What is the diagnostic approach to amenorrhea?

Diagnostic Approach to Amenorrhea

Begin by excluding pregnancy with a urine or serum pregnancy test in all women of reproductive age presenting with amenorrhea, regardless of sexual history, as this is the most common cause and must be ruled out before any further evaluation. 1, 2

Initial Clinical Assessment

Obtain a focused history targeting specific etiologic clues:

• Document menstrual history: Age of menarche, prior cycle regularity, and duration of amenorrhea (primary amenorrhea = no menarche by age 15, or age 13 without secondary sexual characteristics; secondary amenorrhea = cessation of regular menses for 3 months or irregular menses for 6 months). 1, 3, 2

• Assess for functional hypothalamic amenorrhea (FHA) triggers: Calculate energy availability (target >30 kcal/kg fat-free mass/day), document exercise patterns (>10 hours/week intense training is concerning), evaluate for eating disorders, recent weight loss >5% body weight, and psychological stressors. 1, 3

• Screen for hyperandrogenic symptoms: Hirsutism (use Ferriman-Gallwey scoring), acne, androgenetic alopecia, and truncal obesity suggest PCOS or other androgen excess. 1, 3

• Identify hyperprolactinemia clues: Ask specifically about galactorrhea, headaches, and visual disturbances. 1, 3

• Calculate BMI and waist-to-hip ratio: BMI >25 kg/m² suggests PCOS; BMI <18.5 kg/m² favors FHA; waist-to-hip ratio >0.9 indicates truncal obesity associated with PCOS. 1, 3

Physical Examination

• Perform Tanner staging in primary amenorrhea to assess pubertal development. 3
• Check for galactorrhea by nipple expression. 3
• Examine for signs of estrogen deficiency: Vaginal atrophy, thin endometrium on ultrasound (<5 mm). 4, 1
• Assess for hyperandrogenism: Male-pattern hair distribution, acne, androgenetic alopecia. 3

First-Line Laboratory Testing

Order the following hormonal panel (draw FSH, LH, and testosterone on cycle days 3-6 if cycles present, or any time in amenorrheic patients):

• Serum prolactin: Obtain a single morning resting sample; avoid post-stress, post-exercise, or post-ictal collection. Levels >20 μg/L indicate hyperprolactinemia. 1, 3

• Thyroid-stimulating hormone (TSH): Both hypothyroidism and hyperthyroidism disrupt menstrual cycles. 1, 3

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH): Interpret based on levels and ratio. 1, 3

• Estradiol: Levels <30 pg/mL confirm hypoestrogenism characteristic of FHA. 1, 3

Algorithmic Interpretation by FSH Level

Elevated FSH (>40 mIU/mL): Primary Ovarian Insufficiency

• Confirm diagnosis with repeat FSH 4 weeks later (two elevated values required). 1
• Order karyotype if age <40 years to detect Turner syndrome or chromosomal abnormalities. 1, 3
• Counsel patients that unpredictable ovarian function may persist; they should not be presumed infertile. 1, 2
• Initiate estrogen replacement therapy to prevent osteoporosis and cardiovascular disease. 3, 5

Low or Normal FSH with Low LH: Hypogonadotropic Hypogonadism

• Calculate LH/FSH ratio: Ratio <1 is seen in approximately 82% of FHA cases. 4, 3
• Check estradiol: Low levels (<30 pg/mL) confirm hypoestrogenism. 1, 3
• Perform pelvic ultrasound: Thin endometrium (<5 mm) supports estrogen deficiency. 1
• Evaluate for FHA causes: Energy deficit, excessive exercise, eating disorders, psychological stress. 4, 3
• If prolactin elevated: Obtain pituitary MRI after excluding hypothyroidism. 3
• If amenorrhea persists >6 months: Obtain DXA scan for bone mineral density assessment regardless of age. 3

Normal FSH and LH with LH/FSH Ratio >2: Polycystic Ovary Syndrome

• Order pelvic ultrasound to assess for polycystic ovarian morphology. 1, 3
• Measure androgens if hyperandrogenic signs present: Total testosterone (>2.5 nmol/L suggests PCOS), androstenedione (>10.0 nmol/L warrants tumor evaluation), and age-adjusted DHEA-S. 1, 3
• Assess metabolic parameters: Fasting glucose (>7.8 mmol/L suggests diabetes), glucose/insulin ratio (>4 indicates reduced insulin sensitivity). 1
• Perform progesterone challenge test: Positive withdrawal bleed confirms adequate estrogen and patent outflow tract. 1, 6

Additional Testing Based on Clinical Context

• Mid-luteal progesterone (<6 nmol/L indicates anovulation) if cycles are present but irregular. 1, 3

• Pelvic ultrasound indications: LH/FSH ratio >2, palpable adnexal mass, concern for structural abnormality, or to assess endometrial thickness. 1, 3

• Pituitary MRI indications: Prolactin >100 μg/L, persistent hyperprolactinemia after excluding thyroid disease, headaches, or visual field deficits. 3

Differentiating FHA-PCOM from PCOS

This distinction is critical as FHA with polycystic ovarian morphology (FHA-PCOM) can mimic PCOS but requires different management:

• FHA-PCOM features: Low or normal BMI, low energy availability, stress/excessive exercise history, LH/FSH ratio <1, low estradiol, thin endometrium (<5 mm), negative progesterone challenge test. 4

• PCOS features: Higher BMI, LH/FSH ratio >2, normal/elevated estradiol, positive progesterone challenge test, higher testosterone and AMH, lower SHBG. 4

Critical Pitfalls to Avoid

• Never draw prolactin immediately after seizures, stress, breast examination, or sexual activity; wait at least 24 hours to avoid false-positive elevations. 1, 3

• Do not assume amenorrhea in athletes or stressed adolescents is benign; exclude other pathology even when clinical picture suggests FHA. 3

• Do not prescribe oral contraceptives as first-line for FHA; this masks the underlying energy deficit without addressing the cause and does not protect bone density as effectively as physiologic estrogen replacement. 3

• Do not delay bone density assessment; DXA scanning is indicated if amenorrhea extends beyond 6 months regardless of age. 3

• Avoid measuring prolactin post-ictally; seizures cause transient elevation. 1

Urgent Referral Criteria

• Prolactin >100 μg/L or any elevation with headaches/visual disturbances (possible pituitary adenoma). 3
• Total testosterone >5 nmol/L or rapid virilization (possible androgen-secreting tumor). 3
• Primary amenorrhea with no puberty by age 13 or failure to progress through puberty for ≥12 months. 3
• Signs of eating disorder or significant weight loss requiring multidisciplinary eating disorder team. 3