Abnormal Menstruation

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[edit] Abnormal Menstruation

Ru-fong Cheng

Steven Sondheimer

Abnormal uterine bleeding has varying significance. It can represent a harmless disruption in the estrogen/progesterone ratio, a complication of pregnancy, or a warning sign of cancer. It can disrupt a woman's lifestyle and is alarming to the patient. Historically the term dysfunctional uterine bleeding was used to describe an event of acute bleeding. Now, with a better understanding of the sequence of hormonal events leading to menstrual bleeding and other functional etiologies of heavy uterine bleeding, dysfunctional uterine bleeding is usually reserved to describe anovulatory uterine bleeding.

Many ways exist to quantify uterine bleeding. The simplest method is by patient history, specifically, information about number of days of bleeding, passage of blood clots, and number of pads used. Menorrhagia is defined as profuse bleeding with flooding of clots or repetitive periods lasting more than 8 days. Because the history is poorly correlated with amount of blood lost, an objective approach would be documentation of anemia caused by chronic blood loss. Ultimately the best measure of menstrual blood loss is the degree of lifestyle disruption and change from a previous bleeding pattern. If the patient is unable to leave her house on days of menses due to fear of an embarrassing menstrual accident, that patient has abnormal uterine bleeding.

To understand abnormal menstruation, normal menstruation must first be defined. Normal menstrual cycles are remarkably consistent in ovulating women, with a similar pattern of flow from menses to menses and frequently an accompanying sense of premenstrual awareness. Cycle length is defined as the time from the first day of bleeding from one cycle to the first day of bleeding in the next cycle. Normal cycle length is 28 ± 7 days. Normal duration of flow is 4 ± 2 days, and normal quantity of blood flow is 40 ± 20 ml per cycle mm^[1]

[edit] PATHOPHYSIOLOGY

The menstrual cycle consists of two distinct phases, each with characteristic physiologic and hormonal events. The proliferative phase, usually days 1 through 14, is characterized by the endometrium preparing to receive the egg. Ovulation occurs in conjunction with the luteinizing hormone (LH) surge on day 14. The corpus luteum that persists from the ovarian follicle secretes progesterone, which then stimulates the endometrium to become inactive secretory endometrium. This marks the beginning of the luteal phase. Without pregnancy the corpus luteum regresses, and the subsequent decrease in estrogen and progesterone levels prepares the endometrium for orderly sloughing. Prostaglandins are released, leading to vasospasm and cellular necrosis. Cellular death, bleeding, and shedding of the functional endometrium ensue.

[edit] PATIENT EVALUATION

The first step is to obtain a complete medical history, with special attention to the menstrual history: age of menarche, frequency of menses, duration of bleeding, severity, cyclicity, and any changes from the previous pattern. Additional important information includes prior pregnancies and contraceptive method, medications, social history (including domestic violence and assault), and review of systems (general well-being, gastrointestinal and genitourinary symptoms). The physical examination should include vital signs and abdominopelvic evaluation. Tests should include a urine pregnancy test, Pap smear, and gonorrhea and chlamydial cultures. In addition, endometrial biopsy should be performed on women over age 35 with abnormal bleeding to rule out endometrial hyperplasia. Serum testing should include complete blood count, prothrombin/partial thromboplastin times, thyroid-stimulating hormone, prolactin, follicle-stimulating hormone, LH, and liver function tests.

Additional studies may include a pelvic ultrasound to rule out fibroids or structural abnormalities. Sonohysterography is a similar study in which the uterus is instilled with sterile saline to separate the uterine walls while ultrasound is employed to visualize the uterus. This study is especially helpful to delineate submucous myomas or endometrial polyps. In dilation and curettage (D&C) with hysteroscopy the endometrium is sampled and the endometrial cavity visualized with a fiberoptic hysteroscope while the uterine walls are distended with carbon dioxide or liquid medium. Magnetic resonance imaging (MRI) can be used to identify uterine anomalies or fibroids, but cost limits its use.^[2]

[edit] DIFFERENTIAL DIAGNOSIS

The approach to the differential diagnosis of abnormal uterine bleeding may be directed by the patient's age and reproductive status (Table 35-1). Menarcheal patients are usually in the teen years; the two etiologies of abnormal uterine bleeding common to this age group are anovulation and bleeding disorders. Anovulation may result from immaturity of the hypothalamic-pituitary axis and lack of appropriate feedback response to circulating estradiol.^[3] Unopposed estrogen action on endometrium leads to irregular shedding. Bleeding disorders should be suspected if patients give a history of easy bruising and nosebleeds. Platelet deficiencies, defects in platelet activity (e.g., von Willebrand's disease), and prothrombin deficiency can be associated with abnormal uterine bleeding.

