CC BY
57
Reproductive health of a girl
Karountzos V.1-3, Tsimaris P.1-3, Deligeoroglou E.
1-3
1 Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, Athens, Greece
2 National and Kapodistrian University of Athens, Medical School, Athens, Greece
3 "Aretaieion" Hospital, Athens, Greece
Corresponding author
Deligeoroglou Efthimlos - MD, PhD, Full Professor of Obstetrics and Gynecology, the Chairman of 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School Address: Vasilissis Sofias Avenue 76, 11528, Athens, Greece Fax number: +302107798111, +302107233330
E-mail: [email protected]; [email protected] https://orcid.org/0000-0002-7327-493X
Abnormal uterine bleeding during adolescence. State of the art in evaluation, management and treatment
Abnormal Uterine Bleeding (AUB) is a term used to describe several different types of bleeding patterns during adolescence, including heavy menstrual bleeding, intermenstrual and coexistence of heavy and prolonged menstrual bleeding. The International Federation of Gynecology and Obstetrics (FIGO) Menstrual Disorders Working Group proposed a new classification system for the diagnosis of AUB in reproductive age nulli-gravid women. The term PALM-COEIN was suggested, standing for the following causes of AUB: Polyp, Adenomyosis, Leiomyoma, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not otherwise classified. More than 95% of AUB cases in adolescence are due to anovulation. Menstrual history, past medical history, family history and surgical history is of great importance during evaluation and management of an adolescent with AUB, while a thorough examination of all systems, should be offered in these girls. Even though, more than 95% of AUB cases during adolescence are due to ovulatory dysfunction, several pathologies should be excluded (some of them immediately, such as ectopic pregnancy), in order to set the diagnosis. Management of AUB is based on the underlying etiology, the amount of blood loss, the severity of associated anemia and adolescent's comfort with different treatment modalities. These are oral contraceptive pills, non-steroidal anti-inflammatory drugs, progestin only therapy, tranexamic acid, GnRH analogues, danazol and levonorgestrel releasing intra uterine device (LNG IUD). Keywords: abnormal uterine bleeding, dysfunctional uterine bleeding, adolescence
For citation: Karountzos V., Tsimaris P., Deligeoroglou E. Abnormal uterine bleeding during adolescence. State of the art In evaluation, management and treatment. Reproduktivnoe zdorov'e detey i podrostkov [Pediatric and Adolescent Reproductive Health]. 2019; 15 (3): 44-52. doi: 10.24411/1816-2134-2019-13005. Received 29.06.2019. Accepted 19.08.2019.
Abnormal uterine bleeding (AUB) is a widely used term, which has been used to describe different types of bleeding patterns during adolescence. These include heavy menstrual bleeding, intermenstrual but also the coexistence of heavy and prolonged menstrual bleeding. In adolescent girls, it is usually seen in the first two years after menarche, while seems to affect up to 37% of adolescents [1]. As it is understandable, it is not only a frequent cause of visits in the emergency department and division of pediatric-adolescent gynecology, but also a cause of concern among adolescents and their families, with serious physical, emotional and social impact. For years, the term dysfunctional uterine bleeding (DUB), has been consolidated for adolescents, representing all these cases of abnormal bleeding, without any underlying cause, resulting from immaturity of hypothalamic-pituitary ovarian (HPO) axis. This term, has been nowadays been included in the new Classification system of the International Federation of Gynecology and Obstetrics (FIGO), named PALM-COEIN, as will be described below [2].
Definitions
In well-nourished adolescents menarche occurs 2-3 years after breast development [3] with a mean age of 12.7 years for non-hispanic white girls [4]. Therefore, by age of 15, 98% will have had menarche. As mentioned above, at the first two post menarchal years, the range of menstrual cycle may be between 21 and 45 days, due to incomplete maturity of HPO axis, lasting 2 to 7 days, with an average blood loss of 20 to 80 mL [5].
As long as abnormal bleeding cases, "Menorrhagia" concerns bleeding at regular intervals, that lasts more than 7 consecutive days and/or blood loss greater than 80 mL, "Metrorrhagia" stands for bleeding at irregular intervals, while "Menometrorrhagia", is heavy irregular bleeding. Moreover, as mentioned above, "DUB" is defined as any type of abnormal bleeding from the uterus, in the absence of any underlying
cause, occurring in 95%, due to immaturity of HPO axis [5, 6].
