Disordered uterine bleeding

OVERVIEW: What every practitioner needs to know

Are you sure your patient has disordered uterine bleeding? What are the typical findings for this disease?

Disordered uterine bleeding can be used as a very broad term describing uterine bleeding that is irregular, heavy, or otherwise considered problematic. Historically, there is a variety of medical terminology for irregular menses; more recent terminology substitutes abnormal uterine bleeding (AUB) for dysfunctional uterine bleeding (DUB). The most common description of AUB includes some history of irregular, heavy, and/or prolonged menses. AUB is a diagnosis of exclusion having ruled out: genital tract pathology; systemic disease; iatrogenic causes (including contraceptive hormones).

The most common causes of AUB in adolescents are anovulation due to normal hyperandrogenism of adolescence or an immature hypothalamic-pituitary-ovarian (HPO) axis that resolves over time. It is important to rule out both normal or abnormal pregnancy as well as hemodynamic compromise early on when evaluating a teen reporting any menstrual irregularity.

Defining normal periods using the menstrual history:

Cycle length between 21-45 days, duration of menses from 2-8 days long, and amount of blood loss 20-80 cc

Clues to blood loss >80 cc

Detailed menstrual history including: soaking through a pad every 1-2 hours, blood clots >1 cm, soaking through pads especially overnight

Pictorial Blood Assessment Chart, measuring frequency and degree of saturation, flooding, clots, overall duration of menses (See Figure 1.)

Iron deficiency anemia with a history of AUB or heavy menses is another objective way to assess degree of menstrual blood loss

Figure 1.n

TIPS

1. Menstrual history alone is not a reliable or accurate way to assess for severity of AUB.2. Best objective way to assess for severity is by obtaining hemoglobin or CBC.

3. Direct observation of blood loss (i.e., look at pad and degree of saturation) correlated with patient assessment of amount of bleeding helps determine objective versus subjective heaviness of menses.

Common Medical Definitions:

Menorrhagia: prolonged or heavy bleeding at regular intervals

Metrorrhagia: frequent irregular bleeding

Menometrorrhagia: prolonged or heavy bleeding at irregular intervals

Polymenorrhea: regular but short intervals (<21 days)

Intermenstrual bleeding or spotting: light bleeding between menses

Oligomenorrhea: intervals greater than 35 days

Amenorrhea: no menses for 6 or more months

DUB or AUB: heavy, irregular, or prolonged painless endometrial bleeding not attributable to underlying structural or systemic disease

What other disease/condition shares some of these symptoms?

Diseases/conditions that can mimic AUB (comprehensive list)

AUB is a diagnosis of exclusion ruling out other pathologies including:

• Pregnancy

  Normal: Implantation, Normal gestation, Placenta accreta

  Abnormal: Miscarriage, Ectopic, Hyatidiform mole, Post-abortion retained products of conception

• Genital tract pathology including

  Vulva: Trauma, Sexual abuse, Sexually transmitted infection (STI), Lichen sclerosis, Cancer

  Vagina: sexually transmitted infection (STI), Trauma, Foreign bodies, Cancer

  Cervix: STI, Dysplasia/Cancer

  Ovarian: polycystic ovarian syndrome, tumor, corpus luteum defect

  Uterus: STI/Infection, Endometriosis, Polyps, Fibroids, Myoma, Hyperplasia/Cancer

  Cancer and fibroids very rare in prepubertal and pubertal ages

• Systemic Disease including

  Hematologic : Von Willebrand disease, Platelet deficiencies or dysfunctions, Factor deficiencies, Coagulation defects, Leukemia

  Gastrointestinal : Crohn’s disease, Liver disease/failure

  Endocrine : Hyperandrogenism/Polycystic ovarian syndrome, Hypothalamic disease, Hypogonadism, Hypo/hyperthyroidism, Hyperprolactinemia, Premature ovarian failure, Adrenal disorder

  Other : Neurologic disorders (seizures and other chronic neurologic diseases), Renal failure, Eating disorders

• Other sources of abnormal bleeding may include

  Immature hypothalamic-pituitary-ovarian axis, other estrogen progestin imbalances

  Weight changes (gain or loss), significant exercise

  Contraceptive use including hormonal contraceptives, starts/stops of hormones, problems with hormonal adherence, intrauterine devices

  Medications: antipsychotics, anticoagulants, platelet inhibitors

  Stress

TIPS

Common causes of adolescent abnormal uterine bleeding:

• Less common but urgent to rule out:

  Pregnancy, including ectopic: may present with symptoms of light spotting with implantation to hemorrhage with miscarriage or ectopic

  STI, including pelvic inflammatory disease (PID): usually post coital spotting or light bleeding

  Severe anemia, with cardiovascular instability (Hb<9): most common adolescent presentation is a young woman who has had menometrorrhagia who finally presents with syncope, fatigue and a recently decompensating severe anemia

• Non emergent but more commonly, adolescent irregular menses are attributed to AUB/DUB

  Immature hypothalamic-pituitary-ovarian axis (anovulatory periods)

  Hyperandrogenism/Polycystic ovarian syndrome (PCOS)

  Adherence problems with contraceptive hormones

  Stress

What caused this disease to develop at this time?

