Pediatric and Adolescent Gynecology - Abnormal Uterine Bleeding
 

Abnormal vaginal bleeding is a presenting complaint for many gynecologic and nongynecologic conditions, and it is a common problem encountered by physicians providing health care for adolescents. Possible etiologies include (a) organic causes such as pregnancy complications, infections, trauma, cancer lesions and tumors of the genital tract, blood dyscrasias, and endocrine and systemic disorders; (b) abnormal consequences of contraceptive methods such as oral contraceptives and intrauterine devices; and (c) dysfunctional uterine bleeding (DUB), which refers to abnormal uterine bleeding for which no demonstrable organic cause can be found.

In the adolescent, DUB is the most common cause of abnormal bleeding, comprising about 48% to 97% of the causes (1,2,3 and 4). The underlying problem is anovulation or oligoovulation, with the maturational process of the hypothalamic-pituitary-ovarian (HPO) axis often taking 2 to 5 years to complete (5,6 and 7). Menarche, which occurs at an average age of 12.8 years in the United States, is an anovulatory bleeding episode, and as many as 82% of the cycles in the first postmenarcheal year (5,6) and up to 28% of the cycles in the fifth postmenarcheal year are anovulatory (6). However, most adolescents who have irregular bleeding in the first and second postmenarcheal years do not require long-term management (2,8). Yet, when irregular bleeding persists after 4 years from the onset of bleeding, serious gynecologic sequelae, such as problematic uterine bleeding, reduced fertility potential, and a high rate (1.3%) of endometrial cancer in women under 40 years of age, were observed (8).
Normal variations in bleeding patterns are important to understand in order to establish when to consider to the bleeding as abnormal. The mean amount of blood loss in a normal cycle is about 35 mL (range 20 to 60 mL). Chronic blood loss of more than 80 mL per cycle results in a high frequency of iron deficiency anemia (9). Outside of research protocols, estimating the amount of blood loss is difficult at best, and frequently the perception of how much blood has been lost is not reliable (10). Even using estimates based on the number of well-soaked regular perineal pads, such as eight, or the number of tampons, such as 12, as upper limits of normal may not correlate with actual blood loss when pads and tampons are changed frequently or blood clots are present (10). The duration of flow averages 3 to 7 days, with more than 7 days considered prolonged. The frequency of bleeding occurs between 24 and 36 days in normal cycles. However, cycle lengths as short as 21 days and as long as 40 days may be normal. In general, an adolescent's established menstrual pattern can serve as a reference to determine how the problematic bleeding differs from her “normal” menstrual flow, but in the absence of previously regular menstrual bleeding, these values may be used as guidelines.

Bleeding abnormalities may be classified according to the amount of flow, duration of flow, and regularity or interval between bleeding episodes. Certain descriptive terms such as “menorrhagia” (hypermenorrhea), “metrorrhagia,” and “menometrorrhagia” may be used to classify the types of bleeding and assist in establishing a differential diagnosis. These terms and others are defined in Table 14.1, and some of the possible etiologic conditions are included. With the inherent difficulties in assessing irregular bleeding in the adolescent and the numerous organic causes that must be excluded before DUB can be designated as the etiology, the health care provider is faced with a significant diagnostic challenge. In addition, the physician must be aware of both the treatment options in order to individualize the management as well as the potential psychoemotional impact of the problem on the adolescent and her parents.

MENSTRUAL CYCLE

Before one can understand the abnormalities of the adolescent cycle, a thorough understanding of the normal cycle is needed. Except for the extremes of reproductive life, the menstrual cycle has a medial duration of 28 days due to a 14-day follicular phase and a 14-day luteal phase (11). The cyclic expression of the HPO axis leads to functional and structural changes in several target tissues, particularly the endometrium. In the absence of a conception, the demise of the corpus luteum leads to the withdrawal of ovarian steroids from the endometrium, which in turn leads to an orderly withdrawal menses. Any aberration in this orderly sequence of events can lead to asynchronous development and shedding of the endometrium with subsequent abnormal uterine bleeding.
The actual event responsible for the initiation of puberty and subsequent maturation of the hypothalamus is unknown. Before the onset of puberty, insufficient hypothalamic gonadotropin-releasing hormone (GnRH) stimulation to the pituitary causes low gonadotropin levels and subsequent absent follicular development (7). As the hypothalamus begins to mature, sleep-induced luteinizing hormone (LH) pulses are seen that disappear after puberty (12,13). In early adolescence, follicular recruitment and episodic estrogen secretion lead to development of the endometrium, but this often is followed by an inability of the immature hypothalamus to respond with an LH surge (14). This leads to the frequent occurrence of anovulation and DUB, as described later.
The human menstrual cycle can be divided into three distinct phases. The follicular phase, which probably begins in the preceding luteal phase, is characterized by the selection of the dominant follicle and growth of the endometrium under the influence of estrogen. The ovulatory phase, which begins with the onset of the luteinizing surge, is characterized by a dramatic switch from estrogen to progesterone production and final release of the oocyte. The luteal phase, which lasts 13 to 14 days after ovulation, is characterized by preparation of the endometrium for implantation under the influence of the corpus luteum. The HPO axis and the endometrial changes for each phase will be described in the following section. The hormone pattern of the adult human menstrual cycle is shown in Fig. 14.1 and Fig. 14.2.

