New insights in prolactin: pathological implications

Key Points

  • The major 23 kDa prolactin isoform exerts its action via a transmembrane receptor, prolactin receptor (PRL-R), which belongs to the class of haematopoietic cytokine receptors

  • Binding of prolactin to its predimerized receptor induces a conformational change in the receptor, which enables signal transduction

  • Hyperprolactinaemia causes hypogonadotropic hypogonadism by inhibiting kisspeptin-1 secretion, which in turn disrupts hypothalamic gonadotropin-releasing hormone I secretion

  • The first germline loss-of-function mutation in the gene that encodes PRL-R was reported in three sisters with familial idiopathic hyperprolactinaemia

  • The 16 kDa isoform of prolactin has antitumoral and antiangiogenic actions and is involved in peripartum cardiomyopathy

Abstract

Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR.

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Figure 1: Prolactin isoforms.
Figure 2: Mouse and human PRL-R proteins.
Figure 3: Major signalling cascades triggered by the long PRL-R isoform.
Figure 4: Model of mechanisms of hyperprolactinaemia-induced anovulatory infertility.
Figure 5: Possible pathological effects of the PRL-R His188Arg heterozygous loss-of-function mutation on circulating levels of prolactin and on reproductive phenotypes.88

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V.B. wrote the manuscript and researched data for the article. N.B., J.Y. and P.C. provided substantial contribution to discussions of the content. All authors contributed to reviewing and/or editing the manuscript before submission.

Correspondence to Nadine Binart.

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Bernard, V., Young, J., Chanson, P. et al. New insights in prolactin: pathological implications. Nat Rev Endocrinol 11, 265–275 (2015). https://doi.org/10.1038/nrendo.2015.36

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