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Dysfunctional Uterine Bleeding (DUB)

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(Functional Uterine Bleeding)

by JoAnn V. Pinkerton, MD

Dysfunctional uterine bleeding is abnormal uterine bleeding that, after examination and ultrasonography, cannot be attributed to the usual causes (structural gynecologic abnormalities, cancer, inflammation, systemic disorders, pregnancy, complications of pregnancy, use of oral contraceptives or certain drugs). Treatment is usually with hormone therapy, such as oral contraceptives, or with NSAIDs.

Dysfunctional uterine bleeding (DUB), the most common cause of abnormal uterine bleeding, occurs most often in women > 45 (> 50% of cases) and in adolescents (20% of cases).

About 90% of cases are anovulatory; 10% are ovulatory.

Pathophysiology

During an anovulatory cycle, the corpus luteum does not form. Thus, the normal cyclical secretion of progesterone does not occur, and estrogen stimulates the endometrium unopposed. Without progesterone, the endometrium continues to proliferate, eventually outgrowing its blood supply; it then sloughs incompletely and bleeds irregularly, and sometimes profusely or for a long time. When this abnormal process occurs repeatedly, the endometrium can become hyperplastic, sometimes with atypical or cancerous cells.

In ovulatory DUB, progesterone secretion is prolonged; irregular shedding of the endometrium results, probably because estrogen levels remain low, near the threshold for bleeding (as occurs during menses). In obese women, ovulatory DUB can occur if estrogen levels are high, resulting in amenorrhea alternating with irregular or prolonged bleeding.

Complications

Chronic bleeding may cause iron deficiency anemia. If DUB is due to chronic anovulation, infertility may also be present.

Etiology

Anovulatory DUB can result from any disorder or condition that causes anovulation (see Some Causes of Anovulatory Amenorrhea). Anovulation is most often secondary to polycystic ovary syndrome or is idiopathic (sometimes occurring when gonadotropin levels are normal); sometimes anovulation results from hypothyroidism. During perimenopause, DUB may be an early sign of ovarian failure; follicles are still developing but, despite increasing levels of follicle-stimulating hormone (FSH), do not produce enough estrogen to trigger ovulation. About 20% of women with endometriosis (see Endometriosis) have anovulatory DUB due to unknown mechanisms.

Ovulatory DUB may occur in polycystic ovary syndrome (because progesterone secretion is prolonged) or in endometriosis, which does not affect ovulation. Other causes are a short follicular phase and luteal phase dysfunction (due to inadequate progesterone stimulation of the endometrium); a rapid decrease in estrogen before ovulation can cause spotting.

Symptoms and Signs

Compared with typical menses, bleeding may

  • Occur more frequently (menses < 21 days apart—polymenorrhea)

  • Involve more blood loss (> 7 days or > 80 mL) during menses (menorrhagia, or hypermenorrhea)

  • Occur frequently and irregularly between menses (metrorrhagia)

  • Involve more blood loss during menses and frequent and irregular bleeding between menses (menometrorrhagia)

Ovulatory DUB tends to cause excessive bleeding during regular menstrual cycles. Women may have other symptoms of ovulation, such as premenstrual symptoms, breast tenderness, midcycle cramping pain (mittelschmerz), a change in basal body temperature after ovulation (see Ovulatory Dysfunction), and sometimes dysmenorrhea. Anovulatory DUB occurs at unpredictable times and in unpredictable patterns and is not accompanied by cyclic changes in basal body temperature.

Diagnosis

  • Exclusion of other potential causes

  • CBC, pregnancy test, and hormone measurement (eg, thyroid-stimulating hormone [TSH], prolactin)

  • Usually transvaginal ultrasonography and endometrial sampling

Women should be evaluated for DUB when the amount or timing of vaginal bleeding is inconsistent with normal menses. DUB is a diagnosis of exclusion; other conditions that can cause similar bleeding must be excluded (see Vaginal Bleeding). Pregnancy should be excluded, even in young adolescents and perimenopausal women. Coagulation disorders should be considered, particularly in adolescents who have anemia or require hospitalization for bleeding. Regular cycles with prolonged or excessive bleeding (possible ovulatory DUB) suggest structural abnormalities.

Laboratory testing

Several tests are typically done:

  • A urine or blood pregnancy test

  • CBC

  • TSH, prolactin, and progesterone levels

All women of reproductive age should have a pregnancy test. CBC is routinely done. However, Hct may be normal in women who report heavy bleeding, or anemia may be severe in women who regularly have heavy periods. The serum ferritin level, which reflects body iron stores, is measured if women have chronic, heavy bleeding.

Thyroid-stimulating hormone levels are usually measured, and prolactin levels are measured, even when galactorrhea is absent, because thyroid disorders and hyperprolactinemia are common causes of abnormal bleeding. To determine whether bleeding is anovulatory or ovulatory, some clinicians measure serum progesterone levels during the luteal phase (after day 14 of a normal menstrual cycle or after basal body temperature increases, as occurs during this phase). A level of 3 ng/mL ( 9.75 nmol/L) suggests that ovulation has occurred.

