Dysfunctional Uterine Bleeding
Laurie A. P. Mitan
Gail B. Slap
Dysfunctional uterine bleeding (DUB) is a common menstrual problem during adolescence. When severe, it can result in life-threatening anemia. Even when mild, it is usually both a concern and a nuisance for the adolescent. By definition, DUB is irregular and/or prolonged vaginal bleeding due to endometrial sloughing in the absence of structural pathology. In adolescents, anovulation secondary to physiological immaturity explains most cases of irregular bleeding. Although structural pathology accounts for < 10% of abnormal uterine bleeding during adolescence, it must be excluded before the diagnosis of DUB can be established.
- Normal menstrual cycles during adolescence are 21 to 40 days long, with 2 to 8 days of bleeding and 20 to 80 mL blood loss per cycle.
- Ovulatory cycles are characterized by a follicular phase ending with ovulation and a luteal phase ending with menstruation. During the follicular phase, rising serum levels of follicle-stimulating hormone (FSH) stimulate ovarian follicular maturation and estrogen production. The rising serum estrogen levels stimulate endometrial proliferation and progressive thickening. A preovulatory surge in estrogen is followed by a surge in luteinizing hormone (LH), which triggers ovulation. During the luteal phase, the residual follicle converts to a corpus luteum that produces increasing levels of progesterone and estrogen. The progesterone stabilizes the thickened endometrium and stops further proliferation. In the absence of fertilization, the corpus luteum involutes, estrogen and progesterone levels fall, and the endometrium sloughs, resulting in menstrual bleeding.
Up to 80% of menstrual cycles are anovulatory in the first year after menarche. Cycles become ovulatory at an average of 20 months after menarche.
- DUB during adolescence is abnormal endometrial sloughing in the absence of structural pathology or anomaly, usually due to anovulation.
- Menorrhagia is prolonged or heavy uterine bleeding that occurs at regular intervals.
- Metrorrhagia is uterine bleeding that occurs at irregular intervals.
- Menometrorrhagia is prolonged or heavy uterine bleeding that occurs at irregular intervals.
- Oligomenorrhea is uterine bleeding that occurs at prolonged intervals of 41 days to 3 months but is of normal flow, duration, and quantity.
An estimated 10% of adolescents managed as outpatients for abnormal bleeding, compared with 25% of those requiring hospitalization, have an identifiable structural, infectious, or clotting abnormality. Among adolescents hospitalized with hemorrhage at menarche resulting in a hemoglobin level < 10 g/dL, 50% have a systemic bleeding disorder (Claessens and Cowell, 1981).
The differential diagnosis of abnormal bleeding is quite different in the adolescent than the adult. Uterine fibroids and endometrial malignancy lead the differential diagnosis in the adult but are rare in the adolescent. Conversely, congenital anomalies of the outflow tract may be subclinical until menarche, but rarely remain unrecognized until adulthood. Apart from DUB, the differential diagnosis of abnormal bleeding during adolescence includes the following conditions:
- Pregnancy-related causes: Ectopic pregnancy; spontaneous, threatened, or incomplete abortion; placental polyp; hydatidiform mole
- Local pathology: Foreign body in the vagina (e.g., retained tampon) or uterus (e.g., intrauterine device); cervicitis or endometritis due to a sexually transmitted disease (STD) or instrumentation; laceration or other trauma; polyp of the cervix or uterus; congenital anomaly of the outflow tract; premalignant or malignant lesion of the cervix or uterus
- Bleeding diathesis: Idiopathic thrombocytopenic purpura; von Willebrand disease; abnormal platelet function due to drugs (e.g., aspirin) or systemic illness (e.g., renal failure); bone marrow suppression (e.g., chemotherapy) or infiltration (e.g., leukemia); coagulopathy due to inherited clotting factor deficiency, systemic illness (e.g., liver failure), or anticoagulant therapy (e.g., warfarin)
- Hormonal causes: Anovulatory bleeding
Anovulatory causes usually relate to one of three hormonal imbalance conditions:
- Estrogen breakthrough bleeding: This occurs when excess estrogen stimulates the endometrium to proliferate in an undifferentiated manner. With inadequate
progesterone levels to provide support to the endometrium, portions of the lining will slough at irregular intervals. In addition, the vasoconstriction mediated through progesterone and prostaglandin levels does not occur, often resulting in profuse bleeding.
