Dysfunctional Uterine Bleeding

Jennifer Bergquist M.D. September 6, 2005

Case #1
You are evaluating a 13yr old girl in your office. She is c/o heavy menstrual bleeding. She experienced menarche ~1yr ago and says her periods never occur at the same time. They last ~10days. Her previous menses occurred ~2 months ago. She denies dysmenorrhea. Her current period started 2 days ago and is especially heavy. She denies sexual activity or h/o STDs. Physical exam findings are notable for mild orthostatic hypotension and pallor; Exam is otherwise normal

Case #2
You are evaluating a 13yr old girl in your office. She is c/o heavy menstrual bleeding. She experienced menarche ~1yr ago and says her periods never occur at the same time. They last ~10days. Her previous menses occurred ~2 months ago. She denies dysmenorrhea. Her current period started 2 days ago and is especially heavy. She denies sexual activity or h/o STDs. Physical exam is notable for mild orthostatic hypotension and pallor. She is mildly overweight and is noted to have acne. Exam is otherwise normal

Case #3
You are evaluating a 13yr old girl in your office. She is c/o heavy menstrual bleeding. She experienced menarche 6 months ago and says her periods have always been heavy and last up to 12 days. Although, she thinks they occur at regular intervals. She frequently experiences dysmenorrhea. She denies sexual activity or h/o STDs. Physical exam findings are notable for mild orthostatic hypotension, pallor and a large amount of menstrual blood at the vaginal introitus. Exam is otherwise normal.

Questions
1.

What is the differential diagnosis?

2. What additional information would be helpful?

3.

What laboratory evaluation would you pursue?

4. What initial therapy would help the patients symptoms?

Definition
Dysfunctional uterine bleeding (DUB) is defined as abnormal uterine bleeding that is excessive or occurs outside the normal cycle In Adolescents, 95% is secondary to anovulation Patterns of abnormal bleeding:
Menorrhagia prolonged bleeding at regular intervals Metrorrhagia uterine bleeding at irregular intervals Menometrorrhagia uterine bleeding that is prolonged, excessive and occurring at irregular intervals

Menarche
Mean age of menarche in the United States:
12.88 years for Caucasian girls 12.16 years for African American girls

90% reach menarche by the time breast and pubic hair development has reached SMR stage 4. On average, menarche occurs 2 years after thelarche

Menstrual Cycle
Follicular Phase
Pulsatile GnRH FSH and LH stimulate ovarian follicle growth Predominant follicle secretes estrogen Endometrium proliferates

Ovulation
LH > FSH Occurs 12hrs after LH surge

Luteal Phase
Corpus Luteum secretes progesterone Secretory endometrium Corpus luteum regresses if no implantation occurs Estrogen/progesterone fall; endometrial lining sloughs

Anovulatory Menstrual Cycle

Endometrium experiences continued estrogen stimulation that is unopposed by progesterone Increased estrogen should cause a negative feedback on the H-P axis; estrogen levels fall; endometrium sloughs and mimics an ovulatory cycle In DUB, impairments in the feedback system cause the endometrium to be continuously stimulated, thickened and unstable Uterine bleeding occurs when endometrium outgrows its blood supply Uterine bleeding becomes asynchronous, prolonged and sometimes profuse

Dysfunctional Uterine Bleeding

differential diagnosis

Pregnancy-related Physiologic Anovulation Hormonal contraceptives Hypothalamic-related

Systemic illness (DM, renal, liver disease) Functional (diet, stress, exercise) Eating disorders Hypothyroid prolactinoma Post-menarchal (immature H-P-O Axis) Ectopic pregnancy Abortion

Outflow tract-related
Trauma Foreign body Polyps Uterine myomas Neoplasms

Androgen Excess

Coagulation defects Infectious

PCOS Adrenal or ovarian tumor Adrenal hyperplasia (nonclassic type) Clotting factor deficiency Von Willebrand disease PID, cervicitis, vaginitis

Pituatary-related

Evaluation
Detailed menstrual history Age of menarche Menstrual pattern Amount of blood loss Duration of menses +/- menstrual cramps Recent changes in cycles symptoms of hypovolemia Genital trauma Weight loss or gain Non-menstrual bleeding
(easy bruising)

Emotional stress Exercise patterns Sexual history Gestational events Symptoms of chronic illness Family history of menstrual or bleeding disorders

Physical Exam
Vital signs (including orthostatics) Gen: obesity, cachexia HEENT: fundoscopic exam/visual field testing Neck: thyroid Breasts: SMR, evaluate for galactorrhea Abdominal: uterine/ovarian mass Skin: hirsutism, acne, acanthosis nigrans External genital exam: SMR, clitoral size Internal genital exam (if sexually active or has painful bleeding):uterine/adnexal masses, motion tenderness, trauma, cervical os (size, color, discharge)

Laboratory Assessment
Urine B-HCG* Hematocrit* CBC, PT/PTT
Even in adolescents who claim they are not sexually active!

