Pelvic lacerations/trauma Intrauterine device Intravaginal foreign body
Drug-related (including hormonally active agents)
Modified from: Phipps WR. Abnormal vaginal bleeding. In: Leppert PC, Peipert JF, eds. Primary Care for Women, 2nd Ed. Philadelph
excluded with reasonable certainty prior to treatment. Accordingly, the diagnosis of either anovulatory or ovulatory DUB is one of exclusion.
The pathophysiology and optimal treatment of anovulatory DUB are best understood by comparison to the bleeding that occurs as part of the normal menstrual cycle. In the follicular or proliferative phase of the cycle, estradiol produced by the enlarging dominant follicle causes endometrial glands and stroma to proliferate. After ovulation, during the luteal or secretory phase, the corpus luteum produces large amounts of progesterone in addition to estrogen, resulting in secretory changes in the endometrium. In the absence of pregnancy and the secretion of human chori-onic gonadotropin, regression of the corpus luteum is associated with the withdrawal of progesterone and estrogen. The result is a normal menses, an orderly and self-limited event that involves desquamation of the entire endometrium.
The initiation of normal menstruation involves enzymatic degradation of the functional layer of the endometrium and associated breakdown of blood vessels. Subsequent hemostasis is provided first by normal coagulation mechanisms and then by arterial vasoconstriction and reepithelialization. The normal coagulation mechanisms include the formation of platelet plugs, involving von Willebrand factor (VWF), as well as thrombin-induced fibrin generation. Typically, clots are not passed because of endometrial fibrinolytic proteins that promote clot liquefaction.
Unlike normal menstrual bleeding, anovulatory DUB involves exposure of the endometrium to estrogen unopposed by progesterone for relatively long time periods. This leads to abnormally high and structurally unstable endometrium. The tissue is delicate and undergoes essentially spontaneous breakdown with associated bleeding related to the presence of increased numbers of often dilated, irregular, and fragile venous capillaries. The process is not an orderly one, may go on more or less indefinitely, and involves different portions of the endometrium at different times. Additionally, clot passage may occur on the basis of an exhaustion of endometrial fibrinolytic proteins.
Ovulatory DUB differs from anovulatory DUB in that ovulation occurs on a regular basis, and thus the abnormal bleeding usually has a regular pattern. The heavy nature of ovulatory DUB is thought in part to be a consequence of abnormal arachidonic acid metabolism on endometrial function with excess production of vasodilatory as opposed to vasoconstrictive prostaglandins. As well, women with ovulatory DUB have been shown to have abnormally increased levels of endome-trial fibrinolysis.
As for other causes of abnormal vaginal bleeding, pregnancy-related bleeding may occur in both abnormal and essentially normal pregnancies, and thus the possibility of pregnancy must always be considered prior to intervention. In particular it is important to make a diagnosis of an ectopic pregnancy as early as possible, allowing for early medical or surgical treatment. The abnormal bleeding that occurs vaginally during a tubal pregnancy is nearly always a consequence of endometrial shedding secondary to abnormal corpus luteum function. This bleeding often precedes pelvic pain symptoms which are generally a consequence of tubal rupture and/ or intrapelvic bleeding.
The possibilities of a disorder of hemostasis or both benign and malignant anatomic lesions should also be considered in all patients presenting with abnormal vaginal bleeding. In particular platelet disorders often present as menor-rhagia, especially in adolescents. In older patients, malignancies are relatively more common, and it is especially important to rule out endometrial hyperplasia and adenocarcinoma. In this same vein, cancer always needs to be ruled out in the presence of any bleeding that occurs in a postmenopausal woman who is not taking hormone replacement therapy. The mechanisms by which heavy abnormal bleeding occurs in conditions such as uterine myomas and endometrial cancer are not well understood, but in many cases large and fragile surface blood vessels are present, seemingly related to the release of angiogenic factors produced by the tumors themselves.
