Dysfunctional Uterine Bleeding Mary E. Rimsza Pediatrics in Review 2002;23;227 DOI: 10.1542/pir.

23-7-227

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2002 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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Article

genitourinary disorders

Dysfunctional Uterine Bleeding

Mary E. Rimsza, MD*

Objectives
1. 2. 3. 4. 5.

After completing this article, readers should be able to:

Identify the primary cause of dysfunctional uterine bleeding (DUB). Characterize the management of DUB. Explain how coagulation disorders can cause menorrhagia. Describe methods of reducing menstrual blood loss. Delineate the most common ovarian cause of DUB.

Introduction
The normal menstrual cycle is dened as having a mean interval of 287 days, with a mean duration of 43 days. The amount of blood loss averages 30 mL per cycle but may be as high as 80 mL. Although abnormal endometrial bleeding occurs in women of all ages, it is particularly common in adolescence. Dysfunctional uterine bleeding (DUB) is dened as abnormal endometrial bleeding in the absence of pelvic pathology. Approximately 95% of the abnormal endometrial bleeding in adolescence is DUB due to anovulation. Patterns of abnormal endometrial bleeding include menorrhagia (prolonged bleeding occurring at regular intervals), metrorrhagia (uterine bleeding occurring at irregular intervals), and menometrorrhagia (uterine bleeding that is prolonged, excessive, and occurring at irregular intervals).

Epidemiology
DUB is most common during the rst 2 years after menarche, when approximately 55% to 82% of menstrual cycles are anovulatory. Even after 5 years of menstruation, 20% of cycles remain anovulatory. The earlier the onset of menarche, the shorter the duration of anovulatory cycles. If menarche occurs before 12 years of age, 50% of cycles are ovulatory after 1 year, whereas if menarche occurs after 13 years of age, it may be 4.5 years until 50% of cycles are ovulatory. In the United States, the mean age of menarche is 12.88 years for Caucasian and 12.16 years for African-American girls. Approximately 90% of adolescents reach menarche by the time their breast and pubic hair development has reached sexual maturity rating (SMR) stage 4. Thelarche (onset of breast development) usually occurs 2 years before menarche.

Normal Menstrual Cycle

Ovulation leads to normal repetitive menstrual bleeding. The rst phase of the ovulatory menstrual cycle is the follicular phase during which pulsatile release of gonadotropinreleasing hormone (GnRH) from the hypothalamus stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which stimulates ovarian follicular growth (Fig. 1). The growing follicle predominantly secretes estrogen, which induces proliferation of the endometrium. The second phase of the menstrual cycle is the ovulatory phase. In this phase, the pituitary gland releases increased amounts of LH, and ovulation occurs within 12 hours of this midcycle surge in LH. The third phase of the ovulatory cycle is the luteal phase, which follows ovulation. In this phase, the corpus luteum that is formed by luteinization of the follicular cells begins producing progesterone, which counteracts the effects of estrogen on the endometrium. Progesterone inhibits proliferation of the endometrium and produces glandular changes
*Director of Health, Arizona State University, Professor of Pediatrics, Mayo Graduate School of Medicine and University of Arizona College of Medicine, Tempe, AZ. Pediatrics in Review Vol.23 No.7 July 2002 227

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genitourinary disorders dysfunctional uterine bleeding

Figure 1. The ovulatory menstrual cycle.

that make the endometrium receptive to implantation by a fertilized ovum. Without fertilization and the production of human chorionic gonadotropin, the corpus luteum cannot survive. As the corpus luteum regresses, estrogen and progesterone levels fall, triggering the synchronous sloughing of the endometrial lining (menstruation) approximately 14 days after ovulation.

