Menstrual disorders

Normal menstrual bleeding at the end of an ovulatory cycle results from estrogen-progesterone withdrawal. The same mechanism operates when the corpus luteum is removed or when its gonadotropin support is suddenly interrupted during the luteal phase. Other examples include the bleeding that follows discontinuation of both estrogen and progestin in women receiving cyclic postmenopausal hormone therapy and the bleeding that comes at the end of a standard cycle of oral contraceptives. Under these circumstances, bleeding generally is regular, predictable, and consistent in volume and duration. However, estrogen-progesterone withdrawal is not the only pattern of steroid hormone signals that can provoke endometrial bleeding. Bleeding can also result from estrogen withdrawal, estrogen breakthrough, progesterone withdrawal, and progesterone breakthrough.
Estrogen Withdrawal Bleeding
One clinical example of estrogen withdrawal bleeding is that which may follow bilateral oophorectomy during the follicular phase of the cycle. The bleeding that occurs after removal of the ovaries can be delayed by exogenous estrogen therapy, but will occur when treatment stops. Other examples include cyclic estrogen-only hormone therapy in castrate or postmenopausal women and the midcycle bleeding that coincides with the transient but abrupt fall in estrogen levels immediately before ovulation.
Estrogen Breakthrough Bleeding
The best clinical examples of estrogen breakthrough bleeding are the different patterns of bleeding observed in women with chronic anovulation. The amount and duration of estrogen breakthrough bleeding can vary widely, depending on the amount and duration of unopposed estrogen stimulation that the endometrium has received. Relatively low levels of chronic estrogen exposure typically result in intermittent spotting or staining that is generally light in volume but may be prolonged. In contrast, sustained high level estrogen stimulation commonly results in long intervals of amenorrhea punctuated by acute episodes of often profuse bleeding that vary in duration.
Progesterone Withdrawal Bleeding
Progesterone withdrawal bleeding is observed when treatment with exogenous progesterone or a synthetic progestin is discontinued. Progesterone withdrawal bleeding usually occurs only when the endometrium has first been primed with endogenous or exogenous estrogen. The amount and duration of bleeding can vary widely and generally correlates with the level and duration of previous estrogen-stimulated endometrial proliferation. In women with marginal to frankly low estrogen levels or short intervals of amenorrhea, bleeding is generally light to scant and may not occur at all. In those with
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sustained high estrogen levels or long intervals of amenorrhea, bleeding can be heavy and somewhat prolonged, but is still self-limited. Between the extremes, the amount and duration of bleeding induced by progesterone withdrawal is typically similar to that observed at the end of a normal ovulatory cycle. In women receiving cyclic hormone therapy with exogenous estrogen and progestin, bleeding follows withdrawal of progesterone even if estrogen treatment continues; progestin withdrawal bleeding can be delayed, but only if estrogen levels are increased 10–20-fold.45
Progesterone Breakthrough Bleeding
Progesterone breakthrough bleeding occurs when the ratio of progesterone to estrogen is unfavorably high. Unless there is sufficient estrogen to balance its action, continuous treatment with exogenous progesterone or synthetic progestins results in intermittent bleeding of varying duration that is generally light, a pattern very similar to low level estrogen breakthrough bleeding described above. Clinical examples of progesterone breakthrough bleeding are the bleeding observed in women using the progestin-only contraceptive “mini-pill” or other long-acting progestin-only contraceptive methods (progestin implants, depot medroxyprogesterone acetate).46 The breakthrough bleeding observed in women using combination estrogen-progestin oral contraceptives is also a form of progesterone breakthrough bleeding. Although all standard oral contraceptive pill regimens contain pharmacologic quantities of both estrogen and progestin, the progestin component is always the dominant hormone and the net effect of oral contraceptives on the endometrium is profoundly progestational


Anovulatory Bleeding
Part of "15 - Dysfunctional Uterine Bleeding"
Anovulatory bleeding can represent estrogen withdrawal bleeding, reflecting the transient fall in estrogen levels resulting from regression of the most recent follicular cohort, or estrogen breakthrough bleeding due to focal breakdown of an overgrown and structurally fragile endometrium under continuous estrogen stimulation. The heaviest episodes of anovulatory bleeding tend to occur in women with sustained high levels of estrogen; women with polycystic ovary syndrome, obese women, postmenarcheal adolescents, and perimenopausal women are common clinical examples. The clinical presentation spans the spectrum from the pale, frightened teenager who has bled for weeks to the older woman who is deeply concerned that she may have cancer.
In contrast to the organized predictable pattern of sequential estrogen-progesterone stimulation and withdrawal that characterizes the normal ovulatory menstrual cycle, the patterns of ovarian steroid hormone production and endometrial stimulation in anovulatory women are disorganized and unpredictable. By definition, the anovulatory woman is always in the follicular phase of the ovarian cycle and in the proliferative phase of the endometrial cycle. There is no luteal or secretory phase because there is no cycle. The only ovarian steroid signal the endometrium receives is estrogen, levels, which constantly fluctuate, rising and falling as each new cohort of follicles begins to grow but ultimately loses its developmental momentum, sooner or later, and lapses into atresia. Although the amplitude of the signal may vary, the message, growth, stays the same.
