eMedicine Specialties > Obstetrics and Gynecology > Reproductive Endocrinology and Infertility

Dysfunctional Uterine Bleeding

Millie A Behera, MD, Assistant Professor, Director of Clinical Research, Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center
Thomas Michael Price, MD, Associate Professor of Reproductive Endocrinology, Director of Reproductive Fellowship Training Program, Duke University Medical Center

Updated: Jun 11, 2009

Introduction

Background

Dysfunctional uterine bleeding (DUB) is irregular uterine bleeding that occurs in the absence of pathology or medical illness. It reflects a disruption in the normal cyclic pattern of ovulatory hormonal stimulation to the endometrial lining. The bleeding is unpredictable in many ways. It might be excessively heavy or light, prolonged, frequent, or random.

This condition usually is associated with anovulatory menstrual cycles but also can present in patients with oligo-ovulation. DUB occurs without recognizable pelvic pathology, general medical disease, or pregnancy. It is considered a diagnosis of exclusion.

Pathophysiology

Patients with dysfunctional uterine bleeding (DUB) have lost cyclic endometrial stimulation that arises from the ovulatory cycle. As a result, these patients have constant, noncycling estrogen levels that stimulate endometrial growth. Proliferation without periodic shedding causes the endometrium to outgrow its blood supply. The tissue breaks down and sloughs from the uterus. Subsequent healing of the endometrium is irregular and dyssynchronous.

Chronic stimulation by low levels of estrogen will result in infrequent, light DUB. Chronic stimulation from higher levels of estrogen will lead to episodes of frequent, heavy bleeding.

Frequency

United States

Dysfunctional uterine bleeding is a common diagnosis, making up 5-10% of cases in the outpatient clinic setting.

Mortality/Morbidity

Single episodes of anovulatory bleeding generally carry a good prognosis.

Patients who experience repetitive episodes might experience significant consequences. Frequent uterine bleeding will increase the risk for iron deficiency anemia. Flow can be copious enough to require hospitalization for fluid management, transfusion, or intravenous hormone therapy. Chronic unopposed estrogenic stimulation of the endometrial lining increases the risk of both endometrial hyperplasia and endometrial carcinoma. Timely and appropriate management will prevent most of these problems.

Many individuals with dysfunctional uterine bleeding are exposed to unnecessary surgical intervention, such as repeated uterine curettage, endometrial ablative therapy, or hysterectomy, before adequate workup and a trial of medical therapy can be completed.

• Iron deficiency anemia: Persistent menstrual disturbances might lead to chronic iron loss in up to 30% of cases. Adolescents might be particularly vulnerable. Up to 20% of patients in this age group presenting with menorrhagia might have a disorder of hemostasis.
• Endometrial adenocarcinoma: About 1-2% of women with improperly managed anovulatory bleeding eventually might develop endometrial cancer.
• Infertility associated with chronic anovulation, with or without excess androgen production, is frequently seen in these patients. Patients with polycystic ovarian syndrome, obesity, chronic hypertension, and insulin-resistant diabetes mellitus particularly are at risk.

Sex

The condition only affects females.

Age

Because most cases are associated with anovulatory menstrual cycles, adolescents and perimenopausal women are particularly vulnerable. About 20% of affected individuals are in the adolescent age group, and 50% of affected individuals are aged 40-50 years.

Clinical

History

• Suspect dysfunctional uterine bleeding (DUB) when a patient presents with unpredictable or episodic heavy or light bleeding despite a normal pelvic examination.
  • Typically, the usual moliminal symptoms that accompany ovulatory cycles will not precede bleeding episodes.
  • Exclude the diagnosis of pregnancy first.
  • Address the presence of local and systemic disease. Rule out the presence of signs or symptoms indicative of bleeding disorders. Screening for personal and family history of easy bruising, bleeding gums, epistaxis, and excessive bleeding episodes during childbirth, surgery, or dental procedures may be useful.
  • Rule out iatrogenic causes of bleeding, including bleeding secondary to steroid hormone contraception, hormone replacement therapy, or other hormone treatments, which are common causes.
  • Most patients are adolescents or are older than 40 years.
• Patients who report irregular menses since menarche may have polycystic ovarian syndrome (PCOS). PCOS is characterized by anovulation or oligo-ovulation and hyperandrogenism. These patients often present with unpredictable cycles and/or infertility, hirsutism with or without hyperinsulinemia, and obesity.
• Patients with adrenal enzyme defects, hyperprolactinemia, thyroid disease, or other metabolic disorders also might present with anovulatory bleeding.

