AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Dysfunctional uterine bleeding (DUB) is classically defined as excessively heavy, prolonged, or frequent bleeding of uterine origin that is not caused by pregnancy or recognizable pelvic or systemic disease.

DUB usually results from disordered functioning of the hypothalamic-pituitary-ovarian (HPO) axis and is often associated with anovulatory cycles. The classic definition has proved less useful because of the current understanding of the pathophysiology of DUB. However, it does highlight the fact that this is a diagnosis of exclusion. DUB occurs most often in women at the extreme ends of their reproductive lifetime. Because perimenarchal women have several anovulatory cycles per year, DUB is a common problem in adolescent females.

The normal menstrual cycle, characterized by sequential growth, maturation, and eventual sloughing of the endometrial mucosa, is produced by the cyclic release of estrogen and progesterone from the ovary. This occurs (orchestrated by the HPO axis) with amazing regularity throughout most of a woman's reproductive lifetime. An understanding of the normal cyclic fluctuations of the 2 gonadotropins (ie, luteinizing hormone [LH], follicle-stimulating hormone [FSH]) and the primary female reproductive hormones (ie, estrogen, progesterone) helps clarify the derangements associated with anovulation.

See Image 1. The first 14 days of a typical 28-day menstrual cycle (day 1 is defined as the first day of menstrual flow) are characterized by rising FSH levels, which stimulate ovarian follicle development and the subsequent production of estrogens (primarily estradiol). Serum progesterone levels are extremely low during this stage. LH levels climb more slowly but abruptly peak on day 12 or 13 in positive response to rising estrogen levels.

During that first 14 days, the endometrium, under the influence of estrogen, undergoes proliferation. The LH surge stimulates ovulation (on or about day 14) and conversion of the ovulatory follicle to a corpus luteum, which is responsible for estrogen and progesterone production. Under the influence of this progesterone, the endometrium is converted to a secretory state in preparation for implantation if fertilization of the ovum should occur. Progesterone is produced only if ovulation occurs. As LH levels drop (assuming fertilization and production of human chorionic gonadotropin [HCG] by the developing conceptus did not occur), the corpus luteum regresses, estrogen and progesterone levels plummet, and the endometrium deteriorates and is sloughed.

The normal cycle is 28-29 days (range 23-39 d) and is fairly consistent from month to month in any given woman. Normal menstrual flow lasts 7 or fewer days and produces an average total blood loss of 25-69 mL. Flow longer than 7 days and blood loss exceeding 80 mL is considered abnormal.

Pathophysiology

With anovulation, estrogen levels rise as usual in the early phase of the cycle. In the absence of ovulation, a corpus luteum never forms and progesterone is not produced. The endometrium moves into a hyperproliferative state, ultimately outgrowing its estrogen supply. This leads to irregular sloughing of the endometrium and excessive bleeding from spiral arteries that have not undergone physiological senescence.

Frequency

United States

The exact incidence of DUB is unknown. The understanding of the epidemiology comes from case series reports from tertiary institutions with patients who are unlikely to reflect the general population. Nearly one half of all women have irregular periods in the first year after menarche, and over one half of the cycles are anovulatory. Irregular periods can persist for up to 5 years after menarche in 20% of women.

International

International rates should reflect those of the United States.

Mortality/Morbidity

The main complication of DUB is anemia.

• Acute blood loss can occasionally lead to a profound anemia. Blood product transfusion (with the attendant risks and complications) is occasionally required.
• Chronic or recurrent DUB can result in an iron-deficient state.
• Blood loss in the healthy adolescent is only rarely of a fatal magnitude.

Race

Race does not seem to contribute significantly to the incidence of DUB.

Age

The average age of menarche in the United States is 12.8 years. Irregular and anovulatory cycles may persist for as long as 1-5 years after the onset of menstrual periods.

CLINICAL

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History

Patients present with unexpected and often heavy vaginal bleeding. Irregular menstrual periods are common during the first few years after menarche. Because dysfunctional uterine bleeding (DUB) is largely a diagnosis of exclusion, exploring the more common and serious conditions on the Differential diagnosis list is prudent.

