Primary care management of dysfunctional uterine bleeding

Hormonal abnormalities are the most frequent cause of dysfunctional uterine bleeding, which may be acute or chronic, severe or mild, ovulatory or anovulatory. Treatment is tailored to the patient’s needs and preferences.

Megan S. Walden, PA-C

The author works in adult medicine at Community Health Care, Inc, Davenport, Iowa. She has indicated no relationships to disclose relating to the content of this article.

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Dysfunctional uterine bleeding (DUB) is abnormal uterine bleeding (AUB) without an organic cause. Before diagnosing DUB, the clinician should rule out such causes, including pregnancy, tumor, infection, coagulopathy, and pelvic or systemic disease. At some time, virtually every woman will experience bleeding that she considers abnormal (see Table 1). AUB interferes with a woman’s work, home, and sex life, causing emotional, medical, and financial burdens. Ineffective, inefficient management of this common disorder significantly drains health care and financial resources. The patient may suffer negative medical consequences such as anemia, missed serious pathology, discontinuation of contraception or hormone replacement therapy (HRT), or even unnecessary hysterectomy.¹  

Incidence and prevalence

AUB can account for 10% of visits to family physicians and PAs^2,3 and approximately 5% of visits to general practitioners annually.¹ Most cases occur 5 to 10 years before menopause or after menarche. A common reason for referral from primary to secondary care, AUB comprises one third of all outpatient gynecology visits.⁴

Up to 20% of women with DUB will seek consultation.² DUB affects approximately 5% of menstruating women, comprising about 80% of cases of menorrhagia, the most common cause of iron-deficiency anemia in the developed world.⁵ Unfortunately, most primary care practitioners do not understand the pathophysiology and principles of management of DUB, although the disorder can be managed in primary care.  

Etiology

Interaction among the hypothalamus, anterior pituitary, ovaries, and endometrium govern the menstrual cycle (see Figure 1). Dysfunction in this system can result in anovulation or AUB. With many systems and substances involved, the opportunities for aberration are abundant.

The span of the normal menstrual cycle is 23 to 39 days, averaging 29 days.⁶ Menstruation generally lasts 2 to 7 days, with blood loss ranging from 25 to 69 mL, averaging 40 mL, and with the heaviest flow during the first 2 days.⁶ Loss of 80 mL or more of blood during a cycle is considered excessive and increases the risk for iron-deficiency anemia.⁶ While the length, amount of blood loss, and duration of menses are variable, these parameters remain relatively constant from cycle to cycle for any woman of reproductive age. Deviation is common and expected, however, in the perimenarchal and perimenopausal years because of the ovaries’ unstable responsive state and hormonal fluctuations.  

AUB and DUB

AUB is often due to administration of exogenous hormones. DUB, however, results from endogenous hormonal etiologies. The pathophysiology underlying DUB depends upon ovulatory status.

Anovulatory DUB, most common in the perimenarchal and perimenopausal years, results from a disturbance in the hypothalamic-pituitary-ovarian (HPO) axis. During menarche, there is a delay in maturation of the positive feedback mechanism for a surge of luteinizing hormone (LH), which leads to ovulation. Light to medium bleeding results from estrogen withdrawal.⁷ In perimenopause, there is a diminution of primordial ovarian follicles and reduced sensitivity to follicle-stimulating hormone (FSH) and LH, resulting in estradiol levels insufficient to induce an LH surge and ovulation. The follicles continue to produce estrogen, causing the endometrium to continue growing. Eventually, either the estrogen levels drop and withdrawal bleeding occurs, or estrogen levels accumulate, causing an LH surge followed by ovulation and heavy bleeding.³

High levels of estrogen unopposed by progesterone, as in polycystic ovary syndrome (PCOS) and obesity, stimulate continual growth of the endometrium. The lining eventually becomes so thick it outgrows its vascular support, resulting in superficial breakage and often heavy bleeding.⁸ Vascular tone, inhibition of vasopressin release, and disturbed angiogenesis also contribute to heavy bleeding.⁹ Conversely, there may be minimal bleeding if the estrogen level is not high enough to stimulate endometrial growth, as in amenorrhea associated with stress, exercise, or weight loss.

