The molecular basis of hypoprolactinaemia

Hypoprolactinaemia is an endocrinopathy which is typically encountered as part of a combined pituitary hormone deficiency picture. The vast majority of genetic causes identified to date have been in the context of congenital hypopituitarism with multiple co-existent endocrinopathies. This is primarily with its closest hormonal relation, namely growth hormone. Acquired hypoprolactinaemia is generally rare in paediatric patients, and usually occurs together with other hormonal deficiencies. Congenital hypopituitarism occurs with an incidence of 1:4,000-10,000 cases and mutations in the following transcription factors account for the majority of documented genetic causes: PROP-1, POU1F1, LHX3/4 as well as documented case reports for a smaller subset of transcription factors and other molecules implicated in lactotroph development and prolactin secretion. Isolated prolactin deficiency has been described in a number of sporadic case reports in the literature, but no cases of mutations in the gene have been described to date. A range of genetic polymorphisms affecting multiple components of the prolactin signalling pathway have been identified in the literature, ranging from RNA spliceosome mutations (RNPC3) to loss of function mutations in IGSF-1. As paediatricians gain a greater understanding of the long-term ramifications of hypoprolactinaemia in terms of metabolic syndrome, type 2 diabetes mellitus and impaired fertility, the expectation is that clinicians will measure prolactin more frequently over time. Ultimately, we will encounter further reports of hypoprolactinaemia-related clinical presentations with further genetic mutations, in turn leading to a greater insight into the molecular basis of hypoprolactinaemia in terms of signalling pathways and downstream mediators. In the interim, the greatest untapped reserve of genetic causes remains within the phenotypic spectrum of congenital hypopituitarism.