Anovulatory Menstrual Cycle

When anovulatory cycles occur, the endometrium experiences continued estrogen stimulation that is unopposed by progesterone. Growth of the vascular and glandular elements of the endometrium that are stimulated by estrogen are not accompanied by the stromal support that usually is provided by progesterone. For most adolescents who are anovulatory, increasing levels of estrogen cause a negative feedback on the hypothalamicpituitary axis. This feedback causes a decrease in estrogen
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levels, which results in endometrial bleeding that mimics an ovulatory cycle. Adolescents who develop DUB seem to have impairments in this negative feedback system. Thus, increasing levels of estrogen do not cause a decrease in FSH secretion with subsequent suppression of estrogen secretion. In these girls, many different follicles are stimulated, none becomes dominant, and progesterone levels remain low. The endometrium becomes excessively thickened and unstable. Eventually, the endometrial lining begins to break down asynchronously and irregularly. Thus, endometrial bleeding in the absence of ovulation becomes prolonged, irregular, and sometimes profuse. The more prolonged an adolescents anovulation, the greater the risk for DUB because even an occasional ovulatory cycle stabilizes and coordinates sloughing of the endometrium. Although immaturity of the hypothalamic-pituitaryovarian axis is the most common cause of anovulation in adolescence, there are many other causes. Almost any systemic illness, especially if the illness is prolonged or associated with excessive weight loss, can cause anovulation. For example, poorly controlled diabetes mellitus, inammatory bowel disease, and cystic brosis are associated with anovulation. Poor nutritional status as well as emotional distress can cause anovulation. Girls who have anorexia nervosa frequently have anovulatory cycles due to both of these factors. In contrast, bulimia generally is not associated with menstrual irregularities, perhaps because the bulimic adolescent usually maintains a normal weight. It is hypothesized that 17% total body fat is needed to initiate menses and that 22% total body fat is needed for regular ovulatory cycles. Aromatization of androgen precursors in fat provides another source of estrogen; it is theorized that this additional estrogen is necessary for hypothalamic pituitary regulation and the onset and maintenance of vaginal bleeding. If this hypothesis is correct, any medical or psychological disorder that results in a decrease in total body fat potentially can cause anovulation. Thus, it is important to obtain both a dietary and weight history in the evaluation of the adolescent who has DUB. Other causes of anovulation include endocrine disorders and primary ovarian dysfunction. The most common endocrine disorder associated with anovulation and DUB is hypothyroidism. In a recent study, approximately 25% of women who had hypothyroidism had DUB. Hyperprolactinemia due to a pituitary tumor also is a rare cause of anovulation. Adrenal causes of anovulation include Cushing syndrome (Fig. 2), Addison disease, and congenital adrenal hyperplasia (Fig. 3). The most common primary ovarian cause of anovula-

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genitourinary disorders dysfunctional uterine bleeding

Figure 3. Clitoromegaly in a child who has congenitcl adrenal hyperplasia.

Figure 2. Cushing syndrome.

tion is polycystic ovarian syndrome (PCOS), which affects 5% to 10% of women. PCOS is associated with irregular menses, usually from the time of menarche, and physical signs of hyperandrogenism. The classic ndings on ultrasonography are multiple 2 to 8 mm follicles arranged in a peripheral pattern and associated with increased stroma relative to follicles (string of pearls). However, many adolescents have normal-appearing ovaries on ultrasonography because the prevalence of polycystic ovaries increases with increasing gynecologic age (years since menarche). Small follicular cysts are consistent with the diagnosis of PCOS, but they are nonspecic ndings because other conditions that cause anovulation also may be associated with multiple ovarian cysts. Indeed, young adolescents who are anovulatory due to immature hypothalamic-pituitary-ovarian axis often have multiple ovarian cysts on ultrasonography due to continued FSH secretion. Signs of hyperandrogenism in the adolescent who has PCOS include hirsutism, acne (Fig.

4), and rarely clitoromegaly. Obesity occurs in 50% of patients and often is associated with other metabolic abnormalities, including insulin resistance, glucose intolerance, and lipid abnormalities. On physical examination, acanthosis nigrans, a thickening and increased pigmentation of the skin, frequently is noted on the nape of the neck, axilla, and intertriginous areas (Fig. 5). Anovulatory menstrual cycles usually are painless. Thus, questioning the adolescent about symptoms of dysmenorrhea can help the physician determine the cause of abnormal endometrial bleeding. In adolescence, the most common causes of painful uterine bleeding are primary dysmenorrhea, pregnancy complications (eg, ec-

Figure 4. Facial acne in an adolescent who has polycystic ovarian syndrome.