Physical

The physical examination can elicit several anatomic and organic causes of abnormal uterine bleeding.

• A complete physical examination should begin with assessment of hemodynamic stability (vital signs) and proceed with evaluation of the following:
  • Obesity (BMI)
  • Signs of androgen excess (hirsutism, acne)
  • Thyroid enlargement or manifestations of hyperthyroidism or hypothyroidism.
  • Galactorrhea (may suggest hyperprolactinemia)
  • Visual field deficits (raise suspicion of intracranial/pituitary lesion)
  • Ecchymosis, purpura (signs of bleeding disorder)
  • Signs of anemia or chronic blood loss
• A careful gynecologic examination, including Papanicolaou test (Pap smear) and sexually transmitted disease (STD) screening, is warranted.
• The hallmark of DUB is a negative pelvic examination despite the clinical history. In such cases, management might rest on a clinical diagnosis.
  • Rule out the presence of uterine fibroids or polyps.
  • Rule out endometrial hyperplasia or carcinoma.

Causes

In ovulatory cycles, progesterone production from the corpus luteum converts estrogen primed proliferative endometrium to secretory endometrium, which sloughs predictably in a cyclic fashion if pregnancy does not occur. Heavy but regular uterine bleeding implies ovulatory bleeding and should not be diagnosed as DUB. Subtle disturbances in endometrial tissue mechanisms, other forms of uterine pathology, or systemic causes might be implicated.

Anovulatory cycles are associated with a variety of bleeding manifestations. Estrogen withdrawal bleeding and estrogen breakthrough bleeding are the most common spontaneous patterns encountered in clinical practice. Iatrogenically induced anovulatory uterine bleeding might occur during treatment with oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy.

• Estrogen breakthrough bleeding
  • Anovulatory cycles have no corpus luteal formation. Progesterone is not produced. The endometrium continues to proliferate under the influence of unopposed estrogen.
  • Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy. This pattern is known as estrogen breakthrough bleeding and occurs in the absence of estrogen decline.
• Estrogen withdrawal bleeding
  • This frequently occurs in women approaching the end of reproductive life.
  • In older women, the mean length of menstrual cycle is shortened significantly due to aberrant follicular recruitment, resulting in a shortened proliferative phase. Ovarian follicles in these women secrete less estradiol. Fluctuating estradiol levels might lead to insufficient endometrial proliferation with irregular menstrual shedding. This bleeding might be experienced as light, irregular spotting.
  • Eventually, the duration of the luteal phase shortens, and, finally, ovulation stops. Dyssynchronous endometrial histology with irregular menstrual shedding and eventual amenorrhea result.
• Oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy
  • Treatment with oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy might be associated with iatrogenically induced uterine bleeding.
  • Progesterone breakthrough bleeding occurs in the presence of an unfavorably high ratio of progestin to estrogen.
  • Intermittent bleeding of variable duration can occur with progestin-only oral contraceptives, depo-medroxyprogesterone, and depo-levonorgestrel.
  • Progesterone withdrawal bleeding can occur if the endometrium initially has been primed with endogenous or exogenous estrogen, exposed to progestin, and then withdrawn from progestin. Such a pattern is seen in cyclic hormonal replacement therapy.
• Adolescents
  • The primary defect in the anovulatory bleeding of adolescents is failure to mount an ovulatory luteinizing hormone (LH) surge in response to rising estradiol levels. Failure occurs secondary to delayed maturation of the hypothalamic-pituitary axis. Because a corpus luteum is not formed, progesterone levels remain low.
  • The existing estrogen primed endometrium does not become secretory. Instead, the endometrium continues to proliferate under the influence of unopposed estrogen. Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy, such as that seen in estrogen breakthrough bleeding.
• Climacteric
  • Anovulatory bleeding in menopausal transition is related to declining ovarian follicular function.
  • Estradiol levels will vary with the quality and state of follicular recruitment and growth.
  • Bleeding might be light or heavy depending on the individual cycle response.
• Bleeding disorders: An international expert panel including obstetrician/gynecologists and hematologists has issued guidelines to assist physicians in better recognizing bleeding disorders, such as von Willebrand disease, as a cause of menorrhagia and postpartum hemorrhage and to provide disease-specific therapy for the bleeding disorder.¹ Historically, a lack of awareness of underlying bleeding disorders has led to underdiagnosis in women with abnormal reproductive tract bleeding. The panel provided expert consensus recommendations on how to identify, confirm, and manage a bleeding disorder. An underlying bleeding disorder should be considered when a patient has any of the following: 
  • Menorrhagia since menarche
  • Family history of bleeding disorders
  • Personal history of 1 or more of the following:
    • Notable bruising without known injury
    • Bleeding of oral cavity or gastrointestinal tract without obvious lesion
    • Epistaxis greater than 10 minutes duration (possibly necessitating packing or cautery)
  • If a bleeding disorder is suspected, consultation with a hematologist is suggested.

