Life in Medical World: 2009

Abnormal Uterine Bleeding in Adolescents

Elisabeth H. Quint, MD, Yolanda R. Smith, MD

Posted 06/13/2003

Abstract and Introduction

Abstract

Menarche is an important event during adolescence. For most girls, it marks completion of puberty and the onset of reproductive capability. Menarche usually occurs when both breast and pubic hair development are at Tanner stage 4. Menstrual problems are common during adolescence due to slow maturation of the hypothalamic-pituitary-ovarian axis and can last 2 to 5 years after menarche. Although most problems are explained by anovulation, other causes must be considered and excluded in a logical and cost-effective manner. Frequently, the bleeding problems observed in adolescence require evaluation and intervention.

Introduction

Menstrual irregularities are a common gynecologic problem, especially in adolescents. Abnormal uterine bleeding (AUB) is any form of bleeding that is irregular in amount, duration, or frequency. It can be characterized by excessive uterine bleeding that occurs regularly (menorrhagia), by heavy bleeding at irregular times (metrorrhagia), or a combination of both (menometrorrhagia). It can also be intermittent bleeding or sparse cyclical bleeding (oligomenorrhea). Dysfunctional uterine bleeding (DUB) is a subset of AUB and is defined as excessive, prolonged, or unpatterned bleeding from the endometrium without an organic cause and is frequently used synonymously with anovulatory bleeding. In adolescents, up to 95% of AUB is DUB. However, because DUB is a diagnosis of exclusion, other potential causes of abnormal bleeding must be ruled out. This article discusses the physiology, evaluation, diagnostic testing, and treatment of anovulatory bleeding in the adolescent.

Dysfunctional Uterine Bleeding or Anovulation

The normal menstrual cycle usually consists of a mean interval of 28 days (± 6 days) with a mean duration of 4 days (±2 to 3 days). Normal blood loss is approximately 30 mL per cycle, with an upper limit of 60 to 80 mL. Thirty percent of women who present with a complaint of AUB have clinically significant menorrhagia.^[1] The mean age of menarche in the United States is 12.8 years, with the range from 9.1 to 17.7 years.^[2]

Physiology

The normal menstrual cycle is divided into proliferative, ovulatory, and secretory phases. In the proliferative phase, gonadotropin-releasing hormone (GnRH) is secreted in a pulsatile fashion by the hypothalamus and stimulates the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates a group of ovarian follicular cells to grow, from which one dominant follicle is selected. The dominant follicle produces increasing amounts of estradiol. Estradiol stimulates the endometrium to proliferate and develop many progesterone receptors. When estradiol reaches a certain sustained level, a surge of LH is released from the pituitary, causing the dominant follicle to ovulate (ovulatory phase) and become the corpus luteum, which then produces estrogen and progesterone. Progesterone halts endometrial growth and stabilizes the endometrium (secretory phase). Involution of the corpus luteum in the absence of a conception causes a rapid decline in estrogen and progesterone. The endometrium collapses and sheds as menstruation occurs, approximately 14 days after ovulation. Menstrual flow stops as a result of the combined effect of prolonged vasoconstriction, tissue collapse, vascular stasis, and estrogen-induced "healing." Thrombin generation as a result of extravasation of blood is essential for hemostasis.

Therefore, normal ovulatory cycles involve regular cyclic production of estradiol, initiating ovarian follicular growth and endometrial proliferation. Following ovulation, the production of progesterone stabilizes the endometrium. Without ovulation and subsequent progesterone production, a state of "unopposed" continuous estrogen secretion occurs. This stimulates excessive dilation of the spiral arterial supply in the endometrium and abnormal endometrial growth without adequate structural support. The consequence is spontaneous breakage and sloughing of the endometrium with unpredictable bleeding. Eventually, continued elevated estrogen levels have a negative feedback effect on the hypothalamic-pituitary-ovarian axis, causing a decrease in FSH, LH, and estrogen.^{[3, 4]} This results in a vasoconstriction and collapse of the thickened hyperplastic endometrial lining with heavy and often prolonged bleeding. In anovulatory cycles, the estrogen levels can either be high or low. With chronic high levels, there is intermittent heavy bleeding, and chronically low levels may result in prolonged light bleeding.^[5]

The maturation of the hypothalamic-pituitary-ovarian axis occurs slowly in the first 18 to 24 months after menarche in the adolescent female. Anovulatory cycles may last up to 5 years.