History: A thorough history and review of multiple systems and symptoms is critical in determining the etiology of AUB. It is especially important to take a detailed history for the following systems:

• cardiovascular

• sexual-gynecologic-reproductive

• endocrine

Many teens do not realize what normal or abnormal menstruation is and so AUB often presents indirectly. Patients with AUB may not present initially by reporting heavy and/or irregular menstrual bleeding but with other symptoms such as syncope, fatigue, malaise, pallor, palpitations, or other symptoms of recently increasing cardiovascular decompensation. Other patients may come in for dysmenorrhea and/or premenstrual syndrome (PMS) and with further history taking, reveal AUB. Teens with bleeding diathesis may report additional past history of bleeding problems and or familial bleeding concerns. However, for many young women with a bleeding disorder, menometrorrhagia is the first indication of a propensity to bleed.

Reproductive age patients presenting with abdominal or pelvic pain, heavy active bleeding, and amenorrhea require immediate evaluation for pregnancy, including miscarriage and ectopic pregnancy (See sections on ectopic pregnancy and spontaneous abortion).

It is also important to note that for reproductive age women, adolescence is a time of transient hyperandrogenism. Resulting anovulation and irregular menses from hyperandrogenism typically resolves with time and maturation of the hypothalamic-pituitary-ovarian axis. Endocrine related screening questions are important for both early and late teens. These might include detailed description of skin and hair, secondary sexual characteristics and development, as well as family endocrine and reproductive histories.

Patients may also present urgently with concerns regarding lack of bleeding (i.e., amenorrhea or oligomenorrhea) with concerns for unplanned pregnancy, especially if they are sexually active. Again, not all adolescents will report this directly, necessitating a private and confidential interview and frank discussion regarding sexual activity. It is important to make clear to the patient how important truth telling and accurate information is regarding actual or typical use of condoms and or contraception.

A detailed sexual history regarding specific sexual behaviors (kissing, oral, digital, vaginal, anal sex) and last unprotected and protected sexual activity is important. Including the question: “when was the last time you had unprotected sex (i.e., sex without a condom or birth control?” allows providers to determine how accurate their pregnancy test will be (i.e., urine pregnancy tests may be false negative in very early pregnancy) as well as allow providers to prescribe emergency contraception up to 5 days after last unprotected sex.

All youth deserve some evaluation for trauma and/or non-consensual sexual activity. Additionally, pre-pubertal children may be evaluated for signs of early puberty, peri-vaginal or vulvar infection, malignancy, foreign body (usually toilet paper), secondary estrogen exposure.

• Menstrual history: menarche, last menstrual period (LMP), regularity of cycles, duration of bleeding, number/degree soaked pads/tampons used in 24 hour period, clots, flooding, soaking through during day or night

• Sexual history: ever sexually active (yes-currently; yes previously but not currently; never-ever, non-consensual assault); genital injury/trauma

  Most recent sexual activity including most recent unprotected sexual activity (i.e. no birth control, no condom), pattern of condom use, contraceptive use (actual adherence versus idealized), specific sexual behaviors (digital, oral, anal, vaginal sex)

• General: participation and/or change in activities of daily living (ADLs) related to menses, change in diet and/or exercise, new or additional stresses in life

• Review of Systems (ROS): fatigue, tired easily, short of breath, weight loss or gain, change in skin and/or hair, heat or cold intolerance, diarrhea or constipation, abdominal or pelvic pain, vaginal discharge, dysuria, fevers, masses, easy bruising, nose or gum bleeds, excessive bleeding with surgeries

• Past Medical History (PMH): prior problems with bruising, nose bleeds, bleeding with dental extraction or surgeries, neurologic conditions, other chronic diseases

• Medication review: hormones or contraceptives, antipsychotic or mood drugs, anti-epileptic drugs

• Family History (FH): family members with bleeding problems (both general and gynecologic), early hysterectomy for bleeding, infertility, mother and maternal female relatives’ menstrual patterns

Vitals: Hemodynamic assessment and LMP is a vital first step in the physical assessment of the patient:

• General appearance: body habitus assessment: weight, height, body mass index (BMI)

• Cardiovascular (CV) assessment: pulse, respiratory rate, BP including orthostatics if low

• Other: temperature and LMP

Physical Exam: A general physical exam with attention to cardiovascular and endocrine status, abdominal masses or pregnancy is more important than a detailed genital exam for the non-sexually active female with mild to moderate chronic AUB.

