Sections

Abnormal (Dysfunctional) Uterine Bleeding

Sections Abnormal (Dysfunctional) Uterine Bleeding
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
Tables
References

Overview

Practice Essentials

The definition of "normal" uterine bleeding, as well as its variations, has evolved over time. In the past, abnormal uterine bleeding (AUB) was a broad term with many etiologies. In 2011 the Fédération International de Gynécologie et d'Obstétrique (FIGO) defined causes of AUB using the acronym PALM-COEIN to standardize etiologies. PALM respresents structural causes: Polyp, Adenomyosis, Leiomyoma, Malignancy [and hyperplasia]. COEIN represents nonstructural causes: Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic, and Not otherwise classified.^{[1, 2]} Of note, AUB does not describe abnormal bleeding associated with pregnancy.

AUB is defined as a change in volume, regularity, or timing that has been present for 6 months or longer.^[3]Previously, descriptive terms were used to describe AUB, including menorrhagia (heavy menses), metrorrhagia (bleeding in between regular menses), polymenorrhea (regular bleeding more often than 21 days), and oligomenorrhea (regular bleeding greater than every 35 days). Although pelvic pain may be associated with some of the causes of AUB, it is not part of the diagnostic criteria and is defined by the term dysmenorrhea.

One of the most common gynecological complaints, AUB affects 14-25% of women of reproductive age^[4]and is a major cause of loss of work and productivity.^[5]

Signs and symptoms

AUB is defined as bleeding that deviates from typical in regard to regularity and/or volume. Regular menstrual cycles refers to bleeding every 21-35 days. Excessive volume refers to an amount that interferes with a woman’s physical, emotional, or social quality of life. In quantitative research studies, abnormal is defined as an amount of > 80 mL.^[6]

There is substantial overlap in the signs and symptoms based on the etiology, but some common characteristics may be seen.

AUB-P: The bleeding with endometrial polyps is typically intermenstrual and light. However, approximately one-third of polyps are asymptomatic.^{[7, 8]}. Diagnosis is made with ultrasound and confirmed by histology.

AUB-A: Classic symptoms of adenomyosis include heavy menses, dysmenorrhea, and midline dyspareunia.^[9] Diagnosis is clinical, but can be supported by ultrasound or MRI findings suggestive of asymmetric myometrial wall thickening. Histology confirms diagnosis.

AUB-L: The symptoms from leiomyomata (fibroids) depend on their size and location. Submucosal fibroids (types 0-2) tend to result in heavy unpredictable bleeding, since bleeding may occur directly from the benign tumors that lack any true overlying endometrium. Intramural fibroids (types 3-5) more likely result in heavy but predictable bleeding. This is because the fibroids increase the surface area of the endometrial cavity resulting in more tissue to bleed from during regular menses. Large fibroids may also be associated with dysmenorrhea and dyspareunia. Subserosal fibroids are generally unrelated to complaints of bleeding and more related to bulk symptoms associated with their location (bladder or bowel changes).

AUB-M: Endometrial cancer is the most common cause of AUB-M. The vast majority of patients with endometrial cancer (91%) will have postmenopausal bleeding (PMB). However, about 9% of women with PMB will have endometrial cancer.^[10]There is no specific pattern of abnormal bleeding related to endometrial malignancy in premenopausal women; the most common types are heavy menses, intermenstrual bleeding, and heavy irregular bleeding.^[11]

AUB-C: In patients with coagulopathies, AUB typically presents in adolescence with the most common patterns of heavy menses and heavy irregular menses. The latter irregularity may be due to age-related immaturity of the hypothalamic-pituitary-ovarian axis instead of the coagulation abnormality.^[12]Associated symptoms may include easy bruising, dental extraction bleeding, post-surgical bleeding, and epistaxis.^[13]

AUB-O: The most common type of AUB, ovulatory dysfunction leads to chronic, episodic lack of ovulation and progesterone production. The continuous, unopposed action of estrogen on the endometrium leads to proliferation and ultimately breakdown of the endometrial structure. Bleeding is unpredictable and may be heavy and prolonged depending on the etiology of the anovulation.^[14]

AUB-E: Primary endometrial dysfunction may result in AUB and is mainly a diagnosis of exclusion based on the lack of hormonal or structural abnormalities. Since the patient is ovulatory, bleeding is typically regular but heavy or prolonged.

AUB-I: Iatrogenic causes of AUB are extremely varied, with the etiology accounting for the bleeding pattern. For example, the use of a copper intrauterine device (IUD) may result in predictable heavy menses, whereas the use of a progestin-secreting intrauterine system results in hypomenorrhea and irregular cycles.