A careful history is of course essential to the management of any patient presenting with abnormal bleeding. The date of onset of the presenting episode and her prior menstrual history need to be determined along with the presence of concomitant symptoms of any kind. Also important are the patient's general obstetrical and gynecologic history, including her pregnancy and infertility history, prior pelvic surgeries, abnormalities noted on prior exams, Pap smear results, and contraceptive method. A history of any significant medical problems should be noted, and inquiries made about symptoms suggestive of endocrine and bleeding disorders and about family members having similar problems.
The typical history in cases of anovulatory DUB is one of irregular episodes of often painless bleeding occurring in an unpredictable fashion with episodes ranging from a day of spotting to several weeks of continuous, heavy bleeding, often with passage of clots vaginally. Long periods of amenorrhea may or may not be interspersed among bleeding episodes. The cyclic symptoms of mittelschmerz and premenstrual molimina are absent. Patients particularly at risk include postmenarchal teenagers, women with polycystic ovarian syndrome or obesity-related ovulatory dysfunction, and perimenopausal women, up to 50% of whom report episodes of heavy abnormal bleeding.
Women with ovulatory DUB in general present with menorrhagia. Monthly blood loss greater than 80 ml is considered abnormal and often associated with iron-deficiency anemia. As a practical matter, it is difficult to precisely quantify blood loss, and thus decisions about both investigating and treating a patient for menorrhagia largely hinge on her subjective complaints. If a more objective assessment is desired for whatever reason, however, the quantity of flow can be assessed by using a pictorial blood flow chart developed by Higham et al. Less accurately, the number of standard tampons or pads used by a patient during her menses can be counted, with each standard tampon or pad corresponding very roughly to 5 ml of blood loss.
A history of mucocutaneous bleeding, such as epistaxis, gingival bleeding, or easy bruising, may suggest von Willebrand disease (VWD), idiopathic thrombocytopenia purpura, or another bleeding diathesis. In particular patients with VWD, the most common bleeding disorder of hemostasis, often have a history of excessive menstrual bleeding since menarche, postpartum hemorrhage, bleeding associated with surgery or dental procedures, or anemia. Von Willebrand disease is an autosomal-dominant condition with considerable molecular and clinical heterogeneity. It has an overall prevalence of about 1%, and in particular should be considered when an adolescent patient presents with abnormal uterine bleeding. The family history may not always be helpful, because of the variable penetrance associated with mild to moderate VWD (type 1), and because males especially may not be symptomatic. Of note, individuals with blood type O have on average 25% lower von Willebrand factor (VWF) levels, and on this basis many women have what can considered to be a relatively mild nongenetic form of VWD, as opposed to having an inherited mutation involving the von Willebrand protein gene. Furthermore, hypothyroidism can result in an acquired form of VWD, which resolves with thyroid replacement.
The history will also often provide diagnostic clues when a benign or malignant anatomic lesion is the cause of abnormal bleeding. An enlarging submucosal myoma in a patient with regular menstrual cycles will often present with a regular bleeding pattern associated with a gradually increasing amount and/or duration of bleeding over time, and perhaps increasing dysmenorrhea. Ovulatory women with bleeding from an endometrial or endocervical polyp may present with a pattern of erratic bleeding episodes essentially superimposed on a normal menstrual cycle pattern. Women with endometrial hyperplasia or adenocarcinoma will often have a long history of obvious anovulation and symptoms consistent with polycystic ovarian syndrome.
It is also important to note that some women with conditions usually associated with menorrhagia, such as ovulatory DUB, a submucosal myoma, or a bleeding diathesis, may be oligo-ovulatory. Accordingly such women would be expected to present with irregular and heavy menses, mimicking the usual pattern encountered with anovulatory DUB. Other combinations of causes may also be present, and thus in general the identification of one cause should not necessarily preclude a search for others that may be contributing to an individual patient's abnormal bleeding symptoms.
