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
  • Always rule out pregnancy 
  • Initial tests should include: TSH, prolactin, FSH, LH and E2
  • Elevated prolactin: Brain MRI to check pituitary  
  • High FSH: Consider premature ovarian failure (POF) if <40 years  
    • Amenorrhea | Persistent estrogen deficiency | Elevated FSH levels  
    • Causes of POF include: Genetic abnormality such as FMR1 | 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 
    • 21 hydroxylase deficiency testing (the commonest form of late-onset congenital adrenal hyperplasia) based on serum levels of 17 hydroxyprogesterone
• Imaging
  • First line: Transvaginal ultrasound
    • Endometrial thickness / trilaminar endometrial echo reflect estrogen levels
    • Ovarian assessment (e.g., follicle count) can help assess ovarian reserve, presence of PCOS and hormone secreting ovarian tumors

• Progesterone withdrawal test (PWT)
  • Bleeding after progesterone challenge consistent with anovulation
  • Absence of bleeding
    • Hypoestrogenic state or
    • Endometrium cannot respond (e.g., Asherman syndrome)
  • “Although the PWT may still have a role in the evaluation of amenorrhea, other described approaches may result in a more rapid and accurate diagnosis”

KEY POINTS:

When evaluating patients with secondary amenorrhea consider the following etiologies

• Pregnancy: Most common cause of secondary amenorrhea in women of reproductive age
• Functional hypothalamic anovulation (e.g., due to excessive exercise, eating disorders, or stress)
  • Common and FSH levels will be normal or low
  • Treat with lifestyle modifications aimed at underlying cause 
• Use or abuse of drugs: e.g., oral contraceptives, depoprogesterone, antidepressants, antipsychotics, antihypertensives, cocaine, chemotherapy, OTC products 
• Breastfeeding 
• PCOS 

Learn More – Primary Sources:

Amenorrhea: an approach to diagnosis and management

ASRM Committee Opinion: 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

Related ObG Topics:

Managing Abnormal Uterine Bleeding with Ovulatory Dysfunction

Polycystic Ovary Syndrome: Making the Diagnosis