Information concerning the age that adolescents become ovulatory is conflicting. McDonough and Gantt^[6] observed anovulation in 55 to 82% of adolescents between menarche and 2 years postmenarche, 30 to 55% from 2 to 4 years postmenarche, and 20% from 4 to 5 years postmenarche. The World Health Organization (WHO) conducted a 2-year longitudinal study on menstrual and ovulatory patterns in females aged 11 to 15 and found that 19% of girls had regular cycles within the first three cycles and 67% had regular cycles by the end of 2 years.^[7] In addition, adolescents with earlier menarche tend to develop ovulatory cycles sooner than those with later onset of menarche.^[8] Gynecologic age, defined as the number of years from menarche, is therefore a much stronger predictor of ovulatory cycles than chronological age. Apter and colleagues^[9] found that the majority of cycles were still anovulatory by a gynecologic age of 2 years, but after 5 years more than 80% achieved ovulation as measured by midluteal phase progesterone levels.

Besides physiologic causes, anovulation can also have organic pathologic causes. These include hyperandrogenic states (e.g., polycystic ovary syndrome [PCOS]), hypothalamic dysfunction (e.g., anorexia nervosa and excessive exercise), endocrinopathies, and premature ovarian failure. Occasionally, the bleeding is caused by an anatomic cause (e.g., polyps or fibroids), although this is very rare in adolescents. Therefore, the differential diagnosis of DUB in adolescents prioritizes differently than does the differential diagnosis in adult women.^[10]

Differential Diagnosis of Aub in Adolescents

Although the majority of adolescents with abnormal bleeding have anovulation due to age, DUB is a diagnosis of exclusion (Table 1).

Coagulation Disorder

Blood loss in the normal menstrual cycle is self-limited due to the action of platelets and fibrin. Individuals with thrombocytopenia or coagulation deficiency may have excessive menstrual bleeding. Several studies of the incidence of coagulopathy in teenagers admitted or evaluated for menorrhagia found coagulopathies in 12 to 33% in all admissions for menorrhagia.^[11-13] The most common coagulation disorders include thrombocytopenia, due to idiopathic thrombocytopenic purpura (ITP), von Willebrand's disease, which affects up to 1% of the population, and platelet function defects.^[14] Of the adolescents presenting with severe menorrhagia or hemoglobin less than 10 g/dL, 25% were found to have a coagulation disorder. In those presenting with menorrhagia at the first menses, 50% were found to have a coagulation disorder.^[13]

Pregnancy Complications

The possibility of pregnancy should be considered in any adolescent with abnormal bleeding, and a pregnancy test is mandatory even if the client denies sexual intercourse. Any bleeding in early pregnancy should lead to suspicion of miscarriage or ectopic pregnancy.^[15]

Reproductive Tract Pathology

Any trauma, infection, or neoplasm can cause AUB. Infections, such as chlamydia^[16] or pelvic inflammatory disease (PID), may present with abnormal bleeding. Vaginal trauma or a foreign body may cause bleeding that might be assumed by the adolescent to be uterine in origin. Women with a foreign body in the vagina generally present with a bloody, odorous discharge. Cervical polyps, cervical carcinoma, and cervical inflammation can cause bleeding. Cervical cancer is fairly rare in adolescents but may be encountered in those who had sexual experiences at a very early age (including those with a history of sexual abuse). Ovarian estrogen-producing tumors need to be excluded in the adolescent with very heavy persistent bleeding. Finally, although rare, uterine pathology, such as polyps and fibroids, may lead to abnormal bleeding.

Endocrinopathies

The most common endocrine disorder to cause abnormal bleeding is thyroid disease.^[17] In general, hypothyroidism presents with hypermenorrhea, and hyperthyroidism presents with hypomenorrhea. Hyperprolactinemia caused by a prolactinoma^[18] or certain medications, such as neuroleptics, can also cause anovulation and AUB. PCOS is underdiagnosed in adolescents and should be suspected in obese teens with hirsutism, acne, and continued irregular cycles.^[19] There is some recent evidence that PCOS is more common in women with epilepsy.^[20] Other diseases to consider are congenital adrenal hyperplasia, Cushing syndrome, hepatic dysfunction, and adrenal insufficiency.