• Skin for hirsuitism, acne, acanthosis, striae, petechiae, bruising, color/pigment, perfusion

• Head, ears, eyes, nose and throat (HEENT) for brittle hair or nails, thyroid changes, adenopathy or masses, visual field defects

• Cardiovascular and respiratory for clinical evaluation of anemia and or hemodynamic compromise (rate, murmurs, pulse)

• Thoracoabdominal for pain, masses, hepatosplenomegaly

• Endocrine and Gynecologic

  Secondary sexual characteristics

  Pubertal development using Tanner staging

  Evaluate concordance versus discordance between chronologic age and sex characteristics

  Galactorrhea

  Pelvic exam indicated if sexually active, concerns about pregnancy, PID, cervicitis, foreign body, trauma, obstruction

  External genitourinary (GU) inspection- groin for adenopathy, vulva for lesions, introitus for lesions and estrogen effects, anus

  Internal bimanual palpation- masses, location and size, +/- tenderness of uterus and ovaries

  Internal speculum inspection- vaginal wall and cervix for discharge, odor, foreign bodies, masses, trauma

  May perform limited external genital exam or no genital exam other than Tanner staging of pubic hair

  If not sexually active (and no concerns about pregnancy, pelvic inflammatory disease)

  No concerns regarding foreign body, or trauma, obstruction

  Patient has no concerns about genital abnormalities and declines initial exam

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Epidemiology

AUB is most commonly due to HPO axis resulting in anovulatory cycles. During the first year after menarche, up to 85% cycles are anovulatory; at years 2-4 30%-50%, and years 4-5 20%-40% of cycles are still anovulatory. Later menarche is associated with increased risk and persistence of anovulatory cycles. Approximately one in five adolescents with persistent menorrhagia requiring hospital admission have a coagulation problems including von Willebrand’s disease, thrombocytopenia, and leukemia. 65% of women with von Willebrand disease report menorrhagia at menarche.

Predictors of organic cause for uterine bleeding, and not AUB, include hospitalization, hb<10 g/dl, transfusion. Hyperandrogenism or PCOS has an estimated prevalence of 5% and is one of the most common endocrinopathies affecting women.

Predisposing and resultant factors

HPO axis dysfunction and anovulation creates a situation with no corpus luteum, and thus no progesterone production and unopposed estrogen. Estrogen levels eventually fall and can no longer support thick proliferative endometrium, resulting in withdrawal bleeding. Asynchronous development of stroma, glands, and vessels lead to unstable shedding of endometrium. Low levels of uterine prostaglandins may result in lower than normal uterine muscle and vascular contractions that decrease/stop blood flow. Prolonged AUB or oligomenorrhea associated with hyperandrogenism, anovulation requires progestin supplementation to decrease risk of future endometrial hyperplasia and eventual clomiphene for ovulation and fertility.

TIPS

1. For the minor or adolescent patient with a parent/guardian present, it is critical to assure privacy and confidentiality in order to obtain an accurate sexual history.

2. Three critical factors determining which pathway a provider takes in the evaluation:

• Symptoms or signs of severe anemia and cardiovascular instability

• Sexual activity

• Signs of hyperandrogenism

See Figure 2, Figure 3, Figure 4
, Figure 5, Figure 6, Figure 7: Algorithm for AUB Evaluation and Treatment

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

It is important to rule out both pregnancy and severe anemia with hemodynamic compromise early on in the evaluation of AUB. Asking for an LMP during intake, and last unprotected sexual activity enables you to assess for possible pregnancy. Urine human chorionic gonadotropin (hCG) can diagnose pregnancy as early as 14 days after conception and can be done rapidly in the clinical setting. Stat hemoglobin (Hb) allows for objective evaluation of reported heavy bleeding. This can be followed by CBC with indices, ferritin, and other hematologic labs to get more detailed information as to the source and outcome of the abnormal bleeding.

Second line labs to consider are based on findings from the H&P. Labs should focus on systems and potential common etiologies as described above.