Differential Diagnoses

Other Problems to Be Considered

Adenomyosis
Endometrial polyps
Submucous leiomyomata (fibroids)
Surface lesions of the genital tract
Uterine sarcoma

Various coagulopathies

Metabolic conditions associated with reduced estrogen metabolism
Chronic hepatic disease
Chronic renal failure
Congestive heart failure

Other pregnancy related conditions such as ectopic pregnancy

Iatrogenic causes
Adrenal steroids
Anticoagulants
Aspirin
Estrogen replacement therapy
Ginseng use
Intrauterine devices (IUDs)
Progestins
Psychotropic medications
Steroid contraceptives
Tranquilizers affecting neurotransmission

Workup

Laboratory Studies

Laboratory studies for patients with dysfunctional uterine bleeding (DUB) include human chorionic gonadotropin (HCG), complete blood count (CBC), Pap smear, endometrial sampling, thyroid functions and prolactin, liver functions, coagulation studies/factors, and other hormone assays as indicated.

• Human chorionic gonadotropin
  • The most common cause of abnormal uterine bleeding during the reproductive years is abnormal pregnancy.
  • Rule out threatened abortion, incomplete abortion, and ectopic pregnancy.
• Complete blood count
  • Document blood loss. Charting the number of menstrual pads used per day or keeping a menstrual calendar is helpful.
  • When in doubt, obtain a baseline CBC count for hemoglobin and hematocrit.
  • Rule out anemia.
  • Obtain a differential with platelet count if hematologic disease is suspected.
• Pap smear should be up to date. Cervical cancer still is the most common gynecologic cancer affecting women of reproductive age in the world population.
• Endometrial sampling
  • Perform a biopsy to rule out endometrial hyperplasia or cancer in high-risk women >35 years and in younger women at extreme risk for endometrial hyperplasia/carcinoma. Women with chronic eugonadal anovulation, obesity, hirsutism, diabetes, or chronic hypertension are at particular risk.
  • Most biopsies will confirm the absence of secretory endometrium.
• Perform thyroid function tests and prolactin because hyperthyroidism, hypothyroidism, and hyperprolactinemia are associated with ovulatory dysfunction. Identify and treat these conditions.
• Obtain liver function tests if alcoholism or hepatitis is suspected. Any condition affecting liver metabolism of estrogen can be associated with abnormal uterine bleeding.
• Coagulation factors
  • Von Willebrand disease and factor XI deficiency initially might manifest during adolescence.
  • Primary or secondary thrombocytopenia can be factors in the mature patient.
  • Tailor the choice of laboratory tests to the presenting clinical situation. Generally speaking, when coagulopathies are present, heavy bleeding is regular (menorrhagia) and associated with ovulation.
• Other hormone assays as indicated
  • For the patient with recurrent anovulatory bleeding, the mainstay of management is treatment of correctable disease.
  • Obtain a hormonal complete evaluation in women with signs of hyperandrogenism, such as those with polycystic ovarian syndrome, 21 hydroxylase deficiency, or ovarian or adrenal tumors, as dictated by their respective conditions.
  • Women in menopausal transition usually can be followed without an extensive hormonal evaluation.

Imaging Studies

• Generally, patients with DUB can be managed appropriately without the use of expensive imaging studies.
• In obese patients with suboptimal pelvic examination or in patients with suspected ovarian or uterine pathology, pelvic ultrasonographic evaluation might be helpful.
• Ultrasound can be used to examine the status of the endometrium. Endometrial hyperplasia, endometrial carcinoma, endometrial polyps, and uterine fibroids can be identified easily by this technology.