In cases of abnormal vaginal bleeding, a careful physical exam may reveal findings pointing towards a specific diagnosis. Obviously the patient's vital signs are important, especially in the presence of acute or substantial bleeding, or when an abnormal pregnancy may be present, situations in which immediate surgical or medical intervention may be in order. The presence of a goiter may suggest hy-pothyroidism, and acne and hirsutism may suggest polycystic ovarian syndrome (PCOS), often associated with anovulatory DUB. The pelvic exam is particularly important. The vagina and cervix should be thoroughly inspected for lesions, and the amount of ongoing bleeding noted. Bimanual exam may reveal evidence for an intrauterine or ectopic pregnancy, uterine myomas or adenomyosis, a Mullerian anomaly with partial outflow obstruction, or an ongoing pelvic infection.
Laboratory, Imaging and Other Diagnostic Studies
Decisions about what diagnostic studies should be performed in cases of abnormal vaginal bleeding need to be individualized. Table 4.3 provides a list of evaluative measures that should be considered, and most patients should at least have a complete blood cell count (CBC) that includes platelets if not done recently. In general, it is mandatory to rule out pregnancy with a serum or sensitive urine pregnancy test in anyone that could possibly be pregnant, regardless of contraceptive method or the specific bleeding pattern present. If pregnancy is not present, most premeno-pausal women should have their ovulatory status established. This may involve basal body temperature charting, serum progesterone determinations, or endometrial sampling. Given the high prevalence of autoimmune thyroid disease in women, the concentration of thyroid-stimulating hormone (TSH) should also be routinely assessed, even in the absence of more specific evidence for thyroid disease.
Table 4.3. Diagnostic studies in cases of abnormal vaginal bleeding Rationale, Comments
To assess for anemia and to rule out thrombocytopenic bleeding.
About two thirds of patients with menorrhagia are iron-deficient.
Mandatory whenever the possibility of pregnancy is present.
May be particularly useful in of ovulatory DUB when the diagnosis is unclear and for monitoring treatment results.
Women with hypothyroidism may have DUB on the basis of ovulatory dysfunction and acquired VWD.
Progesterone levels may be used to assess for either regular or irregular ovulation. Other hormonal testing may be needed to delineate the nature of ovulatory dysfunction (e.g., PCOS, impending menopause, or hyperprolactinemia).
Either test can be used to screen for platelet dysfunction. The PFA-100 closure time is more reproducible and is substantially more sensitive than the BT for VWD but is still often normal in mild cases of VWD.
In cases of an inherited procoagulant deficiency, or bleeding due to chronic liver disease or vitamin K deficiency, the PT or aPTT is generally abnormal, but these tests frequently do not identify several common disorders of hemostasis. Patients with VWD generally have abnormal VWF antigen, ristocedin cofactor assay of VWF, and factor VIII results.
Individuals with blood type O have decreased VWF and factor VIII levels.
Sensitivity for detecting intracavitary lesions similar to that of hysteroscopy.
Less sensitive for detection of intracavitary lesions than SSH or hysteroscopy, but may be warranted when a less common Mullerian anomaly is suspected or in infertilty patients when tubal status is also a concern.
Particularly helpful when adenomyosis is suspected and other testing is nondiagnostic.
Miniaturized instrumentation may allow for coupling of diagnostic and therapeutic procedures in the office setting.
Critically important if concern about hyperplasia, adenocarcinoma, or endometritis.
Iron profile (serum iron, total iron binding capacity, ferritin)
Serum or sensitive urine pregnancy test
Pictorial blood assessment charting
Other endocrine studies
Ivy BT and/or PFA-100 closure time
PT, aPTT, VWF antigen, ristocedin cofactor assay of VWF, factor VIII
Saline sonohysterogram Hysterosalpingogram
Especially younger patients should usually be assessed for the presence of disorders of hemostasis. When such a disorder is suspected, in addition to a CBC, testing should include a prothrombin time (PT), an activated partial thromboplastin time (aPTT), an Ivy bleeding time (BT) and/or platelet function analyzer-100 (PFA-100) closure time, as well as studies more specific for VWD, namely the ristocetin cofac-tor assay of VWF, quantification of VWF antigen, and a factor VIII assay. In this context both the BT and the PFA-100 closure time serve to screen nonspecifically for platelet dysfunction, but these tests, especially the BT, have relatively poor sensitivity for VWD. Furthermore, even if the more specific tests to assess for VWD are done, its diagnosis can still be problematic as the results can be ambiguous. Consultation with a hematologist may be in order in such cases, as well as in cases with negative results but nonetheless a high level of suspicion for a bleeding diathesis. In both of these situations, additional testing, especially platelet aggregation and release studies, may be warranted, but the determination of what testing is appropriate is best left to the consulting hematologist.