Follicular Phase
Hypothalamic-Pituitary-Ovarian Axis

Knobil (15) showed that gonadotropin output by the pituitary is directly controlled by the GnRH pulse generator located in the accurate nucleus of the hypothalamus. Administration of a GnRH agonist leads to rapid pituitary gonadotropin suppression, which is reversed quickly on discontinuation of the drug (16). In the absence of either implantation or exogenous human chorionic gonadotropin (hCG), there is demise of the corpus luteum followed by a fall in serum progesterone. This declining steroid output by the ovary causes an alteration in the GnRH pulse generator, leading to more frequent pulses of GnRH. Decreasing serum steroid levels combined with a change in the pulse generator cause a rise in pituitary follicle-stimulating hormone (FSH) output, which can be detected 1 to 2 days before menses (17). It is this rise in serum FSH that is believed to initiate the subsequent follicular phase.
The first half of the follicular phase is marked by selection of the dominant follicle. At the start of each cycle, there exists a cohort of follicles destined for either atresia or ovulation (18). During the early follicular phase, all follicles show growth up to 10 mm; however, after selection of the dominant follicle, the remaining follicles show a decrease in size (19). The cohort of follicles ranges from 3 to 11 per ovary. The selection of the dominant follicle depends on both its microenvironment and its capacity for estrogen synthesis (20).
Although LH has multiple target sites, FSH appears to act only on the granulosa cells. Before selection of the dominant follicle, increasing levels of FSH causes an increase in the number of FSH receptors and induce granulosa cells to convert androgens to estrogens via an aromatizing enzyme (21). These two actions lead to an increase in estrogen within the follicle. Estrogen then is able to increase the number of its own receptors. The follicle that is best able to utilize this synergistic relationship between FSH and estrogen is destined to change from an androgenic microenvironment to an estrogenic microenvironment and thus selection as the dominant follicle.

Once the dominant follicle has been selected (day 7), the next half of the follicular phase is marked by growth of the dominant follicle and preparation for ovulation. Declining serum levels of pituitary FSH, secondary to inhibin B production from the dominant follicle, leads to withdrawal of support from the secondary follicles. Thus, the dominant follicle produces the most inhibin B, whereas follicles destined to die produce smaller amounts of inhibin B. At the same time, activin proteins, which augment FSH activity, are produced in higher concentrations in the early follicular period (22). This ensures that only one oocyte will be ovulated each cycle. During the early part of the cycle, FSH has no effect on LH receptors. However, after exposure to increasing levels of estrogen, there is induction of LH receptors in the granulosa cells of the dominant follicle. Although LH stimulation of the theca interna is responsible for androgen production (which subsequently is aromatized to estrogen in the dominant follicle), it is the appearance of LH receptors in the granulosa cells that is responsible for subsequent progesterone production (23,24).

Endometrium

The anatomic changes that occur in the endometrium in response to ovarian steroids have been studied extensively in the human (25). The early follicular phase endometrium (i.e., menstrual endometrium) is marked by tissue breakdown in the form of necrosis, white cell infiltration, and glandular disruption. It is composed primarily of a nonfunctioning basalis component, which is left after the majority of the endometrium has sloughed. If the breakdown is secondary to the programmed withdrawal of progesterone, then the loss is orderly and complete and occurs in all segments of the endometrium.

Once estrogen levels start to rise in response to follicular recruitment, the process of growth and healing begins in the endometrium. The two structures that respond dramatically to estrogen are the glands and spiral arterioles. During the next several days, the endometrium will grow from 0.5 up to 5 mm due to an increase in the number and size of the glands. In stimulated cycles, the number of glands is positively correlated to the serum estrogen level (26). The glandular epithelium, marked by mitosis and pseudostratification, extends to form an epithelial lining facing the endometrial cavity. The spiral vessels also extend through the stroma.
Estrogen has been shown to have a significant effect on endometrial blood vessels (27). When estrogen levels fluctuate, changes can be seen in vessel permeability and fragility. Therefore, in an estrogen-primed endometrium, fluctuations in estrogen levels that are seen in the typical anovulatory cycles during adolescence lead to vessel fragility and incomplete and disorderly endometrial breakdown. This disorderly endometrial breakdown leads to the classic anovulatory uterine bleeding seen in early adolescence.