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genitourinary disorders dysfunctional uterine bleeding

Figure 5. Acanthosis nigrans.

topic pregnancy, missed abortion), and infection (eg, endometritis, pelvic inammatory disease). Other less common causes include trauma and gynecologic tumors. Abnormal uterine bleeding sometimes is the initial presentation of a blood dyscrasia. Indeed, in one study of adolescent females, 20% of the girls who had menorrhagia were found to have a blood dyscrasia. These disorders are most likely to present as regular but heavy menses. An underlying coagulation disorder should be considered especially if menorrhagia is severe or presents at the time of menarche. In one study of young adolescent Canadian girls, 25% of adolescents who had hemoglobin measurements less than 10 g/dL (100 g/L) and 50% of adolescents who presented with menorrhagia at menarche were found to have a coagulation disorder. Because platelets and brin are directly involved in the hemostasis achieved in a bleeding menstrual endometrium, thrombocytopenia and disorders associated with platelet dysfunction (eg, platelet storage pool diseases, von Willebrand disease) are some of the most common blood dyscrasias associated with menorrhagia.

Evaluation
The evaluation of the adolescent who has abnormal endometrial bleeding should begin with a detailed menstrual history, including age of menarche, frequency and amount of menstruation, and character and duration of ow. If the menstrual pattern has changed, it is important to ask about other events that may have coincided with the change, including weight change, family or personal stress, and illness. One should also seek a history of unusual nonmenstrual bleeding, including easy bruisability or prolonged bleeding after minor cuts or dental surgery. A sexual history is critical because the differential diagnosis of abnormal bleeding in the sexually active girl includes sexually transmitted diseases (eg, pelvic inam230 Pediatrics in Review Vol.23 No.7 July 2002

matory disease) and gestational events (eg, ectopic pregnancy, missed abortion). A comprehensive general medical history and review of systems also is important because many chronic illnesses are associated with anovulation. Pertinent aspects of the family history include bleeding disorders, infertility, menstrual disorders, and thyroid disease. The physical examination should begin with vital signs. Postural changes in heart rate and blood pressure may provide objective evidence of hypovolemia. The complete physical examination should focus particular attention on evidence of nongenital bleeding, thyroid examination, and signs of PCOS (eg, hirsutism, acne, obesity, acanthosis nigrans). The breast examination is important not only to assess sexual maturity, but to determine if galactorrhea is present. Funduscopic examination and visual eld testing may provide evidence of a pituitary lesion. An abdominal examination may reveal an ovarian or uterine mass. An external genital examination always is indicated. Sexual maturity rating, clitoral size, and hymenal characteristics should be assessed. An internal genital examination is mandatory if the adolescent is sexually active or has painful bleeding. The goals of the internal bimanual genital examination are assessment of adnexal and uterine size; determination of abdominal, ovarian, or cervical motion tenderness; and presence of any lower abdominal or pelvic mass. A speculum examination also allows assessment of the vagina and cervix. A bluish coloration of the cervix may be a sign of early pregnancy, and a widened cervical os in association with active endometrial bleeding may indicate a spontaneous abortion. The amount and character of the bleeding should be noted. The presence of large clots may suggest a spontaneous abortion, but this also can occur with severe primary dysmenorrhea. In the sexually active adolescent, cervical swabs should be obtained for determining the presence of Neisseria gonorrhoeae and Chlamydia trachomatis. A Papanicolau smear should be obtained if there is no active bleeding at the time of the examination. If there is active bleeding, it is best to defer the Papanicolau test until the bleeding has stopped. It usually is possible to perform an internal bimanual examination in a virginal adolescent, but a speculum examination may be more difcult. In some situations, a rectal examination may be helpful in assessing uterine size. Pelvic ultrasonography can aid in the assessment of the virginal adolescent when the bimanual examination is not possible. Laboratory testing should be guided by ndings of the history and physical examination. For the patient who is actively bleeding, the most important tests to

