Secondary Amenorrhea

Aka: Secondary Amenorrhea

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II. Definitions

  1. Secondary Amenorrhea
    1. Previously regular cycles: 3 months of no Menses
    2. Previously irregular cycles: 6 months of no Menses

III. Causes: Axis Associated

  1. See Hypogonadism
  2. Axis 1: Hypothalamic or Central
    1. Anovulation (50% of secondary causes)
    2. Post-Hor monal Contraception (Post-Pill Amenorrhea)
    3. CNS injury
      1. Traumatic Brain Injury
      2. Meningitis
      3. CNS Neoplasm
    4. Functional Hypothalamic Amenorrhea
      1. Eating Disorder (e.g. Anorexia Nervosa)
      2. Malabsorption, Malnutrition or rapid weight loss
  3. Axis 2: Pituitary
    1. Hyperprolactinemia (25% of secondary causes)
      1. See Medication Causes of Hyperprolactinemia
    2. Sheehan Syndrome (rare)
    3. Hypothyroidism (1% of secondary causes): Prolactin-like effect
    4. Pituitary infiltration (e.g. Sarcoidosis)
    5. Cushing Syndrome
  4. Axis 3: Ovary
    1. Polycystic Ovary Syndrome (8% of secondary causes)
    2. Premature Ovarian Failure (10% of secondary causes)
    3. Oophoritis (rare)
      1. Chemotherapy or Radiation
      2. Infection (e.g. Mumps, Tuberculosis)
  5. Axis 4: Uterus
    1. Asherman's Syndrome (5%)
    2. Endometritis
    3. Cervical stenosis

IV. Causes: Miscellaneous

  1. Other endocrine causes
    1. See Hypoandrogenism
    2. Adrenal hyperplasia (adult onset)
    3. Androgen-Secreting tumor
    4. Cushing Syndrome
    5. Polycystic Ovary Syndrome
    6. Severe Hyperthyroidism
  2. Physiologic causes
    1. Pregnancy!
    2. Lactation
    3. Contraception
    4. Menopause
    5. Exogenous androgens

V. Pathophysiology: Mechanisms

  1. Luteal Phase dysfunction
    1. Insufficient Progesterone
  2. Anovulation
    1. Unopposed Estrogen leads to long cycles
  3. Hypoestrogenemia (Most common)
    1. Able to conceive

VI. History

  1. See Amenorrhea

VII. Exam

  1. See Amenorrhea

VIII. Labs

  1. See Amenorrhea
  2. Pregnancy Test (HCG)
  3. See Markers of Ovarian Reserve
  4. Anti-Mullerian Hormone
  5. Serum LH
  6. Serum FSH
  7. Serum Prolactin
  8. Serum TSH

IX. Imaging

  1. See Amenorrhea
  2. Pelvic Ultrasound

X. Evaluation: Based on FSH, LH

  1. See Amenorrhea
  2. Step 0: Evaluate labs in Amenorrhea as above (HCG, Serum LH, Serum FSH, TSH, Serum Prolactin)
    1. Pregnancy
    2. Hypothyroidism or Hyperthyroidism
    3. Hyperprolactinemia (especially if >100 ng/ml)
  3. Step 1: Serum FSH and Serum LH increased
    1. Confirm with repeat Serum LH and Serum FSH in one month
    2. Additional labs if confirmed elevated Serum LH and Serum FSH
      1. Obtain karyotype for Turner Syndrome if Short Stature
      2. Consider Serum Estradiol
    3. Diagnosis
      1. Primary Ovarian Insufficiency (Premature Ovarian Failure)
      2. Menopause
      3. Turner Syndrome (Short Stature, 45 XO)
  4. Step 2a: Hyperandrogenism findings
    1. Evaluation
      1. Serum Androgens (Serum Testosterone and DHEA-S)
        1. Consider adrenal or ovarian tumor if very high androgen levels or rapid onset of symptoms
      2. 17-Hydroxyprogesterone (at 8 am)
        1. Consider late-onset Congenital Adrenal Hyperplasia
    2. Diagnosis (if normal serum androgens and 17-Hydroxyprogesterone)
      1. Polycystic Ovary Syndrome (PCOS)
  5. Step 2b: Pituitary or other CNS Lesion suspected (e.g. Headache, Vision change)
    1. Evaluation
      1. Head MRI or Head CT with cone-down sella turcica views
    2. Diagnosis
      1. Pituitary Lesion
  6. Step 2c: Functional Hypothalamic Amenorrhea suspected
    1. Evaluation
      1. Nutritional History
      2. Eating Disorder history
    2. Diagnosis
      1. Femal athlete triad
      2. Poor nutritional status
  7. Step 2d: Structural abnormality suspected
    1. Evaluation
      1. Consider Oral Contraceptive cycling trial (failed trial suggests structural abnormality)
      2. Consider Hysteroscopy
    2. Diagnosis
      1. Outflow obstruction
      2. Uterine abnormality