If concerns about heavy bleeding, anemia, bleeding disorder:

Review PMH for prior problems with bruising, nose bleeds, bleeding with dental extraction or surgeries. Review medications for anything that would iatrogenically promote bleeding. In the FH, specifically ask if family members have bleeding problems (both general and gynecologic), early hysterectomy for bleeding. It can be important to review the mother’s and maternal female relatives’ menstrual patterns.

LABS:

CBC with indices

Ferritin

PT PTT INR

Von Willebrand Antigen, Factor VIII, Ristocetin CoFactor, collagen binding assay

If concerns about endocrine disorders, hyperandrogenism, etc:

Conduct a thorough ROS for fatigue or tiring easily, shortness of breath, weight loss or gain, change in skin and/or hair, heat or cold intolerance, diarrhea or constipation, abdominal or pelvic pain, vaginal discharge, dysuria, fevers, masses, easy bruising, nose or gum bleeds, excessive bleeding with surgeries. The physical exam should include careful evaluation of skin for hirsutism, acne, acanthosis, striae, petechiae, bruising, color/pigment, perfusion; HEENT for brittle hair or nails, thyroid changes, adenopathy or masses, visual field defects; Endocrine and Gynecologic for secondary sexual characteristics, pubertal development using tanner staging, concordance versus discordance between chronologic age and sex characteristics, galactorrhea.

LABS:

FSH, LH, testosterone, DHEAS, 17OH-Progesterone, prolactin

If no signs of endocrine disorder by H&P, then hormone studies not generally useful and expensive

TSH, if abnormal get full panel

Electrolytes

If concerns about systemic or chronic disease, obtain labs relative to that chronic condition (i.e., liver function tests, creatinine, other)

If concerns about sexual activity, high risk behaviors, or reliability of history:

Get a thorough sexual history including questions as to ever sexually active (yes-currently; yes previously but not currently; never-ever, non-consensual assault); last sex, last unprotected sex, sex with multiple partners or high risk partners, genital injury/trauma. More details regarding recent sexual activity including most recent unprotected sexual activity (i.e., no birth control, no condom), pattern of condom use, contraceptive use (actual adherence versus idealized), specific sexual behaviors (digital, oral, anal, vaginal sex) is helpful in assessing risks of STI or PID. If the pelvic exam is indicated and concerning then test for STIs.

LABS:

Urine chlamydia and gonorrhea nucleic acid amplification test (NAAT)

Cervical or vaginal chlamydia NAAT, vaginitis panel (bacterial vagininosis, trichomonas, yeast), ESR or CRP, CBC

TIPS

1. Lab work up should initially focus on ruling out the most urgent diagnoses such as pregnancy and severe anemia.

2. Urine pregnancy tests in clinical setting typically very accurate 14 days after last unprotected sexual activity.

– If unprotected sexual activity < 14 days, urine hcg may be a false negative and require blood hcg or repeat pregnancy test in 2-3 weeks.

– False negative urine pregnancy tests also occur later in pregnancy

2. CBC and degree of anemia helps guide how aggressive (or not) the treatment recommendations should be.

Would imaging studies be helpful? If so, which ones?

• Pelvic ultrasound is usually not necessary for otherwise well non-pregnant hemodynamically stable teens

  May occasionally be helpful in cases

  Which do not respond to therapy as expected

  Thin atrophic lining may help guide practitioners to estrogen (builds up endometrium) over progestin therapy

  Thick heavy lining (> 1 cm diameter) may indicate that progesterone may be more helpful in stabilizing this lining than estrogen

  If uterine size out of proportion to expected non-pregnant status

  Ultrasound options

  Transvaginal- better visualization of uterus but is a more invasive test

  Transabdominal- less invasive and used in girls who have not been sexually active but with decreased visualization

  Both modalities can date a pregnant uterus, detect an ectopic pregnancy location, delineate normally cystic and polycystic ovaries, outline fibroids or other masses, or image other abnormalities

• Most imaging studies are not generally recommended for first line use with AUB in pre-menopausal women

  Computed tomography (CT) – may provide better delineation of pelvic structures

  Magnetic resonance imaging (MRI) – considered “gold standard” for delineating pelvic structures and anatomy including fibromas, adenomyosis

  Hysteroscopy or hysterosonography with endometrial biopsy- is gold standard in evaluating endometrium but usually not necessary in adolescents and young adults

Confirming the diagnosis

• See Figure 2: Algorithm for AUB Evaluation and Treatment

TIPS

1. Although underlying clinical abnormality is responsible for < 10% of AUB, AUB is a diagnosis of exclusion requiring other clinical sources to be ruled out.