Ovulatory DUB is thought to be secondary to defects in local hemostasis; no disturbance in the HPO axis occurs, nor are there abnormalities in the steroid hormone profiles.⁹ Hemostatic mechanisms have also been implicated in menorrhagia.   

History and physical examination

A thorough history is crucial to the diagnosis and management of DUB. Most likely, the patient will present with the chief complaint of AUB. Because a wide range of physiologically normal menstrual bleeding requires no further workup, the clinician should take time to fully characterize the bleeding that the patient perceives as abnormal. Most organic causes of AUB can be ruled out with a history and physical examination.

The history is imperative in characterizing the bleeding; specific dates can most accurately assess its timing and length. The severity of the bleeding is best indicated by the presence of clots, frequency of sanitary napkin and tampon use, soiling of clothes or sheets, and signs and symptoms of anemia or volume depletion.⁷ Associated premenstrual symptoms, pain, and hirsutism are also important concerns.¹⁰ Thorough gynecologic, medical, family, and social histories are essential, particularly in assessing for endometrial cancer risk factors including anovulation, obesity, nulliparity, age older than 35 years, diabetes, and tamoxifen therapy.¹¹

The physical examination should include determinations of orthostatic BPs, nutrition status, weight, and body mass index. All patients should have pelvic and speculum examinations to rule out trauma and foreign bodies, a Pap smear, and a bimanual examination to detect uterine fibroids, ovarian masses, ectopic pregnancy, or signs of pelvic inflammatory disease (PID) or pregnancy. The pelvic examination may be omitted in an abstinent, oligomenorrheic adolescent who is within 18 to 24 months of menarche with no increase in the amount of bleeding.^5,8  

Diagnosis

To arrive at the diagnosis of DUB, the results of all tests that would indicate pregnancy or pregnancy-related complications, systemic disorders, and structural abnormalities (with the exception of an unrelated intracavitary lesion) must be negative.^12,13

Laboratory tests Urinalysis and a stool guaiac test are indicated if the source of bleeding is in question.¹⁴ A CBC is needed to determine hemodynamic stability in all patients with AUB, as is a test for serum quantitative beta human chorionic gonadotropin to rule out pregnancy if the woman is of reproductive age. Other initial tests depend on age, ovulatory status, risk of sexually transmitted disease, and presentation suggesting hepatic, renal, thyroid, or other systemic disorders. Diabetes screening is suggested for women with long or irregular cycles.¹¹ Order a coagulation profile for patients with anovulatory DUB that has not responded to medical or surgical therapy, those with ovulatory DUB without an anatomic uterine lesion, and all adolescents with menorrhagia.¹⁵ If no coagulopathy is found in the teenage patient, anovulatory DUB is the assumed diagnosis and therapy should be initiated.¹⁴

The key to effectively managing DUB is determining whether the patient is ovulatory or anovulatory, usually by the timing of bleeding and the associated symptoms. If ovulatory status cannot be determined by history alone, a record of basal body temperature (an increase of 0.3°C-0.6°C [32.54°F-33.08°F] indicates ovulation), a serum progesterone level (higher than 9.5 nmol/L indicates ovulation), or an endometrial biopsy at the onset of bleeding (confirming a secretory endometrium) may be used to indicate ovulation.⁶ Obtain levels of LH, FSH, prolactin, thyrotropin, and free T₄ when evaluating the anovulatory patient. Measure levels of dehydroepiandrosterone sulfate, testosterone, and 17-OH progesterone if the patient’s presentation suggests that hyperandrogenism is a possibility.⁶

