Steve N. London
This chapter presents a simplified diagnostic and therapeutic approach to the woman with abnormal uterine bleeding, discusses imaging studies that facilitate accurate diagnosis and management, and presents therapeutic plans for management of acute hemorrhage, menorrhagia, bleeding on oral contraceptives, and the dysfunctional bleeding associated with perimenopause. This chapter does not address abnormal bleeding in the postmenopausal woman either on or off hormone replacement.
This chapter is divided into three sections: the first is a simplified diagnostic approach with discussion about the differential diagnosis and therapeutic options for each condition. This is followed by section on imaging modalities available to aid in the diagnosis of abnormal uterine bleeding. Special emphasis is placed on the role of pelvic ultrasound, saline infusion sonogram, and magnetic resonance imaging (MRI). The third section presents a therapeutic approach in special clinical situations, including the patient presenting with acute hemorrhage, bleeding on oral contraceptives, menorrhagia, and perimenopause.
DIAGNOSIS
The differential diagnosis for all women presenting with abnormal uterine bleeding can be encompassed by the mnemonic PHIMIC (pregnancy, hormones, iatrogenic, mechanical, infection, and cancer) (Table 35.1). The use of this mnemonic simplifies the approach and allows the clinician to cover a vast array of possibilities in the most efficient and treatment focused manner. This category/group approach provides for patient safety by assuring that serious conditions such as pregnancy, cancer, or unrecognized infections are not overlooked.
|
|
|
TABLE 35.1. PHIMIC—differential diagnosis for abnormal uterine bleeding |
Before evaluating what is abnormal uterine bleeding, we must begin with a definition of what is normal uterine bleeding. Normal menstrual flow is the result of a withdrawal of an estrogen-primed endometrium. This should occur at regular intervals that vary by no more than 3 days from the woman's mean menstrual interval. Typically, normal ovulatory menses occur every 24 to 35 days with most women experiencing a predictable interval. Ovulatory women will set their own mean cycle length, which is defined as from the first day of bleeding, cycle day 1, to the next first day of bleeding in the subsequent cycle and will not vary more than 3 days. For example, if a woman's mean cycle interval is 26 days; her menstrual calendar should reflect menses varying from between 23 and 29 days. A variation greater than 3 days is suggestive of either oligoovulation or estrogenized anovulation and is classified as abnormal. The mean duration of normal menstrual flow is 3 to 7 days. Bleeding that persists longer than 7 days or decreases hemoglobin levels is considered, by definition, excessive. Unfortunately, there is no simple clinical way to quantitate the amount of blood lost during a menstrual period. Counting the number of sanitary protectives used in a menstrual cycle has proven to be inaccurate based on differences in personal hygiene and cultural backgrounds. When accurately quantitated, blood loss during an entire normal ovulatory menstrual cycle is approximately 60 to 80 mL. This amount of blood loss will not cause a decrease in hemoglobin in women consuming a normal balanced diet.
Traditionally, aberrations in menses have been classified as either menorrhagia, defined as an excessive amount of menstrual blood loss, metrorrhagia, defined as intermenstrual, irregular or otherwise noncyclic bleeding, or menometrorrhagia, which combines both menorrhagia and metrorrhagia leading to heavy irregular uterine bleeding (Table 35.2). While these terms are traditionally used they require that the clinician make a cognitive decision based on the patient's description of her symptomatology. This has the potential to alter the ability to make an accurate diagnosis, as the differential diagnosis of a woman with menorrhagia is different than that of metrorrhagia. Since menstrual histories are sometimes difficult to obtain due to the frequent miscommunication between the patient and her physician, limiting the description of the symptomatology to abnormal uterine bleeding without narrowing it to the more scientific term is encouraged. By approaching every woman, irrespective of whether she has menorrhagia, metrorrhagia, or menometrorrhagia with a generalized mnemonic such as PHIMIC, the clinician avoids narrowing the differential diagnosis too quickly, thus assuring that all possibilities are considered. Therefore, when a patient presents with abnormal uterine bleeding, its etiology will be found within one of six broad diagnostic categories: pregnancy, hormonal, iatrogenic, mechanical, infection, or cancer. This allows the same diagnostic approach for every woman, regardless of her age.
|
|
|
TABLE 35.2. Definitions |
Pregnancy
Pregnancy should be considered in any woman who presents with abnormal uterine bleeding unless she has had a hysterectomy or is over the age of 60. Even women who have had tubal ligations as well as women who are in their 50s and have not menstruated in 1 to 2 years may have the occasional pregnancy. It is safe, on a clinical basis, to say that a physician will never regret ordering too many pregnancy tests, but may regret not ordering enough.
