Uterine Bleeding

 

The most probable etiology of abnormal uterine bleeding relates to the patient's reproductive age, as does the likelihood of serious endometrial pathology. The specific diagnostic approach depends on whether the patient is premenopausal, perimenopausal or postmenopausal. In premenopausal women with normal findings on physical examination, the most likely diagnosis is dysfunctional uterine bleeding (DUB) secondary to anovulation, and the diagnostic investigation is targeted at identifying the etiology of anovulation. In perimenopausal patients, endometrial biopsy and other methods of detecting endometrial hyperplasia or carcinoma must be considered early in the investigation. Uterine pathology, particularly endometrial carcinoma, is common in postmenopausal women with abnormal uterine bleeding. Thus, in this age group, endometrial biopsy or transvaginal ultrasonography is included in the initial investigation. Premenopausal women with DUB may respond to oral contraceptives, cyclic medroxyprogesterone therapy or cyclic clomiphene. Perimenopausal women may also be treated with low-dose oral contraceptives or medroxyprogesterone. Erratic bleeding during hormone replacement therapy in postmenopausal women with no demonstrable pathology may respond to manipulation of the hormone regimen. (Am Fam Physician 1999;60:1371-82.)

 

 

Patients with DUB have lost cyclic endometrial stimulation that arises from the ovulatory cycle.

As a result, these patients have constant, noncycling estrogen levels that stimulate endometrial growth.

Proliferation without periodic shedding causes the endometrium to outgrow its blood supply.

The tissue breaks down and sloughs from the uterus.

Subsequent healing of the endometrium is irregular and dyssynchronous.

Chronic stimulation by low levels of estrogen will result in infrequent, light DUB.

Chronic stimulation from higher levels of estrogen will lead to episodes of frequent, heavy bleeding

  • Suspect DUB when a patient presents with episodic heavy or light bleeding despite a normal pelvic examination.
    • Typically, the usual moliminal symptoms that accompany ovulatory cycles will not precede bleeding episodes.
    • Exclude the diagnosis of pregnancy first.
    • Address the presence of local and systemic disease.
    • Rule out iatrogenic causes of bleeding, including bleeding secondary to steroid hormone contraception, hormone replacement therapy, or other hormone treatments, which are common causes.
    • Most patients are adolescents or are older than 40 years.
  • Patients who report irregular menses since menarche are likely to have polycystic ovarian syndrome with or without hirsutism, hyperinsulinemia, or obesity.
  • Patients with adrenal enzyme defects, hyperprolactinemia, thyroid disease, or other metabolic disorders also might present with anovulatory bleeding.

Physical: The physical examination can elicit several anatomic and organic causes of abnormal uterine bleeding.

  • A complete physical examination should include evaluation for the following:
    • Obesity
    • Signs of androgen excess
    • Thyroid enlargement
    • Galactorrhea
    • Visual field deficits
    • Ecchymosis
    • Purpura
  • A careful gynecologic examination, including Papanicolaou test (Pap smear) and sexually transmitted disease (STD) screening, is warranted.
  • The hallmark of DUB is a negative pelvic examination despite the clinical history. In such cases, management might rest on a clinical diagnosis.

 

 

 

Terminology Used to Describe Abnormal Uterine Bleeding [see also below]


 

Term


Definition


Menorrhagia

Prolonged or excessive bleeding at regular intervals

Metrorrhagia

Irregular, frequent uterine bleeding of varying amounts but not excessive

Menometrorrhagia

Prolonged or excessive bleeding at irregular intervals

Polymenorrhea

Regular bleeding at intervals of less than 21 days

Oligomenorrhea

Bleeding at intervals greater than every 35 days

Amenorrhea

No uterine bleeding for at least 6 months

Intermenstrual

Uterine bleeding between regular cycles

Characteristics of Ovulatory and Anovulatory Menstrual Cycles


Ovulatory cycles
Regular cycle length
Presence of premenstrual symptoms
Dysmenorrhea
Breast tenderness
Change in cervical mucus
Mittleschmertz
Biphasic temperature curve
Positive result from use of luteinizing-hormone predictor kit

Anovulatory cycles
Unpredictable cycle length
Unpredictable bleeding pattern
Frequent spotting
Infrequent heavy bleeding
Monophasic temperature curve

Single episodes of anovulatory bleeding generally carry a good prognosis.

