SYNOPSIS:

Menstruation requires functionality of the hypothalamus, pituitary, ovary, uterus and outflow tract. Secondary amenorrhea occurs when menses stop for 3 or more months.  The most common causes of secondary amenorrhea include pregnancy, polycystic ovary syndrome, hypothalamic amenorrhea, hyperprolactinemia, and ovarian failure.  Most secondary amenorrhea is anovulatory. When ovulatory dysfunction occurs, menstrual flow may not occur, and anovulatory amenorrhea is the result. Ovulatory amenorrhea occurs when anatomic abnormalities (outflow obstruction, intrauterine adhesions) prevent normal menstrual flow despite normal hormonal cycles. 

An evaluation for secondary amenorrhea should be considered if menses have been absent for over 3 months, or there is oligomenorrhea resulting in less than 9 cycles a year 

• Take a thorough history 
  • Menstrual history | Sexual history | Past medical history | Current medications | Lifestyle factors | 
• Physical exam: particular attention to galactorrhea, virilization, signs of estrogen deficiency, acanthosis nigricans 
  • • Constitutional features: height, weight, BMI 
    • Thyroid palpation 
    • Tanner staging 
    • Genital exam: inner and outer genitalia 
• Laboratory/Imaging
• • • • Always rule out pregnancy! 
      • Initial tests should include: TSH, prolactin, FSH, LH 
      • Brain MRI to check pituitary if elevated prolactin 
      • High FSH, consider premature ovarian failure (POF) and genetic follow up
        • Should be confirmed with multiple FSH levels in the menopausal range 
        • Causes of POF include: gene abnormality | autoimmune disorder | Addison’s disease | iatrogenic causes (radiation, chemotherapy) 

• If history or physical are suggestive of hyperandrogenism, check serum free testosterone and dehydroepiandrosterone sulfate (DHEAS) 
  • Pelvic ultrasound and adrenal CT if elevated to check for androgen secreting tumor
  • Consider polycystic ovary syndrome (PCOS) diagnosis if testosterone and DHEAS normal
    • Rotterdam Criteria: 1. Oligo- or anovulation 2. Clinical or biochemical signs of hyperandrogenism 3. Ultrasound evidence of polycystic ovaries 
• Estrogen-progestin trial to stimulate withdrawal bleeding is no longer recommended
  • Unreliability in correlation with estrogen status and high false positive rate
• Functional hypothalamic amenorrhea: a low estrogen state independent of structural disease
  • Occurs when HOP access is suppressed from stress, weight loss, exercise, eating disorder
  • Low FSH, LH, and estradiol (although this can fluctuate)
  • Female athelete triage: insufficient caloric intake, low bone density, amenorrhea
  • Treatment: aim to correct underlying cause via nutritional rehabilitation, reduction in stress and exercise
    • Combined OCs should not be used for bone density correction

KEY POINTS:

When evaluating patients with secondary amenorrhea consider the following:

• Pregnancy is the most common cause of secondary amenorrhea in women of reproductive age
• Functional hypothalamic anovulation (e.g., due to excessive exercise, eating disorders, or stress) is another causeis common and FSH levels will be normal or low. Treat with lifestyle modications aimed at underlying cause 
• Use or abuse of drugsDrug use (e.g. oral contraceptives, depoprogesterone, antidepressants, antipsychotics, antihypertensives, cocaine, chemotherapy, OTC products) 
• Breastfeeding 
• PCOS diagnosis
• Progestin challenge test has fallen out of favor due to unreliability in correlation with estrogen status

Learn More – Primary Sources:

Amenorrhea: an approach to diagnosis and management

ASRM: Current Evaluation of Amenorrhea

Functional hypothalamic amenorrhea and its influence on women’s health

Evaluation of Amenorrhea, Anovulation, and Abnormal Bleeding

Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

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