Procedures

• Rule out endometrial carcinoma in all patients at high risk for the condition, including patients with the following characteristics:
  • Morbid obesity
  • Diabetes or chronic hypertension
  • Age >35 years
  • Longstanding, chronic eugonadal anovulation
• Traditionally, carcinoma was ruled out by endometrial sampling via dilation and curettage (D&C). More recently, endometrial sampling in the office via aspiration, curetting, or hysteroscopy has become popular and is also relatively accurate.
• Real-time ultrasound measurement and evaluation of the endometrial stripe can be helpful in distinguishing individuals bleeding with thick endometrium from those with thin, denuded endometrium, endometrial polyps, uterine fibroids, or other uterine pathology.
• Saline-infusion sonohysterography is also very useful in evaluating for intracavitary (submucosal) fibroids and endometrial polyps.

Histologic Findings

Most endometrial biopsy specimens will show proliferative or dyssynchronous endometrium.

Treatment

Medical Care

Options for medical care of dysfunctional uterine bleeding are as follows.

• Oral contraceptives
  • Oral contraceptive pills (OCPs) suppress endometrial development, reestablish predictable bleeding patterns, decrease menstrual flow, and lower the risk of iron deficiency anemia.
  • Acute episodes of heavy bleeding suggest an environment of prolonged estrogenic exposure and buildup of the lining.
  • Bleeding usually is controlled within the first 24 hours, as the overgrown endometrium becomes pseudodecidualized. Seek alternate diagnosis if flow fails to abate in 24 hours.
• Estrogen
  • Estrogen alone, in high doses, is indicated in certain clinical situations.
  • Prolonged uterine bleeding suggests the epithelial lining of the cavity has become denuded over time. In this setting, a progestin is unlikely to control bleeding. Estrogen alone will induce return to normal endometrial growth rapidly.
  • Hemorrhagic uterine bleeding requires high-dose estrogen therapy. If bleeding is not controlled within 12-24 hours, a D&C is indicated.
  • Beginning progestin therapy shortly after initiating estrogen therapy to prevent a subsequent bleeding episode from treatment with prolonged unopposed estrogen is wise.
• Progestins
  • Chronic management of DUB requires episodic or continuous exposure to a progestin. In patients without contraindications, this is best accomplished with an oral contraceptive given the many additional benefits, including decreased dysmenorrhea, decreased blood loss, ovarian cancer prophylaxis, and decreased androgens.
  • In patients with a pill contraindication, cyclic progestin for 12 days per month using medroxyprogesterone acetate (10 mg/d) or norethindrone acetate (2.5-5 mg/d) provides predictable uterine withdrawal bleeding, but not contraception. Cyclic natural progesterone (200 mg/d) may be used in women susceptible to pregnancy, but may cause more drowsiness and does not decrease blood loss as much as a progestin.
  • In some women, including those who are unable to tolerate systemic progestins/progesterone, a progestin secreting IUD may be considered that controls the endometrium via a local release of levonorgestrel, avoiding systemic levels.
• On rare occasions, a young patient with anovulatory bleeding also might have a bleeding disorder. Desmopressin, a synthetic analog of arginine vasopressin, has been used as a last resort to treat abnormal uterine bleeding in patients with documented coagulation disorders. Treatment is followed by a rapid increase in von Willebrand factor and factor VIII, which lasts about 6 hours.

Surgical Care

Most cases of DUB can be treated medically. Surgical measures are reserved for situations when medical therapy has failed or is contraindicated.

