What is the initial approach for a 30-year-old female with 2 months of amenorrhea (absence of menstruation), secondary infertility, and a negative pregnancy test?

Initial Outpatient Management for 30-Year-Old Female with 2 Months Amenorrhea, Negative Pregnancy Test, and Secondary Infertility

Order a comprehensive hormonal panel immediately including serum FSH, LH, prolactin, TSH, and testosterone to identify the underlying cause of secondary amenorrhea, as endocrine dysfunction accounts for the vast majority of cases in reproductive-age women. 1

Immediate Laboratory Workup

The following tests should be ordered at the first visit:

• Serum prolactin: Hyperprolactinemia accounts for approximately 20% of secondary amenorrhea cases and may indicate a pituitary adenoma requiring urgent MRI evaluation 1, 2
• TSH (thyroid-stimulating hormone): Thyroid dysfunction is a reversible cause of amenorrhea and must be excluded in all cases 1, 2
• FSH and LH: These differentiate between primary ovarian insufficiency (elevated FSH >40 mIU/mL) and hypothalamic-pituitary dysfunction (low or normal FSH/LH) 1, 2
• Testosterone and androstenedione: Measure if signs of hyperandrogenism are present (acne, hirsutism, male-pattern hair loss) to support PCOS diagnosis 1
• Repeat pregnancy test: Despite initial negative result, confirm non-pregnant status 2, 3

Physical Examination Focus

Perform targeted examination looking for:

• BMI calculation: Obesity significantly increases likelihood of PCOS, which presents with oligomenorrhea/amenorrhea and anovulation 1
• Signs of androgen excess: Acne, hirsutism, male-pattern baldness, acanthosis nigricans (suggests PCOS) 2
• Thyroid examination: Palpable goiter or nodules (suggests thyroid dysfunction) 4
• Galactorrhea: Breast discharge suggests hyperprolactinemia 2, 5
• Pelvic examination: Assess for anatomical abnormalities, masses, or signs of estrogen deficiency 4

Transvaginal Ultrasound

Order pelvic ultrasound to assess:

• Endometrial thickness: Thin endometrium (<5 mm) suggests estrogen deficiency; thick endometrium (>8 mm) suggests chronic anovulation with unopposed estrogen, increasing endometrial cancer risk 1
• Ovarian morphology: Polycystic ovarian appearance (≥12 follicles per ovary or ovarian volume >10 mL) supports PCOS diagnosis 1, 2
• Uterine anatomy: Rule out structural abnormalities or fibroids 4

Detailed History to Obtain

Document the following specific information:

• Duration of infertility: How long has the couple been attempting pregnancy 4
• Menstrual history: Age at menarche, previous cycle regularity, date of last menstrual period 4, 2
• Weight changes: Recent weight loss, excessive exercise, or eating disorder symptoms (suggests functional hypothalamic amenorrhea) 1, 2
• Stress factors: Major life stressors, psychiatric conditions 2, 5
• Medications: Current and recent medications that may affect ovulation 6
• Galactorrhea or visual symptoms: Suggests prolactinoma 1
• Previous pregnancies: Outcomes, complications 4
• Male partner evaluation status: Has semen analysis been performed 4

Algorithmic Interpretation of Results

If Prolactin Elevated (>20 μg/L):

• Order pituitary MRI immediately to rule out prolactinoma 1
• Delaying imaging when prolactin is elevated can lead to visual field defects requiring urgent intervention 1

If FSH Elevated (>40 mIU/mL):

• Diagnose primary ovarian insufficiency 1
• Confirm with repeat FSH 4 weeks later (two elevated values required) 1
• Note: These patients can maintain unpredictable ovarian function and should not be presumed infertile 1, 2

If LH/FSH Ratio >2 with Normal or Elevated LH:

• Suspect PCOS (most common cause of secondary amenorrhea in obese patients) 1, 2
• Ultrasound showing polycystic ovarian morphology confirms diagnosis 1
• Screen for metabolic syndrome: fasting glucose, lipid panel 2, 7

If Low or Normal FSH/LH with Low Prolactin and Normal TSH:

• Suspect functional hypothalamic amenorrhea 1, 2
• Evaluate for eating disorders, excessive exercise, stress, or weight loss 2, 5
• These patients are at risk for decreased bone density 2

If TSH Abnormal:

• Treat thyroid dysfunction first, as this is a reversible cause of amenorrhea 1
• Recheck menstrual function after thyroid normalization 1

Male Partner Evaluation (Simultaneous)

Do not delay male partner evaluation—begin simultaneously with female workup 4:

• Semen analysis: At least two samples, one month apart 4, 3
• Reproductive history and physical examination 4

Critical Pitfalls to Avoid

• Never assume amenorrhea is benign without evaluation: Prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease 1
• Do not delay evaluation in women with secondary infertility: Earlier evaluation is recommended for women with history of oligo-amenorrhea or known reproductive disorders 4
• Avoid incomplete evaluation: Failing to assess both partners simultaneously delays diagnosis 4

Follow-Up Timing

• If hormonal testing reveals significant abnormalities or amenorrhea extends beyond 6 months: Consider DXA scan for bone mineral density assessment, as prolonged hypoestrogenism increases fracture risk 1
• Schedule follow-up within 1-2 weeks to review laboratory results and imaging findings 1

Treatment Considerations Based on Diagnosis

For PCOS (Most Likely Given Obesity and Secondary Infertility):

• Lifestyle modification first: Weight loss improves ovulation and pregnancy rates 3, 7
• For ovulation induction when pregnancy desired: Clomiphene citrate or letrozole are first-line agents 8, 7
• Clomiphene citrate is indicated for ovulatory dysfunction in women desiring pregnancy, particularly those with PCOS 8

For Functional Hypothalamic Amenorrhea:

• Address underlying causes: Nutritional counseling, stress reduction, exercise modification 5
• Hormone replacement therapy: Sequential estrogen-progestogen to prevent bone loss if amenorrhea persists 5

For Hyperprolactinemia:

• Dopamine agonists (bromocriptine or cabergoline) are first-line treatment 5

For Primary Ovarian Insufficiency:

• Hormone replacement therapy: Long-term estrogen therapy to prevent osteoporosis and cardiovascular disease 5
• Counsel regarding fertility: Unpredictable ovarian function may persist; not absolutely infertile 1, 2