• Bleeding associated with complications of pregnancy: Consider any woman of reproductive age pregnant until proven otherwise (with a negative pregnancy test result). Frequently, adolescents do not report sexual behavior, and assuming the history may be less than accurate is prudent. Nevertheless, ask the patient about risk factors for pregnancy and about symptoms of pregnancy, including the following:
• • Symptoms of breast tenderness, nausea, urinary frequency, and fatigue
  • Bleeding associated with severe pain or cramping
  • Bleeding associated with the passage of tissue
• Coagulation defects: Depending on the population studied, adolescents with acute menorrhagia could have a 20-30% incidence of a coagulation disorder. Von Willebrand disease, idiopathic thrombocytopenic purpura (ITP), and leukemia are the more common etiologies. Focus questioning on the following:
• • Family history of bleeding disorders
  • Excessive bleeding associated with minor injuries (eg, small cuts, dental procedures), phlebotomy, or their first period
  • Frequent or prolonged nose bleeds
  • Easy bruising, purpura, or petechiae
• Bleeding from an anatomic cause: Anatomic causes of abnormal bleeding can occur anywhere along the female genital tract. Survey the entire organ system with a systematic series of questions, including the following:
• • Recent traumatic intercourse
  • History of sexually transmitted infections, abnormal discharge, or pelvic pain
  • Change in abdominal girth
• Medication-related DUB: Obtain a complete history of recent medication use. Specific medications to look for include use of hormonal contraceptive methods, anticoagulants, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs).
• Polycystic ovarian syndrome (PCOS): PCOS is a common cause of anovulation and oligomenorrhea and should always be considered in the differential diagnosis. Some of the physical manifestations of this syndrome (usually due to elevated androgen levels) can be avoided if the diagnosis is made and treatment is begun at an early stage. Common symptoms include the following:
• • Irregular periods
  • Male-pattern hair growth and/or acne
  • Excessive body weight
  • Infertility
• Systemic disease: These disease states often cause abnormal bleeding through their impact on the HPO axis. Ask the patient about typical symptoms of diabetes or thyroid disease. Additionally, questions aimed at discovering a history suggestive of an eating disorder are important.

Physical

As in the history, focus the physical examination on uncovering signs of the more common or serious items on the Differential diagnosis list.

• General physical examination: A complete examination is always important and should pay special attention to the following:
• • Inadequate or excessive weight gain
  • Physical signs of a bleeding dyscrasia (ie, petechiae or purpura)
  • Physical signs of anemia (ie, pale coloring, dry mucus membranes)
  • Acne and/or hirsutism
  • Thyroid enlargement
  • Tanner breast stage and evidence of nipple discharge
  • A palpable abdominal mass, liver enlargement, and/or splenic enlargement
• Pelvic examination: Perform pelvic examination with careful consideration of the patient's age, sexual history, and use of tampons. Make every effort to make this portion of the examination as comfortable and atraumatic as possible. Considerable psychological damage can result from an examination that is performed in a rushed and insensitive manner. If the practitioner is inexperienced in adolescent pelvic examinations, a review of the proper techniques is in order. If the patient is not sexually active, the bimanual examination may be more comfortable when performed using a single, well-lubricated finger in the rectum rather than in the vagina. Most significant pelvic pathology can be felt in this manner.
• • Tanner stage and distribution of pubic hair
  • Discharge and excoriations suggesting chronic vaginal candidiasis
  • Old or acute vulvar and vaginal lacerations and condition of hymnal ring
  • Retained foreign bodies, such as toilet tissue, tampons, or tampon fragments (These occasionally cause a chronic blood-tinged vaginal discharge.)
  • Microscopic examination of the vaginal discharge, cervical cultures or DNA probe for Neisseria gonorrhoeae and Chlamydia infection, and Papanicolaou test (Pap smear) if indicated by sexual history
  • Evidence of cervical lesions, cervical motion tenderness, or an open cervical os
• Uterine size and any pelvic masses or tenderness

Causes

Anovulation can result from dysfunction in any compartment of the HPO axis. In the pediatric age group, the vast majority of cases can be attributed to an immature axis with acyclic hormonal stimulation of the endometrium. Although anovulatory bleeding can occur in any reproductive-aged female, the following patients may be at greater risk for DUB:

