What are the effects of hyperprolactinemia on the hypothalamic‑pituitary‑gonadal axis and its clinical management?

What Happens with Elevated Prolactin in Your Body

Elevated prolactin disrupts your reproductive system by suppressing the hypothalamic-pituitary-gonadal axis, leading to hypogonadism, menstrual irregularities in women, sexual dysfunction in men, and potential bone loss. 1

Mechanism of Reproductive Disruption

Hyperprolactinemia inhibits the secretion of gonadotropin-releasing hormone (GnRH) through suppression of hypothalamic kisspeptin, which then reduces luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release from the pituitary. 1 This cascade creates hypogonadotropic hypogonadism—your gonads receive insufficient signals to function properly. 2, 3

The pattern of gonadotropin suppression varies with prolactin severity:

• Modest elevation (<4,000 mU/L): Progressive reduction in GnRH pulsatility causes increasingly FSH-predominant gonadotropin patterns 4
• Severe elevation (>4,000 mU/L): Both FSH and LH levels drop, indicating direct pituitary gonadotrope dysfunction 4

Gender-Specific Clinical Effects

In Women

• Menstrual disturbances: Oligomenorrhea, primary or secondary amenorrhea due to anovulation 1, 5
• Galactorrhea: Inappropriate breast milk production occurs in a significant proportion of affected women 1
• Infertility: Anovulatory cycles prevent conception; mid-luteal progesterone <6 nmol/L confirms anovulation 3
• Delayed or arrested puberty in adolescent girls 1, 5

In Men

• Sexual dysfunction: Decreased libido and erectile dysfunction 1
• Gynecomastia: Breast tissue development secondary to hypogonadism 1, 5
• Infertility: Impaired spermatogenesis and reduced semen volume 6
• Delayed or arrested puberty in adolescent boys 1, 5

Systemic Effects Beyond Reproduction

Bone Health

Chronic hypogonadism from hyperprolactinemia leads to osteopenia and osteoporosis due to prolonged estrogen or testosterone deficiency. 7, 8 This is particularly concerning in pediatric patients on medications like risperidone, where persistent elevation causes reduced bone mineral density. 1

Mass Effect Symptoms (When Caused by Prolactinoma)

• Visual field defects: Occur in 73% of giant prolactinomas when the tumor compresses the optic chiasm 1
• Headaches: Present in roughly half of patients with macroadenomas 1
• Growth failure: In children when the tumor compromises growth hormone secretion 1, 5
• Pituitary apoplexy: Rare but serious complication with large tumors 1

Common Causes to Consider

The Endocrine Society identifies multiple etiologies that determine clinical approach: 1

• Prolactinomas: Most common pathological cause; prolactin levels typically correlate with tumor size, usually exceeding 4,000 mU/L 1
• Medications: Dopamine antagonists (antipsychotics, antiemetics) are among the most common causes 1, 9
• Primary hypothyroidism: Present in 43% of women and 40% of men with frank hypothyroidism 1
• Chronic kidney disease: Affects 30-65% of adult patients due to increased secretion and reduced renal clearance 2, 1
• Pituitary stalk compression: Non-functioning adenomas interrupt dopaminergic inhibition 1

Critical Diagnostic Pitfalls

The "Hook Effect"

Approximately 5% of macroprolactinomas show paradoxically normal or mildly elevated prolactin due to assay saturation at very high concentrations. 1, 5 When you see a large pituitary mass on MRI with disproportionately low prolactin, request manual serial dilutions of the serum sample. 1, 3

Macroprolactinemia

This benign condition accounts for 10-40% of all hyperprolactinemia cases, where large, biologically inactive prolactin complexes circulate. 1, 3 However, 20% still have galactorrhea, 45% have oligo-amenorrhea, and 20% have pituitary adenomas, indicating some may have concurrent true hyperprolactinemia. 1 Always screen for macroprolactin in cases of mild or incidental elevation, especially in asymptomatic patients. 1, 5

Stress-Related Elevation

Stress can elevate prolactin levels up to five times the upper limit of normal. 1 For modestly elevated levels, repeat measurement is essential to exclude transient elevation. 5, 3

Treatment Principles

Dopamine agonists are first-line therapy for prolactinomas, effectively normalizing prolactin levels, shrinking tumors, and restoring gonadal function. 3, 7 Cabergoline is preferred over bromocriptine due to superior effectiveness and better tolerability. 1, 3, 7

For medication-induced hyperprolactinemia, addressing the underlying drug is paramount. 1, 3 For secondary causes like hypothyroidism or renal disease, treating the primary condition often resolves the hyperprolactinemia. 5

In men with persistent hypogonadism after prolactin normalization, gonadotropin therapy (hCG ± FSH) is preferred over testosterone replacement to preserve spermatogenesis if fertility is desired. 3