Version May 2024
INTRODUCTION — Menstrual disorders and abnormal uterine bleeding (AUB) are among the most frequent gynecologic complaints in adolescents. AUB refers to bleeding that is excessive or occurs outside of normal cyclic menstruation [1]. AUB is described by a variety of terms and may be caused by a number of genital and nongenital tract diseases, systemic disorders, and medications (table 1). (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)
Anovulatory uterine bleeding is the primary cause of AUB in adolescents and generally resolves with maturation of the hypothalamic-pituitary-ovarian axis.
The management of AUB in otherwise healthy adolescents is the focus of this topic review. The management of AUB in adolescents who have chronic disease, have underlying coagulation disorders, or are undergoing chemotherapy or solid organ or hematopoietic stem cell transplantation is beyond the scope of this topic review. Such patients should be managed in conjunction with the appropriate subspecialist. As an example, (see "Management of menorrhagia during chemotherapy").
The normal menstrual cycle, the evaluation of AUB in adolescents, and the evaluation and management of causes of AUB other than anovulatory uterine bleeding in premenopausal women are discussed separately:
●(See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)
●(See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)
TERMINOLOGY AND ETIOLOGY
●AUB refers to bleeding that is excessive or occurs outside of normal cyclic menstruation in the absence of hormonal therapy [1,2]. AUB has multiple causes (table 1).
●Anovulatory uterine bleeding refers to noncyclic menstrual blood flow that results from anovulatory production of sex steroids [1]. Immaturity of the hypothalamic-pituitary-ovarian axis is the most common cause of anovulatory uterine bleeding in adolescents and is expected for the first one to two years after menarche [2,3]. Other causes include systemic illness and neoplasms, medications, sudden weight loss, and intense exercise (particularly if associated with food restriction and weight loss) (table 1). (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations" and "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Anovulatory uterine bleeding'.)
SEVERITY CLASSIFICATION — The treatment of anovulatory uterine bleeding varies with severity, which is classified as follows:
●Mild – Longer than normal menses (>7 days) or shortened cycles (<24 days) for ≥2 months, with slightly or moderately increased menstrual flow; hemoglobin is usually normal (≥12 g/dL) but may be mildly decreased (10 to 12 g/dL) [4] (see "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Terminology')
●Moderate – Moderately prolonged (eg, >7 days) or frequent menses every one to three weeks, with moderate to heavy menstrual flow and hemoglobin ≥10 g/dL [3,4]
●Severe – Disruptive menstrual cycles with heavy bleeding that causes a decrease in hemoglobin (to <10 g/dL) and may or may not cause hemodynamic instability [3,4]
GOALS OF MANAGEMENT — The goals of management of anovulatory uterine bleeding include [3,5]:
●Establishment and/or maintenance of hemodynamic stability
●Correction of acute or chronic anemia
●Return to a pattern of normal menstrual cycles
●Prevention of recurrence
●Prevention of long-term consequences of anovulation (eg, anemia, infertility, endometrial cancer)
GENERAL PRINCIPLES
Pretreatment evaluation — It is important to exclude pregnancy and pelvic infections before initiating treatment of anovulatory uterine bleeding [3]. In addition, causes of AUB and anovulatory uterine bleeding other than an immature hypothalamic-pituitary-ovarian axis (table 1) should be evaluated as indicated based upon clinical findings. The necessary laboratory studies should be obtained before initiation of hormone therapy or blood transfusion.
Appropriate management of underlying causes of AUB may prevent potential short- and long-term sequelae such as anemia and endometrial cancer, respectively [2,6]. Thus, it is crucial to establish the correct diagnosis before any therapy is administered. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis".)
Appropriate treatment of the underlying problem usually permits return to a normal menstrual pattern. The treatment for the various conditions associated with AUB or anovulatory uterine bleeding is discussed in specific topic reviews. For example, (see "Treatment of polycystic ovary syndrome in adolescents" and "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis').
Management of iron deficiency — Patients with anovulatory uterine bleeding are at risk for iron deficiency anemia and should be monitored and treated as indicated [7]. (See "Iron requirements and iron deficiency in adolescents", section on 'Screening'.)
●For those with mild or moderate anovulatory uterine bleeding and mild, asymptomatic anemia (eg, hemoglobin 10 to 12 g/dL), we initiate iron supplementation with 60 mg elemental iron per day. (See "Iron requirements and iron deficiency in adolescents", section on 'Management'.)
●For those with severe anovulatory uterine bleeding, we initiate iron supplementation as soon as the patient is stable and able to take pills by mouth. Depending upon the severity of iron deficiency, we use 60 mg of elemental iron once or twice per day.
Hormone effects — In adolescents with anovulatory uterine bleeding and sustained acyclic estrogen secretion, bleeding occurs when the endometrium proliferates beyond the ability of endogenous estrogen to maintain the integrity of the endometrium. Administration of exogenous estrogen permits additional endometrial proliferation which heals the sites of endometrial bleeding, and provides hemostasis [3,8,9]. Administration of progestin stabilizes the endometrial lining [3].
Clinicians may be concerned that the high doses of estrogen that are sometimes necessary to control severe AUB may cause premature closure of the growth plates, reducing ultimate adult height. However, by the time of menarche, most female adolescents have already undergone their growth spurt (figure 1) and achieved approximately ≥95 percent of adult height. Oral contraceptive therapy has not been associated with reductions in expected height. (See "Normal puberty", section on 'Growth spurt'.)
The risks and side effects of hormonal contraception are discussed separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns" and "Contraception: Issues specific to adolescents", section on 'Pill, patch, or ring'.)