• D&C is an appropriate diagnostic step in a patient who fails to respond to hormonal management.
  • The addition of hysteroscopy will aid in the treatment of endometrial polyps or the performance of directed uterine biopsies.
  • As a rule, apply D&C rarely for therapeutic use in DUB because it has not been shown to be very efficacious.
• Abdominal or vaginal hysterectomy might be necessary in patients who have failed or declined hormonal therapy, have symptomatic anemia, and who experience a disruption in their quality of life from persistent, unscheduled bleeding.
• Endometrial ablation is an alternative for those who wish to avoid hysterectomy or who are not candidates for major surgery.
  • Ablation techniques are varied and can employ laser, rollerball, resectoscope, or thermal destructive modalities. Most of these procedures are associated with high patient satisfaction rates.
  • Pretreat the patient with an agent, such as leuprolide acetate, medroxyprogesterone acetate, or danazol, to thin the endometrium.
  • The ablation procedure is more conservative than hysterectomy and has a shorter recovery time.
  • Some patients may have persistent bleeding and require repeat procedures or move on to hysterectomy. Rebleeding following ablation has raised concern about the possibility of an occult endometrial cancer developing within a pocket of active endometrium. Few reported cases exist, but further studies are needed to quantify this risk.
  • Endometrial ablation is not a form of contraception. Some studies report up to a 5% pregnancy rate in postablation procedures.

Medication

Estrogens, progestins, androgens, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, antifibrinolytics, and gonadotropin-releasing hormone (GnRH) agonists have been used to treat dysfunctional uterine bleeding (DUB). More recently, desmopressin has been used to control bleeding when associated with diagnosed bleeding disorders that do not respond entirely to traditional management.

Ergot derivatives are not recommended for treatment of DUB because they have been shown to be effective rarely in clinical studies and have many side effects.

At the onset of menses, secretory endometrium contains a high concentration of plasminogen activator. A reduction in menstrual blood loss has been demonstrated in some ovulatory patients taking e -aminocaproic acid (EACA) or aminomethylcyclohexane-carboxylic acid (AMCHA) tranexamic acid, both potent antifibrinolytics. However, this therapeutic effect was no greater than that seen with oral contraceptive therapy. Antifibrinolytics are associated with significant side effects, such as severe nausea, diarrhea, headache, and allergic manifestations, and cannot be used in patients with renal failure. Because of the high side-effect profile and expense, these agents rarely are used today for this indication.

Estrogens

Very effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood, as well as platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Most DUB is secondary to anovulation. In these patients, endometrium continues to proliferate with asynchronous development. As blood supply is outgrown, irregular shedding occurs. Bleeding might be controlled acutely with high-dose estrogen for a short period of time. Several hours are required to induce mitotic activity, so most regimens require 48 h of therapy before continued bleeding is ruled a treatment failure.

Estrogen therapy only controls bleeding acutely and does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.

Conjugated equine estrogen (Premarin)

Women in perimenopause generally are estrogen deficient and might experience bouts of estrogen withdrawal bleeding. Many of these patients will recover regular menses and develop an improved sense of well-being with the initiation of hormonal replacement therapy, including estrogen and a progestin.

Dosing

Adult

Acute hemorrhagic episode: 2.5 mg PO q6h or 25 mg IV q4h for 48 h; followed by addition of a progestin when acute bleeding stops
Chronic anovulatory bleeding in perimenopause: 0.625-1.250 mg/d PO for 1 mo; add a progestin for 10-12 d/mo

Pediatric

Not established

Interactions

Might reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes might reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids might occur as a result of estrogen-induced inactivation of hepatic P450 enzyme; loss of seizure control has been noted with concurrent administration of hydantoins

Contraindications

Documented hypersensitivity; known or suspected pregnancy; breast cancer; undiagnosed abnormal genital bleeding; active thrombophlebitis or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use, except when used in treatment of breast malignancy (or prostatic malignancy in males)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding, mastodynia) might develop; might cause some degree of fluid retention (exercise caution); prolonged unopposed estrogen therapy might increase risk of endometrial hyperplasia

Progestins

Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins. Progestins inhibit estrogen receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less active estrone. Medroxyprogesterone acetate (Provera) is the most commonly used progestin in this country, but other types, including norethindrone acetate (Aygestin) and norethindrone (Micronor), are equally efficacious. In some patients in which systemic progestins are intolerable due to side effects, a progestin secreting IUD (Mirena) may be considered.

Synthetic progestins have an antimitotic effect, allowing the endometrium to become atrophic if administered continuously. These drugs are very effective in cases of endometrial hyperplasia. In patients with chronic eugonadal anovulation who do not desire pregnancy, treatment with a progestin for 10-12 d/mo will allow for controlled, predictable menses and will protect the patient against the development of endometrial hyperplasia.