Ovulatory Phase
Hypothalamic-Pituitary-Ovarian Axis

The increasing amounts of estrogen produced by the dominant follicle exert a positive feedback on the hypothalamic-pituitary axis (28). The onset of the midcycle gonadotropin surge (LH and FSH) is related to the peak estradiol level and lasts roughly 48 hours, as shown in Fig. 14.2. The LH surge is characterized by a rapid ascending limb (accompanied by a rapid decline of serum estradiol) followed by a longer descending limb. The shift in steroidogenesis begins roughly 12 hours before the onset of the LH surge, when progesterone levels start to rise and estradiol levels begin to plateau. During the 48 hours of the LH surge, progesterone abruptly rises as estradiol continues to decline. An abnormal LH surge often is seen in adolescence where the hypothalamic-pituitary axis is unable to respond to the rising estradiol levels (14).

In addition to a shifting of steroidogenesis from estrogen to progesterone in the granulosa cells, the LH surge serves two other important functions. First, it causes resumption of meiosis; and second, it causes an alteration in the follicular environment, which leads to the physical process of ovulation (28). Tissue levels of cAMP rise in the preovulatory follicle and are followed by digestion of the follicular wall (29). Follicular fluid levels of prostaglandins are highest at ovulation (30) and appear to be involved in the actual process of ovulation. Plasminogen activator, which is produced after the LH surge, forms plasmin by granulosa and theca cells. Plasmin and other collagenases degrade the collagen connective tissue in the follicle, which ultimately facilitates follicle rupture (31). Prostaglandins and hydroxyeicosatetraenoic acids, in addition to plasminogen activator, may help facilitate follicular rupture (32,33).

Endometrium

During the 48 hours of the LH surge, the switch to progesterone fixes the height of the endometrium and begins the process of moving glandular secretions to the lumen of the glands. The early secretory endometrium is remarkable for movement of the intracellular vacuoles from the subnuclear region into the lumen. This is most prominent from days 16 to 19. Due to continued growth in fixed structure, the glands and spiral vessels begin to coil. As long as steroid output by the corpus luteum is adequate, the vessels will maintain their structure.
Once follicular recruitment begins and estrogen levels start to rise in early adolescence, the endometrium responds by growth and development of the glands and arterioles. In the absence of an LH surge and subsequent progesterone production, estrogen levels begin to fluctuate, which leads to vessel fragility in the endometrium. This causes incomplete breakdown of the endometrium and prolonged DUB.

Luteal Phase
Hypothalamic-Pituitary-Ovarian Axis

As the most steroidogenically active tissue in the body, the corpus luteum produces about 25 mg of progesterone per day (Table 14.2) (34). This progestogenic dominance serves to slow the GnRH pulse generator, thereby preventing further recruitment of follicles. In addition, inhibin A, mediated by LH, is secreted by the corpus luteum (35) and aids in preventing new follicular development in the luteal phase (36). The corpus luteum progesterone also serves to prepare the endometrium for implantation. Serum progesterone levels reach a peak roughly 8 days after the LH peak, and there is a parallel increase of 17-hydroxyprogesterone, estradiol, and estrone levels.

The health of the corpus luteum appears to depend on the preceding follicular phase (i.e., the development of LH receptors on the granulosa cells) (37,38). Selective suppression of FSH during the follicular phase results in a decreased luteal cell mass and a decreased progesterone production by the corpus luteum (39). The health of the corpus luteum also appears to depend on proper vascularization and the delivery of cholesterol for progesterone synthesis (40).
Pituitary LH is vital for the survival of the corpus luteum. This has been demonstrated by several studies. First, in hypophysectomized women, ovulation induction with gonadotropins is followed by low progesterone levels and a short luteal phase (41). Second, administration of a potent GnRH agonist or antagonist in the luteal phase results in a dramatic decline of progesterone (42). Cell culture experiments have shown that luteinized granulosa cells produce large amounts of progesterone, which peaks on day 3 of culture and is greatly increased in the presence of hCG (43). Thus, even though the GnRH pulse generator is slowed, pituitary LH is the vital luteotropic hormone in adult women.

Without hCG or LH stimulation, the lifespan of the human corpus luteum generally is 13 to 14 days. Prostaglandin F2a is but one luteolytic that has been described. It stimulates endothelin 1, which induces luteal regression (44). The process of luteolysis has been further elucidated. Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes. Tissue inhibitors of metalloproteins (TIMPs) are products of the corpus luteum. They inhibit MMPs. Luteolysis may occur with an increase in MMPs, as TIMPs do not increase during the luteal phase. When a woman becomes pregnant and hCG is exposed to the corpus luteum, “luteal rescue” is associated with a decrease of MMPs (45). With the demise of the corpus luteum, there is a dramatic fall in serum progesterone, estrogen, and inhibin A (46), with a resultant increase in pulses from the GnRH pulse generator. The increase in GnRH frequency leads to a rise in serum FSH levels and initiation of the next follicular phase with recruitment of a new cohort of follicles.