Monitoring response — Adolescents who are being treated for anovulatory uterine bleeding should maintain a menstrual calendar (figure 2) to monitor response to therapy and subsequent episodes of anovulatory uterine bleeding [10]. Several smart phone applications, or "apps," available at no cost, may facilitate recording and may be preferred by young teens over paper charting [11]. A list of accurate "apps" that are available at no cost is available in the full text of reference [12]. "Apps" developed for tracking menstrual flow generally should not be used as the primary (or only) means to prevent pregnancy.
ACUTE MANAGEMENT OF MILD ANOVULATORY UTERINE BLEEDING — Mild anovulatory uterine bleeding is characterized by longer-than-normal menses or shortened cycles for ≥2 months, with slightly to moderately increased flow [4]. Hemoglobin is usually normal (≥12 g/dL) but may be mildly decreased (eg, 10 to 12 g/dL). Decisions regarding management of mild anovulatory bleeding are individualized according to the preferences of the patient and guardian and the need for contraception [13,14].
●For those with mild anovulatory uterine bleeding, normal hemoglobin, and no desire for contraception who report that their quality of life is not affected by bleeding, we suggest observation and reassurance.
●For those with mild anovulatory uterine bleeding and hemoglobin between 10 and 12 g/dL, observation and reassurance or hormonal therapy to stabilize endometrial proliferation and promote cyclic shedding are both acceptable options. The hormonal therapy regimens for mild anovulatory uterine bleeding are the same as for moderate anovulatory uterine bleeding. (See 'Acute management of moderate anovulatory uterine bleeding' below.)
We also recommend iron supplementation for patients with mild anovulatory uterine bleeding and hemoglobin between 10 and 12 g/dL. (See 'Management of iron deficiency' above.)
Patients with mild anovulatory uterine bleeding should keep a menstrual calendar (paper (figure 2) or mobile phone "app" version [11]). (See 'Monitoring response' above.)
They should follow up in three to six months [15] unless bleeding becomes more severe or prolonged, in which case they should be seen acutely. We obtain a complete blood count in patients whose initial hemoglobin was <12 g/dL. (See 'Long-term management' below and 'Acute management of moderate anovulatory uterine bleeding' below and 'Acute management of severe anovulatory uterine bleeding' below.)
ACUTE MANAGEMENT OF MODERATE ANOVULATORY UTERINE BLEEDING — Moderate anovulatory uterine bleeding is characterized by moderately prolonged (eg, >7 days) or frequent menses every one to three weeks, with moderate to heavy menstrual flow and hemoglobin ≥10 g/dL [3,14].
Moderate anovulatory uterine bleeding usually can be managed in the outpatient setting. Treatment typically involves hormonal therapy to stabilize endometrial proliferation and shedding. The hormonal therapy regimen depends upon whether the patient is currently bleeding [8]. A 2012 systematic review found no relevant randomized trials evaluating progestin-only or combined estrogen-progestin therapy in the treatment of anovulatory uterine bleeding and no consensus about the optimal approach [16]. The dose of estrogen, dose and type of progestin, and schedule of administration vary widely.
Most adolescents with anovulatory uterine bleeding respond to hormonal therapy [17,18]. Among those who do not, an alternative diagnosis (eg, bleeding disorder, polycystic ovary syndrome, infection, uterine pathology) should be considered. Additional evaluation and consultation may be warranted if bleeding cannot be controlled despite hormonal therapy [8]. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Approach to diagnosis'.)
Patients with moderate anovulatory uterine bleeding often have mild anemia (hemoglobin 10 to 12 g/dL), which should be treated with iron supplementation [4]. (See 'Management of iron deficiency' above and "Iron requirements and iron deficiency in adolescents", section on 'Management'.)
Not currently bleeding — Decisions regarding management of moderate anovulatory bleeding in patients who are not currently bleeding are individualized according to the preferences of the patient and guardian and the need for contraception. For patients with moderate anovulatory uterine bleeding who are not actively bleeding, we suggest either progestin-only hormone therapy or combined estrogen-progestin oral contraceptives.
●Progestin/progesterone-only regimen – Among the oral progestin-only regimens for patients with moderate to severe anovulatory bleeding who are not actively bleeding (table 2), we suggest a maintenance regimen of either:
•Norethindrone acetate 5 mg orally nightly for the first 5 to 10 days of each calendar month, or
•Oral micronized progesterone 200 mg nightly for the first 12 days of each calendar month, or
•Medroxyprogesterone acetate 10 mg orally nightly for the first 10 days of each calendar month
Norethindrone helps to stabilize the endometrium and, in our experience, is usually rapidly effective. Oral micronized progesterone is chemically identical to endogenous progesterone for those patients who prefer a more bioidentical approach. Medroxyprogesterone is another commonly used option based on patient insurance coverage. Scheduling the pills to start on the first day of each calendar month is easy for teenagers to follow.
We warn patients that irregular spotting is common initially, but, if heavy vaginal bleeding occurs while the patient is taking progesterone, they should see their provider to discuss whether oral progestin is the optimal regimen.
●Combination estrogen-progestin regimen – For patients who are not actively bleeding and choose combination estrogen-progestin therapy, we suggest monophasic oral contraceptives (ie, pills that contain the same dose of estrogen and progestin in each of the hormonally active pills) with a minimum of 30 mcg ethinyl estradiol (table 3) to ensure a sufficient amount of estrogen to prevent breakthrough bleeding [1].
We generally initiate combination estrogen-progestin oral contraceptives according to the usual schedule (ie, one pill per day, including the pills that do not contain hormones). (See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use", section on 'Administration and use'.)
Currently bleeding — For patients with moderate anovulatory uterine bleeding who are actively bleeding, we suggest combined estrogen-progestin oral contraceptives rather than progestin-only hormone therapy because estrogen provides hemostasis. (See 'Hormone effects' above.)
