Primary Amenorrhea

Aka: Primary Amenorrhea, Delayed Menarche, Late Menarche

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II. Definitions

  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
  3. Oligomenorrhea
    1. Cycle greater than 35 day cycles (>45 days in adolescents)

III. Causes

  1. See Hypogonadism
  2. Axis 1: Hypothalamus or Central
    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
  3. Axis 2: Pituitary
    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
  4. Axis 3: Ovarian
    1. Polycystic Ovary Syndrome (10% of primary causes)
      1. Findings: Obesity, Hirsutism, and Acne Vulgaris
    2. Turner Syndrome and Mosaics (30% of primary causes)
      1. Findings: Short Stature, Web neck, and Shield Chest
      2. May present as Amenorrhea and Short Stature alone
    3. Genetic Male (10% of primary causes)
    4. Gonadal dysgenesis
  5. Axis 4: Uterus
    1. Mullerian Agenesis (20% of primary causes)
      1. Mayer-Rokitansky-Kuster-Hauser Syndrome
    2. Imperforate Hymen
    3. Transverse vaginal septum
    4. Complete androgen resistance

IV. History

  1. See Amenorrhea

V. Exam

  1. See Amenorrhea

VI. Labs

  1. See Amenorrhea
  2. First Line
    1. Pregnancy Test (HCG)
    2. Serum LH
    3. Serum FSH
    4. Serum Prolactin
    5. Serum TSH
  3. Advanced Testing for Hyperandrogenism Findings
    1. Serum Free Testosterone
    2. Serum Total Testosterone
    3. Dehydroepiandrosterone
  4. Other testing
    1. 17-Hydroxyprogesterone (8 am, Congenital Adrenal Hyperplasia)
    2. Antimullerian Hormone (premature ovarian insufficiency)
    3. Karyotype Indications
      1. Hypergonadotropic Hypogonadism
      2. Short Stature
      3. Abnormal female anatomy
      4. Noniatrogenic premature ovarian insufficiency

VII. Imaging

  1. See Amenorrhea
  2. Pelvic Ultrasound (first-line)
    1. Evaluate for Uterine presence (or signs of outflow obstruction)
  3. Advanced Imaging
    1. Abdomen and Pelvis MRI Indications
      1. Abnormal reproductive anatomy
      2. Androgen Secreting tumors (Adrenal Adenoma)
    2. Brain MRI Indications
      1. Pituitary and other CNS Lesions

VIII. Evaluation: Protocol based on LH, FSH and Pelvic Ultrasound

  1. Obtain first-line testing as above
    1. Manage positive Pregnancy Test (including Ectopic Pregnancy consideration)
    2. Manage Hypothyroidism
    3. Evaluate Hyperprolactinemia
  2. Uterus Present
    1. Low Serum FSH and Serum LH (Hypogonadotropic Hypogonadism)
      1. GnRH Deficiency (rare)
      2. Functional Hypothalamic Amenorrhea (e.g. Relative Energy Deficiency in Sport)
      3. Constitutional delay of Puberty
    2. Normal Serum FSH and Serum LH (Normogonadotropic Hypogonadism)
      1. Consider Obstruction to flow
        1. Imperforate Hymen
        2. Transverse vaginal septum
      2. Consider Hyperandrogenism (e.g. Hirsutism)
        1. Polycystic Ovary Syndrome
        2. Adrenal tumor
        3. Ovarian tumor
      3. Consider other causes
        1. See Secondary Amenorrhea
        2. Delayed Puberty
        3. New pituitary Tumor
    3. High Serum FSH and Serum LH (Hypergonadotropic Hypogonadism)
      1. Reflects Primary Ovarian Insufficiency
      2. Karyotype
        1. Karyotype 46 XX (normal)
          1. Suggests pituitary Defect
        2. Turner Syndrome
          1. Monosomy X (45,X)
          2. Mosaicism (e.g. 45,X / 46,XX)
        3. Y Chromatin (Y Chromosome)
          1. Swyer syndrome (46,XY gonadal dysgenesis)
          2. Mosaic Turner Syndrome
      3. Other Primary Ovarian Insufficiency labs
        1. FMR1 Gene Premutation (fragile-X gene)
        2. 21-Hydroxylase autoantibodies (Autoimmune Adrenalitis and Addison's Disease)
        3. Premature Ovarian Insufficiency secondary to Autoimmune Polyendocrine Syndrome
  3. Uterus Absent
    1. Obtain Karyotype, Free Testosterone and Total Testosterone
    2. Female range Serum Testosterone and 46 XX
      1. Mullerian Agenesis
    3. Male range Serum Testosterone and 46 XY (genetic male)
      1. Androgen Insensitivity Syndrome (Male Pseudo-Hermaphrodite)
      2. 5a-Reductase Deficiency

IX. Evaluation: Protocol based on Growth and Development (Female Tanner Stage, Delayed Linear Growth, Uterus Presence)

  1. Obtain first-line testing as above
    1. Manage positive Pregnancy Test
    2. Manage Hypothyroidism
    3. Manage Hyperprolactinemia
  2. Abnormal Breast development and Female Tanner Stage
    1. Normal Height with low gonadotopins (FSH, LH <5 IU)
      1. See Hypogonadotropic Hypogonadism
      2. Obtain Karyotype (previously Buccal Smear)
        1. Karyotype normal
          1. GnRH Deficient (rare)
          2. Functional Hypothalamic Amenorrhea
          3. Constitutional delay of Puberty
        2. Karyotype abnormal
          1. Pure Gonadal dysgenesis
    2. Short Height and excess gonadotropins (FSH>20, LH>40)
      1. See Hypergonadotropic Hypogonadism
      2. Reflects Primary Ovarian Insufficiency
      3. Obtain Karyotype (previously Buccal Smear)
        1. Karyotype 46 XX
          1. Pituitary Defect
        2. Karyotype 45 XO
          1. Turner's Syndrome
  3. Normal Breast development and Female Tanner Stage
    1. See Normogonadotropic Hypogonadism
    2. Uterus Absent on Ultrasound
      1. Karyotype (previously Buccal Smear)
      2. Karyotype 46 XX
        1. Mullerian agenesis (Mullerian Dysgenesis)
        2. Serum Testosterone in normal female range
      3. Karyotype 46 XY (genetic male)
        1. Androgen insensitivity syndrome (Male Pseudo-Hermaphrodite)
        2. 5a-Reductase Deficiency
        3. Serum Testosterone in normal Male range
    3. Uterus Present on Ultrasound
      1. Consider obstruction to flow
        1. Imperforate Hymen
        2. Transverse vaginal septum
      2. Consider Hyperandrogenism (e.g. Hirsutism)
        1. Polycystic Ovary Syndrome
        2. Adrenal tumor
        3. Ovarian tumor
      3. Consider other causes
        1. See Secondary Amenorrhea
        2. Delayed Puberty
        3. New pituitary Tumor

X. 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. Pletcher (1999) Pediatr Clin North Am 46:505-18 [PubMed]
  6. Timmreck (2003) Obstet Gynecol Clin North Am 30:287-302 [PubMed]

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