- Estrogen withdrawal bleeding: This bleeding results from a sudden decrease in estrogen levels. This could occur after stopping exogenous estrogen therapy or just before ovulation in the normal menstrual cycle. This type of withdrawal bleeding is usually self-limited.
- Progesterone breakthrough bleeding: This occurs when the ratio of progesterone to estrogen is high, such as with progesterone-only contraceptive methods. In these individuals, the endometrium becomes atrophic and more prone to frequent, irregular bleeding.
Hormonally mediated DUB therefore tends to be less associated with dysmenorrhea than normal menses following ovulation or abnormal bleeding due to a structural or infectious problem. The most common causes of hormonally mediated DUB (anovulatory bleeding) during adolescence are the following:
- Gynecological immaturity: Immaturity of the hypothalamic-pituitary-ovarian axis is the leading cause of DUB during adolescence. After menarche, anovulation is associated with 50% to 80% of bleeding episodes during the first 2 years, 30% to 55% during years 2 to 4, and 20% during years 4 to 5. The likelihood of anovulatory bleeding increases with menarcheal age. More than 50% of bleeding episodes are anovulatory for 1 year when menarche occurs before age 12 years, for 3 years when menarche occurs at age 12 to 13 years, and for 4 years when menarche occurs after age 13 years. Despite these high rates of anovulation, the negative feedback of estrogen on the hypothalamic-pituitary axis protects most adolescents from DUB. Even when ovulation does not occur, gonadotropin levels decrease in response to increasing estrogen levels. Estrogen production then declines before the endometrium becomes excessively thickened, and withdrawal bleeding occurs. Most anovulatory cycles therefore tend to be fairly regular, and the bleeding tends to be limited in duration and quantity.
- Defective corpus luteum: DUB can occur in an ovulatory cycle with early involution of the corpus luteum and inadequate progesterone production.
- Hormonal contraception or replacement therapy: Exogenous estrogen and/or progestins, whether intended for contraception or replacement therapy, may cause anovulation and irregular bleeding. If a uterus is present, unopposed estrogen is associated with an increased risk for endometrial carcinoma. In any postpubertal patient with a uterus, the regimen therefore should include both estrogen and a progestin administered cyclically or in a fixed daily dose. Among patients using hormonal contraception, irregular bleeding is more common with progestin-only than combined estrogen-progestin methods.
- Hypothyroidism or hyperthyroidism: Although either condition may cause DUB, hypothyroidism is more commonly associated with menorrhagia than hyperthyroidism.
- Polycystic ovary syndrome (PCOS): See Chapter 52.
- Late-onset congenital adrenal hyperplasia (e.g., partial 21-hydroxylase deficiency): See Chapter 58.
- Hypothalamic hypogonadism: Eating disorders, weight loss from other causes, excessive exercise, and emotional or physical stress typically present with amenorrhea or oligomenorrhea rather than DUB. However, there may be intermittent ovulatory cycles with withdrawal bleeding or sufficient endogenous estrogen to produce breakthrough bleeding over time.
The evaluation of any patient with bleeding begins with an assessment of hemodynamic stability. The next objective is to determine the site of the bleeding (e.g., gastrointestinal, urinary, vaginal, cervical, or uterine). Once the bleeding is found to be uterine, the evaluation focuses on determination of its cause.
Part of the history should be obtained from the adolescent and, if possible, the parent or guardian. The sexual history should be obtained from the adolescent alone unless she makes it clear that she is comfortable discussing it with the parent present.
