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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