Dysfunctional Uterine Bleeding

INTRODUCTION

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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 a diagnosis of exclusion.

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Pathophysiology: Patients with 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:

• In the US: DUB 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 DUB 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, frequently is 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.

CLINICAL

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History:

• Suspect DUB when a patient presents with 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 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 are likely to have polycystic ovarian syndrome with or without hirsutism, hyperinsulinemia, or 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 include evaluation for the following:

• Obesity

• Signs of androgen excess

• Thyroid enlargement

• Galactorrhea

• Visual field deficits

• Ecchymosis

• Purpura

• 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.

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.

WORKUP

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Lab Studies:
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• Lab studies include human chorionic gonadotropin (HCG), CBC, Pap smear, endometrial sampling, thyroid functions and prolactin, liver functions, coagulation 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 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.

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• Tailor the choice of laboratory tests to the presenting clinical situation. Generally speaking, 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.

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• 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.

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• Women in menopausal transition usually can be followed without an extensive hormonal evaluation.

Imaging Studies:
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• 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 tumors, pelvic ultrasound evaluation might be most helpful.

• Pelvic ultrasound also might be confirmatory for polycystic ovaries (PCO), which frequently are present in individuals with chronic eugonadal anovulation.

• Confirmation of PCO by imaging is not mandatory for the diagnosis.

• The absence of the traditional string of pearls appearance does not exclude polycystic ovarian syndrome diagnosis.

• 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:
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• 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.

• 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.

Histologic Findings: Most endometrial biopsy specimens will show proliferative or dyssynchronous endometrium.

TREATMENT

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Medical Care:

• Oral contraceptives

• Oral contraceptive pills (OCPs) suppress endometrial development, reestablish predictable bleeding patterns, decrease menstrual flow, and lower the risk of iron deficiency anemia.

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• Acute episodes of heavy bleeding suggest an environment of prolonged estrogenic exposure and buildup of the lining.

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• 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.

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• 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.

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• Hemorrhagic uterine bleeding requires high-dose estrogen therapy. If bleeding is not controlled within 12-24 hours, a D&C is indicated.

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• Beginning progestin therapy shortly after initiating estrogen therapy to prevent a subsequent bleeding episode from treatment with prolonged unopposed estrogen is wise.

• 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.

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• 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.

• 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.

• High rates of rebleeding following ablation have raised concern about the possibility of an occult endometrial cancer developing within a pocket of active endometrium. Further studies are needed to quantify this risk.

MEDICATION

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Estrogens, progestins, androgens, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, antifibrinolytics, and gonadotropin-releasing hormone (GnRH) superagonists have been used to treat 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 -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.
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