Uterine Bleeding

Abnormal Uterine Bleeding

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Dysfunctional uterine bleeding (DUB) is the most common cause of abnormal vaginal bleeding during a woman's reproductive years. The diagnosis of DUB should be used only when other organic and structural causes for abnormal vaginal bleeding have been ruled out.

A normal menstrual cycle occurs every 21-35 days with menstruation for 2-7 days. The average blood loss is 35-150 mL total, which represents 8 or fewer soaked pads per day with usually no more than 2 heavy days.
Pathophysiology

During the normal menstrual cycle, the first day corresponds to the first day of menses. The menstrual phase usually lasts 4 days and involves the disintegration and sloughing of the functionalis layer of the endometrium. The proliferation (follicular) phase extends from day 5 to day 14 of the typical cycle. It is marked by endometrial proliferation brought on by estrogen stimulation. The estrogen is produced by the developing ovarian follicles under the influence of follicle-stimulating hormone (FSH). Cellular proliferation of the endometrium is marked, and the length and convolutedness of the spiral arteries increases. This phase ends as estrogen production peaks, triggering the FSH and luteinizing hormone (LH) surge.

Rupture of the ovarian follicle follows, with release of the ovum (ovulation). The secretory (luteal) phase is marked by production of progesterone and less potent estrogens by the corpus luteum. It extends from day 15 to day 28 of the typical cycle. The functionalis layer of the endometrium increases in thickness, and the stroma becomes edematous. If pregnancy does not occur, the estrogen and progesterone feedback to the hypothalamus, and FSH and LH production falls. The spiral arteries become coiled and have decreased flow. At the end of the cycle, they alternately contract and relax, causing a breakdown of the functionalis layer and menses to begin.

Approximately 90% of DUB results from anovulation, and 10% occur with ovulatory cycles. During an anovulatory cycle, the corpus luteum fails to form, which causes failure of normal cyclical progesterone secretion. This results in continuous unopposed production of estradiol, stimulating overgrowth of the endometrium. Without progesterone, the endometrium proliferates and eventually outgrows its blood supply, leading to necrosis. The end result is overproduction of uterine blood flow.

In ovulatory DUB, prolonged progesterone secretion causes irregular shedding of the endometrium. This probably is related to a constant low level of estrogen that is around the bleeding threshold. This causes portions of the endometrium to degenerate and results in spotting. Progesterone causes the enzymatic conversion of estradiol to estrone, a less potent estrogen. The changes in the endometrium remain secretory within the glands. Patients who exhibit these symptoms in the reproductive years often have ovulatory cycles or secondary reasons for altered hypothalamic function (eg, polycystic ovary disease).

Dysfunctional bleeding from the uterus can be described as follows:

* Menorrhagia - Prolonged (>7 d) or excessive (>80 mL daily) uterine bleeding occurring at regular intervals
* Metrorrhagia - Uterine bleeding occurring at irregular and more frequent than normal intervals
* Menometrorrhagia - Prolonged or excessive uterine bleeding occurring at irregular and more frequent than normal intervals
* Intermenstrual bleeding (spotting) - Uterine bleeding of variable amounts occurring between regular menstrual periods
* Polymenorrhea - Uterine bleeding occurring at regular intervals of less than 21 days
* Oligomenorrhea - Uterine bleeding occurring at intervals of 35 days to 6 months
* Amenorrhea - No uterine bleeding for 6 months or longer

The major categories of DUB include the following:

* Estrogen breakthrough bleeding
* Estrogen withdrawal bleeding
* Progestin breakthrough bleeding

Frequency
United States

As many as 10% of women with normal ovulatory cycles reportedly have experienced DUB. Obese females tend to have irregularities in their menstrual cycles due to nonovarian endogenous production of estrogen often related to their degree of adipose tissue. This usually results in prolonged cycles of amenorrhea that alternate with cycles of metrorrhagia or menometrorrhagia.
International

No cultural predilection is present with this disease state. However, note that countries, including the United States, that have a large population of female athletes have more recognition of this entity. In athletes, a loss of the LH surge, as well as, a luteal phase deficiency tends to be present. This is characterized by a shortened luteal phase from insufficient progesterone production or effect. This inadequate progesterone stimulation may be coexistent with high, low, or normal estrogen levels and often results in similar problems in anovulatory cycles such as amenorrhea.
Mortality/Morbidity

Morbidity is related to the amount of blood loss at the time of menstruation, which occasionally is severe enough to cause hemorrhagic shock.

Although, DUB in itself is rarely fatal, distinguishing this presentation from that of endometrial cancer is important. Development of endometrial cancer is related to estrogen stimulation and endometrial hyperplasia. Symptoms include postmenopausal bleeding, which is usually considered cancer until proven otherwise.
Race

DUB has no predilection for race; however, black women have a higher incidence of leiomyomas and higher levels of estrogen. As a result, they are prone to experiencing more episodes of abnormal vaginal bleeding.
Age

DUB is most common at the extreme ages of a woman's reproductive years, either at the beginning or near the end, but it may occur at any time during her reproductive life.

