Fatigue Workup in Childbearing Women: Not a Fishing Trip

Four tests. That’s the starting line: CBC, ferritin, TSH, pregnancy test. Not a 30-tube rainbow draw.

“I'm just so tired all the time.” It's one of the most common complaints in primary care, and in women of childbearing age, the differential is simultaneously broad and predictable. The temptation is to order everything—a CMP, CBC, iron studies, B12, folate, vitamin D, cortisol, ANA, Lyme, EBV, celiac panel, ferritin, TSH, free T4, testosterone—and hope something lights up. That's not a workup. That's a fishing trip. And fishing trips catch incidental abnormalities that generate more tests, more anxiety, and no answers.

This post makes the case for a disciplined, stepwise approach.

The Core Four: Start Here, Every Time

The First-Line Panel

1. CBC: Anemia is the most common lab-identifiable cause of fatigue in this population. Look at hemoglobin AND MCV (microcytic = iron deficiency until proven otherwise).
2. Ferritin: Iron deficiency causes fatigue before anemia develops. A normal hemoglobin does NOT rule out iron deficiency. Ferritin is the test that catches the pre-anemic state.
3. TSH: Hypothyroidism is common in women of reproductive age. One test, high yield.
4. Pregnancy test (urine hCG): Fatigue is often the first symptom of early pregnancy, before a missed period is noticed. In any woman of childbearing age with new-onset fatigue, rule it out. It changes everything about your workup and management.

These four tests cover the most common and most treatable causes of fatigue in this population. If all four are normal, then you expand.

Iron Deficiency Without Anemia: The Under-Recognized Entity

This is the clinical pearl that separates a good fatigue workup from a mediocre one. Iron deficiency exists on a spectrum:

• Stage 1: Depleted iron stores (low ferritin, normal hemoglobin, normal MCV). The patient is symptomatic—fatigued, brain fog, exercise intolerance, restless legs—but the CBC is “normal.”
• Stage 2: Iron-deficient erythropoiesis (low ferritin, low transferrin saturation, normal or borderline hemoglobin, possibly low MCV)
• Stage 3: Iron deficiency anemia (low ferritin, low hemoglobin, low MCV, microcytic hypochromic RBCs on smear)

If you only check a CBC and the hemoglobin is 12.5, you'll call it normal and send the patient home. But her ferritin might be 8. She has iron deficiency without anemia—and she'll feel dramatically better with iron replacement.

The Ferritin Threshold Debate

What ferritin level defines iron deficiency? This is more contentious than it should be.

• WHO/traditional cutoff: Ferritin <15 ng/mL = iron deficiency
• Most hematologists and current evidence: Ferritin <30 ng/mL = iron deficiency in the context of symptoms
• Functional iron deficiency (especially with inflammation): Ferritin <100 ng/mL with transferrin saturation <20% may indicate iron deficiency despite “normal” ferritin (ferritin is an acute phase reactant)

For a symptomatic woman of childbearing age, ferritin <30 should be treated as iron deficiency. Multiple RCTs have demonstrated symptom improvement with iron supplementation in non-anemic women with ferritin <50, particularly for fatigue and cognitive function.

When the Core Four Are Normal: Expanding the Workup

Tier 2 (If Core Four Are Normal and Fatigue Persists >4 Weeks)

• BMP: Electrolyte abnormalities (hyponatremia, hypercalcemia), renal insufficiency, glucose (diabetes or hypoglycemia)
• Vitamin D: Deficiency is endemic but its role in fatigue is debated. Check it, but manage expectations—correcting vitamin D may or may not resolve fatigue.
• Depression screening (PHQ-9): This should arguably be Tier 1. Depression and fatigue are intimately linked, and no lab test diagnoses depression. If the PHQ-9 is positive, treat the depression.
• Sleep history: Obstructive sleep apnea is underdiagnosed in women. Ask about snoring, witnessed apneas, morning headaches. STOP-BANG questionnaire.

