About one out of every five women of reproductive age suffers from menorrhagia, which translates into about 2.7 million office
visits in the United States each year.1 Of course, "menorrhagia" is only one of several confusing terms used to define the various forms of abnormal uterine bleeding
(AUB), as Table 1 illustrates.
Table 1: What is normal—and what is not
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Before one can diagnose AUB, it's important to first define normal menstrual bleeding. The normal menstrual cycle is 21 to
35 days long, with blood flow lasting no more than 7 days.2 AUB occurs at unexpected times or is of abnormal duration or amount. Heavy menstrual bleeding, or menorrhagia, is clinically
defined as blood loss of 80 mL or more per menstrual cycle.3,4 Dysfunctional uterine bleeding (DUB) is often used to describe many types of AUB, but specifically refers to AUB for which
an organic, systemic, iatrogenic, or anatomic cause cannot be found. It's most often, but not exclusively, a result of anovulatory,
noncyclic bleeding associated with disordered steroid hormone action. DUB is common immediately after menarche because of
the immaturity of the hypothalamic-pituitary-ovarian axis, and in the perimenopause, as a result of declining ovarian function.
Given the confusion surrounding the nomenclature of AUB, it's important for clinicians to take a structured approach to the
problem. A detailed history will clarify the time sequence of the bleeding to determine if it's cyclic or noncyclic. Determining
the amount of bleeding is more difficult. Patients often over-and underestimate the amount of blood they lose.5 Although pad counts can help, they too can be unreliable given differences in pad absorbency and interpersonal variation
in hygiene and pad changing behaviors. For clinical studies, menstrual blood loss per cycle has been measured by the alkaline
hematin method or the pictorial chart method.6,7 You'll also want to take a thorough medical history to search for organic causes of AUB. A family history of bleeding disorders
or gynecologic problems can be helpful. It is important to establish any relationship between bleeding and intercourse. A
review of systems may elicit undiagnosed conditions that may be related to AUB, including the presence of fever, pain, bowel/bladder
changes, weight changes, galactorrhea, or hirsutism.
Table 2: Common causes of ovulatory AUB
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The most important function of the physical exam is to determine the source of the bleeding. Occasionally, you will find that
the bleeding does not originate from the uterus, but from the vagina or other gynecologic site, or from the urethra, bladder,
or rectum. Also assess body habitus, and search for hyperandrogenism, galactorrhea, and skin changes associated with thyroid
disease. A thorough pelvic exam is necessary to establish uterine size and assess the adnexal structures.
Table 3: Causes of anovulatory AUB
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From this information one can begin to form a differential diagnosis. It's useful to distinguish ovulatory from anovulatory
AUB. Ovulatory bleeding is cyclic. Two main types of disordered cyclic bleeding can occur: bleeding can be heavier than normal
(menorrhagia) or can occur consistently between each menses (intermenstrual spotting). The common causes for each are listed
in Table 2. Anovulatory AUB is most often a result of disordered steroid hormone production. Potential causes of this type
of bleeding are listed in Table 3.
Figure 1. Workup for AUB
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After the clinical assessment is complete, consider several tests (Figure 1). Depending on a patient's age and reproductive
potential, a urinary or serum β-hCG should be performed early in the workup. Early pregnancy complications and losses alter
management significantly and may be life threatening, especially if undiagnosed. Additionally, some treatments for menorrhagia
may adversely impact a desired pregnancy. The workup should include a complete blood count (CBC), which provides an indirect
but objective assessment of the magnitude of blood loss. Thyroid-stimulating hormone (TSH) and prolactin levels are commonly
measured to rule out easily diagnosed and treatable endocrinologic causes of AUB.
Establishing a patient's ovulatory status is vital to form a differential diagnosis and guide treatment. A prospective menstrual
diary is often more informative than a retrospective account. Patients can also chart their basal body temperatures to look
for evidence of ovulation. Alternatively, luteal phase (cycle day 21 of a 28-day cycle) serum progesterone above 6 ng/mL indicates
ovulation has occurred. Ovulation is also suggested by a urinary LH surge (monitored for by over-the-counter LH kits), or
a secretory endometrial pattern on endometrial biopsy.
An endometrial biopsy will also help rule out neoplastic disease and should be performed on any woman with (1) risk factors
for endometrial hyperplasia such as chronic anovulation, obesity, or unopposed estrogen therapy; (2) postmenopausal bleeding;
and (3) menorrhagia over age 35. A transvaginal ultrasound (TVS) can be used to assess the endometrial stripe in women with
postmenopausal bleeding to screen for endometrial hyperplasia or cancer. Clinicians can use TVS, sonohysterography, magnetic
resonance imaging (MRI), hysterosalpingogrphy, and hysteroscopy to assess pelvic and/or intrauterine anatomy for structural
causes of AUB, including fibroids, polyps, or adnexal masses.
