II. Epidemiology

  1. Anovulation causes 90% Dysfunctional Uterine Bleeding
  2. Age breakdown of Anovulatory Bleeding
    1. Women over age 40 years represent 50% of this group
    2. Adolescent women represent 20% of anovulatory group
  3. Common at the extremes between Menarche and Menopause
    1. Menarche: First 2-3 years with irregular cycles (immature hypothalamic-pituitary-ovarian axis)
    2. Perimenopause: Up to 8 years prior to Menopause

III. Associated Conditions

IV. Pathophysiology

  1. Anovolution results in no LH surge and no formation of a corpus luteum
    1. Progesterone is not produced
    2. Estrogen continues to stimulate endometrium (Unopposed Estrogen) for a prolonged period
  2. Unopposed Estrogen (Progesterone deficiency)
    1. Excessive endometrial proliferation, instability and variable timing of bleeding
    2. Risk of Endometrial Hyperplasia and Endometrial Cancer
  3. See Menses
  4. See Menstrual Cycle

V. Causes

  1. Immature Hypothalamic-Pituitary-Ovarian axis
    1. Frequently seen in Adolescents
    2. Follicle Stimulating Hormone released
      1. Stimulates Unopposed Estrogen release
      2. Lacks Luteinizing hormone (LH) surge
        1. No Ovulation
        2. Progesterone deficiency
      3. Results in breakthrough bleeding
  2. Polycystic Ovary Syndrome (Stein Leventhal Syndrome)
    1. Most common cause (6-10% of Abnormal Uterine Bleeding cases)
  3. Pending ovarian failure (Peri-Menopause)
    1. Common for up to 8 years prior to Menopause
  4. Body Habitus and Nutritional Status
    1. Obesity
    2. Very low calorie diets
    3. Eating Disorder (e.g. Anorexia)
  5. Intense Exercise (Female Athlete Triad)
    1. Norepinephrine affects Luteinizing hormone (LH) pulse
  6. Psychological stress
  7. Medical disorders
    1. Diabetes Mellitus (uncontrolled)
    2. Hypothyroidism or Hyperthyroidism
    3. Hyperprolactinemia
  8. Medications
    1. Anti-Seizure medications (especially Valproic Acid or Depakote)
      1. Related to associated weight gain and Hyperandrogenism
    2. Antipsychotics
      1. Related to Serum Prolactin level increase
      2. Typical Antipsychotics (Haloperidol, chlorpromazine, thiothixene)
      3. Atypical Antipsychotics (Clozapine, Risperidone)

VI. Symptoms

  1. Change in Amount and Frequency of Menstrual Bleeding
    1. General
      1. Irregular, typically infrequent menstrual periods
      2. Progesterone deficiency
    2. Low Levels of Unopposed Estradiol or Estrogens
      1. Lighter and Less Frequent Menses
    3. High Levels of Unopposed Estradiol or Estrogens
      1. Prolonged periods of Amenorrhea
      2. Heavy Withdrawal Bleeding
  2. Lack of premenstrual signs
    1. Progesterone absent: no bloating or Breast Pain

VII. Differential Diagnosis

  1. Pregnancy
  2. Immature Hypothalamic-Pituitary-Ovarian axis (Adolescent)
  3. Uncontrolled Diabetes Mellitus
  4. Eating Disorder (e.g. Anorexia)
  5. Hyperthyroidism
  6. Hypothyroidism
  7. Hyperprolactinemia
  8. Medications (see causes above)
  9. Perimenopause
  10. Polycystic Ovary Syndrome

VIII. Precautions

  1. Recurrent Anovulation causes endometrial abnormalities in 14% of cases
    1. Endometrial Hyperplasia
    2. Endometrial Cancer
  2. High risk groups
    1. See Endometrial Cancer Risks (Unopposed Estrogen)
    2. Adolescents rarely get Endometrial Cancer
      1. However, 2-3 years of recurrent Anovulation and morbid Obesity warrants evaluation

IX. Exam

  1. Observe for systemic or structural disease
  2. See Dysfunctional Uterine Bleeding causes
  3. Observe for signs of Hyperandrogenism or Polycystic Ovary Syndrome
    1. Hirsutism
    2. Obesity

XI. Indications: Abnormal Bleeding requiring evaluation

  1. Recurrent anovulatory cycles
  2. Perimenopause
    1. Increased bleeding volume or duration of bleeding
    2. Menstrual periods more often than every 21 days
    3. Postcoital bleeding
    4. Intermenstrual bleeding
  3. Adolescents (especially if morbidly obese)
    1. More than 3 months between cycles or
    2. More than 3 years of irregular cycles