Patients who experience repetitive episodes might experience significant consequences.

Frequent uterine bleeding will increase the risk for iron deficiency anemia.

Flow can be copious enough to require hospitalization for fluid management, transfusion, or intravenous hormone therapy.

Chronic unopposed estrogenic stimulation of the endometrial lining increases the risk of both endometrial hyperplasia and endometrial carcinoma.

Timely and appropriate management will prevent most of these problems.

Many individuals with DUB are exposed to unnecessary surgical intervention, such as repeated uterine curettage, endometrial ablative therapy, or hysterectomy, before adequate workup and a trial of medical therapy can be completed.

  • Iron deficiency anemia: Persistent menstrual disturbances might lead to chronic iron loss in up to 30% of cases. Adolescents might be particularly vulnerable. Up to 20% of patients in this age group presenting with menorrhagia might have a disorder of hemostasis.
  • Endometrial adenocarcinoma: About 1-2% of women with improperly managed anovulatory bleeding eventually might develop endometrial cancer.
  • Infertility associated with chronic anovulation, with or without excess androgen production, frequently is seen in these patients.
  • Patients with polycystic ovarian syndrome, obesity, chronic hypertension, and insulin-resistant diabetes mellitus particularly are at risk

 

 

Lab Studies:

  • Lab studies include human chorionic gonadotropin (HCG), CBC, Pap smear, endometrial sampling, thyroid functions and prolactin, liver functions, coagulation factors, and other hormone assays as indicated.
  • Human chorionic gonadotropin
    • The most common cause of abnormal uterine bleeding during the reproductive years is abnormal pregnancy.
    • Rule out threatened abortion, incomplete abortion, and ectopic pregnancy.
  • Complete blood count
    • Document blood loss. Charting the number of menstrual pads used per day or keeping a menstrual calendar is helpful.
    • When in doubt, obtain a baseline CBC for hemoglobin and hematocrit.
    • Rule out anemia.
    • Obtain a differential with platelet count if hematologic disease is suspected.
  • Pap smear should be up to date. Cervical cancer still is the most common gynecologic cancer affecting women of reproductive age in the world population.
  • Endometrial sampling
    • Perform a biopsy to rule out endometrial hyperplasia or cancer in high-risk women >35 years and in younger women at extreme risk for endometrial hyperplasia/carcinoma. Women with chronic eugonadal anovulation, obesity, hirsutism, diabetes, or chronic hypertension are at particular risk.
    • Most biopsies will confirm the absence of secretory endometrium.
  • Perform thyroid function tests and prolactin because hyperthyroidism, hypothyroidism, and hyperprolactinemia are associated with ovulatory dysfunction. Identify and treat these conditions.
  • Obtain liver function tests if alcoholism or hepatitis is suspected. Any condition affecting liver metabolism of estrogen can be associated with abnormal uterine bleeding.
  • Coagulation factors
    • Von Willebrand disease and factor XI deficiency initially might manifest during adolescence.
    • Primary or secondary thrombocytopenia can be factors in the mature patient.
    • Tailor the choice of laboratory tests to the presenting clinical situation. Generally speaking, heavy bleeding is regular (menorrhagia) and associated with ovulation.
  • Other hormone assays as indicated
    • For the patient with recurrent anovulatory bleeding, the mainstay of management is treatment of correctable disease.
    • Obtain a hormonal complete evaluation in women with signs of hyperandrogenism, such as those with polycystic ovarian syndrome, 21 hydroxylase deficiency, or ovarian or adrenal tumors, as dictated by their respective conditions.
    • Women in menopausal transition usually can be followed without an extensive hormonal evaluation.