AUB-N: Bleeding abnormalities from etiologies “not otherwise classified” may include rare conditions such as uterine arteriovenous malformation and endometrial pseudoaneurysm, which result in unpredictable heavy bleeding. Some authors place chronic endometritis (CE) in this category, whereas it could also go into the AUB-E category. Light intermenstrual bleeding may occur in patients with CE; however, some cases are asymptomatic.^[15]

Diagnosis and testing

Differential diagnoses should be established based on a complete history and physical examination in order to perform targeted laboratory and imaging studies. In addition, not all cases of AUB are from one cause. It is important to note that cases may have mixed picture, such as a combination of fibroids and adenomyosis (AUB:A,M).

All women with abnormally heavy bleeding should have a complete blood cell (CBC) count to exclude anemia. If anemia is present, the standard workup based on the mean corpuscular volume (MCV) value is recommended.

Irregular, unpredictable cycles are diagnostic of ovulatory dysfunction; thus, laboratory testing is necessary to establish an etiology. These tests may include the following:

Human chorionic gonadotropin (hCG) in all sexually active reproductive age females
Thyroid-stimulating hormone (TSH)
Prolactin
Follicle-stimulating hormone (FSH)
Estradiol (E2)
Luteinizing hormone (LH)

Women with signs of androgen excess, such as hirsutism, acne, or virilization, should have the following tests:

Total testosterone
Dehydroepiandrostenedione sulfate (DHEAS)
17-hydroxyprogesterone (17OHP), drawn fasting, in the AM and in the follicular phase if cycling

Screening for Cushing disease may include the following:

Salivary cortisol obtained between 10 PM and 12 midnight
24-Hour urinary free cortisol

AUB-C should be higher on the differential in cases of heavy bleeding in a younger patient, especially with a history of easy bruising, bleeding with dental procedures, post-surgical bleeding, and epistaxis.^[13]Specific testing includes prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, von Willebrand panel, platelet function, and coagulation factor levels. Testing for these conditions is best done during bleeding and prior to initiation of therapy.

All women should have an up-to-date Pap test and human papillomavirus (HPV) testing based on current guidelines.^[16]

Imaging

Women who have an abnormal uterus on pelvic examination with complaints of bleeding characterized by heavy menses, intermenstrual bleeding, or unpredictable frequent bleeding need uterine evaluation. The optimal imaging study is dependent on the disease process. For a polyp, hysteroscopy has the best diagnostic parameters (sensitivity, specificity, positive predictive value, and negative predictive value) but is not appropriate for screening. The best screening test is a saline infusion sonogram (SIS), which substantially exceeds the diagnostic capabilities of a standard transvaginal ultrasound (TVUS) scan.^[17] On the other hand, adenomyosis is best evaluated with a magnetic resonance imaging (MRI) scan, but it does not far exceed the diagnostic capabilities of TVUS. Thus, given the cost difference, TVUS should be the initial test in evaluating for suspected adenomosis.^[18] For fibroids, SIS should be the initial test since it allows mapping of location and size.

Adenomyosis has specific findings on imaging. With MRI or TVUS, the following may be seen:

Thickening of the transition zone of 12 mm or greater
Global myometrial enlargement
Asymmetry of anterior/posterior walls, usually with the posterior being larger
Cystic anechoic spaces in myometrium
Subendometrial echogenic linear striations
Lack of homogeneity within the myometrium
Obscure endometrial/myometrial border

Procedures

For women aged 45 years or older, it is suggested to have endometrial testing to exclude endometrial cancer. However, in premenopausal patients, there is no specific ultrasound finding or endometrial thickness to exclude endometrial cancer. In postmenopausal women who are not receiving exogenous hormones, an endometrial thickness of 4 mm or less has an approximate 94.8% sensitivity for excluding cancer.^[19]Endometrial evaluation should be considered in women aged younger than 45 years in the settings of obesity, diabetes, polycystic ovary syndrome (PCOS), failed previous therapy, and prolonged unopposed estrogen exposure.

The special population of women with Lynch syndrome should be monitored by a gynecological oncologist for annual screening, starting at age 25, with endometrial biopsy and TVUS. Women on tamoxifen with bleeding should also have endometrial evaluation. Women who are found to have an estrogen-producing ovarian tumor, such as a granulosa cell tumor, also require endometrial evaluation.

Initial evaluation should begin with a TVUS scan or SIS. If specific lesions are visualized, consideration should be given to hysteroscopy with site-directed biopsies and/or curettage. Alternatively, an initial Pipelle suction biopsy may be performed, with a sensitivity of detecting endometrial cancer of 91% in premenopausal women and 99% in post-menopausal women.^[20]Most failures of the Pipelle are related to localized disease in a polyp or a cornual region not easily accessed by the cannula. It is important to note that on average, the Pipelle samples approximately 4% of the endometrium.

Management

Treatment is dependent on the etiology.

AUB-P: Polyps are typically removed via hysteroscopy, but the question remains as to whether all polyps require removal (see Pathophysiology).