Progestin-only therapy is an alternative for patients who cannot tolerate, dislike, or have a contraindication to estrogen therapy (eg, migraine with aura, systemic lupus erythematosus, arterial or venous thromboembolic disease, estrogen-dependent tumors, and hepatic dysfunction or disease [19]) or who object to taking combination oral contraceptives.
Treatment with tranexamic acid may be an option for patients with moderate anovulatory bleeding who are currently bleeding and decline hormonal options.
●Combination estrogen-progestin regimen – For combined estrogen-progestin therapy in patients with moderate to severe anovulatory bleeding, we suggest monophasic oral contraceptives (ie, pills that contain the same dose of estrogen and progestin in each of the hormonally active pills) with a minimum of 30 mcg ethinyl estradiol (table 3) to ensure a sufficient amount of estrogen to prevent breakthrough bleeding [1]. The benefits and risks of estrogen-progestin contraceptives are discussed separately. (See 'Hormone effects' above and "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use" and "Combined estrogen-progestin contraception: Side effects and health concerns".)
Randomized trials regarding the treatment of anovulatory uterine bleeding in adolescents are lacking [16]. However, in a systematic review of randomized trials in adult women with AUB presumed to be secondary to endometrial dysfunction, a variety of combined estrogen-progestin contraceptive regimens appeared to be equally effective (with 35 to 65 percent reductions in menstrual blood loss) [9,20].
For patients who are actively bleeding, we use the following regimen (the pills that do not contain hormones should be discarded):
•One pill every eight hours until the bleeding stops (usually within 48 hours [8]), then
•One pill every 12 hours for 2 days, then
•One pill once per day for a total of at least 21 days
Alternative tapering regimens are described in the literature [3,21-25].
Close follow-up (in person or by phone) is essential while the pills are being taken two or three times per day. High-dose estrogen therapy can cause nausea, which may result in decreased adherence. If nausea occurs, we suggest antiemetic therapy (eg, promethazine 12.5 to 25 mg orally or per rectum or ondansetron 4 to 8 mg orally) before each combination estrogen-progestin pill [3].
The patient and parent or guardian should be instructed to call the provider if the patient has an increase in or continued heavy vaginal bleeding during the taper or once the taper is complete and the patient is taking one pill per day. Management of breakthrough bleeding following the taper is individualized. If the patient is hemodynamically stable, some clinicians discontinue hormones for at least three days to permit shedding of the potentially excessively proliferated/dyssynchronous endometrium. However, the possibility that the withdrawal bleed may be very heavy must be weighed against the risk of irregular vaginal bleeding if hormones are not discontinued. Another option, particularly for patients with anemia, is to revert to twice per day dosing, which may be necessary for the full 21 days. Once anemia resolves, allowing a menses in a controlled fashion (ie, by discontinuing hormones for at least three days) is optimal to prevent irregular vaginal bleeding.
Management of hormonal therapy after the initial 21-day course is discussed below. (See 'Long-term management' below.)
●Progestin-only regimen – In patients with mild-to-moderate anovulatory uterine bleeding, progestin-only therapy may be used to mature and slough the endometrium [23,26-28]. (See 'Hormone effects' above.)
Among the oral progestin-only regimens for acute management (table 2), we suggest norethindrone acetate. Norethindrone provides enough estrogenic activity to minimize side effects but not enough to stimulate endometrial bleeding.
We instruct patients to take norethindrone 5 to 10 mg nightly until the bleeding stops and the anemia is resolved. We warn patients that irregular spotting is common initially, but, if heavy vaginal bleeding occurs while the patient is taking progesterone, they should see their provider to discuss whether oral progestin is the optimal regimen.
Once anemia has resolved, the initial course of oral progestin should be followed by at least five to seven days of no hormonal therapy to permit shedding of the endometrium.
Management of hormonal therapy following the hormone-free period and the schedule of follow-up are discussed below. (See 'Long-term management' below.)
●Tranexamic acid – Treatment with cyclic tranexamic acid may be an option for patients with moderate anovulatory bleeding who are currently bleeding and decline hormonal options [21]. The regimen is 1300 mg orally up to three times per day for the first one to five days of each menstrual cycle. It is uncertain how long adolescents with heavy menstrual bleeding should be treated with cyclic tranexamic acid. We ask patients to follow up in one to three months to monitor hemoglobin. A switch to hormonal therapy may be warranted if hemoglobin continues to decline or fails to stabilize.
Cyclic tranexamic acid does not regulate menstrual cycles. However, in a small pilot study, it appeared to be as effective in reducing menstrual blood loss and improving quality of life as combined estrogen-progestin in adolescents with heavy menstrual bleeding [29]. A network meta-analysis of studies of interventions for heavy menstrual bleeding found moderate quality evidence that antifibrinolytics probably reduce menstrual blood loss [30].
ACUTE MANAGEMENT OF SEVERE ANOVULATORY UTERINE BLEEDING — Severe anovulatory uterine bleeding is defined by disruptive menstrual cycles with heavy bleeding that causes a decrease in hemoglobin (to <10 g/dL) with or without hemodynamic instability [3,4]. Control of severe anovulatory uterine bleeding may involve hormonal therapy, hemostatic agents, and (rarely) surgical intervention.
We initiate iron supplementation as soon as the patient is stable and able to take pills by mouth. Depending upon the severity of iron deficiency, we use 60 mg of elemental iron once or twice per day. (See "Iron requirements and iron deficiency in adolescents", section on 'Management'.)
