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.
The dopamine neurons that control prolactin secretion are located within the arcuate nucleus of the hypothalamus. While it seems likely that they serve functionally as a single population, these neurons have been subdivided into three sub-populations based on the anatomy of their projections: the tuberoinfundibular (TIDA), tuberohypophyseal (THDA), and periventricular hypophyseal (PHDA) dopaminergic neurons (Freeman et al. 2000). TIDA neurons arise from the dorsomedial arcuate nucleus and project to the external zone of the median eminence (Bjorklund et al. 1973). The other two populations have their cell bodies located slightly more rostrally, but their projections pass in the hypothalamo-hypophyseal tract through the median eminence to the hypophysis. The THDA neurons originate in the rostral arcuate nucleus and project to the intermediate and neural lobes of the pituitary gland (Fuxe 1964, Holzbauer & Racke 1985), while the PHDA neurons originate in the periventricular nucleus, with axons terminating in the intermediate lobe (Goudreau et al. 1992). The TIDA neurons produce the classical hypothalamic hormone secretion into the pituitary portal blood vessels, while THDA and PHDA neurons contribute to basal regulation of prolactin secretion, after transport of dopamine to the anterior pituitary gland through short portal vessels from the neurohypophysis (Peters et al. 1981). While anatomically distinct, there is considerable overlap in their dendritic fields (van den Pol et al. 1984), and all three populations appear to be regulated similarly. For example, all are stimulated by prolactin (DeMaria et al. 1999). Hence, it is reasonable to consider them as a functional unit of prolactin-inhibiting neurons.
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Of the five dopamine receptors, the two members of the D2-like receptor family, D2 and D4 are found in the pituitary gland (Valerio et al. 1994, Matsumoto et al. 1995) and it is through these D2-like receptors that dopamine acts to inhibit lactotroph cell function (Mansour et al. 1990, Ben-Jonathan & Hnasko 2001). Uniquely among anterior pituitary cells, lactotrophs display spontaneous electrical activity in the absence of hypothalamic stimulation and Ca2+ influx through voltage-gated Ca2+ channels (VGCC) stimulates to prolactin secretion (Gregerson 2006). This accounts for the high levels of basal prolactin secretion, and is consistent with a regulatory mechanism primarily based on inhibition. Dopamine inhibits calcium influx resulting in membrane hyperpolarisation (Gregerson et al. 1994, Gregerson 2003) and reduced prolactin secretion (Lledo et al. 1990). In addition to its effect on secretion, dopamine-induced suppression of adenylate cyclase leads to a reduction in prolactin gene expression (Maurer 1982, Elsholtz et al. 1991, Ishida et al. 2007). Dopamine also has a significant role to regulate lactotroph proliferation, as demonstrated in cultures of pituitary cells (Ishida et al. 2007), as well as in vivo by suppression of oestradiol-induced proliferation (Borgundvaag et al. 1992). When dopamine levels are increased, such as caused by the loss of the dopamine transporter, there is a severe post-natal reduction in lactotroph proliferation leading to a dramatic reduction in the number of lactotrophs by 8 weeks of age (Bosse et al. 1997). In contrast, there is marked lactotroph hyperplaisia following loss of the D2 receptor (Kelly et al. 1997, Saiardi et al. 1997), leading to the formation of prolactinomas. This is exacerbated by age, and more prevalent in females than males (Saiardi et al. 1997, Asa et al. 1999). A bias towards lactotroph hyperplasia and more rapid generation of pituitary tumours in females may be expected from the direct actions of estradiol to stimulate prolactin production by lactotrophs, but this may not be the sole factor leading to the increased female hyperplasia. Gonadectomy has been shown to reduce lactotroph hyperplasia and tumour formation in D2 knockout mice, but that this could not be fully rescued by estradiol replacement, suggesting that ovarian factors other than estradiol may contribute to the proliferation of lactotrophs (Hentges & Low 2002).
Some significant insight has been provided by recent advances in mapping the neuronal pathways conveying the sucking stimulus through to specific neuronal populations within the hypothalamus. A direct neuronal pathway is involved, transmitting the somatosensory afferent information from the nipple via the spinal cord to the hypothalamus (Berghorn et al. 2001). Recent evidence suggests that there is a direct pathway from the subparafascicular nucleus and posterior thalamus to the ventrolateral arcuate nucleus, possibly connecting with the dynorphin neurons located in this region (Szabo et al. 2011). Neurons in this pathway express the peptide tuberoinfundibular peptide of 39 residues (TIP39), and this peptide may be a critical regulator of prolactin secretion in response to suckling (Cservenak et al. 2010, Dobolyi 2011), acting through the parathyroid hormone 2 receptor (Dobolyi et al. 2012) to suppress activity of TIDA neurons. 2ff7e9595c
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