The treatment of AUB depends on the cause. Of course, it's important to treat any underlying medical or systemic illness that
might contribute to the abnormal bleeding but ultimately the approach to management is dictated by the severity of bleeding.
Treating acute severe menorrhagia
Usually accompanied by hemodynamic instability, this medical emergency requires IV access, volume support with crystalloids,
and blood products as necessary. The first-line agent for medical management of acute severe menorrhagia is estrogen, which
induces rapid proliferation of the denuded epithelium and enhances clotting factor production, thereby stabilizing the endometrium
and stopping the bleeding. Estrogen may be given IV, intramuscularly (IM), or by mouth (PO). The IV route is preferred in
acute blood loss for a more rapid response and to prevent possible loss via vomiting from the nausea that typically accompanies
large doses of oral estrogen.
Typically, 25 mg of conjugated estrogen is given IV every 4 to 6 hours until bleeding is controlled, for approximately 24
hours.8 Patients may be converted to oral estrogen at that time. Alternatively, 2.5 mg of estrogen may be given orally for acute
menorrhagia every 6 hours. Estrogen should be continued for 3 to 4 weeks, with progesterone added for the last 10 days. Make
sure the patient understands a heavy, but more controlled, withdrawal bleed will occur after progesterone is stopped. OCs
may also be used for menorrhagia by combining estrogen and progesterone to eliminate the need for adding a second agent at
a later time. Typically we use 20 to 35 μg of ethinyl estradiol, given 2 to 4 times per day until bleeding subsides, often
within 48 hours. The dosage can be tapered after bleeding is controlled to a maintenance dose for at least 1 week; one study
showed a reduction in menstrual blood loss by 43%, which was similar to traditional agents like mefenamic acid, naproxen,
or low dose danazol.9
Keep in mind, however, that OCs are a less favored regimen during acute bleeding because the concomitant presence of progesterone
inhibits the actions of estrogen. Progesterone inhibits synthesis of estrogen receptors and increases estradiol dehydrogenase
in the endometrial cell, preventing the rapid proliferation of the endometrium. However, subsequent treatment with progesterone
is crucial since it will induce decidual reaction with enhanced endometrial stromal cell tissue factor (thromboplastin) and
PAI-1 production to create a hemostatic environment and prevent estrogen-induced breakthrough bleeding.10
In patients using long acting progesterone contraceptives such as Depo-Provera and Norplant, bleeding often is a result of
an atrophic and fragile endometrium as well as aberrant angiogenesis.11 This bleeding is most appropriately treated with conjugated estrogens 0.3 to 1.25 mg PO, daily for 2 to 3 weeks.
Nonmedical management in the acute setting of severe menorrhagia includes temporizing measures such as inserting a Foley catheter
with a 30-mL balloon into the uterine cavity, and inflating it to tamponade uterine bleeding. Dilation and curettage (D&C)
is often performed for menorrhagia, but is most appropriate in the acute/severe setting, or in women at high risk for endometrial
adenocarcinoma in whom a D&C will also provide a pathologic specimen for diagnosis. Finally, acute severe menorrhagia may
be treated by uterine artery embolization, surgical ligation of uterine arteries, endometrial ablation or, ultimately, hysterectomy.
(We'll discuss these surgical options in more detail in part 2 of this 2-part article.)
Treating chronic bleeding
The subacute nature of chronic menorrhagia affords more time to determine causes and attempt medical therapy, before resorting
to surgery. Here are the options to consider:
Nonsteroidal anti-inflammatories (NSAIDs). These agents are often effective in reducing the amount of menstrual blood loss. Although we don't fully understand their
mechanism of action, it's thought that decreased prostaglandin production plays a primary role. NSAIDs inhibit synthesis of
prostacyclin, a vasodilatory, antiplatelet aggregation prostaglandin.12 A Cochrane review of 16 randomized controlled trials indicates that NSAIDs significantly reduce menstrual blood loss (MBL),
when compared to placebo.13 The drugs decrease MBL by 20% to 50%, and have the added benefit of treating dysmenorrhea.14 However, they appear to be most effective in treating ovulatory, rather than anovulatory AUB.
Antifibrinolytic agents. Often used to treat various hemorrhagic conditions, these agents are more effective than NSAIDs, decreasing MBL in women
with menorrhagia by about 50%.15 Tranexamic acid is administered either at a dose of 1 g TID or QID during menstruation, or 6 g for 3 days and then tapered
off. The risk of thromboembolic events is comparable to placebo, NSAIDs, OCs, and luteal phase progestins.16 Antifibrinolytics don't interfere with fertility, can be combined with other therapies, and have a fast onset of action,
making them suitable in an acute setting.
