Amenorrhea

Aka: Amenorrhea, Amenorrhea Causes, Uterine Outflow Tract Obstruction

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II. Types

  1. Primary Amenorrhea
    1. No secondary sexual characteristics by 13 years old or
    2. No menstrual period by (failure to reach Menarche by):
      1. Fifteen years old or
      2. Three years after initial Breast development (Thelarche)
  2. Secondary Amenorrhea
    1. Previously regular cycles: 3 months of no Menses
    2. Previously irregular cycles: 6 months of no Menses

III. Causes: Axis 1 - Hypothalamus

  1. Primary Amenorrhea (congenital causes)
    1. Anovulation (10% of primary causes)
    2. Constitutional (6% of primary causes): Family History
    3. Gonadotropin deficiency such as Kallmann's Syndrome (Rare): Associated with Anosmia
  2. Secondary Amenorrhea (acquired causes)
    1. Anovulation (50% of secondary causes)
    2. Post-Hor monal Contraception (Post-Pill)
    3. CNS injury
      1. Traumatic Brain Injury
      2. Meningitis
      3. CNS Neoplasm
      4. Brain Radiation
      5. Infiltrative or autoimmune (e.g. Sarcoidosis)
    4. Functional Hypothalamic Amenorrhea
      1. Eating Disorder (e.g. Anorexia Nervosa)
      2. Female Athlete Triad
      3. Malabsorption, Malnutrition or rapid weight loss

IV. Causes: Axis 2 - Pituitary

  1. Primary Amenorrhea (congenital causes)
    1. Hyperprolactinemia (2% of primary causes)
    2. Pituitary Tumor (8% of primary causes)
      1. Pituitary Adenoma (Hormone producing)
      2. Pituitary Null Cell Tumor (No Hormone produced)
      3. Empty Sella Syndrome
      4. Pituitary Tuberculosis
      5. Pituitary Schistosomiasis
  2. Secondary Amenorrhea (acquired causes)
    1. Hyperprolactinemia (25% of secondary causes)
      1. See Medication Causes of Hyperprolactinemia
    2. Sheehan Syndrome (infarction, rare)
    3. Hypothyroidism (1% of secondary causes): Prolactin-like effect
    4. Pituitary infiltration (e.g. Sarcoidosis)
    5. Cushing Syndrome

V. Causes: Axis 3 - Ovarian insufficiency

  1. Primary Amenorrhea (congenital causes)
    1. Polycystic Ovary Syndrome (10% of primary causes)
      1. Findings: Obesity, Hirsutism, and Acne Vulgaris
    2. Turners Syndrome and Mosaics (30% of primary causes)
      1. Findings: Short Stature, Web neck, and Shield Chest
    3. Genetic Male (10% of primary causes)
    4. Gonadal dysgenesis (other than Turner Syndrome)
  2. Secondary Amenorrhea (acquired causes)
    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)

VI. Causes: Axis 4: Uterus (Uterine Outflow Tract Obstruction and abnormalities)

  1. Primary Amenorrhea (congenital causes)
    1. Mullerian Agenesis (20% of primary causes)
      1. Mayer-Rokitansky-Kuster-Hauser Syndrome
    2. Imperforate Hymen
    3. Transverse vaginal septum
    4. Complete androgen resistance or androgen insensitivity syndrome
    5. 5a-reductase Deficiency
  2. Secondary Amenorrhea (acquired causes)
    1. Asherman Syndrome (5% of secondary causes)
    2. Endometritis
    3. Cervical stenosis

VII. Causes: Miscellaneous

  1. Other endocrine causes
    1. See Hypoandrogenism
    2. Late-Onset Congenital Adrenal Hyperplasia (adult onset)
    3. Androgen-Secreting tumor
    4. Adrenal Insufficiency
    5. Cushing Syndrome
    6. Diabetes Mellitus (uncontrolled)
    7. Polycystic Ovary Syndrome
    8. Hypothyroidism
  2. Chronic Disease
    1. Celiac Disease
    2. Inflammatory Bowel Disease
  3. Physiologic causes
    1. Pregnancy!
    2. Lactation
    3. Contraception
    4. Menopause
    5. Exogenous androgens

VIII. History

  1. Sexual Development History (if possible Primary Amenorrhea)
    1. Breast development
    2. Pubic hair development
  2. Menstrual and Gynecologic history
    1. Age at Menarche
    2. Menstrual Cycle characteristics
    3. Premenstrual symptoms
    4. Sexual Activity
  3. Family History
    1. Genetic anomaly
    2. Menarche age of onset in first degree relatives
  4. Obstetric history
  5. Past medical history
    1. Chronic disease history
    2. Chemotherapy
    3. Radiation Therapy
  6. Medications (including Substance Abuse)
    1. See Medication Causes of Hyperprolactinemia
    2. See Medication Causes of Abnormal Uterine Bleeding
  7. Eating Disorder or Female Athlete Triad (Functional Hypothalamic Amenorrhea)
    1. Diet, Weight change, or Eating Disorder
    2. Overtraining or Exercise addiction
    3. History of Stress Fractures
  8. Prolactinoma symptoms
    1. Galactorrhea
    2. Headache
    3. Bitemporal field cut
  9. Hyperandrogenism or Polycystic ovary symptoms and signs
    1. Hirsutism
    2. Acne Vulgaris
  10. Growth abnormalities
    1. Short Stature (Turner Syndrome)
  11. Other history
    1. Vasomotor Symptoms of Menopause (e.g. Hot Flushes)
    2. Hypothyroidism symptoms (cold intolerance, Palpitations, Constipation, Major Depression)
    3. Anosmia (Kallmann Syndrome)

