You are in: eMedicine Specialties > Pediatrics: Surgery > Gynecology Dysfunctional Uterine BleedingArticle Last Updated: May 22, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Tod C Aeby, MD, Generalist Division Director, Assistant Professor, Department of Obstetrics, Gynecology and Women's Health, University of Hawaii, John A Burns School of Medicine Tod C Aeby is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, and Hawaii Medical Association Coauthor(s): LeighAnn C Frattarelli, MD, Assistant Professor, Department of Obstetrics and Gynecology and Women's Health, University of Hawaii, John A. Burns School of Medicine Editors: Elizabeth Alderman, MD, Director of Fellowship Training Program, Director, Adolescent Ambulatory Service, Clinical Professor, Department of Pediatrics, Division of Adolescent Medicine, Albert Einstein College of Medicine and Montefiore Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Wayne Wolfram, MD, MPH, Clinical Associate Professor, Departments of Pediatrics, Children's Hospital and University of Cincinnati; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Maureen Strafford, MD, Arnold P Gold Foundation Associate Professor, Departments of Anesthesiology and Pediatrics, Tufts University and Tufts-New England Medical Center Author and Editor Disclosure Synonyms and related keywords: dysfunctional uterine bleeding, anovulatory bleeding, DUB, immature hypothalamic-pituitary-ovarian axis, immature HPO axis INTRODUCTIONSection 2 of 11
  BackgroundDysfunctional 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. PathophysiologyWith 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. FrequencyUnited StatesThe 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. InternationalInternational rates should reflect those of the United States. Mortality/MorbidityThe main complication of DUB is anemia.
RaceRace does not seem to contribute significantly to the incidence of DUB. AgeThe 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. CLINICALSection 3 of 11
HistoryPatients 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.
PhysicalAs in the history, focus the physical examination on uncovering signs of the more common or serious items on the Differential diagnosis list.
CausesAnovulation 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:
DIFFERENTIALSSection 4 of 11
Cervicitis Child Abuse & Neglect: Sexual Abuse Chlamydial Infections Endometritis Gonorrhea Hemophilia A and B Hemophilia C Menstruation Disorders Precocious Pseudopuberty Thrombocytopenia-Absent Radius Syndrome Trichomoniasis Von Willebrand Disease
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| Drug Name | Estrogen, conjugated (Premarin) |
|---|---|
| Description | Administered PO, IM, or IV. Studies have demonstrated that similar blood levels are achieved at the same rate by any route. Parenteral therapy is reserved for patients who are unable to tolerate PO intake. Equivalent doses of other forms of estrogen (eg, estradiol, esterified estrogens, ethinyl estradiol, estropipate) are likely to be equally effective although clinical studies are lacking. Only the conjugated estrogens are approved by the FDA for this indication. |
| Adult Dose | 0.625-3.75 mg PO, repeat q6-24h, depending on the severity of bleeding and the patient's response; alternatively, 25 mg IV/IM as a single dose, may repeat q6-12h prn |
| Pediatric Dose | For menstruating adolescents: Administer as in adults |
| Contraindications | Documented hypersensitivity; known or suspected pregnancy; estrogen-dependent cancers; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use |
| Interactions | May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic CYP450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Long-term use of this medication can lead to an increased risk of thromboembolism; prolonged use, without progestin opposition, increases the risk of endometrial hyperplasia and adenocarcinoma of the endometrium; caution in hepatic dysfunction |
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 | Medroxyprogesterone (Amen, Provera, Depo-Provera) |
|---|---|
| Description | May be administered PO, in a cyclic or continuous fashion, or as a parenteral depot formulation. When managing acute and heavy uterine bleeding, should be administered concurrently with an estrogen preparation. Progestins alone do not address the underlying pathophysiology of a hyperproliferative endometrium that has outgrown its estrogen supply. |
| Adult Dose | 5-10 mg PO qd during the last 12-14 d of each cycle (start on day 14 or 16 of a typical 28-d cycle) 10-30 mg PO qd (ie, on a continuous basis) to induce amenorrhea Depot formulation: 150-300 mg IM q1-3mo to induce amenorrhea |
| 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 | May decrease effects of aminoglutethimide |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Advise patients about increased weight gain and fluid retention, may aggravate existing condition; may cause depression, headache, and acne; caution in active liver disease |
| 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 |
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 Name | Ethinyl estradiol and desogestrel (Desogen) |
