What is the evaluation and treatment approach for a woman of reproductive age with no prior medical history experiencing amenorrhea?

Evaluation and Treatment of Amenorrhea in Women of Reproductive Age

Begin by ruling out pregnancy with a urine or serum pregnancy test, then obtain initial laboratory testing including FSH, LH, prolactin, and TSH to categorize the cause and guide treatment. 1

Initial Diagnostic Approach

First-Line Laboratory Testing

• Pregnancy test is mandatory as the first step in all cases of amenorrhea, regardless of patient history 1, 2
• Measure serum FSH, LH, prolactin, and TSH levels simultaneously 1, 3
• These four hormone levels will categorize amenorrhea into one of four endocrine patterns that direct further workup 4

History Elements to Elicit

• Menstrual history: age at menarche (if applicable), previous cycle patterns, duration of amenorrhea 2
• Nutritional status: caloric intake, restrictive eating patterns, weight loss history, current BMI 1
• Exercise patterns: hours per week of training, intensity level (>10 hours/week of intense training warrants evaluation) 1
• Psychological stressors: academic pressure, life changes, anxiety, depression 1
• Medication use: antiepileptic drugs (carbamazepine, phenobarbital, phenytoin), hormonal contraceptives 5, 6
• Symptoms of hyperandrogenism: hirsutism, acne, male-pattern hair loss 1
• Galactorrhea, headaches, or visual changes suggesting pituitary pathology 1
• Symptoms of thyroid dysfunction 2

Physical Examination Priorities

• Height, weight, and BMI calculation 5
• Assessment for signs of androgen excess: hirsutism, acne, male-pattern baldness 5
• Thyroid examination for enlargement, nodules, or tenderness 5
• Clinical breast examination and assessment for galactorrhea 5
• Pelvic examination to assess for anatomic abnormalities, masses, or tenderness 5

Interpretation of Laboratory Results and Diagnostic Categories

Pattern 1: Elevated FSH (>40 mIU/mL)

This indicates primary ovarian insufficiency (POI), which requires hormonal replacement therapy to prevent long-term complications. 1

• Elevated FSH in the menopausal range with amenorrhea in a woman <40 years defines POI 1
• Critical point: Patients with POI can maintain unpredictable ovarian function and should not be presumed infertile 3, 2
• Obtain karyotype analysis to identify chromosomal abnormalities 7
• Initiate estrogen replacement therapy with cyclic progestogen to prevent osteoporosis, cardiovascular disease, and urogenital atrophy 1
• Refer to endocrinology or reproductive endocrinology for specialized management 1

Pattern 2: Low or Normal FSH with Elevated Prolactin (>25 ng/mL)

Hyperprolactinemia requires MRI of the pituitary to exclude prolactinoma before initiating dopamine agonist therapy. 1

• Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases 1
• Obtain MRI of the pituitary with gadolinium contrast to evaluate for prolactin-secreting adenoma 8
• If prolactinoma is confirmed: Initiate bromocriptine 1.25-2.5 mg daily, titrating up as tolerated 8
• Critical warning: Monitor for visual field changes, as tumor expansion can cause optic nerve compression requiring emergency surgery 8
• If pregnancy occurs during treatment, discontinue bromocriptine and monitor closely for signs of tumor expansion 8
• Functional hyperprolactinemia can occur with epilepsy, particularly temporal lobe seizures 5

Pattern 3: Low FSH and Low LH (<5 mIU/mL)

This indicates hypothalamic amenorrhea (functional hypothalamic amenorrhea), which requires addressing underlying energy deficits before considering hormonal therapy. 1, 6

Primary Treatment: Address Underlying Causes

• Calculate energy availability: Target >30 kcal/kg fat-free mass/day 1, 6
• Energy availability below 30 kcal/kg fat-free mass/day suppresses bone formation 6
• Document exercise volume: reduce if >10 hours/week of intense training 1
• Screen for eating disorders using validated tools; refer to eating disorder specialist if positive 1, 6
• Provide nutritional counseling by a sports dietitian experienced with energy availability assessment 1
• Important: Recovery may take >6 months despite addressing energy deficits 1, 6

Bone Health Protection

• Obtain DXA scan for bone mineral density if amenorrhea extends beyond 6 months, regardless of age 1, 6
• Functional hypothalamic amenorrhea is associated with 2-fold increased fracture risk 1
• 90% of peak bone mass is attained by age 18, making early intervention critical in adolescents 1