- Menstrual history: Age at menarche, cycle regularity, cycle duration, flow duration, change in cycle or flow, change in number of saturated pads or tampons, dysmenorrhea, pelvic pain between menses, change in pain associated with menses
- Sexual history: Age at coitarche, use of condoms, contraception, pregnancies, deliveries, miscarriages, abortions, past STDs, past pelvic inflammatory disease (PID), number of partners, recent new partner, vaginal discharge, known exposure to a partner with an STD
- History of systemic illness
- Endocrine history: Symptoms suggestive of hypothyroidism (e.g., fatigue, weight gain, dry skin), hyperthyroidism (e.g., palpitations, increased appetite, weight loss), or hyperandrogenism (e.g., hirsutism, acne, weight gain); use of hormonal contraception or exogenous hormones
- Family history: PCOS, bleeding diathesis
- Review of systems: Fatigue, lightheadedness, rapid heart beat, palpitations, gum bleeding, epistaxis, significant weight changes, stress
- Vital signs: Blood pressure and heart rate in supine, sitting, and standing positions to detect orthostatic changes; height, weight, and body mass index (BMI)
- Sexual maturity ratings: Breasts and pubic hair
- Skin, hair, and mucosa: Scalp hair thinning or dryness, hirsutism, acanthosis nigricans, acne, petechiae, purpura, ecchymoses, gum bleeding, epistaxis
- Thyroid: Enlargement, tenderness, nodules
- Breasts: Galactorrhea
- Lymph nodes: Lymphadenopathy
- Abdomen: Hepatosplenomegaly, palpable uterus, mass
- Pelvic examination: Essential in all sexually active adolescents; also indicated if the history suggests structural pathology as the cause of the bleeding; can be deferred in the adolescent with suspected anovulatory DUB, who has never had sexual intercourse
Laboratory testing may not be necessary in the adolescent with mild anovulatory DUB associated with physiological immaturity. Depending on the history and physical examination results, other patients may require the following laboratory evaluation:
- Pregnancy test: A urine test for β-human chorionic gonadotropin (β-hCG) should be done in all patients if there is any question of past sexual intercourse. If the urine test result is positive, a quantitative serum test for β-hCG should be performed. In these cases of possible ectopic pregnancies, an ultrasound and gynecology referral should strongly be considered.
- Complete blood cell count: Unless the bleeding is mild and of recent onset, all patients should have hemoglobin, hematocrit, and platelet count evaluation. A white blood cell count with differential is helpful if PID is suspected.
- STD screening: Endocervical tests for gonorrheal and chlamydial infections are indicated for all adolescents who have ever had sexual intercourse.
- Erythrocyte sedimentation rate: May help support a diagnosis of PID or underlying systemic illness.
- Thyroid function tests for all patients with moderate to severe menorrhagia.
- Prothrombin time, partial thromboplastin time, and PFA-100 as a preliminary screen for a bleeding disorder. The PFA-100 has a negative predictive value of 91% for von Willebrand disease and common platelet function disorders (Buyukasik et al., 2002). Anemia decreases the performance of the PFA-100 and concomitant use of estrogens can falsely elevate von Willebrand factor levels. Patients with moderate to severe anemia, personal history of bleeding in addition to menorrhagia, or family history of significant bleeding should be evaluated with more specific diagnostic tests such as von Willebrand factor antigen and ristocetin cofactor activity. Hematology consultation may be necessary.
- Liver function tests and blood urea nitrogen are required if there is evidence of abnormal clotting factors or platelet function.
- Antinuclear antibody: Preliminary screen for autoimmune disease.
- LH, FSH, testosterone (total and free), and dehydroepiandrosterone sulfate levels, if PCOS is suspected (see Chapter 52).