Indications for hospitalization — Indications for hospitalization include [3,7,13,26]:
●Hemodynamic instability (eg, tachycardia, hypotension, orthostatic vital signs)
The need for blood transfusion is assessed on a case-by-case basis, depending upon the hemoglobin, blood loss, orthostatic vital signs, and the ability to rapidly gain control of hemodynamic stability and bleeding through prompt administration of intravenous (IV) fluid, plasma expanders, and hormonal therapy [3,4,7]. (See "Approach to the adult with vaginal bleeding in the emergency department", section on 'Determine hemodynamic status'.)
●Hemoglobin concentration <7 g/dL or <10 g/dL with active heavy bleeding
Home management with daily monitoring may be possible for patients with hemoglobin between 8 and 10 g/dL if the patient is hemodynamically stable, able to take a regimen of hormones that can stop the bleeding, and the patient and caregivers are reliable and can maintain close telephone contact. Home management with hormonal therapy is described below. (See 'Hormonal therapy' below.)
●Symptomatic anemia (eg, fatigue, lethargy)
●Need for intravenous conjugated estrogen (eg, cannot take oral medications, continued heavy bleeding after 24 hours of estrogen-progestin combination therapy) (see 'Intravenous estrogen' below and 'Combination therapy' below)
●Need for surgical intervention; patients who may require surgery should be treated with intravenous therapy and maintained "nil per os" (see 'Refractory uterine bleeding' below)
The patient may be discharged to home when the bleeding has stopped and they are hemodynamically stable. Close follow-up must be maintained after discharge. (See 'Long-term management' below.)
Additional evaluation — Patients who require hospitalization for anovulatory uterine bleeding should undergo evaluation for a bleeding disorder and may warrant pelvic ultrasonography to evaluate pelvic pathology (eg, polyps, ovarian tumors), particularly if they do not respond to initial therapy [7]. Any underlying disorder that is detected should be promptly treated. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Bleeding disorders'.)
Additionally, heavy menstrual bleeding requiring hospitalization or transfusion may be the initial presentation of a coagulation disorder, particularly von Willebrand disease. It is estimated that up to 20 percent of adolescents with heavy menstrual bleeding have von Willebrand disease or platelet dysfunction [31,32]. (See "von Willebrand disease (VWD): Gynecologic and obstetric considerations", section on 'Heavy menstrual bleeding'.)
The laboratory evaluation for patients who require hospitalization for heavy menstrual bleeding generally includes screening for pregnancy, hypothyroidism (with thyroid stimulating hormone), a complete blood count (to include a platelet count), prothrombin time, activated partial thromboplastin time, plasma von Willebrand factor (VWF) antigen, plasma VWF activity (ristocetin cofactor activity), factor VIII activity, and blood group typing [33]. Of note, blood group O is associated with lower levels of VWF. Evaluation in conjunction with a hematologist is suggested, especially if there is a concern that requires testing for additional bleeding disorders. Blood samples for laboratory evaluation of bleeding disorders should be obtained before administration of blood products or estrogen (exogenous estrogen may elevate VWF into the normal range) [17,34]. Repeat testing and/or consultation with a hematologist may be necessary to establish the diagnosis [34]. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Causes of heavy menstrual bleeding' and "Approach to the child with bleeding symptoms" and "Clinical presentation and diagnosis of von Willebrand disease".)
Hormonal therapy — We suggest hormonal therapy as the initial intervention for patients with severe anovulatory uterine bleeding, whether they are hospitalized or treated as outpatients. The addition of hemostatic agents may be warranted if bleeding is not controlled within 24 to 48 hours of hormonal therapy alone. If bleeding is not controlled after the addition of hemostatic agents, surgical intervention (eg, dilation and curettage or uterine vacuum aspiration) may be indicated but is considered a last resort in adolescents. (See 'Addition of hemostatic therapy' below and 'Refractory uterine bleeding' below.)
Combination therapy — Combination oral contraceptive pills are the first-line hormonal therapy for the acute management of severe anovulatory uterine bleeding. Progestin-only therapy and IV conjugated estrogen are potential alternatives for patients who cannot take combination oral contraceptive pills. (See 'Progestin-only pills' below and 'Intravenous estrogen' below.)
In adolescents who have severe anovulatory bleeding and anemia or who are at risk for anemia, the author of this topic review suggests starting with a monophasic combination oral contraceptive pill with a higher dose of estrogen (ie, 50 mcg ethinyl estradiol, which is equivalent to the dose in intravenous estrogen) and either 0.5 mg norgestrel or 1 mg norethindrone (table 3) to promote control of bleeding as soon as possible; she suggests tapering according to the regimen below.
●One pill every four to six hours until the bleeding subsides (usually within 24 hours), then
●One pill every eight hours for three days, then
●One pill every 12 hours for up to two weeks, then one pill once per day. Once the patient is weaned to one pill per day and their anemia has resolved, they should be allowed to have a withdrawal bleed (ie, by discontinuing hormones for at least three days).
The adolescent must be instructed to discard the pills that do not contain hormones. Antiemetic therapy (eg, promethazine 12.5 to 25 mg orally or per rectum or ondansetron 4 to 8 mg orally) may be required for patients who are taking more than one pill per day.
Other experts may use the regimen described above with combination oral contraceptive pills with 30 or 35 mcg ethinyl estradiol and/or a different tapering schedule [3,21-25]. Regardless of the schedule, if bleeding recurs during tapering, we temporarily increase the total daily dose to the lowest dose that controls bleeding [8].
Close follow-up (in person or by phone) is essential. High-dose estrogen therapy can cause nausea, which may result in decreased adherence [3]. Additional adverse effects and risks of with estrogen-progestin contraceptives are discussed separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)
Management of hormonal therapy after the initial tapering and the schedule of follow-up are discussed below. (See 'Long-term management' below.)