Particularly when there is a distinct possibility of an anatomic lesion, a variety of imaging studies may be of use, but again the specific studies warranted depend on the individual circumstances. Transvaginal ultrasonography may immediately reveal obvious lesions such as submucosal or intramural myomas, adenomyosis, or polyps, but especially in premenopausal women both polyps and myomas associated with cavity distortion are frequently missed. Thus in many cases the instillation of saline solution into the uterus coupled with real-time ultrasonography, or a saline sonohysterogram (SSH), should be performed. This allows for much better delineation of intracavitary mass lesions, with sensitivity very similar to that of hysteros-copy. Transvaginal ultrasonography by itself, however, can be particularly helpful in cases of younger obviously anovulatory patients when there is concern about the possibility of endometrial hyperplasia or adenocarcinoma. In such cases, a thicker endometrial lining (greater than 10-11 mm) as measured by ultrasound should lower the threshold for performing an endometrial biopsy. Transvaginal ultrasonography by itself is also useful in cases of postmenopausal bleeding in that an endometrial thickness measurement of less than 4-5 mm makes endometrial cancer very unlikely, thus obviating the need for an endometrial biopsy.
Another option to evaluate the anatomy of the uterine cavity is of course the hysterosalpingogram (HSG), which has the additional benefit of assessing for tubal disease in cases of abnormal bleeding in which infertility is also an issue. However, the HSG has inferior sensitivity and specificity as compared to SSH for detecting intracavitary mass lesions and should not be done routinely in cases of abnormal bleeding. An exception is situations in which an unusual Mullerian anomaly is suspected, for example uterus didelphys in combination with an obstructed hemivagina in which partial outflow obstruction can occur and result in an abnormal bleeding pattern. Pelvic magnetic resonance imaging (MRI) may also occasionally be warranted, especially in cases in which other imaging studies are inconclusive and an unusual Mullerian anomaly or adenomyosis is suspected.
Hysteroscopy is another diagnostic measure that should be considered early on, particularly if this can be done in an office setting using a flexible instrument with a small outer diameter. Hysteroscopy is better for assessing for focal lesions such as polyps or submucosal myomas than for diffuse lesions such as endometrial hyper-plasia, but is still considered to be highly accurate for the detection of frank en-dometrial adenocarcinoma. One advantage of office hysteroscopy over SSH is the increasingly available option of performing directed biopsies or removing focal lesions such as small endometrial or endocervical polyps.
When a tentative diagnosis of anovulatory DUB is made, the decision about whether or not to perform endometrial sampling depends primarily on the risk for endometrial hyperplasia or adenocarcinoma, two conditions that also occur as a consequence of chronic anovulation. Most women older than 35 and virtually all women older than 40 who present with apparent anovulatory bleeding should undergo endometrial sampling, as should many younger women with a long history of anovulation, particularly if obesity, hyperinsulinemia, or a thick endometrial stripe by ultrasound is present. Such sampling can usually be accomplished easily in the office setting using a Pipelle endometrial suction curette or similar device. From a diagnostic standpoint, there is little if any place for traditional dilatation and curet-tage, except in conjunction with hysteroscopy.
Once a diagnosis of either anovulatory or ovulatory DUB is made, either tentatively or more definitively, treatment is tailored to the individual circumstances of the case. These include a host of factors, including the degree of ongoing bleeding and the presence or absence of hemodynamic stability, whether or not causes of bleeding other than DUB are also present, and future fertility considerations. The focus of the treatment modalities discussed here is those for DUB, but many of these same modalities may be indicated for other causes of abnormal bleeding. For example, many of the treatments effective in cases of ovulatory DUB can also be applied successfully in cases of VWD.