Tier 3 (If Tier 2 Normal and Specific Symptoms Suggest)

• Celiac panel (tTG-IgA + total IgA): If GI symptoms, iron-refractory iron deficiency, or family history
• ANA: Only if joint pain, rash, photosensitivity, or other autoimmune features are present. Do NOT order ANA as a fishing expedition—the false positive rate in young women is high, and it generates referrals and anxiety without answers.
• Cortisol (AM): Only if Addisonian features (orthostasis, hyperpigmentation, salt craving, weight loss)
• EBV panel: Only if acute-onset fatigue with pharyngitis, lymphadenopathy, splenomegaly. Chronic EBV is not a validated diagnosis; don't order it for chronic fatigue.
• B12/MMA: Lower yield in this population (more relevant for elderly, vegans, post-bariatric surgery)

What NOT to Order (and Why)

Choosing Wisely for Fatigue

• Lyme titers in non-endemic areas: False positives abound. Only test if exposure history + clinical features support it.
• EBV titers for chronic fatigue: Most adults are EBV seropositive. A positive IgG means past exposure, not active disease. It doesn't explain chronic fatigue.
• ANA without autoimmune features: Up to 20% of healthy young women have low-titer positive ANA. A positive ANA without clinical findings generates rheumatology referrals that end with “no autoimmune disease.”
• Morning cortisol without Addisonian features: Random cortisol testing for fatigue has extremely poor specificity. Adrenal insufficiency is rare; poor sleep, depression, and iron deficiency are common.
• Testosterone levels in premenopausal women: Not validated as a fatigue workup tool in this population.
• “Adrenal fatigue” panels: This is not a recognized medical diagnosis. Salivary cortisol panels marketed for “adrenal fatigue” are not evidence-based.

When Labs Are Normal: What Then?

If the Core Four are normal, depression is screened for, sleep is addressed, and Tier 2 labs are unrevealing, the most common diagnoses remaining are:

• Depression/anxiety (may need formal psychiatric evaluation if PHQ-9 doesn't capture it)
• Sleep deprivation (the most undertreated cause of fatigue in working mothers)
• Obstructive sleep apnea (consider sleep study)
• Chronic fatigue syndrome / ME/CFS: Diagnosis of exclusion. Requires ≥6 months of unexplained fatigue + post-exertional malaise + unrefreshing sleep. Validate the patient's experience.
• Lifestyle factors: Overcommitment, caregiving burden, inadequate nutrition, deconditioning

The most important thing at this stage is to believe the patient. “Your labs are normal” doesn't mean “you're fine.” It means the labs didn't find the answer. The fatigue is real.

Iron Replacement: Practical Notes

• Oral iron: Ferrous sulfate 325 mg (65 mg elemental iron) every other day is better absorbed than daily (hepcidin rebound with daily dosing). Take with vitamin C, empty stomach, avoid calcium/coffee/tea within 2 hours.
• IV iron: Consider for ferritin <15 with Hgb <10, oral intolerance, malabsorption (celiac, IBD, bariatric surgery), second/third trimester pregnancy with significant anemia, or failure to respond to 4–6 weeks of oral iron.
• Recheck ferritin at 8–12 weeks. Goal: ferritin >50 (some argue >100 for sustained repletion).
• Identify the source: Heavy menstrual bleeding is the most common cause of iron deficiency in this population. Screen with pictorial bleeding assessment chart (PBAC) or menstrual history. If HMB is present, treat the bleeding (hormonal management, referral to GYN) in addition to replacing iron.

Bottom Line

Fatigue in childbearing women is best approached with discipline, not a shotgun. Start with CBC, ferritin, TSH, and a pregnancy test. Ferritin <30 in a symptomatic woman is iron deficiency regardless of hemoglobin. If the Core Four are normal, screen for depression and sleep disorders before adding labs. Don't order ANA, EBV, or cortisol without specific clinical indications. And when all the labs come back normal, the fatigue is still real—acknowledge it, investigate further, and keep advocating for your patient.

Stay sharp out there.

Thyroid Function Tests: TSH, Free T4, Free T3—and When You Actually Need Each One

 

Thyroid Function Tests: TSH, Free T4, Free T3—and When You Actually Need Each One

TSH is almost always enough. Free T3 is almost never needed. And sick euthyroid syndrome fools everyone.

This post complements the thyroid antibody workup from earlier in the series. That post covered which antibody to order when you suspect autoimmune thyroid disease. This one covers the function tests—TSH, free T4, and free T3—and the interpretation patterns that trip up clinicians daily.

The Hierarchy: TSH First, Always

TSH is the single best screening test for thyroid dysfunction in outpatient primary care. The pituitary amplifies small changes in thyroid hormone levels, making TSH far more sensitive than direct hormone measurement. A normal TSH essentially rules out primary thyroid disease in an outpatient setting.

