What are the common causes and workup for amenorrhea?

Common Causes and Workup of Amenorrhea

Amenorrhea should be evaluated systematically based on classification (primary vs secondary) and underlying pathophysiology, with a structured diagnostic approach that identifies the most common causes including PCOS, functional hypothalamic amenorrhea, hyperprolactinemia, and primary ovarian insufficiency. 1

Classification and Definitions

• Primary amenorrhea: Absence of menarche by age 16 years, or within 3 years of thelarche 1, 2
• Secondary amenorrhea: Cessation of previously regular menses for 3+ months or irregular menses for 6+ months 1, 2

Common Causes

Primary Amenorrhea

• Chromosomal abnormalities (e.g., Turner syndrome) 3
• Anatomical abnormalities (e.g., Müllerian agenesis, imperforate hymen, transverse vaginal septum) 3, 4
• Constitutional delay of growth and puberty 4
• Hypothalamic dysfunction 5

Secondary Amenorrhea

1. Polycystic Ovary Syndrome (PCOS) - most common cause 3

   • Features: oligomenorrhea/amenorrhea, hyperandrogenism, polycystic ovaries on ultrasound
   • Often associated with insulin resistance, obesity, hirsutism 6

2. Functional Hypothalamic Amenorrhea (FHA) - second most common cause 6

   • Triggered by: stress, excessive exercise, weight loss, energy deficit 1
   • Characterized by reduced GnRH pulsatility and low LH levels 6
   • Affects 20-35% of secondary amenorrhea cases 6

3. Hyperprolactinemia 1, 3

   • May be associated with pituitary adenoma
   • Can cause galactorrhea
   • May result from medications or post-ictal states in epilepsy 6

4. Primary Ovarian Insufficiency 3

   • Premature depletion of ovarian follicles
   • May occur earlier in women with epilepsy 6
   • Can be caused by autoimmune disorders, genetic factors, or iatrogenic causes (chemotherapy, radiation) 1

5. Other causes:

   • Thyroid disorders (hypo/hyperthyroidism) 5
   • Pregnancy (most common physiological cause) 7
   • Anatomical abnormalities 4
   • Chronic diseases 2
   • Medication-induced 2

Diagnostic Workup Algorithm

Initial Evaluation for All Patients

1. Detailed history:

   • Menstrual patterns
   • Pubertal development
   • Weight changes
   • Exercise habits
   • Stress levels
   • Medication use
   • Galactorrhea
   • Symptoms of hyperandrogenism (hirsutism, acne)
   • Neurological symptoms
   • Hot flashes

2. Physical examination:

   • Height, weight, BMI
   • Secondary sexual characteristics
   • Signs of hyperandrogenism
   • Thyroid examination
   • Breast examination for galactorrhea
   • Pelvic examination to assess genital tract anatomy

3. Initial laboratory tests 1, 2:

   • Pregnancy test (essential first step)
   • FSH, LH levels
   • Prolactin
   • TSH
   • Estradiol

Further Testing Based on Initial Results

If FSH/LH elevated:

• Suspect primary ovarian insufficiency
• Karyotype analysis
• Ovarian antibodies
• Bone density testing 1

If FSH/LH normal or low with normal prolactin:

• Consider PCOS or hypothalamic causes
• Testosterone, DHEAS, androstenedione
• Fasting glucose, lipid profile
• Pelvic ultrasound 6

If prolactin elevated:

• MRI of pituitary 1
• Review medications

If anatomical abnormality suspected:

• Pelvic ultrasound
• MRI of pelvis if needed 4

For suspected FHA-PCOM (functional hypothalamic amenorrhea with polycystic ovarian morphology):

• Progestin challenge test (often negative in FHA) 6
• Assess for energy deficit, stress
• Evaluate LH, testosterone, and SHBG levels 6

Management Considerations

• PCOS: Lifestyle modifications, hormonal contraceptives, metformin for metabolic issues 3
• Functional hypothalamic amenorrhea: Address underlying stressors, optimize nutrition and energy availability, modify excessive exercise 1
• Hyperprolactinemia: Bromocriptine or other dopamine agonists 8
• Primary ovarian insufficiency: Hormone replacement therapy to prevent osteoporosis and cardiovascular disease 1

Important Clinical Pearls

• Always exclude pregnancy before extensive workup 3
• Patients with primary ovarian insufficiency can maintain unpredictable ovarian function and should not be presumed infertile 3, 2
• Patients with hypothalamic amenorrhea are at risk for decreased bone density 5
• PCOS patients require screening for metabolic syndrome, glucose intolerance, and dyslipidemia 3
• FHA-PCOM is a diagnostic challenge that can be misdiagnosed as PCOS; careful evaluation of stress factors and energy balance is crucial 6
• Bone health monitoring is essential in prolonged hypogonadal states 1

By following this systematic approach, the underlying cause of amenorrhea can be identified and appropriate management initiated to address both the immediate symptoms and long-term health implications.