Screening for pregnancy is typically accomplished by using a highly accurate urinary pregnancy test. It is not necessary to do a serum quantitative human chorionic gonadotropin (hCG) evaluation on every woman who presents with abnormal uterine bleeding. Currently available urinary pregnancy tests are immunometric or “sandwich” assays that use antibodies directed to the intact hCG molecule. This makes the urine pregnancy test extremely sensitive and specific. It is important that every clinician know what the limits are in sensitivity of the pregnancy test and the reference preparation that their practice uses. The two reference preparations currently in use are the First and the Third International Reference preparations. The original reference preparation was the Second International Reference Preparation (2nd-IRP) which measured intact and free β-hCG subunits. One unit of the 2nd-IRP is approximately equivalent to two units of the first or third IRP.
If the woman with abnormal uterine bleeding is found to have a positive urinary pregnancy test, a serum quantitative β-hCG assay should be obtained. While this result is pending, it is appropriate to perform a pelvic sonogram to determine whether there is an identifiable intrauterine pregnancy, an adnexal mass, or a negative exam (no pregnancy within the uterus and no adnexal masses). If the β-hCG returns above the discriminatory zone, then the finding of an empty uterus is suggestive of an ectopic pregnancy and management of ectopic pregnancy can be instituted. If the β-hCG is below the discriminatory zone and the patient is asymptomatic and reliable, she can return in 48 hours for a repeat β-hCG assay to determine the probability of a viable intrauterine pregnancy. Upon return, the patient can be rescanned if her β-hCG is expected to be over the discriminatory zone or a repeat ultrasound can be scheduled based upon the projected time period interval when the level will be anticipated to exceed the discriminatory zone maximum. It is important to remember that 10% to 15% of all ectopic pregnancies have normal β-hCG doubling times and that rupture of ectopic pregnancies has occurred with falling β-hCG values. If the level has remained constant or is falling this is suggestive of a nonviable pregnancy, whether in the uterus or in an ectopic location, this can be followed for another 48 hours.
Many pregnancies are lost without being able to determine if it was an early intrauterine loss or a nonviable ectopic pregnancy which resolved without becoming clinically symptomatic.
Hormones
Hormonal disorders that can cause abnormal bleeding can be grouped under four broad categories: coagulation disorders, prolactin disorders, thyroid disorders, and chronic anovulation (Table 35.3). Coagulation disorders are relatively rare. Coagulation disorders are most commonly found in girls who are within 1 year of their first menstrual cycle and have a falling hemoglobin level. Von Willebrand disease needs to be excluded in every adolescent presenting with excessive menstruation (menorrhagia). Women with coagulopathies may present with acute hemorrhage and hypovolemic symptoms. These women almost invariably present with anemia or frank hemorrhage to the emergency department within a short interval after the onset of menstruation. They also need to be evaluated for conditions associated with abnormal bone marrow function or rapid turnover of platelets such as leukemia, idiopathic thrombocytopenic purpura, or aplastic anemia.
|
|
|
TABLE 35.3. Hormonal causes: disorders to consider |
While hyperprolactinemia is a significant cause of abnormal bleeding in women, the prolactin itself is not the direct cause of the abnormal bleeding. The high prolactin levels are the result of alterations in neurotransmitters within the hypothalamus and prolactin down-regulates gonadotropin-releasing hormone (GnRH) secretion resulting in altered gonadotropin release, ovarian dysfunction, and subsequent abnormal uterine bleeding. A prolactin-secreting pituitary adenoma is the most common pituitary tumor in women and should be the first concern of a health care provider when evaluating a patient with an elevated prolactin level. It is reasonable to perform an MRI of the sella turcica in all women with a prolactin level greater than 60 ng/mL. In general, prolactin excess should be treated with bromocriptine if pregnancy is desired. If pregnancy is not desired and the patient has enough endogenous estrogen to prevent osteoporosis, then the prolactin level can simply be followed. Whether or not the woman has enough estrogen to prevent osteoporosis can be determined by the patient's response to progestin administration. If the patient fails to menstruate in response to this progestin challenge then consideration of estrogen replacement or other drug for prevention of osteoporosis is necessary. However, the abnormal bleeding will not resolve unless the prolactin level is returned to normal by treatment with a dopamine agonist such as bromocriptine. Even after the prolactin level has returned to normal there may be enough hypothalamic dysfunction that ovulation induction by other means may be required in women desirous of pregnancy. If the patient has a small microadenoma and desires contraception then oral contraceptives are the treatment of choice. If the patient does not need or desire contraception, cyclic progestin therapy with medroxyprogesterone acetate 10 mg for 14 days every other month can be used.
