Amenorrhea

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Today we will be tackling the topic of amenorrhea.  We will dive into the etiologies, diagnosis, and management of both primary and secondary amenorrhea. Several condition can cause amenorrhea. These underlying conditions present with varying findings; therefore, it is crucial to keep your mind open, and your differential broad.

Primary Amenorrhea

Primary amenorrhea is defined as the failure to reach menarche. An evaluation should be considered if:

  • At age 13, the patient has not had menses and has had no development of secondary sex characteristics
  • At age 15, the patient has not had menses, but has developed normal secondary sex characteristics
  • Or if menarche has not occurred five years after initial breast formation.

Secondary Amenorrhea

The halting of previously regular menses for three months or past irregular menses for six months is considered secondary amenorrhea. 

 

Causes of Primary Amenorrhea

 

Primary amenorrhea will often be found to be due to chromosomal irregularities that lead to primary ovarian insufficiency such as Turner syndrome, or anatomic abnormalities such as Mullerian agenesis. 

 

Causes of Secondary Amenorrhea

 

The majority of pathologic cases of secondary amenorrhea are caused by:

  • Polycystic ovarian syndrome (PCOS)
  • Hyperprolactinemia
  • Hypothalamic amenorrhea
  • Primary ovarian insufficiency

 

The Evaluation of Amenorrhea

 

It can be helpful to think about all of the potential causes of amenorrhea in subsets.  These can include:

  • Primary dysfunction of the ovary
  • Anatomic defects in the outflow tract
  • Systemic disease affecting the hypothalamic-pituitary-gonadal axis
  • Disruption of hypothalamic or pituitary function
  • Pathology of other endocrine organs
Major Causes of Amenorrhea

Am Fam Physician. 2013;87(11):781-788. Copyright © 2013 American Academy of Family Physicians

 

First things first, as with every patient, take a history and complete the physical examination.  These two things along with laboratory studies will often point you towards the right direction.

 

Findings in the Evaluation of Amenorrhea
Am Fam Physician. 2013;87(11):781-788. Copyright © 2013 American Academy of Family Physicians

 

Initial Evaluation

 

In all cases, pregnancy should be initially ruled out as a cause for the patient's amenorrhea.  The initial evaluation steps are similar in patients with either type of amenorrhea; however, in those patients with primary amenorrhea, the need to figure out if these patients have a uterus or not is paramount.

 

Diagnosis of Primary Amenorrhea
Am Fam Physician. 2013;87(11):781-788. Copyright © 2013 American Academy of Family Physicians

 

 

History

Patients should be asked:

  • about their exercise and eating patterns
  • past menstrual history
  • unwanted weight loss or gain
  • chronic illnesses
  • medications
  • presence of galactorrhea
  • abnormal thyroid function
  • androgen excess
  • or vasomotor symptoms

 

Family and Social History

 

Taking a sexual history can help support the results of, but cannot replace, the pregnancy test.  Family history should include a history of chronic illnesses as well as the age of menarche of other females in the patient’s family (if known).

 

Physical Examination

 

On physical examination, the patient’s height, weight, and BMI should be measured. Additionally, the following should be completed: 

  • Tanner staging
  • Palpation of the thyroid gland

 

Breast Development on Exam

 

Breast development is a good indication that ovarian estrogen is being produced. 

Acne, hirsutism, or virilization can be signs of hyperandrogenism. 

A genital examination may show findings of:

  • Virilization
  • Missing or malformed anatomy/organ
  • Outflow tract obstruction.

 

Thin vaginal mucosa may be identified as a finding of low estrogen levels. 

Dysmorphic features such as a low hairline or webbed neck may suggest Turner syndrome.

 

Laboratory and Radiologic Testing

The initial laboratory testing for amenorrhea includes:

  1. Pregnancy test
  2. Serum follicle-stimulating hormone (FSH)
  3. Luteinizing hormone (LH)
  4. Thyroid stimulating hormone (TSH)
  5. And prolactin levels.

If a patient’s history and physical examination are concerning for a hyperandrogenic state:

  1. a serum total and free testosterone measurement
  2. a dehydroepiandrosterone sulfate measurement

Can prove to be helpful.

 

If a patient has short stature with amenorrhea:

  1. Karyotype testing should be completed to assess for Turner syndrome.

 

Turner syndrome is a disorder characterized by a karyotype showing 45, X.  Turner Syndrome will often present with:

  • A low hairline
  • Webbed neck
  • Lymphedema
  • And cardiac defects.

All patients with short stature along with amenorrhea should be screened annually with a karyotype test.

 

Due to the complexity of Turner Syndrome, those diagnosed with Turner syndrome should seek an endocrinologist for management and screening of:

  • Cardiac malformations
  • Coarctation of the aorta
  • Hypothyroidism
  • Renal abnormalities
  • And hearing problems.

 

Lack of Breast Development on Exam

 

If there is no evidence of endogenous estradiol secretion on examination (breast development):

  1. Draw a serum estradiol

 

Additionally, a CBC and CMP can be helpful if there are concerns for chronic illness.

Diagnosis of secondary amenorrhea

Am Fam Physician. 2013;87(11):781-788. Copyright © 2013 American Academy of Family Physicians

 

Imaging

 

Pelvic ultrasonography:

  • Aids on determining the presence/absence of a uterus
  • Helps identify structural abnormalities of reproductive tract organs.

