What is the appropriate initial evaluation and management for a reproductive‑age woman presenting with secondary amenorrhea (no menses for ≥3 months after previously regular cycles)?

Initial Evaluation and Management of Secondary Amenorrhea

Perform a pregnancy test immediately, followed by measurement of serum FSH, LH, prolactin, and TSH to identify the underlying cause, as endocrine dysfunction accounts for the vast majority of secondary amenorrhea cases in reproductive-age women. 1

Definition and Initial Assessment

Secondary amenorrhea is defined as cessation of previously regular menses for ≥3 months (or irregular menses for ≥6 months). 2 This affects approximately 3-4% of women in the general population. 3

Critical First Step: Exclude Pregnancy

• Always perform a pregnancy test first before any other hormonal evaluation, as pregnancy is the most common cause of amenorrhea and failing to exclude it leads to misinterpretation of all subsequent hormonal results. 2, 1

Essential Laboratory Panel

Once pregnancy is excluded, obtain the following hormonal assessment:

Core Hormonal Tests (All Patients)

• Serum prolactin: Hyperprolactinemia accounts for ~20% of secondary amenorrhea cases; levels >20 μg/L indicate hyperprolactinemia and may signal a pituitary adenoma. 3, 1
• TSH: Thyroid dysfunction is a reversible cause that must be excluded in all cases; both hypothyroidism and hyperthyroidism disrupt menstrual cycles. 3, 1
• FSH and LH: These differentiate between primary ovarian insufficiency (elevated FSH >40 mIU/mL) and hypothalamic-pituitary dysfunction (low-normal FSH/LH). 3, 1
• Draw FSH, LH, and testosterone between cycle days 3-6 (or any time in amenorrheic patients) for accurate interpretation. 2

Additional Tests Based on Clinical Context

• Estradiol: Check when functional hypothalamic amenorrhea (FHA) is suspected; levels <30 pg/mL confirm hypoestrogenism. 3, 2
• Testosterone and androstenedione: Measure if signs of hyperandrogenism are present (hirsutism, acne, androgenetic alopecia); testosterone >2.5 nmol/L suggests PCOS. 2, 1

Clinical History: Key Elements to Document

• Weight changes: Document any weight loss >5% over the past 6 months; calculate BMI (obesity [>25 kg/m²] suggests PCOS, low BMI [<18.5 kg/m²] suggests FHA). 2
• Exercise patterns: Document hours per week and intensity; >10 hours/week of intense training warrants evaluation for Relative Energy Deficiency in Sport (RED-S). 3
• Nutritional assessment: Evaluate for restrictive eating, disordered eating behaviors, and calculate energy availability (>30 kcal/kg fat-free mass/day is adequate). 3
• Stress factors: Assess psychological stressors, as stress is a major precipitant of FHA. 3
• Medication use: Document hormonal contraceptives, antipsychotics, antiepileptics (especially valproate), as these can cause amenorrhea. 2
• Associated symptoms: Ask specifically about galactorrhea (hyperprolactinemia), headaches or visual changes (pituitary pathology), hirsutism/acne (PCOS/hyperandrogenism). 2

Physical Examination Essentials

• Calculate BMI and waist-to-hip ratio: Ratio >0.9 suggests PCOS. 2
• Examine for hyperandrogenism: Male-pattern hair distribution, acne, androgenetic alopecia. 2
• Perform nipple expression: Check for occult galactorrhea. 2
• Assess for signs of estrogen deficiency: Vaginal atrophy suggests hypoestrogenism. 3

Imaging Studies

• Pelvic ultrasound: Obtain when LH/FSH ratio >2, to evaluate for polycystic ovarian morphology, or when structural abnormality is suspected. 3, 2, 1
  • Assess endometrial thickness: Thin endometrium (≤5 mm) indicates estrogen deficiency; thick endometrium (>8 mm) suggests chronic anovulation with unopposed estrogen (endometrial cancer risk). 3, 1
• Pituitary MRI: Order if prolactin is elevated (>20 μg/L) after excluding hypothyroidism, or if headaches/visual disturbances are present. 2, 1

Algorithmic Interpretation of Results

Elevated Prolactin (>20 μg/L)

• First exclude hypothyroidism by checking TSH; hypothyroidism can cause secondary hyperprolactinemia. 2
• If prolactin remains elevated and TSH is normal, order pituitary MRI to evaluate for prolactinoma. 2, 1
• Refer urgently if prolactin >100 μg/L or any elevation with headaches/visual disturbances. 2
• Timing pitfall: Never draw prolactin post-ictally (seizures cause transient elevation), after breast examination, sexual activity, or stress; obtain a morning resting sample. 2

Elevated FSH (>40 mIU/mL)