A woman's lifetime risk of developing thyroid disease is approximately 15% and excess or a deficiency of thyroid hormone can affect a woman's menstrual cycle. The most common disorder is hypothyroidism and approximately two-thirds of women with hypothyroidism will develop an aberration of menses. Any woman who develops abnormal uterine bleeding, postpartum depression, premenstrual syndrome, or depression should be screened for thyroid disease (Table 35.4). The principal screening test for thyroid disease is a measurement of serum thyroid-stimulating hormone (TSH). No further testing is required if the TSH is within normal limits. If the TSH is low this suggests hyperthyroidism and measurement of free thyroxine (T4) and free triiodothyronine (T3) should be performed. If either one is elevated the diagnosis of hyperthyroidism is made. After diagnosing hyperthyroidism, a radioactive iodine uptake scan is performed. If the T4 and T3 are normal a diagnosis of subclinical hyperthyroidism may be entertained. If the TSH is high then a free T4 should be obtained. If the free T4 is low, replacement with synthetic thyroxine is begun. A dose of 25 µg per day of synthetic thyroxine is given and increased every 4 weeks by 25 µg per day until the patient's TSH normalizes and her clinical symptoms have resolved. Menstruation will usually return to normal 8 to 10 weeks after the patient has achieved a euthyroid state.
|
|
|
TABLE 35.4. Thyroid dysfunction: when to screen |
The most common hormonal disorder causing abnormal uterine bleeding is estrogenized anovulation (World Health Organization type II anovulation). Anovulatory bleeding in the past has been described as dysfunctional uterine bleeding. Dysfunctional uterine bleeding refers to bleeding unrelated to mechanical factors, iatrogenic causes, infectious agents, cancer, or pregnancy. There is no one particular pattern of bleeding that unequivocally defines dysfunctional uterine bleeding. A woman may present with anything from complete secondary amenorrhea to frank hemorrhage. Therefore, characterizing the menstrual flow is of no diagnostic advantage.
Syndromes of chronic anovulation can be grouped etiologically as either hypothalamic (central nervous system), adrenal (adrenal androgen production), ovarian (polycystic ovarian syndrome; PCOS), or perimenopausal in origin. None of these groups have a clear-cut laboratory profile and a precise classification often proves difficult. PCOS is one of the more confusing causes of chronic anovulation. The exact etiology of this syndrome remains elusive, although a large percentage of women with PCOS have been noted to have hyperinsulinemia secondary to insulin resistance. The National Institutes of Health (NIH) consensus conference has defined PCOS as amenorrhea or oligoovulation with clinical or biochemical evidence of hyperandrogenemia. While many authorities have frequently found insulin resistance in women with PCOS, there currently is no practical and reliable method to clinically diagnose insulin resistance. The use of insulin sensitizers in this group, despite being somewhat controversial, is enjoying widespread use, primarily for women desirous of pregnancy. Because of the controversy in the use of insulin sensitizers in the treatment of the abnormal uterine bleeding associated with PCOS, it is best to treat these patients with cyclic progestin, oral contraceptives, or clomiphene citrate if pregnancy is desired and reserve insulin sensitizers for those women in whom clomiphene citrate has failed and who want to become pregnant.
Another common hormonal cause of anovulatory uterine bleeding is the perimenopausal transition. Most women experience a 5- to 8-year transition from regular menstrual cycles to frank amenorrhea with an interval of abnormal uterine bleeding in between. This interval is marked by intervals of hypoestrogenism with symptoms such as hot flashes, irritability, and some vaginal atrophy, alternating with intervals of estrogenized anovulation. Usually the first sign of the perimenopausal transition is a shortening of the menstrual cycle accompanied by an increase in premenstrual symptomatology. Women over the age of 35 who present with a change in their mean menstrual cycle interval irrespective of other symptomatology who desire future childbearing should be screened for impending ovarian failure with a day 3 follicle-stimulating hormone (FSH) level. There are two therapeutic options for women with abnormal bleeding in the perimenopausal transition. The first is the cyclic administration of progestins. Typically, this is accomplished by the administration of 10 mg of medroxyprogesterone acetate for 14 days each month or every other month. This therapy may be associated with intermenstrual bleeding and occasionally may precipitate premenstrual symptoms. There is no place for the use of injectable progestins in the management of perimenopausal bleeding. The best choice to control abnormal bleeding in the perimenopausal transition, if the patient is a healthy nonsmoking woman, is the use of continuous combined oral contraceptives. The use of oral contraceptives in perimenopause will ease the transition by enforcing regular menstrual shedding, decrease blood loss, reduce premenstrual symptoms, preserve bone mass, and reduce the lifetime risks of endometrial and ovarian cancers without increasing the risk of breast cancer. The use of hormone replacement therapy, as used in frankly menopausal women, is to be discouraged as this provides additional estrogen and progestin without suppressing the endogenous production and thus increases the total amount of sex steroid exposure to the uterus.
