Causes of abnormal uterine bleeding

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Almost every woman will experience abnormal uterine bleeding (AUB) at least once in her lifetime. AUB accounts for approximately one third of gynecologic outpatient visits1 and about 10% of visits to primary-care providers.2 Such bleeding can be very disruptive, and without proper evaluation and treatment, it can lead to anemia or other medical consequences. Undiagnosed or untreated bleeding may also cause the woman to undergo unnecessary gynecologic procedures or needless initiation or disruption of oral contraceptives (OCs) or HRT.

The majority of AUB episodes occurs within 5-10 years of menarche and 5-10 years before menopause begins.3 Approximately 25% of AUB cases can be traced to an organic cause4 (e.g., uterine fibroids, polyps, infection, endometriosis, adenomyosis, or other anatomic or structural problems of the uterus or its lining).5 AUB can also be related to the administration of exogenous hormones, such as the incorrect use or dosage of OCs.

However, when AUB has no discernible physical cause and is instead the result of endogenous hormonal fluctuations, it is referred to as “dysfunctional uterine bleeding” (DUB). DUB affects up to 5% of menstruating women and accounts for approximately 80% of cases of menorrhagia, the most common cause of iron deficiency anemia in the developed world.6 DUB can be managed successfully in a primary-care setting provided the clinician has a proper understanding of the pathophysiology of normal vs. abnormal bleeding and goes through a step-by-step evaluation of the bleeding.

Disturbances in the normal cycle

On average, the normal menstrual cycle is 29 days, and the mean length of menses is two to seven days. The average total blood loss during menses is 50 cc, with the heaviest flow occurring in the first two days.7

The length of the menstrual cycle and duration of menses should remain consistent throughout a woman's life. The first half of the cycle is the follicular phase and can vary in length. The second half is the luteal phase, which remains mostly constant at 14 days. However, variations do occur.

The normal menstrual cycle is based on interaction of the hypothalamic-pituitary-ovarian (HPO) axis: The hypothalamus uses gonadotropin-releasing hormone to signal the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates the ovaries' production of ovarian follicles and more estrogen. Estrogen triggers the growth of the endometrium.

The estrogen also provides negative feedback to the pituitary gland, stopping the release of FSH. This action allows one or two dominant follicles to persist, while stimulating the pituitary to produce more LH. (The main role of LH is to cause ovulation, but it also helps raise estrogen production of the follicle cells.) LH, in turn, initiates a small amount of progesterone production by the ovaries.

The rising serum estrogen and progesterone levels provide positive feedback to the pituitary for a sudden LH surge—the sudden increase in LH production 34-36 hours before the ovarian follicle ruptures and ovulation occurs.5 The surge represents a switch from the negative feedback to the positive feedback effect and causes a 10-fold increase in serum LH concentration.8 We know other ovarian factors contribute to the LH surge as well because it cannot be recreated by simply administering estrogen and progesterone during the follicular phase to induce serum levels close to what we see mid-cycle.9

After the LH surge, the corpus luteum cyst (ovarian tissue that secretes progesterone) forms and survives approximately 14 days (luteal phase). If pregnancy does not occur in that time frame, the corpus luteum cyst involutes and the endometrium sheds, resulting in menstruation.

Any dysfunction in this feedback system can cause DUB, which may be excessively light, heavy, unpredictable, or prolonged. It can be divided into two categories: DUB in the absence of ovulation (anovulatory DUB) and DUB despite normal ovulation (ovulatory DUB). A glossary of terms relating to DUB appears in Table 1.

Anovulatory DUB

The most common cause of DUB seen in the primary-care setting is anovulation. This occurs most frequently in the early reproductive years, when the HPO axis is still immature. With the delayed maturation of the feedback system, there often is not enough estrogen release for a positive feedback and an LH surge, which means ovulation does not occur.

Among teens, 80% of abnormal bleeding is DUB related to anovulatory cycles in the first years of menarche; the rest involve an underlying disorder requiring further evaluation.10

Light-to-medium and often prolonged bleeding can occur as a result of estrogen withdrawal. In the absence of organic causes, reassure a patient in her first few years after menarche that light, irregular bleeding is a normal consequence of her immature hormonal feedback system. If the condition persists for more than three to six months, consider prescribing OCs to help regulate the bleeding cycle and control the amount of bleeding.

In the perimenopausal years, decreased ovarian sensitivity to FSH and LH renders estrogen levels insufficient to produce the LH surge and ovulation. The corpus luteum cyst therefore does not form, so progesterone is not secreted. Progesterone not only stimulates ovulation, it blocks estrogen's ability to increase endometrial growth. In the absence of the LH surge, then, the follicles continue to produce estrogen, and the endometrium grows and thickens. Eventually the endometrium will outgrow its vascular support and shed, causing unpredictable medium-to-heavy bleeding.