Over a period of time, an unrelenting, uninterrupted estrogen growth stimulus can stimulate the endometrium to proliferate to abnormal heights where it becomes fragile. Without the growth limiting and organizing effects of progesterone, the endometrium lacks the stromal support structure to maintain stability. Focal areas breakdown and bleed and, as those areas heal under the influence of continued estrogen stimulation, others break down and bleed. Persistent proliferative and hyperplastic endometrium characteristically exhibits numerous discrete foci of stromal breakdown near the epithelial surface, associated with pools of extravasated red blood cells, capillary platelet/fibrin thrombi, and repair-related changes recognized as ball-like aggregates of tightly packed stromal cells beneath a cap of intact but hypertrophied epithelium.24 The cause for the focal breakdowns in persistent proliferative endometrium is not entirely clear. However, abnormal endometrial growth involves not only epithelial and stromal cells but also the microvasculature.
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Venous capillaries in persistent proliferative and hyperplastic endometrium are increased, dilated, and often form abnormal irregular channels; ultrastructural studies have revealed a number of abnormal structural elements that predispose to fragility.47, 48 The abnormal microvasculature could be the result, but is more likely the proximate cause of abnormal bleeding. The weight of available evidence from histologic and molecular studies indicates that anovulatory bleeding results from an increased density of abnormal vessels having a fragile structure prone to focal rupture, followed by release of lysosomal proteolytic enzymes from surrounding epithelial and stromal cells and migratory leukocytes and macrophages. Once initiated, the process is further aggravated by local release of prostaglandins, with greater sensitivity to those that vasodilate (PGE2) than to those that vasoconstrict (PGF2α).49 Other molecules (perforins) inhibit capillary plug formation and further degrade the capillary venous network. Vasoconstriction of basal endometrial and superficial myometrial vessels does not occur because tissue loss is only focal and superficial, and does not typically reach the basal layer where denudation triggers an intense vasoconstrictive response. The final mechanism that normally controls menstrual bleeding, surface epithelial reconstruction, operates in persistent proliferative endometrium, but not in a normal way. Epithelial repair is focal, in the areas of breakdown, not universal; the result is a constantly changing patchwork of small repairs instead of an organized and well structured remodeling.24
Traditional Definitions
Oligomenorrhea: Intervals greater than 35 days.
Polymenorrhea: Intervals less than 24 days.
Menorrhagia: Regular normal intervals, excessive flow or duration.
Metrorrhagia: Irregular intervals, excessive flow or duration.

Diagnostic Evaluation of Abnormal Bleeding
Part of "15 - Dysfunctional Uterine Bleeding"
A careful menstrual history is the single most useful tool in differentiating anovulatory bleeding from other causes. Detailed information regarding intermenstrual intervals (number of days, regularity), volume (heavy, light, or variable), duration (normal or prolonged, consistent or variable), the onset of abnormal menses (perimenarcheal, sudden, gradual), temporal associations (postcoital, postpartum, postpill, weight gain or loss), associated symptoms (premenstrual molimina, dysmenorrhea, dyspareunia, galactorrhea, hirsutism), underlying systemic illnesses (renal, hepatic, hematopoietic, thyroid), and medications (hormonal, anticoagulants) can provide important clues and help to quickly determine whether additional evaluation is needed before treatment begins. Physical examination should exclude visible vaginal or cervical lesions and define uterine size (normal or enlarged), contours (smooth and symmetrical or irregular), consistency (firm or soft), and tenderness.
In the majority of women with true anovulatory bleeding, menstrual history alone can establish the diagnosis with sufficient confidence that treatment can begin without additional laboratory evaluation or imaging. Infrequent, irregular, unpredictable menstrual bleeding that varies in amount, duration, and character and is not preceded by any recognizable or consistent pattern of premenstrual molimina generally is not difficult to interpret. Conversely, regular monthly periods that are heavy or prolonged are more likely related to an anatomical lesion or a bleeding disorder than to anovulation.
Laboratory tests can be helpful but are not always necessary. A sensitive pregnancy test can quickly exclude any realistic possibility that the bleeding relates to an accident or complication of pregnancy. A complete blood count to exclude anemia and thrombocytopenia is prudent in women with a history of prolonged or extremely heavy bleeding. A well-timed serum progesterone determination during what should be the luteal phase of the cycle can help to document ovulation or anovulation, when doubt exists; any value greater than 3 ng/mL provides reliable evidence that ovulation has recently occurred.68 However, when bleeding episodes are frequent or poorly documented, proper timing for a progesterone measurement can be difficult to determine. In anovulatory women, a serum thyroid-stimulating hormone (TSH) level can quickly exclude any associated thyroid disorder. In adolescents, those with a suspicious personal or family history, and those with unexplained menorrhagia, suspicion of a bleeding disorder is sufficient indication for screening coagulation studies.54, 69 The ristocetin cofactor assay for the von Willebrand's factor function may be the best single screening test for von Willebrand's disease,69, 70, 71 but consultation with a hematologist is recommended because test methods, preferences, and interpretation vary.72, 73 Liver or renal function tests are indicated only for those with known or strongly suspected disease.