Other tests (depending on history/physical)

Should be performed in pts with + family history of bleeding d/o and/or personal h/o excessive non-menstrual bleeding Secondary evaluation includes a von Willebrand panel (vWF antigen; ristocetin cofactor activity) FSH, LH, prolactin, androgen panel (free/total testosterone, DHEA), TSH, Cortisol Pelvic ultrasound- always indicated in pts suspected of having ectopic pregnancy, pts who have a palpable mass or if PCOS is suspected * Should be performed in all patients with irregular uterine bleeding

Diagnostic Evaluation
Progesterone Challenge
Evaluates uterine response to endogenous estrogen Progesterone is administered X 12 days to mimic physiologic secretion Menstrual bleeding within 1 week after the challenge suggests FSH/LH secretion is sufficient to maintain normal estradiol secretion and endometrial proliferation, but insufficient to cause ovulation Lack of menstrual bleeding suggests an endometrial pathology or marked hypoestrogenemia

Physiologic Anovulation
Immaturity of the hypothalamic-pituitaryovarian axis is the most common cause (in the absence of pregnancy) Most common during the first 2 years after menarche when 55-80% of cycles are anovulatory Regardless of cause, anovulation can present as either amenorrhea or DUB Laboratory evaluation may reveal elevated FSH:LH ratio It is a diagnosis of exclusion
Rising levels of estrogen do not cause suppression of FSH; sustained estrogen secretion ensues

Polycystic Ovarian Syndrome

Should be considered in any adolescent girl with hirsutism, menstrual irregularity or obesity 2/3 have anovulatory symptoms Metabolic abnormalities
Primary or secondary amenorrhea or DUB Obesity (50%), insulin resistance, glucose intolerance and lipid abnormalities Elevated LH:FSH ratio, elevated free testosterone Pelvic ultrasound finding of polycystic ovaries (string of pearls); Exclusion of other disorders that mimic PCOS
~45% of adolescents have normal-appearing ovaries Useful to exclude tumor from the differential

Diagnosis (clinical + biochemical criteria)

Virilizing tumors, hyperprolactinemia, non-classical CAH, Cushing

Coagulation Disorders
Often presents as menorrhagia at regular intervals When to consider bleeding disorders:
extremely heavy first menses, bleeding requiring blood transfusion, refractory menorrhagia w/ anemia

All patients requiring hospitalization for uterine bleeding requires an evaluation for a coagulation disorder Approximately 20% of adolescents with menorrhagia were found to have a coagulation defect Von Willebrand disease was the most common defect (Factor XI deficiency was second) Blood for evaluation of bleeding disorders should be obtained before administration of blood products or estrogen (may elevate vWF into the normal range)

Hormonal Therapy
Primary purpose is to stabilize endometrial proliferation and promote shedding >90% of adolescents with DUB respond to hormonal therapy
Alternative diagnosis should be considered for nonresponders

Treatment:

Estrogen heals sites of bleeding by causing further proliferation and providing hemostasis Progesterone stops proliferation and stabilizes the endometrial lining

Treatment:

Mild DUB

Longer than normal menses or shortened cycles for >2 months Observation and Reassurance
If anemia is not present/normal physical exam

Menstrual calendar recommended Iron supplementation recommended despite normal hemoglobin Follow-up in 3-6 months

Moderate DUB
Moderately prolonged or frequent menses every 1-3 weeks w/ moderate-heavy menstrual flow Mild anemia is often present w/out signs of hypovolemia Outpatient management with hormonal therapy
Active bleeding: combination oral contraceptives in tapering doses (minimum 30mcg estradiol)
1 pill TID until bleeding ceases 1 pill BID X 5 days 1 pill QD X 21 days

Treatment:

No Active bleeding: Daily/Cyclic OCP

progestin-only regimens are an alternative option: Medroxyprogesterone 10mg X first 12 days of the month

Severe DUB
Heavy menstrual bleeding causing a decrease in Hgb <10 with or without hemodynamic instability Hospitalization indications include:
Initial Hgb <7g/dL Orthostatic signs Heavy active bleeding with Hgb <10g/dL

Treatment:

Girls who require hospitalization should undergo evaluation for a bleeding disorder

Severe DUB
Combination OCPs (estradiol 50mcg)
1 pill Q4 until bleeding subsides (usually within 24 hrs) 1 pill QID X 4 days 1 pill TID X 3 days 1 pill BID X 2 weeks

Treatment:

Conjugated IV estrogen 25mg IV Q4-6 is required for unstable patients

Anti-emetic therapy is recommended Blood transfusion is indicated in symptomatic patients

No more than 6 doses Bleeding subsides 4-24 hrs Persistent bleeding > 24hrs requires hemostatic therapy (antifibinolytic) or uterine curettage should be considered (rare) Combined OCPs should be initiated within 24-48 hrs of IV estrogen

Maintenance Therapy
Combination OCPs
Without significant anemia (Hgb >10) With significant anemia (Hgb <10)
Cyclic therapy w/21 days + 7 days placebo

Discontinue hormonal therapy after 3-6 months to determine if a normal menstrual pattern has been established Progestin-only regimens (10mg QD X first 12 days of the month) is an alternative in pts who do not prefer contraception

Continuous daily OCPs (no placebo) until Hgb returns to normal (~3mo) followed by cyclic therapy for total of 6 months

Other Considerations
Iron therapy should be included in ALL therapeutic regimens NSAIDs
Randomized control trials have shown reduction in menstrual blood loss of 30-50% Should be started at onset of menstruation and continued until end of menses Helpful adjunct to hormonal therapy in pts with DUB and menorrhagia

Therapy:

Prognosis
DUB should resolve with maturation of the H-P-O axis Duration of time to maturity appears to be related to the age of menarche
<12 years: 50% at 1 year (% of ovulatory cycles) 12-13 years: 50% at 3 years >13 years: 50% at 4.5 years

Prognosis depends upon underlying cause