Uterine fibroids or leiomyomas are the most common cause and account for about one third of cases, occurring in 20% to 25% of women before age 40 years and in up to one half of all women overall. Prevalence peaks in the fifth decade and declines markedly after menopause. As suggested by this epidemiology, growth is hormone dependent, with high concentrations of estrogen and progesterone receptors and aromatase found in these benign tumors. A collagen-rich extracellular matrix composition accounts for their fibrous quality. Fibroids may be subserosal, intramural, submucosal, or intracavitary; however, only those that are submucosal and involve the uterine cavity cause bleeding, most typically menorrhagia. Because fibroids are so common, they may coexist with another cause of abnormal vaginal bleeding. The bleeding can be a source of significant iron deficiency anemia, fatigue, and impaired quality of life. With menopause, fibroids shrink and symptoms regress; significant continued growth raises the question of a sarcoma as the cause of the presumed “fibroid.”

These common sources of bleeding may present as mild intermenstrual bleeding or as menorrhagia. They are more frequent with increasing age until menopause, when their prevalence decreases again. Although the vast majority of endometrial polyps are benign, bleeding polyps and those in postmenopausal women are associated with a higher risk of malignancy.

This increasingly recognized condition entails hormonally responsive endometrial tissue lying within the myometrium, causing an enlarged, “globular” uterus. Heavy periods are typically present, often with significant dysmenorrhea and occasionally chronic pelvic pain. Although the diagnosis can only be made pathologically, it may be suggested by typical appearance on pelvic ultrasound or magnetic resonance imaging.

This cancer is more typically a disease of abnormal vaginal bleeding in postmenopausal women (see later discussion), but 20% of women have the disease while still menstruating (generally older than the age of 40 years). Heavier-than-normal periods are noted, as well as an intermenstrual watery discharge containing small amounts of blood.

Cervical polyps, cervical erosions, cervical ectropion, and vaginal lesions present similarly, with slight spotting noted intermenstrually, especially after coitus. Pelvic inflammatory disease, usually but not always associated with fever, pelvic pain, and discharge, may lead to postcoital, intermenstrual, or heavy menstrual bleeding by causing cervicitis, endometritis, or salpingitis.

Copper intrauterine devices (IUDs) alter the endometrial surface and can be responsible for heavy menstrual bleeding or intermenstrual bleeding. Progesterone-releasing IUDs tend to decrease menstrual blood flow; they may cause irregular spotting initially, progressing to amenorrhea in 50% of women by 2 years. Vaginal wall irritation from tampon use may lead to minor vaginal bleeding.

The pathophysiologic common denominator for hypothalamic dysfunction is inadequate progesterone production, most often due to lack of a luteinizing hormone (LH) surge at midcycle, a consequence of an alteration in the normal pattern of gonadotropin-releasing hormone (GnRH) release from the hypothalamus. This pattern is typical of patients with mild hypothalamic dysfunction, who may experience irregular menses in the context of moderate situational stress, weight loss, or exercise training.
If the functional disturbance is more severe, impairing folliclestimulating hormone (FSH) secretion and estrogen production, oligomenorrhea and amenorrhea may follow (see Chapter 112). Hyperprolactinemia, hypothyroidism, and excess production of androgen and cortisol can also disturb hypothalamic rhythmicity. Even iron deficiency anemia has been found to inhibit ovulation.

In the ovary, unruptured follicles persist, and functioning corpora lutea, the main source of progesterone, are absent. The endometrium shows hyperplasia resulting from unopposed estrogen. There is little if any secretory pattern because of the lack of progesterone. Ovulation does not occur, and anovulatory bleeding results when progesterone production returns or excessive proliferation causes sloughing of the overstimulated endometrium. There is irregularity of the menstrual interval, periods of amenorrhea, and episodes of heavy and prolonged bleeding if there has been sufficient estrogen-induced buildup of the endometrium.

Polycystic ovary syndrome (PCOS) is an incompletely understood but common condition affecting between 6% and 12% of reproductive-age women. It represents a leading cause of chronic anovulatory bleeding, and appears to have complex genetic and environmental triggers. In addition to a lifelong history of irregular periods and/or amenorrhea, patients may report infertility, hirsutism, obesity, and acne. Abnormalities at multiple levels of the hypothalamic-pituitary-ovarian axis appear to contribute to androgen overproduction in the ovaries and an imbalance of gonadotropins in women with PCOS. Inadequate endogenous FSH production appears to result from disordered hypothalamic rhythmicity, with an increased frequency of hypothalamic GnRH pulses favoring pituitary production of LH over FSH. Despite the increased frequency and amplitude of LH pulses, women with PCOS rarely have adequate follicular development or estradiol levels to trigger a midcycle LH surge and ovulation. Chronic anovulation permits exposure of the endometrium to high levels of unopposed estrogen, with bleeding occurring if the endometrium is unable to sustain further growth. Unopposed endometrial estrogen stimulation may lead over time to adenomatous hyperplasia, cellular atypicality, and even endometrial carcinoma.

Hyperandrogenism, likely mediated by LH-related ovarian overproduction of testosterone and androstenedione, is another key element of PCOS, accounting for the associated hirsutism, acne, and occasional frank virilization (see Chapter 98), although the latter is uncommon. Insulin resistance with hyperinsulinism, present in 50% to 70% of women with PCOS, is believed to act synergistically with LH to enhance ovarian androgen overproduction. Women with PCOS are recognized to have an increased prevalence of diabetes mellitus and other risk factors for coronary disease, including dyslipidemia and hypertension. They appear to share a phenotype similar to that seen in the metabolic syndrome, with the prevalence of metabolic syndrome in women with PCOS ranging from 33% to 47%, more than twice as high as the prevalence in women without PCOS.

The anovulatory bleeding of puberty is a consequence of immaturity of the positive feedback mechanism responsible for the LH surge that triggers progesterone secretion. In the absence of adequate progesterone production, estrogen withdrawal bleeding takes place. The pattern of anovulatory bleeding is irregular and may occur at any time between 22 and 45 days.

The irregular menstrual bleeding typical of the perimenopausal period is also an anovulatory estrogen withdrawal phenomenon. As the number of functioning ovarian follicles declines, insufficient estrogen is produced to cause an LH surge and ovulation. In the absence of adequate progesterone production, bleeding occurs when the endometrium can no longer sustain growth. Such perimenopausal bleeding can continue for months to years, but it eventually stops when estrogen production ceases.

Here, the major concern is cancer, although endometrial polyps and endometrial atrophy account for most cases. Women who have had chronic unopposed estrogen stimulation are at increased risk of endometrial carcinoma or hyperplasia. Early on, bleeding may be subtle and little more than minor vaginal staining (see Chapter 123). Postmenopausal women with atrophic vaginitis, cervical or endometrial polyps, uterine fibroids, or cervicitis from a prolapsed uterus may also experience some blood-stained vaginal discharge or minor spotting. Cervical carcinoma is uncommon after age 55 years in women who have had Papanicolaou (Pap) smears regularly but may be the cause of bleeding in the early postmenopausal period.

One of the most serious causes of acute abnormal vaginal bleeding in women of reproductive age is ectopic pregnancy, which is characterized by delay of the regular period followed by vaginal blood spotting, often in conjunction with unilateral pelvic pain. Intraperitoneal hemorrhage can ensue if tubal rupture occurs, but this happens in fewer than 5% of cases. A spontaneous abortion may be heralded by onset of bleeding. Retained products of gestation are a very common cause of abnormal uterine bleeding after an incomplete abortion; blood loss is often heavy and may persist for more than 7 days.