AUB-A: Symptomatic adenomyosis is treated similarly to endometriosis, with the strategies of having a constant progestin exposure, temporary elimination of systemic estrogen, or surgical intervention. These options are dependent on the patient’s characteristics of pain and desire for future pregnancy. Constant progestin exposure may be obtained with a progestin-secreting intrauterine device (IUD), continuous combined oral contraceptive (COC), or constant oral or injectable progestin. Bleeding may be decreased with the use of tranexamic acid during days of bleeding of menses, but this treatment is unlikely to provide much pain relief.

In women who do not respond to continuous progestin therapy, estrogen deprivation may be induced with a gonadotropin-releasing hormone (GnRH) agonist (such as depot-leuprolide) or the oral GnRH antagonist, elagolix. With estrogen deprivation, “add-back” therapy with a COC or 5 mg of oral norethindrone may be used to decrease bone loss and vasomotor symptoms. Danazol, a synthetic derivative of ethisterone, is a steroid molecule with significant androgen activity and is effective in the treatment of adenomyosis and endometriosis. Its use is associated with androgenic side effects. Vaginal symptoms may benefit from a vaginal moisturizer, such as Replens, and/or low-dose vaginal estrogen, such as Vagifem or Femring. Although these have not been studied in adenomyosis, the lack of significant endometrial stimulation would suggest a lack of adenomyosis stimulation.

In women who do not desire future pregnancy, hysterectomy provides the best pain relief, whereas uterine artery embolization (UAE) is a choice for those who do not wish to have a hysterectomy. Endometrial ablation has no role in the treatment of adenomyosis.

AUB-L: The treatment of fibroids is dependent on size, location, and symptoms. Submucosal fibroids (types 0-2) are less likely to respond to medical therapy, because there may not be an overlying endometrium and thus bleeding could be directly from the tumor. Hysteroscopic myomectomy is the preferred choice in women who desire childbearing, with hysterectomy being an option in patients whose families are complete. Patients who have significant anemia or who need to delay surgery may undergo estrogen deprivation, as described above, to induce amenorrhea until surgery. Although fibroids decrease in size with estrogen deprivation, the effects are temporary, and the uterus usually returns to pretreatment size in 4-6 months.

Intramural fibroids (types 3-5) typically cause heavy bleeding by increasing the surface area of the overlying endometrium. Thus, some patients benefit from suppressing endometrial growth with constant progestin therapy, as described above. If that fails, more aggressive temporary treatment may be considered with estrogen deprivation. Unlike estrogen deprivation for adenomyosis, the use of progestin add-back therapy may attenuate the shrinkage of the fibroids. Surgical intervention options depend on the desire for childbearing. For patients who have completed their families, options include hysterectomy, endometrial ablation, and UAE.

AUB-M: Management of endometrial cancer is best performed by a gynecological oncologist and is not described in this article.

AUB-C: Coagulation disorders are treated according to the etiology and the severity of bleeding. The most likely causes include inherited platelet dysfunction, von Willebrand disease, idiopathic thrombocytopenia (ITP), and hematological cancer or chemotherapy. With platelet disorders, the antifibrinolytic drug tranexamic acid may be useful to stabilize the clot and decrease endometrial bleeding. For von Willebrand disease, acute or chronic administration of desmopressin (DDAVP) is beneficial. In severe or refractory cases, use of von Willebrand factor (vWF) concentrates, recombinant activated factor VII (rFVIIa) may be considered. In almost all cases, medical induction of amenorrhea is the best option, using the same strategies of chronic persistent progestin exposure to render the endometrium atrophic or transient estrogen deprivation, depending on the severity of the bleeding and the anticipated length of the condition.

AUB-O: AUB due to chronic anovulation secondary to PCOS is the most common bleeding disorder. Bleeding patterns vary, with examples including prolonged amenorrhea for months followed by an episode of heavy prolonged bleeding versus frequent less severe bleeding. The hallmark of PCOS is prolonged unopposed estrogen with continuous endometrial proliferation combined with unpredictable structural breakdown.

Control of the bleeding requires chronic therapy unless clinical symptoms improve, which is usually associated with weight loss in obese individuals. Treatment requires continuous or sequential progestin exposure. COCs, either sequential or continuous, provide control of bleeding, endometrial protection from hyperplasia and malignancy, contraception, and decreased androgenic effects. For patients who have contraindications to estrogen or who prefer not to take “the pill,” options include a progestin-secreting IUD, etonogestrel implant, micronized progesterone at 400-600 mg/day, medroxyprogesterone acetate (MPA) at 5-10 mg/day, or norethindrone acetate (NETA) at 2.5-5 mg/day. Typically, the lower end of dosing is used in continuous therapy and the upper end of dosing in sequential therapy. Sequential therapy should be every 3 months at a minimum.^[21]The frequency of treatment from every 1 to 3 months may correlate with the heaviness of withdrawal bleeding. Sequential oral therapy does not guarantee contraception, and pregnancy is possible owing to intermittent, unpredictable ovulation. Continuous micronized progesterone and MPA may not provide contraception; NETA should provide the same protection as the progestin-only pill.

