Dysfunctional Uterine Bleeding

Dysfunctional uterine bleeding is defined as abnormal uterine bleeding in the absence of uterine pathology or medical illness. It is more often seen in the pubertal and perimenopausal periods, and in most cases, it is associated with anovulation, leading to lack of estrogen-induced negative feedback on the pituitary gland, resulting in unopposed estrogen stimulation to the endometrium.

Dysfunctional uterine bleeding is a common problem faced by the gynecologist today, with many treatment options existing and newer ones being developed. With a complete understanding of the menstrual cycle and a carefully obtained history and physical examination, a diagnosis of ovulatory or anovulatory abnormal uterine bleeding and its cause is attainable. Once determined and appropriate treatment option selected, the goals of the physician should be to:

1. Stop acute bleeding
   
2. Prevent further bleeding episodes
   
3. Prevent long-term complications
   

To diagnose and treat dysfunctional uterine bleeding properly, it is important to review the key features in the normal menstrual cycle.

The normal menstrual cycle occurs at regular intervals of 24–35 days. The average duration of flow is 4–6 days but can be as few as 2 and as many as 7 days. A flow of longer than 7 days deserves evaluation.^{1, 2} The average blood loss during one menses is approximately 30 mL.³ A flow of 80 mL or more can lead to anemia. However, it is not necessary to measure menstrual flow; a patient's perception of abnormal or excessive menses deserves evaluation and treatment. Physiologically, a flow of more than 80 mL deserves evaluation.

The menstrual cycle is a hormonally controlled process of events occurring through the hypothalamic-pituitary-ovarian axis and reflected by the histologic changes in the endometrium. Normal ovulatory endometrial changes throughout the menstrual cycle can be divided into five phases:⁴

1. Menstrual endometrium phase
   
2. Proliferative phase
   
3. Secretory phase
   
4. Implantation phase
   
5. Exfoliative or ischemic phase
   

In the first phase, the menstrual endometrium is a thin, dense tissue composed of stable, nonfunctioning basalis and varying amounts of residual stratum spongiosum. During menstruation, the spongiosum displays a variety of functional states, including disarray and breakage of glands; fragmentation of vessels and stroma with white cell infiltration; and red cell interstitial diapedesis. This is a transitional state that joins the exfoliative (final) phase with the proliferative phase. As much as 60% of functioning endometrium remains during menstruation. The next phase, the proliferative phase, results from increased estrogen secretion produced by the growing follicle. The endometrium grows to approximately 3–5 mm in height. The major component of this height increase is caused by reinflation of the stroma, although there is actual growth as well. The secretory phase is a result of the combined action of estrogen and progesterone. The total endometrial height is fixed to pre-ovulatory levels because of the progesterone. Within this fixed structure, the individual components continue to grow, resulting in more tortuous glands and increased coiling of the spiral arteries. Inside the glandular cells, vacuoles move from an intracellular to an intraluminal location approximately 7 days postovulation. The implantation phase lasts from postovulatory days 6–10. The endometrium differentiates into three distinct zones. One fourth remains as the unchanged basalis. Approximately half consists of a lacelike stratum spongiosum composed of loose edematous stroma and tightly coiled spiral arteries and dilated glandular ribbons. The top one-fourth is an overlying layer of superficial endometrium called the stratum compactum, distinguished by large polyhedral stromal cells. At this point in the cycle, the endometrium is a compact sturdy layer composed of less-prominent glands, subepithelial capillaries, and engorged spiral arteries. The exfoliative or endometrial breakdown phase is a result of the absence of fertilization and implantation. Because of the absence of human gonadotropin hormone production by the trophoblast, there is a decline in estrogen and progesterone levels because of the involution of the corpus luteum. This leads to three endometrial events:

1. Vasomotor reaction
   
2. Tissue loss
   
3. Menstruation
   

This results in a decrease in tissue height, diminished blood flow, and decreased venous return. The spiral arteries undergo increasing vasoconstriction and relaxation, causing endometrial ischemia and sloughing. White cells migrate through the capillary wall of the stroma. Red cells escape into the interstitial space, and thrombin platelets appear in the superficial vessels. Interstitial hemorrhage occurs secondary to breaks in the superficial blood vessels. Newer thrombin-platelet plugs form upstream and help limit blood loss. Further tissue ischemia with cellular necrosis and defects in the vessels add to menstrual flow. The lamina propria exists as a natural cleavage plane between the basalis and spongiosum. Menstrual flow is halted secondary to the effects of vasoconstriction, vascular stasis, and estrogen-induced healing. When a disruption occurs in any of these events, abnormal uterine bleeding may result.

