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Abnormal uterine bleeding.

Abstract: Disorders of the menstrual cycle are common problems in ambulatory medicine. Abnormal uterine bleeding describes bleeding that is excessive or outside the normal menstrual cycle. In the premenopausal woman, the differential diagnosis is broad, and pregnancy must always be considered. Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation, as anovulation is one of the most common causes of abnormal uterine bleeding. In patients with anovulatory bleeding, the goal of treatment is to minimize blood loss and prevent complications from chronic unopposed estrogen. In women with oligomenorrhea or amenorrhea, after establishing the etiology, it is necessary to maintain adequate estrogen to support bone health. In the peri- and postmenopausal population, because the incidence of endometrial hyperplasia and malignancy rises, it is important to have a low threshold for endometrial assessment.

Key Words: uterine bleeding, anovulation, menorrhagia, oligomenorrhea

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Disorders of the menstrual cycle are a common problem in ambulatory medicine, accounting for up to 30% of outpatient visits to gynecologists. (1) While there are many terms used, abnormal uterine bleeding (AUB) is the most accurate, and describes bleeding that is excessive or occurs outside of normal cyclic menstruation. (2) In this article, we describe the differential diagnosis of abnormal uterine bleeding, review the diagnostic workup, define an approach to etiology, and discuss treatment options for women with uterine bleeding abnormalities.

The Normal Menstrual Cycle

To understand abnormal uterine bleeding, it is important to review the normal menstrual cycle. There is tremendous cycle variability among women. A typical cycle interval varies from 21 to 35 days, with an average duration of blood flow of two to eight days. Estimated blood loss in a normal menstrual cycle is between 30 and 80 mL. (3) Traditional methods for estimating blood loss have been notoriously inaccurate. The best predictors of heavy bleeding are the passage of clots, the presence of iron deficiency anemia, and signs of volume depletion such as orthostasis or tachycardia.

The menstrual cycle is regulated by the pituitary-hypothalamic axis. Pulsatile production of GnRH from the hypothalamus causes secretion of FSH and LH from the pituitary. Under the influence of FSH, several ovarian follicles begin to develop. The ovary subsequently produces more estrogen with this stimulation, which functions as a negative feedback on FSH, allowing all but one or two dominant follicles to persist. During this phase, estradiol feedback on the pituitary causes increase in LH secretion, which causes a small amount of progesterone production, stimulating an LH surge 34 to 36 hours before follicle rupture and ovulation. Once this occurs, the ovarian granulose cells produce progesterone for about 14 days but involute thereafter unless pregnancy is established. Estrogen acts to increase the thickness and vascularity of the endometrial lining; progesterone increases its glandular secretion and vessel tortuosity. Withdrawal of sex steroids by involution of the corpus luteum results in endometrial sloughing and menstrual bleeding. The follicular phase (first half of the cycle) is variable in length. The luteal phase (from the time of ovulation to menses) is fairly constant at 14 days.

Definitions

Abnormalities in menstrual bleeding are described by a number of terms, depending on the presence or absence of blood flow, regularity and amount of blood loss, as well as etiology (Table 1).

Differential Diagnosis and Approach

The issues raised by abnormal uterine bleeding vary depending on a woman's reproductive status. The evaluation of symptoms is most easily approached by considering whether a patient is premenopausal, perimenopausal, or postmenopausal. While considerable overlap in etiology may occur, there are important differences regarding differential diagnosis, evaluation and management in each group.

The Premenopausal Woman: Excessive or Irregular Bleeding

In all women, it is important to take a thorough history to differentiate between various etiologies of bleeding (Table 2). Questions should elicit information about the timing, duration and amount of bleeding. A sexual history should be obtained, with specific attention to the possibility of trauma or domestic violence. Associated symptoms, such as abdominal pain, vaginal discharge, and fever are important to investigate. A focused review of symptoms is recommended as well, specifically, questions regarding temperature intolerance, abnormal hair growth, galactorrhea and any recent dramatic weight loss or gain, as these may point to an endocrine etiology. Other relevant past medical history should be sought, including history of bleeding diathesis, and renal or liver disease.

A thorough physical examination is critical, including a pelvic examination, even if the patient is actively bleeding. The focus of the examination is to identify whether there is an alternative source of bleeding (ie, rectum, urethra), to identify suspicious anatomic lesions on the vulva, vagina, or cervix, and to palpate the uterus for size and tenderness. In addition, the clinician should look for systemic signs, including hirsutism, bruising, and galactorrhea; perform a thyroid examination and, in the appropriate setting, calculate body mass index (BMI).