Acute treatment for heavy bleeding depends on the stability of the patient, the amount of bleeding, and the degree of anemia. Sample regimens are as follows:

In severe cases, 25 mg IV conjugated equine estrogens (CEE) is given every 4 to 6 hrs for a maximum of 24 hrs. Decrease in bleeding is typically rapid and lack of response brings into question the correct etiology.
In less severe cases, oral monophasic COC, at a dose of 35 mcg ethinyl estradiol, can be given 3-4 times per day for up to a week. After a week or when bleeding has diminished, the dose is gradually decreased until normal dosing is reached.
In patients with a contraindication to estrogen, MPA can be administered at 20 mg, three times per day, for up to 7 days, then with a gradual decrease until a standard dose is reached.
Tranexamic acid at an oral dose of 1.3 g/day in 3 divided doses for 5 days.

Common side effects with hormonal therapy include nausea and/or vomiting and mastodynia. A significant risk with estrogen is venous thrombotic event (VTE), and non-estrogen treatment should be considered in women with thrombophilia or other known risk factor.

Tranexamic acid has an FDA warning against concomitant use with estrogen products because of a theoretical increased risk of VTE. European agencies do not have this warning. Appropriate studies are lacking. In a large trial of tranexamic acid for postpartum hemorrhage, no increase in VTE was seen.^[22]

Cases of severe acute AUB-O not responding to medical therapy may respond to dilation and curettage.

AUB-E: Primarily a diagnosis of exclusion, AUB-E is an endometrial abnormality resulting in heavy menses in ovulatory women. Treatment options include progestin-secreting IUS, COC, tranexamic acid, and nonsteroidal anti-inflammatory drugs (NSAIDs). Some authors also place chronic endometritis in this category, whereas others use AUB-N. Endometritis is diagnosed by the finding of plasma cells in a follicular phase endometrial biopsy, although there is no agreement as to the threshold number of cells to make the diagnosis. Empiric antibiotic treatment with 2 weeks of 100 mg doxycycline twice daily results in elimination of plasma cells in approximately 85% of cases. Alternate treatment includes a combination of a quinolone and metronidazole.

In women who have completed their families, endometrial ablation or hysterectomy is an option.

AUB-I: Iatrogenic causes include medications that affect the integrity of the endometrium such as continuous progestins (especially depot medroxyprogesterone acetate [DMPA]) and induction of chronic endometritis with intrauterine devices. DMPA induces both hypoestrogenemia and endometrial atrophy associated with loss of capillary integrity. This commonly responds to a short course of vaginal estrogen for 1-2 weeks. Treatment for IUD-related inflammation is covered above.

AUB-N: There are no specific diagnoses in the “non-specific” category. A possibility includes delayed postpartum hemorrhage secondary to subinvolution of the placental site. This diagnosis is by exclusion of retained products by sonography. This condition responds well to IV CEE therapy, whereas a dilation and curettage is counterproductive.

Background

AUB is a common diagnosis, making up 5-10% of cases in the outpatient clinic setting. Currently, AUB is classified according to the underlying pathophysiology, instead of the bleeding patterns, using the PALM-COEIN acronym.

AUB-A: The prevalence of adenomyosis is estimated at 1%, based on ultrasound findings with classic symptoms of heavy menses, dysmenorrhea, and dyspareunia.^[9]

AUB-L: The self-reported prevalence of leiomyomata (fibroids) varies between 4.5% and 9.8%.^[23]

Pathophysiology

Polyps: Endometrial polyps are growths within the uterine cavity consisting of endometrial glands, stroma, and often blood vessels. The growths extend beyond the surface of the normal endometrium and may be pedunculated or sessile in appearance. Polyps are very common, found in about 50% of patients with AUB and about 35% of those with infertility. Up to 80% are thought to be asymptomatic. Predisposing factors are conditions of excessive and unopposed estrogen, usually due to chronic anovulation. Malignancy rates related to polyps tend to correlate with age, with an approximately 1% rate in premenopausal women and up to 9% in postmenopausal women.^[24] Changes in polyps can vary, including a decrease in size or in some cases even resolution. In one study of 112 women, 6.3% had spontaneous resolution, which was more likely in premenopsausal subjects and smaller polyps. Of asymptomatic women with polyps, 15% developed AUB during the 6- to 136-month follow-up. Given the low malignancy rate, premenopausal women with small polyps could be followed up with repetitive evaluations, but given the low risk of hysteroscopic polypectomy, the procedure is the preferred choice. Polyps in postmenopausal women should be removed upon diagnosis due to the increased risk of malignancy mentioned above.

