Abnormal Uterine Bleeding

Abnormal uterine bleeding

1. What every clinician should know

Abnormal uterine bleeding is a term used to describe any departure from normal menstruation or from a normal menstrual cycle pattern. Heavy menstrual bleeding is the most common type of abnormal uterine bleeding and affects 1 in 3 women. Five percent of reproductive age women in the United States consult their physician annually with a menstrual complaint. Evaluation and treatment of abnormal uterine bleeding costs the United States approximately $1 billion annually. Annual cost of work impairment attributable to heavy menstrual bleeding is approximately $12 billion.

Key characteristics of abnormal uterine bleeding include regularity, frequency, and heaviness of flow and duration of flow. (See Table I)

Table I.

Menstrual Parameters	Descriptive Terms	Normal Limits (5th-95th %)
Frequency (days)	FrequentNormalInfrequent	<2424-38>38
Cycle-to-cycle variation over 12 months (days)	AbsentRegularIrregular	No bleeding+/- 2-20>20
Duration of flow (days)	ProlongedNormalShortened	>84.5-8<4.5
Volume of monthly blood loss (mL)	HeavyNormalLight	>805-80<5

Menorrhagia is defined as prolonged or heavy menstruation. Metrorrhagia describes intermenstrual bleeding. Menometrorrhagia is a combination of both bleeding patterns. Amenorrhea is absent menses. Oligomenorrhea is infrequent menses and polymenorrhea is frequent menses. Unfortunately, many of these traditional terms used to describe menstrual symptoms and causes of abnormal menstrual bleeding are ill-defined and confusing.

The FIGO Menstrual Disorders Working Group has recently proposed a list of recommended terminology for the purpose of describing patterns of abnormal uterine bleeding. Irregular menstrual bleeding is defined as greater than 20 days in individual cycle lengths over a period of one year. Amenorrhea, or absent menstrual bleeding, is no bleeding in a 90-day period. However, some authorities prefer to use a longer denominator. Oligomenorrhea, or infrequent menstrual bleeding, is 1 or 2 episodes of bleeding in a 90-day period. Frequent menstrual bleeding is more than 4 episodes of bleeding in a 90-day period, and it includes frequent menstruation but not erratic intermenstrual bleeding. This pattern of menstrual bleeding is very uncommon.

Heavy menstrual bleeding is the most common presentation of abnormal uterine bleeding. It is defined as excessive menstrual blood loss, which interferes with the woman’s physical, emotional, social, and material quality of life, and which can occur alone or in combination with other symptoms. Light menstrual bleeding is usually a cultural complaint in those communities where a heavy, red bleed is valued as a perceived sign of health. This pattern of menstrual bleeding is rarely related to pathology. Prolonged menstrual bleeding are menstrual periods exceeding 8 days in duration on a regular basis and commonly associated with heavy menstrual bleeding. Shortened menstrual bleeding is menstrual bleeding of no longer than 2 days in duration that is usually light in volume. This category of menstrual bleeding is rarely associated with serious pathology and is very uncommon. Irregular, non-menstrual bleeding is defined as occasional episodes of intermenstrual or postcoital bleeding often associated with minor surface lesions of genital tract.

2. Diagnosis and differential diagnosis

An objective measure for evaluating menstrual bleeding includes extraction of hemoglobin from sanitary products with a known volume of 5 percent sodium hydroxide solution as described by Hallberg and Nilsson in 1964. This process converts hemoglobin to a stable pigment, alkaline hematin, and a colorimeter can be used for quantification of pigment concentration. A significant decline in iron parameters was noted in women with persistently greater than 80 mL of monthly blood loss. On the other hand, less than 50 percent of women complaining with heavy menstrual bleeding experience greater than 80 mL of monthly blood loss. In addition, almost half of these women have less than 40 mL of monthly blood loss. Questionnaires, standardized interviews and other patient based outcome measures are methods to assess health and illness from the patient’s perspective. Patient based outcome measures for abnormal uterine bleeding include bleeding assessment charts (i.e. pictorial bleeding assessment chart; see Figure 1) and questionnaires on menstrual symptoms and menstrual-related quality of life.

Abnormal uterine bleeding has an extensive differential diagnosis, and broadly, it includes dysfunctional uterine bleeding, organic lesions and systemic causes.