2. Hospitalization, Hb <10, and need for transfusion are associated with a organic source for severe uterine hemorrhage.

If you are able to confirm that the patient has disordered uterine bleeding, what treatment should be initiated?

• Severe or heavy uterine bleeding with anemia (hb<=9) and CV instability is a medical emergency

  Initial therapy focuses on stabilizing CV status with hemodynamic support

  CR monitor, oxygen, IV access

  IVFs

  Labs: type, cross, CBC, and other bleeding disorder labs work up as above

  Transfusion of PRBC if necessary

  Begin estrogen therapy

  NPO if CV unstable and/or using IV estrogen

  Antiemetic for nausea prevention

  25 mg IV estrogen every 6 hours for maximum of 24 hrs (may be used as often as every 4 hours if necessary)

  Do not want to use IV estrogen for more than 24 hours as this may lead to increased risk of thromboembolic event (TE)

  Must begin oral estrogen-progestin pills. i.e. oral contraceptive pills (OCP) within 24-48 hours

  Add progestin to stabilize endometrium

  Not cause additional bleeding with acute estrogen withdrawal

  Discharge home when

  CV stable

  Bleeding decreased significantly (may not be completely stopped)

  Tolerating oral hormones with a plan for taper (See Table I. Examples of Hormone and Tapering Regimens)

  Additional prescription for anti-emetics

  Follow up within a week

• Moderate to heavy bleeding with mild to moderate anemia (hb 10-12), mild symptoms of anemia (fatigue, pallor, pica, dizziness) but hemodynamically stable (no changes in HR and BP)

  Labs: CBC and other bleeding disorder labs work up as above

  Begin estrogen therapy using OCP with multiple dosing and taper (Table I)

  Antiemetic for nausea prevention

  Add NSAIDS

  Follow up via phone call or visit to establish decreased or cessation of menses within 3-5 days

• Light to moderate bleeding with no hemodynamic signs or symptoms and HB >=12

  Labs: CBC to establish objective assessment of degree of bleeding and anemia; consider additional labs depending on history and physical

  Offer a range of options depending on

  Patient preference and goals

  Management of additional medical problems (dysmenorrhea, PMS, acne, hirsutism)

  Impact of menses on activities of daily living (ADLs)

  Need for additional contraceptive benefits and desire to delay pregnancy/parenting

  Options may include

  Watch and wait with careful observation and follow-up

  Menstrual diary

  NSAIDs

  Iron supplementation

  Repeat CBC and/or other labs

  Menstrual regulation with the variety of hormonal and non-hormonal options (Table II. Treatment Options Comparison Table)

Table I.n

Table II.n

Other hormonal options for menstrual regulation

Progestins are useful when estrogens are contraindicated (current/prior deep vein thrombosis (DVT), current/prior stroke, other hypercoagulable conditions) [See WHO Medical Eligibility Criteria for Contraceptive Use. 4th Ed. 2010 located online at www.who.int/reproductivehealth] .

High dose progestins may be used for urgent treatment of heavy bleeding and/or severe anemia. Oral medroxyprogesterone or norethindrone 5-10 mg can be used as often as every 4-6 hours with taper over 2 or more weeks. With mild to moderate bleeding with no cardiovascular instability and minimal anemia, oral medroxyprogesterone can be given in a 10 mg daily for 10-14 days.

If using oral progestins to manage cycles long term, you may use the calendar method (days 1-14 of LMP) or cyclic method (days 14-23 of LMP). Oral progestins are less effective than LNG-IUD, tranexamic acid, and danazol and offer no contraceptive benefits. Intramuscular medroxyprogesterone DMPA may be used at a dose of 150 mg for 12 weeks or in critical cases as much as 100 mg IM daily for 1 week then weekly and tapering to monthly to induce endometrial atrophy.

Consider LNG-IUD (20 mcg levonorgestrel daily intrauterine device) as a progestin only device with additional benefits of ease of use, improved adherence, improved continuation rates, and superior long acting reversible contraception. LNG-IUD offers a 90% reduction in menstrual blood loss with 50% of women having amenorrhea after 1 year of treatment. This increases to 80% amenorrhea in 2 years. LNG-IUD can be used in women with bleeding disorders and/or anticoagulant therapy.

Gonadotropin Releasing Hormone Analogues (GnRH agonists) work by continuous stimulation of the pituitary down-regulating LH and FSH secretion. Methods include: leuprolide, gosrelin, triptorelin. These can be used short term (approximately 6 months) in urgent situations but are not necessarily a good long term solution. Of note, if starting an older adolescent on GnRH agonists, it is important to warn them that they may experience a variety of menopausal like symptoms. Mood changes, irritability, and depression can sometimes be severe and disruptive if the patient is not forewarned.