Endometrium

During the luteal phase, the endometrium continues to prepare for implantation. The vacuoles have moved into the lumen of the glands, the glands have become exhausted, and the stroma has become edematous. Although the precise role of the glandular secretions is unknown, a teleologic view would hold that they provide nourishment for the embryo. The glandular secretions are prominent at a time when the embryo is in the endometrial cavity and preparing for implantation, between 4 and 7 days after ovulation.
Progesterone also has an effect on endometrial stroma cells, leading to edema, decidualization, and prolactin production (47). Around day 22 to 23, the spiral arterioles acquire a cuff of pseudodecidualized stromal cells. This is the earliest predecidual change. Pseudodecidualized stromal cells extend to beneath the epithelium by day 25, and by day 27 the endometrium appears as solid sheets of pseudodecidualized cells (25). Prostaglandin F2a (PGF2a), which is believed to be important in the process of both implantation and menstruation, rises in late luteal endometrium (48) and appears to be decreased by the addition of progesterone (49).
Inadequate progesterone production after estrogen priming of the endometrium leads to thin endometrium without stromal edema or decidualization (50). Treatment during the follicular phase with an antiestrogen leads to lower levels of cytoplasmic progesterone receptors in the luteal endometrium (51). This could be a factor leading to lower conception rates in these cycles. Progesterone also has an effect on endometrial vessels and probably acts synergistically with estrogen to maintain an intact endometrium (52). Administration of an antiprogesterone during the early luteal phase results in decreased glandular secretory activity, vascular changes, and accelerated degenerative changes (53). Furthermore, administration of an antiprogesterone during the late luteal phase leads to a prompt withdrawal menses and shortening to the luteal phase (54). Although the precise role of decidualization and endometrial prolactin production is unclear, they may be involved in the initial establishment of an intact fetomaternal unit. Women who have delayed or abnormal decidualization show an increased incidence of both infertility and recurrent pregnancy loss (55,56). Furthermore, embryos implanted in tissue other than the endometrium show an abnormal amount of trophoblastic invasion (57) and abnormal development (57,58).

In the absence of implantation and subsequent hCG, there is demise of the corpus luteum and waning estrogen and progesterone levels. Withdrawal of steroids from the endometrium leads to vessel fragility and spiral arteriole constriction. Tissue necrosis, white cell migration, and menstruation follow. The edematous stoma of the spongiosum is sloughed, leaving behind the basalis and a residual spongiosum. Progesterone withdrawal also leads to an alteration in the GnRH pulse generator and a subsequent rise in FSH levels. This serves to initiate the next follicular phase and aid in the healing process of the endometrium. Menstrual flow stops due to prolonged vasoconstriction, platelet aggregation, and estrogen-induced vessel stability and healing.

CAUSES OF ABNORMAL UTERINE BLEEDINGM

Anovulatory DUB is the most frequent cause of abnormal bleeding in the adolescent, but its diagnosis requires the exclusion of many disorders (Table 14.3). Less commonly observed is ovulatory DUB, which may present as polymenorrhea, periovulatory (midcycle) bleeding, or premenstrual spotting. Midcycle bleeding may be attributed to the decrease in estrogen before ovulation and occasionally may be due to uterine polyps or fibroids. Premenstrual spotting may be seen with luteal phase inadequacy and decreased progesterone effect on the endometrium, although a fairly high association with endometriosis has been observed (59).

The frequency of the other causes of abnormal bleeding is different depending on the presentation. Extremely heavy menses requiring transfusions and beginning with or shortly after menarche is likely to be due to a coagulation disorder. Studies of acute adolescent menorrhagia showed that 3% to 19% of these patients have a coagulation disorder as the etiology for their bleeding (1,60). von Willebrand's disease is the most common inherited blood dyscrasia, affecting 1% of the population (61). Type 1 von Willebrand's disease accounts for 70% of all cases (62) and presents clinically with menorrhagia epistaxis, bruising, and gum bleeding (62). Many of the coagulation disorders are familial; a family history of bleeding problems frequently is elicited. Leukemia may present with either menorrhagia or menometrorrhagia, usually as a result of decreased plasma fibrinogen.

Adolescent pregnancy is an all too common occurrence in the United States. As many as 70% of women have sexual intercourse by age 19 years, and only half used contraception during their first intercourse (63). Consequently, a high index of suspicion of a possible pregnancy complication, such as a threatened or spontaneous abortion and ectopic pregnancy, is required when evaluating abnormal bleeding.

