60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis

Abstract

The hypothalamic control of prolactin secretion is different from other anterior pituitary hormones, in that it is predominantly inhibitory, by means of dopamine from the tuberoinfundibular dopamine neurons. In addition, prolactin does not have an endocrine target tissue, and therefore lacks the classical feedback pathway to regulate its secretion. Instead, it is regulated by short loop feedback, whereby prolactin itself acts in the brain to stimulate production of dopamine and thereby inhibit its own secretion. Finally, despite its relatively simple name, prolactin has a broad range of functions in the body, in addition to its defining role in promoting lactation. As such, the hypothalamo-prolactin axis has many characteristics that are quite distinct from other hypothalamo-pituitary systems. This review will provide a brief overview of our current understanding of the neuroendocrine control of prolactin secretion, in particular focusing on the plasticity evident in this system, which keeps prolactin secretion at low levels most of the time, but enables extended periods of hyperprolactinemia when necessary for lactation. Key prolactin functions beyond milk production will be discussed, particularly focusing on the role of prolactin in inducing adaptive responses in multiple different systems to facilitate lactation, and the consequences if prolactin action is impaired. A feature of this pleiotropic activity is that functions that may be adaptive in the lactating state might be maladaptive if prolactin levels are elevated inappropriately. Overall, my goal is to give a flavour of both the history and current state of the field of prolactin neuroendocrinology, and identify some exciting new areas of research development.

Keywords: lactation; pregnancy; prolactin; prolactin-releasing factor; tuberoinfundibular dopamine neurons.

Figure 1

Diagrammatic representation of the neuroendocrine regulation of prolactin secretion. Anterior pituitary prolactin release is inhibited by dopamine coming from the tuberoinfundibular dopamine neurons (shown in the coronal section on the top left using immunohistochemistry against tyrosine hydroxylase, brown) whose cell bodies are found in the arcuate nucleus of the hypothalamus, with axons projecting to the external layer of the median eminence. Images on the right show examples of both rapid feedback (electrophysiological activation) and delayed feedback (phosphorylation of STAT5, black nuclear staining) in TIDA neurons. In each example, 1) illustrates prior to prolactin treatment, and 2) after administration of prolactin (reproduced, with permission, from Brown RS, Piet R, Herbison AE & Grattan DR (2012) Differential actions of prolactin on electrical activity and intracellular signal transduction in hypothalamic neurons. Endocrinology 153 2375–2384. Copyright 2012 The Endocrine Society). Prolactin stimulates dopamine secretion, to inhibit its own secretion by short loop feedback.

Figure 2

(A) Diagrammatic representation of short loop feedback control of prolactin secretion. (B) Adaptive changes in the regulation of prolactin secretion during pregnancy and lactation. Note that there are multiple adaptive processes to ensure elevated levels of lactogenic hormones present both in the blood and in the brain of the mother, potentially regulating a wide range of functions to facilitate lactation: 1) Production of prolactin-like molecules from the placenta to bypass feedback regulation of pituitary prolactin secretion. 2) Plasticity in the TIDA neuronal response to prolactin, with reduced secretion of dopamine and induction of enkephalin expression. 3) Maternal behavioural adaptation to suckle the pups, providing the most powerful prolactin-releasing stimulus known. 4) Increased transport of prolactin into the brain during lactation.