 

Brain MRI:

  • If there is a concern of a pituitary tumor, then an MRI of the brain should be completed.

 

Other Diagnostic Testing

 

Hormonal challenge testing with medroxyprogesterone acetate, 10 mg daily for seven to ten days with anticipation of withdrawal bleeding occurring can aid in confirmation of functional anatomy and normal estrogenization.

 

Causes of Amenorrhea

 

First, let us start off with anatomic abnormalities that can lead to amenorrhea. 

  • Mullerian agenesis is a condition where there is a congenital malformation of the genital tract.
    • This can present with normal breast development without menarche
    • Along with fused vertebrate and urinary tract defects

 

Other congenital abnormalities include:

  • Transverse vaginal septum and imperforate hymen.
    • In both of these conditions, products of menses gather behind the structural defect and can cause acute or cyclic pelvic pain

 

Definitive Diagnosis

 

Physical exam along with pelvic ultrasonography or MRI are the keys to completing the diagnosis, and often surgical intervention will be needed for correction.

 

Rare Causes of Amenorrhea

 

Rare causes of amenorrhea include:

  • Androgen insensitivity syndrome
    • Will present with normal breast development, a blind vaginal pouch, and reduced or absent pubic or axillary hair.
  • 5-alpha reductase deficiency
    • Presents with partially virilized genitalia.

In these diseases, serum testosterone levels will be the same as in males of the same age.  Karyotype will be 46, XY and testicular tissue should be identified and removed to avoid malignant changes.

 

Structural causes of secondary amenorrhea

 

Structural causes of secondary amenorrhea include:

  • Asherman syndrome
    • This is an intrauterine synechiae that is caused by uterine instrumentation during gynecologic procedures. This can be evaluated, diagnosed, and treated with hysteroscopy.

 

  • Primary ovarian insufficiency
    • Characterized by follicle dysfunction or depletion causing a series of impaired ovarian function.
    • Lab findings will reveal:
      • An FSH level in the menopause range (a high FSH)
      • This should be confirmed on two tests separated by one month in women less than 40 years of age.
    • Treatment usually includes hormone therapy with estradiol or Premarin until around the average age of menopause.
    • This is to decrease the risk of osteoporosis, vasomotor symptoms, and ischemic heart disease. Combined oral contraceptives provide higher amounts of estrogen and progesterone that what is needed for hormone replacement.  If used, this can increase the risk of VTE and may be ineffective at suppressing FSH levels.

 

Functional causes of secondary amenorrhea

 

  • Functional hypothalamic amenorrhea
  • Presents when the hypothalamic-pituitary-ovarian axis is suppressed, often due to weight loss, stress, an eating disorder, or excessive exercise.
  • The ovaries naturally require stimulation from the pituitary gland for follicular development and production of estrogen.

 

  • Female athlete triad
  • Patients will often have low estrogen, FSH, and LH levels without other organic or anatomical disease.
  • These patients may have the features of the female athlete triad:
    • (Insufficient caloric intake, low bone density, and amenorrhea).
    • Patients should be screened for eating disorders as well as absorptive disease, such as celiac disease.
  • Treatment often includes increased nutrition as well as a reduction in the patient's stress and exercise level.

 

  • Hypothyroidism, medication, or pituitary adenoma
    • Prolactin levels can be found to be elevated. An elevated prolactin level inhibits the secretion and effect of gonadotropins. 
    • Treatment of Prolactinomas include surgical excision or dopamine agonists.

 

  • Central nervous system infection, trauma, or autoimmune disease/ Kallmann syndrome
    • Even though rare, primary gonadotropin-releasing hormone deficiency, such as in Kallmann syndrome should be considered.
  • PCOS
    • Polycystic ovarian syndrome (PCOS) is a complex endocrine disorder that is characterized by:
      • Hyperandrogenism, ovulatory dysfunction, and polycystic ovaries.
      • Insulin resistance - therefore, these patients should be screened for hyperlipidemia and overall cardiovascular risks.
    • The Rotterdam Consensus Criteria requires two of the three above criteria for diagnosis, whereas the Androgen Excess Society requires hyperandrogenism with one of the other two criteria to be met for diagnosis.
    • In patients who are overweight, treatment includes weight loss combined with exercise
    • Metformin can increase insulin sensitivity, therefore, improve glucose tolerance and ovulatory dysfunction, as well as high androgen levels and may also be used in PCOS.

 

Other endocrine disorders such as hyperthyroidism, hypothyroidism, congenital adrenal hyperplasia, Cushing syndrome, and androgen-secreting tumors can also be other potential etiologies of amenorrhea.

 

Over 90 percent of cases are idiopathic, but other cases can often be due to radiation, infection, tumor, chemotherapy, empty sella syndrome, or autoimmune disease.  These patients should be counseled about potential infertility.

 

References

  1. Am Fam Physician. Amenorrhea: An Approach to Diagnosis and Management 2013;87(11):781-788. Copyright © 2013 American Academy of Family Physicians
  2. Evaluation and Management of Secondary Amenorrhea. Accessed: April 29, 2019.
  3. Evaluation and Management of Primary Amenorrhea. Accessed: April 29, 2019.

 

This article or blog post should not be used in any legal capacity whatsoever, including but not limited to establishing standard of care in a legal sense or as a basis of expert witness testimony. No guarantee is given regarding the accuracy of any statements or opinions made on the podcast or blog.