In some situations, bleeding may be accompanied by pain.
During a spontaneous miscarriage, heavy bloody discharge with clots is accompanied by severe cramping pain. In case of an interrupted ectopic pregnancy, against the background of a slight delay in menstruation and acute pain in the lower abdomen, signs of severe internal bleeding are observed.
Internal bleeding is very dangerous for the patient's life. After a pregnant fallopian tube ruptures, there may be up to a liter of liquid blood with clots in the abdominal cavity. In this case, emergency surgical treatment is indicated.
With premature abruption of a normally located placenta, there may be no external bleeding. If the abruption occurs in the central part of the placenta, then internal uterine bleeding occurs. That is, blood accumulates between the placenta and the wall of the uterus, saturating the latter. The so-called Cuveler's uterus appears. In this case, the doctor, in the interests of saving the mother’s life, is forced to send the patient to have the uterus removed.
Diagnostics
Determining the degree of blood loss, the level of decrease in hemoglobin, red blood cells, platelets, and the state of the coagulation system is relatively easy. To determine the causes in order to prescribe correct and timely treatment, additional research methods are required. First of all, this is a vaginal examination and examination of the cervix in the speculum, transvaginal ultrasound.
To confirm extragenital pathology, the following is required:
- Ultrasound of the thyroid gland, abdominal organs and retroperitoneal space.
- Biochemical tests.
- Study of hormone levels.
- Examination by other specialists.
It is also necessary to carefully study the data regarding the use of drugs that can cause disturbances in the hemostatic system, and family history to identify hereditary abnormalities of blood clotting. Information about obstetric and gynecological history and surgical interventions performed shortly before bleeding is very useful.
It is important to find out from the patient how the formation of menstruation proceeded, whether problems were noted during menstrual bleeding.
Treatment
Treatment has two goals: to stop the bleeding and to prevent relapse in the future. But before starting treatment, it is necessary to clearly determine its cause. Spontaneous miscarriage, placental polyp, formed myomatous node require surgical intervention. Ectopic pregnancy, uterine rupture, placental abruption, ovarian rupture or cysts - operations involving entry into the abdominal cavity.
Treatment of anovulatory AUB is carried out in 2 stages. We will look at them in more detail.
Stage I. Stop bleeding
The choice of tactics depends on the age of the patient. In girls and young women, treatment should begin with non-hormonal treatment. To stop bleeding, therapy is carried out with antifibrinolytic drugs and non-steroidal anti-inflammatory drugs.
The “gold standard” in the prescription of antifibrinolytics is tranexamic acid. It suppresses the protein fibrinolysin, which interferes with normal blood clotting, making it more fluid. It also has anti-inflammatory, anti-allergic and analgesic effects, which is especially important during menstruation.
The drug is prescribed by a doctor, the regimen of use is individual. Treatment for more than 3 menstrual cycles is not recommended.
Nonsteroidal anti-inflammatory drugs have also proven themselves to be very positive in the treatment of AUB. Ibuprofen, Naproxen, Sulindac, and mefenamic acid have been successfully used. In addition to their anti-inflammatory effect, they reduce the volume of blood lost by inhibiting the synthesis of thromboxane and prostacyclin.
If during this stage it is not possible to achieve cessation of bleeding, then urgently resort to curettage of the uterine cavity or proceed to the second stage.
Stage II. Hormonal treatment
For young women, COCs with a high estrogen content (Desogestrel, Gestoden) are recommended, sometimes combined with IV administration of estrogens. Progestins (Medroxyprogesterone, micronized progesterone Utrozhestan) are also prescribed according to indications.
In women who have given birth, you should start with curettage of the uterine cavity.
It has now been proven that oxytocin cannot stop bleeding.
Anti-relapse complex
Abnormal uterine bleeding may recur after treatment. That is why it is very important to carry out preventive treatment in time to prevent recurrence of AUB during the next menstruation. It includes the following activities:
- General strengthening agents (iron supplements, vitamins).
- Antifibrinolytic drugs (tranexamic acid, aminocaproic acid, vitamin C, zinc preparations).
- Antiprostaglandin agents (mefenamic acid).
- Stabilization of central nervous system function (Glycine, Trental, Cinnarizine).
- Hormonal correction. Assignment in the 2nd phase: Marvelon, Regulon, Rigevidon. The gestagen Duphaston is also recommended (for ovulatory periods from 15 to 25 days, for anovulation from 11 to 25 days).