Progestin-only pills — Oral progestin-only therapy is an alternative to combination oral contraceptive pills in the acute management of patients with severe anovulatory bleeding in whom estrogen is contraindicated (eg, migraine with aura, systemic lupus erythematosus, arterial or venous thromboembolic disease, estrogen-dependent tumors, and hepatic dysfunction or disease) or who refuse to take combination oral contraceptives [19,23,26,27].
Among the oral progestin-only alternatives (table 2), we suggest norethindrone for acute bleeding. Norethindrone provides enough estrogenic activity to minimize side effects but not enough to stimulate endometrial bleeding. Norethindrone 5 to 10 mg can be given up to four times a day based on the severity of the patient's bleeding. Once bleeding has stopped, it can be tapered over several days. Two commonly used tapering regimens are provided below [27]:
●Norethindrone 5 to 10 mg twice per day for seven days, followed by 5 to 10 mg once per day until maintenance therapy is initiated (see 'Maintenance therapy' below)
●Norethindrone 5 to 10 mg three times per day for three days, followed by 5 to 10 mg twice per day for seven days, followed by 5 to 10 mg once per day until maintenance therapy is initiated (see 'Maintenance therapy' below)
Management of hormonal therapy once bleeding is controlled and the schedule of follow-up are discussed below. (See 'Long-term management' below.)
Intravenous estrogen — IV conjugated estrogen therapy is reserved for patients with severe anovulatory uterine bleeding who are unstable and cannot take oral medications [3]. In addition, IV conjugated estrogen therapy may be indicated if bleeding is not controlled after 24 hours of combination hormonal therapy.
The dose of IV conjugated estrogen is 25 mg every four to six hours until the bleeding stops. No more than six doses should be administered. Thromboembolism is a potential complication [35]. For additional information about adverse effects of conjugated estrogen, refer to the Lexicomp drug information monograph for conjugated equine estrogens included within UpToDate.
Administration of antiemetics (eg, promethazine 12.5 to 25 mg orally, transdermally [not available in the United States], IV, or per rectum) one hour before each dose of IV estrogen may alleviate the side effects of nausea and vomiting.
Bleeding usually subsides within 4 to 24 hours of the initiation of IV estrogen [26]. Hemostatic therapy may be warranted if bleeding persists beyond 24 hours [8]. If bleeding lasts longer than 24 to 48 hours after initiation of IV estrogen, oral progesterone should be added to stabilize the endometrium (table 2); oral progesterone should be discontinued when oral contraceptive pills are initiated [3,15]. (See 'Addition of hemostatic therapy' below.)
After the bleeding subsides, the patient should be switched to a taper of combination monophasic oral contraceptive. We use a monophasic oral contraceptive that contains at least 50 mcg estradiol (table 3) and suggest the following schedule:
●One pill every four to six hours until the bleeding stops
●One pill every eight hours for three days, then
●One pill every 12 hours for two weeks
Multiple alternative tapering regimens are described in the literature [3,22-24].
Antiemetic therapy (eg, promethazine 12.5 to 25 mg orally or per rectum or ondansetron 4 to 8 mg orally) may be required for patients who are taking more than one pill per day. As long as hemostasis is maintained, the treatment regimen may be altered as necessary to prevent side effects and accommodate the needs and wishes of the patient.
Management of hormonal therapy after the initial tapering and the schedule of follow-up are discussed below. (See 'Long-term management' below.)
The effectiveness of IV estrogen was demonstrated in a randomized trial in which 34 patients with anovulatory uterine bleeding were assigned to treatment with conjugated equine estrogen 25 mg IV every four hours for up to 24 hours or placebo [36]. IV conjugated estrogen treatment successfully controlled bleeding in 72 percent of patients compared with 38 percent of those given placebo. In most cases, bleeding diminished within three hours of initiating hormone therapy.
Addition of hemostatic therapy — The addition of hemostatic therapy to hormonal therapy may be warranted for severe anovulatory uterine bleeding that continues after 24 hours of hormonal therapy and in patients with platelet dysfunction [37].
Hemostatic therapies include tranexamic acid, aminocaproic acid, and desmopressin, which is classically used for the treatment of von Willebrand disease [7,20,38-41]. Among these agents, we prefer tranexamic acid unless the patient has increased risks for thromboembolism [42]. Aminocaproic acid should be avoided in patients with renal impairment.
●Tranexamic acid is administered orally: 1300 mg three times per day for up to five days
●Aminocaproic acid may be administered orally or IV as follows:
•Aminocaproic acid 5 g orally during the first hour, followed by a continuous dose of 1 to 1.25 g per hour; treatment is continued for approximately eight hours or until the bleeding has been controlled, or
•Aminocaproic acid 4 to 5 g IV during the first hour of treatment, followed by a continuous infusion at a rate of 1 g per hour; treatment is continued for approximately eight hours or until the bleeding has been controlled
●Desmopressin is administered IV as follows:
•Desmopressin 0.3 mcg/kg IV over 15 to 30 minutes; the dose may be repeated in 48 hours if there is no response
Refractory uterine bleeding — In the rare cases in which treatment with hormones and antifibrinolytics agents fails, additional evaluation (examination under anesthesia, endometrial sampling) may be necessary to assess causes of AUB other than anovulatory uterine bleeding.
Dilation and curettage (D&C) also may be used as a therapeutic intervention. However, therapeutic D&C is rarely required in adolescents with AUB. It should be reserved as a last resort for the rare patient who continues to have life-threatening bleeding despite other therapies [43]. If D&C is performed in adolescents, care must be taken to prevent scarring of the endometrial lining (Asherman syndrome). (See "Intrauterine adhesions: Clinical manifestation and diagnosis", section on 'Etiology and risk factors' and "Dilation and curettage", section on 'Therapeutic indications'.)