Pregnancy

In the premenopausal woman, the differential diagnosis of abnormal menstrual bleeding is broad. Pregnancy must be considered in any woman of reproductive age; the differential diagnosis of vaginal bleeding differs during pregnancy and includes some diagnoses that can be life-threatening to mother and/or child (Table 3). Light spotting is common in early pregnancy and may represent implantation. Abdominal cramps may accompany this, but should be mild and not disabling. Implantation bleeding occurs at approximately 6 to 12 days post ovulation. (4) For women who are actively trying to become pregnant and who know their menstrual history, these symptoms and appropriate timing suffice to make this diagnosis. Heavy bleeding and/or moderate-to-severe abdominal pain, however, may indicate ectopic pregnancy. Risk factors for ectopic pregnancy include a history of a previous ectopic pregnancy, history of pelvic inflammatory disease, prior tubal surgery, cigarette smoking and advanced maternal age, but the vast majority of time, ectopic pregnancies are spontaneous, with no history of risk factors; thus, this diagnosis must always be considered. (5)

In a woman who is known to be pregnant, vaginal bleeding may indicate spontaneous abortion--threatened, complete, or missed. Placenta previa may present with vaginal bleeding, as can impending placental abruption. Finally, bleeding may occur after a therapeutic abortion, and represent retained products of conception.

Anovulation

Anovulation is one of the most common causes of abnormal bleeding. Estrogen is produced by the effect of FSH on the ovary, but since ovulation never occurs, no progesterone is produced and the uterine lining begins to build up. Over time, this results in sporadic loss of the endometrial lining. This creates either extended periods of vaginal bleeding or episodic menstruation at shorter-than-expected intervals (ie, every two weeks), and eventually results in endometrial hyperplasia. Anovulation is common during adolescence and at perimenopause. (6) In adolescent girls, this is due to a delay in the maturation of the hypothalamic pituitary axis. In the perimenopausal period, cyclic hormone production becomes disturbed, and ovulation occurs intermittently, interspersed with anovulatory cycles. As a result, irregular heavy bleeding can occur during longer periods of anovulation.

The most common cause of chronic anovulation in reproductive-aged women is polycystic ovarian syndrome (PCOS). Revised criteria for this diagnosis mandate that two of the following be present: oligomenorrhea or anovulation, clinical or laboratory evidence of androgen excess and polycystic ovaries on ultrasound. (7) Ultrasound findings are neither necessary nor sufficient to make the diagnosis. Controversy persists regarding the mechanism of disease. The syndrome is felt to be due to abnormal stimulation of the theca cells by leuteinizing hormone (LH), which causes them to produce excess androgens, some of which are in turn converted to estrogens. The amount of LH produced exceeds FSH production; thus, androgens are produced preferentially to estrogen by the ovary. It is clear that there is an increased pulse frequency of GnRH production in PCOS, which is thought to be the reason for LH excess. As a result of these biochemical changes, no ovulation occurs. Because of the constant endometrial stimulation with estrogen, irregular breakthrough bleeding can occur, as well as endometrial hyperplasia. While PCOS has commonly been associated with obesity, many women have a normal BMI; thus, clinicians must consider the diagnosis in all women with irregular bleeding.

Anovulation occurs in a variety of other settings, such as at times of stress or systemic illness, and with sudden weight changes. Such conditions are often classified broadly as "hypothalamic dysfunction," where a pattern of irregular bleeding may precede the development of overt amenorrhea. (8) Endocrine etiologies must also be kept in mind in the differential diagnosis of anovulatory bleeding. An increase in prolactin either because of a structural pituitary lesion or as a side effect of a medication (eg, neuroleptic) will cause anovulation. Menorrhagia is often reported in women with subclinical and overt hypothyroidism. Cushing syndrome commonly causes menstrual irregularities, likely secondary to suppression of GnRH by hypercortisolemia.