Dysfunctional uterine bleeding:

Anovulatory (perimenarcheal secondary to immature hypothalamic-pituitary-ovarian axis, perimenopausal secondary to decreased ovarian follicles, endocrinopathies, drugs such as depressants and steroids)
Ovulatory

Organic lesions:

Pregnancy-associated causes (implantation spotting, abortion, ectopic pregnancy, gestational trophoblastic disease, postabortal or postpartum infection)
Neoplasms (leiomyomas, polyps, endometrial hyperplasia, cancer)
Atrophic endometrium
Infection (sexually transmitted diseases, tuberculosis)
Mechanical causes (intrauterine device, perforation)
Arteriovenous malformation (congenital versus acquired; cesarean section, dilatation and curettage of the uterus, cancer, gestational trophoblastic neoplasia, intrauterine device)
Partial outflow obstruction (congenital mullerian defect, Asherman syndrome)
Anatomic nonuterine lesions (ovarian including hormonally functional neoplasms, fallopian tube including salpingitis and cancer, cervical/vaginal including cancer, polyp, infection, atrophic vaginitis, foreign body, and trauma)

Systemic causes:

Exogenous hormone administration (sex steroids, corticosteroids)
Coagulopathies (von Willebrand disease, coagulation factor deficiencies)
Hepatic failure
Renal failure
Endocrinopathies (hypothyroidism, hyperthyroidism, adrenal disorders, diabetes mellitus, hypothalamic-pituitary disorders, polycystic ovarian disorder, obesity)

A comprehensive history and physical examination, with focus on the menstrual history and genitourinary exam, is most helpful in determining the diagnosis; however, based on these findings, additional laboratory evaluation or imaging may be necessary.

Laboratory evaluation may include any of the following:

Urine or blood pregnancy test
CBC
Iron studies (if CBC reveals anemia)
Thyroid-stimulating hormone
Prolactin
Follicle-stimulating hormone
PAP +/- endocervical culture
Endometrial biopsy (especially if 35 years of age or older)
Coagulopathy evaluation (bleeding time or platelet function analyzer, prothrombin time, activated partial thromboplastin time, von Willebrand factor levels, ristocetin cofactor activity, factor VIII level)

Of note, premenopausal endometrial sampling should also be considered in any patients with risk factors including obesity, history of chronic anovulation, infertility or diabetes, family history of endometrial cancer or prolonged exposure to unopposed estrogens. In addition, sonographic endometrial thickness of less than 5 mm in postmenopausal women reliably excludes endometrial cancer with a sensitivity of 95 to 97 percent. Sonographic endometrial thickness greater than or equal to 5 mm needs additional evaluation with endometrial biopsy, saline infusion sonography, dilatation and curettage of uterine cavity and/or hysteroscopy. Sonographic endometrial thickness guidelines have not been established for premenopausal women. A coagulopathy evaluation should be considered in all patients presenting with heavy menstrual bleeding since menarche, especially if these patients also report any of the following:

Excessive postpartum hemorrhage
Excessive bleeding during or after surgery
Excessive bleeding associated with dental work
Significant bruising 1-2 times per month
Epistaxis 1-2 times per month
Frequent gum bleeding
Family history of excessive bleeding symptoms

Pelvic ultrasound, either 2D or 3D, accurately and easily identifies most organic pelvic lesions and is often the initial imaging procedure of choice. However, further imaging may include any of the following:

Saline infusion sonography (evaluates the endometrial cavity for polyps and submucosal leiomyomas) (Figure 3)
Hysteroscopy (gold standard for evaluation of the endometrial cavity) (Figure 2)
Pelvic MRI (defines uterine anatomy, distinguishes between leiomyomas versus adenomyosis, mapping of leiomyomas)

Pictorial Blood Assessment Chart and Scoring System for Assessment of Menstrual Blood Loss

3. Management

Aims of abnormal uterine bleeding management include: 1) excluding any cervical or endometrial carcinomas, 2) treating any underlying causes of abnormal uterine bleeding, 3) correcting anemia and replenishing iron stores, and 4) correcting or preventing heavy menstrual blood loss.

Oral ferrous preparations ranging from 60 to 180 mg daily may be administered to correct anemia and replenish iron stores. Absorption may be inhibited by tea, coffee, milk products, and calcium. Gastrointestinal side effects are common but symptoms are usually mild. The reticulocyte count increases in 2 to 3 days, and the hemoglobin level increases 10 g/L weekly starting from the second week of treatment. In order to replenish iron stores, therapy needs to be continued for 4 to 6 months.

Medical management includes antifibrinolytic agents, NSAIDs, progestins, combined oral contraceptive pills, GnRH agonists, and danazol. (See Table II)

Table II.