Other diagnostics Transvaginal ultrasonography (TVUS) is noninvasive and helpful in detecting intracavitary polyps, submucous fibroids, or ovarian masses and in measuring endometrial thickness to determine whether the patient requires further evaluation with hysteroscopy and biopsy.¹⁴ It is the most cost-effective initial test in women with medically refractory DUB who are at low risk for endometrial cancer.¹¹ When performed accurately, TVUS demonstrating an endometrial thickness of less than 5 mm has a 97% negative predictive value for endometrial hyperplasia in postmenopausal women and an 85% negative predictive value in premenopausal women.⁸

TVUS is less sensitive for polyps and myomas. Saline infusion sonography (SIS) improves specificity and sensitivity in the detection of intracavitary lesions.¹⁶ Lesions may or may not be related to the abnormal bleeding. Hysteroscopy helps to further characterize and determine a specific diagnosis for lesions or endometrial hyperplasia suggested by ultrasonography.¹⁴ Hysteroscopy with biopsy is the gold standard for diagnosis of AUB but is costly and invasive and requires skill.

Endometrial biopsy Because the risk of endometrial cancer increases with age, the American College of Obstetricians and Gynecologists recommends endometrial biopsy in all women older than 35 years who have AUB.¹⁷ Biopsy is also indicated for patients aged 18 to 35 years with risk factors for endometrial cancer, for all women who have been anovulatory for at least 1 year,^6,12,18 or when necessary to determine ovulatory status.¹⁰ Office hysteroscopic sampling provides histopathologic diagnostic accuracy equivalent to that of dilation and curettage (D&C). Although less sensitive for polyps, myomas, and atypical endometrial hyperplasia, office sampling is well tolerated, less costly, and does not require anesthesia. Currently, SIS with biopsy gives the most cost-effective complete evaluation with the least risk.¹¹

D&C This procedure is indicated if there are contraindications to endometrial sampling, such as acute PID, cervical stricture, or bleeding disorders; if endometrial sampling was inadequate; or if symptoms continue despite medical management.³ Offer D&C to postmenopausal women with AUB who are not taking HRT or have taken it for more than 12 months. If the patient refuses or is a poor surgical candidate, she should have TVUS or SIS with biopsy.¹¹

Assessment and differential diagnosis

Assessing hemostatic stability is of primary importance in managing DUB. Indicators of volume status such as orthostatic BP, blood loss, CBC results, and iron levels provide the most objective insight to the acuity of DUB. Although many cases of DUB can be managed by primary care providers, a specialist should be consulted if there are complications of pregnancy, known or suspected underlying gynecologic pathology, or a poor response to treatment.⁶ Also consider consultation for patients with fertility concerns, severe anemia, bleeding that persists for more than 15 days per month, menorrhagia (when the patient is older than 35 years), or ovulatory DUB.⁶ Consult other specialists as necessary when a specific underlying pathology, such as coagulation disorders or liver or renal disease, is suspected.

Abnormal bleeding may originate from vulvar, vaginal, cervical, or uterine sources and may be systemic or localized.⁵ The differential diagnosis of DUB may be divided into anovulatory and ovulatory etiologies. Chronicity, quantity of bleeding, phase of reproductive life, functional state, and endometrial thickness give clues to the underlying cause and so direct evaluation and management.

The presentation and causes of anovulatory DUB vary with stage of reproductive life. DUB occurring in the perimenarchal years or related to excess weight loss or heavy exercise is often irregular and light. Heavy, irregular bleeding can result from PCOS, androgen overproduction by the adrenal glands or ovaries, or obesity. Other causes of anovulatory bleeding include hyperprolactinemia, thyroid dysfunction, ovarian failure, medications, and insulin resistance.⁶    

Ovulatory DUB causes regular intervals of bleeding, most often heavy, associated with premenstrual symptoms. Possible patterns include oligomenorrhea with menorrhagia, polymenorrhea with menorrhagia, premenstrual spotting, delayed-onset menses with menorrhagia, and menorrhagia or midcycle spotting.⁹  