Imaging Studies:

  • Generally, patients with DUB can be managed appropriately without the use of expensive imaging studies.
  • In obese patients with suboptimal pelvic examination or in patients with suspected ovarian tumors, pelvic ultrasound evaluation might be most helpful.
  • Pelvic ultrasound also might be confirmatory for polycystic ovaries (PCO), which frequently are present in individuals with chronic eugonadal anovulation.
    • Confirmation of PCO by imaging is not mandatory for the diagnosis.
    • The absence of the traditional string of pearls appearance does not exclude polycystic ovarian syndrome diagnosis.
  • Ultrasound can be used to examine the status of the endometrium. Endometrial hyperplasia, endometrial carcinoma, endometrial polyps, and uterine fibroids can be identified easily by this technology.

Procedures:

  • Rule out endometrial carcinoma in all patients at high risk for the condition, including patients with the following characteristics:
    • Morbid obesity
    • Diabetes or chronic hypertension
    • Age >35 years
    • Longstanding, chronic eugonadal anovulation
  • Traditionally, carcinoma was ruled out by endometrial sampling via dilation and curettage (D&C). More recently, endometrial sampling in the office via aspiration, curetting, or hysteroscopy has become popular.
  • Real-time ultrasound measurement and evaluation of the endometrial stripe can be helpful in distinguishing individuals bleeding with thick endometrium from those with thin, denuded endometrium, endometrial polyps, uterine fibroids, or other uterine pathology.

Histologic Findings: Most endometrial biopsy specimens will show proliferative or dyssynchronous endometrium.

 

 

Types and characteristics of abnormal uterine bleeding

 

Type

Characteristics

 

Oligomenorrhea

Cycle length >35 days

 

Polymenorrhea

Cycle length <21 days

 

Amenorrhea

Absence of menses for 5 mo or three cycles

 

Menorrhagia

Regular cycles; excessive flow, duration

 

Metrorrhagia

Irregular cycles

 

Menometrorrhagia

Irregular cycles; excessive flow, duration

 


 

Compiled from Petrozza and Poley (2) and Speroff et al (3).

Medical treatment options for dysfunctional uterine bleeding

Type of bleeding

Treatment option

Comments


Acute

Oral contraceptive, 1 tablet PO bid or tid X 7d; allow withdrawal bleed, then 1 tablet PO qd X 3 mo

Use low-dose (35-microgram) monophasic formulation; some clinicians omit withdrawal bleed to avoid exacerbating anemia

 

Conjugated estrogen (Cenestin, Premarin), 25 mg IV q4-6h X 1 day or 1.25 mg PO q4-6h X 1 day, then oral contraceptive as above

All estrogen-only therapy must be followed by progestin coverage


Chronic

Oral contraceptive, 1 tablet PO qd

Perimenopausal women should use 20-microgram pills

 

Medroxyprogesterone acetate, 10 mg PO qd X 10 days/mo

Bleeding occurs 2-7 days after last dose

 

Clomiphene citrate (Clomid, Milophene, Serophene), 50-150 mg qd on days 5-9

Use for patients who wish to become pregnant; if pregnancy does not occur in 3 to 6 mo, consider referral


Adapted from Speroff et al (3).

 

  • Oral contraceptives
    • Oral contraceptive pills (OCPs) suppress endometrial development, reestablish predictable bleeding patterns, decrease menstrual flow, and lower the risk of iron deficiency anemia.
    • Acute episodes of heavy bleeding suggest an environment of prolonged estrogenic exposure and buildup of the lining.
    • Bleeding usually is controlled within the first 24 hours, as the overgrown endometrium becomes pseudodecidualized. Seek alternate diagnosis if flow fails to abate in 24 hours.
  • Estrogen
    • Estrogen alone, in high doses, is indicated in certain clinical situations.
    • Prolonged uterine bleeding suggests the epithelial lining of the cavity has become denuded over time. In this setting, a progestin is unlikely to control bleeding. Estrogen alone will induce return to normal endometrial growth rapidly.
    • Hemorrhagic uterine bleeding requires high-dose estrogen therapy. If bleeding is not controlled within 12-24 hours, a D&C is indicated.
    • Beginning progestin therapy shortly after initiating estrogen therapy to prevent a subsequent bleeding episode from treatment with prolonged unopposed estrogen is wise.
  • On rare occasions, a young patient with anovulatory bleeding also might have a bleeding disorder.
    • Desmopressin, a synthetic analog of arginine vasopressin, has been used as a last resort to treat abnormal uterine bleeding in patients with documented coagulation disorders.
    • Treatment is followed by a rapid increase in von Willebrand factor and factor VIII, which lasts about 6 hours.