- Pelvic ultrasonography: Transabdominal ultrasonography performed through a full bladder is essential in the virginal patient with possible structural pathology who cannot tolerate a pelvic examination. Transabdominal and transvaginal ultrasonography is indicated if the pregnancy test is positive or if a mass is palpated on pelvic examination.
- Endometrial aspirate and/or biopsy are rarely indicated in adolescents.
The severity and cause of the bleeding guide its management. Severe bleeding with hemodynamic instability, regardless of cause, requires immediate intervention with intravenous fluids and/or blood transfusion. Adolescents without underlying cardiovascular disease usually respond quickly to intravenous fluids and supplemental iron therapy, without the need for transfusion. Severe anemia that developed over months or years of abnormal bleeding is better tolerated than the same level of anemia that developed over hours or days of acute bleeding. Bleeding secondary to pregnancy, infection, or structural pathology requires prompt treatment of the underlying condition. Bleeding secondary to a systemic problem, such as a clotting abnormality or thyroid dysfunction, may require short-term hormonal therapy identical to that for anovulatory bleeding until the systemic problem is brought under control.
Anovulatory Dysfunctional Uterine Bleeding
The approach to anovulatory DUB depends on bleeding severity, hemoglobin and/or hematocrit value, hemodynamic tolerance, and emotional tolerance. It can generally be divided into the following categories:
- Light to moderate flow, hemoglobin level of at least 12 g/dL: Reassurance, multivitamin with iron, menstrual calendar, reevaluation within 3 months.
- Moderate flow, hemoglobin level of 10 to 12 g/dL: Begin a 35-µg combined oral contraceptive pill to be taken every 6 to 12 hours for 24 to 48 hours until the bleeding stops, along with an antiemetic if necessary for nausea and vomiting. Oral supplemental iron therapy should be initiated as early as possible but may not be tolerated during the first 2 days of high-dose hormonal therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used as adjunctive therapy, along with the oral contraceptive to decrease both bleeding and, when present, dysmenorrhea. Taper the oral contraceptive to one pill daily by day 5. Begin a new 28-day pill packet and inform the patient that a withdrawal bleed is likely during the week of placebo pills. Continue the combined oral contraceptive for 3 to 6 months.
Medroxyprogesterone acetate (Provera) has been used alone by some providers, although it does not appear to be as effective and leads to breakthrough bleeding.
- Heavy flow, hemoglobin level < 10 g/dL: If the patient is hemodynamically stable, reliable, and able to tolerate the oral contraceptive, management is as stated earlier. Otherwise, hospitalization is indicated until the bleeding stops on the previously described regimen. A 50-µg combined oral contraceptive every 6 hours may be necessary to control the bleeding in some patients. If the bleeding does not slow within two doses of the 50-µg pill, add conjugated estrogen intravenously (25 mg every 6 hours for a maximum of six doses). Then taper the oral contraceptive to one pill daily by day 7. If the bleeding does not stop within six doses of intravenous estrogen plus the combined oral contraceptive, cervical dilation with endometrial curettage is usually necessary.
Dysfunctional Uterine Bleeding Secondary to Hormonal Contraception
- Persistent bleeding on a 20-µg combined oral contraceptive pill usually stops when a higher-dose estrogen (e.g., 30–35 µg) pill is prescribed.
- Persistent bleeding on a 30 to 35-µg pill requires either a 50-µg pill for one cycle or the addition of conjugated estrogen at 0.625 mg daily to the 35-µg pill for one cycle.
- Persistent bleeding on progesterone-only contraceptives can be managed with the short-term addition of conjugated estrogen (1.25–2.50 mg daily for 5–7 days) and/or NSAIDs. Although this will stop the bleeding, the likelihood of subsequent spotting is also increased because of the estrogen-induced endometrial proliferation.