Some perimenopausal patients will not respond well to progestin therapy because of an inherent estrogen deficiency. Also, patients with thin, denuded endometrium occurring after several days of chronic bleeding might require induction of new endometrial proliferation by estrogen therapy first.

Avoid synthetic progestins in early pregnancy. They induce an endometrial response that is different from normal preimplantation secretory endometrium. Also, several reports suggest an association between intrauterine exposure to synthetic progestins in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5-8 per 1000 male births, might be doubled with early in-utero exposure to these drugs. Some synthetic progestins might cause virilization of female external genitalia in utero.

Patients at risk for conception can be treated safely with natural progesterone preparations. These preparations induce a normal secretory endometrium appropriate for implantation and subsequent growth of a developing conceptus.

Medroxyprogesterone acetate (Provera)

Short-acting synthetic progestin. Drug of choice for patients with anovulatory DUB. After acute bleeding episode is controlled, can be used alone in patients with adequate amounts of endogenous estrogen to cause endometrial growth. Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until positive feedback system matures.
Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Dosing

Adult

10 mg/d PO for 10-12 d/mo

Pediatric

Not established

Interactions

Might decrease effects of aminoglutethimide

Contraindications

Documented hypersensitivity; cerebral apoplexy; undiagnosed vaginal bleeding; thrombophlebitis; liver dysfunction; missed abortion; known or suspected malignancy of breast or genital tract; active or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy (based on past experience with combination oral contraceptive medications; little data suggests that progestin therapy used without estrogen is associated with an increased risk of thrombotic events)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in asthma, depression, renal or cardiac dysfunction, or thromboembolic disorders; perform complete physical examination, document recent Pap smear, and take family history prior to therapy; give special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical annually; progestins can cause fluid retention (address any condition aggravated by this factor); monitor patients with epilepsy, migraine, asthma, renal or cardiac dysfunction, and history of psychic depression

Combination oral contraceptives

Contraceptive pills containing estrogen and progestin have been advocated for nonsmoking patients with DUB who desire contraception. Therapy also used to treat acute hemorrhagic uterine bleeding but is not as effective as regimens previously mentioned. Apparently takes longer to induce endometrial proliferation when progestin is present. In long-term management of DUB, combination oral contraceptives are very effective.

Ethinyl estradiol and a progestin derivative (examples: Ovral, Lo-Ovral, Ortho-Novum, Ovcon, Genora, Orthocyclen, and others)

Reduces secretion of LH and FSH from pituitary by decreasing amount of GnRH.

Dosing

Adult

1 tab PO qd for 3 wk; followed by inactive pill on week during which withdrawal bleed generally will occur; alternatively, active pills can be taken in continuous fashion up to several months, with inactive pills intermittently for menses to occur

Pediatric

Not established

Interactions

Hepatotoxicity might occur with concurrent administration of cyclosporine; concomitant use of rifampin, barbiturates, phenylbutazone, phenytoin sodium, and, possibly, griseofulvin, ampicillin, and tetracyclines might influence efficacy of oral contraceptives and increase amount of breakthrough bleeding and menstrual irregularity

Contraindications

Documented hypersensitivity; pregnancy; active or inactive thrombophlebitis or thromboembolic disorders, cerebral vascular disease, myocardial infarction, coronary artery disease, or a past history of these disorders; known or suspected breast cancer; known or suspected genital cancer; history of cholestatic jaundice in pregnancy or jaundice with prior pill use; past or present liver tumors

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Complete physical examination, documentation of recent Pap smear and family history recommended; pay special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical annually as long as patient is on hormonal therapy; oral contraceptives can cause fluid retention (address any condition aggravated by this factor); monitor patients with epilepsy, migraine, asthma, or renal or cardiac dysfunction; history of psychic depression might be aggravated (observe patient closely); progestin compounds might elevate LDL levels, making control of hyperlipidemia more difficult (observe closely); certain forms of congenital hypertriglyceridemia might be aggravated by oral contraceptives, with resultant pancreatitis; discontinue if jaundice develops; contact lens wearers with visual changes should be examined by ophthalmologist; patients might develop hypertension secondary to increase in angiotensinogen production (reevaluate blood pressure approximately 3 mo after initiating therapy in all patients)

Androgens

Certain androgenic preparations have been used historically to treat mild to moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. These regimens offer no real advantage over other regimens and might cause irreversible signs of masculinization in the patient. They seldom are used for this indication today.