- If pregnancy is not planned, then a COC with a reduced estrogen component is prescribed (for example, Tri-Mercy in a cyclic mode). If a woman wants to become pregnant in the near future, it is better to use the drug Femoston.
You can often read on forums: “No time to go to the doctor, bleeding for 10 days. Please advise what to drink." You are presented with many causes of AUB, and until the doctor makes a diagnosis, we categorically do not recommend using medications that helped stop the bleeding of a friend, neighbor, etc. Your visit to the doctor is mandatory!
Abnormal uterine bleeding is a general term that includes any discharge of blood from the reproductive organ that does not correspond to the normal parameters of menstruation for women in their reproductive years. This pathology is considered one of the most common in medical practice and requires immediate placement of the woman in a medical facility. It is important to understand that the appearance of abnormal bleeding that occurs during the intermenstrual period poses a serious threat to the female body.
Features of the pathology
If blood discharge does not correspond to normal menstruation, then experts talk about abnormal uterine bleeding. With this pathological condition of the female body, menstruation is released from the genital tract for a long period and in large quantities. In addition, such heavy periods cause exhaustion of the patient’s body and provoke the development of iron deficiency anemia. Specialists are especially concerned about blood from the reproductive organ, which appears during the intermenstrual period for no reason.
In most cases, the main reason for the development of such a pathological condition in the patient’s body is changes in hormonal levels. It is important that a woman can independently distinguish abnormal discharge from normal menstruation, which will help her promptly seek help from a specialist.
Young girls are often diagnosed with dysfunctional uterine bleeding, which is accompanied by menstrual irregularities. In patients of reproductive age, such discharge is often observed during the progression of various inflammatory processes and endometriosis in the body.
Dangerous to a woman’s health is the appearance of abnormal uterine discharge during menopause, when the functioning of the reproductive system has already ended and menstruation has completely stopped. In most cases, the appearance of blood is considered a dangerous signal that a dangerous disease, and even oncology, is progressing in a woman’s body. Not the least important role in the development of this pathological condition is occupied by hormonal disorders that develop due to the influence of estrogens.
Experts classify abnormal uterine bleeding as the appearance of blood discharge due to a disease such as fibroids. With this pathology, menstruation becomes profuse and can occur in the middle of the menstrual cycle.
Types of pathology
There is a medical classification that identifies several types of abnormal bleeding from the reproductive organ, taking into account the etiological factor:
- Blood discharge that is associated with the pathological condition of the uterus. The reasons for the development of such uterine bleeding may be associated with pregnancy and cervical pathologies. In addition, such discharge develops with the progression of various diseases of the reproductive organ in the female body and with dysfunction of endometrioid tissue.
- Bleeding from the uterus, which is in no way related to the pathological condition of the reproductive organ. The reasons for the development of such an unpleasant condition may be different. This is the progression in the female body of various diseases of the appendages of the genital organ, ovarian tumors of various types and premature puberty. A woman taking hormonal contraceptives. Frequent anovulatory bleeding
- Abnormal discharge from the uterus that develops as a result of various systemic diseases. Most often, this pathological condition of the female body develops with pathologies of the circulatory and nervous systems, as well as with disorders of the liver and kidneys.
- Discharge of blood from the reproductive organ, which is closely related to iatrogenic factors. The reasons for the development of such a pathological condition of the female body are biopsies and cryodestruction. In addition, the release of large amounts of blood may be the result of taking neurotropic drugs and anticoagulants.
- Abnormal bleeding from the uterus of unknown etiology
Taking into account the nature of the disorder, abnormal bleeding from the reproductive organ may have the following manifestations:
- Discharge of blood that begins along with menstruation at the right time or after a slight delay.
- The appearance within 1-2 months of minor bleeding or heavy blood loss, which provokes the development of anemia and requires immediate medical attention.
- The appearance of discharge from the reproductive organ with clots, which can be large in size.
- The development of iron deficiency amenorrhea in a woman, which causes the appearance of characteristic symptoms in the form of increased pallor of the skin and unhealthy appearance.
The development of any bleeding from the reproductive organ is considered a dangerous pathological condition of the female body, which can result in the death of the woman.
The specific treatment for this disease is determined by:
- The reasons that caused the appearance of blood from the reproductive organ.
- The degree of blood loss.
- General condition of the woman.
