Interaction between the pelvic anatomy and the brain determines the success or failure of the menstrual cycle. Making an accurate diagnosis of DUB requires an understanding of endocrine biochemistry, reproductive neuroendocrinology, the menstrual cycle and its unique phases, and the subsequent impact and response on different organ systems.

The uterus is lined with endometrium, a glandular epithelium. Menstrual flow is the visible result of the fragmentation of the endometrial glands that line the endometrium. The disorganization of cell adhesion molecules within the endometrial lining is associated with this fragmentation and subsequent shedding of the endometrium (Tabibzadeh et al, 1995).

The two ovaries are round glandular tissues covered by a firm fibrous membrane. Each measures about 3.5 by 1.5 by 2 cm. The ovaries are located at the back of the broad ligament on either side of the uterus. On stimulation by luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the ovary produces the sex steroids, estrogen and progesterone.

The functional portions of the pituitary gland, the adenohypophysis and the neurohypophysis, contain cells that secrete a number of peptide hormones, including thyroid-stimulating hormone (TSH), ACTH, FSH, and LH. These specialized cells synthesize and then release hormone through fusion of the secretory granule with the cell surface and exocytosis.

The synthesis and release of the gonadotropic hormones, FSH and LH, are under the control of gonadotropin-releasing hormone (GnRH). GnRH is discharged in a pulsatile pattern from the hypothalamus. The frequency of pulses varies during each menstrual cycle, depending on feedback mechanisms. A disturbance in the pulse pattern of GnRH, merely by stress-induced norepinephrine release, can disrupt ovulation.

Menstruation is controlled by an interacting system of hormones derived mainly from the hypothalamus, the anterior pituitary, and the ovaries. Taken together, these are referred to as the hypothalamus–pituitary–gonad axis. The ovaries and the uterus each have unique cycle phases. The ovaries experience follicular, ovulatory, and luteal phases. The uterus undergoes menstrual, proliferative, and secretory phases (Speroff et al, 1994).

The purpose of the follicular phase is the maturation of one follicle. This phase normally lasts 10 to 14 days. The onset of the follicular phase is stimulated by the falling levels of progesterone and inhibin at the end of the luteal phase of the previous cycle. As a result, GnRH is released from the hypothalamus, resulting in the release of FSH and some LH from the anterior pituitary. The rise in FSH prompts a dramatic response from follicles, and eventually a single, dominant follicle emerges from the maturation process.

By day 5 to 7, the dominant follicle continues the maturation process. By the midfollicular phase, a crucial rise in estrogen determines whether the LH surge will take place. The feedback effect of estrogen on LH production can be either negative or positive, depending on the concentration of estrogen and the duration of that concentration. When a concentration of 200 pg/mL is sustained for 50 hours, positive feedback results and the LH surge is initiated (Speroff et al, 1994). At the same time, a negative feedback on FSH production is occurring.

At this time, the uterine lining has shed as a result of a loss of hormonal support in the previous cycle. By day 7, rising estrogen levels are sufficient to influence secretory changes on the endometrium. By midcycle, the lining is 5 to 10 times its original size.

On initiation of the ovulatory phase, luteinization of the granulosa cells in what is now the preovulatory follicle results in progesterone production. Ovulation occurs approximately 10 to 12 hours after the LH peak and 24 to 36 hours after the estradiol peak (Speroff et al, 1994). The effects on the uterine lining at this stage are notable only for the occasional spotting experienced by some patients as a result of the drop in estrogen that occurs at ovulation.

In the luteal phase, progesterone production peaks by day 22 to 23. The corpus luteum, the remaining structure
of the follicle, becomes a significant source of estrogen and progesterone in the postovulatory phase. In the absence of implantation, the corpus luteum develops into the corpus albicans. As it undergoes slow atresia, LH production diminishes, along with estrogen and progesterone production.

The uterus enters the secretory phase during the ovary’s luteal phase. Under the influence of progesterone, cell reorganization produces mucus-secreting glands, increased arterial flow into the lining, and numerous thick cell layers. The loss of hormonal support induces both immunoreactive changes and rhythmic vasoconstriction of the spiral arteries within the endometrium. In a normal menstrual cycle, this process results in an orderly separation of the outer layer of the endometrium, and bleeding ensues. The fall in progesterone and inhibin exerts a positive effect on FSH production, and another cycle begins.