Infections as a cause of abnormal bleeding are more likely in acute episodes, although chronic endometritis may present with menorrhagia. Cervicovaginitis, including trichomoniasis, gonorrhea, herpes, condylomata, and chlamydia, may cause vaginal bleeding. When painful bleeding is observed, pelvic inflammatory disease must be considered as a possible cause. Local irritation and trauma from a foreign body left in the vagina may present with a bloody, malodorous discharge and requires differentiation from an infection. The most common foreign body is a tampon. Atrophic vaginitis from premature ovarian failure may be seen rarely in the adolescent presenting with spotting and vaginal discharge.

Sexual intercourse and/or abuse may present with vaginal trauma and bleeding. It requires a thorough history and examination for legal documentation when identified or suspected. Neoplasms of the cervix, vagina, uterus, and ovaries are rare causes of bleeding in the adolescent, but because of the often more serious nature of both benign and malignant tumors, a physician should always be concerned about these etiologies when performing an examination.

Endocrine causes most often present with recurrent abnormal bleeding, with thyroid disorders most commonly found. Hypothyroidism often is associated with hypermenorrhea, whereas hyperthyroidism usually results in hypomenorrhea. Signs of hyperandrogenism in the adolescent with abnormal bleeding may occur with polycystic ovarian disease, congenital adrenal hyperplasia, androgen-secreting neoplasms of the ovary or adrenal glands, and Cushing's disease. Anovulatory uterine bleeding frequently results from these endocrinopathies, as is also the case with weight disorders, chronic illnesses, and psychogenic causes. Polycystic ovarian syndrome should be suspected in any adolescent with androgen excess (hirsutism, acne, acanthosis nigricans), virilization, obesity, oligomenorrhea, and anovulatory bleeding. It is one of the most common causes of anovulation in this age group. Ovarian hyperandrogenism and anovulation are due to hyperinsulinemia during puberty (64). These adolescents are at risk for endometrial hyperplasia, cardiovascular disease (65), and noninsulin-dependent diabetes mellitus (Table 14.4) (66).

Endometriosis presents with chronic pelvic pain, dysmenorrhea, and bowel dysfunction. Studies have shown that up to 69% of adolescents presenting with pelvic pain will have endometriosis, and 9.4% of these adolescents will have abnormal vaginal bleeding (67).
Congenital anomalies of the reproductive tract, although rare, can cause vaginal bleeding. A transverse septum can bleed after trauma from tampon placement or intercourse. An imperforate transverse vaginal septum with obstruction can lead to hematocolpos. Symptoms include severe cyclic abdominal and pelvic pain, and no menstrual flow with the development of a central pelvic or abdominal mass. If the septum develops a tract, abnormal vaginal bleeding ensues (68). This bleeding will be red during a menstrual cycle then change to brown blood if it appears between periods. In addition to the patient's personal history, the family history is important, as polycystic ovarian syndrome, endometriosis, and blood dyscrasias all have an inherited tendency.

DIAGNOSIS AND EVALUATION

As noted in Table 14.3, the causes of abnormal bleeding in adolescence are numerous. Even though the majority of cases represent anovulatory uterine bleeding, the more serious causes need to be excluded. The investigation of the adolescent with abnormal bleeding consists of three initial phases: history, physical examination, and laboratory tests. Table 14.4 outlines the essential evaluation and additional tests in the evaluation of adolescent bleeding.
As with most presenting complaints, a careful history will enable the clinician to make the diagnosis in the majority of cases. The history should be obtained with and without the patient's parent in the room. The patient's menstrual history needs to be reviewed in detail. Age of first menses and the nature of this first period, along with the frequency, duration, and regularity of their current menstrual cycle, are noted. Coagulopathies, polyps, or submucous myomas may present as heavy menses with no intermenstrual bleeding, whereas endometriosis, infections, congenital anomalies, foreign bodies, and malignancies can present with heavy periods and intermenstrual bleeding.

Reviewing the sequence of pubertal events is important. The absence of secondary sexual characteristics along with uterine bleeding should alert the physician to some of the more unusual and rare causes of abnormal bleeding, because menarche is the final event in puberty and therefore DUB should occur only after the development of secondary sexual characteristics. Systems of systemic progesterone (breast tenderness, mood swings, bloating) should alert the physician to ovulatory cycles and the probable diagnosis of DUB. Even though teenagers are poor at estimating the amount of blood loss, an attempt should be made to determine if the blood loss is excessive.

The remainder of the history should be directed toward the possibility of pregnancy and its complications, coagulation defects, sexually transmitted disease, sexual abuse or trauma, diet and/or exercise extremes, drug and/or medication use, and central nervous system tumors. After a thorough history, the physical examination is performed with these disorders in mind. An initial height and weight will help determine pubertal events, diet abnormalities, and overall health. The general physical examination may reveal systemic signs of a coagulation defect (petechiae or ecchymoses), endocrinopathy (hirsutism, hair changes, obesity, acne, acanthosis nigricans, galactorrhea, virilization, striae), a central nervous system tumor (visual changes) or chronic illness.