For abnormal discharge from the uterus, treatment is aimed at solving the following problems:
- Stopping further blood loss.
- Carrying out preventive measures to prevent relapse.
In order to find out the cause of bleeding, a specialist will prescribe laboratory tests and a procedure such as colposcopy.
In medical practice, the following methods are used to help stop the further development of the pathological condition of the body:
- Carrying out surgical homeostasis, which is curettage of the uterine cavity.
- Purpose of hormonal homeostasis.
- Treatment with hemostatic agents.
The gynecologist is often faced with the task of diagnosis and treatment (AMC). Complaints about abnormal uterine bleeding (AUB) account for more than a third of all complaints made during a visit to a gynecologist. The fact that half of the indications for hysterectomy in the United States are abnormal uterine bleeding (AUB) indicates how serious this problem can be.
Inability to detect any histological pathology in 20% of specimens removed during hysterectomy indicates that the cause of such bleeding may be potentially treatable hormonal or medical conditions.
Every gynecologist should strive to find the most appropriate, cost-effective and successful method of treating uterine bleeding (UB). Accurate diagnosis and adequate treatment depend on knowledge of the most likely causes of uterine bleeding (UB). and the most common symptoms that express them.
Anomalous(AUB) is a general term used to describe uterine bleeding that goes beyond the parameters of normal menstruation in women of childbearing age. Abnormal uterine bleeding (AUB) does not include bleeding if its source is located below the uterus (for example, bleeding from the vagina and vulva).
Usually to abnormal uterine bleeding(AUB) refers to bleeding originating from the cervix or fundus of the uterus, and since they are clinically difficult to distinguish, both options must be taken into account in case of uterine bleeding. Abnormal bleeding can also occur in childhood and after menopause.
What is meant by normal menstruation, is somewhat subjective, and often differs from one woman to another, and even more so from one culture to another. Despite this, normal menstruation (eumenorrhea) is considered to be uterine bleeding after ovulation cycles, occurring every 21-35 days, lasting for 3-7 days and not being excessive.
The total volume of blood loss for normal menstrual period is no more than 80 ml, although the exact volume is difficult to determine clinically due to the high content of the rejected endometrial layer in the menstrual fluid. Normal menstruation does not cause serious pain and does not require the patient to change a sanitary pad or tampon more than once an hour. There are no visible clots in normal menstrual flow. Therefore, abnormal uterine bleeding (AUB) is any uterine bleeding that goes beyond the above parameters.
For description abnormal uterine bleeding(AMC) often use the following terms.
Dysmenorrhea is painful menstruation.
Polymenorrhea - frequent menstruation at intervals of less than 21 days.
Menorrhagia - excessive menstrual bleeding: the volume of discharge is more than 80 ml, the duration is more than 7 days. At the same time, regular ovulatory cycles are maintained.
Metrorrhagia is menstruation with irregular intervals between them.
Menometrorrhagia - menstruation with irregular intervals between them, excessive in volume of discharge and/or duration.
Oligomenorrhea - menstruation occurring less than 9 times a year (that is, with an average interval of more than 40 days).
Hypomenorrhea - menstruation, insufficient (scanty) in terms of the volume of discharge or its duration.
Intermenstrual bleeding is uterine bleeding between obvious periods.
Amenorrhea is the absence of menstruation for at least 6 months, or only three menstrual cycles per year.
Postmenopausal uterine bleeding is uterine bleeding 12 months after the cessation of menstrual cycles.
Such classification of abnormal uterine bleeding(AUB) can be helpful in establishing its cause and diagnosis. However, due to the existing differences in the presentation of abnormal uterine bleeding (AUB) and the frequent existence of multiple causes, the clinical picture of AUB alone is not sufficient to exclude a number of common diseases.
Dysfunctional uterine bleeding- an outdated diagnostic term. Dysfunctional uterine bleeding is a traditional term used to describe excessive uterine bleeding when uterine pathology cannot be identified. However, a deeper understanding of the issue of pathological uterine bleeding and the advent of improved diagnostic methods have made this term obsolete.
In most cases uterine bleeding, not related to uterine pathology, are associated with the following reasons:
chronic anovulation (PCOS and related conditions);
use of hormonal drugs (for example, contraceptives, HRT);
hemostasis disorders (for example, von Willebrand disease).