Surgical Care: Most cases of DUB can be treated medically. Surgical measures are reserved for situations when medical therapy has failed or is contraindicated.

  • D&C is an appropriate diagnostic step in a patient who fails to respond to hormonal management.
    • The addition of hysteroscopy will aid in the treatment of endometrial polyps or the performance of directed uterine biopsies.
    • As a rule, apply D&C rarely for therapeutic use in DUB because it has not been shown to be very efficacious.
  • Abdominal or vaginal hysterectomy might be necessary in patients who have failed or declined hormonal therapy, have symptomatic anemia, and who experience a disruption in their quality of life from persistent, unscheduled bleeding.
  • Endometrial ablation is an alternative for those who wish to avoid hysterectomy or who are not candidates for major surgery.
    • Ablation techniques are varied and can employ laser, rollerball, resectoscope, or thermal destructive modalities.
    • Pretreat the patient with an agent, such as leuprolide acetate, medroxyprogesterone acetate, or danazol, to thin the endometrium.
    • The ablation procedure is more conservative than hysterectomy and has a shorter recovery time.
    • High rates of rebleeding following ablation have raised concern about the possibility of an occult endometrial cancer developing within a pocket of active endometrium. Further studies are needed to quantify this risk.


Estrogens, progestins, androgens, nonsteroidal anti-inflammatory drugs (NSAIDs), ergot derivatives, antifibrinolytics, and gonadotropin-releasing hormone (GnRH) superagonists have been used to treat DUB. More recently, desmopressin has been used to control bleeding when associated with diagnosed bleeding disorders that do not respond entirely to traditional management.

Ergot derivatives are not recommended for treatment of DUB because they have been shown to be effective rarely in clinical studies and have many side effects.

At the onset of menses, secretory endometrium contains a high concentration of plasminogen activator. A reduction in menstrual blood loss has been demonstrated in some ovulatory patients taking e-aminocaproic acid (EACA) or aminomethylcyclohexane-carboxylic acid (AMCHA) tranexamic acid, both potent antifibrinolytics. However, this therapeutic effect was no greater than that seen with oral contraceptive therapy. Antifibrinolytics are associated with significant side effects, such as severe nausea, diarrhea, headache, and allergic manifestations, and cannot be used in patients with renal failure. Because of the high side-effect profile and expense, these agents rarely are used today for this indication.

Drug Category: Estrogens -- Very effective in controlling acute, profuse bleeding. Exerts a vasospastic action on capillary bleeding by affecting the level of fibrinogen, factor IV, and factor X in blood, as well as platelet aggregation and capillary permeability. Estrogen also induces formation of progesterone receptors, making subsequent treatment with progestins more effective.

Most DUB is secondary to anovulation. In these patients, endometrium continues to proliferate with asynchronous development. As blood supply is outgrown, irregular shedding occurs. Bleeding might be controlled acutely with high-dose estrogen for a short period of time. Several hours are required to induce mitotic activity, so most regimens require 48 h of therapy before continued bleeding is ruled a treatment failure.

Estrogen therapy only controls bleeding acutely and does not treat underlying cause. Appropriate long-term therapy can be administered once the acute episode has passed

Conjugated equine estrogen (Premarin) -- Women in perimenopause generally are estrogen deficient and might experience bouts of estrogen withdrawal bleeding. Many of these patients will recover regular menses and develop an improved sense of well-being with the initiation of hormonal replacement therapy, including estrogen and a progestin.

Progestins -- Occasional anovulatory bleeding that is not profuse or prolonged can be treated with progestins, antiestrogens given in pharmacologic doses. Inhibit estrogen receptor replenishment and activate 17-hydroxysteroid dehydrogenase in endometrial cells, converting estradiol to the less active estrone.

Synthetic progestins have an antimitotic effect, allowing the endometrium to become atrophic if administered continuously. These drugs are very effective in cases of endometrial hyperplasia. In patients with chronic eugonadal anovulation who do not desire pregnancy, treatment with a progestin for 10-12 d/mo will allow for controlled, predictable menses and will protect the patient against the development of endometrial hyperplasia.