Use of androgens might stimulate erythropoiesis and clotting efficiency. Androgens alter endometrial tissue so that it becomes inactive and atrophic.

Danazol (Danocrine)

Isoxazole derivative of 12 alpha-ethinyl testosterone.

Dosing

Adult

200-400 mg/d PO in divided doses

Pediatric

Not established

Interactions

Prolongation of PT occurs in patients on warfarin; carbamazepine levels might rise with concurrent use of danazol; danazol might interfere with laboratory determinations of DHEA, androstenedione, and testosterone

Contraindications

Documented hypersensitivity, breast-feeding, seizure disorders, markedly impaired hepatic function, porphyria

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Perform complete physical examination, document recent Pap smear, and take family history prior to administration; give special attention to blood pressure, breasts, abdomen, and pelvic organs; repeat physical annually; can cause fluid retention (address any condition aggravated by this factor); carefully observe patients with epilepsy, migraine, asthma, or renal or cardiac dysfunction; hepatic dysfunction manifested by modest elevations of serum transaminase levels reported (monitor periodic liver function tests)

Nonsteroidal anti-inflammatory drugs

Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. NSAIDs have been shown to treat menorrhagia in ovulatory cycles but generally are not effective for the management of DUB.

Naproxen (Anaprox, Naprelan, Naprosyn)

Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Dosing

Adult

550 mg PO initially; followed by 275 mg q6h for 5 d

Pediatric

500 mg PO; followed by 250 mg q6-8h; not to exceed 1.25 g/d

Interactions

Probenecid might increase toxicity of NSAIDs; coadministration with ibuprofen might decrease effects of loop diuretics; coadministration with anticoagulants might prolong PT (watch for signs of bleeding); might increase serum lithium levels and risk of methotrexate toxicity (eg, stomatitis, bone marrow suppression, nephrotoxicity)

Contraindications

Documented hypersensitivity, peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis might occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and might require discontinuation

GnRH agonists

Work by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking ongoing cycle of abnormal bleeding in many anovulatory patients. Because prolonged therapy with this form of medical castration is associated with osteoporosis and other postmenopausal side effects, its use is often limited in duration and add back therapy with a form of low-dose hormonal replacement is given. Because of the expense of these drugs, they usually are not used as a first line approach but can be used to achieve short-term relief from a bleeding problem, particularly in patients with renal failure or blood dyscrasia.

Depot leuprolide acetate (Lupron)

Suppresses ovarian steroidogenesis by decreasing LH and FSH levels.

Dosing

Adult

3.75 mg IM q mo; not to exceed 6 mo without addition of low-dose estrogen and progestin therapy

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity, breast-feeding, undiagnosed vaginal bleeding, spinal cord compression

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Some patients might develop ovarian enlargement from initial release of gonadotropins (this will pass in about 10 d; treat conservatively with bed rest and fluid management)

Arginine vasopressin derivatives

Indicated in patients with thromboembolic disorders.

Desmopressin acetate (DDAVP)

Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.

Dosing

Adult

Intranasal spray or 0.3 mcg/kg diluted in 50 mL saline IV over 15-30 min

Pediatric

Not established

Interactions

Coadministration with demeclocycline and lithium decrease effects; fludrocortisone and chlorpropamide increase effects

Contraindications

Documented hypersensitivity, platelet-type von Willebrand disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Platelet aggregation might be induced in type IIB von Willebrand disease; ingest enough fluid to satisfy thirst in order to decrease potential for water intoxication and hyponatremia; slight elevation or transient fall in blood pressure might occur after administration; caution in hypertensive cardiovascular disease or coronary insufficiency

Follow-up

Patient Education

• The goals of therapy for dysfunctional uterine bleeding (DUB) are to control and prevent recurrent bleeding, correct or treat any pathology present, and induce ovulation in patients who desire pregnancy. Age, past history, and bleeding amount influence management.
• After initial treatment and resolution of an episode of dysfunctional uterine bleeding, patients need to be educated that most often chronic therapy is mandatory to prevent further episodes.
• Reassure patients that most bleeding stops with the appropriate hormonal therapy. Explain the physiologic reason for the anovulatory bleeding pattern. This is particularly true for the adolescent patient who establishes a predictable ovulatory type of menstrual pattern over time.
• Perhaps the best measure of successful treatment is a good menstrual calendar. Encourage patients to keep a calendar to record daily bleeding patterns. This will serve to document severity of blood loss and impact on daily activities.
• For excellent patient education resources, visit eMedicine's Women's Health Center and Pregnancy and Reproduction Center. Also, see eMedicine's patient education articles Vaginal Bleeding, Birth Control Overview, Birth Control FAQs, and Pap Smear.

