Abnormal (Dysfunctional) Uterine Bleeding

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]

Polyps: Endometrial polyps are growths within the uterine cavity consisting of glands, stroma, and blood vessels. The growths extend above the surface of the normal endometrium and may be pedunculated or sessile in appearance. Polyps are very common; they are 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. Contributing factors include higher levels of estrogen receptor alpha, with increased markers of proliferation and inhibitors of apoptosis. Malignancy rates correlate with age, with an approximately 1% rate in premenopausal women and up to 9% in postmenopausal women.[24] Longitudinal changes in polyps may vary from a decrease in size to growth. 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, that it is likely the better choice. Polyps in postmenopausal women should be removed upon diagnosis.

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 Blacks compared with other races. Both endometriosis and fibroids are more common in women with adenomyosis. Histology shows the presence of endometrial tissue within the myometrium. The etiology is not clear, with theories of: (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 increased persistent proliferation and lower levels of apoptosis. As with endometriosis, symptoms improve with the hormone cessation of menopause.

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 50 and greater than 70% in White women.[26]  Twenty-five percent to 50% of women are symptomatic. Black women 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. Experimental mutation of MED12 in a myometrial cell line increased proliferation and decreased autophagia, 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.

A great fear with fibroids is missing the rare uterine leiomyosarcoma (LMS). Although uncommon, 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.

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.

Suspect abnormal uterine bleeding (AUB) when a patient presents with unpredictable or episodic heavy or light bleeding despite a normal pelvic examination.

Note the following:

• Typically, the usual moliminal symptoms that accompany ovulatory cycles will not precede bleeding episodes.

• Exclude the diagnosis of pregnancy first.

• Address the presence of local and systemic disease. Rule out the presence of signs or symptoms indicative of bleeding disorders. Screening for personal and family history of easy bruising, bleeding gums, epistaxis, and excessive bleeding episodes during childbirth, surgery, or dental procedures may be useful.

• Rule out iatrogenic causes of bleeding, including bleeding secondary to steroid hormone contraception, hormone replacement therapy, or other hormone treatments, which are common causes.

• Many patients are adolescents or are older than 40 years.

Patients who report irregular menses since menarche may have polycystic ovarian syndrome (PCOS).[43] PCOS is characterized by anovulation or oligo-ovulation and hyperandrogenism. These patients often present with unpredictable cycles and/or infertility, hirsutism with or without hyperinsulinemia, and obesity. A retrospective study by Maslyanskaya et al identified 125 female patients, 8-20 years of age, who were admitted for treatment of abnormal uterine bleeding and reported that PCOS accounted for 33% of admissions and was the most common underlying etiology. Other underlying causes were hypothalamic pituitary ovarian axis immaturity (31%); endometritis (13%); and bleeding disorders (10%).[44]

Patients with adrenal enzyme defects, hyperprolactinemia, thyroid disease, or other metabolic disorders also might present with anovulatory bleeding.

The physical examination can elicit several findings that suggest an etiology for AUB (see the Table below).

Table. Physical Findings in AUB (Open Table in a new window)

Laboratory studies for patients with abnormal uterine bleeding (AUB) may include human chorionic gonadotropin (HCG), complete blood count (CBC), Pap smear, endometrial sampling, thyroid functions and prolactin, liver functions, coagulation studies/factors, and other hormone assays as indicated.[43]

Human chorionic gonadotropin

The most common cause of abnormal uterine bleeding during the reproductive years is abnormal pregnancy. Rule out threatened abortion, incomplete abortion, and ectopic pregnancy.

Complete blood count

Document blood loss. Charting the number of menstrual pads used per day, or keeping a menstrual calendar is helpful.

Obtain a baseline CBC count for hemoglobin and hematocrit to evaluate for anemia. Obtain a differential with platelet count if hematologic disease is suspected.

Pap smear

Pap smear should be up to date. Cervical cancer still is the most common gynecologic cancer affecting women of reproductive age in the world population.