LONG-TERM MANAGEMENT
Maintenance therapy — Management after the acute episode of bleeding is controlled and the initial course of hormonal therapy is complete depends upon the initial hormonal regimen, the patient's desire for contraception, and whether they remain anemic.
Oral regimens for maintenance therapy are described below. The levonorgestrel-releasing intrauterine device (LNG IUD) and depomedroxyprogesterone acetate (DMPA) are additional options for patients who desire contraception or are unable to take pills effectively [30,44]. In observational studies, the LNG IUD was associated with improvement in heavy menstrual bleeding and anemia in adolescents with heavy menstrual bleeding and bleeding disorders [45-47]. In an electronic survey, almost all of 312 respondents considered the LNG IUD to be safe and effective for adolescents with heavy menstrual bleeding in adolescents [48]. As with most progesterone-only hormonal contraceptives, these longer-term methods may be associated with regular unpredictable bleeding for up to six months and sometimes longer. They are discussed separately. (See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration" and "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUD'.)
Initial control with estrogen-containing regimen — For patients with anovulatory uterine bleeding that was initially controlled with an estrogen-containing regimen, we suggest the oral contraceptive regimens below as general guidelines. Adjustments may be necessary to increase effectiveness and/or the adolescent's tolerance.
●Hemoglobin <10 g/dL – For patients whose acute bleeding was controlled with an estrogen-containing regimen (intravenous or oral) and whose hemoglobin remains <10 g/dL, the author of this topic review suggests monophasic combination oral contraceptive pills with at least 50 mcg ethinyl estradiol (table 3) once per day continuously (to avoid withdrawal menses) for at least three months (until the hemoglobin is ≥10 g/dL) [3,8]. Other experts may use different regimens (eg, combination oral contraceptive pills with 30 to 35 mcg ethyl estradiol) [22]. During continuous oral contraceptive therapy, it may be helpful to prescribe 21-day packages or to remove the placebo (nonhormone-containing) pills from 28-day packages so the adolescent does not inadvertently take hormone-free pills [8]. We monitor hemoglobin monthly until it is ≥10 g/dL and then every three to six months until it is >12 g/dL.
Patients should be counseled that breakthrough bleeding is common during the first three months of continuous hormonal therapy and possibly longer. Maintenance of an accurate menstrual calendar will guide therapy.
The author of this topic review suggests that continuous oral contraceptive therapy be followed by cyclic therapy (ie, 21 days of hormone-containing pills, followed by three to seven days of placebo [nonhormone-containing] pills or no pills to induce withdrawal bleeding) with oral contraceptive pills with 30 to 50 mcg ethinyl estradiol to complete a total of six months. Other experts may use different regimens [22]. When the adolescent begins cyclic therapy, they should understand that withdrawal bleeding typically begins two to four days after the last hormone-containing pills are taken and that menstrual flow during the initial withdrawal period may be heavier than normal but should not last longer than seven days [3,8].
Hormonal therapy with combination oral contraceptive pills can be discontinued after six months if anemia has resolved to determine whether a normal menstrual pattern has been established [49]. However, combination oral contraceptive pills may be continued in sexually active adolescents and adolescents who wish to continue. (See 'Follow-up schedule' below.)
A menstrual calendar (paper (figure 2) or mobile phone "app" version [11]) should be maintained to monitor subsequent episodes of anovulatory uterine bleeding. Such a calendar, if appropriately highlighted, can serve to remind patients on which days to take their medication. (See 'Monitoring response' above.)
●Hemoglobin ≥10 g/dL – For patients whose acute bleeding was controlled with an estrogen-containing regimen and whose hemoglobin remains is ≥10 g/dL, we suggest monophasic combination oral contraceptive pills with at least 30 mcg ethinyl estradiol be continued cyclically (ie, 21 days of hormone-containing pills, followed by three to seven days of placebo [nonhormone-containing] pills or no pills to induce withdrawal bleeding) for three to six months. We monitor hemoglobin every three to six months until it is >12 g/dL.
Hormonal therapy with combination oral contraceptive pills can be discontinued after three to six months to determine whether a normal menstrual pattern has been established [49]. However, combination oral contraceptive pills may be continued in sexually active adolescents and adolescents who wish to continue. (See 'Follow-up schedule' below.)
A menstrual calendar (paper (figure 2) or mobile "app" version [11]) should be maintained to monitor subsequent episodes of anovulatory uterine bleeding. Such a calendar, if appropriately highlighted, can serve to remind patients on which days to take their medication. (See 'Monitoring response' above.)
Initial control with oral progestin
●Patients who do not desire contraception – For patients with moderate to severe anovulatory uterine bleeding who were initially controlled with oral progestin-only regimens and do not desire contraception, we suggest continuation of an intermittent oral progestin-only regimen for at least six months after bleeding is controlled, after which hormonal therapy can be discontinued to determine whether a normal menstrual pattern has been established [49]. (See 'Long-term monitoring' below.)
Progestin-only regimens for maintenance therapy in patients who do not desire contraception include cyclic (ie, intermittent) norethindrone, oral micronized progesterone, or medroxyprogesterone (table 2).
Among cyclic oral progestin-only regimens, we prefer either:
•Norethindrone 5 mg orally each night for the first 5 to 10 days of each calendar month, or
•Oral micronized progesterone 200 mg each night for the first 12 days of each calendar month
Norethindrone helps to stabilize the endometrium and, in our experience, is usually rapidly effective. Oral micronized progesterone is chemically identical to endogenous progesterone. Scheduling the pills on the first 5 to 12 days of the calendar month is easy for teenagers to follow.
With cyclic progesterone, bleeding usually begins two to three days after the last dose of progestin but may be delayed for up to one week. If bleeding occurs while the patient is taking maintenance progesterone, they should discontinue progesterone and allow menses to occur. (See 'Monitoring response' above.)