In 2011, FIGO Menstrual Disorders Working Group proposed a new classification system for the diagnosis of AUB in reproductive age nulli-gravid women. The term PALM-COEIN was suggested, standing for the following causes of AUB: Polyp, Adenomyosis, Leio-myoma, Malignancy and hyperplasia, Coagu-lopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not otherwise classified. The new classification system has gradually begun to replace the term DUB, which has been used for many years at the past and can now be integrated in ovarian dysfunction in the acronym of PALM-COEIN. As already mentioned, more than 95% of AUB cases in adolescence, are due to anovulation [6].
History
Menstrual history, past medical history, family history and surgical history is of great importance during evaluation and management of an adolescent with AUB. Age at menarche, should be very carefully assessed, due to the fact that girls who are older at menarche, will more likely have anovulatory cycles, later in their life [7]. A menstrual calendar, with menstrual intervals, length of bleeding, irregular bleeding if any and number of pads used daily, should be thoroughly completed. More than three soaked pads or six full tampons per day for 3 or more days, concern for a blood loss greater than 80 mL [8], while when an adolescent complains for clots or leaking, especially during the night, this might be the indication of a clotting disorder. Furthermore, a very "heavy" first menstrual period may directs the diagnosis of an underlying bleeding disorder [9].
The presence of a systemic disease, such as anemia, past and current medications, such as anticoagulants and surgical history, such as abortion and/or dilation and curettage should be recorded. Risk factors for sexually transmitted infections and pregnancy, including history of a sexually transmitted infection, number of partners, age at first sexual inter-
course, last sexual intercourse and methods of contraception used, should be closely evaluated. Questions regarding diet, exercise and other psychosocial stress factors, that can cause an abnormal bleeding, should be asked. Finally, a family history regarding other female relatives with menstrual irregularities, bleeding disorders, autoimmune diseases, endocrine disorders and cancer, must well written during first visit [6].
Review of systems
It is of great importance to examine all systems, when dealing with adolescents suffering from AUB. Hemodynamically assessment and evaluation of vital signs must be the first step for all clinicians. Fatigue, palpitation and/or tachycardia are not uncommon when the amount of bleeding loss is great, while change in weight, night sweats and/or hot flashes may indicate an endocrine disorder, such as hypothyroidism. Easy or nose bleeding and bruising may be diagnostic of a bleeding disorder [10]. Hirsutism, acne and hair loss are characteristics of polycys-tic ovarian syndrome and nipple discharge may indicate a pituitary prolactinoma [11]. Systems' examination should be completed with genitourinary evaluation. All clinicians should begin with careful inspection of the external genitalia, while the verification that the bleeding is in fact from the vagina and the absence of a foreign body must be clarified. Pain during bimanual palpation of the cervix, the adnexa or the uterus should be always sought, as indicative of a possible pelvic inflammatory disease (PID). All non-sexually active adolescents must undergo a rectal examination, while symptoms such as vaginal discharge, dyspareunia and dys-menorrhea should be always taken under consideration [12].
Differential diagnosis
As mentioned above, even though, more than 95% of AUB cases during adolescence are due to ovulatory dysfunction, several pathologies should be excluded in order to
set the diagnosis. These are summarized in Table 1. Some of them require immediate exclusion, in order to avoid a significant morbidity and a possible mortality for the young girl. These, are mainly pregnancy related complications, which can present with any pattern of abnormal bleeding, at the top of which lies the ectopic pregnancy. The possibility of a bleeding disorder must be ruled out as soon as possible because great amount of blood loss is correlated with higher morbidity. History of cyclic heavy, prolonged bleeding (menorrhagia) or very heavy first menstrual period are indicative of a bleeding disorder [13]. The same bleeding patterns may also seen in young girls receiving anticoagulants. Other medications, such as glucocorticoids, should be always kept in mind when dealing with these adolescents. Furthermore, an endocrine disorder, such as hypothyroidism is not uncommon and must be taken under consideration, while PID and endometritis, caused by Neisseria gonorrheae or Chlamydia trachomatis frequently present with heavy or irregular bleeding, but is usually accompanied by low abdominal pain. Other reproductive tract pathologies, usually seen in adult women, such as, fibroids, polyps, dysplasia or cancer are very rare during adolescence [14].