Danazol (200-400 mg every 12 hrs) is a synthetic testosterone that has been demonstrated to decrease menstrual blood flow and can be used short term (for 6-9 months). It is much less commonly used because it is only recommended for short term use and can have significant masculinizing effects and fetal teratogenicity. Sexually active persons using Danazol should always also use contraception.

Non-hormonal management

Nonsteroidal antiinflammatories (NSAIDs) are more effective than placebo but less effective than LNG-IUD, tranexamic acid, Danazol. NSAIDs do not appear to be superior to OCPs or progestins, but most studies are underpowered. There seems to be no difference in effectiveness among the different NSAIDs. Typical NSAIDs that have been used for AUB include: Ibuprofen 800 mg every 6-8 hrs; Naproxen 500 mg BID; Mefenamic acid 500 mg BID.

Tranexamic acid’s antifbrinolytic activity has been shown to reduce blood loss by 40%. Dosing is typically 1 gm every 6 hrs for days 1-4 of menstrual cycle.

Aminocaproic acid can reduce menstrual blood loss but has less tolerable side effects, so is much less frequently used.

Desmopressin increases VWF FVIII and platelet adhesiveness for Type 1 Von Willebrand and other bleeding disorders but is less effective than tranexamic acid, LNG-IUD.

Factor concentrates may be used for patients with factor deficiencies as determined by hematology.

What about longer term treatment?

When providing long-term treatment for an adolescent with AUB, providers need to consider multiple factors such as lifestyle and impact of menses on ADLs, ability to adhere to a treatment plan, length of treatment and trial off medications, changes in teen’s sexual behaviors and contraceptive needs, changes in hormone and contraceptive technologies.

Any estrogen-progestin or progestin hormone can be used to regulate menses as well as provide contraception. Again, the needs of adolescents change over time and an early adolescent diagnosed with AUB may eventually appreciate a medication with the “side effect” of excellent contraception. OCP and Nuvaring can be continuously cycled for extended cycling of menses and menses 4x a year, decreasing the total number of menstrual cycles and allowing for convenient timing of menses.

DMPA IM can offer a generally predictable bleeding patterns over time with a majority of persons experiencing amenorrhea or lighter spotting/bleeding after 6-9 months of treatment. Overall, the LNG-IUD seems to offer the most significant and predictable decrease in menses as well as an excellent forgettable method of contraception.

TIPS

1. Estrogen is the most effective immediate medication for stabilizing the endometrium and treating AUB

-Direct effect on clotting: increases platelet aggregation, fibrinogen, factors V and IX; decreases bradykinin

-Longer term effect on reproliferating a healthy endometrium, which eventually requires some progestin to halt excessive growth, decrease hormone receptors

2. When estrogen is contraindicated there are additional hormonal and non-hormonal options in the treatment of adolescent AUB.

3. Surgery is almost never required for managing adolescent AUB.

What are the adverse effects associated with each treatment option?

(See Table II. Treatment Options Comparison Table)

• Estrogen

  Early, usually limited to the first several weeks to 3 months

  Nausea, vomiting, breast bloating and tenderness, pelvic bloating

  Melasma, candida vaginitis

  Brief provision of higher dose estrogen for AUB by IV or oral methods does not change the risk for TE

  Ex. providing a twice daily dose of OCPs for 1-2 weeks does not double the risk of TE

  Risk of TE with daily OCP use is very low for most healthy teens

  TE risks highest especially in the first 6-12 months

  Limiting IV estrogen use to less than 24 hours helps minimize TE risk

  See Table III. Absolute Risk Venous Thromboembolism

• Progestin

  Less reliable and predictable control of uterine lining and bleeding profile

  Minimal to no contraceptive benefits for progestin only or “mini pills”

• Iron

  Nausea, vomiting, constipation

Table III.n

What are the possible outcomes of disordered uterine bleeding?

Prognosis is dependent on the etiology of the AUB. AUB related to one of the most common etiologies, anovulation secondary to immaturity of HPO axis will resolve over time. Patients and parents can take a variety of approaches including watch and wait, NSAIDS, estrogen and/or progestin hormones, among other medications as mentioned above.

Hyperandrogenism/PCOS will likely persist and patients will benefit in the long run from the addition of progestin in order to decrease risks of endometrial hyperplasia. Patients with hyperandrogrenism benefit from early diagnosis that minimize additional androgen excess effects such as hirsutism, acne, irregular menses.