Uterine Disease

An anatomic or structural problem of the uterus or its lining may cause abnormal bleeding. Uterine fibroids or leiomyomata are the most common solid pelvic tumors in women, occurring in approximately 20% of women age 35 and older. (9) They most commonly lead to regular but heavy menstrual cycles (menorrhagia), but may also present as intermenstrual bleeding. Intramural and submucosal fibroids may distort the endometrium enough to cause menorrhagia in one third of women. (10) Other benign uterine growths in the differential include adenomyosis (endometrial glands infiltrating the myometrial wall), endometrial polyps (a common cause of peri- and postmenopausal bleeding), and endometrial hyperplasia. Endometriosis, a disorder involving ectopic endometrial tissue outside the uterine cavity, is associated with pelvic pain, dyspareunia, dysmenorrhea, and abnormal bleeding. Malignant uterine disease is uncommon in the premenopausal population, but must still be considered in the differential, particularly in women with risk factors for endometrial hyperplasia, such as prolonged unopposed estrogen and tamoxifen use. Endometrial cancer is the most common female genital tract malignancy, and abnormal vaginal bleeding is the most frequent symptom. (11) In contrast, uterine sarcomas represent only a small percentage of uterine tumors. (12) Their usual presentation is that of abnormal bleeding, or as a rapidly growing fibroid.

Intrauterine devices (IUDs) frequently produce abnormal uterine bleeding. Endometritis, which is an infection of the uterine lining, can cause intermenstrual bleeding, and is most often associated with pregnancy. It is a common complication associated with a cesarean section, but may also occur after a spontaneous vaginal delivery, a spontaneous or therapeutic abortion, as well as IUD insertion.

Cervical Disease

Most cervical etiologies are associated with light intermenstrual bleeding. Cervicitis is caused by a variety of infectious organisms, including Neisseria gonorrhea, Chlamydia trachomatis, Trichomonas vaginalis, or herpes simplex (HSV) infection. Cervical polyps are benign growths that commonly cause postcoital bleeding. Ectropian, or endocervical glandular tissue on the exocervix, may also be associated with postcoital bleeding. Cervical cancer commonly presents with abnormal vaginal bleeding. (13) Diagnosis of this critical finding is often delayed because clinicians delay or avoid the necessary Pap smear because the patient is bleeding.

Vaginal/Vulvar Disease

Vaginal or vulvar disease may also be associated with intermenstrual bleeding. Etiologies include vaginitis/vulvitis, sexually transmitted disease (eg, syphilitic chancre, HSV simplex infection, chancroid), or vaginal/vulvar cancer. External or internal trauma should also be considered. Bleeding may occur with intercourse, sexual abuse, foreign bodies (ie, tampons, adult toys), or accidental injury.

Medications

Several medications are associated with abnormal menstrual bleeding. Oral contraceptives commonly cause breakthrough (intermenstrual) bleeding, reflecting endometrial adjustment to a thinner state. This is a larger problem with lower estrogen preparations, since estrogen serves to stabilize the endometrium. It is more prevalent in smokers, secondary to increased metabolism of estrogen in this population. Progestin-only containing contraceptives frequently cause breakthrough bleeding. Similarly, medroxyprogesterone acetate injection is commonly associated with prolonged and irregular spotting. Hormone replacement therapy in the postmenopausal population is also commonly associated with irregular bleeding, particularly when taken in continuous form. Other medications include those that cause a relative prolactin excess, such as phenothiazines, as they induce anovulatory cycles. Anticoagulants may also be associated with increased menstrual loss.

Systemic Illness

A variety of illnesses may be associated with abnormal vaginal bleeding. Disorders of hemostasis, such as a coagulopathy or thrombocytopenia, must always be considered. Adolescents with heavy menstrual bleeding should be screened for partial von Willebrand disease, as this is a fairly common means of presentation. Up to 20% of adolescents with menorrhagia have a bleeding disorder. (6)

As previously noted, a variety of endocrine disorders are associated with anovulation. Cirrhosis can cause excessive bleeding as it reduces the ability of the liver to metabolize estrogen, and also decreases production of coagulation factors. Renal failure may have similar consequences because of interference with the normal excretion of estrogen and progesterone, as well as secondary to abnormal platelet function.