XI. Evaluation: Based on Progesterone Challenge

  1. See Amenorrhea
  2. Step 0: Evaluate labs in Amenorrhea as above (HCG, Serum LH, Serum FSH, TSH, Serum Prolactin)
    1. Pregnancy
    2. Hypothyroidism or Hyperthyroidism
    3. Hyperprolactinemia (especially if >100 ng/ml)
  3. Step 1: Progesterone Challenge Test
    1. Precaution: Inconsistent results
  4. Step 2a: Any bleeding with Progesterone Challenge Test (within 7 days)
    1. Suggests Progesterone insufficiency (Anovulation)
      1. Unopposed Estrogen with risk of Endometrial Cancer
    2. Option 1: Treat Anovulation empirically (especially if otherwise asymptomatic)
      1. Provera 10 mg daily for 10 days per month or
      2. Oral Contraceptives
    3. Option 2: Check serum Luteinizing Hormone (LH)
      1. Luteinizing Hormone (LH) High
        1. Polycystic Ovary Syndrome
          1. Androgen Excess
          2. Unopposed Estrogen
        2. Management
          1. Progesterone cycling (see above regarding Unopposed Estrogen)
      2. Luteinizing Hormone (LH) Low or Normal
        1. Hypothalamic Amenorrhea
          1. Eating Disorder
          2. Chronic illness
          3. Pituitary Lesion (may present with Headaches and Vision changes)
        2. Evaluation
          1. Check Pituitary MRI or CT (Cone down Sella)
  5. Step 2b: No Bleeding occurs with Progesterone Challenge
    1. Ascertain Estrogen Level
      1. Perform Estrogen-Progesterone Challenge Test or
      2. Check Serum Estrogen level
    2. Estrogen Normal (no bleeding occurs with OCP)
      1. Suggests uterine bleeding outflow obstruction
      2. Example: abnormal Uterus (e.g. Asherman's Syndrome)
    3. Estrogen Low (bleeding occurs with OCP)
      1. Obtain Serum FSH and Serum LH
      2. Serum FSH and Serum LH <5
        1. See Hypogonadotropic Hypogonadism
        2. Hypothalamic origin
        3. Check Pituitary MRI or CT (Cone down Sella)
      3. Serum FSH >20 and Serum LH >40
        1. See Hypergonadotropic Hypogonadism
        2. Suggests ovarian failure
        3. Female Athlete Triad
        4. Premature Ovarian Failure

XII. References

  1. (2008) Fertil Steril 90(5 suppl): S219-25 [PubMed]
  2. Klein (2019) Am Fam Physician 100(1): 39-48 [PubMed]
  3. Klein (2013) Am Fam Physician 87(11): 781-88 [PubMed]
  4. Master-Hunter (2006) Am Fam Physician 73:1374-87 [PubMed]
  5. Mclver (1997) Mayo Clin Proc 72:1161-9 [PubMed]

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