A urine pregnancy test and/or quantitative serum p-HCG should be the first laboratory investigation during AUB evaluation, in order to exclude pregnancy especially, ectopic. Complete blood cell count will help the clinician to estimate the severity of anemia, while prothrombin time, partial thromboplastin time, bleeding time and platelet aggregation, may aid the diagnosis of a bleeding disorder. In these cases, a von Willebrand panel, as well as a coagulation factor levels/activity must be done prior to hormonal therapy. In case of an endocrine disorder, hyroid stimulating hormone (TSH) levels, for thyroid disorders, prolactin (PRL) levels >100 ng/mL for pituitary adenoma and total and free testosterone (Testo, FTesto), for PCOS are mandatory. Moreover, FSH and LH levels may help the
Table 1. Dysfunctional uterine bleeding [12]
Hematologic • Von Willebrand disease
• Thrombocytopenia
• Platelet dysfunction
• Coagulation defects
• Factor deficiencies
Pathology of the reproductive • Fibroid
tract • Myoma
• Polyp
• Endometriosis
• Cervical dysplasia
• Infections
• Cervicitis (especially Chlamydia)
Pregnancy • Ectopic pregnancy
• Implantation
• Placenta accrete
• Retained products of conception
• Threatened, spontaneous or missed abortion
• Hormonal contraceptives
Other • Excessive exercise
• Eating disorders
• Stress
• Systemic disease
• Intrauterine device
Endocrine • Hyperprolactinemia
• Thyroid disorders
• Adrenal disorders
• Polycystic ovarian syndrome
• Ovarian failure
Trauma • Sexual abuse
• Laceration
• Foreign body
• Related to abortion or other surgical procedure
Medication • Antipsychotics
• Platelet inhibitors
• Anticoagulants
evaluation of pituitary and ovarian function. Finally, a pelvic ultrasound scan may be very helpful in order to exclude any other pathology during AUB evaluation, while in adolescents, in whom a PID is suspected a swab culture of the discharge and a urethral meatus swab for gonorrhea and chlamydia testing should be taken [6, 15].
Management
Management of AUB is based on the underlying etiology, the amount of blood loss, the severity of associated anemia and adolescent's
comfort with different treatment modalities. The goal is to eliminate any morbidity complications and to reestablish the menstrual cycle. A multidisciplinary approach with other specialists is usually needed for further evaluation and management of pathologies such as an endocrinopathy or a bleeding disorder. Adolescents' management is summarized into four major categories [16].
Category I includes adolescents with light to moderate flow and hemoglobin >12 g/dl. In these cases reassurance is needed, iron supplementation may be very helpful and a
Table 2. Different treatment modalities according to suggested dosage, dose schedule and potential contraindications and precautions. Adapted from American College of Obstetricians and Gynecologists [24]
Drug Source Suggested dose Dose schedule Potential contraindications and precautions
Conjugated equine estrogren DeVore G.R., Owens O., Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding - a doubleblind randomized control study. Obstet Gynecol 1982;59: 285-91 25 mg IV Every 4-6 hours for 24 hours Contraindications include, but are not limited, to breast cancer, active or past venous thrombosis or arterial thromboembolic disease, and liver dysfunction ordisease. The agent should be used with caution in patients with cardiovascular or thromboembolic risk factors
Combined oral contraceptives Munro M.G., Mainor N., Basu R., Brisinger M., Barreda L. Oral medroxy-progesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol 2006; 108: 924-9 Monophasic combined oral contraceptive that contains 35 micro-grams of ethinyl estradiol Three times per day for 7 days Contraindications include, but are not limited to, cigarette smoking (in women aged 35 years or older), hypertension, history of deep vein thrombosis or pulmonary embolism, known thromboembolic disorders, cerebrovascular disease, ischemic heart disease, migraine with aura, current or past breast cancer, severe liver disease, diabetes with vascular involvement, valvular heart disease with complications, and major surgery with prolonged immobilization
Medroxypro- gesterone acetate Munro M.G., Mainor N., Basu R., Brisinger M., Barreda L. Oral medroxyprogesterone acetate and combination oral contraceptives for acute uterine bleeding: a randomized controlled trial. Obstet Gynecol 2006; 108: 924-9 20 mg orally Three times per day for 7 days Contraindications include, but are not limited to, active or past deep vein thrombosis or pulmonary embolism, active or recent arterial thromboembolic disease, current or past breast cancer, and impaired liver function or liver disease
Tranexamic acid James A.H., Kouides P.A., Abdul-Kadir R., Dietrich J.E., Edlund M., Federici A.B., et al. Evaluation and management of acute menorrhagia in women with and without underlying bleeding disorders: consensus from an international expert panel. Eur J Obstet Gynecol Reprod Biol 2011; 158: 124-34 1.3 g orally or 10 mg/kg IV (maximum 600 mg/ dose) Three times per day for 5 days (every 8 hours) Contraindications include, but are not limited to, acquired impaired color vision and current thrombotic or thromboembolic disease. The agent should be used with caution in patients with a history of thrombosis (because of uncertain thrombotic risks), and concomitant administration of combined oral contraceptives needs to be carefully considered
nonsteroidal anti-inflammatory drug (NSAID), can be used in order to decrease blood loss. A follow up is essential and the girl should be re-evaluated in 3 months.