Due to the lack of progesterone, there is no vasoconstriction of the spiral vessels within the endometrium and no orderly collapse to induce hemostasis as in normal menstrual bleeding. As a result, the bleeding can be spontaneous, heavy, and prolonged. Conversely, bleeding may be very light if estrogen release is too low to allow the endometrium to grow.

Always rule out pregnancy when a patient presents with anovulatory DUB. Other organic causes, such as extreme stress or anorexia, warrant further counseling. To this end, ask about the patient's nutrition and eating habits and pose questions that can identify a dramatic weight loss, excessive exercise patterns, an unusually high stress level, or depression. These factors can halt ovulation and cause abnormal bleeding. In a nutritionally depleted female, for example, the body won't put its resources toward ovulation because it recognizes that the reproductive system isn't healthy enough to support a pregnancy. Similarly, a depressed person may have associated weight loss, weight gain, or hormonal changes that result in anovulation.

A woman with heavy anovulatory DUB may benefit from iron supplementation, which will help the bone marrow manufacture more RBCs to compensate for the blood being lost. Heavy bleeding related to anovulation in the perimenopausal years is often treated with progesterone tablets for 10 days each month. This should be recommended only after ruling out pregnancy, fibroids, polyps, cancer, and other potential causes of AUB.

Ovulatory DUB

Bleeding despite normal ovulation is often related to a physical cause, such as uterine fibroids, endometrial polyps, adenomyosis, endometrial hyperplasia, or endometrial cancer. These conditions need to be ruled out based on the patient's age, risk factors, and results of a physical examination with pelvic ultrasound and endometrial visualization/sampling (dilation and curettage/hysteroscopy). To help differentiate between ovulatory and anovulatory DUB, ask whether the patient is experiencing premenstrual symptoms, such as breast tenderness, bloating, fullness, or mood changes. The presence of such symptoms suggest that she is ovulating.

 


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Ovulatory DUB is thought to be related to an imbalance between endometrial prostacyclin and prostaglandin production, which would cause a defect in hemostasis. The imbalance can be treated with naproxen (Aleve) or ibuprofen (Motrin) (which will raise prostaglandin levels), OCs to regulate the menstrual cycle, or endometrial ablation (only in the perimenopausal years).

During the young reproductive years, ovulatory DUB is mainly caused by persistent corpus luteum cyst, which delays the menstrual period, and mid-cycle spotting, which occurs in some women during ovulation. (Pregnancy should be ruled out before considering other causes of delayed menses.) If the corpus luteum cyst lasts beyond the usual 10 to 16 days, menstruation will be delayed. The resulting menses can be heavy and prolonged. The etiology of persistent corpus luteum cyst is unknown, and no treatment is indicated.

Light mid-cycle bleeding or spotting is related to the transient decline in physiologic estrogen after ovulation. Patients will sometimes describe a pain in the right or left lower pelvis that occurs midway through the menstrual cycle, around the time of ovulation. This is known as “mittelschmerz” (German for “middle pain”). Mittelschmerz can be a sharp pain that lasts for a few minutes, or it can strike intermittently over the course of a few hours. No treatment is indicated.

This light mid-cycle bleeding of ovulatory

DUB can also occur when the woman misses OC doses, uses low-dose OCs, or uses the long-acting injectable progestin contraceptive medroxyprogesterone (Depo-Provera). No treatment is indicated beyond increasing the estrogen dose of the OC pills or switching from Depo-Provera to an OC if the bleeding continues.

Patient evaluation

Medical history. The first step in the evaluation of AUB is to take a thorough history that begins by establishing the patient's age, birth-control method, date of last menstrual period, and whether she could be or could have been pregnant. (A miscarriage may cause unpredictable heavy bleeding.)

The next step is to gather detailed information on the woman's bleeding pattern to help determine whether the DUB is ovulatory or anovulatory. Questions that help clinicians zero in on the cause of the bleeding include the following:

• How often does the patient menstruate?
• What is the flow like—is the bleeding very light, or is it heavy enough that anemia is a concern? Could any precipitating factors have caused or increased the bleeding, such as a recent gynecologic procedure?
• How long does the patient's menstrual period last?
• Does the patient have premenstrual symptoms that indicate ovulation?
• Is there any history of abnormal Pap smears? If so, the patient could have cervical cancer; the bleeding may in fact be coming from the cervix, not the uterus. The clinician should check for this.
• Is the patient up to date on her Pap smears?
• Does the patient have any symptoms of perimenopause, such as hot flushes, insomnia, and mood changes? Because the perimenopausal ovary isn't functioning well, a perimenopausal woman may ovulate some months and not others, so periods become very irregular and may be very heavy after a month is skipped.
• Is there a personal or family history of thyroid dysfunction, bleeding disorders, or cancer (uterine, colon, ovary, or breast)?
• Does the patient take any blood-thinning medications, such as warfarin (Coumadin) or clopidogrel (Plavix)?