Iatrogenic DUB is common in patients receiving chemotherapeutic or other interventions that alter bone marrow production, platelet function, or clotting factor synthesis. The management of DUB in these patients attempts to decrease menstrual frequency or induce endometrial atrophy. Options are as follows:
- Combined oral contraceptive pill (21-day packet), one pill daily continuously. The pill should be discontinued for 1 week every 3 months to allow a withdrawal bleed and thereby prevent excessive endometrial proliferation.
- Depot medroxyprogesterone (DMPA), 150 mg intramuscularly every 12 weeks. Would consider potential deleterious skeletal effects associated with long-term (>2 year) use of this agent (see Chapter 47).
- Progesterone, 10 mg orally daily for an unlimited number of months.
- Gonadotropin-releasing hormone analog (e.g., leuprolide acetate). Owing to its hypoestrogenemic side effects, this option should be used for no more than 6 months. It is an excellent choice for prophylactic use in conditions associated with short-term thrombocytopenia, such as bone marrow transplantation, and should be started at least 2 weeks before onset of thrombocytopenia (Ghalie et al., 1993).
For Teenagers and Parents
www.youngwomenshealth.org. From Children's Hospital Boston.
www.healthfinder.gov. Government health information finder.
www.kidshealth.org., From Nemours Foundation.
www.nlm.nih.gov, The National Library of Medicine health information site.
http://www.womenshealthchannel.com/dub/index.shtml. From the Women's Health Channel.
For Health Professionals
www.acog.org. American College of Obstetricians and Gynecologists (ACOG).
www.naspag.org, North American Society for Pediatric and Adolescent Gynecology (NASPAG)
http://www.sh.lsuhsc.edu/fammed/OutpatientManual/DUB. htm. From the Family Practice Program, Louisiana State University Health Sciences Center
http://www.aafp.org/afp/991001ap/1371.html. From the American Academy of Family Physicians. Patient information handout provided by link within.
References and Additional Readings
Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993;14: 1823.
Bevan JA, Maloney KW, Hillery CA, et al. Bleeding disorders: a common cause of menorrhagia in adolescents. J Pediatr 2001;138(6):856.
Bravender T, Emans SJ. Menstrual disorders. Dysfunctional uterine bleeding. Pediatr Clin North Am 1999;46(3):545.
Buyukasik Y, Karakus S, Goker H, et al. Rational use of the PFA-100 device for screening of platelet function disorders and von Willebrand disease. Blood Coagul Fibrinolysis 2002; 13:349.
Chiusolo P, Salutari P, Sica S, et al. Luteinizing hormone-releasing hormone analogue: leuprorelin acetate for the prevention of menstrual bleeding in premenopausal women undergoing stem cell transplantation. Bone Marrow Transplant 1998;21:821.
Claessens EA, Cowell CA. Acute adolescent menorrhagia. Am J Obstet Gynecol 1981;139:277.
Cowan BD, Morrison JC. Management of abnormal genital bleeding in girls and women. N Engl J Med 1991;324: 1710.
Emans SJ. Dysfunctional uterine bleeding. In: Emans SJ, Laufer MR, Goldstein DP, eds. Pediatric and adolescent gynecology, 5th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005, 270.
Ghalie R, Porter C, Radwanska E, et al. Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation. Am J Hematol 1993; 42:350.
Iglesias EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Adolesc Med 1999;10:255.
Minjarez DA, Bradshaw KD. Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am 2000;27:63.
Mitan LAP, Slap GB. Adolescent menstrual disorders: update. Med Clin North Am 2000;84:851.
Ragni MV, Bontempo FA, Hassett AC. von Willebrand disease and bleeding in women. Haemophilia 1999;5:313.
Shaw RW. Assessment of medical treatments for menorrhagia. Br J Obstet Gynaecol 1994;101(Suppl 11):15.
Shwayder JM. Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:219.
Winikoff R, Amesse C, James A, et al. The role of haemophilia treatment centres in providing services to women with bleeding disorders. Haemophilia 2004;10(Suppl 4):196.