Iatrogenic
Iatrogenic causes of abnormal uterine bleeding appear to be increasing as many drugs used for cancer, renal disease, and transplantation either mimic or modify endogenous hormones and cause abnormal uterine bleeding. Every woman presenting with a change in her menstrual cycle requires that a careful history be taken with respect to her general health as well as use of any prescription or over-the-counter medications. The physician should inquire about drugs prescribed within the past 6 months even if the patient is not currently taking any medications (Table 35.5). Drugs that can effect the menstrual cycle include prednisone, tamoxifen, coumadin, heparin, and Depo-Provera.
|
|
|
TABLE 35.5. Drugs associated with abnormal uterine bleeding |
Mechanical
Uterine leiomyomata are one of the most common causes of abnormal uterine bleeding and one of the leading causes of hysterectomy in the United States. Approximately one fourth of all women have uterine leiomyomata, but fortunately only a small fraction of that number will be clinically symptomatic and come to medical attention. Submucous or intracavitary myomas most commonly cause abnormal uterine bleeding. Submucous myomas may cause bleeding by frank erosion and ulceration of the endometrial surface, and intracavitary myomas prevent the normal hemostatic mechanisms required to stop normal menstruation. An intramural myoma may cause bleeding by creating large venous lakes and preventing the uterus from appropriately constricting blood vessels supplying the endometrium at the time of menstruation (Fig. 35.1). Bleeding from a myoma can vary from frank hemorrhage to slight intermenstrual spotting. Uterine leiomyomata are estrogen-dependent. Therefore, any agent that blocks estrogen's biosynthesis or action could theoretically cause regression of myoma. Currently, there is no medical therapy that truly causes regression of leiomyomata. GnRH agonists block gonadotropin secretion resulting in hypoestrogenism and, hence, cause a reduction in the size of the estrogen-dependent muscle cells within the myoma. However, there is rapid return of myoma volume and symptomatology once the GnRH agonist is discontinued and estrogen production by the ovary resumes. RU-486 and other antiprogesterone drugs have been shown to shrink myomas in clinical trials. The long-term effect of these agents on leiomyomata however is unknown. Depo-Provera is often effective in reducing the amount of abnormal bleeding and may even cause some regression in myoma size. Oral contraceptive agents do not cause regression of the myoma but they may stabilize the endometrium enough to effectively control the abnormal bleeding associated with uterine myoma. It is very reasonable to make an attempt to control abnormal uterine bleeding with a trial of oral contraceptive agents in women with leiomyomata before attempting more expensive and hazardous therapies. Despite the use of oral contraceptives, the abnormal bleeding in many women will not be controlled or they may not want to take oral contraceptives on a continuous basis. It is reasonable to consider a hysterectomy or a uterus-sparing operation such as myomectomy when more conservative medical methods have proven unsuccessful. There is not enough outcome evidence in the literature to recommend one surgical approach over the other. Until more data are available, management of uterine leiomyomata will remain empirical.
|
|
|
FIG. 35.1. Ultrasound of uterine leiomyoma. This is a transvaginal ultrasound in a woman who has an intramural myoma (arrows). The myoma clearly does not impinge on the endometrial cavity with intervening myometrium. The endometrial stripe is defined by a double arrow. |
Endometrial polyps are found in up to 50% of women presenting with abnormal uterine bleeding. There is no precise etiology for the formation of these polyps but they clearly originate from the endometrium. Detecting polyps can often be difficult. Endometrial polyps are best diagnosed by either hysteroscopy (Fig. 35.2) or saline infusion sonogram (SIS). The SIS is extremely sensitive but may overdiagnose the polyps. It is not uncommon at the time of hysteroscopy and dilation and curettage (D&C) for removal of the polyps diagnosed by SIS to find none present. Additionally, many small polyps will regress spontaneously. Since small polyps are found in asymptomatic women, the role of small endometrial polyps in a woman complaining of abnormal uterine bleeding is unknown.
|
|
|
FIG. 35.2. Hysteroscopic visualization of an endometrial polyp. An endometrial polyp is present on the anterior fundal aspect of the endometrial cavity (arrow). |
Infection
Infection is one of the most overlooked causes of abnormal uterine bleeding. Historically, endometritis has been considered a cause of abnormal uterine bleeding, despite a paucity of evidence in the literature. Endometritis is diagnosed by the finding of an increased number of plasma cells on endometrial biopsy. Culture of the endometrial cavity is not clinically useful and is complicated by the high rate of contamination by vaginal organisms. Studies have failed to show any significant endometrial infection associated with abnormal uterine bleeding. The absence of culture-positive studies and the subjective diagnostic criteria used casts doubt whether chronic endometritis truly causes abnormal uterine bleeding. However, endocervicitis is a known cause of abnormal bleeding, particularly intermenstrual and postcoital bleeding. It is appropriate for women with abnormal bleeding to have cultures or DNA probe tests performed for chlamydia and gonorrhea to rule out those organisms as a cause. Due to the false-negative rate of these diagnostic procedures it is often prudent to treat empirically for chlamydia, if no other cause is found.