Table 35-1 Diagnosis of Uterine Bleeding Based on Patient's Age and Reproductive Status

Ovulatory patients, from teenage girls to women in their 40s, have the most possible reasons for abnormal uterine bleeding. Pregnancy is the most obvious etiology and may be a normal intrauterine pregnancy or a threatened, incomplete, or complete abortion. Because of life-threatening implications, ectopic pregnancy must also be considered. Trophoblastic disease is a variant of pregnancy in which malignant trophoblastic tissue produces human chorionic gonadotropin (hCG) and may cause bleeding. After recent pregnancy the woman may have retained placental tissue, a placental polyp, or subinvolution of the placental implantation site. Infection of the vagina, cervix, endometrium, and fallopian tubes may present with abnormal bleeding. Anovulation may also occur sporadically in menstruating women. If anovulation is chronic, it is called polycystic ovarian syndrome (PCOS). Initially characterized by Stein-Leventhal syndrome, PCOS involves androgen excess, with small ovarian follicles visualized on ultrasound.^[1] Fibroids (leiomyomata, myomas) are benign smooth muscle tumors of the uterine muscle that can disrupt normal menstrual patterns by altering the endometrial vasculature, impairing normal hemostatic mechanisms (e.g., platelet adherence, fibrin plug formation). Endometriosis, characterized by growth of endometrial glands and stroma outside the uterus, and adenomyosis, characterized by endometrial glands and stroma in the myometrium, can also cause abnormal uterine bleeding. Thyroid disease, especially hypothyroidism, can cause heavy menses. Hypothalamic etiologies of heavy menses may be caused by stress and changes in weight. Lesions on the cervix and vagina caused by dysplasia, cancer, or trauma can cause bleeding. Iatrogenic causes of bleeding include use of oral contraceptives (OCs), Depo-Provera, Norplant, and intrauterine device (IUD). Other medications associated with abnormal bleeding include phenytoin, antidepressants, digitalis, anticoagulants, corticosteroids, and tranquilizers. Finally, disease in other organ systems can result in abnormal bleeding. Liver cirrhosis causes decreased metabolism of estrogen; decreased conjugation leads to increased circulating estrogen levels, which stimulate the endometrium and cause irregular bleeding.^[1]

In perimenopausal women in their 40s and 50s, abnormal bleeding is caused by malignancy until proved otherwise. Endometrial hyperplasia is a particular concern in chronic anovulatory women and is characterized as simple or complex and with or without atypia. Hyperplasia with atypia can progress to endometrial cancer. The incidence of endometrial cancer increases with increasing age, although malignant transformation may also occur in younger women. Polyps of endometrial or cervical origin can also be a cause of abnormal uterine bleeding.

[edit] MANAGEMENT

[edit] Treat Condition

Treatment of abnormal uterine bleeding is directed toward the underlying etiology. For menarcheal patients with anovulation, withdrawal bleeding may be induced with cyclic medroxyprogesterone acetate, 10 mg/day for 10 days, or cyclic OCs. Patients with abnormal bleeding but no anatomic lesions who do not respond to medical treatments should be evaluated for bleeding disorders. Von Willebrand's disease is a heterogenous disorder with defective functioning of von Willebrand's factor (vWF). Its estimated prevalence is 1% of the population. Treatment is with desmopressin (a synthetic analog of vasopressin) nasal spray or intravenous injection, which promotes the release of vWF from storage sites. Treatment is effective in achieving hemostasis in 75% of those affected.^[3]