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genitourinary disorders dysfunctional uterine bleeding

obtain are those that will assist in determining the best treatment for the bleeding. At a minimum, all patients should have a hemoglobin and complete blood count (CBC) done. Beta-human chorionic gonadotropin testing usually is indicated to rule out pregnancy. Coagulation studies, including, at a minimum, platelet count, prothombin time (PT), and partial thromboplastin time (PTT), also generally are indicated. These studies always should be performed if the adolescent has a family history of bleeding disorders and a personal history of excessive nonmenstrual bleeding or anemia. It is important to remember that the CBC, PT, and PTT results may be normal in patients who have von Willebrand disease, especially when there is active bleeding. Thus, if this disorder is suspected, a von Willebrand screen or referral to a hematologist should be considered. Additional laboratory tests often can be deferred until the bleeding is controlled to minimize further blood loss due to testing. If galactorrhea is present, serum prolactin should be measured. If there are signs of PCOS, measurement of FSH, LH, and testosterone levels will be helpful. Thyroid screening should be considered, even in patients who do not have clinical signs or symptoms of hypothyroidism. Abdominal and pelvic ultrasonography may be helpful in assessing the patient and always are indicated for patients who are suspected of having an ectopic pregnancy or who have a palpable pelvic or abdominal mass.

Treatment
If the history, physical examination, and laboratory test results are consistent with the diagnosis of DUB, treatment can be guided by the severity of the bleeding and the need for contraception. For the young virginal adolescent who is not anemic and is in her rst or second gynecologic year, a conservative approach is warranted if the history and physical examination ndings are normal. The cause of the DUB should be discussed with the patient and her parent. A menstrual calendar and follow-up visit in 3 to 6 months should be scheduled. Appropriate iron supplementation should be provided to prevent anemia. If the irregular menses are bothersome, hormonal treatment can be considered, but this rarely is necessary. For the adolescent who is anemic, hormonal and iron therapy are indicated. Both estrogen and progesterone should be used to stop the bleeding. Estrogen provides hemostasis, and progesterone stabilizes the endometrial lining. Combined oral contraceptive pills (OCPs) containing both hormones are the most convenient method of administering these hormones. If the adolescent is not

actively bleeding, OCPs can be given in a once-daily regimen. Pills containing at least 30 mcg of ethinyl estradiol should be prescribed. If there is active bleeding, the OCPs should be given in a daily multiple-pill regimen that is followed by a tapering dosage. The regimen begins with four pills every 6 hours until the bleeding has stopped for at least 24 hours. An antiemetic may be needed to control any nausea. For most patients, bleeding will cease within 48 hours. If the bleeding persists for more than 2 days, additional evaluation and consultation should be considered because patients who have persistent bleeding despite high-dose OCPs often have an underlying bleeding disorder or pelvic pathology. After the bleeding has stopped, the dosage of OCPs is decreased to three pills per day for the next 3 days, followed by two pills per day for 3 days. The patient then is maintained on a once-a-day regimen. If bleeding recurs during tapering, the dosage can be increased to the lowest effective dose necessary to control bleeding. If the hemoglobin is less than 10 mg/dL (100 g/L), the OCPs can be administered continuously without placebos for 6 to 9 weeks. The patient should be instructed to take only the rst 21 pills of each pack. This regimen delays withdrawal menses until the hemoglobin concentration has increased. When withdrawal bleeding does occur, the patient should be advised that the menstrual ow might be heavier and more prolonged than normal because the OCPs have been taken continuously for more than 1 month. After tapering the dosage of OCPs, the patient continues cycling on OCPs for 3 to 6 months. Generally, no further treatment is needed for the young adolescent who has had DUB due to anovulatory cycles. However, many adolescents wish to continue the OCPs if they are sexually active. It is important to talk to the adolescent privately about the need for contraception. If estrogen is contraindicated or not tolerated by the patient, cyclic progesterone therapy can be substituted for the daily OCP regimen. Progesterone induces stromal stability that is followed by withdrawal menstrual ow, but this regimen is not as effective as OCPs because estrogen improves hemostasis by increasing platelet aggregation and levels of brinogen and factors V and IX. Medroxyprogesterone acetate 10 mg daily can be administered for 10 days per month. The therapy should be continued for 3 to 6 months. If the hemoglobin level is very low (10 mg/dL [100 g/L]) or there is hemodynamic instability, intravenous conjugated estrogen can be used to stop the bleeding rapidly. Usually one to three intravenous doses of 25 mg conjugated estrogen administered at 4- to 6-hour intervals will stop the bleeding. If bleeding does not stop
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genitourinary disorders dysfunctional uterine bleeding