TSH	Free T4	Free T3	Interpretation
↑ High	↓ Low	—	Overt hypothyroidism. Treat with levothyroxine.
↑ High	Normal	—	Subclinical hypothyroidism. Repeat in 6–12 weeks to confirm. Treat if TSH >10, or if symptomatic + anti-TPO positive, or if pregnant/trying to conceive.
↓ Low	↑ High	—	Overt hyperthyroidism. Order TSI to confirm Graves'. Consider radioactive iodine uptake if diagnosis unclear.
↓ Low	Normal	↑ High	T3 thyrotoxicosis. One of the few times free T3 is needed. Seen in early Graves' or toxic nodule.
↓ Low	Normal	Normal	Subclinical hyperthyroidism. Repeat to confirm. Consider treatment if TSH <0.1, age >65, atrial fibrillation, or osteoporosis risk.
Normal or Low	↓ Low	—	Central hypothyroidism (pituitary or hypothalamic). TSH is inappropriately normal/low despite low T4. Rare but missed if you only check TSH.
Variable	Variable	—	Sick euthyroid syndrome (nonthyroidal illness). See below.

When to Order Free T3 (Almost Never)

Free T3 is overordered in primary care. The only validated indications:

• Suppressed TSH + normal free T4: Check free T3 to detect T3 thyrotoxicosis
• Monitoring amiodarone-induced thyroid disease (complex T3/T4 dynamics)
• Suspected T3 thyrotoxicosis (early Graves', toxic adenoma)

Free T3 should NOT be ordered for: hypothyroidism monitoring (it's the last to fall and the most variable), fatigue workup, or routine screening. Treat hypothyroidism by normalizing TSH, not by chasing T3 levels.

Sick Euthyroid Syndrome (Nonthyroidal Illness)

Acutely ill hospitalized patients frequently have abnormal thyroid function tests despite having no thyroid disease. The classic pattern: low T3, low or normal T4, low/normal/slightly elevated TSH. This is an adaptive response to illness, not hypothyroidism.

The Rule

Do not check thyroid function tests in acutely ill hospitalized patients unless you have a specific clinical reason to suspect thyroid disease (myxedema coma, thyroid storm, new atrial fibrillation). Abnormal results in acute illness are almost always sick euthyroid and do not warrant treatment. Recheck 6–8 weeks after recovery if needed.

Pregnancy: Trimester-Specific TSH Ranges

TSH normally drops in the first trimester due to HCG-mediated thyroid stimulation. Using non-pregnant reference ranges will over-diagnose hypothyroidism in early pregnancy:

• First trimester: Upper limit of TSH ~4.0 mIU/L (or ideally population-based trimester-specific ranges from your lab, typically 0.1–2.5)
• Second/third trimester: TSH gradually returns toward non-pregnant range
• Gestational thyrotoxicosis: Suppressed TSH with elevated free T4 in the first trimester, driven by high HCG (hyperemesis gravidarum). TSI-negative. Self-limited. Do NOT treat with antithyroid drugs—it's not Graves'.
• Overt hypothyroidism in pregnancy should be treated aggressively (target TSH <2.5 in first trimester). Levothyroxine dose typically increases 25–50% in pregnancy.

The Pitfalls

• Checking only TSH and missing central hypothyroidism: If a patient has symptoms of hypothyroidism + a pituitary history (surgery, radiation, tumor, postpartum hemorrhage/Sheehan's), check free T4 even if TSH is "normal."
• Biotin interference (from the antibody post): Biotin causes falsely low TSH and falsely high free T4, mimicking hyperthyroidism. Stop biotin supplements 48–72 hours before testing.
• Checking TFTs too soon after dose changes: TSH takes 6–8 weeks to re-equilibrate after a levothyroxine dose change. Don't recheck sooner.
• Ordering total T4 instead of free T4: Total T4 is affected by binding protein changes (pregnancy, estrogen, liver disease). Free T4 is the clinically relevant measurement.
• Over-checking in stable patients: Once hypothyroid patients are stable on levothyroxine, annual TSH is sufficient. More frequent testing creates dose-chasing.
• Treating subclinical hypothyroidism reflexively: TSH 5–10 with normal T4 doesn't always need treatment. Consider symptoms, anti-TPO status, age, cardiovascular risk, and fertility plans.

Pediatric Note

Congenital hypothyroidism is screened on the newborn metabolic panel. A high TSH on newborn screen requires urgent confirmatory testing and treatment—delayed treatment causes irreversible intellectual disability. In children, acquired hypothyroidism (usually Hashimoto's) should be suspected with growth deceleration, delayed puberty, fatigue, and constipation. TSH is the first-line test at any age.

Bottom Line

TSH first. Free T4 if TSH is abnormal. Free T3 only for suppressed TSH with normal T4. Don't test acutely ill patients unless you suspect a thyroid emergency. Use trimester-specific ranges in pregnancy. And stop biotin before testing.

Stay sharp out there.