• Adolescents during the first 3-5 years after menarche
• Patients with eating disorders (eg, anorexia nervosa, bulimia)
• Adolescents with a body mass index (BMI) higher than 30
• Morbidly obese women
• Adolescents under significant psychological stress
• Athletes
  

DIFFERENTIALS

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Other Problems to be Considered

Pregnancy complications (eg, threatened abortion, incomplete abortion, missed abortion, ectopic pregnancy, trophoblastic neoplasia)
Thyroid disease
Cervical polyps
Uterine polyps
Exogenous hormones (eg, oral contraceptive pills)
Vaginal trauma or foreign body
Ovarian cysts
Pelvic inflammatory disease

WORKUP

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Lab Studies

• Focus routine laboratory studies to discover common complications and rule out serious medical conditions that can mimic dysfunctional uterine bleeding (DUB).
• • CBC - Useful to reveal anemia, infections, and thrombocytopenia
  • Prothrombin time (PT), activated partial thromboplastin time (aPTT), and bleeding time - For possible blood dyscrasias and clotting disorders
  • Pregnancy test - Must be performed even in patients who deny sexual activity
  • Cervical cultures or DNA probe - To determine existence of chlamydia and gonorrhea, especially if sexual activity is suspected
• Reserve secondary laboratory studies for patients with abnormal bleeding; for patients who are unresponsive to therapy; and for patients with findings on history, physical examination, or laboratory studies suggestive of a systemic disorder.
• • Thyroid-stimulating hormone (TSH) test - As a screening test for thyroid disease
  • Fasting glucose - To rule out occult diabetes
  • Prolactin - To rule out hyperprolactinemia
  • Dehydroepiandrosterone sulfate (DHEAS) and free testosterone - To evaluate for PCOS
  • Bleeding time, ristocetin cofactor - If von Willebrand disease is suspected

Imaging Studies

• Reserve imaging studies for women who do not respond to routine management.
• • Ultrasonography is the method of choice for evaluation of the female pelvis. It is useful for demonstrating structural abnormalities of the uterus and ovarian neoplasms.
  • MRI has adequate resolution but only rarely is superior to ultrasonography and is significantly more expensive.
  • CT scanning is useful for the workup of the rare woman in this age group with a confirmed neoplasm.

Procedures

• Uterine curettage is rarely indicated in the adolescent with DUB. This procedure is usually reserved for women with significant and prolonged hemorrhage unresponsive to medical therapy.
• Diagnostic hysteroscopy can be used to look for structural abnormalities as a cause of persistent DUB.
• Sonohysterography is a less invasive but less accurate method of evaluating the uterine cavity. The procedure consists of injecting fluid into the uterus under ultrasonographic visualization.

Histologic Findings

Endometrial biopsy is rarely required and should be reserved for adolescents with unresponsive uterine bleeding. Endometrial curetting often demonstrates a disordered proliferative pattern without secretory activity (absence of progesterone effect). Findings of endometrial biopsies in patients who are currently receiving hormonal therapy demonstrate the hormonal effects and sometimes interfere with biopsy interpretation.

TREATMENT

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Medical Care

Patients with dysfunctional uterine bleeding (DUB) may present with a chronic light flow in the form of irregular, prolonged, or intermenstrual bleeding that is a nuisance but not a significant health threat. Alternatively, patients with DUB can present with acute torrential hemorrhage requiring immediate medical attention. Tailor management to the condition of the individual patient. For most patients, treatment consists of oral contraceptive pills and iron supplementation. Only patients with acute severe hemorrhage require more intensive therapy. Some authors classify DUB as mild, moderate, or severe based on hemoglobin (Hgb) levels and tailor therapy accordingly.