within 24 hours, a gynecologic surgical consultation is indicated. Blood transfusions are rarely needed, even in patients who have hemoglobin levels as low as 6 mg/dL (60 g/L). Dilatation and curettage is used as a last resort and seldom is needed in adolescents. Systematic reviews of randomized control trials have shown that nonsteroidal anti-inammatory drugs (NSAIDs) reduce menstrual blood loss. When administered during menses, blood loss may be reduced by 30% to 50%. The NSAIDs should be started at the onset of menstruation and continued until the end of menses. These drugs are a helpful adjunct to hormonal therapy for adolescents who have DUB and may be especially useful in the adolescent who has menorrhagia. In one systematic review of NSAIDs versus placebo, mefenamic acid, naproxen, meclofenamic acid, and diclofenac reduced menstrual blood loss by 23 to 74 mL. Ibuprofen may be less effective than mefenamic acid or naproxen in reducing blood loss. Other drugs that have been used to control menstrual blood loss in adult women include desmopressin, antibrinolytic drugs (eg, tranexamic acid, aminocaproic acid), danazol, and GnRH agonists. There is little experience with any of these drugs in adolescents, however. Desmopressin may help in the management of the adolescent who has von Willebrand disease or hemophilia A. Antibrinolytic therapies may reduce blood loss by up to 50%, but adverse effects are frequent and include nausea, diarrhea, headaches, and abdominal pain. In addition, systemic thrombosis has been reported. Administration of GnRH agonists suppresses gonadotropin secretion and, thus, estradiol levels, resulting in amenorrhea. Long-term use is associated with osteoporosis similar to that seen in ovarian failure. However, GnRH agonists have been used as a short-term therapy for the adolescent who has severe but transitory thrombocytopenia associated with chemotherapy if there is a poor response to hormonal medications. Danazol is an androgen deriva-

tive that induces amenorrhea. Anabolic and androgenic adverse effects, such as weight gain, acne, and hirsutism, are very common. The long-term prognosis for the adolescent who has abnormal uterine bleeding depends on the underlying cause. For the young adolescent who has anovulatory cycles due to immaturity of the hypothalamic-pituitaryovarian axis, the prognosis is excellent. In contrast, adolescents who have PCOS often continue to have abnormal uterine bleeding, and retrospective studies suggest that they are at increased risk for adverse cardiovascular events. Recent research suggests that increased insulin resistance may be one of the key pathophysiologic factors in the development of PCOS. Use of insulin-sensitizing agents (eg, metformin, troglitazone) recently has been shown to decrease hyperandrogenism and induce ovulation, thus causing a return of regular menses. The use of these agents for the long-term management of adolescents is under investigation. Adolescents who have a blood dyscrasia often continue to have menorrhagia and require therapy throughout their reproductive years.

