Anovulatory Bleeding

Aka: Anovulatory Bleeding, Metrorrhagia, Polymenorrhea, Oligomenorrhea

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II. Definitions

  1. Metrorrhagia
    1. Change in Amount and Frequency of bleeding, associated with Anovulatory Bleeding
    2. Deprecated term ("imprecise")
  2. Polymenorrhea
    1. Cycle less than 21 day cycles
  3. Oligomenorrhea
    1. Cycle greater than 35 day cycles (>45 days in adolescents)
    2. Typically approached as Amenorrhea

III. 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

IV. Associated Conditions

  1. Endometrial Cancer
    1. Unopposed Estrogen Relative Risk: 3 fold
    2. See Endometrial Cancer for evaluation indications

V. 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

VI. 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)

VII. 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 (Oligomenorrhea)
      2. Heavy Withdrawal Bleeding
  2. Lack of premenstrual signs
    1. Progesterone absent: no bloating or Breast Pain

VIII. 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

IX. 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

X. 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. Labs

  1. Initial
    1. Urine Pregnancy Test (hCG)
    2. Thyroid Stimulating Hormone (TSH)
    3. Serum Prolactin
  2. Additional labs to consider
    1. Complete Blood Count (CBC)
    2. Glucose to Insulin Ratio
      1. Abnormal in Polycystic Ovary Syndrome

XII. 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

XIII. 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

XIV. Management

  1. See Metrorrhagia Management
  2. See Endometrial Cancer Screening

XV. References

  1. Nelson (1997), Fam Prac Recert 19(8):14
  2. Buchanan (2009) Am Fam Physician 80(10): 1075-88 [PubMed]
  3. Sweet (2012) Am Fam Physician 85(1): 35-43 [PubMed]
  4. Wouk (2019) Am Fam Physician 99(7): 435-43 [PubMed]

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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, ｹﾞ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, ｹﾞｯｹｲｷｶﾞｲｼｮｳｼｭｯｹﾂ, 子宮出血-不正, 機能不全性子宮出血, ｷﾉｳﾌｾﾞ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
Russian METRORRAGIIA, МЕТРОРРАГИЯ
Croatian METRORAGIJA
Polish Krwotok maciczny
Hungarian Dysfunctionalis méhvérzés, közti vérzés, Metrorrhagia, Mentruációk közötti vérzés, Mensesek között peccséltelés
Norwegian Metroragi, Uregelmessig intermenstruell blødning
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Oligomenorrhea (C0028949)

Definition (NCI) Infrequent menstrual periods.(NICHD)
Definition (MSH) Abnormally infrequent menstruation.
Concepts Pathologic Function (T046)
MSH D009839
ICD10 N91.5
SnomedCT 52073004, 266670003, 52788002, 198416007, 156042004
English Oligomenorrhea, Oligomenorrheas, OLIGOMENORRHEA, OLIGOMENORRHOEA, Oligomenorrhea, unspecified, Oligomenorrhoea, unspecified, Oligomenorrhea NOS, Abnormal long menstrual cycle, oligomenorrhea (diagnosis), oligomenorrhea, Menses infrequent, Oligomenorrhoea NOS, Oligomenorrhea [Disease/Finding], oligomenorrhoea, Oligomenorrhoea (disorder), Infrequent periods, Oligomenorrhoea, Relative amenorrhea, Relative amenorrhoea, Infrequent menstruation, Oligomenorrhea (finding), Infrequent menstruation (finding)
French OLIGOMENORRHEE, Oligoménorrhée SAI, Spanioménorrhée, Oligoménorrhée
Portuguese OLIGOMENORREIA, Oligomenorreia NE, Menstruação infrequente, Oligomenorreia
Spanish OLIGOMENORREA, Menstruación infrecuente, Oligomenorrea NEOM, amenorrea relativa, ciclo menstrual anormalmente largo, menstruación infrecuente, oligomenorrea (hallazgo), oligomenorrea, períodos infrecuentes, Oligomenorrea
German OLIGOMENORRHOE, Oligomenorrhoe NNB, Menses selten, Oligomenorrhoe, nicht naeher bezeichnet, Oligomenorrhoe
Dutch oligomenorroe NAO, infrequente menses, Oligomenorroe, niet gespecificeerd, oligomenorrhoea, Oligomenorroe
Italian Mestruazioni infrequenti, Oligomenorrea NAS, Oligomenorrea
Japanese 希発月経, 希発月経ＮＯＳ, ｷﾊﾂｹﾞｯｹｲ, ｷﾊﾂｹﾞｯｹｲNOS
Swedish Menstruation, sällan förekommande
Czech oligomenorea, Oligomenorea NOS, Málo časté menses, Oligomenorea
Finnish Oligomenorrea
Russian OLIGOMENORRAGIIA, ОЛИГОМЕНОРРАГИЯ
Korean 상세불명의 희발월경
Polish Miesiączkowanie sporadyczne
Hungarian Ritka menses, oligomenorrhoea, Oligomenorrhoea, Oligomenorrhoea k.m.n.
Norwegian Oligomenoré, Lange menstruasjonsintervaller
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Polymenorrhea (C0032519)

