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Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 571–581 (2006)Cite this article

Abstract

Prolactin is a polypeptide hormone whose major biological actions are related to normal lactation and reproduction. Abnormally high prolactin levels, referred to as hyperprolactinemia, can result in various reproductive disorders. Currently, therapeutic management of hyperprolactinemia relies on dopamine agonists, since dopamine is the primary physiological suppressor of pituitary prolactin production. Epidemiologic studies have shown that prolactin levels in the high-normal range, as well as medications that interfere with dopamine action (e.g. certain antipsychotic drugs), might correlate with increased breast cancer risk. In addition to circulating prolactin, it is now well established that prolactin is also produced locally within various tissues, including breast and prostate. Increasing evidence, mainly from animal studies at present, suggests that excess locally produced prolactin may promote the growth of breast and prostate tumors via an autocrine or paracrine mechanism. These findings have renewed the interest in finding alternative strategies to suppress prolactin actions when dopamine agonists are ineffective. Our studies of the relationship between prolactin structure and function have resulted in the development of pure prolactin-receptor antagonists. These molecules prevent endogenous prolactin from exerting its actions via a competitive mechanism for receptor binding. In this review, we discuss the possible future therapeutic utility of this novel class of compounds.

Key Points

  • Experimental, clinical and/or epidemiologic evidence supports the role of prolactin as a promoter of benign and malignant tumors of the breast and the prostate; recent data have shown that this effect involves prolactin produced locally by these tissues, indicating that the autocrine loop of action of this hormone may be a new therapeutic target

  • Dopamine agonists, the classical drugs used to decrease prolactin production and release from the pituitary, do not affect production of prolactin in nonpituitary tissues

  • Prolactin-receptor antagonists are engineered prolactin mutants designed to bind but not activate this receptor, with the aim of preventing the actions of endogenous prolactin by competing for receptor binding

  • We have recently developed a new generation of human prolactin mutants that have no residual agonistic activity: in contrast to first-generation antagonists, these new compounds behave as pure antagonists

  • Potential indications for this novel class of compounds involve breast and prostate tumors, as well as prolactin-secreting pituitary tumors that are resistant to dopamine-agonist treatment

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Figure 1: Modeling the function and structure of prolactin-receptor antagonists
Figure 2: An overview of the major causes, consequences and therapeutic approaches of systemic and local hyperprolactinemia

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Acknowledgements

The authors are grateful to all who have been involved in the prolactin antagonist project, including current and former students and postdoctoral workers in our unit, as well as external collaborators who participated in the biological characterization of the compounds. The authors are grateful to Thierry Brue for very helpful discussions during the writing process of this review, and to Birthe Kragelund for providing the 3D model of the prolactin-receptor antagonist.

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Authors and Affiliations

  1. Professor of Cell Biology and Senior Scientist, of INSERM, Unit 808, Laboratory “GH, PRL and Tumors”, and University Paris Descartes, Faculty of Medicine René Descartes, Paris 5—Necker site, Paris, France

    Vincent Goffin, Philippe Touraine, Michael D Culler & Paul A Kelly

  2. Director of the Necker Research Institute,

    Vincent Goffin, Philippe Touraine, Michael D Culler & Paul A Kelly

  3. Faculty member of the Reproductive Endocrinology Unit at the Pitie Salpétrière Hospital, Assistance Publique-Hôpitaux de Paris, and Full Professor at University René Descartes, Paris

    Vincent Goffin, Philippe Touraine, Michael D Culler & Paul A Kelly

  4. Senior Director of Endocrinology Research for IPSEN, Boston, Paris, MA, USA, France

    Vincent Goffin, Philippe Touraine, Michael D Culler & Paul A Kelly

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  1. Vincent Goffin
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Correspondence to Vincent Goffin.

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Goffin, V., Touraine, P., Culler, M. et al. Drug Insight: prolactin-receptor antagonists, a novel approach to treatment of unresolved systemic and local hyperprolactinemia?. Nat Rev Endocrinol 2, 571–581 (2006). https://doi.org/10.1038/ncpendmet0270

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