Some perimenopausal patients will not respond well to progestin therapy because of an inherent estrogen deficiency. Also, patients with thin, denuded endometrium occurring after several days of chronic bleeding might require induction of new endometrial proliferation by estrogen therapy first.

Avoid synthetic progestins in early pregnancy. They induce an endometrial response that is different from normal preimplantation secretory endometrium. Also, several reports suggest an association between intrauterine exposure to synthetic progestins in the first trimester of pregnancy and genital abnormalities in male and female fetuses. The risk of hypospadias, 5-8 per 1000 male births, might be doubled with early in-utero exposure to these drugs. Some synthetic progestins might cause virilization of female external genitalia in utero.

Patients at risk for conception can be treated safely with natural progesterone preparations. These preparations induce a normal secretory endometrium appropriate for implantation and subsequent growth of a developing conceptus.

Drug Name

Medroxyprogesterone acetate (Provera) -- Short-acting synthetic progestin. DOC for patients with anovulatory DUB. After acute bleeding episode is controlled, can be used alone in patients with adequate amounts of endogenous estrogen to cause endometrial growth. Progestin therapy in adolescents produces regular cyclic withdrawal bleeding until positive feedback system matures.
Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Adult Dose

10 mg/d PO for 10-12 d/mo

Androgens -- Certain androgenic preparations have been used historically to treat mild to moderate bleeding, particularly in ovulatory patients with abnormal uterine bleeding. These regimens offer no real advantage over other regimens and might cause irreversible signs of masculinization in the patient. They seldom are used for this indication today.

Use of androgens might stimulate erythropoiesis and clotting efficiency. Androgens alter endometrial tissue so that it becomes inactive and atrophic.

Drug Name

Danazol (Danocrine) -- Isoxazole derivative of 12 alpha-ethinyl testosterone.

Adult Dose

200-400 mg/d PO in divided doses

 

NSAIDs -- Blocks formation of prostacyclin, an antagonist of thromboxane, which is a substance that accelerates platelet aggregation and initiates coagulation. Prostacyclin is produced in increased amounts in menorrhagic endometrium. Because NSAIDs inhibit blood prostacyclin formation, they might effectively decrease uterine blood flow. NSAIDs have been shown to treat menorrhagia in ovulatory cycles but generally are not effective for the management of DUB.

Drug Name

Naproxen (Anaprox, Naprelan, Naprosyn) -- Used for relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Adult Dose

550 mg PO initially; followed by 275 mg q6h for 5 d

GnRH superagonists -- Work by reducing concentration of GnRH receptors in the pituitary via receptor down regulation and induction of postreceptor effects, which suppress gonadotropin release. After an initial gonadotropin release associated with rising estradiol levels, gonadotropin levels fall to castrate levels, with resultant hypogonadism. This form of medical castration is very effective in inducing amenorrhea, thus breaking ongoing cycle of abnormal bleeding in many anovulatory patients. Because prolonged therapy with this form of medical castration is associated with osteoporosis and other postmenopausal side effects, many practitioners add a form of low-dose hormonal replacement to the regimen. Because of the expense of these drugs, they usually are not used as a first line approach but can be used to achieve short-term relief from a bleeding problem, particularly in patients with renal failure or blood dyscrasia.

Drug Name

Depot leuprolide acetate (Lupron) -- Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.

Adult Dose

3.5-7.5 mg IM qmo; not to exceed 6 mo without addition of low-dose estrogen and progestin therapy

Arginine vasopressin derivatives -- Indicated in patients with thromboembolic disorders.

 

 

 

Treatment Options for Dysfunctional Uterine Bleeding

 

 

Age group

Treatment*

Comments

Premenopausal

Oral contraceptives

Low-dose (35 g) monophasic or triphasic oral contraceptives can regulate cycles while providing contraception.

 

Medroxyprogesterone, 10 mg per day for 10 days

If contraception is not an issue, medroxyprogesterone can be used to regulate cycles. In a woman who has amenorrhea or oligomenorrhea, medroxyprogesterone every 3 months can protect against endometrial hyperplasia.