Medication	Commonly Prescribed Dosages
Mefenamic acid	500 mg thrice daily for 5 days, beginning with menses
Naproxen	550 mg on first day of menses, then 275 mg daily
Ibuprofen	600 mg daily throughout menses
Flurbiprofen	100 mg twice daily for 5 days, beginning with menses
Meclofenamate	100 mg thrice daily for 3 days, beginning with menses
LNG-IUS	Intrauterine placement
Combination OCPs	1 orally daily
Tranexamic acid	1 g four times daily for 5 days, beginning with menses
Norethindrone	5 mg thrice daily days 5-26 of cycle
Danazol	100-200 mg daily throughout cycle
GnRH agonists	3.75 mg IM each month

Antifibrinolytics, such as tranexamic acid, reduce tissue plasminogen activator in the uterine endometrium and reduce blood loss up to 50 percent. Minor side effects of this medication include nausea and leg cramps. NSAIDs inhibit prostaglandin synthesis by inhibiting the enzyme cyclooxygenase and increasing vasoconstriction. When taken with menses, NSAIDs reduce blood loss by 20 to 50 percent. In addition, dysmenorrhea is improved in 70 percent. Side effects include gastrointestinal symptoms and possibility of asthma exacerbation.

Progestins act as powerful antiestrogens by stimulating 17beta-hydroxysteroid dehydrogenase and sulfotransferase activity which converts estradiol to its inactive form, estrone sulfate, for excretion from the body and inhibiting estrogen’s induction of its own receptor. This results in halted endometrial growth and allows for organized sloughing with their withdrawal. Progestins have several forms of administration, including oral short or long cycles, long-acting injectable or intrauterine system. Oral short cycles of progestins are helpful in reducing bleeding in anovulatory cycles. Oral long cycles of progestins are taken 21 out of 28 days; therefore, compliance may be poor secondary to side effects (including mood changes, weight gain, bloating, and headaches) and often results in breakthrough bleeding.

DMPA is an intramuscular form of progestin lasting one to three months and creates an atrophic endometrium. Eighty percent of patients experience amenorrhea within the first year of treatment. Levonorgestrel-releasing intrauterine system releases 20 micrograms of levonorgestrel daily and causes pronounced decidualization and thinning of the endometrium. Menstrual blood loss is reduced by 74 to 97 percent after 3 months and 20 to 30 percent experience amenorrhea by 1 year and over 50 percent by 5 years. This therapy is preferably restricted to uterine cavities measuring 6 to 9 cm in length without distortion by submucous leiomyomas.

Combined oral contraceptive pills reduce menstrual flow by at least 60 percent compared to natural cycles and decreases bleeding by up to 40 percent in women with unexplained heavy menstrual bleeding. GnRH agonists are commonly used preoperatively for induction of amenorrhea to provide temporary relief from further bleeding and normalization of hemoglobin. However, it also reduces the size of leiomyomas and overall uterine mass possibly allowing vaginal surgery as well as thinning endometrium before ablation improving operating conditions and outcomes. Danazol is a derivative of 17alpha-ethinyl testosterone with net effect of creating a hypoestrogenic and hyperandrogenic environment. Androgen side effects such as weight gain, oily skin, and acne may occur.

Surgical therapies include myomectomy, hysterectomy, uterine artery embolization, and endometrial ablation. There are several approaches to myomectomy, including hysteroscopy, laparotomy, minilaparotomy, laparoscopy, and robot-assisted. Following myomectomy, heavy menstrual bleeding improves in approximately 70 to 80 percent of patients. In addition, hysterectomy can be performed via laparotomy, laparoscopy, robot-assisted, and vaginal surgery.

Removal of the uterus is obviously an effective treatment for bleeding and overall patient satisfaction rates approximate 85 percent. Disadvantages to hysterectomy include more frequent and severe intraoperative and postoperative complications compared with either conservative medical treatments or ablation procedures. Operating time, hospitalization, recovery times and costs are also greater.

Uterine artery embolization is an angiographic interventional procedure that delivers polyvinyl microspheres or other particulate emboli into both uterine arteries. Uterine blood flow is, therefore, obstructed, producing ischemia and necrosis. Because vessels serving leiomyomas have a larger caliber, these microspheres are preferentially directed to the tumors, sparing the surrounding myometrium. A postembolization syndrome, usually lasting 2 to 7 days, commonly occurs and classic symptoms include pelvic pain, cramping, nausea, vomiting, low-grade fever, and malaise. Embolization is effective for leiomyoma related symptoms and a clinical success rate of 80 percent for bleeding and 91 percent patient satisfaction has been reported. Uterine artery embolization is associated with shorter hospital stays and quicker postoperative recovery than hysterectomy. However, long-term data following uterine artery embolization is limited.