Evaluation

All women who present with abnormal vaginal bleeding should have a pregnancy test and a complete blood count. If a recent Pap smear (within the past year) has not been performed, this also should be done. Any suspicious lesions should be referred for biopsy. If there is a suspicion for cervicitis, cervical cultures should be obtained. In the premenopausal population, ovulatory status helps to determine subsequent evaluation. There are a variety of methods to ascertain ovulatory status. Ovulatory cycles tend to be regular, with the presence of premenstrual symptoms, such as breast tenderness, water weight gain, abdominal cramping, mood swings, and cervical mucous changes. Basal body temperature (BBT) and serum progesterone concentrations are two other ways in which the presence of ovulation can be detected. BBT increases by 0.5 degrees with ovulation. Serum progesterone concentrations >4.0 to 6.0 mIU/mL (normal luteal phase 6-25 mIU/mL) in the second half of the cycle is consistent with luteinization (ovulation has occurred). (3) Unfortunately, none of these objective methods are entirely accurate, because a woman may be ovulating intermittently, thus it depends on when the assessment is done. Prolonged bleeding that occurs at irregular intervals following several months of amenorrhea is likely anovulatory. Anovulatory bleeding is also suggested by the suspicion of any of the commonly associated conditions (eg, stress, systemic illness, thyroid disease, sudden weight loss, PCOS, etc.).

If anovulatory cycles are suspected, thyroid function and a prolactin level should be obtained. In an adolescent with heavy bleeding, screening for a coagulopathy is important. Patients should be assessed via history for a hypothalamic disorder (stress, eating disorder, excessive exercise). In patients with hirsutism or other signs of androgen excess, evaluation should be directed toward the possible diagnosis of PCOS versus chronic anovulation secondary to an alternative hyperandrogenic state. An LH/FSH ratio >2:1 is highly suggestive of a diagnosis of PCOS, but is not a sensitive finding. A DHEA-S level should be obtained to evaluate for adrenal sources of androgen excess, and a serum testosterone level, preferably early in the cycle, to evaluate for ovarian sources.

In the case of heavy ovulatory bleeding (menorrhagia), evaluation should include a complete blood count and coagulation tests, as well as a transvaginal pelvic ultrasound to evaluate for a structural problem. Leiomyomas (fibroids) are the most common structural etiology of abnormal bleeding in the premenopausal population. Submucosal or large fibroids are more likely to present in this fashion, (14) though a myoma of any size or location may cause bleeding. Recent evidence suggests that the cause of bleeding may be most highly correlated with growth factor dysregulation causing abnormalities in the vasculature. (15) A transvaginal ultrasound is particularly helpful in delineating the position and size of fibroids, endometrial thickness, and occasionally, the presence of endometrial polyps. A sonohysterogram, which involves instillation of saline into the uterine cavity during a transabdominal or transvaginal ultrasound, may be necessary to better delineate the position and size of intrauterine pathology. It is particularly useful in identifying structural lesions of the endometrial cavity that can be hidden within the endometrial stripe of premenopausal women. Its use is limited by the fact that it is an uncomfortable procedure for the patient. Referral for endometrial biopsy, hysteroscopy, or dilation and curettage (D & C) may be warranted in patients over the age of 35 in whom the bleeding cannot be controlled, or those with risk factors for endometrial hyperplasia/carcinoma, including a positive family history, prolonged anovulation (typically defined as greater than one year), and obesity. (3,8)

Treatment

In ovulatory bleeding, NSAIDs are helpful in controlling menorrhagia by modulating PGE2 and PGI2, two vasodilating prostaglandins. By inhibiting prostaglandin synthesis, the amount of bleeding decreases by approximately 30%. (16) NSAIDs may also be very helpful if dysmenorrhea exists. Oral contraceptives are also effective in modulating blood loss, on average providing a 50% decrease. (17) Progestin-containing IUDs have been found to be effective as well, decreasing menstrual blood flow by 80 to 90%. (17) Given concerns about impaired fertility, they are more appropriate for women who have completed childbearing. Tranexamic acid is an option for more severe cases, functioning as a plasminogen activator inhibitor. Studies have demonstrated a reduction in blood loss by 34 to 59%, with no evidence that the treatment increases the risk of thromboembolic disease. (18)

For anovulatory bleeding disorders, the etiology of the anovulation must be addressed--eg, correct any underlying thyroid disease, advise the patient regarding weight loss or gain, and discontinue any offending medications. However, in many cases, an etiology is not found. When there is no identifiable cause for anovulatory bleeding, the disorder is called "dysfunctional uterine bleeding" or DUB. This is a diagnosis of exclusion and can usually be treated medically.

