Hypoprolactinemia
Definition and Clinical Significance
Hypoprolactinemia is a rare, neglected endocrine disorder characterized by abnormally low or undetectable serum prolactin levels, most commonly presenting with failure of lactation postpartum, though recent evidence links it to metabolic dysfunction, sexual dysfunction, and serves as a marker for extensive pituitary damage. 1, 2
Prolactin has over 300 physiological actions beyond lactation, including reproduction, homeostasis, neuroprotection, immunoregulation, and metabolic regulation. 1 Unlike hyperprolactinemia, hypoprolactinemia remains poorly understood and is notably absent from clinical hypopituitarism guidelines—prolactin is the only anterior pituitary hormone not addressed in standard hypopituitarism classifications. 1, 2
Causes of Hypoprolactinemia
Acquired Causes (Most Common)
Large pituitary tumors with mass effect causing global pituitary failure—prolactin is typically the last hormone affected, after growth hormone, gonadotropins, TSH, and ACTH. 3
Pituitary apoplexy leading to acute pituitary destruction. 3
Sheehan syndrome (postpartum pituitary necrosis). 3
IgG4-related hypophysitis and immune checkpoint-inhibitor-induced hypophysitis. 3
Iatrogenic hypoprolactinemia from excessive dopamine agonist therapy (cabergoline, bromocriptine) used to treat prolactinomas—very low prolactin levels should be avoided to prevent metabolic and sexual complications. 1
Congenital Causes (Rare)
PROP1 and POU1F1 (Pit-1) gene mutations causing combined pituitary hormone deficiency. 3
X-linked IGSF1 deficiency syndrome. 3
Isolated prolactin deficiency—extremely rare, with only case reports in the literature. 4
Clinical Manifestations
Reproductive and Lactation Effects
Alactogenesis (failure of lactation) is the hallmark clinical manifestation in postpartum women. 1, 3, 4
Oligomenorrhea and menstrual irregularities may occur. 4
Fertility problems and sexual dysfunction in both sexes. 5
Metabolic Consequences
Increased cardiovascular disease risk. 5
Neuropsychological Effects
- Metabolic, sexual, and neuropsychological alterations have been documented in recent human studies. 2
Diagnostic Work-Up
Laboratory Diagnosis
Measure basal serum prolactin levels using gender-specific cut-offs:
Males: Basal prolactin <5 ng/mL suggests hypoprolactinemia. 5
Females: Basal prolactin <7 ng/mL suggests hypoprolactinemia. 5
Perform TRH (thyrotropin-releasing hormone) stimulation test for confirmation:
Administer TRH and measure prolactin response at baseline and peak.
Males: Peak prolactin response <18 ng/mL confirms hypoprolactinemia. 5
Females: Peak prolactin response <41 ng/mL confirms hypoprolactinemia. 5
Gender significantly influences both basal levels and TRH stimulation responses. 5
Note: These cut-offs are based on limited data; larger population studies across age groups and sexes are needed for better standardization. 5
Evaluation for Underlying Causes
Assess all other pituitary hormone axes (TSH, free T4, cortisol, ACTH, LH, FSH, testosterone/estradiol, IGF-1) to determine if hypoprolactinemia is isolated or part of hypopituitarism. 3
Obtain high-resolution pituitary MRI with contrast to evaluate for structural lesions, mass effect, apoplexy, or infiltrative disease. 3
Review medication history for dopamine agonist use (cabergoline, bromocriptine) and assess dosing. 1
Obstetric history: Screen for Sheehan syndrome in women with postpartum hemorrhage and subsequent lactation failure. 3
Consider genetic testing (PROP1, POU1F1, IGSF1) in young patients with combined pituitary hormone deficiencies or family history. 3
Management Options
No Commercially Available Replacement Therapy
Human prolactin is not available commercially for routine replacement therapy. 3, 2
Recombinant human prolactin administered daily has been shown in research settings to restore milk production in women with hypoprolactinemia and alactogenesis, but this is not standard clinical practice. 3
Address Underlying Causes
Treat hypopituitarism: Replace deficient hormones (levothyroxine, hydrocortisone, sex steroids, growth hormone as indicated). 3
Adjust dopamine agonist therapy: If iatrogenic, reduce cabergoline or bromocriptine dose to avoid very low prolactin levels while maintaining control of prolactinoma. 1
Surgical or radiation therapy may be indicated for large pituitary tumors causing mass effect, though this will not restore prolactin secretion. 3
Supportive Management
Lactation support: Counsel women with alactogenesis about alternative feeding methods; experimental recombinant prolactin may be considered in research protocols. 3
Metabolic monitoring: Screen for and manage insulin resistance, dyslipidemia, obesity, and cardiovascular risk factors. 1, 5
Sexual dysfunction: Address with appropriate hormonal replacement (testosterone in men, estrogen in women) and counseling. 5
Important Clinical Pitfalls
Do not overlook hypoprolactinemia as a marker of extensive pituitary damage—it signals severe, global pituitary dysfunction. 1, 5
Avoid excessive dopamine agonist dosing in prolactinoma patients; very low prolactin levels are associated with metabolic and sexual complications. 1
Recognize two types of panhypopituitarism: (1) with normal/high prolactin (stalk effect) and (2) with low prolactin (true global failure)—the latter indicates more severe pituitary destruction. 1
Do not assume isolated prolactin deficiency without comprehensive pituitary evaluation; it is extremely rare and usually part of combined deficiencies. 3, 4
Larger population studies are needed to refine diagnostic cut-offs for basal prolactin and TRH stimulation testing across age and sex. 5