Adenomyosis: The incidence of adenomyosis is estimated at 1% based on ultrasound findings, with classic symptoms of heavy menses, dysmenorrhea, and dyspareunia.^[9]The incidence increases with age during premenopause and is higher in African Americans compared with other races. Histology shows the presence of endometrial tissue within the myometrium. The etiology is not clear; there are theories including: (1) invagination of endometrium into the myometrium, (2) origination from Mullerian remnants in the myometrium, (3) migration of endometrial cells along the intramyometrial lymphatic channels, and (4) origination from bone marrow stem cells displaced into the myometrium through the vasculature.^[25]Endometrial cells within the myometrium do not function as normal endometrium, with persistent proliferation and lower levels of apoptosis. Similar to endometriosis, symptoms improve with the hormonal treatment and cessation of ovulation.

Leiomyomas: Fibroids are a common cause of AUB and are commonly classified by location as follows:

Type 0: Fibroid totally within the cavity
Type 1: Fibroid greater than 50% in the cavity
Type 2: Fibroid less than 50% in the cavity
Type 3: Fibroid in the myometrium but with extrinsic compression and disfigurement of the cavity
Type 4: Fibroid totally in the myometrium
Type 5: Fibroid with greater than 50% below the serosal surface
Type 6: Fibroid with greater than 50% above the serosal surface
Type 7: Pedunculated fibroid
Type 8: Fibroid in other location, such as cervical or broad ligament
Type 2-5: Transmural fibroid extending from submucosal to serosal

These tumors are a huge burden to the female population. Ultrasound studies show a prevalence of greater than 80% in Black women over age 50 and greater than 70% in White women.^[26] About 25-50% of women with fibroids are symptomatic. Black women tend to develop fibroids at an earlier age, have more and larger tumors, and have worse symptoms than Whites. The etiology remains multifactorial, but the majority of tumors harbor a somatic mutation in the MED12 gene. This protein is part of a complex controlling the initiation of transcription. In one study, experimental mutation of MED12 in a myometrial cell line increased proliferation and decreased autophagia, which are characteristics of tumor formation.^[27] This mutation occurs in myometrial stem cells, leading to a clonal tumor. The etiology of this somatic mutation remains to be determined. Other less common mutations contributing to fibroids include HMGA2 (high mobility group), FH (fumarate hydratase), and COL4A5-COL4A6 (collagen genes). Bleeding patterns with fibroids correlate with location and size, with different mechanisms. Type 0-2 fibroids tend to lack an overlying endometrium and thus may bleed directly from the tumor. Type 3 fibroids may have an abnormally thin and poorly developed overlying endometrium, which leads to bleeding. Type 4-5 fibroids may primarily increase the volume of the cavity and thus the surface area of the endometrium, resulting in more tissue from which to bleed.

Uterine leiomyosarcoma (LMS), although uncommon, occurs with an incidence of 0.36 in 100,000 woman-years. The diagnosis can be difficult because most symptoms are the same as those of fibroids. The mean age of presentation is later than that of fibroids, being in the mid-50s.^[28]Diagnostic studies are not ideal. Occasionally, abnormal cells will be seen with endometrial biopsy, but it has low sensitivity. Currently, the best study is an MRI scan. Findings on MRI that suggest LMS include ill-defined infiltrating margins, irregular shape and often solitary mass, hyperintense signal intensity (SI) on T2 images from necrosis, hyperintense SI on T1 images from hemorrhage, and restricted diffusion with a low ADC (apparent diffusion coefficient).^[29]

Endometrial cancer is most commonly diagnosed in postmenopausal women, with an average age of 63, and is found as endometrioid adenocarcinoma (type 1, about 75-90% of cases) and clear cell and papillary tumor (type 2, about 10-25% of cases). Type 1 typically progresses through stages of benign endometrial hyperplasia to endometrial intraepithelial neoplasia (EIN) to endometrioid adenocarcinoma over a span of years. As an example, the average age at diagnosis of EIN is approximately 51 years. This disease is associated with estrogen exposure, with risk factors of nulliparity, obesity, menstrual irregularity, unopposed estrogen, early menarche/late menopause, tamoxifen, and type 2 diabetes. But, mutations are still required for cancer, as shown by increased rates and earlier presentation with Lynch syndrome (MLH1, MSH2, PMS2, or MSH6) and pTEN inherited syndromes. Endometrioid adenocarcinoma generally has a good prognosis, with a 5-year survival rate of about 90%. Although less frequent, serous or papillary endometrial cancer has a much worse prognosis and accounts for approximately 40% of the mortality.^[30]