Empiric treatment begins with oral contraceptives or cyclic progesterone. Oral contraceptives provide added protection against pregnancy in women who intermittently ovulate. For women who have not had a menstrual period for more than six weeks, it may be advisable to induce a withdrawal bleed first with medroxyprogesterone acetate to minimize the amount of breakthrough bleeding. For moderate bleeding that can be managed on an outpatient basis, a monophasic oral contraceptive may be prescribed for q.i.d. dosing for five to seven days, and subsequently reduced to daily dosing for three weeks, followed by a withdrawal bleed. Alternatively, a progestational agent such as medroxyprogesterone acetate or norethindrone can be given for 10 to 21 days. Subsequently, a normal regimen of oral contraceptives can be started with the next cycle. Women with ovulatory bleeding are less likely to benefit from luteal phase progestins than women with an anovulatory source. (17) If fertility is desired, a progestational agent may be administered 15 days each month to control the endometrial lining. In cases of anovulation, clomiphene citrate or pulsatile GnRH agonists may be administered by a gynecologist to induce ovulation.

For very heavy menstrual bleeding, a variety of hormonal options exist. Parenteral conjugated estrogens are approximately 70% effective in stopping the bleeding entirely. (17) In women in whom estrogen is contraindicated, such as those with underlying liver disease, medroxyprogesterone acetate may be substituted. GnRH antagonists such as leuprolide, administered continuously, will induce a reversible chemical menopause by downregulation of GnRH receptors and consequent diminished gonadotropin secretion. Danazol, a synthetic steroid with strong antigonadotropin properties as well as direct inhibitory effects at receptors of gonadal steroids, has also been shown to be effective. Between 50 and 100% of patients will experience a decline in blood loss, depending on the dose. (16,17) Androgenic side effects may be limiting, which include hirsutism, weight gain, and acne. Surgical options are reserved for cases when medical treatment fails, and are necessary in approximately 10% of cases. (8) Options include hysteroscopic endometrial ablation, where selective areas of endometrium are destroyed, nonhysteroscopic (or blind) ablation, or hysterectomy.

The Premenopausal Woman: Oligomenorrhea and Amenorrhea

Oligomenorrhea refers to bleeding that is infrequent or scant. Technically, it is defined as bleeding that occurs at intervals greater than 35 days apart, or fewer than nine menstrual cycles a year. (6) It may progress to amenorrhea, which is an absence of bleeding for at least three months in a woman with previously normal cycles or nine months in a woman with a history of oligomenorrhea. (19) As usual, pregnancy must be considered in the differential, as well as anovulatory states as previously outlined. In particular, patients with PCOS frequently experience oligomenorrhea. It is also important to consider conditions which are primarily associated with low circulating estrogen levels, such as exercise-induced amenorrhea, anorexia nervosa, and premature menopause.

Similar to the evaluation of anovulatory bleeding, all patients should have a UCG, TSH and prolactin level measured. If there are signs of hyperandrogenism, DHEA-S and testosterone should be checked. If all are normal, one may determine if the patient has adequate circulating levels of estrogen with a "progesterone withdrawal test." The patient receives 10 mg of a progestin (usually medroxyprogestone acetate) for 5 to 10 days. On discontinuation, if adequate estrogen is present, there should be a withdrawal bleed. Absence of a withdrawal bleed suggests a hypoestrogenic state (ie, primary or secondary ovarian failure). Alternatively, in a woman with previously normal cycles, many gynecologists will measure FSH, LH and estradiol levels. A high serum FSH indicates ovarian failure. A low normal serum FSH is common in women with hypothalamic amenorrhea. Typically in this scenario, FSH is higher than LH. Head imaging is indicated when no clear etiology of hypothalamic amenorrhea is obvious to rule out pituitary or hypothalamic disease.