The following are definitions of abnormal bleeding:

1. Menorrahagia: Excessive and prolonged uterine bleeding at regular intervals
   
2. Metrorrhagia: Irregular, intermenstrual bleeding
   
3. Menometrorrhagia: Heavy, prolonged, irregular bleeding at frequent, irregular intervals
   
4. Polymenorrhea: Frequent, regular episodes of uterine bleeding at intervals of less than 21 days
   
5. Oligomenorrhea: Irregular bleeding occurring at prolonged intervals of greater than 35 days
   
6. Amenorrhea: Absence of uterine bleeding
   

Dysfunctional uterine bleeding can be separated into four categories: estrogen withdrawal bleeding, estrogen breakthrough bleeding, progesterone withdrawal bleeding, and progesterone breakthrough bleeding.⁴

Estrogen Withdrawal Bleeding

This type of bleeding can occur after bilateral oophorectomy, radiation of mature follicles, chemotherapy for malignancy, or administration of estrogen to a castrated woman followed by discontinuation of therapy. Midcycle spotting can occur secondary to the decrease in estrogen that precedes ovulation.

Estrogen Breakthrough Bleeding

This type of bleeding is a result of the amount of estrogen that is stimulating the endometrium. Low levels of estrogen result in intermittent spotting that may be prolonged but is usually light in the amount of flow. High levels of estrogen for prolonged periods of time result in lengthy periods of amenorrhea followed by acute, often heavy, bleeding with excessive blood loss.

Progesterone Withdrawal Bleeding

Removal of the corpus luteum, or administration and then discontinuation of progesterone or a nonestrogenic synthetic progestin result in endometrial desquamation. For progesterone withdrawal bleeding to occur, the endometrium must first be proliferated by endogenous or exogenous estrogen. Progesterone withdrawal bleeding still occurs if estrogen therapy is continued after progesterone is withdrawn. Only increased estrogen levels of 10- to 20-fold delay progesterone withdrawal bleeding.

Progesterone Breakthrough Bleeding

This occurs with an abnormally high ratio of progesterone to estrogen. Continuous progesterone therapy without adequate estrogen results in bleeding of variable duration as seen in low-dose estrogen breakthrough bleeding. This is the pattern of bleeding that can be seen with long-acting progestin-only contraceptive methods such as Norplant and Depo-Provera and the progesterone-only birth control pill.

Most cases of anovulatory bleeding are the result of estrogen withdrawal or estrogen breakthrough bleeding. High sustained levels of estrogen and heavy bleeding are associated with polycystic ovaries, obesity, immaturity of the hypothalamic-pituitary-ovarian axis as in postpubertal teenagers, and anovulation associated with women in their late 30s and early 40s. When there is unopposed estrogen stimulation to the endometrium and no periodic desquamation, the endometrium reaches abnormal heights and lacks structural support. The resulting tissue consists of increased vascularity, back-to-back glandularity, but without an intervening stromal support system. Because of tissue fragility, spontaneous superficial breakage and bleeding occur.

The bleeding involves random portions of the endometrium at variable times in an asynchronous pattern. The disorderly, abrupt breakdown of tissue along with opening of the multiple vascular channels coupled with the large amount of tissue available for breakdown results in prolonged and excessive flow. Stasis is not induced because of the lack of vasoconstrictive rhythmicity, no tight coiling of the spiral vessels, and their disorderly collapse. Local bleeding can rely only on the healing effects of endogenous estrogen to halt flow. This healing is only temporary in that as soon as one site heals, another fragile tissue site breaks down and the bleeding ensues again.