Endometrial ablation consists of first and second generation techniques. First-generation techniques include neodymium: yttrium-aluminum-garnet (Nd-YAG) laser, rollerball and transcervical resection of the endometrium. Second-generation techniques include hot liquid balloons (Thermachoice I, II and III, Cavaterm and Cavaterm plus, and Thermablate), hydrothermablation, cyroablation (Her option), microwave endometrial ablation and imependance controlled ablation (Novasure). Contraindications to endometrial ablation therapy include genital tract malignancy, preservation of fertility, pregnancy, expectation of amenorrhea, acute pelvic infection, and prior uterine surgery (classic cesarean section, transmural myomectomy). 70 to 80 percent of patients report significantly decreased bleeding, and 15 to 35 percent report amenorrhea. Long term surveillance reveals a 20 percent hysterectomy rate.

4. Complications

The main complication as a consequence of abnormal uterine bleeding is hemorrhage and possible need of blood transfusion. There are several options for treatment of acute bleeding, depending on the urgency of the situation. Tamponade of the uterine bleeding can be performed by placing a 30-mL balloon within the uterine cavity. Dilatation and curettage of the uterine cavity stimulates the normal processes involved with cessation of normal menstrual bleeding. These mechanisms include local clotting mechanisms, vasoconstriction of basal arterioles and reepithelialization. High-dose estrogen therapy may be administered as 25 mg of conjugated estrogens intravenously every four hours until bleeding subsides for up to 24 hours. This therapy is effective in 70 percent of patients, usually within 4 to 8 hours. Oral forms of estrogen, progestin, and combination oral contraceptives may also be administered either initially or following more acute treatment options and eventually tapered to once daily dosing.

Complications arising as a consequence of medical management are unlikely, but could include emergent surgical treatment for uterine hemorrhage and side effects of the medications. Most medication related side effects are mild and reversible with discontinuation. Any operative procedure, such as myomectomy, hysterectomy and endometrial ablation, has risks of complications. These operative risks include bleeding, infection, injury to surrounding structures including bladder, ureters, vessels, nerves, ovaries and intestines, and need for reoperation.

There are a number of complications associated with uterine artery embolization. Leiomyoma tissue passage is common, especially with leiomyomas that have contact with the endometrial surface. Those that do not pass spontaneously may require uterine dilatation and evacuation.

Rarely, serious complications occur following embolization and include necrosis of surrounding tissues such as the uterus, adnexa, bladder and soft tissues. In addition, a number of complications have been identified in women during pregnancy subsequent to uterine artery embolization, including preterm delivery, malpresentation and abnormal placentation.

5. Prognosis and outcome

The prognosis and treatment outcome of abnormal uterine bleeding are overall good and ultimately depend on the underlying diagnosis. Several medical and surgical therapies are available, and each option has its own risks and benefits. NSAIDs and anti-fibrinolytics taken during menses can reduce blood loss by up to 50 percent. Combined oral contraceptives also reduce blood loss by 60 percent compared to natural cycles. Several progestins, including DMPA and levonorgesterol-releasing intrauterine system, can ultimately result in amenorrhea. Myomectomy improves heavy menstrual bleeding in approximately 70 to 80 percent of patients. Embolization has a clinical success rate of 80 percent for bleeding. Endometrial ablation procedures report significantly decreased bleeding in 70 to 80 percent of patients and amenorrhea in 15 to 35 percent. Finally, removal of the uterus is obviously an effective treatment for bleeding and overall patient satisfaction rates approximate 85 percent.

6. What is the evidence for specific management and treatment recommendations

Carr, Bruce R. “(editor-in-chief). Abnormal Uterine Bleeding”. Seminars in Reproductive Medicine. (This entire journal issue includes up-to-date information on this topic, including recommendations from the recent FIGO Menstrual Disorders Working Group meeting.)

Schorge, John O, Schaffer, Joseph I, Halvorson, Lisa M, Hoffman, Barbara L, Bradshaw, Karen D, Cunningham, Gary F. “Williams Gynecology”. 2008. (There is a section titled Abnormal Uterine Bleeding (pp. 174-196) that provides an excellent summary on this topic.)

“ACOG Practice Bulletins. Management of Anovulatory Bleeding.”. Obstetrics & Gynecology,. vol. 94. 2000.

“The ESHRE Capri Workshop Group. Endometrial bleeding”. Human Reproduction Update,. vol. 13. 2007. pp. p421-431. (This review provides a background on the mechanisms of normal endometrial bleeding as a key to the knowledge management of abnormal bleeding and it also discusses clinical management for bleeding occurring during reproductive life and menopause.)

Fritz, Marc A. “and Speroff, Leon. Clinical Gynecologic Endocrinology and Infertility.”. 2011. (There is a section titled Abnormal Uterine Bleeding (pages 591-620) that provides another excellent summary on this topic.)

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