Others Causes of Aub in Adolescents

Other causes of AUB (most commonly amenorrhea) in adolescents are eating disorders, stress, excessive exercise, and weight loss. In addition, common medications, which increase the cytochrome P450 enzymatic processes in the liver, may induce the more rapid metabolism of steroid hormones, thereby decreasing their bioavailability and result in AUB that is secondary to a relative insufficiency of estrogen or progesterone (e.g., antiseizure medications).^[21]

Evaluation

The initial goal in the approach to evaluation of an adolescent with abnormal bleeding is to determine hemodynamic stability, locate the origin of bleeding, identify any organic causes and classify whether the bleeding is ovulatory or anovulatory.

An accurate and complete menstrual history is critical. The history should include age at menarche, frequency, amount, and duration of menses, pain with menses, and last menstrual period. A menstrual calendar can accurately and prospectively keep track of the cycles, especially because adolescents often have difficulty remembering exactly the dates of their cycles. To an adolescent, monthly may mean once every calendar month, so that a period on day 1 and day 27 of the same month, while normal, may strike her as having periods twice a month. Age at menarche, month and year, is important to calculate gynecologic age because it may take at least 2 years to become ovulatory. Menstrual flow needs to be assessed in detail, including number of pads, the saturation of these pads, the passage of clots and the soaking of clothes and bedding. Some have advocated a pictorial chart, but more recent research has found that to be unreliable.^[22] In addition, family history should be obtained to rule out any familial diseases including bleeding disorders.

Special attention should also be paid to a careful sexual history because pregnancy and sexually transmitted infections (STIs) can also present with abnormal bleeding. Medications should also be carefully recorded. A thorough review of systems should be obtained, with particular emphasis on symptoms of bleeding abnormalities (easy bruisability, epistaxis, and gingival bleeding), endocrine disorders, and eating disorders, exercise and sport participation. Because many questions address sensitive areas that may require confidentiality between the adolescent and her health care provider, the young woman should also always be interviewed without her parents in the room.

A thorough physical examination should include height and weight and evaluation of overall health. Generally, pubertal development is assessed by Tanner staging.^[23] Bruises should be noted in search of a bleeding abnormality. Any signs of hyperandrogenism, such as acne or hirsutism, should be noted. The thyroid gland should be assessed for enlargement and the neck for acanthosis nigricans. This is a gray-brown velvety, sometimes verrucous, discoloration of the skin, usually at the neck, groin, axilla, or under the breasts, which is a marker for insulin resistance, as sometimes found in PCOS. The breasts should be examined, not only for pubertal staging but also for nipple discharge (galactorrhea) to screen for hyperprolactinemia. The abdomen should be assessed for masses and hirsutism. The decision to perform a pelvic examination primarily depends on the sexual history. If the client denies sexual activity, it may not be possible or necessary to perform a pelvic examination. She should have an evaluation of the external genitalia, looking for signs of clitoromegaly or hirsutism. If indicated, a rectoabdominal examination can be done. This is usually well tolerated and can be very helpful in girls with severe dysmenorrhea, to rule out an obstruction in the genital tract, endometriosis in the cul-de-sac, or a pelvic mass. All sexually active girls should have an internal examination with a narrow speculum, screening for sexually transmitted diseases, a Papanicolaou smear (if not done in the last 12 months), and a bimanual examination to assess for masses. If there is any evidence of coagulopathy, an endocrine abnormality, such as severe hirsutism, acanthosis nigricans, an enlarged thyroid, galactorrhea, or physical evidence of thyroid abnormalities, the patient should be referred to a physician for further evaluation. A pelvic ultrasound can be obtained if there is a high level of suspicion for an anatomic abnormality or if it impossible to perform a pelvic examination in a patient with severe dysmenorrhea that does not respond to initial treatment.

Initial laboratory studies should include a complete blood count (CBC) with platelets and a thyroid-stimulating hormone (TSH) or prolactin, if indicated. A pregnancy test should also be obtained, even if the patient denies sexual activity. A coagulation profile, including prothombin time, partial thromboplastin time, and a bleeding time, is recommended if the patient is having acute hemorrhage or has hemoglobin of less than 10 g/dL. Experts recommend a von Willebrand panel, including von Willebrand factor antigen and ristocetin cofactor activity if a bleeding disorder is highly suspected. A referral at that time is indicated.