Oral contraceptives. Commonly used to prevent menorrhagia from recurring, OCs act, at least in part, by decreasing endometrial thickness, inducing
endometrial stromal tissue factor and PAI-1.17 OCs have been evaluated for menorrhagia in only one small randomized controlled trial, where they were comparable to mefenamic
acid, naproxen, and low-dose danazol. Mean MBL was decreased by 43%.9 Additional benefits of OCs include contraception and the ability to induce longer amenorrheic intervals between menses with
the use of continuous therapy, particularly if hematopoietic recovery is needed.
Oral progestins. Useful for treating anovulatory menorrhagia, and are most effective when used for at least 14 days of each menstrual cycle.
When given this way, cyclic progestins work best in anovulatory patients who don't desire contraception. Consider progestins
in patients at risk for endometrial hyperplasia, such as women with polycystic ovarian syndrome (PCOS) or diabetes. Keep in
mind, however, that low dose luteal phase progestins are less effective in controlling bleeding than tranexamic acid, danazol,
or the progesterone releasing intrauterine system (IUS).18 AUB in adolescents is often secondary to an immature hypothalamic-pituitary axis. In this group, low dose progestins given
for 10 days each month induces regular withdrawal bleeds until the hypothalamic-pituitary axis matures.12
IUDs. (IUS) and the progesterone impregnated intrauterine device (IUD) are novel ways to administer progestins. However, the progesterone
T, a 1-year system releasing 65 μg of progesterone per day has been discontinued by the FDA. The IUS is a T-shaped device
that releases 15 μg of levonorgestrel daily. It may be effective for up to 7 years, but is FDA approved for only 5 years.
One of the purported advantages of this approach is the direct delivery of hormone directly to target tissue, and only partial
inhibition of ovulatory function. Interestingly, 50% to 75% of both amenorrheic and regularly menstruating patients with the
IUS actually still ovulate, which supports a local mechanism of action.19,20
The levonorgestrel IUS has been studied for use in treating menorrhagia. One study showed an 80% decrease in menstrual blood
loss 3 months, and 100% at the end of 1 year. This reduction was significantly greater than the antifibrinolytic tranexamic
acid and the NSAID flurbiprofen.21
Patient satisfaction rates and continuation rates were higher with the IUS compared to oral progestins.22 The levonorgestrel IUS was less effective than endometrial ablation in reducing menstrual blood loss at 1 year, but equivalent
in increasing hemoglobin values.23,24 An exciting new use for the levonorgestrel IUS was recently reported in patients with leiomyomas. One group has reported
that it causes a significant reduction in uterine volume after just 3 months, and a reduction in total leiomyoma volume after
6 months, as well as decreasing MBL.25 This option may be particularly well suited for younger patients who wish to preserve fertility and desire effective long-term
nonsurgical control of their symptoms.
Danazol. Although effective, this drug is a poorly tolerated approach to chronic menorrhagia and DUB. It's a testosterone derivative
with antiestrogenic, antiprogestogenic, and weakly androgenic properties. A dosage of 200 to 400 mg daily significantly reduced
menstrual blood loss, compared to placebo, progestogens, NSAIDs and OCs.26 The duration of menses was significantly decreased in comparison to NSAIDs and the progesterone IUD. However, side effects
largely related to its androgenic properties were significantly higher with danazol than each of these other regimens, which
included acne, seborrhea, hirsutism, weight gain, irritability, musculoskeletal pains, hot flushes, and breast atrophy. Long-term
treatment with danazol may cause benign hepatic adenomas.26 In addition to its side effects, danazol is expensive. The drug may also promote preoperative endometrial thinning prior
to endometrial ablative procedures.
Gonadotropin releasing hormone (GnRH) agonists. Although highly effective in the treatment of menorrhagia, GnRH agonists are usually reserved for women who have failed other
medical therapies. When given continuously, these agents inhibit pituitary secretion of gonadotropins. They also induce a
reversible menopausal state, causing most women to become amenorrheic. An advantage of this therapy is its high rate of effectiveness.
Drawbacks include high cost, limitation of use to 3 to 6 months due to risk of bone loss, and menopausal symptoms. GnRH agonists
are best used before surgery to increase hematocrit, reduce fibroids, or decrease the thickness of the endometrium prior to
endometrial ablation.
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Article at a glance
- The first-line agent for medical management of acute severe menorrhagia is estrogen, which induces rapid proliferation of
the denuded epithelium and enhances clotting factor production.
- Typically, 25 mg of conjugated estrogen is given IV every 4 to 6 hours until acute menorrhagic bleeding is controlled, for
approximately 24 hours.
- Antifibrinolytic agents are more effective than NSAIDs for treating chronic menorrhagia, decreasing menstrual blood loss in
women with menorrhagia by about 50%.
- Useful for treating anovulatory menorrhagia, progestins are most effective when used for at least 14 days of each menstrual
cycle.