Category II includes girls with moderate flow and hemoglobin between 10 and 12 g/dL. In these cases, combined oral contraceptives (COCs) (e.g., monophasic with 30 to 35 mg
of ethinyl estradiol) must be used. One pill twice daily for 1 to 5 days, until the bleeding stops, while, once the bleeding stops, COCs should be continued, one pill daily, for 3 to 6 months. Iron supplementation may be very helpful for 6 months in order to replenish iron stores.
Category III includes adolescents with heavy menstrual flow and hemoglobin between 8 and 10 g/dL, who are hemodynami-cally stable. These girls can be managed as these of Category II, if the family can assist with the management plan and follow-up. Otherwise, if bleeding persists, increase the COCs to 3 or 4 times a day for a few days until the bleeding slows, then taper to two until the bleeding stops, then one pill daily for 3 to 6 months. Girl may require an antiemetic to help prevent nausea.
Finally, in Category IV, are included adolescents with heavy menstrual flow and hemoglobin <7 g/dL or patients who are hemodynami-cally unstable. These girls need admission to the hospital. Blood transfusion should be offered, depending on degree and persistence of bleeding, as well as severity of hemodynamic instability. Conjugated intravenous estrogen if available at a dose of 25 mg every 6 hours to a maximum of 6 doses should be used, otherwise COCs with 50 mg of ethinyl estradiol every 6 hours until bleeding slows should be offered. Over the next 7 days COCs must be gradually tapered to one pill a day, while antiemetic agents will be likely needed. If bleeding still persists, dilation and curettage should be considered.
Treatment of abnormal uterine bleeding
Even though management of AUB can be summarized in the above four categories, with COCs and NSAIDs representing the major treatment options, there are also more treatment modalities, especially for these adolescents, in whom estrogens are contraindi-cated and/or are inadequate for AUB treatment. Except from COCs and NSAIDs, these include: progestin only therapy, tranexamic
acid (antifibrinolytic), GnRH analogues, dana-zol and levonorgestrel releasing intra uterine system(LNG IUS) [6].
As it is already known, COCs reduce en-dometrial development, reestablish menstrual pattern and decrease blood flow. Usually, 24 hours is needed in order to control with COCs the bleeding, as a result of endometrium pseudodecidualization. On the other hand, progestin only therapy can be used, whenever the pill is contraindicated. Cyclic progestin administration for 12 days per month using medroxyprogesterone acetate (10 mg/d) or norethindrone acetate (2.5-5 mg/d) leads to uterine withdrawal bleeding. Other alternatives include depot medroxyprogesterone acetate, 150 mg intramuscularly every 3 months, but this method is often associated with irregular bleeding and spotting [17, 18].
NSAIDs acting by block of prostacyclin, which is an antagonist of thromboxane, therefore, platelet aggregation is accelerated achieving coagulation. As shown by many studies, prostacyclin is found in in large quantities in endometrium of girls with AUB and that explains the fact of blood flow reduction. Despite NSAIDs' can treat menorrhagia in ovulatory cycles, similar results are not shown in other AUB cases [25]. These studies have also shown that danazol, tranexamic acid and LNG IUS are more effective in reducing abnormal uterine bleeding compared to NSAIDs [19].