The bleeding that occurs in DUB is an extension beyond the processes involved in the normal menstrual cycle. DUB itself is not a pathologic event. DUB is diagnosed when there is no organic cause for the bleeding. The excessive bleeding is thought to be a function of the abnormal hormonal milieu; this affects immunoreactivity and vasoconstriction, both of which play an important role in the normal menstrual cycle. The factors inducing abnormal bleeding may eventually induce pathologic changes.

Approximately 90% of patients with DUB are anovulatory; 10% are ovulatory. Systemic disease, stress, abrupt weight fluctuations, body fat composition, ovarian disease, infection, or medications can induce changes that are crucial in the maturation of an antral follicle. In the case of obesity, that alteration may include extraovarian production of estrogens from androgens in the adipose tissue. The elevated estrogen acts on the feedback mechanisms in the hypothalamus and pituitary, shutting off FSH prematurely and condemning antral follicles to atresia because of the high-androgen environment. Conversely, a direct assault on the pituitary–ovarian axis, as in the case of an ovarian tumor or an endocrine disorder, could disturb steroid hormone production. Anovulation is the result in most cases, setting up the events for abnormal bleeding.

Because a primary follicle fails to emerge despite ongoing recruitment of primordial follicles, the subsequent absence of progesterone production results in absence of ovulation. Anovulation results in chronic stimulation of the endometrium as a result of unopposed estrogen. Endometrial thickening under the influence of estrogen causes its supportive base to become less adhesive. The disorganized estrogen production from failing follicles can lead to intermittent loss of estrogen influence on the endometrium. As a result, the endometrium may begin to slough off. This can happen in an incomplete and irregular fashion or in a prolonged, profuse pattern. This bleeding pattern is referred to as estrogen breakthrough bleeding (Speroff et al, 1994).

The physiology behind these events remains unclear. There is some evidence that elevated levels of prostaglandin E (PGE) may play a role, but the mechanism remains unclear. Early studies on PGE revealed properties that are thought to contribute to menorrhagia, such as its action as an inhibitor of platelet aggregation and adhesiveness, as well as its vasodilatory action.

Recent work suggests that alteration of angiotensin II distribution as well as its receptor levels in the endometrium may play a role in DUB (Li & Ahmed, 1996b). Hyperplastic endometrium, which occurs as a result of unopposed estrogen exposure, has a significantly weaker angiotensin II-like immunoreactivity, in addition to altered angiotensin receptor expression (Li & Ahmed, 1996a).

Reproductive system disorders have a greater incidence in primary care practice than most other medical conditions, including heart disease, hypertension, cancer, allergies, and nonreproductive endocrine problems (Steinberger, 1996). When compared with other gynecologic conditions, menstrual disorders are the most common complaint that brings patients to their primary care provider (Kjerulff et al, 1996; Steinberger, 1996; Wathen et al, 1995). Although adnexal conditions (16.6/1000) and fibroids (9.2/1000) are prominent causes of abnormal bleeding, the most common chronic gynecologic conditions are menstrual disorders (Kjerulff et al, 1996). More than 50% of cases of DUB occur in women older than 45. Steinberger (1996) described common symptoms bringing patients to the provider as an absence of expected menstrual flow or irregular, heavy, or prolonged bleeding. Patients who do no moderate or hard exercise may bleed a quarter of a day longer than patients who engage in moderate exercise.

Women who smoke and use oral contraceptives are 47% more likely to experience abnormal spotting and bleeding than nonsmoking users of oral contraceptives. Smokers also enter menopause earlier because of increased levels of sex hormone-binding globulin and less active estrogen (van der Schouw et al, 1996).

Cultural factors play a greater role in the response of patients to the abnormal bleeding pattern than they do to a cause for DUB. When evaluating the cultural response to abnormal menstruation, a helpful approach is to look at the way communities of people seek health care. In one study, as many as 67% of patients with menstrual disorders had not talked with a health care provider about their experience of DUB (Kjerulff et al, 1996).