The diagnosis of dysfunctional uterine bleeding is made by exclusion. Other causes of uterine bleeding that must be considered before making the diagnosis of dysfunctional bleeding are the following:

1. Anatomic uterine abnormalities (e.g. endometrial hyperplasia, endometrial cancer, polyps, leiomyomas, infection, foreign bodies)
   
2. Pregnancy abnormalities (e.g. abortion, ectopic pregnancy, gestational trophoblastic disease)
   
3. Coagulopathies (e.g. von Willebrand's disease-factor VIII, idiopathic thrombocytopenia purpura); as many as 20% of adolescents with coagulopathies⁵
   
4. Anatomic cervical abnormalities (e.g. cervical cancer, infection, endocervical polyps)
   
5. Liver disease (e.g. cirrhosis, hepatitis)
   
6. Anticoagulant therapy
   
7. Drugs: Narcotics (e.g. morphine and other abused abused substances), reserpine, monoamine oxidase inhibitors, phenothiazines, anticholinergic drugs
   
8. Thyroid disease (e.g. hypothyroidism, hyperthyroidism)
   
9. Chronic renal failure
   
10. Exogenous hormones (e.g. estrogen replacement, oral contraceptives)
    
11. Adrenal disease (e.g. insufficiency, hyperplasia)
    
12. Functional estrogen-producing tumors of the ovary (e.g. granulosa cell tumors of the ovary, Sertoli-Leydig cell tumors)
    
13. Pituitary disease (e.g. prolactin level)

The diagnosis of abnormal uterine bleeding is a diagnosis made by exclusion of uterine or medical pathology. The first and most important step in the diagnostic process is obtaining a physical examination and a detailed clinical history with an in-depth understanding of the patient's menstrual characteristics. Efforts to quantify menstrual blood loss by patients and physicians have been shown to be inaccurate. Approximately half of women reporting excessive menstrual blood loss in actuality do not have an abnormal amount of bleeding.⁶ Rather, they have been experiencing a variation of their own bleeding pattern. It is this variation from normal that brings the patient into a physician's care and warrants evaluation and usually treatment.

Detailed questioning about the medical history should include questions about endocrine or medical illnesses such as galactorrhea, thyroid enlargement, hirsutism, exogenous medicine ingestion, and eating or bleeding disorders. Most important, the possibilities of intrauterine and ectopic pregnancies must be considered. In addition, a careful history and physical examination will exclude other causes of abnormal bleeding, such as infection, foreign bodies, and genital injuries.

A laboratory evaluation may be helpful, but it is not necessary in many cases. The laboratory tests ordered should be specific to help exclude abnormal bleeding causes suggested by the history and physical examination. Blood tests may include the following:

1. Complete blood count
   
2. Quantitative human chorionic gonadotropin
   
3. Thyroid function tests
   
4. Prolactin
   
5. Clotting studies
   1. Prothrombin time
      
   2. Activated partial prothrombin time
      
   3. Antithrombin III
      
   4. Protein C
      
   5. Protein S
      
   6. Fibrinogen
      
   7. Plasminogen
      
   
   
6. Liver and renal function tests
   

Vaginal or abdominal ultrasound, hysterosalpingography, or hysteroscopy most often detects abnormalities of the uterus. Newer methods becoming more popular include hysteroscopy and saline infusion sonohysterography. Hysteroscopy offers the advantages of direct visualization of the uterine cavity and the opportunity to perform directed biopsies. Its uses are limited, however, because of the high cost of equipment and time requirements. Some of the cost can be offset by performing the procedure in the office, but according to a survey by the Association of Gynecologic Laparoscopists, only 28% of reported hysteroscopies were performed as an in-office procedure, hence the majority requiring costly time in the operating room.⁷ Therefore, saline infusion sonohysterography is becoming a more appealing technique in diagnosing abnormal bleeding. Other indications for this procedure include abnormal findings on hystersalpingogram, amenorrhea, as part of an infertility analysis. The technique involves infusing 2–8 mL of saline directly into the uterine cavity after the vaginal probe ultrasound has been inserted. The saline enables better contrast, which can readily expose intrauterine adhesions, submucosal myomas, polyps and septa, as well as better delineation of the uterine lining. Potential complications are severe transient pain, exacerbation of previously undetected infection, vaso-vagal response if the infusing catheter tip hits the fundus of the uterus, and the unlikely but possible uterine perforation.