IX. Examination

  1. Breast Exam
    1. Normal Breast development suggests circulating Estrogens (Primary Amenorrhea)
    2. Galactorrhea (Hyperprolactinemia)
  2. Gynecologic exam
    1. Rule out uterine or ovarian anomaly
    2. Vaginal Atrophy (red or thin vaginal mucosa)
      1. Low Estrogen
    3. Transverse septum or Imperforate Hymen
      1. Outflow tract obstruction
    4. Shortened Vagina
      1. Uterine outflow obstruction
      2. Mullerian Agenesis
    5. Absent Cervix or Uterus
      1. Mullerian Agenesis
      2. Androgen Insensitivity Syndrome
    6. Clitoromegaly
      1. Androgen Secreting tumor
      2. Congenital Adrenal Hyperplasia
      3. 5a-Reductase Deficiency
  3. Body Mass Index (and height and weight)
    1. Low BMI in Functional Hypothalamic Amenorrhea
    2. High in Polycystic Ovary Syndrome
  4. Hyperandrogenism or Polycystic Ovary Syndrome
    1. Hirsutism
    2. Acne Vulgaris
    3. Acanthosis Nigricans
    4. Male pattern baldness
  5. Other focus areas
    1. Cushing's Disease
      1. Central Obesity
      2. Buffalo Hump
      3. Hypertension
      4. Hirsutism
      5. Wide, purple abdominal and thigh striae
    2. Thyromegaly
    3. Turner Syndrome
      1. Webbed Neck
      2. Short Stature
      3. Low hairline

X. Labs: First-Line

  1. Urine Pregnancy Test (UPT)
  2. Thyroid Stimulating Hormone (TSH)
  3. Serum Prolactin
    1. Mildly decreased
      1. Functional Hypothalamic Amenorrhea
    2. Mildly increased
      1. Polycystic Ovary Syndrome (PCOS)
    3. Significantly increased
      1. See Hyperprolactinemia
      2. See Medication Causes of Hyperprolactinemia
      3. Pituitary Adenoma
      4. Hypothyroidism
  4. Serum Luteinizing Hormone (LH) and Serum Follicle Stimulating Hormone (FSH)
    1. Decreased
      1. Functional Hypothalamic Amenorrhea
      2. Constitutional delay of Puberty
      3. Congenital Adrenal Hyperplasia (CAH)
    2. Normal
      1. Outflow tract obstruction
      2. Non-endocrine causes of Amenorrhea
      3. Polycystic Ovary Syndrome (PCOS) - may also be low normal
    3. Increased
      1. Primary Ovarian Insufficiency
      2. Menopause
      3. Turner Syndrome

XI. Labs: Second-Line

  1. Karyotype
    1. Turner Syndrome (45 X with one missing X)
    2. Mullerian Agenesis (46 XX)
    3. Genetic Male (46 XY) with male-range Serum Testosterone
      1. Androgen Insensitivity Syndrome
      2. 5A-Reductase Deficiency
  2. Serum Testosterone
    1. Mildly decreased
      1. Functional Hypothalamic Amenorrhea
      2. Menopause
      3. Primary Ovarian Insufficiency
    2. Mildly increased Testosterone
      1. Polycystic Ovary Syndrome (PCOS)
    3. Increased to male range Testosterone
      1. See Hyperandrogenism
      2. Congenital Adrenal Hyperplasia
      3. Adrenal or ovarian tumor
      4. Cushing Syndrome
      5. Genetic male
        1. Androgen insensitivity syndrome
        2. 5a-Reductase Deficiency
  3. 17-Hydroxyprogesterone (17-OHP, obtained at 8 am)
    1. Increased
      1. Congenital Adrenal Hyperplasia (late onset)
  4. Dehydroepiandrosterone Sulfate (DHEA-S)
    1. Mildly increased
      1. Congenital Adrenal Hyperplasia
      2. Hyperprolactinemia
      3. Polycystic Ovary Syndrome (PCOS)
  5. Anti-Mullerian Hormone (AMH)
    1. Decreased
      1. Primary Ovarian Insufficiency
      2. Menopause
    2. Mildly increased
      1. Polycystic Ovary Syndrome (PCOS)
    3. Increased
      1. Functional Hypothalamic Amenorrhea
  6. Serum Estradiol
    1. Decreased in poor ovarian function (low in most Amenorrhea except for outflow obstruction)

XII. Imaging: First-Line

  1. Pelvic Ultrasound
    1. Evaluate uterine structure
    2. Uterine outflow obstruction

XIII. Imaging: Second-Line (as indicated)

  1. MRI Adrenal Glands
    1. Androgen Secreting adrenal tumor
  2. MRI Brain with sella turcica
    1. Pituitary Adenoma
  3. DEXA Scan
    1. Evaluate Fracture risk
    2. Primary Ovarian Insufficiency
    3. Functional Hypothalamic Amenorrhea

XIV. Evaluation

  1. See Primary Amenorrhea
  2. See Secondary Amenorrhea

XV. References

  1. Klein (2019) Am Fam Physician 100(1): 39-48 [PubMed]
  2. Klein (2013) Am Fam Physician 87(11): 781-88 [PubMed]
  3. (2008) Fertil Steril 90(5 suppl): S219-25 [PubMed]

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