Coagulopathy leading to AUB-C is most commonly due to von Willebrand disease (VWD) or platelet function abnormalities. Less frequent causes include idiopathic thrombocytopenia (ITP) and coagulation factor deficiencies. About 13% of AUB-C is due to VWD, with mutations in the von Willebrand factor (VWF) gene resulting in 3 types correlating with severity and prevalence (type 1, mildest, 70-80%; type 2, moderate, 20%; type 3, severe, 5%). VWF is responsible for stabilizing factor VIII and promoting platelet binding. Type 1 is associated with mildly decreased levels of the protein, type 2 with normal levels but the protein is dysfunctional, and type 3 with severely decreased levels. Type 1 and some type 2 have autosomal dominant inheritance, whereas other type 2 and type 3 are autosomal recessive. Type 1 mutations have variable penetrance and expressivity, and up to 50% of individuals do not have an identifiable mutation.^[31]Multiple rare platelet disorders may lead to AUB-C, and the reader is referred to the reference for a thorough discussion.^[32]Factor VIII or hemophilia A is X-linked recessive and thus rarely found in women. Exceptions include skewed inactivation of the normal X chromosome.

Overall, ovulatory dysfunction accounts for many cases of AUB, with PCOS being predominant. Less common causes include hypogonadotropic hypogonadism, thyroid dysfunction, hyperprolactinemia, and adrenal abnormalities, with differing bleeding patterns among the groups. Patients with AUB have lost cyclic endometrial stimulation that arises from the ovulatory cycle. As a result, these patients have constant, noncycling estrogen levels that stimulate endometrial growth. Proliferation without periodic shedding causes the endometrium to outgrow its blood supply. The tissue breaks down and sloughs from the uterus. Subsequent healing of the endometrium is irregular and dyssynchronous. Chronic stimulation by low levels of estrogen results in infrequent, light AUB. Chronic stimulation from higher levels of estrogen leads to episodes of frequent, heavy bleeding.

PCOS is a clinical diagnosis based on the Rotterdam Consensus Conference criteria of 2 of the following: physical or biochemical evidence of hyperandrogenism, ovulatory dysfunction, polyfollicular ovaries, and exclusion of other conditions with similar symptoms such as hypothyroidism, hyperprolactinemia, congenital adrenal hyperplasia, and possibly Cushing syndrome.^[33]PCOS affects approximately 7% of reproductive age women. AUB is due to chronic or intermittent anovulation with PCOS leading to times of unopposed estrogen with dysregulated endometrial proliferation. The majority of patients have long cycles of more than 35 days to 6 months and/or less than 9 bleeding episodes per year. Due to the endometrial build up, the bleeding is often heavy and prolonged.

Women with hypothyroidism most often have normal menstrual cycles (about 70%). The most common disturbance is cycles of greater than 35 days with heavy bleeding, but short cycles of less than 21 days without heavy bleeding are also seen.^[34]In contrast, women with hyperthyroidism tend to have secondary amenorrhea or irregular cycles greater than 35 days with decreased blood loss, with the severity correlating with the degree of thyroid elevation. Similarly, women with hyperprolactinemia have secondary amenorrhea or irregular cycles greater than 35 days with decreased blood loss, again correlating with the degree of prolactin elevation.^[35]

The differences between the bleeding patterns with PCOS, hypothyroidism, hyperthyroidism, and hyperprolactinemia are due to levels of free estrogen. In PCOS and hypothyroidism, sex hormone binding globulin (SHBG) is decreased, resulting in higher free estradiol and greater peripheral conversion of androgens to estrogens. In hyperthyroidism, SHBG is increased, resulting in lower free estradiol levels. Elevated prolactin results in decreased gonadotropin-releasing hormone (GnRH), with consequential decreased FSH and LH levels and lower ovarian estrogen production.

Endometrial AUB, referred to as “ovulatory dysfunctional uterine bleeding” in the past, is classically a condition in women of heavy regular cycles. Studies have shown that the perception of the amount of bleeding varies widely among women, and quantitative analysis shows only approximately 50% of patients actually exceed 80 mL during menses. This is a diagnosis of exclusion, as there are no specific diagnostic tests. Research studies point to a local disturbance in hemostasis and vasoconstriction. Endometrial tissue has altered vasoconstrictive cytokines such as endothelins and prostaglandins. Endothelin is low with upregulated receptor; PGF2α is decreased with increased PGE2 and PGI2. This hampers vasoconstriction and platelet aggregation. Other factors may involve altered local immune responses.^[36]Some authors also place AUB due to chronic endometritis (CE) in this category. CE originates from colonization of the endometrium with polymicrobial species from the vagina associated with events involving passage through the cervix, such as vaginal delivery, miscarriage, IUD placement, and dilation and curettage. Yet, these events are much more common than CE, concluding that there may be immunological characteristics that diminish the ability to clear these bacteria.