XII. Protocol

  1. See Dysfunctional Uterine Bleeding for overall evaluation
  2. See Endometrial Cancer Screening
  3. Postmenopause
    1. See Postmenopausal Bleeding
    2. See Endometrial Cancer for evaluation indications
  4. Background
    1. Prior recommendations used age cut-off of 35 years, however Endometrial Cancer is uncommon age <45 years
    2. As of 2019, Age over 45 years with Abnormal Uterine Bleeding indicates evaluation
      1. Consider in age >=35, if persistent or refractory Abnormal Uterine Bleeding, or known Unopposed Estrogen
  5. Age >45 years or Endometrial Cancer Risk Factors
    1. See Endometrial Cancer Screening for complete evaluation protocol
    2. Endometrial Biopsy
      1. Required in most cases
      2. If negative then treat with Metrorrhagia Management
    3. Consider Transvaginal Ultrasound
      1. Reassuring if endometrial stripe <5 mm
      2. Does not replace Endometrial Biopsy in high risk patient
  6. Age <45 years and no Endometrial Cancer Risk Factors
    1. Trial of hormone supplementation
      1. See Metrorrhagia Management
      2. Oral Contraceptive (no higher than 35 mcg of Ethinyl Estradiol)
      3. Cyclic Progesterone
        1. Provera 10 mg daily for 10-14 days per month
    2. If results in normal cycles then
      1. Discontinue after 3-6 months
      2. If Abnormal Bleeding then Oral Contraceptive
    3. Indications for Endometrial Cancer Screening (as done for protocol above for those over age 35 years)
      1. Persistent Abnormal Uterine Bleeding despite hormonal supplementation
      2. Long-standing Unopposed Estrogen
      3. Endometrial Cancer Risk Factors
  7. Indications for referral
    1. See Endometrial Cancer Screening
    2. Desired Fertility
    3. Unresolved uterine bleeding

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Ontology: Metrorrhagia (C0025874)