Cancer
Endometrial and cervical cancers are uncommon yet important causes of abnormal uterine bleeding. Cervical cancer often presents with postcoital bleeding or irregular menstruation. Even if the patient has a normal Pap smear within the previous year it is prudent to repeat the smear, particularly if the patient has other risk factors for cervical cancer. Endometrial cancer remains a possibility in any woman presenting with abnormal uterine bleeding and endometrial biopsy should be performed in all women over the age of 35, the age at which the incidence begins to rise. Therapy will depend upon the staging of the disease. Complex endometrial hyperplasia with atypia is usually managed by simple hysterectomy. Other forms of hyperplasia may be safely managed with cyclic or continuous high-dose progestin therapy. If cyclic progestin is chosen, the minimum effective dose is 10 mg of medroxyprogesterone acetate for 14 days each month. Continuous progestin therapy is usually 20 to 40 mg of medroxyprogesterone acetate daily for 90 days. The use of a test-of-cure endometrial biopsy or hysteroscopy with curettage is controversial. However, it is reassuring to the patient and physician to document regression and uncover the rare progesterone receptor–negative hyperplasia.
IMAGING AND SPECIAL STUDIES IN THE MANAGEMENT OF ABNORMAL UTERINE BLEEDING
A transvaginal sonogram (TVS) has become an integral component of the evaluation of women with abnormal uterine bleeding. This is true even if the patient has a normal pelvic exam as the sonogram is focusing on the internal architecture of the uterus not necessarily the overall size. The use of TVS identifies small myoma, adenomyosis, and excessive endometrial thickness. The presence of these factors requires further evaluation with either biopsy or SIS. While TVS is necessary even if the patient has a normal pelvic exam, the TVS does not replace the health care provider performing a thorough and careful pelvic exam.
TVS and SIS in the Evaluation of Abnormal Uterine Bleeding
Hysteroscopy and D&C are not often used as primary diagnostic and therapeutic modalities. While office hysteroscopy does not require anesthesia, the procedure is expensive and requires an experienced operator as compared to TVS and endometrial biopsy. TVS allows acoustic visualization of the endometrium, ovaries, and the myometrium, which is more information than obtained by hysteroscopy. TVS is very sensitive for identification of leiomyomata that are greater 2 cm in diameter. TVS also has the ability to identify adenomyosis and endometrial polyps but its sensitivity and specificity for these conditions is lower. TVS has a 60% sensitivity and a 93% specificity for identifying pathology within the endometrial cavity. Still, TVS should be the first- line diagnostic modality when evaluating disorders of the myometrium and endometrium because of its simplicity and lack of risk. The sensitivity and specificity of TVS can be enhanced with the infusion of saline creating an SIS. Many other names have been used for this procedure including hydrosonogram, sonohysterosalpingography, and saline hysterosonography. No consensus for the appropriate terminology has been reached, but “saline infusion sonography” appears to be gaining acceptance due to its acronym SIS, which avoids confusion with old acronyms of HSG for hysterosalpingogram.
The endometrial thickness in women of reproductive age varies greatly. Still, it should be measured to enhance the sensitivity of TVS in predicting intrauterine pathology. When the endometrial thickness is greater than 8 mm consideration should be given to SIS. The accuracy and precision of SIS can be further enhanced with the addition of an endometrial biopsy. One study has suggested the sensitivity and specificity for the detection of intrauterine pathology at 97% and 70%, respectively, and a positive and negative predictive value of 82% and 94% compared with hysteroscopy/D&C or hysterectomy. Therefore, the use of endometrial biopsy and SIS to identify intrauterine pathology has displaced hysteroscopy and D&C as the primary procedure in the evaluation of abnormal uterine bleeding. Even though surgical evaluation is now a second-line procedure, the health care provider must still remember that hysteoscopy with curettage is more accurate than the less invasive office-based procedures and still has a place in the diagnosis and management of the patient with abnormal uterine bleeding.