Endometrial sampling

Perform a biopsy to rule out endometrial hyperplasia or cancer in high-risk women aged ≥45 years and in younger women at extreme risk for endometrial hyperplasia/carcinoma due to unopposed estrogen (PCOS, obesity), failed medical management, and persistent AUB. Women with chronic eugonadal anovulation, obesity, hirsutism, diabetes, or chronic hypertension are at particular risk.

Most biopsies will confirm the absence of secretory endometrium.

Thyroid and liver function tests

Perform thyroid function tests and prolactin because hyperthyroidism, hypothyroidism, and hyperprolactinemia are associated with ovulatory dysfunction. Identify and treat these conditions.

Obtain liver function tests if alcoholism or hepatitis is suspected. Any condition affecting liver metabolism of estrogen can be associated with abnormal uterine bleeding.

Coagulation factors

Von Willebrand disease and factor XI deficiency initially might manifest during adolescence.

Primary or secondary thrombocytopenia can be factors in the mature patient.

Tailor the choice of laboratory tests to the presenting clinical situation. Generally speaking, when coagulopathies are present, heavy bleeding is regular and associated with ovulation.

Other hormone assays

For the patient with recurrent anovulatory bleeding, the mainstay of management is treatment of correctable disease.

Obtain a hormonal complete evaluation in women with signs of hyperandrogenism, such as those with polycystic ovarian syndrome, 21 hydroxylase deficiency, or ovarian or adrenal tumors, as dictated by their respective conditions.

Women in menopausal transition usually can be followed without an extensive hormonal evaluation.

Generally, patients with abnormal uterine bleeding can be managed appropriately without the use of expensive imaging studies.

Ultrasonography, especially saline infusion sonography, can be used to examine the status of the endometrium, myometrium, and ovaries. Endometrial hyperplasia, endometrial carcinoma, endometrial polyps, uterine fibroids, and ovarian cysts/masses can be suspected or diagnosed with this technology.

Rule out endometrial carcinoma in all patients at high risk for the condition, including patients with the following characteristics:

• Morbid obesity

• Diabetes or chronic hypertension

• Age >45 years

• Longstanding, chronic eugonadal anovulation

Traditionally, carcinoma was ruled out by endometrial sampling via dilation and curettage (D&C). More recently, endometrial sampling in the office via aspiration, curetting, or hysteroscopy has become popular and is also relatively accurate.

Saline infusion sonography can be helpful in distinguishing individuals who have bleeding with thick endometrium from those with thin, denuded endometrium, endometrial polyps, uterine fibroids, or other uterine pathology.

Most endometrial biopsy specimens will show proliferative or dyssynchronous endometrium.

In July 2013, The American College of Obstetricians and Gynecologists issued updated guidelines for the treatment of abnormal uterine bleeding caused by ovulatory dysfunction. They included the following recommendations[45] ​[46] :

• Surgery should be considered only in patients in whom medical treatment has failed, cannot be tolerated, or is contraindicated

• Endometrial ablation is not acceptable as a primary therapy, because the procedure can hamper the later use of other common methods for monitoring the endometrium

• Regardless of patient age, progestin therapy with the levonorgestrel intrauterine device should be considered; contraceptives containing a combination of estrogen and progesterone also provide effective treatment

• Low-dose combination hormonal contraceptive therapy (20-35 μg ethinyl estradiol) is the mainstay of treatment for adolescents up to age 18 years

• Either low-dose combination hormonal contraceptive treatment or progestin therapy is generally effective in women aged 19-39 years; temporary high-dose estrogen therapy may benefit patients with an extremely heavy flow or hemodynamic instability

• Medical treatment for women aged 40 years or older can, prior to menopause, consist of cyclic progestin therapy, low-dose oral contraceptive pills, the levonorgestrel intrauterine device, or cyclic hormone therapy

• If medical therapy fails, patients should undergo further testing (eg, imaging or hysteroscopy)

• An in-office endometrial biopsy is preferable to dilation and curettage (D&C) when initially examining a patient for endometrial hyperplasia or cancer

• If medical therapy fails in a woman in whom childbearing is complete, hysterectomy may be considered

Options for medical care of abnormal uterine bleeding (AUB) usually involve various protocols of estrogen or progesterone supplementation, yet there is no clear consensus on which exact regimen is most effective.[47] Medical therapy options are discussed below.