Bleeding disorders are often best treated hormonally with addition of additional hemostatic medications to supplement. The LNG-IUD is fast becoming a first start option for women with bleeding diatheses though a wide variety of therapies may be used to treat AUB in patients with bleeding diathesis including: LNG-IUD, OCP, depot medroxyprogesterone acetate, danazol, GnRH analogs, tranexamic acid, desmopressin.

Estrogen is typically the hormone linked to a thromboembolism (TE). Estrogen used for AUB in dose and time limited fashion has been shown to be safe for patients. TE related to estrogen use are typically seen in daily users rather than limited short term therapy. Estimates of risk for DVT are rare in generally healthy young adolescent women. Baseline TE risk for all ages is rare – 10 in 100,000 women years. Relative risk increases by 50%, which correlates to a still very rare absolute risk of 15 in 100,000 women years. Risk for TE in pregnancy is estimated at 60 in 100,000 women years. (See Table III.)

Chronic oligomenorrhea or PCOS/hyperandrogenism is often associated with obesity. Obesity and adipose tissues contributes to endometrial hyperplasia with years of unopposed estrogen acting on the endometrial lining. Acute and long term contraceptive benefit of these hormones for sexually active teens is not to be underestimated.

What causes this disease and how frequent is it?

Most common causes of adolescent AUB

Anovulatory cycles are very common in early teens. In the first year post menarche approximately 80% of teens have anovulatory cycles. That number drops to 30-50% by years 2-3 post menarche. By 5 years post menarche, only 20% of teens are expected to be anovulatory. Hyperandrogenism is a common chronic endocrine disregulation leading to long term problems with anovulation.

Von Willebrand disease and other types of bleeding diathesis can be a cause of AUB, particularly severe AUB requiring hospitalization and/or transfusion. It is often more helpful to test the relative who has a possible or known bleeding diathesis prior to extensive testing of the index patient. Overall, there is little known about the genetics of AUB but menstrual disorders may run in families along with hyperandrogenism and obesity.

Other clinical manifestations that might help with diagnosis and management

Some adolescents will present with signs or symptoms of anemia with no complaints about irregular or heavy menses as they may not have a frame of reference for “what is normal” in regards to menstruation. Once girls reach reproductive age, it is important to discuss menses during anticipatory guidance visit. All menstruating teens are recommended to have a hemoglobin at least once in adolescence. Any anemic female needs a thorough menstrual history along with a comprehensive hemodynamic and endocrine assessment as above.

Many young women with irregular menses also have the physical stigmata of PCOS which can be picked up with good general observation skills and followed up with a careful skin and endocrine evaluation. Determining if the patient is hyperandrogenic along with AUB, may prevent additional sequelae from excess testosterone (acne, hirsuitism, overweight, anovulatory infertility).

Patients may not immediately reveal pregnancy or abortion history, especially if in the presence of a parent or partner. Assurances of privacy and confidentiality are critical to getting an accurate sexual history. Providers may need to ask specifically about pregnancy or abortion in order to elicit this history from some teens.

What complications might you expect from the disease or treatment of the disease?

Disease:

Anemia

Interference with ADLs

In more rare but serious cases: hemodynamic instability and cardiovascular compromise or risk of thromboembolic event

Anovulation and difficulties with conception

Treatment (See Table II):

Minor and early side effects from estrogen and progestin as above (nausea, vomiting, bloating)

Minor and later side effects from estrogen and progestin (shorter lighter periods, decreased risk of anemia, melasma, yeast infections)

Rare but serious adverse outcome of estrogen is TE (See Table III.)

Gastrointestinal upset, headaches, and other side effects unique to the variety of less frequently used adjunctive agents to hormones

Are additional laboratory studies available; even some that are not widely available?

While most adolescents may be evaluated and managed in the primary care setting, history and initial labs suggestive of a bleeding diathesis will also benefit from evaluation and collaboration with hematology. Prolongation of the PT, PTT, low platelets, indices not consistent with acute or chronic blood loss and iron deficiency anemia may deserve further evaluation. Patients with low Von Willebrand labs also would benefit from a hematology consult.

How can disordered uterine bleeding be prevented?

AUB or its sequelae can be prevented by regular anticipatory health discussions about reproductive health, including a menstrual and sexual history. During an anticipatory guidance for the nearly pubertal child, physicians should address the changes of upcoming puberty, including what is normal or abnormal menstruation. In early puberty, a careful review of menses (regularity, duration, flow and number of pads or tampons used in 24 hrs, cramping, disruption of ADLs) can allow for education and early intervention.