Exercise-associated amenorrhea (EAA) is a frequent cause of amenorrhea in young women, most commonly seen in runners and ballet dancers, but not limited to any one sport. Disordered eating is common in the young female population, and is especially common among athletes. (20) Excessive exercise and weight loss can suppress GnRH release from the hypothalamus, causing oligomenorrhea. Among other health hazards, low estrogen levels increase the risk for osteoporosis. Trabecular bone (hip, spine and femur) reaches peak density in the mid 20s. After this time, bone density in healthy individuals decreases at a rate of approximately 1% per year. Bone density has been found to be decreased 22 to 29% in young amenorrheic women compared with age-matched controls. (21) Additional research has shown that current menstrual status as well as a past history of menstrual abnormalities are both important in determining decreased bone density. (22) For example, in athletes who regain normal menstrual cycles, bone density rises, but not to the level of normal controls. Thus, it is critically important to begin estrogen replacement, typically in the form of oral contraceptives, in a woman who has had six months of a hypoestrogenemic state. (23)

The Perimenopausal Woman

Abnormal perimenopausal bleeding presents unique challenges to the clinician, as most women will experience a change in regularity of their bleeding pattern before they experience the year of amenorrhea that defines menopause. The irregularity of bleeding that precedes menopause is due to intermittent anovulation. As with any woman who presents with irregular bleeding, a focused history, physical examination, complete blood count, and thyroid testing is indicated. Even if the patient is closer to 51 (the average age of menopause) a pregnancy test should still be performed, as unplanned pregnancies are not uncommon in this population, likely because women believe they are no longer fertile and thus do not always use contraception.

Since chronic anovulation can lead to prolonged periods of unopposed estrogen and an increased risk of endometrial hyperplasia, the clinician should have a low threshold for endometrial assessment in this population. Irregular bleeding of less than 3 months' duration without an episode of menorrhagia can be followed clinically. Irregular bleeding of more than 6 months' duration, an episode of menorrhagia, or cycle length of less than 17 to 19 days is generally an indication for endometrial surveillance. The most common method of assessment is via office-based endometrial biopsy, where a Pipelle is introduced into the cervix and endometrial samples are obtained. Typically, several passes of the Pipelle are performed with an attempt to obtain tissue from the entire uterus, but the procedure is done blindly. Endometrial biopsy is slightly less accurate in the perimenopausal population than the postmenopausal population in detecting endometrial hyperplasia and carcinoma, with detection rates of 91% in perimenopausal women compared with 99% in postmenopausal women. (24) The utility of a transvaginal ultrasound (TVU) as a means of deferring endometrial biopsy is not well studied in this population. Several small studies have demonstrated a high negative predictive value using an endometrial stripe less than 5 to 7 mm, (25-27) with one study demonstrating greater sensitivity of TVU in detecting abnormalities outside the endometrium. Thus, initial assessment should likely include TVU in the perimenopausal population. If the endometrial stripe is less than 4 to 5 mm, and the endometrium shows no areas of heterogeneity, some gynecologists will defer biopsy. In the presence of ongoing bleeding or risk factors for endometrial cancer (family history, obesity, chronic anovulation, tamoxifen use), however, a biopsy is necessary.

In a woman under the age of 45 with no risk factors for endometrial cancer, it may be appropriate to initiate a trial of low-dose oral contraceptives to regulate bleeding. Alternatively, cyclic progestin may be administered to induce monthly withdrawal bleeding.

The Postmenopausal Woman

The most worrisome source of bleeding in the postmenopausal woman is endometrial cancer, but it is not, in fact, the most common source. The risk of endometrial cancer in a postmenopausal woman not on HRT is approximately 10%. (28) Atrophic vaginitis, endometrial atrophy, and endometrial polyps are the most common findings. Endometrial biopsy has long been the gold standard for diagnosis, but it is an uncomfortable procedure for an older patient, especially if cervical stenosis is present. In approximately 2 to 28% of attempts, the biopsy cannot be performed or yields nondiagnostic results. (28) In addition, office-based endometrial biopsy has a false negative rate of up to 5 to 15%. (28) At a threshold of 5 mm, transvaginal ultrasound (TVU) has a high sensitivity for detecting endometrial carcinoma in this population (90%), and has been shown to have a 99% negative predictive value in ruling out serious endometrial disease. (29) While many gynecologists use these data to avoid unnecessary biopsies, there is some data to suggest that a small percentage of malignancies would be missed using this cutoff (30); therefore, in the presence of continued bleeding, a tissue diagnosis with office-based biopsy or dilation and curettage under anesthesia is always warranted.

In the circumstance of a postmenopausal woman who takes continuous hormone replacement therapy, it is not uncommon to have abnormal bleeding for the first 6 months of treatment. However, if bleeding continues or starts after that interval, endometrial biopsy is necessary.