 

Clomiphene, 50 to 150 mg per day on days 5 to 9

Can induce ovulation in a woman who desires pregnancy. If no response or no pregnancy in 3 to 6 months, referralis appropriate.

Perimenopausal

Medroxyprogesterone, 10 mg per day for 10 days

May use monthly to regulate bleeding patterns.

 

Oral contraceptives

Usually use 20-g pills. Can continue oral contraceptives until a woman has finished menopause and then change to HRT. (May be a relative contraindication in women >35 years of age who smoke.)

Postmenopausal (receiving HRT)

Cyclic HRT

May consider increasing the progesterone dose if early withdrawal bleeding occurs. Increase the estrogen dose if intermenstrual bleeding is present.

 

Continuous combined HRT

May increase the estrogen dose for 1 to 3 months to stabilize the endometrium. May also try increasing the progesterone dose. If bleeding continues, consider changing regimen to cyclic HRT or using a different type of estrogen.

 

HRT = hormone replacement therapy.
*--All pathologic, structural and iatrogenic causes excluded.

 

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Initial Approach to Abnormal Uterine Bleeding in Postmenopausal Patients

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FIGURE 3. Algorithm for the diagnostic evaluation of abnormal uterine bleeding in postmenopausal patients. (CBC = complete blood count; HRT = hormone replacement therapy)

 

 

Differential diagnostic considerations in abnormal uterine bleeding

Abnormalities of the reproductive tract
Benign pelvic lesions
   Adenomyosis
   Endometriosis
   Polyps, cervical or endometrial
   Submucosal fibroids
Infection
Malignancy
Trauma

Complications related to pregnancy
Ectopic pregnancy
Gestational trophoblastic disease
Placental polyp
Spontaneous abortion (threatened, incomplete, missed)
Subinvolution of the placental site

Iatrogenic factors
Anticoagulation therapy
Contraceptive use
   Intrauterine device
   Levonorgestrel implant (Norplant System)
   Medroxyprogesterone contraceptive injection (Depo-Provera)
   Oral contraceptives
Hormone replacement therapy
Psychotropic agents

Systemic disease
Cirrhosis
Coagulation disorder
Hypothyroidism

Dysfunctional uterine bleeding

 

Differential Diagnosis of Abnormal Uterine Bleeding


Complications of pregnancy
Intrauterine pregnancy
Ectopic pregnancy
Spontaneous abortion
Gestational trophoblastic disease
Placenta previa

Infection
Cervicitis
Endometritis

Trauma
Laceration, abrasion
Foreign body

Malignant neoplasm
Cervical
Endometrial
Ovarian

Benign pelvic pathology
Cervical polyp
Endometrial polyp
Leiomyoma
Adenomyosis

Systemic disease
Hepatic disease
Renal disease
Coagulopathy
Thrombocytopenia
von Willebrand's disease
Leukemia

Medications/iatrogenic
Intrauterine device
Hormones (oral contraceptives, estrogen, progesterone)
Anovulatory cycles
Hypothyroidism
Hyperprolactinemia
Cushing's disease
Polycystic ovarian syndrome
Adrenal dysfunction/tumor
Stress (emotional, excessive exercise

 

 

Common pathologic findings on endometrial biopsy

Proliferative, secretory, benign, or atrophic endometrium

Simple or complex (adenomatous) hyperplasia without atypia

Simple or complex (adenomatous) hyperplasia with atypia

Endometrial adenocarcinoma


Adapted from Jones MW, Kurman RJ. New ways of managing endometrial hyperplasia. Contemp Obstet Gynecol 1990;35:36-46.

 

 

In ovulatory cycles, progesterone production from the corpus luteum converts estrogen primed proliferative endometrium to secretory endometrium, which sloughs predictably in a cyclic fashion if pregnancy does not occur. Heavy but regular uterine bleeding implies ovulatory bleeding and should not be diagnosed as DUB. Subtle disturbances in endometrial tissue mechanisms, other forms of uterine pathology, or systemic causes might be implicated.