The pelvic examination may reveal the exact site of bleeding and may help rule out infection, cervicitis, sexually transmitted diseases, sexual abuse, trauma, and a foreign body. The examination is initiated after the physician has explained to the patient what he or she is planning to do. First, the external genitalia are examined. A young, apprehensive patient might best be placed on her parent's lap with her legs spread over their thighs. An older adolescent can be examined on an examination table with stirrups. In the very young patient, the pelvic examination may need to be performed under anesthesia. Ultrasound can be an integral part of the initial workup before an examination under anesthesia. In the sexually active, emotionally mature adolescent, transvaginal ultrasound can detect immediate pathology; the transabdominal approach is reserved for any nonsexually active female (69).

The vestibule should be examined with gentle labial retraction. The labia minora and majora, mons pubis, clitoral glans, and hood are evaluated along with the urethra, hymen, and posterior forchette. The cervix and vagina are visualized with a speculum or by vaginoscopy. Additionally, the knee-chest position causes the vagina to open.

When a speculum is used, cervical cultures, wet mount, and Pap smear are obtained if warranted. In the pediatric patient who does not tolerate a speculum examination, vaginal irrigation may provide these specimens. A bimanual examination is performed to evaluate the adnexa and uterus of masses and tenderness. If the hymeneal orifice is too small for digital palpation of the cervix, a rectoabdominal examination should be performed.

Following a careful history and physical examination, laboratory tests should be ordered. The essential laboratory evaluation of acute adolescent bleeding should include a complete blood count, which provides an indication of the severity of the bleeding in both acute and chronic loses, and screens for an infectious etiology. Due to the importance of pregnancy complications, a pregnancy test should always be performed. Because many adolescents will have an underlying coagulation defect, blood should be sent for a platelet count, prothrombin time, partial thromboplastin time, von Willebrand antigen, ristocetin cofactor assay, factor VIII antigen, and bleeding time, especially in cases of either acute hemorrhage or where the hemoglobin is less than 10 g/dL. This coagulation screen, if normal, will rule out all but the most unusual forms of coagulation defects and, if abnormal, indicate additional studies and consultation with a hematologist.

In addition to the essential workup as outlined earlier, other laboratory studies such as endocrine testing may be obtained if clinically indicated. Because the majority of anovulatory uterine bleeding in early adolescence will resolve with maturation of the HPO axis, these further tests also are indicated in nonacute cases where the anovulatory uterine bleeding persists long after menarche. Additional testing to evaluate anovulatory uterine bleeding may include thyroid studies, prolactin level, evaluation of hirsutism, and radiologic evaluation of the pituitary. A blood glucose, pelvic ultrasound, or screen for sexually transmitted disease should be obtained when clinically indicated.

Due to the low yield and potential harm, surgical evaluation in the form of hysteroscopy, and dilatation and curettage seldom are necessary in the evaluation of an adolescent and should be used as last resort when medical treatment fails. This is especially true when anovulatory uterine bleeding is the working diagnosis. Surgical evaluation may be useful in cases where a neoplasm or trauma is suspected. It also may be useful in certain pregnancy complications.
In cases where anovulatory uterine bleeding does not appear to be the diagnosis, a consultation with a specialist may be appropriate. The expertise of a hematologist, reproductive endocrinologist, or psychiatrist may be useful in the evaluation of the adolescent with abnormal bleeding refractory to treatment.

TREATMENT

Frequently the evaluation and the treatment of uterine bleeding are being performed concurrently and overlap significantly. Once specific organic causes and blood dyscrasias have been excluded, a designation of DUB may be made. Because the underlying problem is hormonal in DUB, the bleeding can be managed primarily with hormonal preparations and secondarily with adjunctive measures. With organic causes, endocrine causes, and blood dyscrasias, correcting or treating the disorder is foremost whenever possible. Hormonal treatments are reserved for control of heavy refractory uterine bleeding in appropriate cases.
Organic causes may need to be treated surgically, whereas endocrine disorders including hypothyroidism, congenital adrenal hyperplasia, hyperprolactinemia, and polycystic ovarian disease are treated medically. The blood dyscrasia von Willebrand's disease, type 1, can be treated with desmopressin acetate either as a nasal spray or by intravenous injection.

The most common clinical situation that will be seen in adolescents by health care providers is an irregular interval of bleeding that is neither heavier nor longer than a normal menstrual flow. Reassurance, observation, and recording the days and amount of bleeding (menstrual calendar) are sufficient unless a progression of problematic bleeding is observed. Chronic or recurrent episodes of mild-to-moderate bleeding (Table 14.5) are the next most common presentation, followed in decreasing frequency by chronic or recurrent episodes of heavy bleeding, acute heavy bleeding, and acute hemorrhage.