Definition (MSH) Abnormal uterine bleeding that is not related to MENSTRUATION, usually in females without regular MENSTRUAL CYCLE. The irregular and unpredictable bleeding usually comes from a dysfunctional ENDOMETRIUM.
Concepts Pathologic Function (T046)
MSH D008796
ICD9 626.6
ICD10 N92.1
SnomedCT 64996003, 266605007, 198429007, 156048000, 237131005, 198428004, 198423008, 156047005, 266676009, 178522008, 266675008, 19155002, 237130006
English METRORRHAGIA, DUB - Dysf uterine bleeding, DUH - Dysf ut haemorrhage, DUH - Dysf ut hemorrhage, Dysfunctional ut haemorrhage, Dysfunctional ut hemorrhage, Dysfunctional uterine h'ge NOS, Dysfunctional uterine haemorrhage NOS, Dysfunctional uterine hemorrhage NOS, Intermenstrual bleeding-irreg., metrorrhagia (diagnosis), bleeding between periods, intermenstrual bleeding, dysfunctional uterine bleeding (diagnosis), metrorrhagia, dysfunctional uterine bleeding, bleeding between periods (symptom), DUB (dysfunctional uterine bleeding), Spotting between menses, Bleeding intermenstrual, Metrorrhagia [Disease/Finding], Bleeding;intermenstrual, uterine dysfunctional bleeding, bleeding period, bleeding dub dysfunctional uterine, dysfunctional uterine bleed, bleeding dysfunctional uterine, bleeding periods, spotting between menses, spotting between periods, spotting periods, period spotting, uterine bleeding dysfunctional, bleed period, periods bleeding, periods spotting, Dysfunctional uterine bleeding (& [NOS]) (disorder), Bleeding between periods (disorder), Metrorrhagia (& [irregular]), Bleed-irreg.intermenst., Irreg.intermenst.bleed., Dysfunctional uterine hemorrhage NOS (finding), Metrorrhagia (& [irregular]) (disorder), Dysfunctional uterine bleeding (& [NOS]), Dysfunctional uterine bleeding (disorder), INTERMENSTRUAL BLEEDING, Dysfunctional uterine bleeding, Bleeding unrelated to menstrual cycle, Irregular intermenstrual bleeding, DUB - Dysfunctional uterine bleeding, DUH - Dysfunctional uterine haemorrhage, DUH - Dysfunctional uterine hemorrhage, Dysfunctional uterine haemorrhage, Dysfunctional uterine hemorrhage, Bleeding between periods, IMB - Intermenstrual bleeding, Intermenstrual bleeding, Intermenstrual bleeding - irregular, Spotting between periods, Dysfunctional uterine bleeding (finding), Intermenstrual bleeding - irregular (finding), Bleeding between periods (finding), spotting; intermenstrual, Metrorrhagia, Bleeding, Breakthrough, Breakthrough Bleeding, Spotting, Bleeding Between Periods, Dysfunctional Uterine Bleedings, Dysfunctional Uterine Bleeding, Intermenstrual Bleeding, Uterine Bleeding, Dysfunctional
Portuguese METRORRAGIA, Hemorragia intermenstrual, Microrragia intermenstrual, Sangramento uterino disfuncional, Hemorragia uterina disfuncional, Metrorragia
Spanish METRORRAGIA, Sangrado intermenstrual, Pérdidas entre las menstruaciones, Hemorragia intermenstrual, metrorragia, sangrando no relacionado con el ciclo menstrual, sangrado intermenstrual irregular, metrorragia (hallazgo), sangrado intermenstrual anormal, sangrado intermenstrual irregular (hallazgo), Hemorragia uterina disfuncional, hemorragia uterina disfuncional, SAI (hallazgo), hemorragia uterina disfuncional, SAI, pérdidas entre períodos menstruales, sangrado intermenstrual (hallazgo), sangrado intermenstrual, sangrado uterino disfuncional (hallazgo), sangrado uterino disfuncional, Hemorragia por disfunción uterina, Metrorragia
German METRORRHAGIE, Schmierblutung zwischen Menses, Blutung zwischenmenstruell, Zwischenblutung, dysfunktionelle uterine Blutung, dysfunktionelle Uterusblutung, Metrorrhagie
Italian Emorragia disfunzionale dell'utero, Perdite intermestruali, Sanguinamento intermestruale, Emorragie intermestruali, Sanguinamenti intermestruali, Sanguinamenti tra cicli mestruali, Spotting, Sanguinamento uterino disfunzionale, Emorragia uterina disfunzionale, Metrorragia
Dutch spotting intermenstrueel, intermenstruele bloeding, disfunctionele bloedingen uit de baarmoeder, Intermenstrueel bloedverlies, spotting; intermenstrueel, metrorragie, niet-functionele baarmoederlijke bloeding, Metrorragie
French Pertes intermenstruelles, Hémorragie intermenstruelle, METRORRAGIES, Hémorragie utérine dysfonctionnelle, Metrorragie, Métrorragies fonctionnelles, Métrorragie
Japanese 中間期出血, 月経中間期出血, 月経期外小出血, ゲッケイチュウカンキシュッケツ, フセイシキュウシュッケツ, チュウカンキシュッケツ, ゲッケイキガイショウシュッケツ, 子宮出血-不正, 機能不全性子宮出血, キノウフゼンセイシキュウシュッケツ, 不正子宮出血
Swedish Mellanblödning
Czech metroragie, Intermenstruační krvácení, Dysfunkční děložní krvácení, Špinění mezi menses, Metroragie, Dysfunkční krvácení z dělohy, Dysfunkční děložní hemoragie
Finnish Metrorragia
Polish Krwotok maciczny
Hungarian Dysfunctionalis méhvérzés, közti vérzés, Metrorrhagia, Mentruációk közötti vérzés, Mensesek között peccséltelés
Norwegian Metroragi, Uregelmessig intermenstruell blødning

Ontology: Anovular menstruation (C0404557)

Concepts Pathologic Function (T046)
SnomedCT 27585009
English Anovulatory dysf bleeding, anovulatory bleeding, anovulatory bleeding (diagnosis), Bleeding anovulatory, anovulatory bleed, Anovulatory haemorrhage, Anovulatory hemorrhage, Anovular menstruation, Anovulatory bleeding, Anovulatory dysfunctional bleeding, Anovular menstruation (finding)
Italian Emorragia anovulatoria
Japanese 無排卵性出血, ムハイランセイシュッケツ
Czech Anovulační krvácení, Anovulační hemorhagie, Anovulační hemoragie
Hungarian Anovulatiós vérzés
French Hémorragie anovulatoire, Saignement anovulatoire
German Anovulatorische Haemorrhagie, Blutung anovulatorisch
Spanish menstruación anovular, menstruación anovulatoria (hallazgo), menstruación anovulatoria, sangrado anovulatorio, Hemorragia anovulatoria
Portuguese Hemorragia anovulatória
Dutch anovulatoire bloeding