Endometrial cancer is the fourth most common cancer in women and occurs in approximately 25 per 100,000 women.^5,⁶ This malignant disease develops during the reproductive and menopausal years, with most patients being 50 to 59 years of age. About 5% of women younger than 40 have adenocarcinoma, and it is diagnosed in a quarter of patients before menopause. Many cases of endometrial cancer go undetected given that Papanicolaou smears detect only 50% of cases and the diagnosis is rarely considered in perimenopausal women despite the aforementioned statistics.

Cervical Cancer

Cervical cancer is the second most common malignancy in women worldwide. Approximately 11,000 new cases are diagnosed annually in the United States, and it accounts for around 4000 deaths per year. Minority populations are more commonly affected. The peak incidence of cervical cancer occurs in women 45 to 54 years of age; however, there is a surge in prevalence in women in their 20s and 30s as human papillomavirus (HPV) rates have increased.^5,⁶

Pathophysiology

Common terminology and definitions for vaginal bleeding are listed in Box 124.1. An understanding of the normal female reproductive cycle is useful when caring for patients with vaginal bleeding and pelvic pain. The normal reproductive cycle is 28 days, with a range of 21 to 35 days, and the average age at menarche is approximately 12.5 years. The complex hormonal feedback mechanism that governs the female reproductive cycle is controlled by the hypothalamic-pituitary-ovarian (HPO) axis. Days 1 to 14 are known as the follicular or proliferative phase and are dominated by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus; GnRH in turn stimulates pituitary release of follicle-stimulating hormone (FSH). During this phase a dominant ovarian follicle matures and produces estrogen, which causes the endometrium to thicken and prepare for possible embryo implantation. Positive feedback of estrogen to the pituitary gland induces a surge in luteinizing hormone (LH) on day 14 of the cycle, which results in ovulation. Days 14 to 28 are known as the luteal or secretory phase; this phase is predominated by progesterone production from the corpus luteum, which induces maturation of the endometrium. If conception and implantation do not occur, the corpus luteum involutes, estrogen and progesterone levels fall, and menstruation occurs.

Changes in the endometrium occur at each step of the reproductive cycle. During the proliferative phase the endometrium grows and thickens in response to estrogen as it prepares for implantation of an embryo. During the secretory phase the endometrium matures under the influence of progesterone and glands and secretory vacuoles develop. As progesterone levels drop at the end of the secretory (luteal) phase, prostaglandins are released and cause vasospasm within the endometrial vasculature. This leads to sloughing of the outer layers of the endometrium, and thus menstruation occurs.

Disruption at any point in this feedback loop may cause pelvic pain or abnormal vaginal bleeding.

Presenting Signs and Symptoms

Vaginal bleeding can vary greatly in amount and severity. A thorough history and physical examination should be performed to evaluate the onset, duration, amount, and timing within the menstrual cycle of the bleeding. Assessment of severity includes determining the number of tampons or pads changed over a 12- to 24-hour period, whether they were saturated, and whether any clots were associated with the bleeding. Associated symptoms such as orthostatic complaints, fatigue, and dyspnea on exertion should point to underlying anemia from chronic blood loss or hypovolemia from acute blood loss. Vaginal bleeding may not be the primary disorder, and thus a thorough search for causes of secondary vaginal bleeding is prudent. The age of the patient, medical and surgical history, and medication profiles will also provide clues to the cause of the bleeding.

Dysfunctional Uterine Bleeding

The typical finding of DUB is irregular menses with alternation between heavy and light flow. Women often have signs of hyperandrogenism, including hirsutism, obesity, acne, palpable enlarged ovaries, and acanthosis nigricans (hyperpigmentation typically in the folds of the skin of the neck, groin, or axilla).

Uterine Leiomyomas (Fibroids)

The symptoms that arise from uterine myomas can be classified into abnormal uterine bleeding, pelvic pressure and pain, and reproductive dysfunction. The number, size, and location of these tumors dictate the severity of symptoms. Abnormal uterine bleeding is the most common symptom and is usually manifested as chronic heavy and prolonged menses, or menometrorrhagia. Bulk-related symptoms of fibroids include urinary frequency, difficulty voiding, urinary obstruction, constipation, and occasionally back pain. In addition, leiomyomas have the propensity to degenerate or twist on their stalk and cause torsion. In this setting, pelvic pain may be accompanied by low-grade fevers, uterine tenderness, leukocytosis, or even peritoneal signs. Distortion of the uterine cavity secondary to leiomyomas may result in difficulty conceiving and has been associated with an increased risk for miscarriage, placental abruption, fetal growth restriction, and preterm labor.

Vaginal Foreign Body

Mild vaginal bleeding may be the initial sign in a patient with a retained vaginal foreign body. If associated with infection, the patient may also have a purulent discharge or vaginal irritation.

Endometrial Cancer

Symptoms include painless postmenopausal vaginal bleeding. In perimenopausal patients, the menses typically lighten and become farther apart. Heavy or frequent menstrual periods or intermenstrual bleeding in this patient population should be evaluated.

Cervical Cancer

The typical manifestation of cervical cancer is painless, abnormal vaginal bleeding, often postcoital secondary to localized inflammation.

Differential Diagnosis and Medical Decision Making

The first step in evaluating any woman with vaginal bleeding should be to determine whether the patient is pregnant because this will drastically alter the diagnostic and therapeutic approach.

The most common causes of abnormal vaginal bleeding in nonpregnant patients are DUB and uterine leiomyomas. Tables 124.1 and 124.2 list the differential diagnosis of vaginal bleeding in nonpregnant females. Figure 124.1 details an approach to patients seen in the emergency department (ED) with the complaint of vaginal bleeding.

Table 124.1 Common Terminology and Definitions

TERMINOLOGY	DEFINITION
Amenorrhea	Cessation of menses for >6 mo
Dysmenorrhea	Pain associated with menses
Hypomenorrhea	Menstrual volumes < 20 mL/cycle
Menorrhagia	Menses > 80 mL/cycle or occurring for >7 days
Metrorrhagia	Vaginal bleeding between menstrual cycles or irregular cycles
Menometrorrhagia	Prolonged or heavy bleeding at irregular intervals
Oligomenorrhea	Decreased frequency of cycles (>35 days per cycle)
Polymenorrhea	Increased frequency of cycles (<21 days per cycle)
Postmenopausal bleeding	Bleeding 6-12 mo after menopause

Table 124.2 Systemic Causes of Abnormal Vaginal Bleeding

CAUSE	MECHANISM
Weight loss Stress Excessive exercise	Hypothalamic suppression of GnRH
Polycystic ovarian disease	Excessive estrogen effects on the endometrium Anovulatory cycles
Hypothyroidism	Anovulatory cycles
Hyperthyroidism	Changes in androgen and estrogen production
Hyperprolactinemia (prolactinoma)	Mass effect on the pituitary stalk reduces GnRH secretion
Liver failure	Decreased production of vitamin K–dependent clotting factors Increased estrogen levels secondary to decreased metabolism
Renal failure	Inherent platelet dysfunction
Primary coagulopathies: Immune thrombocytopenia von Willebrand disease Myeloproliferative disorders