Treatment of Aub

The goals of therapy for AUB in adolescent women are threefold. The first goal is to assess how serious the abnormal bleeding is, while ruling out any anatomic or pathologic causes. The second goal is to find out what her expectations and needs are. It is important to realize that often adolescent women may have a different goal for an office visit than she articulates to her parents or office staff; for example, she may have a need for birth control more than she needs regulation of her cycles. The third goal is to educate about normal irregular bleeding in adolescents. If she is not anemic or does not have symptoms that warrant a referral for medical evaluation and she does not need birth control, then reassurance and education may be all the treatment required. Prospective charting of menses will help to document cycle frequency.

Although anovulation is very common in teens, excessive bleeding leading to anemia is uncommon. The WHO study of adolescent menstrual patterns found only 5% of bleeding lasted more than 7 days, and only 0.5% lasted more than 10 days.^[7] The goals of therapy for menorrhagia, once pathology has been ruled out, are to: 1) stop the bleeding, 2) restore synchrony to the endometrium, and 3) replenish iron stores. Most often, this can be achieved with estrogen and/or progesterone therapy. Table 2 outlines a systematic approach to management of dysfunctional uterine bleeding in adolescents, based on symptoms and hemoglobin level.

Hemoglobin is Normal or >10 g/dl

If the bleeding is irregular, but not heavy enough to cause disturbance of the normal activities, reassurance and education should be offered. Prostaglandin inhibitors (ibuprofen or mefenamic acid), which alter the balance between thromboxane and prostacyclin, may relieve cramping and reduce flow volume by 20 to 50%.^[24] Oral contraceptives will establish regular menses and regulate blood loss. Adolescents with DUB should be offered this treatment option, which should be explored with the adolescent in a private conversation. Some parents are uncomfortable with adolescents being on "the pill," and it is important to provide thorough information about side effects and non-contraceptive benefits. Anticipatory education about side effects and consistent self-administration are important, because the discontinuation rate in adolescents is high.^[25]

A pelvic examination and Papanicolaou smear are not absolutely necessary to prescribe birth control pills. Expert consensus developed in the last decade supports initiating hormonal therapy in adolescents as safe when based on a careful review of medical history and blood pressure measurement alone. Performing a Papanicolaou smear and pelvic examination is important to screen for STIs and cervical cancer in women prior to prescribing oral contraceptives for birth control, but these examinations do not provide information necessary to identify women who should avoid hormonal contraceptives.^[26] However, it is important to emphasize that oral contraceptives do not protect against STIs.

Hemoglobin <10,>
If the patient is clearly anemic, oral contraceptives are the treatment of choice, and a 30- or 35-mcg preparation is usually adequate. Because restoration of synchrony is a goal of therapy, a monophasic preparation is preferred. Oral contraceptives and prostaglandin inhibitors both reduce menstrual flow in patients with a normal uterus. Supplemental iron should be encouraged. Reevaluation in 3 to 6 months is recommended. The length of treatment should be dependent on the severity of the anemia but will generally be 1 to 2 years (or as needed for contraception).
Progestins alone are also an effective treatment for anovulatory bleeding. Medroxyprogesterone acetate (Provera) may be prescribed in a dose of 5 to 10 mg per day or micronized progesterone (Prometrium) 100 to 200 mg per day for 10 to 14 days, starting on day 16 of the cycle, to induce stromal stability, which is then followed by a withdrawal flow. Disadvantages of this treatment are that the patient is not protected from pregnancy if she is sexually active and irregular bleeding can occur if the patient ovulates. In addition, cyclic progestins, unlike oral contraceptive pills, will not reduce acne or stop the progression of hirsutism, if these are concomitant problems. The side effects of the progestins can include moodiness, depression, and weight gain.

Hemoglobin <10,>
If the patient had prolonged bleeding and is still bleeding at the time of her visit, but is hemodynamically stable, outpatient therapy with short-term follow-up is adequate. Prolonged asynchronous breakage and shedding results in a thinned endometrium (measurable by ultrasound) and will require higher doses of estrogen to rebuild tissue and replace progesterone receptor sites. Progestin therapy alone will generally not stop the bleeding in this case. Physician consultation is advisable. A cascade of oral contraceptives is started as soon as possible, if the client has no contraindications to the use of estrogen. This should be a 30- or 35-mcg ethinyl estradiol monophasic pill, to be given at high doses with a slow decline. An easy formula is one pill qid for 4 days, then one pill tid for 4 days, then one pill bid for 4 days, then one pill qd. Antinausea medication needs to be offered as part of this regimen, because some patients will not be able to tolerate the high doses of estrogen. With this cascade, the client should have significant slowing of the bleeding in 48 to 72 hours and should be instructed to call if this is not the case or if the dosage is not tolerated. Once the cascade regimen is completed, the severity of the bleeding and the degree of anemia will dictate how long oral contraceptive use is recommended at regular dosing intervals. Recent studies indicate that prolonged episodes of continuous oral contraceptives are efficacious in the treatment of menorrhagia.^[27] If the patient has a contraindication to estrogen, an acute physician referral should be obtained. Depot medroxyprogesterone is an alternative if long-term amenorrhea is desired.