The Role of MRI in the Evaluation of Women with Abnormal Uterine Bleeding
With the development of new high-field strength magnets the evaluation of the uterus by MRI has become much quicker and accurate. MRI has the advantage over computed tomography (CT) by not being limited by the surrounding bony structures. Compared to TVS, the MRI is less dependent on operator experience, uterine position, and size. The uterus on MRI is best seen on the T2 weighted sequence. Three regions within the uterus are normally identified: a central bright area that corresponds to the endometrium, another area of intermediate signal intensity that corresponds to the myometrium, and a third layer between the endometrium and myometrium that is hormonally sensitive and termed the junctional zone. The thickness signal characteristics of these three areas are evaluated independently when looking for uterine pathology. The greatest advantage of MRI is its ability to distinguish between adenomyosis and uterine leiomyomata. While both of these conditions can cause pelvic pain, typically increasing dysmenorrhea as well as abnormal bleeding, there are patients who desire future fertility or for other reasons desire to preserve their uterus and the conservative operations are different for each condition. The MRI image has a sensitivity of 86% and a positive predictive value of 65% in detecting the presence of adenomyosis when junctional zone thickening is greater than 12 mm. The MRI can also be used to determine whether the adenomyosis is diffuse or superficial. If the adenomyosis is superficial it can successfully be treated with roller-ball endometrial ablation, whereas deep adenomyosis is best treated by hysterectomy. Additionally, the MRI has the ability to accurately define myoma less than 2 cm, the limit of TVS. This is important for women undergoing in vitro fertilization. MRI is becoming an efficient and cost-effective complementary tool and may soon supplant hysteroscopy as the second-line diagnostic modality in abnormal uterine bleeding.
MANAGEMENT OF SPECIAL SITUATIONS
Acute Hemorrhage
It is not uncommon for women with chronic anovulation or uterine leiomyomata to present to the emergency department with acute hemorrhage and symptoms of hypovolemia. These patients need rapid control of their hemorrhage and a clinical decision has to be made quickly as to whether to proceed to the operating room or to make an attempt at medical control. If the patient is hemodynamically unstable, a D&C is indicated as it will result in immediate cessation of the bleeding and allow time for transfusion and correction of the underlying pathology. If the patient is stable enough to attempt medical management, fluid resuscitation is begun. Blood products are then given as necessary and high-dose parenteral estrogen therapy initiated. The high dose of estrogen will initiate endometrial proliferation and increase fibrinogen as well as factors V and IX, but most important, it promotes platelet aggregation and clotting at the capillary level. It is appropriate to use i.v. estrogen even when the patient has uterine leiomyomata. Both i.v. and p.o. estrogen work equally as well but the parenteral route is usually chosen if the clinical situation requires rapid cessation of the blood loss. Intravenous conjugated estrogen is given 25 mg every 4 hours until the bleeding stops. The oral regimen is equally efficacious and consists of 2.5 mg conjugated estrogen or 2 mg of micronized estradiol every 4 hours for 24 hours followed by a single daily dose for 7 to 10 days. If the bleeding persists for more than 12 to 24 hours with either one of these regimens, a D&C is indicated. Whether the estrogen is given i.v. or p.o., a progestin should be started at the same time and continued for 5 to 7 days at which time the patient should expect a withdraw bleed. If the patient is not having acute hemorrhage but rather is having heavy menstrual flow and becoming anemic then the use of high-dose oral contraceptives may be considered. In these cases the patient is given 4 pills containing 30 to 35 µg of ethinyl estradiol for 4 days followed by 3 pills for 7 days followed by 2 pills for 11 days then 1 pill a day thereafter. Hysterectomy should be considered in women who have completed childbearing and when medical management has failed.
Menorrhagia
Menorrhagia affects approximately 15% to 20% of women presenting with abnormal uterine bleeding and causes significant social inconvenience as well as the potential for significant anemia. The first line of therapy for the treatment of women with menorrhagia is antiprostaglandin agents, the cyclooxygenase inhibitors or nonsteroidal antiinflammatory drugs (NSAIDs). Women with menorrhagia have significantly higher levels of prostaglandin E (PGE) when compared to prostaglandin F2α. The antiprostaglandin agents affect the balance between PGE and thromboxane. Many prospective trials have shown use of NSAIDs beginning on the day of menstruation and continued throughout menses significantly decrease blood loss. The use of the cyclooxygenase-1 (COX-1) class of agents is contraindicated in women with peptic ulcer disease, asthma, and allergy to aspirin. Numerous regimens have been used all with similar efficacy: mefenamic acid 500 mg t.i.d., ibuprofen 400 mg t.i.d., and naproxen sodium 275 mg q6h after a loading dose of 550 mg. All these regimens have demonstrated a significant decrease in blood loss. The newer COX-2 inhibitors have markedly fewer problems and inhibit the same COX enzyme, but have not been tested in clinical trials. They may improve the overall success of this approach with fewer side effects.