Miscellaneous

Medicolegal Pitfalls

• Patients with chronic anovulation and recurrent bouts of dysfunctional uterine bleeding (DUB) are at increased risk for endometrial hyperplasia and malignancy. Failure to perform a proper evaluation of the endometrium in such patients can be disastrous. Endometrial sampling can be accomplished easily in the office, with minimal requirements for sedation.
• Iatrogenically induced uterine injury from aggressive curettage might lead to intrauterine synechiae or Asherman syndrome. Affected patients might be rendered infertile or placed at high risk for spontaneous abortion in the future. For this reason, always consider medical management of DUB prior to surgical intervention.

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Keywords

dysfunctional uterine bleeding, DUB, abnormal uterine bleeding, anovulatory uterine bleeding, menorrhagia, irregular uterine bleeding, anovulatory menstrual cycles, oligo-ovulation, polycystic ovarian syndrome, polycystic ovaries, PCO, PCOS, chronic eugonadal anovulation, oral contraceptive pills, OCPs, hemorrhagic uterine bleeding, D&C, endometrial ablation, estrogens, progestins, hyperandrogenism

Contributor Information and Disclosures

Author

Millie A Behera, MD, Assistant Professor, Director of Clinical Research, Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center
Millie A Behera, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, and American Society for Reproductive Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas Michael Price, MD, Associate Professor of Reproductive Endocrinology, Director of Reproductive Fellowship Training Program, Duke University Medical Center
Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Phi Beta Kappa, and Society for Gynecologic Investigation
Disclosure: Clinical Advisors Group Consulting fee Consulting; MEDA Corp Consulting Consulting fee Consulting; Gerson Lehrman Group Advisor  Consulting fee Consulting; Roche/GSK Spokesperson  Consulting fee Consulting; Abbott Pharmaceuticals Grant/research funds PI; Adiana Grant/research funds PI

Medical Editor

Anthony Charles Sciscione, DO, Director, Division of Maternal-Fetal Medicine, Professor, Department of Obstetrics and Gynecology, Drexel University College of Medicine
Anthony Charles Sciscione, DO is a member of the following medical societies: American College of Obstetricians and Gynecologists and American Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

A David Barnes, MD, PhD, MPH, FACOG, Consulting Staff, Department of Obstetrics and Gynecology, Mammoth Hospital (Mammoth Lakes, California), Pioneer Valley Hospital (Salt Lake City, Utah), Warren General Hospital (Warren, Pennsylvania), and Mountain West Hospital (Tooele, Utah)
A David Barnes, MD, PhD, MPH, FACOG is a member of the following medical societies: American College of Forensic Examiners, American College of Obstetricians and Gynecologists, American Medical Association, Association of Military Surgeons of the US, and Utah Medical Association
Disclosure: Nothing to disclose.

CME Editor

Frederick B Gaupp, MD, Consulting Staff, Department of Family Practice, Hancock Medical Center
Frederick B Gaupp, MD is a member of the following medical societies: American Academy of Family Physicians
Disclosure: Nothing to disclose.

Chief Editor

Bryan D Cowan, MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Mississippi College of Medicine; Consulting Staff, Department of Obstetrics and Gynecology, Veterans Affairs Medical Center; Medical Director, Wiser Hospital for Women, University of Mississippi Medical Center
Bryan D Cowan, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Gynecological and Obstetrical Society, American Medical Association, American Society for Reproductive Medicine, Association of Professors of Gynecology and Obstetrics, Central Association of Obstetricians and Gynecologists, Endocrine Society, Sigma Xi, Society for Assisted Reproductive Technologies, Society for Gynecologic Investigation, Society for the Study of Reproduction, and Society of Laparoendoscopic Surgeons
Disclosure: Wyeth None Speaking and teaching

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author John T Queenan, Jr, MD to the development and writing of this article.

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