Pregnancy can be confirmed with a urine hCG test. Normal intrauterine pregnancies can be documented with ultrasound as early as 5 to 6 weeks, after quantitative serum β-hCG level reaches 1000 to 2000 mIU/ml, although this number may vary from center to center. Abortions are marked by vaginal bleeding. Threatened abortions usually present with vaginal bleeding and a closed cervical os on examination. Incomplete abortions are preceded by vaginal bleeding, followed by partially extruded products of conception at the dilated cervical os. Missed abortions are classically described as findings of a nonviable fetus and a closed cervical os. In the current age of high-resolution ultrasound, this term may be used for the detection of early fetal demise (absence of cardiac activity). Types of abortion can be differentiated by physical examination and by following serial β-hCG levels. In normal pregnancy, quantitative β-hCG values double every 48 to 72 hours. If levels do not rise as expected, the pregnancy is not normal, and the patient may need a D&C to evacuate the uterus if bleeding persists. If bleeding ceases, the abortion may have completed on its own, and serial quantitative β-hCG levels should be followed until they fall to zero. Ectopic pregnancies may also present with abnormal uterine bleeding (see later discussion). Quantitative β-hCG levels do not rise as expected, and no intrauterine pregnancy is seen on ultrasound. If patients have abdominal pain and acute peritoneal signs, tubal rupture may have occurred, which requires acute surgical intervention with either laparoscopy or laparotomy. Trophoblastic disease is another variant of pregnancy that may present with bleeding. This entity is quite rare and is treated with chemotherapy under the supervision of a gynecologic oncologist.

Abnormal bleeding resulting from trauma may require intervention. If the bleeding is acute, surgical therapy may be necessary. Otherwise, documentation of findings and inquiries about domestic violence are appropriate. If domestic violence is an issue, child abuse may also be occurring. Referrals to local police and support agencies should be offered. Most major cities have counseling resources available.

With infection of the pelvic organs, the physical examination may demonstrate purulent discharge, cervical motion tenderness, or uterine fundal tenderness. Cervicitis is diagnosed by gonorrheal and chlamydial culture and endometritis by endometrial biopsy. Cervicitis is treated with antibiotics and appropriate counseling regarding treatment of sexual partners and use of barrier contraceptives. Endometritis is also treated with antibiotics. If infection of the fallopian tubes or pelvic inflammatory disease (PID) is suspected, inpatient antibiotic therapy is given if the patient is unable to tolerate oral medications, has never been pregnant, is positive for human immunodeficiency virus (HIV), or is unable to comply with outpatient follow-up. Otherwise, outpatient antibiotic treatment is appropriate.

In women with thyroid disease, correction of the underlying disorder will correct the menstrual disturbance. If the etiology of abnormal bleeding is hypothalamic (e.g., stress, recent weight change), efforts should correct the underlying problem. If this is not possible or resumption of regular menses is desired, combination OCs may be used to regulate bleeding. For iatrogenic causes of bleeding, the risks and benefits of continuing the medication responsible for bleeding must be assessed. If the patient cannot discontinue the medication and control of menses is desired, cyclic OCs may be prescribed.

Fibroids may be palpable on examination or identified by ultrasound. Medical treatment of fibroids is with gonadotropin-releasing hormone (GnRH) analogs, which provide only temporary relief. Surgical treatment is technically easier and associated with less blood loss if GnRH agonists are used preoperatively to shrink the size of the myomas and thin the endometrium. Endometrial ablation may be performed with the laser or the resectoscope or roller ball. Interventional radiologists can perform uterine artery embolization for poor surgical candidates or patients who want to maintain their uteri. Myomectomy, which shells out the myomas while leaving the remainder of the myometrium as intact as possible, preserves fertility, but myomas may recur. Myomectomy may be approached hysteroscopically with the resectoscope or abdominally. Hysterectomy definitively treats uterine bleeding.

Adenomyosis and endometriosis are similar entities in which endometrial glands and stroma are found outside the endometrium. Diagnosis is primarily made by the patient history; treatment options are similar to those for fibroids. Endometrial hyperplasia is evaluated with hysteroscopy and D&C and then treated with progestational agents or hysterectomy. Cervical dysplasia is managed with colposcopy and biopsy. Endometrial cancer warrants referral to a gynecologic oncologist and most often results in hysterectomy and staging. Polyps, whether endometrial or cervical, should be removed by hysteroscopically directed D&C.

[edit] Control Bleeding

Once structural abnormalities have been excluded, the management of anovulatory bleeding is aimed at controlling bleeding and preventing recurrence. Historically, D&Cs were performed for treatment. Modern treatment is medical and involves high-dose estrogen to promote rapid endometrial growth, clotting, and healing of denuded epithelial surfaces. Estrogen administration is followed by progesterone to prevent subsequent bleeding. Sometimes progesterone can be used alone to stop bleeding, but if sloughing has already occurred, it may make bleeding worse by creating more decidualized atrophic endometrium. Specific regimens to treat anovulatory bleeding include conjugated equine estrogen and OCs (Box 35-1).^[3] If the patient is hypovolemic or anemic (hemoglobin less than 7.0 mg/dl), hospitalization or prolonged observation in the emergency department should be considered. If the patient does not respond to acute medical treatment, surgical treatment with D&C and concomitant hysteroscopy should be pursued to visualize any anatomic abnormalities (e.g., polyps, submucous fibroids, potential hyperplasia). The exact mechanism of bleeding cessation after D&C is unknown. Theoretically, curettage removes functional endometrial tissue and allows the basal layer to regenerate, which leads to cessation of bleeding. Curettage also stimulates release of prostaglandins, causing vasoconstriction.^[4]