Oral contraceptives

Oral contraceptive pills (OCPs) suppress endometrial development, reestablish predictable bleeding patterns, decrease menstrual flow, and lower the risk of iron deficiency anemia.

OCPs can be used effectively in a cyclic or continuous regimen to control abnormal bleeding.

Acute episodes of heavy bleeding suggest an environment of prolonged estrogenic exposure and buildup of the lining. Bleeding usually is controlled within the first 24 hours, as the overgrown endometrium becomes pseudodecidualized. Seek an alternate diagnosis if the flow fails to decrease in 24 hours.

The type of OCP and underlying patient factors may be important determinants of potential risk for complications associated with OCPs. Studies have shown an increased risk of nonfatal venous thromboembolic events (blood clots) associated with contraceptives that contain drospirenone as compared with those that contain levonorgestrel.[48]

Levonorgestrel-releasing intrauterine system is considered a first-line treatment for adolescents with heavy menstrual bleeding.[46, 49]

A study by Jain et al indicated that in women with AUB, the NuvaRing, which releases a daily dose of 15 μg ethinyl estradiol and 120 μg etonogestrel, can control heavy menstrual bleeding as effectively as a combined oral contraceptive pill containing 30 μg ethinyl estradiol and 150 μg levonorgestrel. The study included 60 women, who used either the NuvaRing or the combined oral contraceptive pill for 3 consecutive months. Both forms of contraception significantly reduced blood loss in each menstrual cycle, with no significant difference between them on the pictorial blood loss assessment chart.[50]

Estrogen

Intravenous estrogen alone is indicated in emergent clinical situations requiring hospitalization but with a clinically stable patient. Premarin at a dose of 25 mg every 4-6 hours up to 24 hours is recommended. Bleeding typically slows very quickly. If bleeding is not controlled within 12-24 hours, a D&C is indicated.

Prolonged uterine bleeding suggests the epithelial lining of the cavity has become denuded over time. In this setting, a progestin is unlikely to control bleeding. Estrogen alone will induce return to normal endometrial growth rapidly.

Progestins

Chronic management of AUB requires episodic or continuous exposure to a progestin. In patients without contraindications, this is best accomplished with an oral contraceptive given the many additional benefits, including decreased dysmenorrhea, decreased blood loss, ovarian cancer prophylaxis, and decreased androgens.

In patients with a pill contraindication, cyclic progestin for 12 days per month using medroxyprogesterone acetate (10 mg/d) or norethindrone acetate (2.5-5 mg/d) provides predictable uterine withdrawal bleeding, but not contraception. Cyclic natural progesterone (200 mg/d) may be used in women susceptible to pregnancy, but may cause more drowsiness and does not decrease blood loss as much as a progestin.

In some women, including those who are unable to tolerate systemic progestins/progesterone or those who have contraindications to estrogen-containing agents, a progestin-secreting IUD may be considered that controls the endometrium via a local release of levonorgestrel, avoiding elevated systemic levels.[51]

Anovulatory bleeding and bleeding disorders

On rare occasions, a young patient with anovulatory bleeding also might have a bleeding disorder. Desmopressin, a synthetic analog of arginine vasopressin, has been used to treat abnormal uterine bleeding in patients with documented coagulation disorders. Treatment is followed by a rapid increase in von Willebrand factor and factor VIII, which lasts about 6 hours.

Most cases of abnormal uterine bleeding (AUB) can be treated medically. Surgical measures are reserved for situations when medical therapy has failed or is contraindicated.

Dilation and curettage

D&C is an appropriate diagnostic step in a patient who fails to respond to hormonal management. The addition of hysteroscopy will aid in the treatment of endometrial polyps or the performance of directed uterine biopsies. As a rule, apply D&C rarely for therapeutic use in AUB because it has not been shown to be very efficacious and may lead to intrauterine scarring.