Other tests are done depending on results of the history and physical examination and include the following:

  • Coagulation tests if women have risk factors for coagulation disorders, bruising, or hemorrhage

  • Liver function tests if a liver disorder is suspected

  • Testosterone and dehydroepiandrosterone sulfate (DHEAS) levels if polycystic ovary syndrome is suspected

  • Follicle-stimulating hormone (FSH) and estradiol levels if premature ovarian failure is possible

  • A cervical cytology test (eg, Papanicolaou [Pap] test) if results are out-of-date

  • Testing for Neisseria gonorrhea and Chlamydia sp if pelvic inflammatory disease or cervicitis is suspected

If all clinically indicated tests are normal, the diagnosis is DUB.

Additional testing

Transvaginal ultrasonography is done if women have any of the following:

  • Age 35

  • Risk factors for endometrial cancer (eg, obesity, diabetes, hypertension, polycystic ovary syndrome, chronic eugonadal anovulation, hirsutism, other conditions associated with prolonged unopposed estrogen exposure)

  • Bleeding that continues despite use of empiric hormone therapy

  • Pelvic organs that cannot be examined adequately during the physical examination

  • Clinical evidence that suggests abnormalities in the ovaries or uterus

These criteria include almost all women with DUB.

Transvaginal ultrasonography can detect structural abnormalities, including most polyps, fibroids, other masses, endometrial cancer, and any areas of focal thickening in the endometrium. If focal thickening is detected, further testing may be needed to identify smaller intrauterine masses (eg, small endometrial polyps, submucous myomas). Sonohysterography (ultrasonography after saline is infused into the uterus) is useful in evaluating such abnormalities; it is used to determine whether hysteroscopy, a more invasive test, is indicated and to plan resection of intrauterine masses.

Pearls & Pitfalls

  • Do sonohysterography to help determine whether hysteroscopy is needed to evaluate abnormalities and to plan resection of intrauterine masses.

In endometrial sampling , only about 25% of the endometrium is analyzed, but sensitivity for detecting abnormal cells is about 97%. This test is usually recommended to rule out hyperplasia or cancer in women with any of the following:

  • Age > 35 yr with one or more risk factors for endometrial cancer (see above)

  • Age < 35 yr with multiple risk factors for endometrial cancer (see above)

  • Bleeding that is persistent, irregular, or heavy

  • Irregular cycles that suggest chronic anovulatory bleeding

  • Endometrial thickness that is > 4 mm, focal, or irregular, detected during transvaginal ultrasongraphy

  • Inconclusive ultrasonography findings

Directed biopsy (with hysteroscopy) may be done to visualize the endometrial cavity directly and target the abnormal tissue. Most endometrial biopsy specimens contain proliferative or dyssynchronous endometrium, which confirms anovulation because no secretory endometrium is found.

Treatment

  • Control of bleeding, usually with an NSAID, tranexamic acid, or hormone therapy

  • In women with endometrial hyperplasia, prevention of endometrial cancer

Bleeding

Nonhormonal treatments have fewer risks and adverse effects than hormone therapy and can be given intermittently, when bleeding occurs. They are used mainly for heavy regular bleeding (menorrhagia). Choices include

  • NSAIDs, which reduce bleeding by 25 to 35% and relieve dysmenorrhea by reducing prostaglandin levels

  • Tranexamic acid, which inhibits plasminogen activator, reducing menstrual blood loss by 40 to 60%

Hormone therapy (eg, oral contraceptives, progestins) is often tried first in perimenopausal women. This therapy does the following:

  • Suppresses endometrial development

  • Reestablishes predictable bleeding patterns

  • Decreases menstrual flow

Hormone therapy is usually given until bleeding has been controlled for a few months.

Oral contraceptives (OCs) are commonly given. OCs, used cyclically or continuously, can control dysfunctional bleeding. Limited data suggest that they do the following:

  • Decrease menstrual blood loss by 40 to 50%

  • Decrease breast tenderness and dysmenorrhea

  • Decrease risk of uterine and ovarian cancer

Combination formulations consisting of an estrogen and a progestin or a progestin alone may be used. Risks of an OC depend on the type of OC and on patient factors (see Adverse effects).