Ferguson (1996) provides a model of health care that describes a patient’s response to DUB. When a woman experiences an abnormal bleeding pattern, cultural influences are an important consideration in how she responds. Her first response may be to deal with it herself. If she is not a careful historian of her cycles, she may decide she has merely forgotten how recent her last period was. Or she may accept the fact that a cycle or two has been “off,” but decides to take a wait-and-see approach. She may also seek information from a bookstore or library.

In some cultures, menstruation imposes restrictions on sexual relations, as well as household and agricultural activities, especially those involving food preparation. Cultural traditions of hot and cold theories dictate how Southeast Asian (Hmong, Cambodian, and Vietnamese) patients cope during menstruation. Warm foods such as rice, chicken, and egg-drop soup with pepper and herbs must be consumed during menstruation (Poirier, 1993). Women must also stay warm, maintain quiet in the house by not allowing visitors, and avoid sexual intercourse. An abnormal bleeding problem thus could lead to social isolation.

If her problem continues, the woman may seek the advice of friends and family. This social support system becomes an important source of help and advice for many patients. Finding that a friend had a similar problem and found relief through a visit to her health care provider may prompt the patient to seek primary professional care. On the other hand, cultural responses to uterine bleeding can be reinforced by family members, further delaying the patient from seeing the primary provider.

The next level of care may find the woman reaching out to self-help networks, such as distant relatives, neighbors, friends of friends, self-help groups, community hotlines, and other self-help resources in the community. With the wide variety of computer resources available, she may also seek help online, perusing news groups, Web pages, list-servers, and forums all devoted to the topic of women’s health or abnormal gynecologic conditions.

These informal networks of natural helpers or community medicine can be helpful sources of factual information as well as valuable support systems (Ferguson, 1996). On the other hand, use of lay practitioners may delay the patient’s entry into the professional health care system.

When self-care, support systems, and community medicine have not been successful at relieving the woman’s symptoms or are not available, she will then usually migrate to a health professional. For some, this may be direct entry into the tertiary level of care—for instance, an emergency room visit with very heavy estrogen breakthrough bleeding.

Consequences of DUB include nonproductivity due to time away from work. Twenty-nine percent of patients report spending 1 or more days in bed as a result of a menstrual irregularity (Kjerulff et al, 1996). Florack et al (1994) found that overall, DUB does not appear to be associated with work-related physical activity or fatigue.

Many concerns are expressed in the lay press about environmental toxins and their effect on health. Many chemicals in use today may mimic the effects of hormones such as estrogen. Much remains unknown, but the theoretical concern postulated by environmental scientists is that exposure to estrogen-mimicking chemicals could add to the estrogenic effects on the endometrium and increase a woman’s chance of both breast and endometrial cancer (Renner, 1995). Chemicals known to have an estrogenic effect include phthalates, alkylphenols, and bisphenol A (Warhurst, 1996). Further research is needed in this area to determine the health-related impact of chemicals and preventive measures people need to take to avoid exposure.

The postovulatory phase of the menstrual cycle is normally 28 days (range 24 to 35 days), with withdrawal bleeding lasting 4 to 6 days (range 2 to 8 days). Because the preovulatory phase can be unpredictable as a result of individual differences in follicle development, many patients have cycles that are shorter or longer than 28 days. Most blood loss occurs in the first 3 days. Any flow lasting longer than 7 days requires evaluation (Brenner, 1996).

Blood loss can vary. The average amount of blood lost during the menstrual cycle is 30 mL. Blood loss greater than 80 mL per cycle is considered excessive (Gleeson, 1994; Speroff et al, 1994). Some authors believe that quantifying blood loss as accurately as possible is an important part of assessing DUB because of subjectivity (Lee, 1996). Others assert that the woman’s perception of blood loss is enough to warrant further investigation (Speroff et al, 1994). Menstrual flow warrants evaluation if it requires two or more sanitary pads per day above the woman’s normal pad use, or lasts 3 or more days above normal (Brenner, 1996). A tool such as the pictorial blood loss assessment chart shown in Figure 71-1 has a greater than 80% sensitivity and specificity as a tool for identifying menorrhagia (Higham et al, 1990).