A sampling of the endometrial cavity should be considered in all cases of abnormal uterine bleeding. Although not mandatory in the perimenarchal patient, it is mandatory in the perimenopausal patient to exclude a premalignant or malignant condition. It is not the age of the patient that is critical when considering an endometrial sampling but rather the duration of unopposed estrogen exposure.⁴ Even young women are at risk of having an endometrial carcinoma develop.⁸

When there is absence of organic pathology as a cause of abnormal bleeding, medical therapy is preferred over surgical therapy. Because anovulation is the most common cause of dysfunctional bleeding, progestational therapy is usually the first line of therapy.

Medical Therapy

ESTROGENS

In cases where bleeding has been prolonged and there is insufficient tissue for progestin action, estrogen therapy is indicated to cause rapid growth of the endometrium. A further action of estrogen is to stimulate clotting at the capillary level.⁹

In patients with acute or heavy bleeding, 25 mg of conjugated estrogen is administered intravenously every 4 hours until the bleeding is under control, or for 12 hours.¹⁰ Oral estrogen can also be used, 1.25 mg of conjugated estrogens or 2 mg estradiol every 4 hours for 24 hours, followed by 1.25 mg daily for 7–10 days. After the course of estrogen therapy, a treatment cycle of low-dose oral contraceptives is indicated to induce a withdrawal bleed. Medroxyprogesterone acetate therapy, concomitant with the estrogen therapy or after the estrogen therapy, can also be given. To avoid future episodes of dysfunctional uterine bleeding, this patient should consider the use of oral contraceptives.

In cases of lesser bleeding, as seen when there has been long-term use of oral contraceptives, depot progestin therapy (Depo-Provera), or the Norplant contraceptive, 1.25 mg of conjugated estrogens orally or 2 mg estradiol orally for 7–10 days can be preferentially used. In these cases of a prolonged progestin influence on the endometrium in the absence of endogenous or exogenous estrogen, a pharmacologic pseudoatrophy of the endometrium is produced. The endometrium is composed of pseudodecidual stroma and blood vessels with minimal glands that lead to endometrial fragility and bleeding. Temporary exposure to a short course of exogenous estrogen effectively suppresses this type of bleeding.

PROGESTATIONAL AGENTS

In the adolescent and perimenopausal period, it is not uncommon for women to either fail to ovulate or to be unable to sustain adequate corpus luteum function. These patients typically present with oligomennorrhea alternating with heavy bleeding. Once pathology has effectively been ruled out, progestin therapy can restore synchrony to endometrial lining and return the menstrual patterns to normalcy.

Medroxyprogesterone acetate, 10 mg daily for 10 days each month, produces regular withdrawal bleeding in patients with adequate endogenous estrogen. Progestins not only stop endometrial growth, but also provide support and organize the endometrium so that sloughing occurs in an organized fashion. Progestins diminish the effect of estrogen on target cells by inhibiting estrogen receptor replenishment in the cell and inducing the activation of 17β-hydroxysteroid dehydrogenase and sulfotransferase activity, which convert estradiol to estrone sulfate.¹¹ These actions of progesterone account for the diminished mitotic activity and decreased growth of endometrium. This also accounts for the prevention or reversal of the hyperplastic process. If contraception is desired, an oral contraceptive can accomplish the same purpose and is a better choice.

When progestins are used to reverse a hyperplastic process, resampling of the endometrium is mandatory. This is usually performed after 3 months of therapy. If the hyperplastic process remains or atypia is seen, further medical or surgical therapy including higher dose progestin therapy with repeated endometrial sampling must be considered.