Office aspiration biopsy can exclude endometrial hyperplasia or cancer. Age 40 years and over is an established risk factor for endometrial disease and widely cited as an indication for biopsy in women with abnormal bleeding. Endometrial hyperplasia and cancer are more commonly detected in older than in younger women, but duration of exposure to unopposed estrogen stimulation is the more critical risk
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factor. Long-term exposure is more likely in older than in younger women, but women under age 30 and even teenagers can develop endometrial cancer.74, 75, 76, 77 In premenopausal women, the likelihood of abnormal endometrial histology is relatively high (14%) when menses are irregular but very low (less than 1%) when cycles are regular.78 The small flexible suction cannulas now widely available cause less discomfort than older traditional biopsy instruments and yield comparable results.79, 80, 81 In addition to revealing any intrinsic endometrial disease, biopsy can help to direct further evaluation or to guide the choice of treatment in women with a confusing history of abnormal bleeding. In women with abnormal bleeding and no recent exposure to exogenous progestational agents, a secretory endometrium provides reliable evidence of recent ovulation and signals the need to search for an anatomical cause.
Uterine imaging can help to differentiate anovulatory bleeding from anatomic causes, myomas and endometrial polyps being by far the most common examples of the latter. Standard transvaginal ultrasound examination can provide accurate information about the size and location of any uterine fibroids that may explain abnormal bleeding or exaggerate the bleeding due to other causes.82
Ultrasound may reveal an obvious cavitary lesion or an abnormally thin or thick endometrial “stripe.” A very thin endometrial stripe (less than 5 mm), like a biopsy that yields minimal or no tissue, suggests an attenuated or denuded endometrium best treated first with estrogen rather than with a progestin or an estrogen-progestin combination (discussed later). In perimenopausal and postmenopausal women with abnormal bleeding, endometrial biopsy is widely considered unnecessary when the endometrial thickness is less than 4 or 5 mm because the risk of endometrial hyperplasia or cancer is remote.83, 84, 85 It seems logical to apply the same criteria for the same reason in premenopausal women with abnormal bleeding, although there is no substantial direct evidence to support the extrapolation. Otherwise, the decision to biopsy or not should be based primarily on clinical suspicion and risk factors rather than on ultrasound measurements of endometrial thickness. That does not mean that endometrial thickness has no bearing on the decision whether to perform a biopsy; a grossly increased endometrial thickness (greater than 12 mm) increases the risk of disease and is an indication for sampling, even when clinical suspicion of pathology is otherwise low.86 In summary, we believe that biopsy is unnecessary when the endometrial thickness is less than 5 mm, that biopsy is indicated when the clinical history suggests long-term unopposed estrogen exposure even when the endometrial thickness is “normal” (5–12 mm), and that biopsy should be performed when endometrial thickness is greater than 12 mm even when clinical suspicion of disease is low.
Sonohysterography, involving transvaginal ultrasound during or after introduction of sterile saline with any of a variety of available catheters (also known as hydrosonography and saline infusion sonography) sharply defines cavity contours and readily demonstrates even small intrauterine lesions; the sensitivity and specificity of sonohysterography exceed that of standard transvaginal ultrasound and compare favorably with hysteroscopy.87, 88, 90 The combination of sonohysterography and endometrial biopsy offers a high sensitivity and high negative predictive value for detection of endometrial and uterine pathology in women with abnormal bleeding.91
Hysteroscopy is the definitive method for both diagnosis and treatment of symptomatic intrauterine pathology but also clearly the most invasive. Traditionally, hysteroscopy has been reserved for treatment of disease identified by other less invasive methods, but modern operative hysteroscopes having an outer diameter of 2 or 3 mm now permit diagnostic and minor operative procedures to be performed in the office setting.92 Major intrauterine pathology generally requires more traditional operative hysteroscopy using instruments having a larger caliber and greater capabilities.
In general, diagnostic uterine imaging can be reserved for those women in whom the menstrual history or the results of other evaluation provide strong evidence for an anatomic cause of abnormal bleeding, including any of the following.
Regular monthly cycles with increasing volume or duration of bleeding.
Regular monthly cycles complicated by intermenstrual bleeding in the absence of a vaginal or cervical lesion.
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Abnormal bleeding despite objective evidence of ovulation from measurement of serum progesterone (more than 3 ng/mL) or from endometrial biopsy (secretory endometrium).
Failed empirical medical management.
As in all aspects of clinical medicine, the success of treatment hinges on an accurate diagnosis. When there is good reason to suspect a coagulopathy or uterine pathology as the cause of abnormal bleeding, diagnostic laboratory tests, endometrial biopsy, or uterine imaging should be carefully considered before beginning empiric medical management. When there is every reason to believe that anovulation is the cause, empiric medical management based on that premise is entirely reasonable, but one should also expect a prompt resolution of the problem with treatment. When bleeding persists despite appropriate empiric medical management, further diagnostic evaluation is likely to be more productive than a higher dose or otherwise different medical treatment regimen.