• Management of light-flow DUB (mild is Hgb >11 g/dL, moderate is Hgb 9-11 g/dL)
• • After obtaining a complete history, performing a physical examination, and obtaining the appropriate laboratory studies, reassure the patient and discuss the usual irregular nature of an adolescent's early menstrual cycles.
  • Offer menstrual regulation in the form of oral contraceptive pills or cyclic progestins if Hgb level is less than 11 mg/dL or if the irregular bleeding has a significant impact on the patient's quality of life.
  • Further workup is indicated only in the case of significant bleeding or when menstrual regulation does not correct the problem.
  • Institute iron therapy if an anemia is detected or if bleeding is persistent. Iron can be offered to any patient after evaluation, according to physician judgment.
• Management of acute DUB (severe is Hgb <9 g/dL)
• • Blood loss often is significant, and may be life threatening. Actively bleeding women who have unstable vital signs need IV access and rapid crystalloid fluid replacement.
  • Because the underlying problem is bleeding from a hyperproliferative endometrium that has outgrown its estrogen supply, the primary therapeutic goal is reestablishment of estrogen supply in the form of high-dose oral or parenteral estrogen. Secondary treatment is aimed at stabilizing the endometrium with exogenous progestin therapy. The physiological response to estrogen is similar, regardless of the route of administration. Therefore, parenteral therapy is reserved for unstable patients or for patients who are unable to tolerate oral medications. Reserve progestin medications alone (such as medroxyprogesterone) for the rare patient with a contraindication to estrogen therapy.
  • Blood product replacement, while infrequently required, is indicated when the patient has persistent heavy bleeding with a low hematocrit or in women with a symptomatic anemia after bleeding has been controlled.

Surgical Care

The rare patient with DUB who does not respond to medical therapy may require endometrial curettage and/or hysteroscopic evaluation. In life-threatening circumstances in which medical therapy is ineffective or contraindicated and future childbearing is not recommended, endometrial ablation or hysterectomy may be the only reasonable alternative.

Consultations

Consultation with a gynecologist (ideally one with expertise in adolescent medicine) is appropriate for any patient with significant bleeding and anemia or when attempts at medical therapy do not resolve the problem. Abnormal laboratory findings should prompt referral to or consultation with an appropriate specialist.

Diet

Teach patients with significant anemia about a diet that is rich in iron and folic acid.

Activity

Limitation of activity is not necessary.

MEDICATION

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Pharmacotherapy is aimed at preventing medical complications of dysfunctional uterine bleeding (DUB).

• Hormone therapy (eg, estrogen, combination estrogen/progestin)
• Antiprostaglandins
• Antifibrinolytics
• Iron supplements

Experimental therapies (eg, gonadotropin-releasing hormone [GnRH] agonists) may have a limited place in the treatment of unresponsive bleeding; however, insufficient evidence currently exists to support their routine use.

Drug Category: Estrogens

Anovulatory bleeding occurs as the hyperproliferative endometrium, lacking a progesterone effect, outgrows its estrogen supply, leading to irregular sloughing. Rapid return of adequate estrogen levels is the quickest way to decrease bleeding. Estrogens alone are primarily used for acute DUB when rapid control of the bleeding is required.

Drug Category: Progestins

Individually, progestins are used to stabilize an estrogen-primed endometrium and are administered in a cyclic fashion. Because the pathophysiology of DUB is based on a relative estrogen deficiency, progestins alone should not be the first-line treatment for acute bleeding. Progestins should be administered along with estrogens, and this combination is discussed under PO contraceptive pills.

Continuous use of high-dose progestins, orally or in a depot form, can induce endometrial atrophy and amenorrhea. This approach is useful for preventing future blood loss while correcting a significant anemia or when combination contraceptive pills do not achieve adequate control of bleeding.

Drug Name	Norethindrone (Aygestin, Micronor)
Description	Administered PO in a cyclic or continuous fashion. When managing acute and heavy uterine bleeding, should be administered concurrently with estrogen. Progestins alone do not address the underlying pathophysiology of a hyperproliferative endometrium that has outgrown its estrogen supply.
Adult Dose	2.5-10 mg PO qd for the last 12-14 d of each cycle (start on day 14 or 16 of a typical 28-d cycle) 5 PO qd continuously to induce amenorrhea initially; increase by 2.5-5 mg/d q2wk until bleeding stops; not to exceed 15 mg/d
Pediatric Dose	For menstruating adolescents: Administer as in adults
Contraindications	Documented hypersensitivity; pregnancy of any type; breast cancer; vaginal bleeding (prior to an adequate workup); while the package insert lists thromboembolic disease as a contraindication, scientific evidence to back this claim is lacking
Interactions	Rifampin may decrease effect
Pregnancy	X - Contraindicated in pregnancy
Precautions	Advise patients about increased weight gain and fluid retention; some patients report increasing symptoms of depression, headache, and acne; caution in active liver disease

Drug Category: Oral contraceptive agents

These agents provide convenient method of rapidly delivering high-dose combination of estrogen and progestin. The monophasic preparations offer the best opportunity for creating a stable endocrine environment. Most of the modern products contain 20, 30, or 35 mcg of ethinyl estradiol in combination with norethindrone or one of the second- or third-generation progestins. For all practical purposes, they are essentially equivalent.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

Studies have demonstrated a prostaglandin imbalance in women with menorrhagia and a reduction in menstrual flow with administration of NSAIDs. Several drugs in this category should have similar efficacy.

