What laboratory and imaging investigations are essential for evaluating a woman with elevated prolactin (hyperprolactinemia), including a fasting serum prolactin level, pregnancy test, thyroid‑stimulating hormone (TSH) and free thyroxine (T4), renal and hepatic function panels, macroprolactin assay, full pituitary hormone panel (luteinizing hormone (LH), follicle‑stimulating hormone (FSH), estradiol, cortisol), and pituitary magnetic resonance imaging (MRI) with visual‑field assessment?

Essential Laboratory and Imaging Investigations for Hyperprolactinemia

Initial Laboratory Testing

The first step is to confirm true hyperprolactinemia with a repeat fasting morning measurement, then systematically exclude secondary causes before proceeding to imaging. 1

Mandatory Initial Tests

• Repeat fasting serum prolactin (morning collection, 08:00-09:00h) to confirm elevation and exclude stress-induced or pulsatile variation 1
• Pregnancy test (β-hCG) in all women of reproductive age—this is non-negotiable before any further workup 1, 2
• Thyroid-stimulating hormone (TSH) and free thyroxine (T4) to exclude primary hypothyroidism, which can cause both hyperprolactinemia and pituitary hyperplasia 1, 3, 2
• Renal function panel (creatinine, BUN) because chronic renal failure can elevate prolactin to >250 ng/mL 4, 2, 5
• Hepatic function panel as cirrhosis is a recognized cause of hyperprolactinemia 2, 5

Critical Medication Review

• Document all medications, particularly antipsychotics, metoclopramide, antidepressants, methyldopa, reserpine, verapamil, and opiates—these are the second most common cause of hyperprolactinemia after prolactinomas 1, 2, 5

Specialized Prolactin Testing

Macroprolactin Assay

• Test for macroprolactin in patients with mildly elevated prolactin (<100 ng/mL), especially if asymptomatic or if clinical presentation doesn't match the prolactin level 1, 4
• Macroprolactinemia accounts for 10-40% of hyperprolactinemia cases and represents biologically inactive prolactin that does not require treatment 1, 4
• Up to 40% of macroprolactinemic patients may still have symptoms (hypogonadism, infertility, galactorrhea), so screening is indicated even in symptomatic patients without obvious cause 4

Hook Effect Testing

• Order 1:100 serum dilution for prolactin measurement in patients with large pituitary masses (≥3 cm) but only modestly elevated prolactin (≤250 ng/mL) to unmask falsely low values from assay saturation 1, 4
• The hook effect can cause prolactin levels to appear normal or only mildly elevated despite a large prolactinoma 4

Full Pituitary Hormone Panel

Measure the complete pituitary axis to assess for hypopituitarism or mass effect, particularly in patients with macroadenomas or visual symptoms. 6

Gonadotropins and Sex Steroids

• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in all patients with confirmed hyperprolactinemia 1
• Estradiol in premenopausal women; mid-luteal progesterone <6 nmol/L indicates anovulation requiring treatment 1
• Testosterone in men, especially those with breast symptoms, gynecomastia, or suspected hypogonadism 1
• Normal LH/FSH with hyperprolactinemia indicates hypothalamic GnRH suppression rather than primary gonadal failure 1

Additional Pituitary Hormones

• Morning (09:00h) cortisol and ACTH if there are features suggesting hypopituitarism or mass effect 6, 7
• IGF-1 to exclude mixed prolactin and growth hormone hypersecretion 1
• These tests are particularly important when visual field defects, headaches, or other mass effect symptoms are present 6

Pituitary Magnetic Resonance Imaging

High-resolution pituitary MRI with gadolinium contrast is mandatory when prolactin is significantly elevated or when clinical features suggest a mass lesion. 6, 1

MRI Indications

• Prolactin >100 ng/mL (>2,000 mU/L)—highly suggestive of prolactinoma 1, 2
• Prolactin >250 ng/mL—virtually diagnostic of prolactinoma and excludes nonfunctioning adenomas 4
• Men with testosterone <150 ng/dL combined with low/low-normal LH, regardless of prolactin level 1
• Any patient with visual symptoms, headaches, or other mass effect features 6, 1

MRI Protocol Specifications

• 3-Tesla MRI preferred over 1.5-Tesla for superior detection of microadenomas 6
• Thin-section imaging (1-3 mm slices) with focused field-of-view on the sella 6, 1
• Gadolinium contrast administration increases conspicuity of microadenomas, which appear as hypoenhancing lesions 6
• Coronal T1- and T2-weighted sequences are generally sufficient for microprolactinomas 2
• Sagittal and axial sections with gadolinium are essential for large lesions to assess suprasellar extension and optic chiasm compression 6, 2

When to Defer MRI

• Defer imaging until after excluding pregnancy, drug-induced hyperprolactinemia, hypothyroidism, and renal failure 2
• Consider macroprolactin screening first if prolactin is only mildly elevated (<100 ng/mL), patient is asymptomatic, or there are wide variations in serial measurements 2

Visual Field Assessment

• Formal visual field testing (perimetry) is indicated when MRI demonstrates suprasellar extension or mass effect on the optic chiasm 6
• Patients with abnormal visual fields must inform driver licensing agencies 6
• Visual field assessment is particularly important for macroadenomas (≥10 mm) 6

Interpretation Algorithm Based on Prolactin Level

Prolactin <100 ng/mL

• Most likely causes: drug-induced, macroprolactinemia, nonfunctioning adenoma with stalk effect, systemic disease 4
• However, 25% of microprolactinomas and cystic macroprolactinomas may present with prolactin <100 ng/mL 4
• Screen for macroprolactin and exclude secondary causes before imaging 4, 2

Prolactin 100-250 ng/mL

• Differential includes prolactinoma, drug-induced, macroprolactinemia, chronic renal failure 4
• Proceed with MRI after excluding secondary causes 2

Prolactin >250 ng/mL

• Highly suggestive of prolactinoma; virtually excludes nonfunctioning adenomas 4
• Immediate MRI indicated (after pregnancy test in women) 4
• If large mass (≥3 cm) with prolactin only modestly elevated, order 1:100 dilution to exclude hook effect 1, 4

Common Pitfalls to Avoid

• Do not order MRI before excluding pregnancy—this is the most critical error 1, 2
• Do not miss drug-induced hyperprolactinemia—review all medications including over-the-counter and herbal products 1, 2
• Do not overlook hypothyroidism—TSH can be profoundly elevated (>250 mIU/L) with prolactin >300 ng/mL and pituitary hyperplasia mimicking adenoma 3
• Do not forget the hook effect—always dilute samples when large masses have unexpectedly low prolactin 1, 4
• Do not ignore macroprolactinemia—present in up to 40% of cases and may cause unnecessary treatment 1, 4
• Do not perform Cushing's screening tests unless cortisol and ACTH levels suggest hypercortisolism—tumor size does not predict hormone output 1