Summary

Abnormal uterine bleeding is a common condition, and evaluation is best approached by stratifying into pre-, peri- and postmenopausal status. In premenopausal women, after pregnancy has been excluded, ovulatory versus nonovulatory bleeding is the most important branch point. Utilizing a systematic approach to the differential diagnosis will help to avoid a misdiagnosis. Much of the evaluation and treatment can be done in the office of the internist. In patients with anovulatory bleeding, the goal of treatment is to regulate cycles, minimize blood loss, and prevent complications from chronic unopposed estrogen. In the patient with oligomenorrhea, it is important to maintain adequate estrogen to support bone health. In the peri- and postmenopausal populations, the incidence of endometrial hyperplasia and malignancy rises; thus, it is important to have a low threshold for endometrial assessment and referral to a gynecological specialist.

References

1. Wren BG. Dysfunctional uterine bleeding. Aust Fam Physician 1998;27:371-377.

2. Obstetrics AoPoGa. Clinical management of abnormal uterine bleeding. In: Smith RP BL, Ke RW, Strickland JL, ed. APGO Educational Series on Women's Health, 2002.

3. Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA 1993;269:1823-1828.

4. Implantation embryogenesis, and placental development. In: Cunningham G, Grant NF, Leveno KJ, et al, ed. Williams Obstetrics. New York, McGraw Hill, 2005.

5. Seeber BE, Barnhart KT. Suspected ectopic pregnancy. Obstet Gynecol 2006;107:399-413.

6. Oriel KA, Schrager S. Abnormal uterine bleeding. Am Fam Physician 1999;60:1371-1380; discussion 1381-1382.

7. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005;352:1223-1236.

8. ACOG Committee on Practice Bulletins--Gynecology. American College of Obstetricians and Gynecologists. ACOG practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet 2001;72:263-271.

9. Ryden J, Blumenthal PD, ed. Practical Gynecology: A Guide for the Primary Care Physician (Women's Health Series). Philadelphia, American College of Physicians, 1998.

10. Uterine leiomyomata. Number 192-May 1994. ACOG technical bulletin. Int J Gynaecol Obstet 1994;46:73-82.

11. Amant F, Moerman P, Neven P, et al. Endometrial cancer. Lancet 2005;366:491-505.

12. Platz CE, Benda JA. Female genital tract cancer. Cancer 1995;75 (1 Suppl):270-294.

13. Pretorius R, Semrad N, Watring W, et al. Presentation of cervical cancer. Gynecol Oncol 1991;42:48-53.

14. Stewart EA. Uterine fibroids. Lancet 2001;357:293-298.

15. Ryan GL, Syrop CH, Van Voorhis BJ. Role, epidemiology, and natural history of benign uterine mass lesions. Clin Obstet Gynecol 2005;48:312-324.

16. Stabinsky SA, Einstein M, Breen JL. Modern treatments of menorrhagia attributable to dysfunctional uterine bleeding. Obstet Gynecol Surv 1999;54:61-72.

17. Munro MG. Dysfunctional uterine bleeding: advances in diagnosis and treatment. Curr Opin Obstet Gynecol 2001;13:475-489.

18. Wellington K, Wagstaff AJ. Tranexamic acid: a review of its use in the management of menorrhagia. Drugs 2003;63:1417-1433.

19. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician 2006;73:1374-1382.

20. Holschen JC. The female athlete. South Med J 2004;97:852-858.

21. Cann CE, Martin MC, Genant HK, et al. Decreased spinal mineral content in amenorrheic women. JAMA 1984;251:626-629.

22. Drinkwater BL, Nilson K, Chesnut CH 3rd, et al. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med 1984;311:277-281.

23. Davis A. A 21-year-old woman with menstrual irregularity. JAMA 1997;277:1308-1314.

24. Dijkhuizen FP, Mol BW, Brolmann HA, et al. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000;89:1765-1772.

25. Taipale P, Tarjanne H, Heinonen UM. The diagnostic value of transvaginal sonography in the diagnosis of endometrial malignancy in women with peri- and postmenopausal bleeding. Acta Obstet Gynecol Scand 1994;73:819-823.

26. Dubinsky TJ, Parvey HR, Maklad N. The role of transvaginal sonography and endometrial biopsy in the evaluation of peri- and postmenopausal bleeding. AJR Am J Roentgenol 1997;169:145-149.