Hysterectomy

Abdominal or vaginal hysterectomy might be necessary in patients who have failed or declined hormonal therapy, have symptomatic anemia, are family complete, and experience a disruption in their quality of life from persistent, unscheduled bleeding.

Endometrial ablation

Endometrial ablation is an alternative for those who wish to avoid hysterectomy or who are not candidates for major surgery.[52] Ablation techniques are varied and can employ laser, rollerball, resectoscope, or thermal destructive modalities. Most of these procedures are associated with high patient satisfaction rates.

Pretreat the patient with an agent, such as leuprolide acetate, medroxyprogesterone acetate, or danazol, to thin the endometrium.

The ablation procedure is more conservative than hysterectomy and has a shorter recovery time. Some patients may have persistent bleeding and require repeat procedures or move on to hysterectomy. Rebleeding following ablation has raised concern about the possibility of an occult endometrial cancer developing within a pocket of active endometrium. Few reported cases exist, but further studies are needed to quantify this risk.

Endometrial ablation is not a form of contraception. Some studies report up to a 5% pregnancy rate in post-ablation procedures. This is a significant issue in women who later desire childbearing after an ablation. These pregnancies are very high risk, with essentially an increase in every potential pregnancy complication.

A study by Vitagliano et al comparing thermal balloon ablation with transcervical endometrial resection in the treatment of AUB indicated that postoperative pain is greater following the thermal ablation procedure. In the study, 47 women with AUB underwent one of the two procedures, with pelvic pain evaluated one and four hours postoperatively and the need for analgesics assessed. Patients treated with thermal balloon ablation were found to have more pain at both evaluations, and the need for analgesic rescue dose was greater in this group. At 30-day postoperative evaluation, pain seemed to still be greater in these patients. However, complications such as heavy blood loss, uterine perforation, and thermal injuries did not occur in any of the study’s patients.[53]

In a study that compared the efficacy and safety of  the Novasure impedance control system and microwave endometrial ablation (MEA) in 66 women with AUB, women in the former treatment group had significantly higher rates of amenorrhea 1 year following treatment (75.8%) compared with those in the MEA treatment group (24.2%).[54]

Endometrial ablation is not an optimal choice in women with adenomyosis or uncorrected submucosal fibroids.

Class Summary

Very effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood, as well as platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Most AUB is secondary to anovulation. In these patients, endometrium continues to proliferate with asynchronous development. As blood supply is outgrown, irregular shedding occurs. Bleeding might be controlled acutely with high-dose estrogen for a short period of time. Several hours are required to induce mitotic activity, so most regimens require 24-48 h of therapy before continued bleeding is ruled a treatment failure.

Estrogen therapy only controls bleeding acutely and does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed.

Conjugated equine estrogen (Premarin)

Class Summary

Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins. Progestins inhibit estrogen receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less active estrone. Medroxyprogesterone acetate (Provera) is the most commonly used progestin in this country, but other types, including norethindrone acetate (Aygestin) and norethindrone (Micronor), are equally efficacious.

Multiple levonorgestrel-secreting intrauterine systems (IUS), also referred to as progestin IUDs, are available for both parous and non-parous patients. These offer the advantage of contraception, along with decreased systemic side effects and excellent compliance. Downsides include the need for placement in a medical office as well as the likelihood of irregular bleeding, although bleeding decreases with time and about 20% of patients will be amenorrheic at 1 year of use.

Synthetic progestins have an antimitotic effect, allowing the endometrium to become atrophic if administered continuously. These drugs are very effective in cases of endometrial hyperplasia. In patients with chronic eugonadal anovulation who do not desire pregnancy, treatment with a progestin for 10-12 d/mo will allow for controlled, predictable menses and will protect the patient against the development of endometrial hyperplasia.

Some perimenopausal patients will not respond well to progestin therapy because of an inherent estrogen deficiency. Also, patients with thin, denuded endometrium occurring after several days of chronic bleeding might require induction of new endometrial proliferation by estrogen therapy first.