Anovulatory cycles are associated with a variety of bleeding manifestations. Estrogen withdrawal bleeding and estrogen breakthrough bleeding are the most common spontaneous patterns encountered in clinical practice. Iatrogenically induced anovulatory uterine bleeding might occur during treatment with oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy.

  • Estrogen breakthrough bleeding
    • Anovulatory cycles have no corpus luteal formation. Progesterone is not produced. The endometrium continues to proliferate under the influence of unopposed estrogen.
    • Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy. This pattern is known as estrogen breakthrough bleeding and occurs in the absence of estrogen decline.
  • Estrogen withdrawal bleeding
    • This frequently occurs in women approaching the end of reproductive life.
    • In older women, the mean length of menstrual cycle is shortened significantly due to aberrant follicular recruitment, resulting in a shortened proliferative phase. Ovarian follicles in these women secrete less estradiol. Fluctuating estradiol levels might lead to insufficient endometrial proliferation with irregular menstrual shedding. This bleeding might be experienced as light, irregular spotting.
    • Eventually, the duration of the luteal phase shortens, and, finally, ovulation stops. Dyssynchronous endometrial histology with irregular menstrual shedding and eventual amenorrhea result.
  • Oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy
    • Treatment with oral contraceptives, progestin-only preparations, or postmenopausal steroid replacement therapy might be associated with iatrogenically induced uterine bleeding.
    • Progesterone breakthrough bleeding occurs in the presence of an unfavorably high ratio of progestin to estrogen.
    • Intermittent bleeding of variable duration can occur with progestin-only oral contraceptives, depo-medroxyprogesterone, and depo-levonorgestrel.
    • Progesterone withdrawal bleeding can occur if the endometrium initially has been primed with endogenous or exogenous estrogen, exposed to progestin, and then withdrawn from progestin. Such a pattern is seen in cyclic hormonal replacement therapy.
  • Adolescents
    • The primary defect in the anovulatory bleeding of adolescents is failure to mount an ovulatory luteinizing hormone (LH) surge in response to rising estradiol levels. Failure occurs secondary to delayed maturation of the hypothalamic-pituitary axis. Because a corpus luteum is not formed, progesterone levels remain low.
    • The existing estrogen primed endometrium does not become secretory. Instead, the endometrium continues to proliferate under the influence of unopposed estrogen. Eventually, this out-of-phase endometrium is shed in an irregular manner that might be prolonged and heavy, such as that seen in estrogen breakthrough bleeding.
  • Climacteric
    • Anovulatory bleeding in menopausal transition is related to declining ovarian follicular function.
    • Estradiol levels will vary with the quality and state of follicular recruitment and growth.
    • Bleeding might be light or heavy depending on the individual cycle response.

 

Diagnostic "rules"

The list of differential diagnostic considerations in abnormal uterine bleeding is extensive, but systematic consideration of each of the five categories has led to our set of six diagnostic "rules." Use of these directives will help protect clinicians from common pitfalls in evaluation of abnormal bleeding.

Rule No. 1: Consider pregnancy
Abnormal uterine bleeding in the reproductive years should be considered a complication of pregnancy until proven otherwise. All women of reproductive age should have a urine or serum pregnancy test (1).

Rule No. 2: Consider coagulopathy
All adolescents with menorrhagia severe enough to require hospitalization or significantly reduce hemoglobin levels (to <10 g/dL) should undergo evaluation for coagulopathy. Disorders of both platelet number and function may cause menorrhagia (2). Von Willebrand's disease, a defect in platelet adhesion and a deficiency of factor VIII, is the most common bleeding disorder, affecting about 1% of the population. Diseases causing thrombocytopenia include idiopathic thrombocytopenic purpura, leukemia, and aplastic anemia. In adolescents, the prevalence of a primary coagulation disorder requiring hospitalization for abnormal uterine bleeding ranges from 3% to 20% (4).

Rule No. 3: Consider pelvic lesions
In women with evidence of ovulation, abnormal uterine bleeding should prompt suspicion of benign pelvic lesions. Evidence of ovulation includes bleeding at regular intervals preceded by premenstrual symptoms (eg, bloating, lower abdominal discomfort) (2), a biphasic temperature curve, a change in cervical mucus, or an endometrial biopsy sample demonstrating secretory endometrium. These patients should undergo thorough endometrial evaluation for pelvic lesions when there is no obvious alternative cause of abnormal bleeding (1).