In each presentation of abnormal bleeding, excluding pregnancy is a necessary prerequisite to initiating therapy. In addition, an endometrial sampling should be performed with heavy bleeding, whether acute or chronic, once a pregnancy has been ruled out. Frequently, a physician may decide to forego endometrial sampling when the history strongly suggests DUB or the adolescent cannot be examined adequately. However, use of intravenous sedation may sufficiently reduce apprehension to allow performance of both the examination as well as endometrial sampling in an office setting. In rare instances, examination under general anesthesia may be required when organic causes are strongly suspected.

The value of endometrial sampling lies in both assisting in the immediate management by assessing the quantity of tissue obtained and evaluating pathologic changes causing the bleeding. Very little tissue or a thin endometrial stripe on transvaginal ultrasound suggests a relatively atrophic endometrium or chronic bleeding with only basal endometrium remaining, which would best respond to estrogen initially. A large amount of tissue is consistent with an unopposed estrogenic milieu and anovulation, which generally responds well to progestin therapy.

The advent of saline infusion sonography (SIS) can aid in differentiating between an organic cause for bleeding and “dysfunctional uterine bleeding.” As an office procedure, the physician can detect polyps, myomas, synechiae, hyperplasia, endometrial cancer, and normal uterine cavities (70). In addition, the adnexa can be evaluated. SIS is an excellent office study that can be done without the need for sedation or an operating room. Hysteroscopy with dilatation and curettage should be reserved for abnormal uterine bleeding refractory to hormonal treatment or when a lesion is seen on SIS. Long-term management of bleeding may require iron supplementation to prevent iron deficiency anemia and may include a prostaglandin synthetase inhibitor to reduce blood loss with each episode (71,72 and 73). When the amount of bleeding is heavy initially or after a period of observation, hormonal treatment also may be prescribed.

ACUTE BLEEDING

There are several regimens of hormonal therapy that have been used in acute episodes of heavy bleeding. The following discussions on hormonal therapy should be viewed as guidelines to be individualized by the health care provider, not necessarily exclusive of alternative regimens. In adolescents with suspected anovulatory type bleeding, consisting of heavy bleeding and oligomenorrhea, with more than usual amounts of endometrial tissue when sampled, or who have been receiving estrogenic preparations, progestin therapy to produce a secretory change of the endometrium and ultimately a progestin withdrawal bleed should be the initial hormonal intervention. Failure to withdraw bleed warrants a workup.
Progestin therapy may be accomplished using (a) progesterone in oil 100 to 200 mg intramuscular injection followed by 10 to 14 days of oral progestin; (b) medroxyprogesterone acetate (MPA) 10 to 20 mg orally per day for 10 to 14 days; or (c) norethindrone acetate 5 to 10 mg orally per day for 10 to 14 days.

Progesterone in oil offers an immediate progestational effect on a bleeding endometrium, with a decrease in bleeding usually occurring within 12 to 24 hours, but it must be followed by 10 to 14 days of oral progestin. Common errors of progestin therapy are inadequate duration of treatment, which should be a minimum of 10 days, and failure to counsel patients to anticipate bleeding after completing the prescribed course of the progestational agent.
After control of the acute bleeding, periodic progestin therapy of 10 to 14 days each month should be given for up to 6 months before observing the bleeding pattern without medication. This is the treatment of choice for chronic or recurrent bleeding due to anovulation in an adolescent who has withdrawal bleeding when progestins are administered. Anovulatory dysfunctional bleeding in adolescents is due to an immaturity of the hypothalamic-pituitary axis. There is no positive feedback of estradiol, which is needed for ovulation. These patients need a progestin withdrawal bleed monthly until their HPO axis matures to induce an orderly endometrial slough and avoid endometrial hyperplasia.

In adolescents with prolonged moderate bleeding, decreased amount of tissue on endometrial sampling (thin endometrial stripe on ultrasound), or suspected hypoestrogenism, estrogen therapy is used to cause proliferation of an otherwise atrophic or “thinned out” endometrium. Initial regimens of estrogen therapy include (a) conjugated estrogens 0.625 to 1.25 mg orally every 4 to 6 hours, (b) conjugated estrone 0.625 to 1.25 mg orally every 4 to 6 hours, and (c) estradiol 1 to 2 mg orally every 4 to 6 hours.