If the patient does not have menses within one week after the last dose of progesterone, exogenous hormones should be discontinued and the patient should return for follow-up and urine pregnancy test. If the pregnancy test is negative, an endocrinology evaluation is initiated. The evaluation typically includes follicle-stimulating hormone, luteinizing hormone, prolactin, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, free and total testosterone, thyroid-stimulating hormone, and fasting insulin and glucose to evaluate potential disorders of the hypothalamic-pituitary-ovarian axis and polycystic ovary syndrome (PCOS). (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
A menstrual calendar (paper (figure 2) or mobile "app" version [11]) should be maintained to monitor subsequent episodes of anovulatory uterine bleeding. Such a calendar, if appropriately highlighted, can serve to remind patients on which days to take their medication. (See 'Monitoring response' above.)
Adolescents being treated with cyclic oral progesterone should understand that it is not a method of contraception. If they become sexually active and desire contraception they will need to switch to a hormonal therapy that controls anovulatory bleeding and prevents pregnancy. If they have unprotected sexual intercourse while using progestin-only therapy, emergency contraception may be warranted. (See "Contraception: Counseling and selection" and "Emergency contraception" and "Contraception: Issues specific to adolescents", section on 'Choosing a method'.)
●Patients who desire contraception – Progestin-only regimens for patients who desire contraception include depot medroxyprogesterone acetate, progestin implants, and levonorgestrel-releasing IUDs. Continuous progestin-only contraceptive pills are another option but are not our first choice given the need to be extremely consistent with the time of day they are taken daily, which may be difficult for many adolescent patients. (See "Contraception: Progestin-only pills (POPs)" and "Contraception: Issues specific to adolescents", section on 'Choosing a method'.)
A menstrual calendar (paper (figure 2) or mobile "app" version [11]) should be maintained to monitor subsequent episodes of anovulatory uterine bleeding. Such a calendar, if appropriately highlighted, can serve to remind patients on which days to take their medication or schedule their injection (for depot medroxyprogesterone acetate). (See 'Monitoring response' above.)
Follow-up schedule — The frequency of follow-up varies depending upon severity of bleeding, severity of anemia, and type of treatment:
●Patients with mild anovulatory uterine bleeding who initiated hormonal treatment or iron therapy should be followed three months after the initial episode to assess effectiveness of treatments. Patients with mild anovulatory bleeding who were initially managed with observation and reassurance should follow up in three to six months to assess improvement in menstrual patterns and/or need for hormonal therapy.
●Patients with moderate anovulatory uterine bleeding should be seen approximately three months after the initial episode. If bleeding is not improved, hormonal therapy is adjusted, with follow-up every three to six months. Hormonal therapy adjustments may include using a higher dose pill and/or addition of tranexamic acid as necessary. If the reason for the lack of improvement in cycle control is compliance with pill taking, an alternative hormonal treatment may be warranted (eg, DMPA or long-acting reversible contraception options). Once menstrual patterns are stable and treatment regimens established, patients can be seen annually.
●Patients with severe anovulatory uterine bleeding who did not require hospitalization should be seen monthly until menstrual patterns and hormonal treatments are stable and hemoglobin is >10 g/dL.
●Patients with severe bleeding who required hospitalization should be seen two weeks after discharge and then at least monthly until menstrual patterns and hormonal treatments are stable and hemoglobin is >10 g/dL.
If irregular or heavy bleeding persists despite three months of hormone therapy or a normal menstrual pattern is not established after discontinuation of hormonal therapy, an endocrinology evaluation is warranted. The evaluation typically includes follicle-stimulating hormone, luteinizing hormone, prolactin, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, free and total testosterone, thyroid-stimulating hormone, and fasting insulin and glucose to evaluate potential disorders of the hypothalamic-pituitary-ovarian axis and PCOS. In addition, pelvic ultrasonography may be warranted to evaluate pelvic pathology (eg, fibroids, polyps, ovarian tumors). (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
Long-term monitoring — Long-term monitoring and follow-up are necessary to prevent the potential sequelae of anovulatory uterine bleeding (eg, chronic anemia, infertility, endometrial cancer).
Long-term follow-up of patients with a history of anovulatory cycles is essential.
Once hormonal therapy has been discontinued, patients who go more than three months without a period (and are not pregnant) should undergo endocrine evaluation and receive progesterone to induce withdrawal bleeding [15].
●The endocrine evaluation typically includes follicle-stimulating hormone, luteinizing hormone, prolactin, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, free and total testosterone, thyroid-stimulating hormone, and fasting insulin and glucose to evaluate potential disorders of the hypothalamic-pituitary-ovarian axis, PCOS, and the metabolic syndrome. (See "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome in adolescents".)
●To induce withdrawal bleeding, we use oral micronized progesterone 200 mg nightly for 12 days per month. Alternative regimens include medroxyprogesterone 10 mg nightly for 10 to 12 days per month or norethindrone acetate 5 to 10 mg nightly for 10 to 12 days per month.
We instruct the adolescent to induce menses at least every three months or to restart combined hormonal contraception [15].