In many cases that in the past would have been classified as dysfunctional uterine bleeding, modern medicine, using new diagnostic methods, identifies uterine and systemic disorders of the following categories:
causing anovulation (for example, hypothyroidism);
caused by anovulation (in particular hyperplasia or cancer);
accompanying bleeding during anovulation, but can be either associated with abnormal uterine bleeding (AUB) or unrelated (for example, leiomyoma).
From a clinical point of view, treatment will always be more effective if it can be determined cause of uterine bleeding(MK). Because grouping different cases of uterine bleeding (UB) into one ill-defined group does not contribute to the diagnostic and treatment processes, the American Consensus Panel recently announced that the term “dysfunctional uterine bleeding” no longer appears to be necessary for clinical medicine.
N.M. PODZOLKOVA, Doctor of Medical Sciences, Professor, V.A. DANSHINA, Russian Medical Academy of Postgraduate Education of the Ministry of Health of Russia, Moscow
Abnormal uterine bleeding has a significant negative impact on the quality of life of patients and has significant economic consequences both for the patients themselves and for the health care system as a whole. The evaluation and management of women of reproductive age with abnormal uterine bleeding is difficult due to the lack of standardized methods for identifying and classifying potential causes. Currently, there are no uniform approaches to the examination and treatment of such patients; inadequate therapy can lead to the development of complications, and unjustified surgical treatment can lead to a complex of somatic problems and increased economic costs.
Abnormal uterine bleeding (AUB) is a collective concept of various types of menstrual irregularities characteristic of the pubertal, reproductive and perimenopausal periods of a woman’s life. This group of conditions accounts for up to 20% of all visits to the gynecologist's office.
AUBs cause a significant number of missed work days and school days, and have significant economic consequences for the patients themselves. For a woman with heavy periods, decreased work ability results in a loss of approximately $1,692 per year.
International studies show that only every fifth patient with AUB seeks help from a doctor. Based on this, it is difficult to estimate the total costs associated with the diagnosis and treatment of AUB. It is believed that most women self-administer nonsteroidal anti-inflammatory drugs (NSAIDs) and over-the-counter hemostatic agents. Direct costs to insurance companies associated with AMCs are approximately $1 billion per year.
A number of authors note the significant negative impact of AUB on a woman’s quality of life, arguing that chronic menstrual irregularities are associated with anger, fear, unmotivated anxiety and aggression. In a study by Chapa (2009), 40% of 100 women with symptoms of menorrhagia reported limitations in daily and social activities, sexual abstinence, and decreased interest in participating in recreational activities. Data from other studies show that AUB correlates with low socioeconomic status, lack of employment, abdominal pain, and psychological distress.
In addition to the direct negative impact on quality of life, AUB can lead to the development of various complications, in particular, menorrhagia is the most common cause of iron deficiency anemia in developed countries.
In order to understand the pathogenesis of AUB, it is necessary to briefly dwell on the processes of regulation of the menstrual cycle and folliculogenesis in healthy women of reproductive age.
There are five levels of regulation of the menstrual cycle: 1st - target organs, 2nd - ovaries, 3rd - pituitary gland, 4th hypothalamus and 5th - highest - areas of the brain that have connections with hypothalamus and affecting its function, including the neocortex. The patterns of functioning of the reproductive system are presented in Figure 1.
The role of extrahypothalamic brain structures, including the cerebral cortex, is the synthesis by neurons of neurotransmitters and neuromodulators, such as acetylcholine, catecholamines, serotonin, dopamine and histamine, which have a regulatory effect on the hypophysiotropic functions of the hypothalamus.
The hypothalamus, through the synthesis of gonadoliberins (GL) and prolactin-inhibiting factor in the arcuate and paraventricular nuclei, has a direct effect on the pituitary gland. The synthesis of gonadotropin-releasing factors is influenced by:
Neurotransmitters and neurotransmitters of extrahypothalamic structures of the central nervous system - direct stimulation and suppression;
- autohegulation of GL secretion - ultrashort feedback;
- tropic hormones of the pituitary gland - short feedback;
- sex steroid hormones - long feedback.
The adenohypophysis synthesizes various substances, including hormones that are directly involved in the regulation of the reproductive system: LH, FSH and prolactin. The level of tonic secretion of tropic hormones is influenced mainly by the circhoral release of GL, i.e., the hypothalamus, and cyclic secretion is regulated mainly by a negative and positive feedback mechanism, and therefore depends on the effect of steroids on the pituitary gland.