THE PROGESTIN INTRAUTERINE CONTRACEPTIVE DEVICE

Progesterone or levonorgestrel can be delivered directly to the endometrium with progestin-containing intrauterine contraceptive devices (IUDs).^{12, 13} Comparison studies using prostaglandin synthetase inhibitors and an antifibrinolytic agent showed the levonorgestrel-releasing IUD superior to medical therapy in the reduction of menstrual flow. In using the progestin IUD, some patients became amenorrheic. This form of therapy is a favorable option in patients with intractable bleeding associated with chronic illness.⁴

LOW-DOSE ORAL CONTRACEPTIVES

In cases of young anovulatory women when there is prolonged, unopposed endogenous estrogen stimulation of the endometrium resulting in prolonged indometrial buildup, heavy bleeding can ensue. A low-dose (less than 50 μg estrogen) oral contraceptive can be very effective in controlling the bleeding both acutely and chronically. Two pills daily for 5–7 days are given even though a decrease in flow is seen in only 12–24 hours.⁴ The patient must be advised that the ensuing withdrawal bleeding may be heavy with cramping because of the endometrial buildup. The acute treatment is followed by oral contraceptive administration in the routine cycle fashion. If contraception is not desired, this regimen would be continued for 3 months and then the patient can be treated with monthly medroxyprogesterone acetate as cited above.

ANDROGENIC STEROIDS

Danazol used in doses of 400–800 mg daily reduces menstrual blood loss.¹⁴ Although its mechanism of action is still not completely understood, danazol has been shown to have multiple mechanisms of action.¹⁵ Included in these actions are the following:

1. Binding to androgen, progesterone, and glucocorticoid receptors producing both antagonistic and agonistic action
   
2. Binding to sex hormone-binding globulin (displacing testosterone and increasing free testosterone)
   
3. Prevention of midcycle follicle-stimulating hormone and luteinizing hormone surges with no significant suppression of basal follicle-stimulating hormone and luteinizing hormone
   
4. Inhibition of enzymes involved in steroidogenesis
   

These combined effects produce a low estrogen environment that does not support growth of the endometrium and amenorrhea is produced. The use of Danocrine is limited by its cost, multiple androgenic side effects, and its negative androgenic effect on the lipid profile.

GONADOTROPIN-RELEASING HORMONE ANALOGS

Gonadotropin-releasing hormone analogs suppress gonadotropin secretion from the pituitary gland and, subsequently, lower serum estradiol levels. The ultimate effect of gonadotropin-releasing hormone analogs is a cessation of menstruation. Effective in reducing blood loss, they can only be used for a 6-month period because of the loss in bone mass and the expense to the patient. Long-term estrogen and progestin add-back therapies limit bone mass loss, but the expense is still a formidable obstacle to long-term therapy.¹⁶

ANTIPROSTAGLANDINS (NONSTEROIDAL ANTI-INFLAMMATORY DRUGS)

Nonsteroidal anti-inflammatory drugs inhibit the action of cyclo-oxygenase, and therefore, a decrease occurs in the various members of the prostaglandin family. The mechanism in patients with dysfunctional uterine bleeding may be an alteration of action in the balance between the platelet-proaggregating vasoconstrictor thromboxane A2 (TXA2) and the antiaggregating vasodilator prostacyclin (PG12), but a complete understanding of the action mechanism of nonsteroidal anti-inflammatory drugs is unknown.¹⁷ Blood loss has been shown to be reduced by as much as 50%.¹⁸ This treatment is especially effective in reducing blood loss in women who ovulate, and it is effective in reducing the dysmenorrhea associated with heavy bleeding.^{19, 20, 21} Non-steroidal anti-inflammatory agents have been shown to be effective in intrauterine device menorrhagia. Non-steroidal anti-inflammatory drugs should not be used in patients with aspirin intolerance, bronchospastic pulmonary disease, peptic ulcer disease, and hepatic or renal disease.²⁰

ANTIFIBRINOLYTIC AGENTS

Antifibrinolytic drugs are potent inhibitors of fibrinolysis and have been shown to reduce menstrual blood loss by as much as 50%.²² This treatment is a last resort for patients with coagulation problems.

DESMOPRESSIN

Desmopressin has been used to treat abnormal uterine bleeding in patients with coagulation disorders.²³ After administration, a rapid increase in coagulation factor VIII occurs that lasts for approximately 6 hours. This agent is limited to acute administration.