Avoid synthetic progestins in early pregnancy. They induce an endometrial response that is different from normal preimplantation secretory endometrium. Also, several reports suggest an association between intrauterine exposure to synthetic progestins in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5-8 per 1000 male births, might be doubled with early in-utero exposure to these drugs. Some synthetic progestins might cause virilization of female external genitalia in utero.

Patients at risk for conception can be treated safely with natural progesterone preparations. These preparations induce a normal secretory endometrium appropriate for implantation and subsequent growth of a developing conceptus.

Medroxyprogesterone acetate (Provera)

Short-acting synthetic progestin. Drug of choice for patients with anovulatory AUB. After acute bleeding episode is controlled, can be used alone in patients with adequate amounts of endogenous estrogen to cause endometrial growth. Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until positive feedback system matures.

Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically, does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Class Summary

Contraceptive pills containing estrogen and progestin have been advocated for nonsmoking patients with AUB who desire contraception. Therapy also used to treat acute hemorrhagic uterine bleeding but is not as effective as regimens previously mentioned. Apparently takes longer to induce endometrial proliferation when progestin is present. In long-term management of AUB, combination oral contraceptives are very effective.

Ethinyl estradiol and a progestin derivative (examples: Ovral, Lo-Ovral, Ortho-Novum, Ovcon, Genora, Orthocyclen, and others)

Reduces secretion of LH and FSH from pituitary by decreasing amount of GnRH.

Class Summary

Certain androgenic preparations have been used historically to treat mild to moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. These regimens offer no real advantage over other regimens and might cause irreversible signs of masculinization in the patient. They seldom are used for this indication today.

Use of androgens might stimulate erythropoiesis and clotting efficiency. Androgens alter endometrial tissue so that it becomes inactive and atrophic.

Danazol (Danocrine)

Isoxazole derivative of 12 alpha-ethinyl testosterone.

Class Summary

Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in bleeding endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. NSAIDs have been shown to decrease heavy bleeding in ovulatory cycles but generally are not effective for the management of AUB.

Naproxen (Anaprox, Naprelan, Naprosyn)

Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Class Summary

Work by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of post-receptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking ongoing cycle of abnormal bleeding in many anovulatory patients. Because prolonged therapy with this form of medical castration is associated with osteoporosis and other postmenopausal side effects, its use is often limited in duration and add back therapy with a form of low-dose hormonal replacement is given. Because of the expense of these drugs, they usually are not used as a first line approach but can be used to achieve short-term relief from a bleeding problem, particularly in patients with renal failure or blood dyscrasia.

Depot leuprolide acetate (Lupron)

Suppresses ovarian steroidogenesis by decreasing LH and FSH levels.

Class Summary

The overall effect is similar to that of GnRH agonists. A GnRH antagonist is a competitive inhibitor of the GnRH receptor, thus blocking binding of GnRH to decrease gonadotropin (FSH and LH) production and secretion. An oral agent (elagolix [Orilissa]) is currently available. Similar to agonists, this results in substantial hypoestrogenemia with vasomotor symptoms and bone loss. This induces amenorrhea but is not intended for long-term management of AUB.

Elagolix (Orilissa)

Class Summary

Indicated in patients with thromboembolic disorders.

Desmopressin acetate (DDAVP)

Has been used to treat abnormal uterine bleeding in patients with coagulation defects. Transiently elevates factor VIII and von Willebrand factor.

Tranexamic acid oral (Lysteda)

Tranexamic acid blocks lysine binding sites on plasminogen resulting in an antifibrinolytic effect, thus decreasing clot breakdown. This is a generalized reaction, not limited to the uterus, enabling use in many surgeries to decrease blood loss. Thus, it is applicable to many causes of AUB, as its action is not hormonal. Initially, there was concern that tranexamic acid, especially with contraceptive estrogen, would increase the risk of venous thrombosis resulting in a black box FDA warning. Thus far, this has not been observed, and the European regulatory agencies do not have a similar warning.