* Most severe cases of DUB occur in adolescent girls during the first 18 months after the onset of menstruation, when their immature hypothalamic-pituitary axis may fail to respond to estrogen and progesterone, resulting in anovulation.
* In the perimenopausal period, DUB may be an early manifestation of ovarian failure causing decreased hormone levels or responsiveness to hormones, thus also leading to anovulatory cycles. In patients who are 40 years or older, the number and quality of ovarian follicles diminishes. Follicles continue to develop but do not produce enough estrogen in response to FSH to trigger ovulation. The estrogen that is produced usually results in late-cycle estrogen breakthrough bleeding.

Clinical
History

* Patients often present with complaints of amenorrhea, oligomenorrhea, menorrhagia, or metrorrhagia. Ask patients to compare the number of pads or tampons used per day in a normal menstrual cycle to the number used at the time of presentation. The average tampon holds 5 mL of blood; the average pad holds 5-15 mL of blood.
* Occasionally, bleeding is profuse with associated signs and symptoms of hypovolemia, including hypotension, tachycardia, diaphoresis, and pallor. These patients usually do not have vaginal or pelvic pain associated with bleeding episodes, and other systemic symptoms rarely are noted unless vaginal bleeding has an organic cause.
* A reproductive history should always be obtained, including the following:
o Menstrual regularity
o Last menstrual period (LMP), including flow and duration
o Gravida and para
o Previous abortion or recent termination of pregnancy
o Contraceptive use

* Questions about medical history should include the following:
o Signs and symptoms of hypovolemia
o Diabetes mellitus
o Hypertension
o Hypothyroidism, hyperthyroidism
o Liver disease
o Medication usage, including exogenous hormones, anticoagulants, aspirin, anticonvulsants, and antibiotics
o Alternative and complementary medicine modalities, such as herbs and supplements

Physical

* Initial evaluation should be directed at assessing patient's volume status and degree of anemia. Examine for pallor and absence of conjunctival vessels to gauge anemia.
* Patients who are hemodynamically stable require a pelvic speculum and bimanual examination to define the etiology of vaginal bleeding. The examination should look for the following:
o Trauma to the vaginal walls or cervix
o Retained foreign body
o Cervical or vaginal laceration
o Bleeding from the cervical os

* Uterine or ovarian structural abnormalities may be noted on bimanual examination, but a negative examination is insensitive for finding abnormalities.
* Patients with hematologic pathology also may have cutaneous evidence of bleeding diathesis. Physical findings include petechiae, purpura, and mucosal bleeding (eg, gums) in addition to vaginal bleeding.
* Patients with liver disease that has resulted in a coagulopathy may manifest additional symptomatology because of abnormal hepatic function. Evaluate patients for spider angioma, palmar erythema, splenomegaly, ascites, jaundice, and asterixis.
* Women with polycystic ovary disease present with signs of hyperandrogenism, including hirsutism, obesity, and palpable enlarged ovaries.
* Hyperactive and hypoactive thyroid can cause menstrual irregularities. Patients may have varying degrees of characteristic vital sign abnormalities, eye findings, tremors, changes in skin texture, and weight change. Goiter may be present.

Causes

* Multiple organic pathologies can present as abnormal vaginal bleeding, including thrombocytopenia, hypothyroidism, hyperthyroidism, Cushing disease, liver disease, hypertension, diabetes mellitus, and adrenal disorders.
* Pregnancy may be associated with vaginal bleeding that the patient may report as "abnormal" for her in terms of timing, amount, or duration.
* Trauma to the cervix, vulva, or vagina may cause abnormal bleeding.
* Carcinomas of the vagina, cervix, uterus, and ovaries always must be considered in patients with the appropriate history and physical exam.
* Other causes of DUB include structural disorders, such as functional ovarian cysts, cervicitis, endometritis, salpingitis, and leiomyomas.
* Polycystic ovary disease, vaginal infection, polyps, ectopic pregnancy, hydatidiform mole, blood dyscrasias, excessive weight gain, increased exercise performance, or stress may also contribute to DUB.

* Breakthrough bleeding may occur in patients taking oral contraceptives that have inadequate doses of estrogen and progestin for the patient.
o Intermenstrual bleeding may occur secondary to missed pills, varied ingestion times, and drug interactions.
o The most common drug interactions with OCPs occur with phenobarbital, carbamazepine, some penicillins, tetracycline, and trimethoprim-sulfamethoxazole.
o Breakthrough bleeding can indicate reduced birth control efficiency; therefore, advise using additional birth control methods until the next menstrual cycle begins.

* An iatrogenic cause of DUB is the use of progestin-only compounds for birth control. Medroxyprogesterone acetate (Depo-Provera), a long-acting injection given every 3 months, inhibits ovulation. An adverse effect of this drug is prolonged uterine breakthrough bleeding; this may continue after discontinuation of the drug because of persistent anovulation. The Norplant system (surgically implanted levonorgestrel), which acts to block some but not all ovulatory cycles, has the same adverse effects as Depo-Provera.
* Contraceptive intrauterine devices (IUDs) can cause variable vaginal bleeding for the first few cycles after placement and intermittent spotting subsequently. The progesterone impregnated IUD (Mirena) is associated with less menometrorrhagia and usually results in secondary amenorrhea.