As patients mature, discussions of personal safety, self-gender-sexual identity, romantic attraction, sexual behaviors, and family planning should be incorporated into anticipatory guidance in a developmentally appropriate way. Youth expect providers to ask them directly about these issues and the burden of introducing these topics is the responsibility of the medical provider.

What is the evidence?

Chi, C, Pollard, D, Tuddenham, EG, Kadir, RA. “Menorrhagia in adolescents with inherited bleeding disorders”. J Pediatr Adolesc Gynecol.. vol. 23. 2010. pp. 215-222. (Retrospective review of management and treatment outcomes (blood loss and quality of life) in adolescents with inherited bleeding diathesis.)

Deligeoroglou, E, Tsimaris, P. “Menstrual disturbances in puberty”. Best Pract Res Clin Obstet Gynaecol.. vol. 24. 2010. pp. 157-171. (2010 overview of a wide variety of menstrual problems in pubertal years.)

Demers, C, Derzko, C, David, DM, Douglas, J. “Gynaecological and obstetric management of women with inherited bleeding disorders”. In J Gynaecol Obstet. vol. 95. 2006. pp. 75-87. (Review of literature from 1975-2003 with levels of evidence and Society of Obstetricians and Gynaecologists of Canada recommendations.)

LaCour, DE, Long, DN, Perlman, SE. “Dysfunctional uterine bleeding in adolescent females associated with endocrine cause and medical conditions”. J Pediatr Adolesc Gynecol.. vol. 23. 2010. pp. 62-70. (2010 review article focusing on etiology of AUB.)

Levine, SB. “Dysfunctional uterine bleeding in adolescents”. (eds. Strickland J, Gibson EJ) J Pediatr Adolesc Gynecol. vol. 19. 2006. pp. 49-51. (Outline format and practical approach to clinically managing AUB.)

Maness, DL, Reddy, A, Harraway-Smith, CL, Mitchell, G, Givens, V. “How best to manage dysfunctional uterine bleeding”. J Fam Practice. vol. 59(8). 2010. pp. 449-458. (2010 lifespan approach to AUB, from puberty to menopause.)

Marret, H, Fauconnier, A, Chabbert-Buffet, N, Cravello, L, Golfier, F, Gondry, J. “Clinical practice guidelines on menorrhagia: management of abnormal uterine bleeding before menopause”. Eur J Obstet Gynecol Reprod Bio. vol. 152. 2010. pp. 133-137. (2010 European clinical practice guidelines focusing on management of AUB in adolescents and younger adults. Gives level and quality of evidence for each recommendation.)

“Heavy menstrual bleeding”. Developed by the National Collaborating Center for Women's and Children's Health. 2007. (Best practice advice out of UK for woman-centered care of heavy and/or irregular menses, although with more of a focus on older women. Gives level of evidence for recommendations in full guideline at www.nice.org.uk/CG044fullguideline.)

Wilkinson, JP, Kadir, RA. “Management of abnormal uterine bleeding in adolescents”. J Pediatr Adolesc Gynecol.. vol. 23. 2010. pp. S22-S30. (2010 review article focusing on treatment options for adolescent.)

Beaumont, H, Augood, C, Duckitt, K, Lethaby, A. “Danazol for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2002.

Farquar, C, Brown, J. “Oral contraceptive pill for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2009.

Lethaby, A, Irvine, G, Cameron, I. “Cyclic progestins for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2008.

Lethaby, A, Augood, D, Duckitt, K, Farquhar, C. “Nonsteroidal antiinflammatory drugs for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2007.

Lethaby, AE, Cooke, I, Rees, M. “Progesterone or progesterone-releasing intrauterine systems for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2005.

Lethaby, A, Faquhar, C, Cooke, I. “Antifibrolytics for heavy menstrual bleeding”. Cochrane Database Syst Rev. 2000.

Ongoing controversies regarding etiology, diagnosis, treatment

There are not many studies looking at AUB in children and teens. Many medicines and many pediatric medical regimens including contraceptives, are used “off label” in the under 16 year old age groups. As reproductive technologies change and improve, it is important to consider their non-contraceptive benefits for menstrual regulation.

While the IUD was developed as a contraceptive, the LNG-IUD has been shown to effectively decrease menstrual bleeding and is now indicated for menometrorrhagia. It is so effective that is now used first line for many women as a less invasive option to hysterectomy. For youth, myths persist regarding the safety and appropriate use of IUDs in teens. Unfounded myths, patient fears of procedural interventions, physician lack of understanding, and up front cost create unduly restrictive barriers for using this excellent contraceptive that has proven menstrual regulation benefits.

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