For women with apparent anovulatory DUB, following initial diagnostic measures, the first goal of therapy is to stop the acute bleeding episode. This can nearly always be accomplished without surgical intervention. If uterine curettage is performed, this by itself does provide a substantial acute therapeutic effect, although in general there is no reason not to start medical therapy immediately after endome-trial sampling of any kind. In most cases of anovulatory DUB, the bleeding can be stopped with the administration of a progestin. A typical progestin regimen is medroxyprogesterone acetate (MPA), 10-20 mg orally once daily for 10 days. This will usually stop the bleeding during the time it is being administered followed by more or less orderly withdrawal bleeding starting immediately after the MPA is discontinued. This sequence of events is similar to that of the secretory phase of the normal cycle. It is important to advise the patient at risk for pregnancy that occasionally ovulation will occur as a result of progestin administration and that she should expect to have bleeding after it has been stopped.
Another therapeutic option useful in stopping acute anovulatory DUB involves oral contraceptives (OCs), each containing 30-35 |ig of ethinyl estradiol and a progestin. A variety of regimens may be used, including, for example, having the patient take 2-4 pills daily for five days, which will often bring the bleeding to a halt within one or two days, followed by another 21 days of one pill daily, after which withdrawal bleeding can be expected. For the patient who has been bleeding heavily for a prolonged period of time, with little residual endometrial tissue, it may be best to initially use high-dose estrogen therapy, for example conjugated estrogens (Premarin), 25 mg by intravenous bolus every 4 hours for two or three doses. The immediate improvement with such therapy is due more to a pharmacologic effect of estrogen on small vessel hemostasis than to estrogen's ability to cause proliferation and healing of endometrial tissue. Once the bleeding has stopped in response to such treatment, in general an OC regimen should be started.
Patients diagnosed as having anovulatory DUB, but not responsive to the regimens outlined above, require additional evaluation. This may include endometrial sampling if not previously performed, SSH, or hysteroscopy.
Once the acute episode of anovulatory DUB has been treated, attention is directed towards the possible need for long-term treatment. For the patient who is usually ovulatory, for whom it is thought that the bleeding episode just treated is unlikely to recur, a period of observation may be all that is necessary. On the other hand, some form of chronic therapy is indicated for patients whose anovulatory state responsible for the DUB is unlikely to abate spontaneously. The goals of this long-term therapy, which must include a progestin component, are to prevent recurrences of the unpredictable bleeding episodes, prevent endometrial hyperplasia, and lower the patient's risk for endometrial cancer. Iron supplementation should be started at this time, if indicated.
Long-term treatment with OCs in the usual cyclic fashion is the best treatment for most patients with anovulatory DUB, although some patients may prefer extended-cycle OCs. Treatment with OCs is particularly useful for those women who occasionally undergo spontaneous ovulation and need birth control, as well as those with polycystic ovarian syndrome, because of amelioration of the associated hyperandrogenism. Patients who are not candidates for OC use may be treated with cyclic progestin treatment, for example, MPA, 10 mg orally once daily the first 10-14 days of each month, or even every second or third month. Anovulatory women with DUB who desire pregnancy should of course have an appropriate hormonal evaluation followed by initiation of ovulation induction therapy.
Patients diagnosed as having ovulatory DUB can be treated successfully with several different regimens, both hormonal and nonhormonal in nature. These include OCs or a nonsteroidal anti-inflammatory drug (NSAID) regimen, such as ibuprofen, 400 mg orally every 6 hours, starting on cycle day 1 and continuing through cessation of menses. Both of these treatments not only decrease the amount of bleeding, but also address the often associated problem of dysmenorrhea. The mechanism by which NSAIDs work is not entirely clear, but appears to involve a disproportionate reduction in the uterine concentrations of vasodilatory prostaglan-dins as compared to that of the prostaglandin F2a, a potent vasoconstrictor.