Chronic anovulation (greater than two to three years in duration) is associated with endometrial hyperplasia and increased risk of endometrial carcinoma [50]. Concomitant obesity promotes peripheral conversion of androgens to estrogens, further enhancing endometrial growth. Endometrial biopsy may be warranted in adolescents who have a history of two to three years of untreated anovulatory bleeding, particularly if they are obese or have a family history of endometrial, ovarian, breast, or colon cancer [22]. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)
PROGNOSIS — Anovulatory uterine bleeding generally resolves with maturation of the hypothalamic-pituitary-ovarian axis. The duration of time that it takes to attain maturity (regular, ovulatory cycles) appears to be related to the age of menarche. In patients who begin menses at <12 years, between 12 and 13 years, and >13 years of age, 50 percent of cycles are ovulatory by one year, three years, and 4.5 years, respectively [51]. However, normal cycle length is not established until the sixth gynecologic year, at an average age of 19 years [52,53]. The long-term prognosis for patients with AUB depends upon the underlying cause [8]. As an example, patients with a long history of anovulatory cycles and anovulatory uterine bleeding, particularly those with polycystic ovary syndrome, have an increased risk of later infertility and endometrial carcinoma [54]. (See "Female infertility: Causes", section on 'Ovulatory disorders' and "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Risk factors'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Abnormal uterine bleeding".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Basics topics (see "Patient education: Absent or irregular periods (The Basics)" and "Patient education: Heavy periods (The Basics)")
●Beyond the Basics topics (see "Patient education: Absent or irregular periods (Beyond the Basics)" and "Patient education: Abnormal uterine bleeding (Beyond the Basics)" and "Patient education: Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: von Willebrand disease".)
SUMMARY AND RECOMMENDATIONS
●Terminology and etiology – Abnormal uterine bleeding (AUB) refers to bleeding that is excessive or occurs outside of normal cyclic menstruation. Anovulatory uterine bleeding refers to noncyclic menstrual blood flow that results from anovulatory production of sex steroids. Immaturity of the hypothalamic-pituitary-ovarian axis is the most common cause of anovulatory uterine bleeding in adolescents. (See 'Terminology and etiology' above.)
●Goals of management – The goals of management of AUB include return to a pattern of normal menstrual cycles and prevention of short- and long-term sequelae (eg, anemia, hemodynamic instability, infertility endometrial cancer). (See 'Goals of management' above.)
●General principles – It is important to exclude pregnancy and pelvic infection before initiating treatment of anovulatory uterine bleeding. Other causes of AUB and anovulatory uterine bleeding should be evaluated as indicated based upon clinical findings (table 1). (See 'Pretreatment evaluation' above.)
Adolescents who are being treated for anovulatory uterine bleeding should maintain a menstrual calendar (paper (figure 2) or mobile "app" version) to monitor response to therapy and subsequent episodes of anovulatory uterine bleeding. Patients with anovulatory uterine bleeding are at risk for iron deficiency anemia and should be monitored and treated as indicated. (See 'Monitoring response' above and 'Management of iron deficiency' above.)
●Acute management – The acute management of anovulatory uterine bleeding depends upon severity, whether the patient is actively bleeding, the preferences of the patient and guardian, and the need for contraception:
•Mild – Mild anovulatory uterine bleeding is characterized by longer-than-normal menses or shortened cycles for more than two months; hemoglobin is usually normal (≥12 g/dL) but may be mildly decreased (10 to 12 g/dL). (See 'Acute management of mild anovulatory uterine bleeding' above.)
-For patients with mild anovulatory uterine bleeding, normal hemoglobin (>12 g/dL), and no desire for contraception who report that their quality of life is not affected by the bleeding, we suggest observation and reassurance rather than hormonal therapy (Grade 2C).
-For patients with mild anovulatory uterine bleeding and hemoglobin between 10 and 12 g/dL, we suggest either observation and reassurance or hormonal therapy to stabilize endometrial proliferation and promote cyclic shedding (Grade 2C).
•Moderate – Moderate anovulatory uterine bleeding is characterized by moderately prolonged or frequent menses every one to three weeks and hemoglobin ≥10 g/dL. Moderate anovulatory uterine bleeding usually can be managed in the outpatient setting. (See 'Acute management of moderate anovulatory uterine bleeding' above.)
-For patients with moderate anovulatory uterine bleeding who are not actively bleeding, we suggest either progestin-only hormone therapy or combined estrogen-progestin oral contraceptives (Grade 2C). (See 'Currently bleeding' above.)
-For patients with moderate anovulatory uterine bleeding who are actively bleeding, we suggest combined estrogen-progestin oral contraceptives rather than progestin-only therapy (Grade 2C). Tranexamic acid may be an alternative for those who prefer to avoid hormonal therapy. (See 'Currently bleeding' above.)
•Severe – Severe anovulatory uterine bleeding is defined by disruptive menstrual cycles with heavy bleeding that causes a decrease in hemoglobin (to <10 g/dL) and may or may not cause hemodynamic instability. (See 'Acute management of severe anovulatory uterine bleeding' above.)
-Indications for hospitalization in patients with severe anovulatory uterine bleeding include hemodynamic instability, hemoglobin concentration <7 g/dL or <10 g/dL with active heavy bleeding, symptomatic anemia, and need for intravenous conjugated estrogen (eg, cannot take oral medications or continued bleeding after 24 hours of estrogen-progestin combination therapy). Patients who require hospitalization for management of anovulatory uterine bleeding should undergo evaluation for a bleeding disorder. (See 'Indications for hospitalization' above.)
-We suggest hormonal therapy as the initial intervention for patients with severe anovulatory uterine bleeding, whether they are hospitalized or treated as outpatients (Grade 2C). Combination oral contraceptive pills are the first-line hormonal therapy for the acute management of severe anovulatory uterine bleeding. (See 'Combination therapy' above.)
●Long-term follow-up – Long-term follow-up is essential. Hormonal treatment should be continued for at least three to six months when possible. Hormonal therapy that has been discontinued can be restarted if heavy menstrual bleeding recurs. Alternatively, patients who go more than three months without a period (and are not pregnant) should undergo an endocrinology workup and receive a course of progesterone to induce withdrawal bleeding. (See 'Long-term management' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate, Inc. acknowledge Dr. Robert Zurawin, who contributed to an earlier version of this topic review.
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