Treatment and follow-up

The goals of treatment are to control bleeding, prevent future episodes, restore synchrony to the endometrium, replenish iron stores, prevent serious long-term consequences of anovulation, and preserve desired fertility. The approach depends upon acuity and severity of the bleeding episode, as well as on the patient’s age, ovulatory status, and desire for contraception. Elemental iron (60-180 mg daily) and folate supplements are essential components of any DUB treatment regimen.¹³ Reassurance, observation, and supplements, if indicated, may be the only treatments necessary for mild bleeding. Hospitalization is indicated when heavy bleeding leads to severe anemia and/or hemodynamic instability. Adolescents should be admitted if the hemoglobin is less than 7 g/dL or is 10 g/dL or less with recurrent heavy bleeding.⁷

Acute bleeding The initial approach to stopping acute bleeding depends on the patient’s hemodynamic stability. In a life-threatening emergency, the patient should be stabilized with IV fluids, transfusions if indicated, and placement of a 30-cc balloon Foley catheter in the uterus to control bleeding until D&C is performed or until medical treatment takes effect.⁶

Acute, heavy bleeding in a hemodynamically stable patient should be managed medically. High-dose conjugated equine estrogens are the most widely prescribed medical treatment¹³ (see Table 2). Various high-dose estrogen regimens are equally effective in stopping a bleeding episode; however, the underlying cause must be investigated and treated.¹⁴ If the patient has contraindications to estrogen therapy, is intolerant of high-dose estrogen, or is suspected to have excess endometrial tissue, progesterone alone may be the preferred treatment.^5,8 Upon completion of treatment for acute bleeding, cyclic oral contraceptives (OCs) should be used for the next three to four cycles to support the endometrium.¹⁴

Drug therapy for chronic DUB The management of chronic DUB should be tailored to the patient’s ovulatory status, age, health risks, and contraception preferences. Anovulatory DUB is estimated to account for 85% of DUB.¹⁴ If the anovulatory patient with DUB desires fertility, clomiphene or gonadotropins are effective in restoring regular bleeding by inducing ovulation (see Table 3).¹⁰ One-time progesterone regimens may also be useful.⁵ If conception is not presently desired, a cyclic progestin regimen is the mainstay of treatment.^6,14 Combination OCs are also used frequently for managing DUB if the patient has no contraindications to estrogen therapy. The patient receiving hormonal therapy should be seen 3 months after initiation of therapy, then every 6 months for reevaluation and monitoring of side effects.

Progesterone is available in both synthetic and natural compounds. Synthetic progestins such as medroxyprogesterone acetate (MPA), megestrol, norethindrone, norethindrone acetate, and norgestrel are inexpensive and effective in a single daily dose but may cause more side effects. Norethindrone, norethindrone acetate, and norgestrel lower HDL cholesterol levels and have androgenic action because they are structurally similar to testosterone.¹⁹ Natural progesterone, derived from plant steroids, is a chemical duplicate of human progesterone and tends to be better tolerated than are synthetic progestins. However, natural progesterone’s short half-life necessitates bid or tid dosing; in addition, natural progesterone is less available and not often covered by insurance because it is not FDA approved.¹⁰

Progesterone treatment of ovulatory DUB has produced mixed results. Some studies have reported that doubling the daily dosage and treating from days 5 to 25 of the cycle increases the success rate.¹⁴ Long-cycle and continuous progesterone treatments, as with progestin-containing intrauterine devices and IM MPA, have been found to reduce menstrual flow (see Table 4).^5,11-13

NSAIDs and antifibrinolytic agents can also be used to treat ovulatory DUB and menorrhagia. NSAIDs, which can be given in combination with OCs or progesterone, have an additive effect in decreasing the amount of flow and are especially beneficial for concomitant dysmenorrhea.^5,14 Antifibrinolytic agents are as effective as OCs and have an additive effect when used in combination with them,¹⁴ but they may increase risk of thromboembolism.¹¹