Another strategy, using the levonorgestrel intrauterine device (IUD), has recently been introduced. Several controlled trials have shown that its use significantly decreases the amount of menstrual blood lost per cycle by causing an intense atrophy of the endometrium. The levonorgestrel IUD should be considered in any woman who needs contraception and who is experiencing menorrhagia. If these therapies fail to control the problem, oral contraceptives can also be considered. Surgical therapy should be considered when medical management has failed or is medically contraindicated. Surgical therapy consists of either endometrial ablation or hysterectomy. Endometrial ablation by any technique is reported to provide 90% to 95% patient satisfaction, with amenorrhea being achieved in approximately 50% of patients. Unfortunately, the long-term problems associated with endometrial ablation are not known. With regard to hormone therapy after menopause, the patient having endometrial ablation must be regarded as having fully responsive endometrium. There is a theoretical risk of concealed endometrial cancer, but this has not been reported to date. Hysterectomy results in amenorrhea 100% of the time and has a higher patient satisfaction rate than endometrial resection 2 years after the procedure.
Abnormal Bleeding on Oral Contraceptives
Abnormal bleeding on oral contraceptives is usually due to an insufficient amount of estrogen in a particular pill to stabilize the endometrium. Strategies to control the bleeding involve increasing the estrogen content of the pill, changing to a different birth control pill which increases the estrogen/progestin ratio, or giving supplemental estrogen. Since most noncompliance with oral contraceptives is related to the progestin content and if a patient is comfortable with the side effects in her particular pill, an attempt should be made to continue with that level of progestin and add supplemental estrogen, either 1.25 mg conjugated estrogen or 2 mg of estradiol starting at the time the patient bleeds and continuing for 7 days. This regimen is repeated at the same time for two consecutive months whether or not the patient has spotting in the two subsequent cycles.
Alternatively, the patient can simply use a pill with a higher estrogen/progestin ratio or a higher-dose estrogen pill to determine if that will be sufficient to control the bleeding. If the patient fails to respond to these regimens then other factors need to be assessed. Abnormal bleeding on pills is significantly increased in women who smoke, due to enhanced estrogen clearance, and when taking antibiotics because of alterations in absorption. All efforts should be made to have the patient stop smoking. Additionally, cultures or DNA probe for chlamydia should be obtained as endocervicitis-related chlamydia is a significant cause of abnormal bleeding in women on birth control pills.
Abnormal Bleeding in Perimenopause
The most common cause of abnormal uterine bleeding in the perimenopausal woman is estrogenized anovulation. Still, every woman in this category needs a complete evaluation as detailed earlier in this chapter, particularly as they are now in the age range where the incidence of endometrial cancer is beginning to be significant. Attributing the abnormal uterine bleeding to the perimenopausal transition is a diagnosis of exclusion and can only be made after a through evaluation. Therapy with oral contraceptives should be initiated provided the patient has no contraindication to their use, primarily smoking. Oral contraceptives have been shown to decrease the amount of blood loss associated with menstruation providing cycle regulation and relief from menorrhagia. Additionally, oral contraceptive agents preserve bone mass during a time when occult bone loss may be occurring. Most significantly, oral contraceptive agents provide reduction in the risk of endometrial and ovarian cancer for 10 to 15 years following their discontinuation. Every effort should be made to encourage the use of oral contraceptives in all perimenopausal woman.
SUMMARY POINTS
· Use of the mnemonic PHIMIC (pregnancy, hormones, iatrogenic, mechanical, infection, and cancer) offers a simplified yet complete approach to the evaluation of abnormal uterine bleeding. Patients presenting with abnormal uterine bleeding should have a pregnancy test, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, Pap smear, DNA probe for gonorrhea and chlamydia, and a transvaginal ultrasound.
· Estrogenized anovulation is the most common cause of abnormal uterine bleeding. Anovulation may be caused by a variety of conditions, including elevated prolactin, hyper- or hypothyroidism, adrenal disorders, and polycystic ovarian syndrome (hyperandrogenic anovulation).
· Von Willebrand disease should be considered in any young woman experiencing menorrhagia within 1 year of menarche.
· No therapeutic advantage of intravenous estrogen over oral estrogen in the control of acute hemorrhage is known.
· Saline infusion sonography and endometrial biopsy, when performed together, have a 97% sensitivity and 70% specificity in determining intrauterine pathology.
· MRI can reliably differentiate between deep and superficial adenomyosis. MRI can accurately identify leiomyomata less that 2 cm in size and determine their location.
SUGGESTED READINGS
Diagnosis
1. Cote, I, Jacobs P, Cumming D. Work loss associated with increased menstrual loss in the United States. Obstet Gynecol 2002;100:683–687.
2. Farquhar CM, Steiner CA. Hysterectomy rates in the United States 1990–1997. Obstet Gynecol 2002;99:229–234.
3. Livingstone M, Fraser IS. Mechanisms of abnormal uterine bleeding. Hum Reprod Update 2002;222:619–627.
4. Long C, Gast M. Menorrhagia in menstrual cycle disorders. In: London SN, Chihal HJ, eds. Obstet Gynecol Clin North Am 1990;17:343–359.