Physical exam. When a woman presents with AUB in the primary-care setting, check her vital signs, noting whether they are stable and if she is tachycardic or hypotensive. The clinician should also look for signs of systemic disease: fever, ecchymosis, enlarged thyroid, hyperandrogenism (characterized, for example, by facial hair or excessive acne), acanthosis nigricans (dark patches of skin on the neck, armpits, elbows, knuckles, or knees—a possible sign of insulin resistance), and galactorrhea (nipple discharge that can indicate elevated prolactin levels).

It is not uncommon for bleeding related to other pathology to be confused with uterine bleeding. Therefore, a pelvic exam should be performed to determine whether bleeding is coming from the uterus or from the vulva, vagina, cervix, or anus. Bleeding at the opening of the cervix (cervical os) indicates uterine bleeding. Any suspicious findings, such as masses, lacerations, bruising, foreign bodies, or unusual vaginal discharge, should be noted.

In the bimanual exam, feel the size of the uterus, noting any irregular shape. A large uterus can signal the presence of cancer, fibroids, polyps, or pregnancy. The clinician should also feel for fullness at both adnexa. Areas of pain or tenderness on palpation may point to infection as a cause of the bleeding.

Diagnostics. Certain initial diagnostics can aid the evaluation of DUB and provide valuable information to the women's-health nurse practitioner, gynecologist, or other specialist to whom the patient is referred. (The primary-care clinician may want to discuss some of these diagnostics with a women's-health specialist before ordering them.)

• Consider ordering a complete blood cell count if the patient reports excessively heavy/prolonged bleeding.
• A beta human chorionic gonadotropin test will identify or rule out pregnancy as a cause of the bleeding.
• Partial thrombin time/prothrombin time/international normalized ratio coagulation studies may help uncover a bleeding disorder.
• A thyroid-stimulating hormone determination may detect thyroid dysfunction, which can cause excessive or unpredictable bleeding.
• If the patient has galactorrhea, measurement of the prolactin level may be in order. In some cases, a pituitary tumor can raise the woman's prolactin level and affect the gland's secretion of FSH, thus disrupting the menstrual cycle.
• A Pap smear can reveal visible cervical lesions. Cervical cancer can present with bleeding.

A women's-health specialist may also run additional tests:

• FSH/LH/estradiol testing will help determine whether the patient's irregular bleeding is related to perimenopause.
• Pelvic/transvaginal ultrasound will visualize the endometrium and determine its thickness. This test will also help detect unusual masses or cysts on the ovaries.
• Endometrial samples collected in the office can be sent to pathology to rule out endometrial cancer and hyperplasia.

Ms. Jairam-Thodla is a nurse practitioner in the gynecologic oncology department at Northwestern Prentice Women's Hospital in Chicago.

References

1. Wren BG. Dysfunctional uterine bleeding. Aust Fam Physician. 1998;27:371-377.

2. Chen BH, Giudice LC. Dysfunctional uterine bleeding. West J Med. 1998;169:280-284.

3. Walden MS. Primary care management of dysfunctional uterine bleeding. JAAPA. 2006;19:32-39.

4. Endotext.com. Evaluation of amenorrhea, anovulation and abnormal bleeding. Available at www.endotext.org/female. Accessed March 19, 2008.

5. Fazio SB, Ship AN. Abnormal uterine bleeding. South Med J. 2007;100:376-382.

6. Johnson CA. Making sense of dysfunctional uterine bleeding. Am Fam Physician. 1991;44:149-157.

7. Bayer SR, DeCherney AH. Clinical manifestations and treatment of dysfunctional uterine bleeding. JAMA. 1993;269:1823-1828.

8. Welt CK. The normal menstrual cycle. In: Rose BD, ed. UpToDate. Wellesley, Mass.: UpToDate; 2007.

9. Taylor AE, Whitney H, Hall JE, et al. Midcycle levels of sex steroids are sufficient to recreate the follicle-stimulating hormone but not the luteinizing hormone midcycle surge: evidence for the contribution of other ovarian factors to the surge in normal women. J Clin Endocrinol Metab. 1995;80:1541-1547.

10. Bradshaw KD, Minjarez DA. Abnormal uterine bleeding in adolescents. Obstet Gynecol Clin North Am. 2000;27:63-78.

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