Tranexamic acid has an antifibrinolytic effect, preventing fibrin degradation. In many countries, tranexamic acid has been used as first-line treatment, especially for adolescents, in whom COCs are contraindicated [20]. On the other hand, GnRH agonists work by reducing the concentration of GnRH receptors in the pituitary, which suppress gonadotropin release. This leads to amenorrhea, thus stops abnormal bleeding in many anovulatory patients. However, the usage of GnRH agonists especially during adolescence for more than 6 months is related with menopausal-like symptoms and consequently in a possible reversible osteopopenia/osteoporosis. In parallel,
an add-back therapy of low-dose hormonal replacement is usually given during GnRH agonists administration [21].
Furthermore, androgens have been used for many years, in order to treat AUB. This kind of treatment is based on endometrial tissue alterations, which becoming inactive and atrophic. Danazol is a synthetic steroid with antiestrogenic and anti-progestogenic activity, acting by suppression of estrogen and progesterone receptors in the endometrium, leading to endometrial atrophy and reduced menstrual loss. However, use of androgens should be done with caution, due to the fact that cause signs of masculinization and might stimulate erythropoiesis and affect clotting efficiency in adolescents [22].
Additionally, there are some adolescents, in whom COCs are contraindicated, they are unable to tolerate systemic progestins and a long term treatment is needed. In these cases, AUB may be treated with an LNG IUS. This, leads to endometrial atrophy and studies have shown that LNG IUS is more effective than oral norethisterone. However, LNG IUS is rarely used during adolescence, due to the fact that the vast majority of them, facing AUB in the first two years after menarche, in a period that are not yet sexually active [23].
Finally, the ACOG has summarized different treatment modalities according to suggested dosage, dose schedule and potential contraindications and precautions. These are reported in Table 2 [24].
Medical treatment is considered adequate and controls more than 90% of severe bleeding cases in adolescents [25]. However, surgery may be required in life-threatening bleeding
cases, when medical treatment is unsuccessful or contraindicated, in case of an underlying medical condition and in situations where a histopathology evaluation is needed. Dilatation and curettage, uterine artery embolization, endometrial ablation and hysterectomy are surgical treatment options [25-27]. The decision to proceed with surgical treatment should be made after taking into account the fertility desire of the patient. In adolescence, future fertility preservation is mandatory, therefore, uterine artery embolization, endometrial ablation and hysterectomy are very rarely used, as a last treatment option. Concomitant hys-teroscopy with dilatation and curettage is of great value, especially in adolescents with suspected intrauterine pathology. Mechanical methods, such as the use of Foley catheter balloons, have also been shown to be useful for bleeding control [25].
Conclusions
In conclusion, AUB is an important clinical condition for adolescents and their families. The first step is to exclude conditions with a possible severe morbidity and even mortality for the adolescent girl. Subsequently, the goal is normalization of menstrual pattern and stabilization of iron stores based on severity of the bleeding and underlying cause. Hormonal treatment can be safely used in adolescents as a long-term treatment, while in case hormonal treatment is contraindicated, other medical treatment options should be offered to adolescents and surgical management should be kept as a last treatment option.
Conflict of interest. The authors declare no conflict of interest.
Information about authors
Karountzos Vasileios - MD, PhD, Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, "Aretaieion" Hospital (Athens, Greece) E-mail: [email protected] https://orcid.org/0000-0001-5338-1853
Tsimaris Pandelis - MD, PhD, Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, "Aretaieion" Hospital (Athens, Greece) E-mail: [email protected] https://orcid.org/0000-0002-3409-5787
Deligeoroglou Efthimios - MD, PhD, Full Professor of Obstetrics and Gynecology, Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, Chairman of 2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Medical School, "Aretaieion" Hospital (Athens, Greece) E-mail: [email protected]; [email protected] https://orcid.org/0000-0002-7327-493X
References
1. Wilkinson K. Management of abnormal uterine bleeding in adolescents. J Pediatr Adolesc Gynecol. 2010; 23: S22—30.
2. Munro M.G., Critchley H.O., Broder M.S., Fraser I.S.; FIGO Working Group on Menstrual Disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011; 113 (1): 3-13.
3. Carswell J., Stafford D. Normal Physical Growth and Development. In: L.S. Neinstein, C.M. Gordon, D.K. Katzman, D.S. Rosen et al. (eds). Adolescent Health Care: A Practical Guide. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2008: 3-26.