Causes of iatrogenic AUB include IUD use (discussed previously) and chronic progestin exposure. AUB associated with depot-medroxyprogesterone acetate (DMPA) is very common and tends to decrease with time. Unlike oral progestins at typically doses, DMPA is more potent and results in suppression of the HPO axis with hypoestrogenemia. This accounts for the associated bone loss while patients are on the drug. The progestin also results in increased endometrial vascular fragility. Abnormal endometrial dilated vessels are evident with DMPA.^[37]Thus, the unpredictable AUB with DMPA is a combination of lack of endometrial proliferation from hypoestrogenemia and vessel fragility from the progestin.

Iatrogenic AUB with use of sequential COCs is common during the initial 3 cycles and then decreases to approximately 20-25% of patients having intermenstrual bleeding.^[38]AUB with extended or continuous COC also decreases with time, with 59% of patients amenorrheic between months 6 and 12 and 79% after month 12.^[39]Several mechanisms may contribute to COC-associated AUB including the progestin effect discussed above, breakthrough ovulation, and noncompliance. In one study with monthly COC, 47% of subjects missed ≥1 pill and 22% missed ≥2 pills.^[40]Patient factors that may contribute to AUB include obesity, smoking, medications, and gastrointestinal malabsorption.

An uncommon but serious cause of postpartum bleeding is placental site subinvolution. This delayed form of postpartum hemorrhage occurs between 24 hours and 6 weeks after delivery. The pathology involves lack of replacement of endovascular extravillous trophoblasts (EVTs) with normal vascular muscularis and endothelia during the 3rd trimester. During implantation, invading EVTs replace arteriole endothelial and muscularis cells to create a low resistance vessel for increased flow. To survive the bleeding of delivery, this process is reversed in the 3rd trimester so that the vessels may contract to aid hemostasis. The molecular mechanisms of EVT replacement remain to be fully elucidated.

Adolescents

The primary defect in the anovulatory bleeding of adolescents is failure to mount an ovulatory luteinizing hormone (LH) surge in response to rising estradiol levels. Failure occurs secondary to delayed maturation of the hypothalamic-pituitary axis. Because a corpus luteum is not formed, progesterone levels remain low. The existing estrogen-primed endometrium does not become secretory. Instead, the endometrium continues to proliferate under the influence of unopposed estrogen. Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy, such as that seen in estrogen breakthrough bleeding.

Physicians often question how long menses should remain abnormal after menarche. Menarche typically occurs between 12 and 13 years and within 2-3 years of thelarche. Lack of menarche by age 15 or within 3 years of thelarche requires evaluation. Similarly, lack of thelarche by age 13 should be evaluated. After menarche, cycles are typically 21-45 days, with 2-7 days of bleeding and the same amount of blood loss as an adult. Thus, heavy bleeding is not normal in adolescence. By 3 years after menarche, a normal adult menstrual pattern should be in place.

Climacteric

Bleeding patterns as the ovaries transition into menopause are best described by the “Stages of Reproductive Aging Workshop (STRAW).”^[41]Seven progressive stages are described: three in the “Reproductive age” (-5, -4, -3), two in the “Menopausal transition” (-2, -1), and two in the “Postmenopause” (+1, 2). Final menses is between stage -1 and +1. A change in cycle characteristics is first seen in stage -3, in which total cycle length shortens by 2-3 days due to a shortened follicular phase but a maintained luteal phase. Associated with earlier and more rapid follicle development, estradiol levels may be higher than that of younger reproductive aged women. In stages -2 and -1 of the menopausal transition, cycles become more variable, initially varying by greater than 7 days and subsequently with skipped cycles and intervals of >60 days. This is due to intermittent anovulation. The final menstrual period is defined retrospectively by absence of menses for 1 year.^[42]Postmenopause stage +1, lasting about 6 years, is characterized by a continuing rise in FSH and a decline in estrogen associated with vasomotor symptoms and vaginal changes. Late postmenopause typically shows improvement in vasomotor symptoms, stabilization of hormone levels, and more urogenital symptoms. Although other hormone levels significantly change including AMH, progesterone and inhibin, FSH, and estradiol remain the most representative.

Morbidity/mortality

Single episodes of anovulatory bleeding generally carry a good prognosis.

Patients who experience repetitive episodes might experience significant consequences. Frequent uterine bleeding will increase the risk for iron deficiency anemia. Flow can be copious enough to require hospitalization for fluid management, transfusion, or intravenous hormone therapy. Chronic unopposed estrogenic stimulation of the endometrial lining increases the risk of both endometrial hyperplasia and endometrial carcinoma. Timely and appropriate management will prevent most of these problems.

Many individuals with abnormal uterine bleeding are exposed to unnecessary surgical intervention, such as repeated uterine curettage, endometrial ablative therapy, or hysterectomy, before adequate workup and a trial of medical therapy can be completed.

Persistent menstrual disturbances might lead to chronic iron loss in up to 30% of patients with iron deficiency anemia. Adolescents might be particularly vulnerable. Up to 20% of patients in this age group presenting with heavy regular menses might have a disorder of hemostasis.