Hormonal Replacement (If Amenorrhea Persists >6 Months)

• Use transdermal estradiol 100 μg patch twice weekly PLUS cyclic micronized progesterone 200 mg for 12 days each month 1, 6
• This regimen protects bone mineral density more effectively than oral contraceptives 1, 6
• Critical pitfall: Do NOT use oral contraceptives as first-line therapy—they mask the problem without addressing the underlying energy deficit and do not protect bone density 1, 6
• Note that transdermal hormones are not contraceptive 6
• Add calcium supplementation 1000-1300 mg daily and optimize vitamin D (target >50 nmol/L in winter, >75 nmol/L in summer) 6

Fertility Treatment (If Pregnancy Desired)

• Ensure BMI ≥18.5 kg/m² and spontaneous menstrual cycles have resumed before offering ovulation induction 1
• Pulsatile GnRH therapy is the most effective treatment for hypothalamic dysfunction, with ovulation rates of 80.8% 1
• Avoid clomiphene citrate as first-line due to uncertain efficacy in functional hypothalamic amenorrhea 1

Pattern 4: Normal FSH and LH with Normal Prolactin

This suggests polycystic ovary syndrome (PCOS) or other normogonadotropic causes; obtain pelvic ultrasound and androgen profile. 1

Diagnostic Confirmation

• Obtain pelvic ultrasound to evaluate for polycystic ovarian morphology 1
• Measure total testosterone, DHEAS, and 17-hydroxyprogesterone to assess for hyperandrogenism 1
• PCOS is one of the most common causes of secondary amenorrhea 1
• LH/FSH ratio >2-3 supports PCOS diagnosis, though not required 5

Treatment Approach

• For cycle regulation: Cyclic progestogen (medroxyprogesterone acetate 10 mg for 10-14 days every 1-3 months) to prevent endometrial hyperplasia 4
• For contraception and hyperandrogenism: Combined oral contraceptives suppress ovarian androgen production and improve hirsutism/acne 4
• For fertility: Refer to reproductive endocrinology for ovulation induction with letrozole or clomiphene citrate 4
• Screen for metabolic complications: fasting glucose, lipid panel, blood pressure 2
• PCOS patients are at increased risk for glucose intolerance, dyslipidemia, and metabolic syndrome 3, 2

Special Considerations

Contraceptive-Induced Amenorrhea

• Amenorrhea from hormonal contraceptives (DMPA, etonogestrel implant, levonorgestrel IUD) requires no treatment—only reassurance 6
• Occurs in approximately 22% of etonogestrel implant users and is common after ≥1 year of DMPA use 6
• These bleeding changes are not harmful and do not require intervention 6
• If amenorrhea develops abruptly in a contraceptive user, rule out pregnancy 6

Red Flags Requiring Urgent Evaluation

• Galactorrhea with headaches or visual changes: Obtain urgent MRI to evaluate for pituitary macroadenoma with mass effect 1
• Significant weight loss or signs of eating disorder: Refer to multidisciplinary eating disorder team 1
• Rapidly progressive visual field loss: Evaluate by neurosurgeon for possible surgical intervention 8
• Hirsutism with rapid onset: Consider late-onset congenital adrenal hyperplasia or androgen-secreting tumor 1

When to Refer

• Refer to endocrinology if persistently abnormal hormone levels despite treatment or signs of pituitary pathology 1
• Refer to reproductive endocrinology for fertility treatment in patients with hypogonadotropic hypogonadism or PCOS 1
• Refer to gynecology for suspected anatomic abnormalities requiring surgical evaluation 7

Common Pitfalls to Avoid

• Never assume amenorrhea in athletes is benign—other pathology must be excluded even when clinical picture suggests functional hypothalamic amenorrhea 1, 6
• Do not prescribe oral contraceptives to treat functional hypothalamic amenorrhea for bone protection—they do not correct the underlying cause and provide false reassurance 1, 6
• Do not overlook eating disorders—adolescents frequently minimize symptoms; direct questioning about specific behaviors is necessary 1
• Do not delay bone density assessment—DXA scanning is indicated if amenorrhea extends beyond 6 months regardless of age 1, 6
• Do not accept amenorrhea as an inevitable consequence of athletic training—amenorrhea for more than 3 months must be investigated 6