What is the evaluation and management approach for a 21-year-old female patient with a missed period?

Evaluation and Management of a 21-Year-Old with Missed Period

The first and most critical step is to perform a pregnancy test, as pregnancy is the most common cause of amenorrhea in reproductive-age women and must be excluded before any further evaluation or treatment. 1, 2, 3

Immediate Initial Assessment

Mandatory First-Line Testing

• Urine or serum pregnancy test must be performed immediately, as most available tests yield positive results before the first missed menses with normal intrauterine pregnancy 4, 1
• This is non-negotiable regardless of contraceptive use or sexual history, as missing this diagnosis has life-threatening implications (ectopic pregnancy) 4

Essential Clinical History to Obtain

• Menstrual history specifics: age of menarche, previous cycle regularity, duration of current irregularity 1
• Weight changes, eating patterns, and exercise habits to screen for Female Athlete Triad or disordered eating 1
• Medication use, particularly hormonal contraceptives, antipsychotics, and antiepileptics that can cause amenorrhea 1
• Symptoms suggesting specific etiologies: galactorrhea (hyperprolactinemia), hirsutism/acne (PCOS), hot flashes (ovarian insufficiency) 1, 5

Physical Examination Priorities

• Calculate BMI, as obesity is strongly associated with PCOS 1
• Thyroid examination for enlargement or nodules 1
• Breast examination for galactorrhea 5
• Signs of hyperandrogenism: hirsutism, acne 5

Laboratory Workup (After Pregnancy Excluded)

Initial Mandatory Hormonal Panel

If pregnancy test is negative, obtain the following labs simultaneously 1, 5:

• TSH - to identify thyroid dysfunction as a reversible cause 1, 5
• Prolactin - elevated levels (>20 μg/L) suggest hyperprolactinemia or pituitary adenoma 1, 5
• FSH and LH - ideally drawn between cycle days 3-6 (or anytime if amenorrheic) 1, 5
• Estradiol - helps differentiate functional hypothalamic amenorrhea (low) from PCOS (normal/elevated) 1

Interpretation Algorithm Based on Results

If Prolactin is Elevated:

• Order pituitary MRI immediately to rule out prolactinoma 5
• Delaying imaging can lead to visual field defects requiring urgent intervention 5

If FSH is Elevated (>40 mIU/mL):

• Diagnose primary ovarian insufficiency 1, 5
• Confirm with repeat FSH 4 weeks later (two elevated values required) 1
• Critical pitfall: These patients can maintain unpredictable ovarian function and should NOT be presumed infertile 1, 3
• Counsel about fertility options and need for hormone replacement 5

If LH/FSH Ratio >2:

• Strongly suggests PCOS 1
• Order pelvic ultrasound to identify polycystic ovaries and assess endometrial thickness 1, 5
• Measure testosterone and androstenedione if signs of hyperandrogenism present 1, 5

If LH/FSH Ratio <1 with Low Estradiol:

• Suggests functional hypothalamic amenorrhea 1
• Evaluate for disordered eating, excessive exercise, or stress 1
• Critical concern: These patients are at high risk for low bone density and require bone mineral density testing 1

Imaging Studies

Pelvic Ultrasound Indications

• Transvaginal ultrasound (more sensitive than transabdominal) when clinical features or hormonal tests suggest ovarian pathology 1
• Assess endometrial thickness: thin (<5 mm) suggests estrogen deficiency; thick (>8 mm) suggests chronic anovulation with unopposed estrogen 1, 5
• If structural abnormalities identified, refer to gynecology 5

Management Based on Diagnosis

For Functional Hypothalamic Amenorrhea

• Address underlying causes: stress, weight loss, excessive exercise 1
• Never assume amenorrhea is benign - prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease 5
• Consider hormone replacement therapy with sequential estrogen and progestogen 5

For PCOS

• Cyclic progestogen administration to induce withdrawal bleeding 5
• Combined oral contraceptives for contraception and to improve hirsutism/acne 5
• Screen for metabolic syndrome components (glucose intolerance, dyslipidemia) 3

For Primary Ovarian Insufficiency

• Long-term hormone replacement therapy essential to prevent cardiovascular disease and osteoporosis 5
• Karyotype testing if age <40 years to identify Turner syndrome 1

Critical Pitfalls to Avoid

• Never proceed with hormonal testing before excluding pregnancy - this can lead to misinterpretation of results and missed ectopic pregnancy 4, 1
• Do not assume amenorrhea on depot medroxyprogesterone or etonorgestrel implants is pathologic - these commonly cause amenorrhea 4
• Do not delay pituitary imaging if prolactin elevated - visual complications can develop 5
• Do not assume primary ovarian insufficiency equals infertility - unpredictable ovarian function can persist 1, 3