About 1-2% of women with improperly managed anovulatory bleeding eventually might develop endometrial cancer. Infertility associated with chronic anovulation, with or without excess androgen production, is frequently seen in these patients. Patients with polycystic ovarian syndrome, obesity, chronic hypertension, and insulin-resistant diabetes mellitus particularly are at risk.

Patient Education

The goals of therapy for abnormal uterine bleeding (AUB) are to control and prevent recurrent bleeding, correct or treat any pathology present, and induce ovulation in patients who desire pregnancy. Age, past history, and bleeding amount influence management.

After initial treatment and resolution of an episode of AUB, patients need to be educated that most often chronic therapy is mandatory to prevent further episodes.

Reassure patients that most bleeding stops with the appropriate hormonal therapy. Explain the physiologic reason for the anovulatory bleeding pattern. This is particularly true for the adolescent patient who establishes a predictable ovulatory type of menstrual pattern over time.

Perhaps the best measure of successful treatment is a good menstrual calendar. Encourage patients to keep a calendar to record daily bleeding patterns. This will serve to document severity of blood loss and impact on daily activities.

For patient education resources, see Women's Health Center and Pregnancy Center, as well as Vaginal Bleeding, Birth Control Overview, Birth Control Methods, and Pap Smear.

Clinical Presentation

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Table. Physical Findings in AUB

Table. Physical Findings in AUB

Examination	Finding	Differential
Vital signs	Tachycardia	Anemia Hypovolemia
Weight	Obesity	PCOS, weight-related anovulation
Eyes	Exophthalmos Periorbital edema	Graves disease Hypothyroidism
Neck	Thyromegaly	Hypothyroidism
Breasts	Galactorrhea	Hyperprolactinemia
Skin	Increased skin tags Acanthosis nigricans Hirsutism Ecchymosis, purpura	PCOS Insulin resistance PCOS, CAH, Cushing syndrome, androgen-secreting tumor Bleeding disorder
Pelvic examination	Cervical polyp/cervicitis/cervical ectropion Globally enlarged uterus Irregular uterus Adnexal mass	Adenomyosis Fibroids Ovarian cyst or mass
AUB = abnormal uterine bleeding; CAH = congenital adrenal hyperplasia; PCOS = polycystic ovary syndrome.

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Author

Olivia C Garcia, DO, MS Resident Physician, Department of Obstetrics and Gynecology, Advocate Lutheran General Hospital

Olivia C Garcia, DO, MS is a member of the following medical societies: American College of Obstetricians and Gynecologists, American College of Osteopathic Obstetricians and Gynecologists

Disclosure: Nothing to disclose.

Coauthor(s)

Kirsten J Sasaki, MD, FACOG Associate Physician, The Advanced Gynecologic Surgery Institute

Kirsten J Sasaki, MD, FACOG is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, Gold Humanism Honor Society, Society of Laparoscopic and Robotic Surgeons

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Pfizer<br/>Received income in an amount equal to or greater than $250 from: Pfizer.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Frances E Casey, MD, MPH Associate Professor, Director of Family Planning Services, Department of Obstetrics and Gynecology, VCU Medical Center

Frances E Casey, MD, MPH is a member of the following medical societies: American College of Obstetricians and Gynecologists, Association of Reproductive Health Professionals, National Abortion Federation, Physicians for Reproductive Health, Society of Family Planning

Disclosure: Nothing to disclose.

Chief Editor

Richard Scott Lucidi, MD, FACOG Associate Professor of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine

Richard Scott Lucidi, MD, FACOG is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Anthony Charles Sciscione, DO Professor, Department of Obstetrics and Gynecology, Drexel University College of Medicine; Director, Maternal and Fetal Medicine, Christiana Care Health System; Director, Delaware Center for Maternal and Fetal Medicine

Anthony Charles Sciscione, DO is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association

Disclosure: Nothing to disclose.

Thomas Michael Price, MD Professor Emeritus, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Former Director of Reproductive Endocrinology and Infertility Fellowship Program, Duke University Medical Center

Thomas Michael Price, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, Phi Beta Kappa, Society for Reproductive Endocrinology and Infertility, Society for Reproductive Investigation

Disclosure: Received research grant from: Insigtec Inc<br/>Received consulting fee from Clinical Advisors Group for consulting; Received consulting fee from MEDA Corp Consulting for consulting; Received consulting fee from Gerson Lehrman Group Advisor for consulting; Received honoraria from ABOG for board membership.

Millie A Behera, MD Assistant Professor (Adjunct), Division of Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecology, Duke University Medical Center; Medical Director, Bloom Reproductive Institute

Millie A Behera, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, AAGL

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous author John T Queenan, Jr, MD, to the development and writing of this article.