In the ovaries, the synthesis of steroid hormones occurs, as well as the maturation and release of gametes and the formation of the corpus luteum. The main hormone-synthesizing tissues of the ovary include theca and granulosa, which contain a full set of enzymes that allow the synthesis of all 3 classes of sex steroids: androgens, estrogens and progesterone.
As a result of complex embryonic processes of differentiation, migration and cell division, by the time a girl is born, her ovaries contain, according to various authors, from 300 thousand to 2 million primordial follicles. By menarche, the number of follicles decreases to 200-400 thousand, of which about 400 subsequently become the source of egg formation.
The mechanism for the exit of the follicle from the primordial stage has not yet been deciphered; it occurs throughout the entire prepubertal, pubertal, reproductive and premenopausal periods, this process depends on the hormonal status of the body. It is not interrupted during pregnancy and lactation, during the period of anovulation, when taking hormonal contraceptives, etc. Once it begins to grow and goes through the hormone-independent, hormone-sensitive and hormone-dependent stages of growth, the follicle either reaches ovulation or undergoes atresia.
The hormone-independent phase lasts about 3 months. until the development of approximately 8 layers of granulosa cells in the premordial follicle and occurs in the absence of vascular nutrition. The processes occurring in the follicles do not depend on circulating hormones; regulation is carried out due to local factors.
During the hormone-sensitive growth phase, which lasts about 70 days, as the granulosa layer thickens, the preantral follicle becomes moderately sensitive to FSH. During this period, a significant change in the morphology and functioning of the oocyte occurs: the zona pellucida appears, and the theca, sensitive to LH, quickly forms from the surrounding stroma.
After the antral follicle reaches 2 mm in diameter, it is able to grow only under the influence of a high concentration of FSH - the hormone-dependent phase begins. In each menstrual cycle, not one follicle enters the hormone-dependent phase, but the so-called. cohort from which the dominant follicle is selected, the rest undergo atresia. In the granulosa of the dominant follicle, receptors for FSH appear, under the influence of which the production of estradiol constantly increases with the formation of a preovulatory peak. At the end of the follicular phase of the menstrual cycle, luteinization of granulosa cells occurs, and receptors for LH are synthesized.
The main events of the follicular phase of the menstrual cycle are the growth of a cohort of follicles, including one dominant follicle (rarely two), and atresia of all follicles of the cohort except the dominant one.
Consecutive changes in the concentration peaks of estradiol and LH with FSH lead to ovulation - rupture of the follicle and release of the egg from the oviductal mound.
In the second phase of the menstrual cycle, an increase in the mass of the corpus luteum occurs with an increase in vascularization under the influence of tonic secretion of LH, and more progesterone and estradiol are synthesized. In the absence of fertilization of the egg, inevitable luteolysis occurs, leading to the elimination of the block of FSH and LH and the onset of a new menstrual cycle.
In the endometrium during the normal menstrual cycle, 3 phases are distinguished:
The desquamation phase, when, under the influence of a decrease in the concentration of steroid hormones in the absence of fertilization, ischemic changes and rejection of the functional layer of the endometrium occur by 2/3 due to a decrease in the lumen and twisting of the spiral arteries;
- the proliferative phase, which begins in the first days of the menstrual cycle, overlapping with the desquamation phase. The lost functional layer of the endometrium is restored due to the increase in cells, and the uterine glands are formed.
- the secretory phase, which begins after ovulation under the influence of progesterone, the mitotic activity of the endometrium decreases, the uterine glands branch and begin to produce secretions.
The harmony of the processes occurring in the menstrual cycle is achieved due to the usefulness of gonadotropic stimulation, adequate functioning of the ovaries, and the synchronous interaction of the peripheral and central parts of regulation - reverse afferentation.
The main causes of dysregulation of the reproductive system are: stress, sudden and/or significant decrease in body weight, increased physical activity, taking medications that affect the synthesis, metabolism, reception and reuptake of neurotransmitters and neuromodulators, functional hyperprolactinemia, increased synthesis of inhibin by ovarian tissue , as well as impaired metabolism of growth factors and prostaglandins by ovarian tissue.
