What Does Low Prolactin Mean?
Low prolactin (hypoprolactinemia) typically indicates extensive pituitary gland damage and is a marker of severe hypopituitarism, as prolactin is usually the last anterior pituitary hormone to be lost when pituitary function fails. 1, 2
Clinical Significance of Hypoprolactinemia
Low prolactin levels signify more advanced pituitary dysfunction compared to deficiencies of other hormones. The typical sequence of hormone loss in progressive pituitary damage follows this pattern: 2
- Growth hormone is lost first
- Gonadotropins (LH/FSH) are affected second
- TSH and ACTH become impaired next
- Prolactin is typically the last hormone affected, making its deficiency a marker of extensive pituitary destruction 2
Common Causes of Low Prolactin
Structural Pituitary Damage
Hypoprolactinemia occurs most commonly with conditions causing global pituitary failure: 1, 2
- Large pituitary tumors with mass effect
- Pituitary apoplexy (sudden hemorrhage or infarction)
- Sheehan syndrome (postpartum pituitary necrosis)
- IgG4-related hypophysitis
- Immune checkpoint inhibitor-induced hypophysitis
- Traumatic brain injury
Congenital Syndromes
Several genetic conditions present with hypoprolactinemia: 2
- PROP1 mutations
- PIT1/POU1F1 mutations
- X-linked IGSF1 deficiency syndrome
Clinical Manifestations
Primary Effect: Lactation Failure
The most well-established clinical consequence of hypoprolactinemia is inability to lactate following childbirth in women. 2, 3
Metabolic and Other Effects
Recent evidence suggests hypoprolactinemia may be associated with: 3, 4
- Insulin resistance and type 2 diabetes
- Abnormal lipid profiles and dyslipidemia
- Obesity and fatty liver disease
- Sexual dysfunction
- Increased cardiovascular disease risk
Diagnostic Approach
Laboratory Criteria
Hypoprolactinemia is diagnosed when: 5
- Basal prolactin levels fall below 5 ng/mL in males or 7 ng/mL in females
- TRH stimulation test shows inadequate response (peak <18 ng/mL in males or <41 ng/mL in females)
Important Caveat
When evaluating pituitary masses, be aware that very high prolactin levels can paradoxically appear normal or only mildly elevated due to the "high-dose hook effect" (assay saturation), which occurs in approximately 5% of macroprolactinomas. Request serial dilutions if a large pituitary mass shows unexpectedly low prolactin. 6, 7
Clinical Context
Hypoprolactinemia is not included in traditional hypopituitarism classifications, which only categorize deficiencies as isolated, partial, or complete (panhypopituitarism) based on other hormones. 3 This represents a gap in current clinical practice, as prolactin is the only anterior pituitary hormone not addressed by hypopituitarism guidelines. 4
Treatment Considerations
For patients on dopamine agonist therapy for prolactinomas, avoid driving prolactin to very low levels, as this may cause unwanted metabolic and sexual effects of iatrogenic hypoprolactinemia. 3
No commercial prolactin replacement therapy is currently available, though recombinant human prolactin has been studied experimentally for women with alactogenesis. 2