Progestins or progesterone can be used alone if estrogen is contraindicated (eg, for patients with cardiovascular risk factors or prior deep vein thrombosis), if estrogen is declined by the patient, or if combination OCs are ineffective after about 3 mo of use. Withdrawal bleeding may be more predictable with cyclic progestin therapy (medroxyprogesterone acetate 10 mg/day po or norethindrone acetate 2.5 to 5 mg/day po) given for 21 days/mo than with a combination OC. Cyclic natural (micronized) progesterone 200 mg/day for 21 days/mo may be used, particularly if pregnancy is possible; however, it may cause drowsiness and does not decrease blood loss as much as a progestin. If patients using cyclic progestins or progesterone wish to prevent pregnancy, contraception should be used. Contraceptive options include

  • A levonorgestrel-releasing intrauterine device (IUD): It is effective in up to 97% by 6 mo, provides contraception, and relieves dysmenorrhea.

  • Depot medroxyprogesterone acetate injections: They cause amenorrhea and provide contraception but may cause irregular spotting and reversible bone loss.

Other treatments that are occasionally used to treat DUB include

  • Danazol: It reduces menstrual blood loss (by causing endometrial atrophy) but has many androgenic adverse effects, which may be lessened by using lower doses or a vaginal formulation. To be effective, danazol must be taken continuously, usually for about 3 mo. It is usually used when other forms of therapy are contraindicated.

  • Gonadotropin-releasing hormone (GnRH) analogs: These drugs suppress ovarian hormone production and cause amenorrhea; they are used to shrink fibroids or the endometrium preoperatively. However, their hypoestrogenic adverse effects (eg, bone loss) limit their use.

  • Desmopressin: It is used as a last resort to treat DUB in patients who have a coagulation disorder; it rapidly increases levels of von Willebrand factor and factor VIII for about 6 h.

Ergot derivatives are not recommended for treatment of DUB because they are rarely effective.

If pregnancy is desired and bleeding is not heavy, ovulation induction with clomiphene (50 mg po on days 5 through 9 of the menstrual cycle) can be tried.

Hysteroscopy with D & C may be therapeutic as well as diagnostic; it may be the treatment of choice when anovulatory bleeding is severe or when hormone therapy is ineffective. Structural causes such as polyps or fibroids may be identified or removed during hysteroscopy. This procedure may decrease bleeding but, in some women, causes amenorrhea due to endometrial scarring (Asherman syndrome).

Endometrial ablation (eg, laser, rollerball, resectoscopic, thermal, or freezing) may help control bleeding in 60 to 80%. Ablation is less invasive than hysterectomy, and the recovery time is shorter. Ablation may be repeated if heavy bleeding recurs after ablation is initially effective. If this treatment does not control bleeding or if bleeding continues to recur, the cause may be adenomyosis and thus is not DUB. Endometrial ablation does not prevent pregnancy. Pregnancy rates may be as high as 5% after ablation.

Hysterectomy , abdominal or vaginal, may be recommended for patients who decline hormone therapy or who, despite other treatments, have symptomatic anemia or poor quality of life caused by persistent, irregular bleeding.

Emergency measures are needed only rarely, when bleeding is very heavy. Patients are stabilized hemodynamically with IV crystalloid fluid, blood products, and other measures as needed. If bleeding persists, a bladder catheter is inserted into the uterus and inflated with 30 to 60 mL of water to tamponade the bleeding. Once patients are stable, hormone therapy is used to control bleeding. Very rarely, in patients with very heavy bleeding due to anovulatory DUB, conjugated estrogens 25 mg IV q 4 to 6 h for a total of 4 doses may be used. This therapy stops bleeding in about in 70% of patients but increases risk of thrombosis. Immediately afterward, patients are given a combination OC, which may be continued until bleeding has been controlled for a few months.

Endometrial hyperplasia

In postmenopausal women, atypical adenomatous endometrial hyperplasia is usually treated with hysterectomy. In premenopausal women, this disorder may be treated with medroxyprogesterone acetate 20 to 40 mg po once/day for 3 to 6 mo. If repeat endometrial sampling indicates resolution of hyperplasia, women may be given cyclic medroxyprogesterone acetate (5 to 10 mg po once/day for 10 to 14 days each month) or, if pregnancy is desired, clomiphene. If sampling shows persistent or progressive atypical hyperplasia, hysterectomy is necessary.

More benign cystic or adenomatous hyperplasia can usually be treated with high-dose cyclic progesterone therapy (eg, cyclic medroxyprogesterone acetate); sampling is repeated after about 3 mo.

Key Points

  • Anovulatory DUB is the most common cause of abnormal uterine bleeding.

  • Test for treatable causes of bleeding; tests may include a pregnancy test, CBC, measurement of hormone levels (TSH, prolactin, progesterone), and often ultrasonography and endometrial sampling.

  • In women at risk, check for and treat endometrial hyperplasia.

  • If drugs are needed to control bleeding, prescribe NSAIDs, tranexamic acid, OCs, or other hormones, which are usually effective.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CRINONE
  • DELATESTRYL
  • ESTRADERM, ESTROGEL, VIVELLE
  • MIRENA, PLAN B
  • PROVERA
  • CLOMID
  • No US brand name
  • AYGESTIN, CAMILA
  • DDAVP, STIMATE

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