Changes in the function of the hypothalamic-pituitary-ovarian system caused by stress persist long after the end of exposure to the stress factor. In primates exposed to short-term stress, menstrual cycles remained ovulatory, but there was a 51.6% reduction in peak LH and progesterone levels when stress began in the follicular phase and by 30.9% in the luteal phase. phases. Menstrual irregularities persisted for 3-4 cycles after the end of stress, which coincides with the persistence of elevated cortisol levels. Obviously, the existence and adequate functioning of the corpus luteum is the most vulnerable phase of the menstrual cycle.
It has been proven that the same menstrual cycle disorder can be caused by various reasons, and the same cause can lead to the formation of various menstrual cycle disorder syndromes. With the long-term existence of a pathological process, all links of regulation are gradually involved in it, up to a change in the dominant factor of pathogenesis, and the clinical picture may change.
The examination and management of women of reproductive age with abnormal uterine bleeding is difficult due to the lack of standardized methods for identifying and classifying potential causes of AUB and the confusion of the nomenclature used. Therefore, in 2009, a new classification of pathological uterine bleeding in the reproductive period was introduced. The causes of uterine bleeding were divided into organic (PALM), determined by objective visual examination and characterized by structural changes, and functional (COEIN), not associated with structural changes; unclassified pathologies (N) were allocated as a separate category (Table 1).
AUB was divided into acute and chronic (bleeding from the uterine cavity, differing in volume, duration and frequency from menstruation and present for 6 months, usually not requiring immediate medical intervention). Acute AUB is an episode of significant bleeding requiring immediate medical intervention to prevent further blood loss, which can occur with or without a history of existing chronic AUB.
According to the recommendations of the FIGO expert group, patients with acute AUB should undergo a general laboratory examination (complete blood count, blood group and Rh factor, pregnancy test), assessment of the hemostatic system (total thromboplastin time, prothrombin time, aPTT, fibrinogen), as well as determination of von Willebrand factor. It can be assumed that 13% of women with AUB have systemic disorders of hemostasis, most often von Willebrand disease. It is not yet clear how often these disorders cause or contribute to AUB and how often they are asymptomatic or with minimal biochemical abnormalities, but it is clear that they are often missed by physicians in testing for causes of AUB. A thorough medical history can reveal systemic hemostatic disorders with 90% sensitivity (Table 2).
Removal of the endometrium by curettage of the walls of the uterine cavity is not required by all patients of the reproductive period with AUB. It is advisable in patients who have several factors predisposing to the development of atypical endometrial hyperplasia and carcinoma (obesity or overweight, hypertension, metabolic syndrome, etc.). When determining the indications for separate diagnostic curettage, a combination of personal and genetic risk factors and M-echo assessment with TV ultrasound should be taken into account. It is believed that curettage of the walls of the uterine cavity is indicated for all patients of the late reproductive period (over 45 years old).
A woman with a family history of colorectal cancer has a lifetime risk of endometrial cancer of up to 60%, with an average age at diagnosis of 48-50 years. Screening for endometrial cancer is now part of the management approach to patients with AUB. This primarily applies to women of the late reproductive and perimenopausal periods. Various techniques can be used to remove the endometrium, the main thing is that an adequate tissue sample is obtained, which will allow us to conclude that there are no signs of malignant growth.
Considering the high probability of AUB occurring during chlamydial infection, it is advisable to exclude chlamydial endometritis (PCR of endometrial biopsy).
In patients with AUB, the incidence of endometrial hyperplasia is 2-10% and can reach up to 15% in women with recurrent menorrhagia during the menopausal transition. Progression of hyperplasia to endometrial cancer occurs in 3-23% of cases over 13 years, with a rate of 5% for hyperplasia and endometrial carcinoma. Selected risk factors include: weight ≥ 90 kg, age ≥ 45 years, history of infertility, previous birth history, and family history of colon cancer.
The listed diagnostic measures will allow us to suggest the cause of AUB, assess the severity of the patient’s condition, and determine the sequence and direction of therapeutic interventions.
The total cost of treating AUB in women requiring surgery is approximately $40,000. Additional treatment costs equate to $2,291 per patient per year (95% CI, $1,847-$2,752). The UK NHS Hospital Episode Statistics database (2010-2011) includes 36,129 episodes of AUB for which specialist consultations were carried out. Hospitalized patients spent 21,148 bed days in hospital, representing an annual cost to the NHS of £5.3 million to £7.4 million. Art., based on the range of the cost of a bed-day from 250 to 350 f. Art. respectively. Most experts believe that in countries with effective national leadership, savings in the treatment of patients with AUB can be achieved primarily by reducing the number of hysterectomies.
