Hypoprolactinemia: Biology, Clinical Relevance, and Diagnostic Challenges

BACKGROUND: Prolactin (PRL) is a pleiotropic hormone, traditionally associated with lactation, but now recognised for its role in reproduction, metabolism, and neuroendocrine and immune regulation. While the clinical features and consequences of hyperprolactinemia are well known, hypoprolactinemia is poorly understood. RESULTS: The causes of PRL deficiency range from genetic mutation to acquired pituitary diseases and rare isolated disorders. Its diagnostic evaluation is often challenging, due to the lack of standardised lower reference limits. Nonetheless, growing evidence links hypoprolactinemia not only to postpartum agalactia, but also to reproductive and sexual dysfunction, and to metabolic alterations and increased cardiometabolic risk. Data from animal models and rare human cases further suggest that PRL exerts unique biological functions that are not fully compensated by other pituitary hormones. PRL measurement, when interpreted alongside gonadotropin levels and clinical context, may help in the differential diagnosis of secondary amenorrhoea. Markedly low PRL levels-especially in association with hypogonadotropic profiles-may support a diagnosis of functional hypothalamic amenorrhoea. CONCLUSIONS: PRL should be recognised as a hormone whose deficiency may cause broader systemic disturbances. A comprehensive understanding of hypoprolactinemia is essential to better define its diagnostic criteria and clinical significance.