Acute Hemorrhage

Refer immediately to physician for admission and treatment. Often intravenous estrogen is used. Surgery is rarely indicated.^[11]

Prognosis

The majority of adolescents with AUB will spontaneously convert to normal menstrual cycles within 1 to 2 years, and this information and reassurance should be relayed to her. Education and support for the adolescent and her family are very important, because sustained heavy bleeding is a confusing and frightening event.

The prognosis is more guarded in the presence of acute anemia and in those women with continued irregular bleeding after several years. A 25-year prospective evaluation of adolescents with dysfunctional uterine bleeding showed that of those who continued to have abnormal bleeding after 2 years, persistent problems were noted in 50% after 4 years and in 30% after 10 years.^[28]

Summary

Most adolescents with AUB have dysfunctional uterine bleeding secondary to anovulatory bleeding and are easily treated with either prostaglandin inhibitors or oral contraceptives. A thorough history and physical examination rules out the majority of disorders in the differential diagnosis. However, if an adolescent does not respond in the expected fashion in 3 to 6 months, or has initial low hemoglobin, a further evaluation and work-up and/or referral is in order.

Tables

Table 1. Differential Diagnosis of Abnormal Uterine Bleeding in Adolescents

Immaturity of the HPO axis
Coagulation disorders
Idiopathic thrombocytopenic purpura (ITP)
Von Willebrand's disease
Platelet function defect
Pregnancy complications
Abortion (complete, incomplete, missed)
Ectopic pregnancy
Trophoblastic disease
Genital tract infection
Vaginitis
Cervicitis
Vaginal foreign body
Salpingo-oophoritis
Endometritis
Endocrinopathies
Polycystic ovary disease
Hyperprolactinemia
Thyroid abnormalities
Premature ovarian failure
Hypothalamic dysfunction
Anorexia, stress, excessive exercise
Benign lesions of the genital tract
Cervical polyp
Vaginal adenosis
Endometriosis
Leiomyoma
Iatrogenic: drugs or hormones
Trauma
Malignant lesions of the genital tract
Vaginal carcinoma
Cervical carcinoma
Ovarian tumors

Table 2. Management of Dysfunctional Uterine Bleeding

Hemoglobin >10 g/dL
Reassurance and education
Iron supplementation
Menstrual calendar
Consider oral contraceptives if desired by patient
Prostaglandin inhibitors
Periodic reevaluation
Hemoglobin <10>
No active bleeding
Consider referral or consult with a physician
Iron supplementation
Therapy: oral contraceptives
Cyclic progestin therapy; prostaglandin inhibitors
Reevaluation in 3 to 6 months
Active bleeding but stable
Consider referral or consult with a physician
Cascade oral contraceptive regimen: 30 to 35-mcg ethinyl estradiol
1 pill qid for 4 days
1 pill tid for 4 days
1 pill bid for 4 days
1 pill qd until two pill packs are finished
Iron supplementation
Reevaluate by phone in a few days; if bleeding not slowed down,
physician consult
Continue treatment for 1 year; then reevaluate
Acute hemorrhage
Immediate consult with physician for possible transfusion and
admission

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Reprint Address

Address correspondence to Elisabeth H. Quint, MD, Department of Obstetrics and Gynecology, University of Michigan Health System, L4000 Women's Hospital, 1500 E. Medical Center Drive, Ann Arbor, MI, USA 48109-0276.

Elisabeth H. Quint, MD, is Clinical Associate Professor of Obstetrics and Gynecology, Division of Gynecology, at the University of Michigan Medical School. She is codirector of the clinic for pediatric and adolescent gynecology.
Yolanda R. Smith, MD, is Assistant Professor in Obstetrics and Gynecology, Division of Reproductive Endocrinology, at the University of Michigan Medical School. She is codirector of the clinic for pediatric and adolescentgynecology.

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