27. Tongsong T, Pongnarisorn C, Mahanuphap P. Use of vaginosonographic measurements of endometrial thickness in the identification of abnormal endometrium in peri- and postmenopausal bleeding. J Clin Ultrasound 1994;22:479-482.

28. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510-1517.

29. Langer RD, Pierce JJ, O'Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial. N Engl J Med 1997;337:1792-1798.

30. Tabor A, Watt HC, Wald NJ. Endometrial thickness as a test for endometrial cancer in women with postmenopausal vaginal bleeding. Obstet Gynecol 2002;99:663-670.

Sara B. Fazio, MD, and Amy N. Ship, MD

From the Division of General Internal Medicine, Harvard Medical School, Boston, MA.

Reprint requests to Sara B. Fazio, MD, Harvard Medical School, Division of General Internal Medicine E-CC631H, 330 Brookline Avenue, Boston, MA 02215. Email: sfazio@bidmc.harvard.edu

Drs. Fazio and Ship have no disclosures to declare.

Accepted August 31, 2006.

RELATED ARTICLE: Key Points

* Abnormal uterine bleeding is common, and evaluation is best approached by stratifying into pre-, peri- and postmenopausal status.

* In the premenopausal woman, one must determine if excessive or irregular bleeding is ovulatory or nonovulatory; pregnancy must always be considered in the differential.

* In the peri- and postmenopausal woman, there is an increased risk of endometrial hyperplasia and malignancy; thus, evaluation should proceed accordingly.

RELATED ARTICLE: Differential diagnosis of abnormal menstrual bleeding in premenopausal women:

1. Pregnancy

a. Ectopic pregnancy

b. Spontaneous abortion

c. Placenta previa abruption

2. Polycystic ovarian syndrome

3. Hypothalamic dysfunction (stress, systemic illness, sudden weight changes)

4. Endocrine dysfunction (hypothyroidism, elevated prolactin, Cushing disease)

5. Uterine disease (fibroids)

6. Cervical disease

7. Vaginal/vulvar disease

8. Medications (oral contraceptives)

9. Systemic illness (von Willebrand disease, coagulopathy, thrombocytopenia)

RELATED ARTICLE: Differential diagnosis of abnormal menstrual bleeding in perimenopausal women:

1. Pregnancy

2. Anovulation

3. Fibroids

4. Endometrial disease
Table 1. Definitions

* Amenorrhea -- no menstrual bleeding for at least 90 days
* Menorrhagia -- excessive or prolonged bleeding at regular intervals.
 Technically defined as blood loss >80 cc or bleeding that lasts >7
 days
* Polymenorrhea -- Increased frequency of bleeding (interval <21 days)
* Oligomenorrhea -- Decrease in frequency of bleeding (interval >35
 days)
* Metrorrhagia -- Irregular interval of bleeding, typically between
 cycles
* Menometrorrhagia -- prolonged or excessive bleeding both at time of
 menstruation and other irregular intervals
* Intermenstrual bleeding -- bleeding that occurs between regular
 menstrual cycles
* Dysfunctional uterine bleeding -- excessive endometrial bleeding that
 is unrelated to anatomic or systemic disease; classically anovulatory
 bleeding, as this is the primary cause

Table 2. Bleeding patterns

Intermenstrual bleeding
* Benign growths (cervical/endometrial polyps, ectropion, fibroids)
* Cancer (uterine, cervical, vulvar, vaginal)
* Drugs (oral contraceptives, hormone replacement)
* Infection (ulcerations, vaginitis, cervicitis, endometritis)
* Intrauterine device (IUD)
* Pregnancy
* Trauma

Menorrhagia
* Benign structural lesions (fibroids, endometrial polyps)
* Cancer (endometrial carcinoma, uterine sarcoma)
* Coagulopathies (von Willebrand disease, thrombocytopenia, leukemia,
 anticoagulants)
* Endometrial hyperplasia
* Other (hypothyroidism, hyperestrogenemic state (ie, renal/liver
 disease), IUD, pregnancy)

Table 3. Differential diagnosis of bleeding during pregnancy

Implantation
Ectopic pregnancy
Threatened/complete/incomplete/therapeutic abortion
Molar pregnancy
Placenta previa
Placental abruption
Uterine rupture
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Title Annotation:CME Topic
Author:Ship, Amy N.
Publication:Southern Medical Journal
Article Type:Disease/Disorder overview
Date:Apr 1, 2007
Words:5553
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