Suggested Reading
Gordon CM. Menstrual disorders in adolescents. Excess androgens and the polycystic ovary syndrome. Pediatr Clin North Am. 1999;46:519 543 Iglesia EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Adolescent Medicine: State of the Art Reviews. 1999;10:255274 Mitan LAP, Slap GB. Adolescent menstrual disorders update. Med Clin North Am. 2000;84:851 868 Sanlippo JS, Hertweck SP. Physiology of menstruation and menstrual disorders. In: Friedman SB, Fisher MM, Schonberg SK, Alderman AM, eds. Comprehensive Adolescent Health Care. 2nd ed. St. Louis, Mo: Mosby; 1998:990 1017 Shwayder JM. Contemporary management of abnormal uterine bleeding. Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am. 2000;27:219 234

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genitourinary disorders dysfunctional uterine bleeding

PIR Quiz
Quiz also available online at www.pedsinreview.org. 1. Which of the following statements regarding menstrual cycles in adolescents is true? A. B. C. D. E. Girls who have a later onset of menarche have a shorter duration of anovulatory cycles. Menstruation occurs because of decreasing levels of estrogen and progesterone. Most adolescents develop ovulatory cycles 6 months after menarche. Ovulation occurs because of increasing levels of follicle-stimulating hormone. Thelarche occurs 1 year before menarche in most adolescents.

2. Which of the following statements regarding dysfunctional uterine bleeding (DUB) is true? A. B. C. D. E. Chronic illness is the most common cause of DUB. DUB can be caused by emotional stress. Excessive bleeding is due to uninhibited progesterone effects on the endometrium. Many girls who have DUB are found to have hyperthyroidism. The risk for developing DUB is unrelated to the duration of anovulatory cycles.

3. You are evaluating a 14-year-old girl who is complaining of heavy bleeding during her menses. She experienced menarche at age 12 years. She reports regular periods, but bleeding is excessive and lasts about 10 days. She does well in school and is active in sports. She appears healthy, and her Sexual Maturity Rating is stage 4 for breasts and pubic hair. Which of the following is the most likely cause of her menorrhagia? A. B. C. D. E. Anorexia nervosa. Bulimia. Immaturity of the hypothalamic-pituitary-ovarian axis. Primary ovarian dysfunction. Underlying illness, such as inammatory bowel disease.

4. You are evaluating a 13-year-old girl who has heavy menstrual bleeding in the emergency department. She experienced menarche 4 months ago. Since then, her periods have been regular and always have lasted more than 14 days. Physical examination ndings are normal, with the exception of pallor and a large amount of menstrual blood at the vaginal introitus. Which of the following conditions should be considered most strongly as the cause of her bleeding? A. B. C. D. E. Ectopic pregnancy. Hypothyroidism. Pelvic inammatory disease. Polycystic ovarian syndrome. von Willebrand disease.

5. One of your adolescent patients has presented to your ofce with a complaint of heavy periods that are irregular and last more than 10 days. Her menarche occurred 1.5 years ago. She is pale and tachycardic, has a hemoglobin of 8 g/dL (80 g/L), and currently is bleeding. Which of the following is the most appropriate course of action? A. B. C. D. E. Admit her to the hospital for a transfusion of packed red blood cells. Admit her to the hospital for administration of intravenous estrogen. Begin a trial of oral iron supplementation and follow her as an outpatient. Consult the gynecology department for a possible dilatation and curettage. Place her on a combination oral contraceptive pill and begin nonsteroidal anti-inammatory drug therapy.

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Dysfunctional Uterine Bleeding Mary E. Rimsza Pediatrics in Review 2002;23;227 DOI: 10.1542/pir.23-7-227

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including high resolution figures, can be found at: http://pedsinreview.aappublications.org/content/23/7/227 This article cites 4 articles, 0 of which you can access for free at: http://pedsinreview.aappublications.org/content/23/7/227#BIBL This article, along with others on similar topics, appears in the following collection(s): Gynecology http://pedsinreview.aappublications.org/cgi/collection/gynecolog y_sub Menstrual Disorders http://pedsinreview.aappublications.org/cgi/collection/menstrual_ disorders_sub Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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