4. Wu T., Mendola P., Buck G.M. Ethnic differences in the presence of secondary sex characteristics and menarche among US girls: the Third National Health and Nutrition Examination Survey, 1988-1994. Pediatrics. 2002; 110 (4): 752-7.
5. Mitan L.A., Slap G.B. Dysfunctional uterine bleeding. In: L.S. Neinstein (ed.). Handbook of Adolescent Health Care. Philadelphia: Lippincott Williams and Wilkins, 2009: 467-9.
6. Deligeoroglou E., Karountzos V., Creatsas G. Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Gynecol Endocrinol. 2013; 29 (1): 74-8.
7. Vihko R., Apter D. Endocrine characteristics of adolescent menstrual cycles: impact of early menarche. J Steroid Bio-chem. 1984; 20 (1): 231-6.
8. Brown D.L. Congenital bleeding disorders. Curr Probl Pediatr Adolesc Health Care. 2005; 35 (2): 38-62.
9. Claessens E.A., Cowell C.L. Acute adolescent menorrha-gia. Am J Obstet Gynecol. 1981; 139: 377.
10. Emans S.J. Dysfunctional uterine bleeding. In: S.J. Emans, M.R. Laufer, D. Goldstein (eds). Pediatric and Adolescent
Gynecology. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2005: 270-86.
11. Deligeoroglou E.K., Karountzos V. Dysfunctional uterine bleeding as an early sign of polycystic ovary syndrome during adolescence: an update. Minerva Ginecol. 2017; 69 (1): 68-74.
12. Dysfunctional Uterine Bleeding. In: L. Speroff, M.A. Fritz (eds). Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia: Lippincott Williams and Wilkins, 2005: 547-70.
13. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 81, May 2007. Obstet Gynecol. 2007; 109 (5): 1233-48.
14. Fraser I.S., Sungurtekin U. Defining menstrual disturbances. In: A. Maclean, P.M.S. O'Brien (eds). Study Group on Menstrual Disorders. Royal College of Obstetricians and Gynecologist, 2000: 141-52.
15. Deligeoroglou E. Dysfunctional uterine bleeding. Ann N Y Acad Sci. 1997; 816: 158-164.
16. Deligeoroglou E., Tsimaris P. Menstrual disturbances in puberty. Best Pract Res Clin Obstet Gynaecol. 2010; 24 (2): 157-71.
17. Teichmann A., Apter D., Emerich J., Greven K., et al. Continuous, daily levonorgestrel/ethinyl estradiol vs. 21-day, cyclic levonorgestrel/ethinyl estradiol: efficacy, safety and bleeding in a randomized, open-label trial. Contraception. 2009; 80 (6): 504-11.
18. Hickey M., Higham J.M., Fraser I. Progestogens versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation. Cochrane Database Syst Rev. 2007; 4: CD001895.
19. Lethaby A., Duckitt K., Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2013; 1: CD000400.
20. Lethaby A., Farquhar C., Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000; 4: CD000249.
21. Jayasinghe Y., Moore P., Donath S., Campbell J., et al. Bleeding disorders in teenagers presenting with men-orrhagia. Aust N Z J Obstet Gynecol. 2005; 45 (5): 439-43.
22. Beaumont H., Augood C., Duckitt K., Lethaby A. Danazol for heavy menstrual bleeding. Cochrane Database Syst Rev. 2007; 3: CD001017.
23. Kingman C., Kadir R., Lee C., Economides D. The uses of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG. 2004; 111 (12): 1425-8.
24. American College of Obstetricians and Gynecologists. ACOG committee opinion No. 557: Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013; 121 (4): 891-6.
25. Bettocchi S., Ceci O., Vicino M., Marello F., et al. Diagnostic inadequacy of dilatation and curettage. Fertil Steril. 2001; 75 (4): 803-5.
26. Nichols C.M., Gill E.J. Thermal balloon endometrial ablation for management of acute uterine hemorrhage. Obstet Gynecol. 2002; 100 (5 Pt 2): 1092-4.
27. Bowkley C.W., Dubel G.J., Haas R.A., et al. Uterine artery embolization for control of life-threatening hemorrhage at menarche: brief report. J Vasc Interv Radiol. 2007; 18 (1 Pt 1): 127-31.