ERGOT DERIVATIVES (METHYLERGONOVINE MALEATE)

Ergot derivatives are not recommended for the treatment of dysfunctional uterine bleeding as they have been found to be ineffective in reducing blood loss in patients with menorrhagia and also have dangerous side effects on blood pressure and central nervous system hemodynamics.^{22, 24}

Dilation and Curettage

Dilation and curettage are appropriate in women with dysfunctional bleeding in whom medical treatment has been unsuccessful or in the perimenopausal women whose office endometrial sample has been unsuccessful.

Endometrial Ablation

In patients in whom no disease exists and medical therapy has been unsuccessful, or when the patient is a poor surgical candidate, endometrial ablation is another alternative therapy. The purpose of endometrial ablation is to destroy the basal layers of the endometrium, preventing the regeneration of the endometrium. This results in complete amenorrhea in approximately 50% of women or reduced bleeding in approximately 90% of women with menorrhagia, but it is not 100% effective.^{25, 26} Currently, in the United States, there are a number of methods for endometrial ablation, including the rollerball technique of electrical desiccation, thermal balloon ablation, and cryoablation. Although rollerball seems to offer a slight statistical advantage to thermal ablation, all increased benefit is lost in other arenas. Thermal balloon ablation carries inherently less risk than rollerball, and the learning curve for thermal balloon technique, an in-office procedure, is far less steep. Rollerball technique is a more technically difficult procedure, and all benefit gained by rollerball is lost through cost, risk to patient, and accessibility due to the number of physicians adequately trained in rollerball technique. Since the original publication of this book several second-generation endometrial ablation devices have found their way onto the market, including: Gynecare ThermaChoice Uterine Balloon Therapy System, Her Option Cryoablation Therapy System, Hydro ThermAblator (HTA) System, NovaSure System Bipolar Radio Frequency Technology, and Microsulis Endometrial Ablation (MEA).  Excellent results can be obtained with use of any second-generation device. Regardless of the ablation method used, the best results are accomplished when the endometrium has been first suppressed with GNHR analogs, danazol, or medroxyprogesterone acetate for 4–6 weeks. One concern worth mentioning regarding endometrial ablation is that obliteration of segments of the uterine cavity can allow isolated residual endometrium to progress to carcinoma without recognition. Long-term follow-up is needed to know whether this risk is real.

Hysterectomy

Hysterectomy, on occasion, is the proper treatment for abnormal uterine bleeding. Unfortunately, its higher rate of mortality, morbidity, and cost makes it an inappropriate choice for the management of abnormal uterine bleeding, except in extreme cases, such as failed medical management and endometrial hyperplasia with atypia.

On successful treatment of the acute episode of anovulatory uterine bleeding, the patient must continue to be followed. Chronic anovulation can lead to further abnormal bleeding episodes, but more important, chronic unopposed estrogen stimulation to the endometrium can lead to atypical tissue changes. Therefore, it becomes extremely important that patients undergo periodic progestational withdrawal bleeding. This can best be accomplished by low-dose oral contraceptive therapy or medroxyprogesterone acetate 10 mg daily for 10 days a month.

A complete understanding of the hormonal events of the menstrual cycle and the endometrial tissue response to these hormones will allow for medical treatment of dysfunctional bleeding in almost all cases. Surgical therapy including dilation and curettage will be the last line of therapy except in rare cases of dysfunctional bleeding and in cases in which a pathologic entity exists.

In patients in whom suspected uterine disease exists, the uterus can be evaluated by hysterosalpingography or directly by hysteroscopy. Operative hysteroscopy has become increasingly more useful in the surgical treatment of uterine fibroids and polyps since they can be diagnosed and treated in one procedure.

Ovulating women with menorrhagia can have their bleeding controlled with the use of nonsteroidal anti-inflammatory agents, progestin administered daily for 7 days preceding menses, or oral contraceptives in the routine manner. Intrauterine devices that release progesterone or a progestin should be considered in patients with chronic illnesses.