The global approach to the treatment of women of reproductive age with chronic AUB is to prevent possible complications. Based on this, the need for anti-relapse treatment of AUB is obvious, the main task of which is to regulate the menstrual cycle to minimize the amount of blood loss and prevent excessive stimulation of the endometrium by estrogen. During the reproductive period, it is possible to use three main methods of treating acute AUB:
Non-hormonal using antifibrinolytics (tranexamic acid) or NSAIDs;
- hormonal hemostasis - use combined hormonal contraceptives (oral and parenteral, mainly containing analogues of natural estrogens), progestogens, including as part of the Mirena intrauterine releasing system, gonadotropin releasing hormone agonists;
- surgical hemostasis - removal of altered tissue with or without visual control, followed by morphological examination of endometrial fragments. Surgical methods of stopping acute AUB are used in cases of patient instability, contraindications, or ineffectiveness of conservative methods.
The algorithm for the prevention and drug treatment of AUB in reproductive age is presented in Figure 2.
One of the combined oral contraceptives used to treat abnormal uterine bleeding is Qlaira. This is the first drug with natural estradiol, identical to natural, including a combination of estradiol valerate with dienogest. Dienogest, which is part of the drug, has pronounced antiproliferative pharmacological properties. The high therapeutic efficacy of Qlaira against AUB has been confirmed in international randomized placebo-controlled studies. An analysis of data from three multicenter clinical trials conducted in Europe and North America, which included 2,266 women, showed that the use of Qlaira was accompanied by a significant reduction in menstrual blood loss and a shortening of the duration of withdrawal bleeding. The drug is 15.5 times superior to placebo in the number of women completely cured of AUB (42.0 vs. 2.7%, p< 0,0001), и в 4,9 раза -- по динамике уменьшения кровопотери (76,2 против 15,5%, p < 0,0001) . Его эффективность составляет 76,2%, при этом терапевтический эффект у женщин с обильными и/или длительными менструальными кровотечениями достигается на первых месяцах лечения и продолжается в течение всего применения независимо от исходного объема кровопотери .
Thus, the relevance of studying the etiology and pathogenesis of AUB in women of reproductive age is obvious. Currently, there are no uniform approaches to the examination and treatment of such patients; inadequate therapy can lead to the development of complications, and unjustified surgical treatment can lead to a complex of somatic problems and increased economic costs.
Literature
1. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins - Gynecology. ACOG Practice Bulletin No. 128. Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstetrics and Gynecology, 2012, 120: 197.
2. AskMayoExpert. What are the most common causes of abnormal uterine bleeding? Rochester, Minn.: Mayo Foundation for Medical Education and Research, 2012.
3. Chongpensuklert Y, Kaewrudee S, Soontrapa S, Sakondhavut Ch. Dysmenorrhea in Thai Secondary School Students in Khon Kaen, Thailand. Thai Journal of Obstetrics and Gynecology, 2008, Jan., 16: 47-53-167.
4. Cote I, Jacobs P, Cumming D. Work loss associated with increased menstrual loss in the United States. Obstet Gynecol 2002, 100: 683-7.
5. El-Gilany AH, Badawi K & El-Fedawy S. Epidemiology of dysmenorrhoea among adolescent students in Mansoura, Egypt. Eastern Mediterranean Health Journal, 11(1/2): 155-163.
6. Grimes DA, Hubacher D, Lopez LM, Schulz KF Non-steroidal anti-inflammatory drugs for heavy bleeding or pain associated with intrauterine-device use (Review). 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7. Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health, 2007, May-Jun, 10 (3): 183-94.
8. Frick KD, Clark MA, Steinwachs DM, Langenberg P, Stovall D, Munro MG, Dickersin K; STOP-DUB Research Group. Financial and quality-of-life burden of dysfunctional uterine bleeding among women agreeing to obtain surgical treatment. Women's Health Issues, 2009, Jan-Feb, 19(1): 70-8.
9. Bushnell DM, Martin ML, Moore KA, Richter HE, Rubin A, Patrick DL. Menorrhagia Impact Questionnaire: assessing the influence of heavy menstrual bleeding on quality of life. Curr Med Res Opin., 2010, Dec., 26 (12): 2745-55.
10. Chapa HO, Venegas G, Antonetti AG, Van Duyne CP, Sandate J, Bakker K. In-office endometrial ablation and clinical correlation of reduced menstrual blood loss and effects on dysmenorrhea and premenstrual symptomatology. J Reprod Med., 2009, Apr., 54(4): 232-8.