• Indicates primary ovarian insufficiency (POI); confirm with repeat FSH 4 weeks later (two elevated values required for diagnosis). 1
• Do not assume infertility: Patients with POI can maintain unpredictable ovarian function. 1, 4
• Initiate estrogen replacement therapy to prevent osteoporosis, cardiovascular disease, and urogenital atrophy. 3
• Order karyotype if age <40 years to identify Turner syndrome or other chromosomal abnormalities. 2
• Obtain DXA scan for bone mineral density assessment. 3

LH/FSH Ratio >2 with Normal/Elevated LH

• Strongly suggests PCOS, especially in obese patients. 2, 1
• Order pelvic ultrasound to identify polycystic ovarian morphology. 1
• Assess for metabolic syndrome: Check fasting glucose and lipid panel; glucose >7.8 mmol/L suggests diabetes. 2
• Measure androgens if hyperandrogenic signs present (testosterone, androstenedione, DHEA-S). 1

LH/FSH Ratio <1 with Low Estradiol (<30 pg/mL)

• Seen in ~82% of functional hypothalamic amenorrhea (FHA) cases. 3
• Assess endometrial thickness: Thin endometrium (<5 mm) confirms estrogen deficiency. 3, 1
• Address underlying causes: Increase caloric intake to >30 kcal/kg fat-free mass/day, reduce excessive exercise, manage stress, screen for eating disorders. 3
• Do not prescribe oral contraceptives as first-line therapy: This masks the problem without addressing the underlying energy deficit and does not protect bone density as effectively as physiologic estrogen replacement. 3
• If amenorrhea persists >6 months despite addressing stressors, initiate transdermal estradiol (100 μg patch twice weekly) with cyclic micronized progesterone (200 mg for 12 days/month) for bone health. 3
• Obtain DXA scan if amenorrhea extends beyond 6 months, as 90% of peak bone mass is attained by age 18 and prolonged hypoestrogenism significantly increases osteoporosis risk. 3

Normal FSH, LH, Prolactin, and TSH

• Consider progesterone challenge test to assess estrogen status and endometrial response. 3
  • Positive withdrawal bleed suggests adequate estrogen (PCOS likely if obese with irregular cycles).
  • Negative test suggests estrogen deficiency (FHA).
• Endometrial thickness on ultrasound is more reliable than progesterone challenge: <5 mm suggests FHA, >8 mm suggests chronic anovulation. 1

Common Etiologies by Frequency

• Polycystic Ovary Syndrome (PCOS): Most common cause, especially in obese patients; characterized by LH/FSH ratio >2, hyperandrogenism, polycystic ovarian morphology. 3, 1
• Functional Hypothalamic Amenorrhea (FHA): Accounts for 20-35% of cases; results from stress, excessive exercise, or nutritional deficiencies; characterized by low estradiol, LH/FSH ratio <1. 3, 1
• Hyperprolactinemia: Accounts for ~20% of cases; may indicate pituitary adenoma. 3, 1
• Primary Ovarian Insufficiency (POI): Characterized by elevated FSH >40 mIU/mL in women <40 years. 3, 1
• Thyroid dysfunction: Reversible cause that must always be excluded. 3, 1

Critical Red Flags Requiring Urgent Evaluation

• Galactorrhea with elevated prolactin: Evaluate for pituitary adenoma; delaying imaging can lead to visual field defects requiring urgent intervention. 3, 1
• Headaches or visual changes: Suggest pituitary pathology; order MRI immediately. 3, 2
• Severe hirsutism or virilization: Testosterone >5 nmol/L or rapid virilization warrants evaluation for androgen-secreting tumor. 2
• Significant weight loss or signs of eating disorder: Requires multidisciplinary eating disorder team. 3

Common Pitfalls to Avoid

• Never assume amenorrhea is benign without evaluation: Prolonged hypoestrogenism increases risks of osteoporosis (2-fold increased fracture risk in FHA) and cardiovascular disease. 3, 1
• Do not overlook eating disorders: Adolescents frequently minimize or deny disordered eating behaviors; direct questioning about specific behaviors is necessary. 3
• Do not assume amenorrhea in athletes is benign: Other pathology must be excluded even when the clinical picture suggests FHA. 3
• Do not delay bone density assessment: DXA scanning is indicated regardless of age if amenorrhea extends beyond 6 months. 3
• Do not misdiagnose FHA-PCOM as PCOS: FHA patients with polycystic ovarian morphology on ultrasound typically have low LH, low estradiol, thin endometrium (<5 mm), and LH/FSH ratio <1, despite ovarian appearance. 3, 2

Referral Indications

• Endocrinology or gynecology: Persistently abnormal hormone levels despite treatment, signs of pituitary pathology, or if primary care provider is not experienced with FHA treatment. 3, 1
• Eating disorder team: Significant weight loss or signs of eating disorder. 3
• Specialist centers: Pituitary adenomas presenting with amenorrhea should be managed by pituitary-specific multidisciplinary teams. 3