What blood work should be ordered for a female of reproductive age presenting with weight gain, amenorrhea (absence of menstruation), and extreme fatigue?

Blood Work for Weight Gain, Amenorrhea, and Extreme Fatigue

Order a comprehensive hormonal panel including TSH, prolactin, FSH, LH, testosterone, and fasting glucose/insulin to evaluate for thyroid dysfunction, hyperprolactinemia, primary ovarian insufficiency, and polycystic ovary syndrome (PCOS)—the most common endocrine causes of this presentation. 1, 2

Essential First-Line Hormonal Tests

Thyroid Function

• TSH level is mandatory as thyroid dysfunction is a reversible cause of amenorrhea and can present with weight gain and fatigue 2, 3
• The American Thyroid Association notes that treating thyroid dysfunction typically restores normal menstrual cycles within 2-5 days of adequate hormone replacement 2

Prolactin Assessment

• Morning resting serum prolactin (not post-exercise or post-stress) should be measured, as hyperprolactinemia accounts for 20% of secondary amenorrhea cases 1, 2
• Abnormal threshold is >20 μg/L 3, 1
• If elevated, immediate pituitary MRI is necessary to rule out prolactinoma 2
• Critical pitfall: Prolactin can be mildly elevated in various conditions; rule out hypothyroidism first as it can cause secondary hyperprolactinemia 3

Gonadotropins (FSH and LH)

• FSH and LH levels ideally measured as an average of three samples taken 20 minutes apart between cycle day 3-6 (or randomly if amenorrheic) 3
• FSH >35-40 IU/L indicates primary ovarian insufficiency and must be confirmed with repeat testing 4 weeks later 3, 2
• LH/FSH ratio >2 suggests PCOS, the most common cause of amenorrhea with weight gain 3, 2
• LH <7 IU/ml suggests hypothalamic amenorrhea 3

Androgen Assessment

• Total testosterone measured on cycle day 3-6 (or randomly if amenorrheic); >2.5 nmol/L is abnormal and suggests PCOS 3
• DHEAS (dehydroepiandrosterone sulfate) to rule out adrenal pathology: age 20-29 >3800 ng/ml or age 30-39 >2700 ng/ml is abnormal 3, 1
• Androstenedione >10.0 nmol/l warrants evaluation for adrenal or ovarian tumor 3

Metabolic Assessment

Glucose and Insulin

• Fasting glucose and insulin levels are essential given the weight gain presentation 3
• Fasting glucose >7.8 mmol/L suggests diabetes 3
• Calculate glucose/insulin ratio: >4 suggests reduced insulin sensitivity associated with PCOS 3
• The American College of Obstetricians and Gynecologists recommends all women with suspected PCOS undergo a 2-hour oral glucose tolerance test with 75-gram glucose load due to increased diabetes risk 3

Lipid Profile

• Fasting lipid panel (total cholesterol, LDL, HDL, triglycerides) should be obtained as women with PCOS frequently have dyslipidemia 3
• This is particularly important as insulin resistance in PCOS is associated with elevated triglycerides, increased small dense LDL, and decreased HDL 3

Ovulation Assessment

• Mid-luteal phase progesterone (blood taken approximately day 21 of a 28-day cycle, or 7 days before expected menses if cycles are longer) 3
• Levels <6 nmol/L indicate anovulation, commonly seen in PCOS, hypothalamic amenorrhea, or hyperprolactinemia 3
• Important caveat: This test is only interpretable if the patient has some menstrual activity; it cannot be performed in complete amenorrhea 3

Algorithmic Interpretation

If TSH is Abnormal

• Treat thyroid dysfunction first, as this alone may restore normal cycles 2
• Recheck other hormones after thyroid function normalizes 3

If Prolactin is Elevated (>20 μg/L)

• Order pituitary MRI immediately to rule out prolactinoma 2
• Recheck TSH as hypothyroidism can cause secondary hyperprolactinemia 3
• Review medications that can elevate prolactin 3

If LH/FSH Ratio >2 with Normal/Low FSH

• Suspect PCOS 3, 2
• Confirm with pelvic ultrasound showing >10 peripheral cysts (2-8 mm diameter) and thickened ovarian stroma 3
• Check for metabolic syndrome components: glucose intolerance, dyslipidemia, obesity 3

If FSH >35-40 IU/L

• Indicates primary ovarian insufficiency 2
• Confirm with repeat FSH 4 weeks later 2
• Measure estradiol to assess degree of estrogen deficiency 1
• Critical: Do not assume infertility; these patients can maintain unpredictable ovarian function 4

If All Gonadotropins are Low (LH <7 IU/ml)

• Suggests hypothalamic amenorrhea 3
• Evaluate for eating disorders, excessive exercise, stress, or significant weight loss 4, 5
• These patients are at risk for decreased bone density and require estrogen replacement 4

Additional Considerations

Cushing's Syndrome Screening

• If clinical features suggest Cushing's syndrome (buffalo hump, moon facies, hypertension, abdominal striae, easy bruising), screen with 24-hour urinary free cortisol or overnight dexamethasone suppression test 3

Iron Studies

• Consider checking ferritin, as iron deficiency is common in reproductive-age women and can worsen fatigue 3
• Iron deficiency can impair T4 to T3 conversion, compounding hypothyroid symptoms 3

Critical Pitfalls to Avoid

• Never assume amenorrhea with these symptoms is simply "stress" or "weight-related" without full hormonal evaluation, as prolonged hypoestrogenism increases risks of osteoporosis and cardiovascular disease regardless of cause 2, 6
• Do not delay testing; time is critical for fertility preservation if primary ovarian insufficiency is confirmed 2, 6
• Always exclude pregnancy first before interpreting any hormonal results 2, 6, 4
• Do not overlook eating disorders, as patients may minimize or deny disordered eating behaviors that cause hypothalamic amenorrhea 6
• Recognize that single abnormal findings without symptoms may not constitute clinically relevant endocrine disorder, but these patients require monitoring for development of symptomatic disease 3