Once significant bleeding has been stopped, which is usually 24 hours, reduction of the dose to a daily or b.i.d. schedule may be tried. Because of the greater potential for thromboembolic sequelae with high-dose synthetic estrogens such as ethinyl estradiol, these regimens discussed are preferable. With heavy bleeding and acute hemorrhage, attempts may be made to control bleeding rapidly. Conjugated estrogens are given 25 mg intravenously every 4 hours until the bleeding stops or for 24 hours (74). Once bleeding has subsided, patients are placed on 10 mg of oral equine estrogen daily for 21 to 25 days, and oral medroxyprogesterone acetate 10 mg daily with estrogen for the last 7 to 10 days. Once both hormones are withdrawn, the patient will have a heavy withdrawal bleed (61). This intravenous regimen may be used for moderate-to-heavy bleeding adolescents unable to tolerate oral estrogen preparations. Although very rare, deaths have occurred with high-dose intravenous estrogen preparations due to thromboembolic complications.

In a sexually active adolescent, monophasic oral contraceptives may be used to control acute moderate-to-heavy bleeding. Therapy is initiated as one pill twice a day for 5 to 7 days. Therapy is maintained despite cessation of flow within 12 to 24 hours. If flow does not stop, one must rule out other causes (polyps, incomplete abortion, and neoplasia) of continued bleeding. After stopping therapy, patients should anticipate heavy and crampy flow for 2 to 4 days. On the fifth day of flow or on the following Sunday, a low-dose combination oral contraceptive medication (one pill a day) is started. This will be repeated for several 3-week treatments (usually three), followed by 1-week withdrawal flow intervals (75). Once the acute episode of bleeding has been controlled, patients need to be followed closely. With anovulatory bleeding, unopposed estrogen can cause endometrial hyperplasia and continual bouts of recurrent bleeding. As we know, young women in their twenties can develop endometrial adenocarcinoma (76). A periodic withdrawal bleed with oral contraceptives in patients needing contraception or with a progestin regimen is mandatory.

Patients who are clinically hypovolemic with low hemoglobins and active bleeding need to be hospitalized and observed. Complete laboratory evaluation should be initiated, including a workup for blood dyscrasias. Hormonal or even surgical treatments may be needed to stop bleeding. Transfusion is reserved for hypovolemic and unstable patients.

Other important measures in the management of uterine bleeding may be beneficial, such as correction of significant abnormalities in coagulation factors when feasible, the use of antinauseants to improve toleration of high-dose hormonal therapies, and the use of antibiotics when prolonged bleeding, moderate-to-severe dysmenorrhea, or a tender uterus is noted. Chronic endometritis may present with menorrhagia (77), and an ascending secondary infection may occur in heavy prolonged bleeding, resulting in the loss of local homeostatic mechanisms in an inflamed or infected endometrium.

Dilatation and curettage rarely are required in the adolescent and should be performed only after failure of hormonal therapies either acutely or after longer-term treatments, or when a high index of suspicion for an organic cause exists. When curettage is to be performed to identify or exclude a suspected intrauterine lesion, hysteroscopy will offer a higher sensitivity than curettage for the identification of intrauterine pathology (78). Transvaginal sonohysterography can identify polyps and submucous myomas, both of which can cause abnormal bleeding.
Long-term suppression of menses may be advantageous in the adolescent who has moderate-to-severe anemia because of heavy bleeding due to blood dyscrasia, chronic illness, or DUB. Danazol 200 to 800 mg daily has been effective in producing an atrophic endometrium and an amenorrheic state (77). However, the cost and the androgenic side effects frequently limit its use. GnRH agonists have become available to the clinician. They produce a reversible hypoestrogenic state and amenorrhea in most individuals. Hot flushes occur in most individuals but can be alleviated with noerthindrone acetate 2.5 mg (half of a 5-mg tablet) daily. Because of loss of calcium from bone, use of GnRH agonists presently is limited to 6 months. Norethindrone acetate 5 mg daily (half tablet, b.i.d.) also may be used to achieve long-term suppression of uterine bleeding.

The intramuscular depot form of MPA may produce prolonged suppression of the HPO axis; therefore, it should only be used in limited situations in the adolescent, such as mentally retarded or chronically ill individuals with problematic bleeding. This approach generally produces amenorrhea, overcomes any compliance or absorption problems of oral preparations, and provides contraception. Initially, 100 to 150 mg of depot MPA is given intramuscularly on a weekly basis for a month; then monthly for 3 to 4 months; and finally every 2 to 4 months as required to suppress uterine bleeding completely.

There is no single method or approach that will control problematic bleeding in every adolescent. Consequently, to achieve optimal results, thoroughness in evaluating the numerous causes, development of a comprehensive, individualized therapeutic plan, and close surveillance of the responses to treatment are required. Nevertheless, the health care provider should remember the importance of being informative, caring, and supportive to the adolescent and her parents during this often frightening and frustrating process.

Spencer S. Richlin and John A. Rock
Pediatric and Adolescent Gynecology 2nd Ed (August 2000): By Sue Ellen K Carpenter MD, John A Rock MD By Lippincott Williams & Wilkins Publishers