For less acute medical treatment of anovulatory bleeding, the goal is to control blood loss. Treatment is with cyclic combination OCs; nonsteroidal antiinflammatory drugs (NSAIDs) may be used the first 3 days of menses or throughout menses (see Box 35-1).^[3] NSAIDs are effective in reducing menstrual blood loss by blocking the formation of prostacyclin, a vasodilator that inhibits platelet aggregation.

Less acute surgical treatment may be accomplished with endometrial ablation; 80% of patients have good long-term results, and about 50% report complete amenorrhea.^[4] Ablation may be performed with the laser or the resectoscope or coagulating roller ball. Another technique involves use of an intrauterine balloon for thermal treatment and ablation of the endometrium. Results are best if (1) the endometrium has been thinned with concomitant use of a GnRH agonist or danazol or (2) suction curettage is done at ablation. This is a good option for patients considering hysterectomy but is not recommended for those interested in future childbearing.

Long-term medical management of patients with anovulatory bleeding is with progestins, which stop endometrial growth and support and organize endometrium that has been primed by estrogen. After progesterone is withdrawn, the endometrium sloughs and bleeding ceases when adequate estrogen is present. This can be accomplished with medroxyprogesterone acetate, 10 mg orally on days 1 to 10 of each month or days 16 to 25 of each cycle. The same effect can be achieved with combination OCs. An IUD that releases progesterone or levonorgestrel may also be an effective treatment for heavy menses.^[3]

Perimenopausal abnormal uterine bleeding can be managed with cyclic conjugated equine estrogen, 0.625 to 1.25 mg/day on days 1 to 25 of each month, along with medroxyprogesterone acetate, 10 mg/day on days 15 to 25 of each month. Alternatively, these patients may be given combination OCs if they are not tobacco users.

Hysterectomy is reserved for patients whose bleeding does not respond to the previous measures or whose frustration with persistent bleeding necessitates definitive treatment.

[edit] ECTOPIC PREGNANCY

Patients at risk for ectopic pregnancy, defined as a pregnancy found outside the uterine cavity, include women with a history of chlamydial infection; previous ectopic pregnancy; tobacco use, which decreases ciliary motility in the fallopian tubes; prior tubal surgery for fertility or tubal reanastomosis; previous diethylstilbestrol (DES) exposure; and increasing maternal age. The rate of ectopic pregnancies has increased, with 4.5:1000 reported pregnancies in 1970 vs. 20:1000 in 1992. The diagnosis is made by documenting inadequately rising β-hCG levels (less than 100% increase in 48 to 72 hours) with no intrauterine gestational sac on ultrasound. A gestational sac is usually visible with transvaginal ultrasound when the β-hCG level reaches 1000 to 2000 mIU/ml, although this value may vary from center to center. An ectopic pregnancy should be also be suspected when a D&C has been performed for a suspected miscarriage and the pathology does not reveal products of conception.

In the past, all patients with suspected ectopic pregnancy underwent surgery, either laparoscopically or by laparotomy, and a salpingostomy (removal of pregnancy tissue while sparing the tube) or salpingectomy (removal of the entire tube) was done. Both procedures have similar postoperative fertility rates of about 60%, with a subsequent ectopic pregnancy rate of 10% to 30%.^[5] Women without a history of surgery for ectopic pregnancy have a 90% fertility rate.^[6]

With the advent of sensitive assays for β-hCG and increasingly high-resolution ultrasound, the diagnosis of ectopic pregnancy can be made before the patient becomes symptomatic and before a life-threatening emergency exists. Currently, patients can be offered medical treatment with methotrexate, a folic acid antagonist that inhibits dihydrofolic acid reductase and interferes with DNA synthesis, repair, and cellular reproduction.^[7] Posttreatment fertility rates are the same as those for surgical treatment.

[edit] REFERENCES