Concepts Disease or Syndrome (T047)
MSH D008599
ICD10 N92.0
SnomedCT 156043009, 266671004, 43619008, 198418008, 52754008
English Polymenorrheas, polymenorrhea, polymenorrhea (diagnosis), Menstrual cycle shortened, Shortening of menstrual cycle, Frequency of menses, Menstruation frequent, Polymennorhoea, menses frequent, frequent menses, Menstruation;frequent, epimenorrhoea, polymenorrheas, Abnormal short menstrual cycle, Abnormal short menstrual cycle (finding), Frequent menses, Unusually frequent menses, Epimenorrhea, Epimenorrhoea, Polymenorrhoea, Polymenorrhea (finding), epimenorrhea, frequent; menstruation, menstruation; frequent, Abnormal short menstrual cycle (finding) [Ambiguous], Polymenorrhea, polymenorrhoea, frequent menstruation
Dutch menstruatiefrequentie, verkorte menstruele cyclus, epimenorroe, verkorting van menstruele cyclus, menstruatie vaak, frequent; menstruatie, menstruatie; frequent, polymenorroe, Polymenorroe
French Menstruation fréquente, Fréquence des règles, Cycle menstruel raccourci, Epiménorrhée, Epimenorrhée, Raccourcissement du cycle menstruel, Polyménnorhée, Polyménorrhée
German Epimenorrhoe, Polymennorhoe, Haeufigkeit der Menses, Menstruation haeufig, Menstruationszyklus verkuerzt, Verkuerzung des Menstruationszyklus, Polymenorrhoe
Italian Frequenza delle mestruazioni, Abbreviazione del ciclo mestruale, Mestruazioni frequenti, Ciclo mestruale abbreviato, Epimenorrea, Polimenorrea
Portuguese Epimenorreia, Ciclo menstrual encurtado, Menstruações frequentes, Encurtamento do ciclo menstrual, Menstruação frequente, Polimenorreia
Spanish Epimenorrea, Menstruaciones frecuentes, Ciclo menstrual acortado, Acortamiento del ciclo menstrual, Menstruación frecuente, Polimenorrea, ciclo menstrual anormalmente corto (hallazgo), ciclo menstrual anormalmente corto, epimenorrea, ciclo menstrual anormalmente corto (concepto no activo), menstruación extraordinariamente frecuente, polimenorrea (hallazgo), polimenorrea
Japanese 月経周期短縮, 頻発月経, ﾋﾝﾊﾟﾂｹﾞｯｹｲ, ｹﾞｯｹｲｼｭｳｷﾀﾝｼｭｸ
Czech Častá menstruace, Časté krvácení, Polymenorea, Polymenorrhoea, Epimenorea, Zkrácený menstruační cyklus, Frekvence menses, Zkrácení menstruačního cyklu, polymenorrhoea, polymenorea
Hungarian Gyakoribb menses, Gyakori menstruatiós vérzés, Polymenorrhea, Epimenorrhoea, Menstruatiós cyclus rövidülés, Gyakori menstruatio, Polymenorrhoea, Megrövidült menstruatiós cyclus
Norwegian Hyppig menstruasjonsblødning, Polymenoré, Korte menstruasjonsintervaller
Derived from the NIH UMLS (Unified Medical Language System)

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
Derived from the NIH UMLS (Unified Medical Language System)

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