Rule No. 4: Consider malignancy
Without exception, perimenopausal or postmenopausal women with abnormal uterine bleeding should undergo endometrial evaluation. Until malignancy has been ruled out, it should be considered the cause (5). About 20% to 25% of cases of endometrial carcinoma occur before the menopause (2). Endometrial evaluation should be considered in women under 35 years of age who show evidence of chronic anovulation. These women are at increased risk for endometrial carcinoma secondary to prolonged unopposed estrogen stimulation of the endometrium (1).

Rule No. 5: Consider hypothyroidism
Hypothyroidism is an uncommon, although important, cause of metrorrhagia or menorrhagia. Women with unexplained severe menorrhagia should undergo thyrotropin assay. With thyroid replacement therapy, abnormal uterine bleeding resolves in 3 to 6 months (1).

Rule No. 6: Consider dysfunctional uterine bleeding
Dysfunctional uterine bleeding is a diagnosis of exclusion. In the vast majority of cases, it is secondary to anovulation, which is more common at the extremes of reproductive age (ie, during the postmenarchal and perimenopausal periods). The positive feedback of estradiol secretion is usually the last step in the process of pubertal neuroendocrine maturation, and until this secretion begins, menstrual cycles are anovulatory (1). When women are in their 40s, anovulation again becomes more prevalent (3).

Chronic anovulation may also be associated with thyroid or prolactin disorders, premature ovarian failure, adult-onset congenital adrenal hyperplasia, or polycystic ovary syndrome (2). Some common causes of hypothalamic anovulation are weight loss or gain, eating disorders, stress, chronic illness, and excessive exercise. Women with chronic anovulation that is not attributable to any of these causes are considered to have idiopathic chronic anovulation (5).

Anovulatory bleeding can be thought of as estrogen breakthrough bleeding. This type of bleeding is related to the levels of estrogen stimulating the endometrium. For example, high levels of estrogen for prolonged periods result in amenorrhea followed by acute intermittent heavy bleeding, and continually low levels of estrogen availability result in intermittent spotting (3).

Evaluation

A logical sequence of evaluation for abnormal uterine bleeding can be constructed on the basis of the preceding information.

History taking
The specifics of the bleeding pattern should be elicited on history taking. The frequency, duration, and severity of flow should be ascertained. It is also critical to determine if the bleeding is acyclic or cyclic, the latter being more consistent with ovulation. Other important considerations include patient age, sexual history (which determines risk for sexually transmitted diseases), previous gynecologic disease, likelihood of pregnancy, use of medications or hormonal contraceptives, and the presence of chronic medical problems.

Physical examination
Evidence of systemic disease should be sought on physical examination. Signs and symptoms of hypothyroidism, liver disease, hyperprolactinemia, eating disorders, and coagulopathies warrant special attention. A thorough pelvic examination, including a Pap smear, is essential. If indicated by history or physical findings, cervical cultures for Neisseria gonorrhoeae and Chlamydia trachomatis should be obtained. Benign lesions of the uterus may be obvious. For example, uterine myomata may result in an irregularly contoured, enlarged uterus that is palpable on bimanual examination.

 

Initial Approach to Abnormal Uterine Bleeding in Premenopausal Patients

 

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FIGURE 1. Algorithm for the diagnostic evaluation of abnormal uterine bleeding in premenopausal patients. (CBC = complete blood count; -HCG = beta human chorionic gonadotropin; OCPs = oral contraceptive pills; IUD = intrauterine device; TSH = thyroid-stimulating hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; DHEA-S = dihydroepiandrosterone sulfate)

Initial Approach to Abnormal Uterine Bleeding in Perimenopausal Patients

 

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FIGURE 2. Algorithm for the diagnostic evaluation of abnormal uterine bleeding in perimenopausal patients. (CBC = complete blood count; -HCG = beta human chorionic gonadotropin; D&C = dilatation and curettage)

 

 

 

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