5. Munro MG. Dysfunctional uterine bleeding: advances in diagnosis and treatment. Curr Opin Obstet Gynecol 2001;13:475–489.
6. Robins JC. Therapies for the treatment of abnormal uterine bleeding. Curr Womens Health Rep 2001;1:196–201.
Pregnancy
7. Storring PL, Gaines-Das RE, Bangham DR. International reference preparation of human chorionic gonadotropin for immunoassay: potency estimates in various bioassays and protein binding assay systems; and international reference preparations of the alpha and beta subunits of human chorionic gonadotropin for immunoassay. J Endocrinol 1980;84:295.
8. Stovall TG, Ling FW. Ectopic pregnancy: diagnostic and therapeutic algorithms minimizing surgical intervention. J Reprod Med 1993;38:807.
Hormones
9. ACOG Committee Opinion. Von Willebrands disease in gynecologic practice. Int J Gynaecol Obstet 2002;76:336–337.
10. Ayala AR, Danese MD, Ladenson PW. When to treat mild hypothyroidism. Endocrinol Metab Clin North Am 2000;29:399–415.
11. Falcone T, Desjardins C, Bourque J, et al. Dysfunctional bleeding in adolescents. J Reprod Med 1994;39:761–764.
12. Freda PU, Wardlaw SL. Clinical review 110: diagnosis and treatment of pituitary tumors. J Clin Endocrinol Metab 1999;84:3859–3866.
13. Goodman-Gruen D, Hollenbach K. The prevalence of von Willebrand disease in women with abnormal uterine bleeding. J Womens Health Gend Based Med 2001;10:677–680.
14. Taylor AE. Insulin-lowering medications in polycystic ovary syndrome. Obstet Gynecol Clin North Am 2000;27:583–595.
Iatrogenic
15. Shwayder JM. Pathophysiology of abnormal uterine bleeding. Obstet Gynecol Clin North Am 2000;27:219–234.
Mechanical
16. DeWaay DJ, Syrop CH, Nygaard IE, et al. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002;100:3–7.
17. Myers ER, Barber MD, Gustilo-Ashby T, et al. Management of uterine leiomyomata: what do we really know. Obstet Gynecol 2002;100:8–17.
18. Santen RJ. To block estrogen's synthesis or action: that is the question. J Clin Endocrinol Metab 2002;87:3007–3012.
Infection
19. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol1989;160:126–131.
20. Pizarro AR, Jamison R, Matthews-Greer J, et al. Organism-specific chronic endometritis is not a cause of abnormal uterine bleeding. J Pelvic Surg7:147–150.
Cancer
21. Clark T, Mann CH, Shah N, et al. Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial cancer: a systematic quantitative review. Br J Obstet Gynecol 2002;109:313–321.
22. Clark TJ, Mann CH, Shah N, et al. Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial hyperplasia. Acta Obstet Gynecol Scand2001;80:784–793.
23. Clark TJ, Voit D, Gupta JK, et al. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA 2002;288:1610–1621.
Imaging and Special Studies in the Management of Abnormal Uterine Bleeding
24. Bradley LD, Falcone T, Magen AB. Radiographic imaging techniques for the diagnosis of abnormal uterine bleeding. Obstet Gynecol Clin North Am2000;2:245–276.
25. de Vries LD, Dijkhuizen PHLJ, Mol BWJ, et al. Comparison of transvaginal sonography, saline infusion sonography, and hysteroscopy in premenopausal women and abnormal uterine bleeding. J Clin Ultrasound 2000;28:217–223.
26. Dueholm M, Lundorf E, Olesen F. Imaging techniques for evaluation of the uterine cavity and endometrium in premenopausal patients before minimally invasive surgery. Obstet Gynecol Surv 2002;57:388–403.
27. Mihm LM. The accuracy of endometrial biopsy and saline sonohysterography in the determination of the cause of abnormal uterine bleeding. Am J Obstet Gynecol 2002;186:858–860.
Management of Special Situations
Acute Hemorrhage
28. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding—a double-blind randomized control study.Obstet Gynecol 1982;59:285–291.
Menorrhagia
29. Fedele L, Bianchi S, Raffaelli R, et al. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel releasing intrauterine device. Fertil Steril 1997;68:426–429.
Abnormal Bleeding on Oral Contraceptives
30. Jones GL. Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review. Am J Obstet Gynecol2002;187:501–511.
Abnormal Bleeding in Perimenopause
31. Jensen JT. Health Benefits of Oral Contraceptives. Obstet Gynecol Clin North Am 2000;27:705–721.