Other medical agents, including ergot derivates, oral danazol, and gonadotropin-releasing hormone (GnRH) agonists, can be considered for refractory cases. These agents are more expensive and less efficacious and have frequent side effects. GnRH agonists are considered a last resort in the medical management of DUB. However, they may be useful for patients with severe blood loss whose bleeding has not responded to other medical management and who want fertility preserved. Adding estrogen and/or progesterone to the GnRH agonist minimizes the side effects and protects the skeletal system.²⁰

Surgical therapy for chronic DUB Surgery may be indicated for heavy bleeding refractory to medical treatment, for bleeding resulting in hemodynamic instability, or for patients who do not desire future fertility and have concomitant pelvic disease that is surgically correctible. Surgical options include D&C, endometrial ablation, hysterectomy, and transcervical resection of the endometrium (TCRE). D&C is the quickest way to stop acute bleeding in hypovolemic patients and provides a tissue sample for histologic examination. However, D&C is no longer considered curative; if it is repeated, it may cause Asherman’s syndrome and impaired fertility. Patients usually resume heavy menstruation within two cycles unless medical treatment with an agent such as cyclic MPA is instituted for 3 to 6 months.²⁰

Endometrial ablation is best for the woman who wants to keep her uterus but does not desire future fertility, has normal cervical cytology and endometrial histology, is not perimenopausal, has no associated pelvic pathology that would benefit more from hysterectomy, has not had PID in the past 3 months, and does not have a coagulopathy. It may also be useful for severe menorrhagia that does not respond to medical treatment or when major surgery and medical treatment are contraindicated. Compared with hysterectomy, ablation offers a shorter operative time, less blood loss, lower complication rates, more rapid postoperative recovery, less discomfort, shorter hospitalization, decreased morbidity, and decreased expense. Satisfaction rates, as defined by amenorrhea, oligomenorrhea, or a return to normal menstrual flow, are 80% to 95%.¹⁴ The rate of complications is similar to that for operative hysteroscopy at 3.9% to 4.4%.¹⁴ Ablation does not prevent premalignant or malignant uterine lesions from developing, however, and does not guarantee sterility.¹⁴

Hysterectomy is the treatment of choice for DUB in women who have concomitant pelvic disease that can be treated with removal of the uterus. Patients undergoing hysterectomy should have tried medical management first and should have severe enough bleeding to lower serum ferritin levels.

TCRE may be an alternative to hysterectomy if the patient has a normal pelvis, has small fibroids or fibroid polyps, and does not have pelvic pain, PID, or endometriosis. One third of patients report amenorrhea after TCRE, and those who undergo this procedure have fewer complications, lower costs, and shorter recovery time compared to women who have had total hysterectomy.²¹  

Prevention and patient education

To prevent complications, significant blood loss, and chronic DUB from developing, the clinician should ask the patient questions about her menstrual cycles, stress levels, recent significant weight changes, and thyroid disease symptoms. The only useful screening test for DUB is taking the time to obtain a thorough menstrual history. Most often, the patient will present with symptoms of AUB and/or anemia.

Practitioners should advise all patients that maintaining a healthy weight and ceasing use of alcohol, cocaine, amphetamines, and tobacco can minimize risks for abnormal bleeding and carcinoma. Women of all ages should be assessed for endometrial carcinoma risk factors and educated appropriately. Endometrial sampling is crucial to rule out malignancy in high-risk patients.

It is important to inform all female patients about the wide range of normal menstruation during the reproductive years to alleviate stress and prevent unnecessary office visits. Also educate women who are postmenopausal and premenarchal girls about seeking care for uterine and vaginal bleeding.

Educating the patient with DUB about the underlying causes and the rationale for treatment is a challenge, as many medical practitioners do not have a thorough understanding of DUB themselves. However, patient education is essential to promoting adherence to treatment and preventing further bleeding episodes and complications.   

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