Another possible treatment modality for ovulatory DUB is an antifibrinolytic agent, such as epsilon aminocaproic acid. In particular, there is strong evidence that the antifibrinolytic agent tranexamic acid is very effective, but unfortunately this agent is not generally available in the United States. Still another option is danazol, for example, 200 mg orally daily. Most patients taking such a dose continue to experience regular menses, and androgenic side effects may be a problem. Furthermore, barrier contraception is needed if the patient is sexually active.
An option for ovulatory DUB that may be underutilized in the United States is the Mirena levonorgestrel-releasing intrauterine system (LNG-IUS). The LNG-IUS is an intrauterine device designed to release 20 |ig of the progestin levonorgestrel daily over a period of 5 years. Although only approved in this country as a birth control measure, many studies have shown the LNG-IUS to be highly effectively for ovulatory DUB, with large reductions (greater than 80%) of blood loss, and overall outcomes comparable to those achieved with endometrial ablation. The effects seen are primarily on the basis of local endometrial effects, as a substantial majority of ovulatory women using the LNG-IUS continue to ovulate regularly. Interestingly, despite continued ovulation, women with endometriosis and ovulatory DUB have reduced dysmenorrhea symptoms after LNG-IUS insertion. Furthermore, women with abnormal bleeding attributed to myomas also experience decreased bleeding after LNG-IUS insertion, and the device provides effective treatment for endome-trial hyperplasia. For women with ovulatory DUB, the most common side effect is breakthrough bleeding, and there is an increased risk of functional cyst formation.
At times, patients with either anovulatory or ovulatory DUB have a consistently poor response to the long-term medical options described, or unacceptable side effects. In that situation, consideration may be given to treatment with a long-acting gonadotropin releasing hormone (GnRH) agonist, such as leuprolide acetate, to induce a menopause-like state. Long-term treatment with a GnRH agonist for most patients is problematic, however, because of the adverse effects on bone density as well as vasomotor symptoms. Thus in general, a patient with DUB failing to respond to the regimens described is best treated surgically, particularly if the patient is older and future fertility is not a concern.
Long-term surgical options for DUB include hysterectomy and endometrial ablation. Both can be performed using several different approaches. Hysterectomy is clearly the most definitive treatment for DUB and can be done by laparotomy, laparoscopically, or vaginally, with the best approach for a given patient determined by the individual circumstances involved. The ovaries may be preserved. In general, hysterectomy is associated with more complications than ablation procedures but also higher long-term patient satisfaction rates and substantially lower rates of the need for repeat surgery. Furthermore women at increased risk for endometrial hy-perplasia or adenocarcinoma are not good candidates for ablation.
For many patients, however, despite the advantages of hysterectomy, endome-trial ablation may be a better choice, particularly if the goal is not amenorrhea. This may be because of medical reasons, such as surgical risks for hysterectomy, or personal preference, such as the desire to avoid a more major surgery. Generally about 40% of women experience amenorrhea after ablation, and a similar proportion experience significantly reduced bleeding. There are now many options available for ablation, both hysteroscopic and nonhysteroscopic, as recently reviewed by Shirk. If a nonhysteroscopic approach is used, in general a diagnostic hysteroscopy should be done beforehand. This primarily has to do with not missing lesions such as carcinomas or submucosal myomas.
Summary and Key Points
1. Many women with abnormal vaginal bleeding have either anovulatory or ovulatory DUB. The diagnosis of DUB is one of exclusion.
2. Diagnostic studies in cases of abnormal bleeding need to be tailored to the individual circumstances present. It is important to rule out pregnancy in any woman presenting with abnormal bleeding. The possibility of a disorder of hemostasis should also always be considered.
3. Transvaginal ultrasonography, SSH, hysteroscopy, and endometrial biopsy are all measures that should be considered early in the evaluation of a woman with abnormal uterine bleeding.
4. Most cases of DUB can be managed medically, both in the short and long run. Consideration should be given to placement of a LNG-IUS before surgical interventions such as hysterectomy or endometrial ablation.
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