11. Heliövaara-Peippo S, Hurskainen R, Teperi J, et al. Quality of life and costs of levonorgestrel-releasing intrauterine system or hysterectomy in the treatment of menorrhagia: a 10-year randomized controlled trial. Am J Obstet Gynecol 2013, 209, 535: e1-14.
12. Podzolkova N.M. Symptom, syndrome, diagnosis. Differential diagnosis in gynecology. Podzolkova N.M., Glazkova O.L. 3rd ed., rev. and additional M.: GEOTAR-Media, 2014.
13. Malcolm G Munro, Hilary OD Critchley, Michael S Broder, Ian S Fraser. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. International Journal of Gynecology and Obstetrics, 2011, 113: 3-13.
14. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. von Willebrand disease in women with menorrhagia: a systematic review. BJOG, 2004, 111 (7): 734-40.
15. Dilley A, Drews C, Lally C, Austin H, Barnhart E, Evatt B. A survey of gynecologists concerning menorrhagia: perceptions of bleeding disorders as a possible cause. J Womens Health Gend Based Med, 2002, 11(1): 39-44.
16. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet, 1998, 351 (9101): 485-9.
17. Lu KH, Broaddus RR. Gynecological tumors in hereditary nonpolyposis colorectal cancer: We know they are common–now what? Gynecol Oncol 2001, 82(2):221-2.
18. Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, et al. Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol 2005, 105(3):569-74.
19. Ely JW, Kennedy CM, Clark EC, Bowdler NC. Abnormal uterine bleeding: a management algorithm. J Am Board Fam Med., 2006, Nov-Dec., 19 (6): 590-602.
20. Sweet Mary G, Tarin A Schmidt-Dalton, Patrice M. Weiss, and Keith P. Madsen. Evaluation and Management of Abnormal Uterine Bleeding in Premenopausal Women. American Family Physician, 2012, 85(1): 35-43.
21. ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 14: management of anovulatory bleeding. Int J Gynaecol Obstet, 2001, Mar., 72 (3): 263-71. PMID: 11296797.
22. ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 59: clinical management guidelines for obstetricians-gynecologists: intrauterine device. Obstet Gynecol 2005 Jan 105(1):223-32. PMID: 15625179.
23. ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 110: noncontraceptive uses of hormonal contraceptives. Obstet Gynecol 2010 Jan 115(1):206-18. PMID: 20027071.
24. ACOG Committee on Practice Bulletins-Gynecology. ACOG Practice Bulletin No. 121: long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol 2011 Jul 118(1):184-96. PMID: 21691183.
25. Grant C, Gallier L, Fahey Tom, Pearson N, Sarangi J. Management of menorrhagia in primary care-impact on referral and hysterectomy: data from the Somerset Morbidity Project. J Epidemiol Community Health 2000, 54: 709-713.
26. Liu J, Wang L, Liu M, Bai YQ. The diagnosis and treatment of abnormal uterine bleeding in nonpregnant patients with hepatic cirrhosis. Zhonghua Gan Zang Bing Za Zhi, 2011, Jan., 19 (1): 52-4.
27. Farquhar CM, Lethaby A, Sowter M, Verry J, Baranyai J. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol., 1999, Sep., 181 (3): 525-9.
28. Vilos GA, Harding PG, Sugimoto AK, Ettler HC, Bernier MJ. Hysteroscopic endomyometrial resection of three uterine sarcomas. J Am Assoc Gynecol Laparosc 2001 Nov 8(4):545-51.
29. Pinkerton JV. Pharmacological therapy for abnormal uterine bleeding. Menopause, 2011, Apr., 18 (4): 453-61.
30. Jensen J, Machlitt A, Mellinger U, Schaefers M et al. A multicenter, double-blind, randomized, placebo-controlled study of oral estradiol valerate/dienogest for the treatment of heavy and/or prolonged menstrual bleeding. Fertil. Steril., 2009, 92 (3, Suppl.): S32.
31. Fraser IS, Römer T, Parke S, Zeun S et al. Effective treatment of heavy and/or prolonged menstrual bleeding with an or al contraceptive containing estradiol valerate and dienogest: a randomized: double-blind Phase III trial. Hum. Reprod., 2011, 26 (10): 26