Drug Category: Antifibrinolytic agents

These agents inhibit fibrinolysis via inhibition of plasminogen activator substances, to a lesser degree, through antiplasmin activity.

Drug Category: Iron salts

These are used to replenish iron stores lost during acute or chronic hemorrhage. The body stores iron in compounds called ferritin and hemosiderin for future use in the production of hemoglobin. Iron absorption is a variable of the existing body iron stores, the form and quantity in foods, and the combination of foods in the diet. The ferrous form of inorganic iron is more readily absorbed.

FOLLOW-UP

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Further Inpatient Care

• Patients require admission for acute poorly controlled bleeding that results in severe symptomatic anemia. Consider transfusion of packed red blood cells for these patients.

Further Outpatient Care

• Consider long-term (6 mo minimum) suppression of the HPO axis in patients with bleeding that results in significant anemia. Mild anemia responds rapidly to once-a-day oral iron supplementation. Iron supplements that are taken 2 or 3 times per day lead to constipation with subsequent noncompliance and should be avoided in most patients.

Deterrence/Prevention

• Place patients with a history of dysfunctional uterine bleeding (DUB) and no desire for attempting conception on oral contraceptive pills or cyclic progestins for cycle control.

Complications

• Complications are related to acute or chronic blood loss and the resulting anemia. Observe patients who receive blood products for the usual transfusion-related complications of acute hemolytic reactions, bacterial sepsis, and viral infections.

Prognosis

• Adolescents with DUB have an excellent prognosis and most outgrow the problem within 3-5 years of menarche.
• Patients on OCPs rarely have recurrent episodes of DUB.
• For patients with DUB related to systemic disease, prognosis depends upon the underlying illness.

Patient Education

• Instruct the patient and her parents about the normal menstrual cycle and the generally benign nature of DUB. Advise them to return if bleeding is recurrent or does not respond to medical therapy.
• For excellent patient education resources, visit eMedicine's Women's Health Center and Blood and Lymphatic System Center. Also, see eMedicine's patient education articles Vaginal Bleeding, Amenorrhea, Anemia, and Mittelschmerz.

MISCELLANEOUS

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Medical/Legal Pitfalls

• While most cases of dysfunctional uterine bleeding (DUB) are the result of an immature HPO axis, significant medical problems can have a similar presentation. Adequate follow-up and evaluation of patients who do not respond to medical management is essential.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  The menstrual cycle.
	View Full Size Image
Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
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• ACOG. Dysfunctional Uterine Bleeding. ACOG Technical Bulletin. 134:1989.
• Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA. Apr 14 1993;269(14):1823-8. [Medline].
• Bravender T, Emans SJ. Menstrual disorders. Dysfunctional uterine bleeding. Pediatr Clin North Am. Jun 1999;46(3):545-53, viii. [Medline].
• Coupey SM, Ahlstrom P. Common menstrual disorders. Pediatr Clin North Am. Jun 1989;36(3):551-71. [Medline].
• Lavin C. Dysfunctional uterine bleeding in adolescents. Curr Opin Pediatr. Aug 1996;8(4):328-32. [Medline].
• Minjarez DA, Bradshaw KD. Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am. Mar 2000;27(1):63-78. [Medline].
• Stabinsky SA, Einstein M, Breen JL. Modern treatments of menorrhagia attributable to dysfunctional uterine bleeding. Obstet Gynecol Surv. Jan 1999;54(1):61-72. [Medline].
• Strickland J, Gibson EJ, Levine SB. Dysfunctional uterine bleeding in adolescents. J Pediatr Adolesc Gynecol. Feb 2006;19(1):49-51. [Medline].

Article Last Updated: May 22, 2006