|---|---|
| Description | This is one example of an OCP preparation. When treating light-flow irregular bleeding, OCPs are administered in the usual contraceptive fashion (ie, 1 tab PO qd for 21 d of a typical 28-d cycle). Treatment of acute heavy uterine bleeding, multiple tab are administered PO each day and then tapered once the heavy flow has ceased. If significant anemia is present, the placebo phase (ie, days 22-28) may be omitted for several mo. |
| Adult Dose | Menstrual regulation: 1 tab PO qd; initiate on either the first day of flow or the first Sunday after starting menses Acute DUB (regimen 1): 1 tab PO bid until bleeding stops, then qd to complete the cycle pack Acute DUB (regimen 2): 4 tab PO qd for 4 d, 3 tab PO qd for 3 d, 2 tab PO qd for 2 d, then 1 tab PO qd to complete a second pack (remove placebo tab [if applicable] from the cycle pack to avoid confusion) |
| Pediatric Dose | For menstruating adolescents: Administer as in adults |
| Contraindications | Prepubertal girls; pregnancy; undiagnosed vaginal bleeding; known hormonally sensitive cancers; active liver disease; history of thromboembolic disorders; use with caution in women with a family history of thromboembolic disorders |
| Interactions | May interact with barbiturates, carbamazepine, griseofulvin, penicillins, phenytoin, protease inhibitors, rifampin, tetracyclines, and troglitazone |
| Pregnancy | X - Contraindicated in pregnancy |
| Precautions | Monitor for increased blood pressure and thromboembolic disease; use with caution in women with a family history of thromboembolic disorders; multidose regimens may cause significant nausea and vomiting; consider prescribing appropriate antiemetic |
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 Name | Ibuprofen (Motrin, Ibuprin) |
|---|---|
| Description | A classic example of this category of medications. For best efficacy, start the NSAID prior to the onset of flow. Have analgesic, anti-inflammatory, and antipyretic activities. Mechanism of action is nonselective inhibition of cyclooxygenases 1 and 2, resulting in reduced synthesis of prostaglandins and thromboxanes. |
| Adult Dose | 400 mg PO q4-6h continuously during menses; not to exceed 3200 mg/d |
| Pediatric Dose | For menstruating adolescents: Administer as in adults |
| Contraindications | Documented hypersensitivity; aspirin- or NSAID-induced asthma; history of gastrointestinal bleeding |
| Interactions | May decrease effects of loop diuretics; coadministration of anticoagulants may increase PT (monitor and watch for signs of bleeding); may increase serum lithium levels and risk of methotrexate toxicity; probenecid may increase toxicity of NSAIDs |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, decreased renal and hepatic function, anticoagulation abnormalities, or during anticoagulant therapy; adjust dose in renal insufficiency; use with caution in patients with nasal polyps; caution patient regarding GI toxicity |
These agents inhibit fibrinolysis via inhibition of plasminogen activator substances, to a lesser degree, through antiplasmin activity.
| Drug Name | Aminocaproic acid (Amicar) |
|---|---|
| Description | Used for acute heavy uterine bleeding in patients with increased fibrinolytic activity. Discontinued once bleeding has stopped. |
| Adult Dose | Oral: 4-5 g PO over first hour, followed by 1 g/h until bleeding stops; not to exceed 30 g/d Intravenous: 4-5 g IV over first hour, then continuous IV infusion of 1 g/h for approximately 8 h or until bleeding is controlled |
| Pediatric Dose | For menstruating adolescents: Administer as in adults |
| Contraindications | Documented hypersensitivity; evidence of active intravascular clotting process; because aminocaproic acid can be fatal in patients with disseminated intravascular coagulation (DIC), differentiating between hyperfibrinolysis and DIC is important |
| Interactions | Coadministration with estrogens may cause increase in clotting factors, leading to a hypercoagulable state |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Avoid rapid infusion, which may cause hypotension, bradycardia, and/or arrhythmias; use with caution in patients with renal or hepatic insufficiency; do not administer unless a definite diagnosis of hyperfibrinolysis has been made |
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.
| Drug Name | Ferrous sulfate (Feosol, Slow FE, Feostat) |
|---|---|
| Description | This is the most common medication for iron therapy though several other formulations are available. |
| Adult Dose | 325 mg PO qd |
| Pediatric Dose | For menstruating adolescents: Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | Absorption is enhanced by ascorbic acid; interferes with tetracycline absorption; food and antacids impair absorption |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Gastrointestinal upset; iron toxicity is observed with ingestion of large amount and can be fatal, especially in children |
| Media file 1: The menstrual cycle. | |
 | View Full Size Image | Media type: Graph |
Dysfunctional Uterine Bleeding excerpt
Article Last Updated: May 22, 2006
